Charged ion channel blockers and methods of use - Patents.com

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compounds, compositions, methods and kits of the present invention are useful for treating pain, itch and neurogenic inflammation.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 62 / 816,434, filed March 11, 2019, and U.S. Provisional Application No. 62 / 931,590, filed November 6, 2019, the entire contents of which are incorporated herein by reference.

[0002] Technical Field The present invention relates generally to quaternary ammonium compounds, pharmaceutical compositions and methods useful as selective inhibitors of pain, cough and itch sensory neurons (nociceptors, cough receptors and pruriceptors) and in the treatment of neurogenic inflammation. [Background technology]

[0003] 2. Background of the Invention The present invention features compounds, compositions and methods for the selective inhibition of sensory neurons (nociceptors, cough receptors and itch receptors) and the treatment of neurogenic inflammation by targeting nociceptors with small molecule drugs while minimizing effects on non-nociceptive neurons or other cell types. According to the methods of the invention, small cationic drug molecules gain access to the intracellular compartment of sensory neurons via entry through large pore receptors / ion channels that are present in pain-, cough- and itch-sensory neurons, but to a lesser extent or not at all in other types of neurons or other types of tissues.

[0004] Local anesthetics such as lidocaine and articaine work by inhibiting voltage-gated sodium channels in neurons. These anesthetics block the sodium channels and thereby the excitability of all neurons that are not just pain-sensing neurons (nociceptors). Thus, the purpose of local or regional anesthesia is to block the transmission of signals in nociceptors to prevent pain, but administration of local anesthetics also produces undesirable or harmful effects such as general numbness due to blockade of low threshold pressure and touch receptors, motor deficits and / or paralysis due to blockade of motor axons, and other complications due to blockade of autonomic nerve fibers. Local anesthetics are relatively hydrophobic molecules that gain access to their blocking sites on sodium channels by diffusing through cell membranes. Charged derivatives of these compounds, which are not membrane permeable, have no effect on neuronal sodium channels when applied to the outer surface of the nerve membrane, but may block sodium channels if somehow introduced into the cell interior, for example by diffusion from a micropipette used for whole-cell electrophysiological recordings from isolated neurons. Neurons that sense pain, cough and itch are different from other types of neurons in that they (most often) express TRPV1 receptors / channels that are activated by painful heat or by capsaicin, the pungent ingredient in chili peppers.Other types of channels that are selectively expressed in various pain-sensing, cough-sensing and itch-sensing (pruriceptor) neurons include, but are not limited to, TRPV2-4, TRPA1, TRPM8, ASIC and P2X(2 / 3) channels.It is well established that some cationic small molecules, such as QX-314, can enter cells via passing through activated large pore channels, such as TRPV1.

[0005] Neuropathic, inflammatory and nociceptive pain differ in their etiology, pathophysiology, diagnosis and treatment. Nociceptive pain occurs in response to activation of a specific subset of nociceptors, which are high-threshold peripheral sensory neurons, by intense or noxious stimuli. It is generally acute, self-limited and serves a preventive biological function by acting as a warning of potential or ongoing tissue damage. It is typically well localized. Examples of nociceptive pain include, but are not limited to, traumatic or surgical pain, labor pain, sprains, fractures, burns, impingement, contusion, injections, dental procedures, skin biopsies and occlusions.

[0006] Inflammatory pain includes pain occurring in the presence of tissue damage or inflammation, including post-operatively (i.e. pain associated with acute surgical pain caused by inflammation caused by tissue trauma (e.g. surgical incision, dissection, burns) or direct nerve damage (e.g. nerve transection, stretching or compression)), post-traumatic pain, arthritic pain (rheumatoid; or osteoarthritis (i.e. joint pain and stiffness due to gradual deterioration of articular cartilage; risk factors include ageing, injury and obesity; commonly affected joints are the hands, wrists, neck, knees, hips and spine), pain and pain associated with damage to joints, muscles and tendons, such as in axial low back pain (i.e. a prevalent painful condition affecting the lower back; common causes include muscle strain, spinal fractures, swollen or ruptured discs and arthritis), and severe nociceptive pain may transition to inflammatory pain if there is associated tissue damage.

[0007] Neuropathic pain is a common type of chronic, non-malignant pain that is the result of injury or dysfunction of the peripheral or central nervous system and does not serve protective biological functions. It is estimated to affect more than 1,600,000 people in the US population. Neuropathic pain has many different etiologies and can occur due to, for example, trauma, surgery, herniation of intervertebral discs, spinal injuries, diabetes, infection with herpes zoster (shingles), HIV / AIDS, late-stage cancer, amputation (including mastectomy), carpal tunnel syndrome, chronic alcohol use, exposure to radiation, and as an unintended side effect of neurotoxic therapeutic agents such as certain anti-HIV and chemotherapy drugs. Peripheral neuropathy is caused by damage to peripheral nerves from injury, trauma, prolonged pressure or inflammation, which causes numbness and pain in the corresponding area of ​​the body.

[0008] Neuropathic pain is frequently described as "burning," "electric," "tingling," or "shooting" in nature. It is often characterized by chronic dynamic allodynia (defined as pain caused by motion stimuli that do not normally elicit a painful response, such as light touch) and hyperalgesia (defined as increased sensitivity to normally painful stimuli) and can persist for months or years beyond the visible healing of any damaged tissue.

[0009] Pain can occur in patients with cancer and can be due to multiple causes; inflammation, compression, invasion, metastatic spread to bone or other tissues.

[0010] There are several conditions in which pain occurs in the absence of noxious stimuli, tissue damage or lesions to the nervous system, referred to as dysfunctional pain, including, but not limited to, fibromyalgia, tension-type headaches and irritable bowel disorder.

[0011] Migraine is a headache associated with activation of sensory fibers that innervate the meninges of the brain.

[0012] Itch (pruritus) is a dermatological condition that can be localized and generalized and can be associated with skin lesions (rash, atopic eczema, wheals). Itch is associated with many conditions, including but not limited to stress, anxiety, UV radiation from the sun, metabolic and endocrine disorders (e.g., liver or kidney disease, hyperthyroidism), cancer (e.g., lymphoma), reactions to drugs or foods, parasitic and fungal infections, allergic reactions, blood disorders (e.g., polycythemia vera), and dermatological conditions. Itch is mediated by pruriceptors, a subset of small diameter primary sensory neurons that share many characteristics of nociceptor neurons, including but not limited to expression of TRPV1 channels and other large pore type channels (e.g., TRPV2-4, TRPA1, TRPM8, ASICs, and P2X(2 / 3). Certain itch mediators, such as eicosanoids, histamine, bradykinin, ATP, and various neurotrophins, have endovanilloid functions. Topical capsaicin inhibits histamine-induced itch. Therefore, pruriceptors, like nociceptors, are suitable targets for this method of delivering ion channel blockers.

[0013] Coughing is a protective reflex designed to protect the airway from foreign bodies and aid in the removal of luminal debris. However, this reflex can become abnormal in some diseases, resulting in a non-productive dry cough in which hyper- or allo-tussive conditions are present. Hyper- and allo-tussive conditions are often chronic in nature, lasting longer than 3 months, and can be expressed in many airway diseases, including asthma, COPD, asthma-COPD overlap syndrome (ACOS), interstitial pulmonary fibrosis (IPF), and lung cancer. Inappropriate cough reflexes can also be expressed acutely and chronically after viral infections. Furthermore, chronic cough can be idiopathic in nature, with unknown etiology.

[0014] Neurogenic inflammation is a form of inflammation mediated by the efferent (motor) function of sensory neurons, in which proinflammatory mediator molecules released into the periphery by pain-sensing neurons (nociceptors) activate various inflammatory pathways in immune cells and act on the vasculature to alter blood flow and capillary permeability.

[0015] Neurogenic inflammation contributes to peripheral inflammation induced by tissue injury, autoimmune diseases, infections, allergies, and exposure to radiation in a variety of tissues, and is thought to play an important role in the pathogenesis of many disorders, such as migraine, arthritis, rhinitis, gastritis, colitis, cystitis, and sunburn. One way to reduce neurogenic inflammation is to block excitability at nociceptors, thereby preventing activation of nociceptor peripheral endings and the release of proinflammatory chemicals.

[0016] Despite the development of various treatments for pain, itch and neurogenic inflammation, there is a need for additional agents. Summary of the Invention

[0017] Summary of the Invention The present invention relates to a compound of formula (I): which can be used to treat or prevent pain, itch and neurogenic inflammation: [ka] ( During the ceremony: Y - is a pharma- ceutically acceptable anion; R A and R B are each independently selected from substituted or unsubstituted alkyl; R C each independently represents H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I , C.N., N.R. J R K , N.R. L C(O)R M , S(O)R N , S(O) 2 R N , S.O. 2 R O R P , S.O. 2 NR Q R R , S.O. 3 R S , CO 2 R T ;C(O)R U and C(O)NR V R W Selected from; R T is selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl; R I 、R J 、R K 、R L 、R M 、R N 、R O 、R P 、R Q 、R R 、R S 、R U 、R V and R W each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; or R J and R K Or R V and R W Or R Q and R R can be taken together with the nitrogen to which they are attached to form a substituted or unsubstituted 5-, 6-, 7-, or 8-membered ring; X1 -NR Z C(O)-; R Z is selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl; R D and R E each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted cycloalkyl; or R D and R E together with the carbon to which they are attached, form substituted or unsubstituted C 3- C 6 cycloalkyl, forming a substituted or unsubstituted heterocycle; R F and R G are the N that they bond to + together with, form a substituted or unsubstituted 5-, 6-, 7-, or 8-membered saturated monocyclic heterocycle having 0, 1, or more nitrogen atoms in addition to N as heteroatoms; and R H is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl ) The present invention provides a compound represented by the formula:

[0018] In another embodiment, R H may be a substituted alkyl. The substituents are preferably ester groups, such as -OC(O)R 1B where R 1B is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R 1B is preferably substituted or unsubstituted phenyl. H is preferably -CH2OC(O)-phenyl. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Detailed Description of the Invention The present invention provides a compound represented by the above formula (I) or its pharma- ceutically acceptable salt, stereoisomer, solvate, hydrate or combination thereof.The present invention also provides a composition comprising a compound having formula (I) or its pharma- ceutically acceptable salt, for example a composition comprising an effective amount of a compound of formula (I) or its pharma- ceutically acceptable salt and a pharma- ceutically acceptable excipient.The composition of the present invention may further comprise a compound of the present invention and a biologically active agent.The composition may be formulated for oral, intravenous, intramuscular, rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, inhalation, vaginal, intrathecal, intrathecal or intraocular administration.

[0020] The invention further provides a method for treating pain, cough, itch or a neuroinflammatory disorder in a patient comprising administering to the patient a composition comprising a compound having formula (I), wherein the compound inhibits one or more voltage-gated ion channels present in a nociceptor and / or cough receptor and / or pruriceptor when exposed to or applied to the inner surface of the one or more channels and does not substantially inhibit the channels when applied to the outer surface of the channels, and wherein the compound can enter the nociceptor, cough receptor or pruriceptor through a large pore channel when the channel is activated and inhibit one or more voltage-gated ion channels present in the nociceptor, cough receptor or pruriceptor.

[0021] In some embodiments, the large pore channel is a transient receptor potential ion channel (TRP channel). In other embodiments, the TRP channel is activated by exogenous or endogenous agonist. In yet other embodiments, the large pore channel is TRPA1, TRPV1-4, TRPM8, ASIC or P2X. In certain embodiments, the compound can enter into nociceptor, cough receptor or pruriceptor through TRPA1 TRPV1-4, TRPM8, ASIC or P2X receptor / channel when the receptor / channel is activated. In yet other embodiments, the compound inhibits voltage-gated sodium channel. In yet another embodiment, the type of pain treated by the methods, compositions and kits of the present invention is selected from the group consisting of neuropathic pain, inflammatory pain, nociceptive pain, pain due to infection, and procedural pain, or wherein the neuroinflammatory disorder is selected from the group consisting of allergic inflammation, asthma, chronic cough, conjunctivitis, rhinitis, psoriasis, inflammatory bowel disease, interstitial cystitis, and atopic dermatitis.

[0022] The present inventors have demonstrated that the agonist agonist of formula (I) can pass through open large pore type channels expressed on nociceptors and / or cough receptors and / or pruriceptors, but not on motor neurons. [ka] The present invention has identified compounds having the following structure. Because the ion channel blocking compounds of the present invention are positively charged, they are not membrane permeable and therefore cannot enter cells that do not express large pore channels. Because large pore channels are often more active in tissue conditions associated with pain (e.g., inflammation) due to the release of endogenous ligands or activation by thermal stimuli, the ion channel blockers of the present invention can be used alone to selectively target activated nociceptors to effectively treat (e.g., eliminate or reduce) pain, cough, itch or neurogenic inflammation. The ion channel blockers of the present invention can also be used in combination with one or more exogenous large pore channel agonists to selectively target nociceptors to effectively treat (e.g., eliminate or reduce) pain, itch or neurogenic inflammation.

[0023] Voltage-gated ion channels in pain sensory neurons are currently of great interest in the development of drugs to treat pain. Blocking voltage-gated sodium channels in pain sensory neurons can block pain signals by blocking the initiation and transmission of action potentials. Furthermore, blocking voltage-gated sodium channels in nociceptors can reduce or eliminate neurogenic inflammation by preventing the activation of nociceptor peripheral terminals and their release of proinflammatory chemicals.

[0024] To date, a limitation in treatment with molecules that block sodium or calcium channels is that most such externally applied molecules are hydrophobic and can cross membranes, thus allowing them to enter all cells and therefore not have the selectivity to affect only nociceptors.

[0025] The inhibitors of the present invention are membrane impermeable and are only effective inside the nociceptor cell, so they must pass through the cell membrane via channels or receptors such as large pore channels (e.g., TRPAV1-4, TRPA1, TRPM8, ASIC and P2X(2 / 3)) to produce an effect. Under normal circumstances, most large pore channels in nociceptors are inactive, but require noxious thermal, mechanical or chemical stimuli to activate them. For example, TRP channels in nociceptors can be activated by exogenous TRP ligands (i.e., TRP agonists), such as capsaicin, which opens TRPV1 channels. Thus, one approach to selectively target nociceptors is to co-administer a membrane impermeable ion channel inhibitor with an exogenous TRP ligand that allows the inhibitor to pass through the TRP channel into the cell. In addition to capsaicin, the exogenous TRP ligand can also be another capsaicinoid, mustard oil or lidocaine. In another example, TRP channels can become active in response to exogenous stimuli activators, such as acrolein inhaled from cigarette smoking or chemical warfare agents such as tear gas.

[0026] Under certain circumstances, large pore channels can be activated in the absence of exogenous large pore channel agonists / ligands by endogenous inflammatory activators resulting from tissue injury, infection, autoimmunity, atopy, ischemia, hypoxia, cellular stress, immune cell activation, immune mediator production and oxidative stress. Under such conditions, endogenous molecules (e.g., protons, lipids and reactive oxygen species) can activate large pore channels expressed on nociceptors, allowing membrane-impermeable voltage-dependent ion channel blockers to gain access to the interior of the nociceptor through the endogenously activated large pore channels. Endogenous inflammatory activators of large pore channels include, for example, prostaglandins, nitric oxide (NO), superoxide (HO), cysteine-reactive immune mediators such as 4-hydroxynonenal, endogenous alkenyl aldehydes, endocannabinoids, and immune mediators whose receptors are linked to large pore channels, such as interleukin-1 (IL-1), nerve growth factor (NGF), and bradykinin.

[0027] definition As used herein, the terms "a" and "an" are meant to include one or more, unless specified otherwise.

[0028] "Biologically active" means that a molecule, including biological molecules such as nucleic acids, peptides, polypeptides, and proteins, exerts a biological, physical, or chemical effect on itself or on other molecules, such as proteins, enzymes, receptors, ligands, antigens, etc. For example, a "biologically active" molecule can have, for example, enzymatic activity, protein-binding activity, or pharmacological activity.

[0029] Biologically active agents that may be used in the methods and kits described herein include, but are not limited to, TRP1A receptor agonists, TRPV1-4 receptor agonists, ASIC agonists, TRPM8 agonists, P2X receptor agonists, NSAIDs, glucocorticoids, anesthetics, anti-proliferative and inflammation modulating agents, antibodies or antibody fragments, antibiotics, polynucleotides, polypeptides, proteins, anti-cancer agents, growth factors and vaccines.

[0030] "Inflammation" means any type of inflammation, including that caused by the immune system (immune-mediated inflammation) and by the nervous system (neurogenic inflammation), and any symptoms of inflammation, such as redness, heat, swelling, pain and / or loss of function.

[0031] "Neurogenic inflammation" means any type of inflammation mediated by or contributed to by neurons (eg, nociceptors) or any other component of the central or peripheral nervous system.

[0032] The term "pain" is used herein in the broadest sense to refer to all kinds of pain, including acute and chronic pain, such as nociceptive pain, e.g. gastric and visceral pain; inflammatory pain, dysfunctional pain, idiopathic pain, neuropathic pain, e.g. centrally occurring pain and peripherally occurring pain, migraine and cancer pain.

[0033] The term "nociceptive pain" is used to include, without limitation, all pain caused by noxious stimuli that threaten or actually injure body tissue, for example, by cuts, bruises, fractures, crush injuries, burns, etc. Pain receptors for tissue injury (nociceptors) are mostly located in the skin, musculoskeletal system or internal organs.

[0034] The term "physical pain" is used to refer to pain originating in the bones, joints, muscles, skin or connective tissue. This type of pain is typically well localized.

[0035] The term "visceral pain" is used herein to refer to pain arising from visceral organs such as the respiratory tract, gastrointestinal tract and pancreas, urinary tract and reproductive organs. Visceral pain includes pain caused by tumor involvement of the organ capsule. Another type of visceral pain, typically caused by obstruction of a hollow viscera, is characterized by intermittent spasms and poorly localized pain. Visceral pain may be associated with inflammation, such as in cystitis or gastroesophageal reflux disease.

[0036] The term "inflammatory pain" includes pain associated with active inflammation which may be caused by trauma, surgery, infection and autoimmune disease.

[0037] The term "neuropathic pain" is used herein to refer to pain resulting from abnormal processing of sensory input by the peripheral or central nervous systems as a result of lesions to these systems.

[0038] The term "procedural pain" refers to pain resulting from a medical, dental or surgical procedure, where the procedure is usually planned for or associated with acute trauma.

[0039] The term "itch" is used herein in the broadest sense to refer to all types of acute intermittent and persistent localized and generalized itching and stinging sensations. Itching can be idiopathic, allergic, metabolic, infectious, drug-induced, due to liver, kidney disease or cancer. "Pruritus" is severe itching.

[0040] "Patient" refers to any animal. In one embodiment, the patient is a human. Other animals that can be treated using the methods, compositions and kits of the present invention include, but are not limited to, non-human primates (e.g., monkeys, gorillas, chimpanzees), domesticated animals (e.g., horses, pigs, goats, rabbits, sheep, cattle, llamas) and companion animals (e.g., guinea pigs, rats, mice, lizards, snakes, dogs, cats, fish, hamsters and birds).

[0041] The compounds useful in the present invention include those described herein in any of their pharmaceutically acceptable forms, including, but not limited to, their isomers, such as diastereomers and enantiomers, salts, esters, amides, thioesters, solvates and polymorphs, as well as racemic mixtures and pure isomers of the compounds described herein.The term "pharmaceutically acceptable anion" as used herein refers to the conjugate base of a pharmaceutically acceptable acid.Such acids are described in Stahl, PH and Wermuth, CG (eds.), Handbook of Pharmaceutical Salts: Properties, Selection and Use, Wiley VCH (2008). Pharmaceutically acceptable acids include, but are not limited to, acetic acid, dichloroacetic acid, adipic acid, alginic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, 4-acetamidobenzoic acid, benzoic acid, p-bromophenylsulfonic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, sulfuric acid, boric acid, citric acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-glucoheptonic acid, D-glucose, and the like. Luconic acid, D-glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, (-)-L-pyroglutamic acid, salicylic acid Examples of aminosalicyclic acid include 4-aminosalicyclic acid, sebacic acid, stearic acid, succinic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, and undecylenic acid.Pharmaceutically acceptable anions include the conjugate bases of any of the acids mentioned above.

[0042] The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, isethionate, tetrahydrofuran ... Acid salts include, for example, salts of the following acids: acid salts, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate (pctinate), persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate.

[0043] In the general description of the compounds of the invention, the number of atoms of a particular type in a substituent is generally in the range, e.g., alkyl groups containing 1 to 4 carbon atoms for C1-C4 alkyl or C 1-4In the embodiment, the alkyl group is given as an alkyl group. Reference to such a range is intended to include specific reference to the group having each of the integer atoms within the specified range. For example, an alkyl group of 1 to 4 carbon atoms includes each of C1, C2, C3 and C4 alkyl groups. Other numbers of atoms and other types of atoms can be indicated in a similar manner.

[0044] "D" is deuterium.

[0045] As used herein, the terms "alkyl" and the prefix "alk-" include both straight chain and branched chain groups as well as cyclic groups, i.e., cycloalkyl. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 6 ring carbon atoms or from 3 to 7 carbon atoms, inclusive. Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0046] "C 1-4 "Alkyl" or "C1-C4 alkyl" means a branched or unbranched hydrocarbon group having 1 to 4 carbon atoms. 1-6 "Alkyl" or "C1-C6" refers to a branched or unbranched hydrocarbon group having 1 to 6 carbon atoms. For example, C 1-4Alkyl or alkyl, including C1-6 alkyl groups, can be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoroalkyl, amino, alkylamino, disubstituted amino, quaternary amino, alkylcarboxy, and carboxyl groups. Exemplary substituents also include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide (F, Cl, Br, or I), hydroxyl, fluoroalkyl, perfluoroalkyl, oxo, amino, alkylamino, disubstituted amino, quaternary amino, amido, ester, alkylcarboxy, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, aryl, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moiety. 1-4 Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and cyclobutyl. 1-6 Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0047] An example of a substituted alkyl is heteroalkyl. "Heteroalkyl" refers to a branched or unbranched alkyl, cycloalkyl, alkenyl, or alkynyl group having 1 to 7 or more carbon atoms in addition to 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S. 1-7 "Heteroalkyl" means a branched or unbranched alkyl, alkenyl, or alkynyl group having from 1 to 7 carbon atoms in addition to 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. Heteroalkyls may include, but are not limited to, tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. Heteroalkyls may optionally include monocyclic, bicyclic, or tricyclic rings, each ring desirably having from 3 to 6 members. Heteroalkyl groups may be substituted or unsubstituted. Exemplary substitutions include alkyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide (F, Cl, Br or I), hydroxyl, fluoroalkyl, perfluoroalkyl, oxo, amino, alkylamino, disubstituted amino, quaternary amino, amido, ester, alkylcarboxy, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, aryl, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. 1-7 Examples of heteroalkyl include, but are not limited to, methoxymethyl and ethoxyethyl.

[0048] Alkenyl is a branched or unbranched hydrocarbon group containing one or more double bonds. For example, "C 2-6 "Alkenyl" or "C2-C6 alkenyl" refers to a branched or unbranched hydrocarbon group containing one or more double bonds and having from 2 to 6 carbon atoms. Alkenyl can optionally include monocyclic or polycyclic rings, each ring desirably having from 3 to 6 members. Alkenyl groups can be substituted or unsubstituted. Exemplary substituents include those listed above for alkyl, specifically alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoroalkyl, amino, alkylamino, disubstituted amino, quaternary amino, alkylcarboxy, and carboxyl groups. C 2-6 Alkenyl includes, but is not limited to, vinyl, allyl, 2-cyclopropyl-1-ethenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, and 2-methyl-2-propenyl.

[0049] Alkynyl is a branched or unbranched hydrocarbon group containing one or more triple bonds. For example, "C 2-6 "Alkynyl" or "C2-C6 alkynyl" refers to a branched or unbranched hydrocarbon group containing one or more triple bonds and having from 2 to 6 carbon atoms. Alkynyl can optionally include monocyclic, bicyclic or tricyclic rings, each ring desirably having 5 or 6 members. Alkynyl groups can be substituted or unsubstituted. Exemplary substituents are those listed above for alkyl, specifically including alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoroalkyl, amino, alkylamino, disubstituted amino, quaternary amino, alkylcarboxy and carboxyl groups. C 2-6 Alkynyl includes, but is not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.

[0050] "Heterocyclyl", "heterocyclic" or "heterocycloalkyl" means a stable monocyclic or polycyclic (including bicyclic or tricyclic) heterocyclic ring that is saturated, partially unsaturated or unsaturated (including heteroaryl or aromatic) and consists of two or more carbon atoms and one, two, three, four or more heteroatoms independently selected from N, O and S, including any bicyclic or polycyclic group in which any of the heterocyclic rings defined above are fused to a benzene ring, heteroaryl, cycloalkyl or heterocycloalkyl. In certain aspects, a heterocyclyl is a 3- to 15-membered ring system, a 3- to 12-membered ring system or a 3- to 9-membered ring system. "C 2-6"Heterocyclyl" means a stable 5- to 7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic ring, saturated, partially unsaturated or unsaturated (including heteroaryl or aromatic), consisting of 2 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, such as any bicyclic group in which any of the heterocyclic rings defined above are fused to a benzene ring, heteroaryl, cycloalkyl or heterocycloalkyl. The heterocyclyl or heteroaryl group may be substituted or unsubstituted. Exemplary substituents include substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoroalkyl, amino, alkylamino, disubstituted amino, tertiary amino, alkylcarboxy, oxo and carboxyl groups. The nitrogen and sulfur heteroatoms may be optionally oxidized. Heterocyclic rings can be covalently bonded through any heteroatom or carbon atom that results in a stable structure, for example, imidazolinyl rings can be bonded at either ring carbon atom or nitrogen atom.Nitrogen atoms in heterocyclic rings can be quaternized.Preferably, when the total number of S and O atoms in heterocyclic ring is more than 1, these heteroatoms are not adjacent to each other. Heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]Tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxa Diazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl , piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, Tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,Examples of preferred 5- to 10-membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzoisoxazolyl, oxoindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl. Preferred 5-6 membered heterocycles include, but are not limited to, pyridinyl, quinolinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl and tetrazolyl. Preferred substituents include phenyl, methyl, ethyl, propyl, butyl, chloro, bromo, fluoro, iodo and oxo.

[0051] "Aryl" means an aromatic group having a ring system made up of carbon atoms with conjugated pi electrons (e.g., phenyl). 6- C 12 Aryl" or "C6-C 10 "Aryl" is an aryl group having 6 to 12 carbon atoms or 6 to 10 carbon atoms, respectively. Aryl groups may optionally include monocyclic, bicyclic or tricyclic rings, each ring desirably having 5 or 6 members. Bicyclic or tricyclic ring systems may be fused (e.g. naphthyl) or unfused (biphenyl). Aryl groups may be substituted or unsubstituted. Exemplary substituents include substituted or unsubstituted alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl, alkylcarboxy, amino, alkylamino, monosubstituted amino, disubstituted amino and quaternary amino groups. A preferred aryl group is phenyl.

[0052] "Aralkyl" means substituted or unsubstituted alkyl substituted with a substituted or unsubstituted aryl (including, for example, benzyl, phenethyl, or 3,4-dichlorophenethyl).

[0053] "C 7-14 "Aralkyl" means an alkyl group having 7 to 14 carbon atoms substituted with an aryl group (eg, benzyl, phenethyl, or 3,4-dichlorophenethyl).

[0054] "C 3-10 "Heterocycloalkyl" means an alkyl substituted heterocyclic group having 3 to 10 carbon atoms in addition to one or more heteroatoms, such as 3-furanylmethyl, 2-furanylmethyl, 3-tetrahydrofuranylmethyl, or 2-tetrahydrofuranylmethyl.

[0055] "Halide" or "halogen" means bromine, chlorine, iodine or fluorine.

[0056] "Fluoroalkyl" means an alkyl group substituted with a fluorine atom.

[0057] "Alkylcarboxy" refers to a group of the formula -(R)-COOH, where R is C 1-7 Alkyl, C 2-7 Alkenyl, C 2-7 Alkynyl, C 2-6 Heterocyclyl, C 6-12 Aryl, C 7-14 Aralkyl, C 3-10 Heterocycloalkyl or C 1-7 heteroalkyl).

[0058] "Alkoxy" refers to a group of the formula -OR, where R is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R is C 1-7 Alkyl, C 2-7 Alkenyl, C 2-7 Alkynyl, C 2-6Heterocyclyl, C 6-12 Aryl, C 7-14 Aralkyl, C 3-10 Heterocycloalkyl or C 1-7 Heteroalkyl) is meant as a chemical substituent.

[0059] "Aryloxy" refers to an aryl group of the formula -OR, where R is C 6-12 "Alkylthio" refers to a chemical substituent of the formula -SR, where R is a C 1-7 Alkyl, C 2-7 Alkenyl, C 2-7 Alkynyl, C 2-6 Heterocyclyl, C 6-12 Aryl, C 7-14 Aralkyl, C 3-10 Heterocycloalkyl or C 1-7 heteroalkyl).

[0060] "Arylthio" refers to a group of the formula -SR, where R is C 6-12 aryl group)。

[0061] "Charged moiety" means a moiety that gains a proton at physiological pH and thereby becomes positively charged (e.g., ammonium, guanidinium, or amidinium) or a moiety that contains a net formal positive charge without being protonated (e.g., quaternary ammonium). Charged moieties can be either permanently charged or temporarily charged.

[0062] By "therapeutically effective amount" or "effective amount" is meant an amount sufficient to produce a desired result, such as reduction or elimination of pain, cough, itch, or neurogenic inflammation, in a patient (e.g., a human) suffering from a condition, disease, or illness caused, in whole or in part, by neurogenic inflammation (e.g., asthma, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, chronic refractory cough, post-viral cough, gastritis, migraine headaches, psoriasis, rhinitis, rosacea, or sunburn).

[0063] "Solvate" means a solvent addition form that contains either stoichiometric or non-stoichiometric amounts of solvent.

[0064] The compounds of the present invention, including the salts of the compounds, can exist in unsolvated and solvated forms, for example hydrated and unhydrated forms.Generally, solvated forms are equivalent to unsolvated forms and are included within the scope of the present invention.Non-limiting examples of hydrates include monohydrates, dihydrates, hemihydrates, etc. In certain aspects, the compounds are hemihydrates.Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0065] The compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0066] Compounds that may be used in the compositions, kits and methods of the invention have the formula (I): [ka] (In the formula: Y - is a pharma- ceutically acceptable anion; R A , R B and R C each independently represents H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR I , N.R. J R K , N.R. L C(O)R M , S(O)R N , S(O)2R N , SO2R O R P , SO2NR Q R R , SO3R S , CO2R T , C(O)R U and C(O)NR V R W Selected from; R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl; X 1 -CR X R Y -, -NR Z C(O)-, -NR Z C(O)CR X R Y -, -OC(O)-, -SC(O)-, -C(O)NR 1A -, -C(O)O-, -C(O)-, -(O)CS-, -NR 1A S(O)-, -S(O)NR 1A -, -NR 1A C(O)NR 1A -, -S(O)-, and -S(O)-; R X , R Y , R Z and R 1A each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl; R D and R E each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted cycloalkyl; or R D and R E together with the carbons to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted heterocyclic (e.g., a 5- to 7-membered heterocyclic ring); RF and R G are the N that they bond to + Together with N + forms an optionally substituted heterocyclic ring having 0, 1 or more nitrogen atoms in addition to R; or R F and R G each independently represents a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, and a substituted or unsubstituted C 3-6 cycloalkyl; R H is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl. or a pharma- ceutically acceptable salt thereof.

[0067] In a preferred embodiment, R H are independently substituted or unsubstituted C 5-10 Aryl or substituted or unsubstituted C 5-10 Heteroaryl is selected from the group consisting of aryl, hetero ...

[0068] In a further preferred embodiment, R H are independently substituted or unsubstituted C 6-10 It is selected from aryl or substituted or unsubstituted 5- to 10-membered heteroaryl.

[0069] In some embodiments, R H is C 1-6 Alkane, C 1-6 Heteroalkane, carbocycle, substituted carbocycle, heterocarbocycle, substituted heterocarbocycle, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, carboxamide, hydroxyl, ether, amide, ester, sulfonamide, sulfone, amino, aminoalkyl, urea, nitrile, or substituted C optionally substituted with halogen. 5-10 Aryl or substituted C 5-10 In a preferred embodiment, C 1-6The alkane is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and n-hexyl. 1-6 The heteroalkane is selected from -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-isobutyl, -O-cyclohexyl, -O-cyclopentyl and -ethyl-O-methyl. In a preferred embodiment, the carbocycle is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In a preferred embodiment, the heterocarbocycle is selected from aziridine, azetidine, furan, pyrrolidine, pyran, piperidine, piperazine, azepine and diazepine.

[0070] In yet another preferred embodiment, R H is a substituted or unsubstituted C 6-10 aryl or substituted or unsubstituted 5- to 10-membered heteroaryl. In certain aspects, R H is the unsubstituted C 6-10 aryl or unsubstituted 5- to 10-membered heteroaryl. H each of which is optionally substituted with substituted or unsubstituted C1-C6 alkyl, halo, nitrile, hydroxyl, and alkoxy; 6-10 aryl or 5- to 10-membered heteroaryl. H each of which is a substituted or unsubstituted C1-C6 alkyl, halo, nitrile, and OR 2B (In the formula, R 2B is hydrogen or a substituted or unsubstituted C1-C6 alkyl 6-10 In a further preferred embodiment, R H is unsubstituted phenyl. In a further embodiment, R H is phenyl substituted with a substituent selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, halo, nitrile, hydroxyl and alkoxy. His a substituted or unsubstituted C1-C6 alkyl, halo, nitrile and OR 2B (In the formula, R 2B is hydrogen or substituted and unsubstituted C1-C6 alkyl. In yet a further embodiment, R H is phenyl substituted with unsubstituted C1-C6 alkyl, halo, nitrile, hydroxyl or alkoxy. H is unsubstituted C1-C6 alkyl, halo, nitrile and OR 2B (In the formula, R 2B is hydrogen or substituted or unsubstituted C1-C6 alkyl.

[0071] In yet a further aspect, R H is selected from the Z groups shown in Tables 1-3.

[0072] In a preferred embodiment, X 1 In another preferred embodiment, X is -NHC(O)- or -C(O)NH-. 1 is -NHC(O)-.

[0073] In a preferred embodiment, R A , R B and R C each independently represents H, D, halogen, or substituted or unsubstituted C 1-4 Alkyl and NR J R K Selected from; R J and R K each independently represents H and a substituted or unsubstituted C 1-4 is selected from alkyl.

[0074] In a preferred embodiment, R A and R B Each of is CH3 and R C is H, CH3, halogen, nitrile, methoxy or ethoxy.

[0075] In yet a further preferred aspect, R A , R B and R C are independently H, D, halogen, OR I , substituted or unsubstituted C 1- C4 alkyl and NR J R K where R is selected from I , R J and R K each independently represents H and a substituted or unsubstituted C 1- In a preferred embodiment, R A and R B Each of is CH3 and R C is selected from the group consisting of H, CH, halogen, nitrile (cyano), methoxy and ethoxy. A and R B Each of is CH3 and R C is selected from the group consisting of H, CH, fluoro, chloro, nitrile, methoxy and ethoxy. A and R B Each of is CH3 and R C is hydrogen.

[0076] In certain other embodiments, R D is halogen, oxygen, C 3-8 C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, or heteroaryl 1-4 alkyl, and / or R E is H, or halogen, oxygen, C 3-8 C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, or heteroaryl 1-4 It is an alkyl.

[0077] In a preferred embodiment, R D and R EEach of R is independently selected from H, D, CH, CHCH, (CH)CH, and (CH)CH. E is hydrogen, and R D is CH3, CH2CH3, (CH2)2CH3 or (CH2)3CH3. In certain other preferred embodiments, R D and R E taken together form a substituted or unsubstituted C3-C6 cycloalkyl.

[0078] In certain preferred embodiments, R D and R E In yet a further preferred embodiment, both of R D is hydrogen, and R E is alkyl, for example, C1-C6 alkyl or C1-C4 alkyl, including, but not limited to, methyl, ethyl, propyl, and butyl. In certain further preferred embodiments, R D and R E together with the carbon to which they are attached form a C3-C6 cycloalkyl, including but not limited to cyclopropyl or cyclobutyl.

[0079] In a preferred embodiment, R F and R G are the N that they bond to + and together form a 5-, 6-, 7- or 8-membered heterocyclic ring, each of which is optionally substituted, of formula Ia: [ka] This produces the compound:

[0080] wherein each variation is as defined above, including preferred or alternative embodiments, and n is 1, 2, 3, 4, or 5; R 1Bis H or a substituent such as H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR 1I , C.N., N.R. 1J R 1K , N.R. 1L C(O)R 1M , S(O)R 1N , S(O)2R 1N , SO2R 1O R 1P , SO2NR 1Q R 1R , SO3R 1S , CO2R 1T , C(O)R 1U and C(O)NR 1V R 1W where R 1I , R 1J , R 1K , R 1L , R 1M , R 1N , R 1O , R 1P , R 1Q , R 1R , R 1S , R 1T , R 1U , R 1V and R 1W Each of R is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl. 1J and R 1K or R 1V and R 1W or R 1Q and R 1R can also be taken together with the nitrogen to which they are attached to form a substituted or unsubstituted 5-, 6-, 7-, or 8-membered ring.

[0081] In a preferred embodiment, R F and RG are the N that they bond to + together with a 5-, 6-, 7-, or 8-membered nitrogen-containing heterocyclic ring, each of which is optionally substituted, such as, but not limited to: [ka] Preferred substituents include phenyl, COR 1T and C(O)NR 1V R 1W Examples include:

[0082] In a further aspect, R F and R G is independently C1-C4 alkyl. In another embodiment, R F and R G is independently selected from CH3 and CH2CH3. In certain other aspects, R F and R G are the same and are substituted or unsubstituted C1-C4 alkyl. F and R G are the same and are methyl, ethyl, propyl or butyl. In yet another embodiment, R F and R G are the same and are CH3 or CH2CH3.

[0083] In some embodiments, Y - is a halide anion, a carboxylate or a sulfonate. - can be, for example, a halide ion, a substituted or unsubstituted alkyl sulfonate, a substituted or unsubstituted aryl sulfonate, a substituted or unsubstituted alkyl or aliphatic carboxylate, a substituted or unsubstituted aryl carboxylate, or a substituted or unsubstituted heterocyclyl carboxylate.

[0084] In certain embodiments, Y- is trifluoroacetate, sulfate, phosphate, acetate, fumarate, formate, carbonate, maleate, citrate, pyruvate, succinate, oxalate, sulfonate (e.g., methanesulfonate, trifluoromethanesulfonate, toluenesulfonate, e.g., p-toluenesulfonate, benzenesulfonate, ethanesulfonate, camphorsulfonate, 2-mesitylenesulfonate, or naphthalenesulfonate, e.g., 2-naphthalenesulfonate), bisulfate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, Glycolate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, 2-furoate, 3-furoate, napadisylate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonate or ethane-1-(sulfonic acid)-2-sulfonate), isethionate (2-hydroxyethylsulfonate), D-mandelate, L-mandelate, propionate, tartarate, phthalate, hydrochloride, hydrobromide and nitrate. - is a halide anion.

[0085] In a preferred embodiment, the anion is selected from the halide ions bromide, chloride or iodide.

[0086] Each of the preferred groups described above may be taken in combination with one, any or all of the other preferred groups.

[0087] In a preferred embodiment, the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein R H is the following: [ka] [ka] is an optionally substituted aryl or an optionally substituted heteroaryl selected from one of:

[0088] In certain preferred aspects, R H is a substituted or unsubstituted phenyl.

[0089] In certain further aspects, the compound has the formula (II): [ka] (In the formula: Y - is a pharma- ceutically acceptable anion; q is 0, 1, 2 or 3; R D is hydrogen, methyl or ethyl; R 1B is as defined above) has.

[0090] In some embodiments, the compound has the formula (II), where Y - is a halide anion, a carboxylate or a sulfonate. - may be, for example, a halide ion, a substituted or unsubstituted alkylsulfonate, a substituted or unsubstituted arylsulfonate, a substituted or unsubstituted alkyl or aliphatic carboxylate, a substituted or unsubstituted aryl carboxylate or a substituted or unsubstituted heterocyclyl carboxylate.

[0091] In certain embodiments, the compound has the formula (II), -are trifluoroacetate, sulfate, phosphate, acetate, fumarate, formate, carbonate, maleate, citrate, pyruvate, succinate, oxalate, sulfonate (e.g. methanesulfonate, trifluoromethanesulfonate, toluenesulfonate, e.g. p-toluenesulfonate, benzenesulfonate, ethanesulfonate, camphorsulfonate, 2-mesitylenesulfonate, or naphthalenesulfonate, e.g. 2-naphthalenesulfonate), bisulfate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, The salt is selected from the group consisting of the salt, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, 2-furoate, 3-furoate, napadisylate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonate or ethane-1-(sulfonic acid)-2-sulfonate), isethionate (2-hydroxyethylsulfonate), D-mandelate, L-mandelate, propionate, tartarate, phthalate, hydrochloride, hydrobromide and nitrate.

[0092] In one embodiment, the compound has the formula (II), - is a halide anion. In a preferred embodiment, Y - is selected from the halide ions bromide, chloride or iodide.

[0093] As will be appreciated, when q is 0, 1, 2 or 3, N in formula (II) + The rings contained are: [ka] In certain preferred aspects, q is 0. In other preferred aspects, q is 1. In other preferred aspects, q is 2. In even more preferred aspects, q is 3.

[0094] In yet a further preferred aspect, the compound has the formula (II) D is hydrogen.

[0095] In a further aspect, the compound has the formula (II) D is methyl.

[0096] In yet another aspect, the compound has the formula (II) D is ethyl.

[0097] In yet a further aspect, the compound has the formula (II), q is 0 and R D is hydrogen.

[0098] In a further preferred aspect, the compound has the formula (II), q is 1 and R D is hydrogen.

[0099] In a further preferred aspect, the compound has the formula (II), q is 2 and R D is hydrogen.

[0100] In a further aspect, the compound has the formula (II), q is 3 and R D is hydrogen.

[0101] In still further preferred embodiments, the compound has formula (II), q is 0, and R D is methyl.

[0102] In a further preferred aspect, the compound has the formula (II), q is 1 and R D is methyl.

[0103] In a further preferred aspect, the compound has the formula (II), q is 2 and R D is methyl.

[0104] In a further aspect, the compound has the formula (II), q is 3 and R D is methyl.

[0105] In a further preferred embodiment, the compound has the formula (II), q is 0 and R D is ethyl.

[0106] In a further preferred aspect, the compound has the formula (II), q is 1 and R D is ethyl.

[0107] In a further preferred aspect, the compound has the formula (II), q is 2 and R D is ethyl.

[0108] In a further aspect, the compound has the formula (II), q is 3 and R D is ethyl.

[0109] In yet a further aspect, the compound is selected from Table A below or a pharma- ceutically acceptable salt thereof, where Y - is a pharma-ceutically acceptable anion. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0110] In further preferred aspects, the compound is selected from the compounds in the following table or a pharma- ceutically acceptable salt thereof, where Y is as shown or is a pharma- ceutically acceptable anion:

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

[0111] Representative compounds according to the present invention, as well as their enantiomers and pharma- ceutically acceptable salts, are those selected from Table C below, where Y - is a pharma- ceutically acceptable anion as defined above, and Z is either an aryl or heteroaryl structure selected from one of the structures in Table 1, or a substituted aryl or substituted heteroaryl structure selected from one of the structures in Tables 2-3. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15] [Table 4-1] [Table 4-2] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 6-1] [Table 6-2] [Table 6-3]

[0112] Preferred compounds according to the invention, as well as their enantiomers and their pharma- ceutically acceptable salts, are represented by formula (III): [ka] wherein the preferred substituent combination R C , R D , N + / R F / R G and Z is as defined in Table 4; Y - is a pharma-ceutically acceptable anion as defined above. The compounds may be made according to the methods generally described below. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8] [Table 7-9] [Table 7-10] [Table 7-11] [Table 7-12] [Table 7-13]

Table 7-14

Table 7-15

Table 7-16

Table 7-17

Table 7-18

Table 7-19

Table 7-20

Table 7-21

Table 7-22

Table 7-23

Table 7-24

Table 7-25

Table 7-26

Table 7-27

Table 7-28

Table 7-29

Table 7-30

[0113] Each preferred embodiment described herein may be taken in combination with one, any or all of the other preferred embodiments, as set forth herein in all permutations.

[0114] The composition of the present invention may comprise racemic mixture, pure enantiomer, or excess of one enantiomer over the other.For example, the composition may comprise at least 5, 10, 20, 30, 40, 50, 60, 70, 80 or 90% enantiomeric excess.In one embodiment, the enantiomeric excess is at least 95%.

[0115] The compounds of the present invention include all enantiomers that may be defined with respect to absolute stereochemistry as (R)- or (S)-, as well as their racemic and optically pure forms, and are not limited to those described herein in any of their pharma- ceutically acceptable forms, including enantiomers, salts, solvates, polymorphs, solvatomorphs, hydrates, anhydrates, and other crystalline forms, and combinations thereof.Similarly, all tautomeric forms are intended to be included.

[0116] Preferably, the pharmaceutical composition comprises the compound of the present invention as the R enantiomer in substantially pure form; or the pharmaceutical composition comprises the compound of the present invention as the S enantiomer in substantially pure form; or the pharmaceutical composition comprises the compound of the present invention as an enantiomeric mixture comprising an excess of the R enantiomer or an excess of the S enantiomer. It is particularly preferred that the pharmaceutical composition comprises the compound of the present invention as a substantially pure optical isomer. To avoid any doubt, the compound of the present invention may be used in the form of a solvate, if desired.

[0117] synthesis Compounds having formula (I) can be prepared according to the following general synthetic scheme: [ka] and [ka] It can be prepared using methods similar to those described above.

[0118] for example, [ka] and [ka]

[0119] Compounds having formula (II) can be prepared according to the methods described in the Examples and the following synthetic scheme: [ka] and [ka] It can be prepared using methods similar to those described above.

[0120] Further biologically active agents and exogenous large pore channel agonists As mentioned above, the compound or composition of the present invention can be administered with biologically active agents.For example, one or more additional biologically active agents, including those typically used to treat neurogenic inflammation, can be used in combination with the compound or composition of the present invention described herein.Biologically active agents include, but are not limited to, TRP1A receptor agonists, TRPV1-4 receptor agonists, TRPM8 agonists, ASIC agonists, P2X receptor agonists, acetaminophen, NSAIDs, glucocorticoids, anesthetics, tricyclic antidepressants, amine transporter inhibitors, anticonvulsants, antiproliferative and immunomodulatory agents, antibodies or antibody fragments, antibiotics, polynucleotides, polypeptides, proteins, anticancer agents, growth factors and vaccines.

[0121] The TRPV1 agonist that can be used in the method, kit and composition of the present invention includes, but is not limited to, any that activates the TRPV1 receptor on nociceptor and allows the entry of at least one inhibitor of voltage-dependent ion channel (such as the compound of the present invention).Suitable TRPV1 agonist is capsaicin or another capsaicinoid, which is a member of the vanilloid family of molecules.Naturally occurring capsaicinoids are capsaicin itself, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, homocapsaicin and nonivamide. Other suitable capsaicinoids and capsaicinoid analogs and derivatives for use in the compositions and methods of the invention include naturally occurring and synthetic capsaicin derivatives and analogs, such as vanilloids (e.g., N-vanillyl-alkanedienamides, N-vanillyl-alkanedienyls, and N-vanillyl-cis-monounsaturated alkene amides), capsiate, dihydrocapsiate, nordihydrocapsiate and other capsinoids, capsiconiate, dihydrocapsiconiate and other coniferyl esters, capsiconiate ... Capsiconinoids include resiniferatoxin, tinyatoxin, civamide, N-phenylmethylalkenamide capsaicin derivatives, olvanil, N-[(4-(2-aminoethoxy)-3-methoxyphenyl)methyl]-9Z-octa-decanamide, N-oleyl-homovanilamide, triprenylphenols (e.g., scutigeral), gingerol, piperine, shogaol, guaiacol, eugenol, zingerone, nuvanil, NE-19550, NE-21610, and NE-28345. Additional capsaicinoids, their structures, and methods for their preparation are described in U.S. Patent Nos. 7,446,226 and 7,429,673, which are incorporated herein by reference.

[0122] Further suitable TRPV1 agonists include, but are not limited to, eugenol, arvanil (N-arachidonoylvanilamine), anandamide, 2-aminoethoxydiphenylborate (2APB), AM404, resiniferatoxin, phorbol 12-phenylacetate 13-acetate 20-homovanillate (PPAHV), olvanil (NE 19550), OLDA (N-oleoyldopamine), N-arachidonyldopamine (NADA), 6'-iodoresiniferatoxin (6'-IRTX), C18 N-acylethanolamines, lipoxygenase derivatives such as 12-hydroperoxyeicosatetraenoic acid, inhibitor cysteine ​​knot (ICK) peptide (vanillotoxin), piperine, MSK195. (N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-2-[4-(2-aminoethoxy)-3-methoxyphenyl]acetamide), JYL79 (N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N'-(4-hydroxy-3-methoxybenzyl)thiourea), hydroxy-alpha-sanshool, 2-aminoethoxydiphenylborate, 10-shogaol, oleyl gingerol, oleyl shogaol and SU200 (N-(4-tert-butylbenzyl)-N'-(4-hydroxy-3-methoxybenzyl)thiourea).Still other TRPV1 agonists include amylocaine, articaine, benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine, prilocaine, procaine (novacaine), proparacaine, propoxycaine, risocaine, ropivacaine, tetracaine (amethocaine), and trimecaine.

[0123] Suitable TRPV2-4 agonists include, but are not limited to, 2-APB, cannabinol, diphenylboronic anhydride, insulin-like growth factor 1, lysophosphatidylcholine, lysophosphatidylinositol, probenecid, Δ9-tetrahydrocannabinol, vanillin, eugenol, cinnamaldehyde, camphor, carvacrol, thymol, citral, farnesyl diphosphate, tetrahydrocannabivarin, incensole acetate, acetate), diphenylboronic anhydride, 6-tert-butyl-m-cresol, dihydrocarveocarveol, borneol, (-)-menthol, GSK1016790A, 4α-PDH, 5,6-epoxyeicosatrienoic acid, 4α-PDD, bisandrographolide, citric acid, phorbol 12-myristate 13-acetate, and RN1747.

[0124] Suitable TRPM8 agonists include, but are not limited to, menthol, icilin, eucalyptus, linalool, geraniol, hydroxy-citronellal, WS-3, WS-23, Frescolat MGA, Frescolat ML, PMD 38, CPS125, Coolact P, M8-Ag, AITC, cryosim-3 and Cooling Agent 10.

[0125] Suitable ASIC agonists include, but are not limited to, chlorophenylguanidine hydrochloride, GMQ hydrochloride, tetrahydropapaveroline (THP), reticuline, the polyamine agmatine, lysophosphatidylcholine, arachidonic acid, and neuropeptide SF.

[0126] Other biologically active agents that can be used in the methods, compositions and kits of the present invention include any that activate the TRP1A receptor on the nociceptor or pruriceptor and allow the entry of at least one inhibitor of voltage-gated ion channels.Suitable TRP1A agonists include, but are not limited to, cinnamaldehyde, allyl-isothiocyanate (mustard oil), diallyl disulfide, icilin, cinnamon oil, wintergreen oil, clove oil, acrolein, hydroxy-alpha-sanshool, 2-aminoethoxydiphenylborate, 4-hydroxynonenal, methyl p-hydroxybenzoate and 3'-carbamoylbiphenyl-3-ylcyclohexylcarbamate (URB597).

[0127] The P2X agonist that can be used in the methods, compositions and kits of the present invention includes any that activates the P2X receptor on the nociceptor or pruriceptor and allows the entry of at least one inhibitor of voltage-dependent ion channels. Suitable P2X agonists include, but are not limited to, ATP, α,β-methylene ATP, 2-methylthio-ATP, 2' and 3'-O-(4-benzoylbenzoyl)-ATP and ATP 5'-O-(3-thiotriphosphate).

[0128] Other biologically active agents which may be used in combination with the compounds of the invention include NSAIDs, glucocorticoids, anesthetics, tricyclic antidepressants, amine transporter inhibitors, anticonvulsants, antiproliferative and immunomodulatory agents, antibodies or antibody fragments, antibiotics, polynucleotides, polypeptides, proteins, anticancer agents, growth factors and vaccines.

[0129] Nonsteroidal anti-inflammatory drugs (NSAIDs) that may be administered in conjunction with the compositions of the present invention to a patient (e.g., a human) suffering from neurogenic inflammation include, but are not limited to, acetylsalicylic acid, amoxiprine, benorylate, benorilate, choline magnesium salicylate, diflunisal, ethenzamide, faislamine, methyl salicylate, magnesium salicylate, salicylsalicylate, salicyl azathioprine, salicyl salicylate ... mide, diclofenac, aceclofenac, acetomethacin, alclofenac, bromfenac, etodolac, indomethacin, nabumetone, oxametacin, proglumetacin, sulindac, tolmetin, ibuprofen, alminoprofen, benoxaprofen, carprofen, dexibuprofen, dexketoprofen ), fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuproxam, indoprofen, ketoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, pirprofen, suprofen, tiaprofenic acid, mefenamic acid, flufenamic acid, meclofenamic acid, tolfenamic acid, phenylbutazone, ampirone, azapropazone, clofesone (c lofezone, kebuzone, metamizole, mofebutazone, oxyphenbutazone, phenazone, sulfinpyrazone, piroxicam, droxicam, lornoxicam, meloxicam, tenoxicam, and the COX-2 inhibitors celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, and pharmaceutically acceptable salts thereof.

[0130] Glucocorticoids that may be administered in conjunction with the compositions of the invention to a patient (e.g., a human) suffering from neurogenic inflammation include, but are not limited to, hydrocortisone, cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, and pharma- ceutically acceptable salts thereof.

[0131] Anesthetics that may be administered in conjunction with the compositions of the present invention to a patient (e.g., a human) suffering from neurogenic inflammation include, but are not limited to, tramadol, hydrocodone, oxycodone, morphine, and pharma- ceutically acceptable salts.

[0132] Anti-proliferative and immunomodulatory agents that may be administered in conjunction with the compositions of the present invention to a patient (e.g., a human) suffering from neurogenic inflammation include, but are not limited to, alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, dihydrofolate reductase inhibitors, antitumor antibiotics, antimitotic agents, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyltransferase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleoside reductase inhibitors, TNF-α agonists, TNF-α antagonists or scavengers, interleukin 1 (IL-1) antagonists or scavengers, endothelin A receptor antagonists, retinoic acid receptor agonists, hormonal agents, antihormonal agents, photodynamic agents, and tyrosine kinase inhibitors.

[0133] Biologically active agents may be administered prior to, concurrently with, or following administration of a composition of the invention using any formulation, dosage, or administration known in the art that is therapeutically effective.

[0134] Formulation of the Composition Administration of the compounds of the present invention may be by any suitable means that results in a reduction in the sense of perceived pain in the target area. The compounds of the present invention may be included in any suitable amount in any suitable carrier material, and are generally present in an amount that accounts for 1-99% by weight of the total weight of the composition. The compositions may be provided in a form suitable for oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intrathecal, epidural or intraocular administration, or by injection, inhalation or direct contact with the nasal or oral mucosa.

[0135] Thus, the compositions may be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels such as hydrogels, pastes, ointments, creams, plasters, soaks, osmotic delivery devices, suppositories, enemas, injections, implants, sprays or aerosols. The compositions may be formulated according to conventional pharmaceutical practice (see, for example, Remington: The Science and Practice of Pharmacy, 22nd edition, 2013, ed. LV Allen, Pharmaceutical Press, Philadelphia and Encyclopedia of Pharmaceutical Technology, 4 th Edition, ed. J. Swarbrick, 2013, CRC Press, New York).

[0136] Each compound can be formulated in various ways known in the art.For example, the compound of the present invention and biologically active agent as defined herein can be formulated together or separately.Desirably, the compound of the present invention and biologically active agent are formulated together for their simultaneous or near-simultaneous administration.In another embodiment, two or more biologically active agents can be formulated together or separately with the compound of the present invention.Other examples include, but are not limited to, two or more compounds of the present invention formulated together, where the compound is formulated together or without one or more biologically active agents.

[0137] Drugs that are formulated individually or separately can be packaged together as a kit.Non-limiting examples include, but are not limited to, a kit that includes, for example, two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc.The kit can include any component that aids in administering a unit dose to a patient, such as a vial for reconstituting a powder form, a syringe for injection, a customized IV delivery system, an inhaler, etc.In addition, the unit dose kit can include instructions for preparing and administering the composition.

[0138] Kits may be manufactured as single-use unit doses for one patient, multiple uses for a particular patient (at fixed doses, or where individual compounds may vary in potency as treatment progresses); or kits may contain multiple doses suitable for administration to multiple patients ("bulk packaging"). Kit components may be assembled in cartons, blister packs, bottles, tubes, and the like.

[0139] Controlled-release formulations Each compound of the present invention, alone or in combination with one or more biologically active agents as described herein, can be formulated for controlled release (e.g., sustained or metered) administration, as described in U.S. Patent Application Publication Nos. 2003 / 0152637 and 2005 / 0025765, each of which is incorporated herein by reference.For example, the compound of the present invention, alone or in combination with one or more biologically active agents as described herein, can be incorporated into a capsule or tablet that is administered to a patient.

[0140] Any pharma- ceutically acceptable vehicle or formulation suitable for local application and / or injection into the treated site (e.g. painful surgical incision, wound or joint) that can provide sustained release of the compound of the present invention can be used alone or in combination with one or more biologically active agents as described herein, to provide prolonged elimination or reduction of inflammation as needed.Controlled release formulations known in the art include specially coated pellets, polymeric formulations or matrices for surgical insertion, or sustained release microparticles, such as microspheres or microcapsules for implantation, insertion, injection or injection, where the delayed release of active pharmaceutical agent is caused by sustained or controlled diffusion from the matrix and / or selective destruction of the coating of the preparation or selective destruction of the polymeric matrix.Other formulations or vehicles for controlled, sustained or immediate delivery of drug to the preferred localized site in the patient include, for example, suspensions, emulsions, gels, liposomes and any other suitable delivery vehicles or formulations known in the art that can be acceptable for subcutaneous or intramuscular administration.

[0141] A wide range of biocompatible materials may be utilized as controlled release carriers to provide controlled release of the compounds of the present invention, either alone or in combination with one or more biologically active agents as described herein. Any pharma- ceutically acceptable biocompatible polymer known to one of skill in the art may be used. It is preferred that the biocompatible controlled release material degrades in vivo within about one year, preferably within about three months, more preferably within about two months. More preferably, the controlled release material significantly degrades within 1-3 months, with at least 50% of the material degrading to non-toxic residues that are removed by the body, and 100% of the compounds of the present invention being released within a time period of about two weeks, preferably within about two to about seven days. The degradable controlled release material degrades hydrolytically, preferably by either surface or bulk erosion, so that the release is not only sustained, but also provides the desired release rate. However, the pharmacokinetic release profile of these formulations may be first-order, zero-order, bi- or multi-phasic to provide the desired reversible local antinociceptive effect over the desired time period.

[0142] Suitable biocompatible polymers can be used as controlled release materials. The polymeric material can include biocompatible and biodegradable polymers, and in some preferred embodiments, is preferably a copolymer of lactic acid and glycolic acid. Preferred controlled release materials useful in the formulations of the present invention include polyanhydrides, polyesters, copolymers of lactic acid and glycolic acid (preferably where the weight ratio of lactic acid to glycolic acid is 4:1 or less, i.e., 20% or more by weight of glycolic acid to 80% or less by weight of lactic acid) and polyorthoesters containing a catalyst or degradation-promoting compound, for example, at least 1% by weight of anhydride catalyst, such as maleic anhydride. Examples of polyesters include polylactic acid, polyglycolic acid, and polylactic acid-polyglycolic acid copolymers. Other useful polymers include protein polymers such as collagen, gelatin, fibrin and fibrinogen, and polysaccharides such as hyaluronic acid.

[0143] The polymeric material may be prepared by any method known to those skilled in the art. For example, when the polymeric material is composed of a copolymer of lactic acid and glycolic acid, the copolymer may be prepared by the procedure described in U.S. Patent No. 4,293,539, which is incorporated herein by reference. Alternatively, the copolymer of lactic acid and glycolic acid may be prepared by any other procedure known to those skilled in the art. Other useful polymers include polylactides, polyglycolides, polyanhydrides, polyorthoesters, polycaprolactones, polyphosphazenes, polyphosphoesters, polysaccharides, proteinaceous polymers, soluble derivatives of polysaccharides, soluble derivatives of proteinaceous polymers, polypeptides, polyesters, and polyorthoesters, or any mixture or blend thereof.

[0144] Pharmaceutically acceptable polyanhydrides useful in the present invention have water-labile anhydride bonds. The rate of drug release can be controlled by the particular polyanhydride polymer used and its molecular weight. The polysaccharide can be a poly-1,4-glucan, such as starch glycogen, amylose, amylopectin, and mixtures thereof. The biodegradable hydrophilic or hydrophobic polymer can be a water-soluble derivative of poly-1,4-glucan, such as hydrolyzed amylopectin, a derivative of hydrolyzed amylopectin, such as hydroxyethyl starch (HES), hydroxyethyl amylose, dialdehyde starch, and the like. The polyanhydride polymer can be branched or linear.

[0145] Examples of polymers useful in the present invention (in addition to homopolymers and copolymers of poly(lactic acid) and / or poly(glycolic acid)) include poly[bis(p-carboxyphenoxy)propane anhydride] (PCPP), poly[bis(p-carboxy)methane anhydride] (PCPM), polyanhydrides of oligomerized unsaturated fatty acids, polyanhydride polymers prepared from amino acids modified to contain additional carboxylic acids, aromatic polyanhydride compositions, and copolymers of polyanhydrides and other substances, such as fatty acid terminated polyanhydrides, e.g., polyanhydrides polymerized from dimer and / or trimer monomers of unsaturated fatty acids or unsaturated aliphatic acids. Polyanhydrides can be prepared according to the methods described in U.S. Pat. No. 4,757,128, which is incorporated herein by reference. Polyorthoester polymers can be prepared, for example, as described in U.S. Pat. No. 4,070,347, which is incorporated herein by reference. Polyphosphoesters can be prepared and used as described in U.S. Patent Nos. 6,008,318, 6,153,212, 5,952,451, 6,051,576, 6,103,255, 5,176,907, and 5,194,581, each of which is incorporated herein by reference.

[0146] Proteinaceous polymers may also be used. Proteinaceous polymers and their soluble derivatives include gelling biodegradable synthetic polypeptides, elastin, alkylated collagen, alkylated elastin, etc. Biodegradable synthetic polypeptides include poly-(N-hydroxyalkyl)-L-asparagine, poly-(N-hydroxyalkyl)-L-glutamine, copolymers of N-hydroxyalkyl-L-asparagine and N-hydroxyalkyl-L-glutamine with other amino acids. Suggested amino acids include L-alanine, L-lysine, L-phenylalanine, L-valine, L-tyrosine, etc.

[0147] In further embodiments, the controlled release material, which essentially serves as a carrier for the compounds of the present invention, may further comprise a bioadhesive polymer such as pectin (polygalacturonic acid), mucopolysaccharides (hyaluronic acid, mucin) or non-toxic lectins, either alone or in combination with one or more biologically active agents as described herein, or the polymer itself may be bioadhesive, e.g., a polyanhydride or a polysaccharide such as chitosan.

[0148] In embodiments in which the biodegradable polymer comprises a gel, one such useful polymer is a thermogelling polymer, such as a polyethylene oxide, polypropylene oxide (PEO-PPO) block copolymer, such as Pluronic from BASF Wyandotte. TM F127. In such cases, the local anesthetic formulation can be injected via a syringe as a free-flowing liquid that gels rapidly (e.g., when injected into a patient) above 30° C. The gel system then releases a stable dose of the compound of the present invention, alone or in combination with one or more biologically active agents as described herein, at the site of administration.

[0149] Dosage forms for oral use Formulations for oral use include tablets containing the active ingredient(s) in admixture with non-toxic pharma- ceutically acceptable excipients. For example, these excipients can be inert diluents or fillers (e.g., sucrose, sorbitol, sugars, mannitol, microcrystalline cellulose, starches such as potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives such as microcrystalline cellulose, starches such as potato starch, croscarmellose sodium, alginates or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelled starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone or polyethylene glycol); and glidants, lubricants and anti-adhesives (e.g. magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil or talc). Other pharma- ceutically acceptable excipients may be colorants, flavorings, plasticizers, wetting agents, buffers, taste-masking agents (e.g. hydroxypropylmethylcellulose, hydroxypropylcellulose), etc.

[0150] One or more compounds of the present invention as defined herein and one or more biologically active agents can be mixed together or separated in a tablet, capsule or other vehicle. In one example, the compounds of the present invention are contained within the tablet and the biologically active agent is on the outside of the tablet, and a substantial portion of the biologically active agent is released prior to the release of the compounds of the present invention.

[0151] Formulations for oral use can be provided as chewable tablets or hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil. Powders, granules and pellets can be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner, for example using a mixer, fluid bed equipment or spray drying equipment.

[0152] Formulations for oral administration in the mouth may also be presented as mouthwash, mouth spray, mouth rinse, mouth ointment or mouth gel.

[0153] Dissolution or diffusion controlled release can be achieved by suitable coating of the compound's tablet, capsule, pellet or granule formulation or by incorporating the compound into a suitable matrix. Controlled release coatings can include one or more of the above-mentioned coating materials and / or, for example, shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxymethacrylate, methacrylic acid hydrogel, 1,3 butylene glycol, ethylene glycol methacrylate and / or polyethylene glycol. In controlled release matrix formulations, the matrix material may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene and / or halogenated fluorocarbons.

[0154] Liquid forms into which the compounds and compositions of the present invention may be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0155] Generally, when administered to humans, the oral dose of any of the compounds of the combination of the present invention can be easily determined by those skilled in the art depending on the nature of the compound.Typically, such dose is usually about 0.001mg to 2000mg per day, preferably about 1mg to 1000mg per day, and more preferably about 5mg to 500mg per day.Dose up to 200mg per day may be necessary.

[0156] Administration of each drug in the combination therapy, as described herein, independently can be from 1 to 4 times per day for a period of from one day to one year, or even for the life of the patient. In many cases, chronic, long-term administration is indicated.

[0157] Parenteral Formulations Suitable formulations for parenteral administration (e.g., by injection) include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions) in which the compound is dissolved, suspended, or otherwise provided (e.g., in liposomes or other microparticles). Such liquids may further contain other pharma- ceutically acceptable ingredients, such as antioxidants, buffers, preservatives, stabilizers, bacteriostats, suspending agents, thickeners, and solutes that render the formulation isotonic with the blood (or other relevant bodily fluids) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Solution. Typically, the concentration of the compound in the liquid is about 1 ng / ml to about 10 μg / ml, e.g., about 10 ng / ml to about 1 μg / ml. The formulations may be presented in unit-dose or multi-dose sealed containers, for example ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

[0158] Topical preparations The compositions of the present invention may also be adapted for topical use with a topical vehicle containing from 0.0001% to 25% (w / w) or more of the active ingredient(s), either alone or in combination with one or more biologically active agents as described herein.

[0159] In preferred combinations, the active ingredients are preferably 0.0001% to 10% (w / w), more preferably 0.0005% to 4% (w / w) of each active agent. Topical formulations, including but not limited to creams, gels, or ointments, may be applied 1 to 4 times daily or as needed. When carrying out the methods described herein, a topical vehicle comprising the composition of the present invention or a combination therapy comprising the composition of the present invention is preferably applied to the site of inflammation in a patient. For example, a cream may be applied to the hands of a patient suffering from arthritic fingers.

[0160] The composition can be formulated using any dermatologically acceptable carrier.Exemplary carriers include solid carriers, such as alumina, clay, microcrystalline cellulose, silica or talc; and / or liquid carriers, such as alcohol, glycol or water-alcohol / glycol mixture.The therapeutic agent can also be administered in liposome preparations, which allows the therapeutic agent to enter the skin. Such liposome formulations are described in U.S. Patent Nos. 5,169,637; 5,000,958; 5,049,388; 4,975,282; 5,194,266; 5,023,087; 5,688,525; 5,874,104; 5,409,704; 5,552,155; 5,356,633; 5,032,582; 4,994,213; 8,822,537 and PCT Publication No. WO 96 / 40061.Other suitable vehicle examples are described in U.S. Patent Nos. 4,877,805, 8,822,537 and European Publication No. 0586106A1. Suitable vehicles of the present invention may also include mineral oil, petrolatum, polydecene, stearic acid, isopropyl myristate, polyoxyl 40 stearate, stearyl alcohol, or vegetable oils.

[0161] The composition may further comprise a skin permeation enhancer, such as those described in "Percutaneous Penetration Enhancers" (eds. Smith EW and Maibach H I. CRC Press 1995). Exemplary skin permeation enhancers include alkyl (N,N-disubstituted aminoalkanoic acid) esters, such as dodecyl 2-(N,N dimethylamino)propionate (DDAIP), described in patents U.S. Pat. Nos. 6,083,996 and 6,118,020, both of which are incorporated herein by reference; water-dispersible acid polymers, such as polyacrylic acid polymers, carbomers (e.g., Carbopol 1, available from BF Goodrich Company (Akron, Ohio)); TM or Carbopol 940P TM), polyacrylic acid copolymers (e.g., Pemulen from BF Goodrich Company), TM or Polycarbophil, A.H. Robbins, Richmond, Va. TM polysaccharide gums such as agar gum, alginates, carrageenan gum, ghatti gum, karaya gum, kadaya gum, rhamsan gum, xanthan gum, and galactomannan gums (e.g., guar gum, carob gum, and locust bean gum) and other gums known in the art (see, e.g., Industrial Gums: Polysaccharides & Their Derivatives, Whistler RL, BeMiller JN (eds.), 3rd Ed. Academic Press (1992) and Davidson, RL, Handbook of Water-Soluble Gums & Resins, McGraw-Hill, Inc., NY (1980)); or combinations thereof.

[0162] Other suitable polymeric skin permeation enhancers are cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, etc. Additionally, known skin permeation enhancers may be added if desired. Examples include dimethyl sulfoxide (DMSO) and dimethylacetamide (DMA), 2-pyrrolidone, N,N-diethyl-m-toluamide (DEET), 1-dodecylazacycloheptan-2-one (Azone), and dimethylacetamide (DMA). TM , a registered trademark of Nelson Research), N,N-dimethylformamide, N-methyl-2-pyrrolidone, calcium thioglycolate and other accelerators such as dioxolanes, cyclic ketones and their derivatives.

[0163] Also illustrative is the group of biodegradable absorption enhancers that are alkyl N,N-2-(disubstituted amino)alkanoates described in U.S. Pat. No. 4,980,378 and U.S. Pat. No. 5,082,866, both of which are incorporated herein by reference, such as: tetradecyl(N,N-dimethylamino)acetate, dodecyl(N,N-dimethylamino)acetate, decyl(N,N-dimethylamino)acetate, octyl(N,N-dimethylamino)acetate and dodecyl(N,N-diethylamino)acetate.

[0164] Particularly preferred skin permeation enhancers include isopropyl myristate; isopropyl palmitate; dimethyl sulfoxide; decyl methyl sulfoxide; dimethylalaninamide of medium chain fatty acids; dodecyl 2-(N,N-dimethylamino)propionate or salts thereof as described in U.S. Pat. No. 6,118,020, such as its organic (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid addition salts) and inorganic salts (e.g., acetic acid, benzoic acid, salicylic acid, glycolic acid, succinic acid, nicotinic acid, tartaric acid, maleic acid, malic acid, pamoic acid, methanesulfonic acid, cyclohexanesulfamic acid, picric acid and lactic acid addition salts); and alkyl 2-(N,N-disubstituted amino)-alkanoic acids as described in U.S. Pat. No. 4,980,378 and U.S. Pat. No. 5,082,866.

[0165] The skin permeation enhancer in the composition by weight ranges from 0.5% to 10% (w / w). The most preferred range is 1.0% to 5% (w / w). In alternative embodiments, the skin permeation enhancer comprises 0.5% to 1%, 1% to 2%, 2% to 3%, 3% to 4%, or 4% to 5% (w / w) of the composition.

[0166] The compositions may be provided in any useful form. For example, the compositions of the present invention may be formulated as solutions, emulsions (including microemulsions), suspensions, creams, ointments, foams, lotions, gels, powders, or other typical solid, semi-solid, or liquid compositions (e.g., topical sprays) used for application to the skin or other tissues where the compositions may be used. Such compositions may be formulated in the form of other ingredients typically used in such products, such as colorants, fragrances, thickeners (e.g., xanthan gum, fatty acids, fatty acid salts or esters, fatty alcohols, modified cellulose, modified mineral materials, Krisgel 100, etc.). TM , or synthetic polymers), antimicrobial agents, solvents, surfactants, detergents, gelling agents, antioxidants, fillers, dyes, viscosity modifiers, preservatives, humectants, emollients (e.g., natural or synthetic oils, hydrocarbon oils, waxes or silicones), hydrating agents, chelating agents, demulcents, solubilizing excipients, adjuvants, dispersing agents, skin penetration enhancers, plasticizers, preservatives, stabilizing agents, demulsifiers, humectants, sunscreens, emulsifiers, moisturizing agents, astringents, deodorants, and optionally anesthetics, anti-itch actives, botanical extracts, conditioning agents, darkening or lightening agents, glitters, humectants, mica, minerals, polyphenols, silicones or derivatives thereof, sunscreens, vitamins and phytomedicinals.

[0167] The compositions may also contain other similar ingredients to provide additional benefits and to enhance the feel and / or appearance of the topical formulation. Specific classes of additives commonly used in these formulations include: isopropyl myristate, sorbic acid NF powder, polyethylene glycol, phosphatidylcholine (including mixtures of phosphatidylcholines such as phospholipon G), Krisgel 100, and the like. TM Dilution ingredients include water, sodium hydroxide, decyl methyl sulfoxide (as a skin permeation enhancer), menthol crystals, lavender oil, butylated hydroxytoluene, ethyl diglycol reagent and 95% percent (190 proof) ethanol.

[0168] Formulations for Ophthalmic Administration The compounds of the present invention may also be formulated with an ophthalmically acceptable carrier in a concentration sufficient to deliver an effective amount of the active compound(s) to the site of the optic nerve of the eye. Preferably, ophthalmic therapeutic solutions contain one or more of the active compounds at a concentration ranging from about 0.0001% to about 5% (weight per volume), and more preferably from about 0.0005% to about 0.1% (weight per volume).

[0169] An ophthalmically acceptable carrier does not cause significant irritation to the eye and does not eliminate the pharmacological activity and properties of the charged sodium channel blocker.

[0170] Ophthalmically acceptable carriers are generally sterile, essentially free of foreign particles, and generally have a pH in the range of 5 to 8. Preferably, the pH is as close as possible to that of lacrimal fluid (7.4). Ophthalmically acceptable carriers are, for example, sterile isotonic solutions, such as isotonic sodium chloride or boric acid solutions. Such carriers are typically aqueous solutions containing sodium chloride or boric acid. Phosphate buffered saline (PBS) solutions are also useful.

[0171] Various preservatives can be used in ophthalmic preparations.Preferred preservatives include, but are not limited to, potassium benzalkonium, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate.Similarly, various preferred vehicles can be used in such ophthalmic preparations.These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose and hydroxyethylcellulose.

[0172] If necessary or convenient, tonicity adjusting agents may be added, including, but not limited to, salts, particularly sodium chloride, potassium chloride, and the like, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjusting agent.

[0173] Various buffers and means for adjusting pH can be used as long as the resulting preparation is ophthalmically acceptable.Thus, buffers include, but are not limited to, acetate buffer, citrate buffer, phosphate buffer and borate buffer.Acid or base can be used to adjust the pH of these preparations as necessary.Antioxidants that are ophthalmically acceptable can also be included.Antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

[0174] Formulations for nasal and inhalation administration The pharmaceutical composition of the present invention can be formulated for nasal or intranasal administration. When the carrier is a solid, a suitable formulation for nasal administration includes a coarse powder having a particle size of about 20 to 500 microns, which is administered by rapid inhalation through the nasal passage. When the carrier is a liquid, such as a nasal spray or nasal drops, one or more preparations can be mixed in an aqueous or oily solution and inhaled or sprayed into the nasal passage.

[0175] For administration by inhalation, the active ingredient can be conveniently delivered in the form of aerosol spray presentation from a pressurized pack or nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.In the case of pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount, and capsules and cartridges of, for example, gelatin, for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0176] Dry powder compositions for localized delivery to the lungs by inhalation may be provided, for example, in capsules and cartridges of, for example, gelatin or blisters of, for example, thin aluminum foil for use in an inhaler or insufflator. Powder mix formulations generally comprise a powder mix for inhalation of a compound of the invention and a suitable powder base (carrier / diluent / excipient material), for example a mono-, di- or polysaccharide (e.g. lactose or starch). The use of lactose is preferred. In one embodiment, each capsule or cartridge may contain from about 2ug to about 100mg of a compound of formula (I), optionally in combination with another therapeutically active ingredient. In a preferred embodiment, each capsule or cartridge may contain from about 10ug to about 50mg of a compound of formula (I), optionally in combination with another therapeutically active ingredient. In another embodiment, each capsule or cartridge may contain from about 20ug to about 10mg of a compound of formula (I), optionally in combination with another therapeutically active ingredient. Alternatively, the compound of the invention may be delivered without excipients.

[0177] Suitably the packaging / medication dispenser is of a type selected from the group consisting of a reservoir dry powder inhaler (RDPI), a single use inhaler (capsule or blister inhaler), a multiple dose dry powder inhaler (MDPI) and a metered dose inhaler (MDI).

[0178] Solutions or suspensions for use in pressurized containers, pumps, sprays, atomizers or nebulizers may be formulated to contain aqueous media, ethanol, aqueous ethanol or a suitable alternative agent to disperse, solubilize or prolong the release of the active ingredient(s); a propellant as a solvent; and / or a surfactant such as sorbitan trioleate, oleic acid or oligolactic acid.

[0179] Compositions formulated for nasal or inhalation administration may include one or more taste masking agents, such as flavorings, sweeteners and other strategies, such as sucrose, dextrose and lactose, carboxylic acids, menthol, amino acids or amino acid derivatives such as arginine, lysine and monosodium glutamate, and / or synthetic flavor oils and flavoring fragrances and / or natural oils, extracts from plants, leaves, flowers, fruits, etc., and combinations thereof. These may include citrus oils such as cinnamon oil, oil of wintergreen, peppermint oil, clover oil, bay oil, anise oil, eucalyptus, vanilla, lemon oil, orange oil, grape and grapefruit oil, fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, apricot, etc. Additional sweeteners include sucrose, dextrose, aspartame, acesulfame-K, sucralose, and saccharin, organic acids (by way of non-limiting example, citric acid and aspartic acid).Such flavorings may be present at about 0.05 to about 4% by weight, and may be present in lower or higher amounts as a function of one or more of the potency of the flavoring effect, the flavorant's solubility, the effect of the flavoring on the solubility or other physicochemical or pharmacokinetic properties of other formulation components, or other factors.

[0180] Applicable The compounds, compositions, methods and kits of the present invention are useful for treating conditions such as trigeminal trophic syndrome, erythromelalgia, back and neck pain, lower back pain, and osteoarthritis. pain, cancer pain, gynecological and childbirth pain, abdominal wall pain, chronic abdominal wall pain, fibromyalgia, allergic rhinitis, arthritis, rheumatoid arthritis, osteoarthritis, rheumatic pain, orthopedic pain, acute post-herpetic neuralgia and other neuropathic pain (including peripheral neuropathy), sickle cell crisis, myalgia, vulvodynia, rectal pain, levator ani syndrome, transient rectal pain, perianal pain, hemorrhoidal pain, stomach pain, ulcers, inflammatory bowel disease, irritable bowel disease, irritable bowel syndrome, oral mucositis, esophagitis, interstitial cystitis, urethritis and other urological pain, toothache, burn pain, headache, eye sensitivity, conjunctivitis (e.g. allergic conjunctivitis), eye redness The compositions may be used to treat pain, cough or itch associated with any of a number of conditions including, but not limited to, chronic eye pain, dry eye, dry eye syndrome (chronic eye pain), complex regional pain syndrome, acute post-operative pain, post-operative pain, post-surgical eye pain, and procedural pain (i.e., pain associated with injections, drainage of abscesses, surgery, dental procedures, ocular procedures, eye irritation, conjunctivitis (e.g., allergic conjunctivitis), eye redness, dry eye, arthroscopy and the use of other medical instruments, cosmetic surgical procedures, dermatological procedures, setting fractures, biopsies, etc.).

[0181] Because subclasses of nociceptors mediate itch sensations, the compounds, compositions, methods and kits of the invention may also be used to treat itch in patients with conditions such as pruritus (including but not limited to brachioradial, chronic idiopathic, genital / anal, dorsal paresthesia, and scalp), allergic dermatitis, atopic dermatitis, contact dermatitis, poison ivy, infection, parasites, insect bites, pregnancy, metabolic disorders, liver or kidney failure, drug reactions, allergic reactions, eczema, hand eczema, genital and anal itch, hemorrhoidal itch, and cancer.

[0182] Because subclasses of nociceptors can initiate an abnormal cough reflex, the compounds, compositions, methods and kits of the invention may also be used to treat cough in patients with conditions such as asthma, COPD, asthma-COPD overlap syndrome (ACOS), interstitial pulmonary fibrosis (IPF), idiopathic pulmonary fibrosis, post-viral cough, post-infectious cough, chronic idiopathic cough and lung cancer.

[0183] The compounds, compositions, methods and kits of the present invention can also be used to treat neurogenic inflammation and neurogenic inflammatory disorders. Inflammation is a complex set of responses to harmful stimuli that produce localized redness, swelling and pain. Inflammation can be innate or adaptive, the latter being antigen-driven and mediated by immune cells (immune-mediated inflammation). Neurogenic inflammation is caused by the efferent function of pain-sensing neurons (nociceptors), where proinflammatory mediators, neuropeptides and other chemicals, are released from the peripheral terminals of nociceptors when activated. This release process is mediated by calcium influx and exocytosis of peptide-containing vesicles, and proinflammatory neuropeptides include substance P, neurokinin A and B (collectively known as tachykinins), calcitonin gene-related peptide (CGRP), and vasoactive intestinal polypeptide (VIP).

[0184] The release of peripheral chemicals stimulates a variety of inflammatory responses. First, the release of substance P can result in increased capillary permeability, such that plasma proteins leak from the intravascular compartment into the extracellular space (plasma extravasation), resulting in edema. This can be detected as a wheal (a firm, raised swelling of the skin), which is one component of the triad of inflammatory responses known as the Lewis triple response-wheal, red spot, and flare. Second, the release of CGRP causes vasodilation, resulting in increased blood flow. This can be detected as flare, which is another component of the Lewis triple response.

[0185] Substance P also has a proinflammatory effect on immune cells (e.g. macrophages, T cells, mast cells and dendritic cells) via their neurokinin-1 (NK1) receptors. This effect has been documented in allergic rhinitis, gastritis and colitis, presenting an interface between the neurogenic and immune-mediated components of inflammation. Substance P released from one nociceptor may also act on NK1 receptors on adjacent nociceptors to sensitize or activate them, causing a spread of activation and afferent / efferent function. These efferent functions of nociceptors can be triggered by: 1) direct activation of the nociceptor terminal by an appropriate peripheral stimulus (e.g., a pinch) applied to the terminal; 2) indirect antidromic activation of unstimulated nociceptor terminals by an axon reflex, in which an action potential input from one terminal of a nociceptor as it reaches a converging axon branching point in the periphery gives rise to an action potential that travels from the branching point to the peripheral terminal of the unstimulated terminal; and 3) activation as a result of activity in the central terminals of nociceptors in the CNS that travels to the periphery (e.g., primary afferent depolarization of the central terminal produced by GABA can be sufficient to initiate an action potential that travels the "wrong way").

[0186] Genomic analysis of lung-resident ILC2 cells revealed the expression of receptors for several neuropeptides released by sensory neurons, such as SP, CGRP, and VIP, providing an opportunity for nociceptors to directly communicate with these cells. In particular, VIP is found to be expressed in NaV1.8+ nodose ganglion neurons, which comprise the afferent portion of the lung, in OVA-exposed mice. Cultured nodose ganglion neurons stimulated with capsaicin or IL5 also released VIP, while BALF from OVA-exposed mice contained increased VIP compared to vehicle-challenged mice (Talbot et al., Neuron. 2015 July 15; 87(2): 341-354). These data indicate that VIP is released in inflamed lungs and can be blocked by silencing neurons with the charged sodium channel blockers of the present invention. In addition, T HWhen CD4+ T cells cultured under skewing conditions were exposed to recombinant murine VIP, the transcription levels of IL-13 and IL-5 were increased, indicating that VIP mediates the transcription of T cells that transcribe these type II regulatory cytokines. H These results suggest that it contributes to the ability of the 2 cells to

[0187] Immune mediator release from immune cells can also activate nociceptors. Mast cells are found close to primary nociceptive neurons and contribute to nociceptor sensitization in several contexts. Injection of the secretagogue compound 48 / 80 promotes mast cell degranulation in the dura, causing excitation of meningeal nociceptors. Mast cell degranulation also contributes to the rapid onset of nerve growth factor-induced thermal hyperalgesia. Macrophages contribute to nociceptor sensitization by releasing several soluble mediators. Expression of the chemokine macrophage inflammatory protein-1α (MIP-1α) and its receptors CCR1 and CCR5 is increased in macrophages and Schwann cells after partial ligation of the sciatic nerve, contributing to the development of neuropathic pain. Lymphocytes contribute to the sensitization of peripheral nociceptors. T cells infiltrate the sciatic nerve and dorsal root ganglion (DRG) after nerve injury. Nerve injury-induced hyperalgesia and allodynia are significantly attenuated or eliminated in rodents lacking T cells, and the immunosuppressant rapamycin attenuates neuropathic pain in rats, in part due to its effects on T cells. Among the subsets of T cells, type 1 and type 2 helper T cells (T H 1 and T H 2 cells) have been shown to have distinct roles in neuropathic pain. H 1 cells promote neuropathic pain behavior by releasing proinflammatory cytokines (IL-2 and interferon-γ (IFNγ)), whereas T H2 cells inhibit it by releasing anti-inflammatory cytokines (IL-4, IL-10 and IL-13). The complement system also has a role in inflammatory hyperalgesia and neuropathic pain. The anaphylatoxin C5a is a key effector of the complement cascade, and upon binding to the C5aR1 receptor on neutrophils it becomes a potent neutrophil attractant (Ren & Dubner, Nat. Med. 16:1267-1276 (2010)).

[0188] Bacterial infection has been shown to directly activate nociceptors, and immune responses mediated by TLR2, MyD88, T cells, B cells, and neutrophils and monocytes are not required for S. aureus-induced pain in mice (Chiu et al., Nature 501:52-57 (2013)). Mechanical and thermal hyperalgesia in mice is associated with live bacterial burden rather than tissue swelling or immune activation. Bacteria induce calcium influx and action potentials in nociceptor neurons through distinct mechanisms, in part via bacterial N-formylation peptides and the pore-forming toxin α-hemolysin. Specific ablation of Nav1.8 lineage neurons containing nociceptors eliminated pain during bacterial infection but simultaneously increased local immune infiltration and lymphadenopathy in draining lymph nodes. Thus, bacterial pathogens generate pain by directly activating sensory neurons that regulate inflammation, an unsuspected role for the nervous system in host-pathogen interactions. Data from Talbot et al., (Neuron. 2015 July 15; 87(2): 341-354.) also suggest that nociceptors are activated during allergen exposure in sensitized animals.

[0189] In certain disorders, neurogenic inflammation contributes to peripheral inflammation induced by tissue damage, autoimmune disease, infection and exposure to irritants in soft tissue, skin, respiratory system, joints, genitourinary and GI tract, liver and brain. Neurogenic inflammatory disorders include, but are not limited to, allergic inflammation, inflammatory bowel disease, interstitial cystitis, atopic dermatitis, asthma, conjunctivitis, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, gastritis, migraine, psoriasis, rhinitis, rosacea, sunburn, pancreatitis, chronic cough, chronic rhinosinusitis, traumatic brain injury, polymicrobial sepsis, tendinopathy, chronic urticaria, rheumatic disease, acute lung injury, exposure to irritants, inhalation of irritants, pollutants or chemical warfare agents, as described herein.

[0190] Assessment of pain, cough, itch and neurogenic inflammation Measurement index can be used to measure the effectiveness of any of the compounds, compositions, methods and kits of the present invention in treating the pain associated with musculoskeletal, immune inflammatory and neuropathic disorders.Useful indexes include visual analog scale (VAS), Likert scale, categorical pain scale, descriptor, Lequesne index, WOMAC index and AUSCAN index, each of which is well known in the art.Such indexes can be used to measure pain, itch, function, stiffness or other variables.

[0191] Visual analog scales (VAS) provide a one-dimensional measure of quantity. VAS typically use a representation of distance, such as a picture of a line with hash marks drawn at regular distance intervals, e.g., 10 1-cm intervals. For example, patients can be asked to grade their pain or itch sensation by selecting a spot on the line that best corresponds to the pain or itch sensation, with one end of the line corresponding to "no pain" (a score of 0 cm) or "no itch" and the other end of the line corresponding to "unbearable pain" or "unbearable itch" (a score of 10 cm). This procedure provides a simple and rapid approach to obtain quantitative information about how a patient experiences pain or itch. VAS scales and their use are described, for example, in U.S. Patent Nos. 6,709,406 and 6,432,937.

[0192] The Likert scale similarly provides a one-dimensional measure of quantity. Typically, the Likert scale has discrete integer values ​​ranging from a low value (e.g., 0, meaning no pain) to a high value (e.g., 7, meaning extreme pain). A patient experiencing pain is asked to select a number between the low and high values ​​to indicate the degree of pain experienced. The Likert scale and its uses are described, for example, in U.S. Patent Nos. 6,623,040 and 6,766,319.

[0193] The Lequesne index and the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index use self-administered questionnaires to assess pain, function, and stiffness in the knee and hip of OA patients. Both knee and hip are encompassed in WOMAC, while there is one Lequesne questionnaire for the knee and another for the hip. These questionnaires are useful because they contain more information content compared to VAS or Likert. Both the WOMAC index and the Lequesne index questionnaire have been extensively validated in OA, including in surgical settings (e.g., knee and hip arthroplasty). Their metric characteristics do not differ significantly.

[0194] The AUSCAN (Australian-Canadian Hand Arthritis) Index uses a valid, reliable and responsive patient-reported questionnaire. In one example, the questionnaire includes 15 questions in three dimensions (pain, 5 questions; stiffness, 1 question; and physical function, 9 questions). The AUSCAN Index may use, for example, a Likert or VAS scale.

[0195] Indices useful in the methods, compositions and kits of the invention for measuring pain include the Pain Descriptor Scale (PDS), visual analog scale (VAS), verbal descriptor scale (VDS), numeric pain intensity scale (NPIS), Neuropathic Pain Scale (NPS), Neuropathic Pain Symptom Inventory (NPSI), Present Pain Inventory (PPI), Geriatric Pain Measure (GPM), McGill Pain Questionnaire (MPQ), mean pain intensity (Descriptor Differential Scale), numeric pain scale (NPS), global evaluation scale (GPA), and the Pain Intensity Scale (PAIS). These include the Generalized Pain Scale (GES), Short-Form McGill Pain Questionnaire, Minnesota Multiphasic Personality Inventory, Pain Profile and Multidimensional Pain Inventory, Child Heath Questionnaire, and Child Assessment Questionnaire.

[0196] Itch can be measured by subjective criteria (VAS, Likert, descriptors). Another approach is to measure scratching, an objective correlate of itch, using a vibration transducer or a motion sensitivity meter.

[0197] Cough can be measured by standard questionnaires such as the Leicester Cough Questionnaire and validated objective instruments to measure cough frequency (eg VitaloJAK). EXAMPLES

[0198] Working Example The following examples are intended to illustrate, but not limit, the invention. Common Acronym Definitions ACN Acetonitrile AcOH Acetic acid aq. Water-based Bn Benzyl Boc tert-Butyloxycarbonyl Brine Saturated solution of sodium chloride in water ℃ Celsius degrees δ Chemical shift (ppm) d Deuterium DCM Dichloromethane DIPEA Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMSO Dimethyl sulfoxide ESI Electrospray Ionization Et2O Diethyl ether EtOAc Ethyl acetate g grams h time HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide MeOH Methanol mHz Megahertz min ml milliliter mmol MS mass spectrometry m / z mass to charge ratio NMR nuclear magnetic resonance Pet Ether Petroleum Ether RT room temperature TEA Triethylamine TLC Thin Layer Chromatography UV ultraviolet light

[0199] 1. Synthesis of N-benzyl-2-((2,6-dimethylphenyl)amino)-N,N-diethyl-2-oxoethan-1-aminium bromide: [ka] To a stirred solution of 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide (0.15 g, 0.640 mmol, 1 equiv; Comb-Blocks, Inc., San Diego, CA Catalog No.: QA-3221) in ACN (3 mL) was added benzyl bromide (0.164 g, 0.960 mmol, 1.5 equiv), the reaction mixture was stirred at 75° C. for 12 h, and the progress of the reaction was monitored by TLC (mobile phase 10% methanol in DCM; UV visualization). The reaction mixture was evaporated under reduced pressure to give the crude product, which was triturated with EtOAc (2×5 mL) to give the product N-benzyl-2-((2,6-dimethylphenyl)amino)-N,N-diethyl-2-oxoethan-1-aminium bromide (0.08 g) as a white solid. MS (ESI): m / z 325.2 [M] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.03 (br s, 1H), 7.66 - 7.39 (m, 5H), 7.13 (s, 3H), 4.82 (s, 2H), 4.17 (s, 2H), 3.52 (q, J = 6.7 Hz, 4H), 2.20 (s, 6H), 1.42 (br t, J = 6.9 Hz, 6H).

[0200] 2. Synthesis of N-benzyl-2-((2,6-dimethylphenyl)amino)-N,N-dimethyl-2-oxoethan-1-aminium bromide: [ka] · Synthesis of intermediate 2-bromo-N-(2,6-dimethylphenyl)acetamide. To a suspension of 2,6-dimethylaniline (30.5 mL, 247.56 mmol, 1.0 equiv.) in water (300 mL) was added bromoacetyl bromide (23.8 mL, 272.31 mmol, 1.1 equiv.) at 10° C. The reaction mixture was maintained at pH 9-10 with 15% Na2CO3(aq.) solution for 1 h and the progress of the reaction was monitored by TLC (mobile phase: 30% EtOAc in hexanes, UV visualization). The reaction mixture was extracted with EtOAc (2×600 mL) and the combined organic extracts were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was triturated with Et2O (2×200 mL) to give 2-bromo-N-(2,6-dimethylphenyl)acetamide (21 g) as a white solid. MS (ESI): m / z 244.02 [M+2] + . 1 H NMR (400 MHz, CDCl3) δ 7.75 (br s, 1H), 7.20 - 7.02 (m, 3H), 4.07 (s, 2H), 2.24 (s, 6H).

[0201] · Synthesis of intermediate 2-(dimethylamino)-N-(2,6-dimethylphenyl)acetamide. To a stirred solution of 2-bromo-N-(2,6-dimethylphenyl)acetamide (5 g, 20.7 mmol, 1.0 equiv) in EtOAc (75 mL) was added a 2.0 M solution of dimethylamine in THF (51.8 mL, 103.5 mmol, 5 equiv) and the reaction mixture was stirred at 75° C. for 18 h in a steel bomb. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2×200 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-(dimethylamino)-N-(2,6-dimethylphenyl)acetamide (4.1 g). 1 H NMR (400 MHz, CDCl3-d) δ ppm 8.63 (1 H, br s), 7.02 - 7.15 (3 H, m), 3.15 (2 H, s), 2.45 (6 H, s),2.24 (6 H, s).

[0202] Synthesis of N-benzyl-2-((2,6-dimethylphenyl)amino)-N,N-dimethyl-2-oxoethan-1-aminium bromide. To a stirred solution of 2-(dimethylamino)-N-(2,6-dimethylphenyl)acetamide (0.2 g, 0.969 mmol, 1.0 equiv) in ACN (3 mL) was added benzyl bromide (0.23 mL, 1.936 mmol, 2.0 equiv) and the reaction mixture was stirred at 90° C. for 16 h and the progress of the reaction was monitored by TLC (mobile phase: 10% MeOH in DCM, UV visualization). The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product, which was triturated with EtOAc (5 mL) to give the product N-benzyl-2-((2,6-dimethylphenyl)amino)-N,N-dimethyl-2-oxoethan-1-aminium bromide (0.14 g). MS (ESI): m / z 297.2 [M] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 9.95 (1 H, s), 7.49 - 7.66 (5 H, m), 7.06 - 7.19 (3 ​​H, m), 4.81 (2 H, s), 4.30 (2 H, s), 3.26 (6 H, s), 2.19 (6 H, s).

[0203] 3. Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)azepan-1-ium bromide: [ka] ·Synthesis of intermediate 2-(azepan-1-yl)-N-(2,6-dimethylphenyl)acetamide. The synthesis of intermediate 2-bromo-N-(2,6-dimethylphenyl)acetamide was as described above for compound 2. To a stirred solution of 2-bromo-N-(2,6-dimethylphenyl)acetamide (0.5 g, 1.9 mmol, 1.0 equiv) in ACN (5.0 mL) was added K2CO3 (0.639 g, 4.6 mmol, 2.5 equiv) and azepane (0.4 mL, 4.0 mmol, 2.0 equiv), the mixture was stirred at 90 °C for 20 h, and the progress of the reaction was monitored by TLC (mobile phase: 5% MeOH in DCM, UV visualization). The crude reaction was concentrated under reduced pressure and the resulting residue was partitioned between water and EtOAc (2 x 50 mL). The combined organic extracts were washed with brine solution, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was triturated with EtOAc (20 mL) to give 2-(azepan-1-yl)-N-(2,6-dimethylphenyl)acetamide (0.47 g). MS (ESI): m / z 261.57 [M + H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.83 (br s, 1H), 7.09 (s, 3H), 3.32 (s, 2H), 2.93 - 2.73 (m, 4H), 2.24 (s, 6H), 1.87 - 1.52 (m, 9H).

[0204] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)azepan-1-ium bromide. To a stirred solution of 2-(azepan-1-yl)-N-(2,6-dimethylphenyl)acetamide (0.2 g, 0.8 mmol, 1.0 equiv.) in ACN (1.0 mL) was added benzyl bromide (0.1 mL, 0.6 mmol, 2.0 equiv.) and the reaction was heated to reflux for 16 h and the reaction progress was monitored by TLC (mobile phase: 10% MeOH in DCM, UV visualization). The crude reaction mixture was concentrated under reduced pressure and the product was triturated with EtOAc (15 mL) to give the product 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)azepan-1-ium bromide (0.12 g). MS (ESI): m / z 351.2 [M] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 7.71 - 7.62 (m, 2H), 7.60 - 7.48 (m, 3H), 7.20 - 7.03 (m, 3H), 4.93 (s, 2H), 4.15 (s, 2H), 3.86 - 3.70 (m, 2H), 3.66 - 3.42 (m, 2H), 2.23 (s, 6H), 1.98 (br d, J = 4.8 Hz, 4H), 1.67 (br s, 4H).

[0205] 4. Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidin-1-ium bromide: [ka] ·Synthesis of intermediate N-(2,6-dimethylphenyl)-2-(piperidin-1-yl)acetamide. The synthesis of intermediate 2-bromo-N-(2,6-dimethylphenyl)acetamide was as described above for compound 2. To a stirred solution of 2-bromo-N-(2,6-dimethylphenyl)acetamide (1.2 g, 5.0 mmol, 1.0 equiv) in EtOAc (40 mL) was added piperidine (0.851 g, 10.0 mmol, 2.0 equiv) and the reaction mixture was stirred at 75° C. for 16 h and the progress of the reaction was monitored by TLC (mobile phase: 50% EtOAc in petroleum ether, UV visualization). The reaction mixture was diluted with EtOAc (20 mL) and washed with water (2 x 50 ml). The organic extracts were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was triturated with n-pentane (25 mL) and dried under vacuum to give the product N-(2,6-dimethylphenyl)-2-(piperidin-1-yl)acetamide (1.05 g). MS (ESI): m / z 247.36 [M + H] + . 1 H NMR (400 MHz, CDCl3-d) δ ppm 8.81 (1 H, br s), 7.04 - 7.11 (3 H, m), 3.14 (2 H, s), 2.62 (4 H, br s), 2.24 (6 H, s), 1.65 (4 H, quin, J=5.61 Hz), 1.44 - 1.54 (2 H, m).

[0206] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidin-1-ium bromide. To a stirred solution of N-(2,6-dimethylphenyl)-2-(piperidin-1-yl)acetamide (0.15 g, 0.6 mmol, 1.0 equiv) in ACN (3 mL) was added benzyl bromide (0.205 g, 1.2 mmol, 2.0 equiv) and the reaction mixture was stirred in a sealed tube at 80° C. for 16 h and the progress of the reaction was monitored by TLC (mobile phase: 10% MeOH in DCM, UV visualization). The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to give the crude product, which was triturated with EtOAc (15 mL) and dried under vacuum to give the product 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidin-1-ium bromide (0.15 g). MS (ESI): m / z 337.2 [M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.07 (1 H, s), 7.49 - 7.66 (5 H, m), 7.07 - 7.21 (3 H, m), 4.96 (2 H, s), 4.21 (2 H, s), 3.65 (2 H, br d, J=12.50 Hz), 3.50 (2 H, dt, J=12.93, 6.69 Hz), 2.21 (6 H, s), 1.91 - 2.05 (4 H, m), 1.64 - 1.76 (1 H, m), 1.55 (1 H, dt, J=13.76, 7.04 Hz).

[0207] 5. Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)pyrrolidin-1-ium bromide: [ka] ·Synthesis of intermediate N-(2,6-dimethylphenyl)-2-(pyrrolidin-1-yl)acetamide. The synthesis of intermediate 2-bromo-N-(2,6-dimethylphenyl)acetamide was as described above for compound 2. Pyrrolidine (0.533 g, 7.5 mmol, 1.5 equiv) was added to a stirred solution of 2-bromo-N-(2,6-dimethylphenyl)acetamide (1.2 g, 5.0 mmol, 1.0) in EtOAc (40 mL), the reaction mixture was stirred at 75° C. for 3 h, and the progress of the reaction was monitored by TLC (mobile phase: 50% EtOAc in petroleum ether, UV visualization). The reaction mixture was diluted with EtOAc (25 mL), washed with water (50 mL), dried over NaSO4, filtered, and concentrated under reduced pressure to give N-(2,6-dimethylphenyl)-2-(pyrrolidin-1-yl)acetamide (1.0 g). MS (ESI): m / z 233.44 [M + H] + . 1 H NMR (400 MHz, CDCl3-d) δ ppm 8.63 (1 H, br s), 7.00 - 7.15 (3 H, m), 3.35 (2 H, s), 2.69 - 2.84 (4 H, m), 2.24 (6 H, s), 1.80 - 1.93 (4 H, m).

[0208] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)pyrrolidin-1-ium bromide. To a stirred solution of N-(2,6-dimethylphenyl)-2-(pyrrolidin-1-yl)acetamide (0.15 g, 0.6 mmol, 1.0 equiv) in ACN (5 mL) was added benzyl bromide (0.205 g, 1.2 mmol, 2.0 equiv) and the reaction mixture was stirred in a sealed tube at 80° C. for 16 h and the reaction progress was monitored by TLC (mobile phase: 10% MeOH in DCM, UV visualization). The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product, which was triturated with EtOAc (15 mL) and dried under vacuum to give 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)pyrrolidin-1-ium bromide (0.14 g). MS (ESI): m / z 323.2 [M] + .1 H NMR (400 MHz, DMSO-d6) δ ppm 2.11 - 2.29 (10 H, m), 3.60 - 3.74 (2 H, m), 3.76 - 3.88 (2 H, m), 4.20 (2 H, s), 4.83 (2 H, s), 7.08 - 7.18 (3 H, m), 7.50 - 7.66 (5 H, m), 9.97 (1 H, s).

[0209] 6. Synthesis of 1-benzyl-1-(1-((2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)piperidin-1-ium bromide: [ka] · Synthesis of intermediate 2-bromobutanoyl chloride. Thionyl chloride (150 mL) was added to 2-bromobutanoic acid (25 g, 149.7 mmol, 1.0 equiv) at 0° C., and then the resulting solution was stirred at 80° C. for 2 h. The reaction mixture was cooled to RT and concentrated under reduced pressure to give crude 2-bromobutanoyl chloride (27.7 g, 99.5%) as a brown residue, which was immediately carried on to the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 4.52 - 4.44 (m, 1H), 2.29 - 2.16 (m, 1H), 2.15 - 2.02 (m, 1H), 1.10 (t, J = 7.3 Hz, 3H).

[0210] ·Synthesis of intermediate 2-bromo-N-(2,6-dimethylphenyl)butanamide. A solution of 2,6-dimethylaniline (15 g, 121.18 mmol, 1.0 equiv) and pyridine (15 mL, 189.6 mmol, 1.5 equiv) in DCM (400 mL) was cooled to 0 °C in an ice bath. To this mixture was slowly added a solution of 2-bromobutanoyl chloride (27.5 g, 148.6 mmol, 1.2 equiv) in DCM (50 mL) and the resulting mixture was allowed to warm to room temperature with stirring for 2 h. The reaction solution was adjusted to pH approx. 5-6 with 2N HCl and extracted with DCM (2 X 200 mL). The combined organic extracts were washed with water (250 mL) and brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was triturated with n-pentane (150 mL) to give 2-bromo-N-(2,6-dimethylphenyl)butanamide (30 g). MS (ESI): m / z 272.13 [M+2] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 7.15 - 7.02 (m, 3H), 4.51 (t, J = 7.3 Hz, 1H), 2.22 - 2.04 (m, 7H), 2.03 - 1.91 (m, 1H), 0.98 (t, J = 7.3 Hz, 3H).

[0211] ·Synthesis of intermediate N-(2,6-dimethylphenyl)-2-(piperidin-1-yl)butanamide. To a stirred solution of 2-bromo-N-(2,6-dimethylphenyl)butanamide (50 g, 259.1 mmol, 1.0 equiv) in toluene (1 L) was added piperidine (54 mL, 544.1 mmol, 2.1 equiv) at RT. The reaction mixture was stirred at 110° C. for 16 h and the reaction progress was monitored by TLC (mobile phase: 30% EtOAc in hexanes, UV visualization). The reaction mixture was concentrated under reduced pressure to give the crude product, which was triturated with n-pentane (500 mL) to give N-(2,6-dimethylphenyl)-2-(piperidin-1-yl)butanamide (55 g). MS (ESI): m / z 275.27 [M + H] +. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 7.06 (s, 3H), 3.06 (dd, J = 5.7, 8.6 Hz, 1H), 2.60 (br t, J = 4.8 Hz, 4H), 2.16 (s, 6H), 1.79 - 1.59 (m, 2H), 1.51 (br s, 4H), 1.44 - 1.35 (m, 2H), 0.93 (t, J = 7.5 Hz, 3H).

[0212] Synthesis of 1-benzyl-1-(1-((2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)piperidin-1-ium bromide. To a stirred solution of N-(2,6-dimethylphenyl)-2-(piperidin-1-yl)butanamide (1.5 g, 5.5 mmol, 1.0 equiv) in ACN (25.0 mL) was added benzyl bromide (1.872 g, 10.9 mmol, 2.0 equiv) and the reaction mixture was heated to 80° C. for 16 h and the reaction progress was monitored by TLC (mobile phase: 10% MeOH in DCM, UV visualization). The reaction mixture was concentrated under reduced pressure and the crude product was triturated with EtOAc (3×10 mL) to give 1-benzyl-1-(1-((2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)piperidin-1-ium bromide (1.2 g). MS (ESI): m / z 365.4 [M]. +. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1 H), 7.57-7.54 (m, 5 H), 7.17-7.11 (m, 3 H), 5.41 (d, 1 H), 4.62 (d, 1 H), 4.39 (bs, 1 H), 3.72 (bs, 2 H), 3.22 (bs, 2 H), 2.43-2.39 (m, 1 H), 2.15-2.07 (m, 9 H), 1.96-1.95 (m, 2 H), 1.61-1.45 (m, 2 H), 1.18 (t, 3 H).

[0213] 7. Synthesis of compounds 7A-27A: Table 5. Table 5 provides further representative examples of the present invention prepared from the intermediate N-(2,6-dimethylphenyl)-2-(piperidin-1-yl)butanamide and the appropriate alkyl halide according to the method described for the synthesis of compound 6. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5]

[0214] 28. Synthesis of 1-(1-((2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)-1-(2-hydroxybenzyl)piperidin-1-ium 2,2,2-trifluoroacetate: [ka] To a stirred solution of 1-(1-((2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)-1-(2-methoxybenzyl)piperidin-1-ium bromide (compound 24, 0.1 g, 0.21 mmol, 1.0 equiv.) in DMC (2 mL) was added boron tribromide (1 M in DCM) (4 mL, 4.0 mmol, 20 equiv.) at 0° C., the reaction mixture was stirred at room temperature for 16 h, and the reaction progress was monitored by TLC (mobile phase: 10% MeOH in DCM, UV visualization). The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (Mobile phase A: 0.1% TFA (aq.); Mobile phase B: ACN; Column: Synergy Polar 250 x 21mm, 4.7u (Phenomenex Inc.); Flow rate: 18mL / min, Method: 0 / 15, 2 / 15, 10 / 50, 15 / 80, 15.2 / 98, 18 / 98, 18.2 / 15, 22 / 15; Temperature: Ambient). The pure fractions were lyophilized to give the product 1-(1-((2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)-1-(2-hydroxybenzyl)piperidin-1-ium 2,2,2-trifluoroacetate (0.056g). MS (ESI): m / z 381.4[M] +. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (3 H, br t, J=7.02 Hz), 1.32 - 1.47 (1 H, m), 1.55 - 1.67 (1 H, m), 1.76 - 2.01 (3 H, m), 2.05 - 2.19 (2 H, m), 2.25-2.3 (6 H, m), 2.30 - 2.41 (1 H, m), 2.99 - 3.26 (1 H, m), 3.64 - 3.85 (2 H, m), 4.35 - 4.61 (2 H, m), 5.41 - 5.50 (1 H, m), 6.88 - 6.95 (1 H, m), 6.99 (1 H, d, J=8.24 Hz), 7.10 - 7.19 (3 ​​H, m), 7.31 - 7.45 (2 H, m), 10.34 (2 H, br d, J=10.07 Hz).

[0215] 29. Synthesis of 1-(1-((2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)-1-(3-hydroxybenzyl)piperidine-1-ium carbonate: [ka] To a stirred solution of 1-(1-((2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)-1-(3-methoxybenzyl)piperidin-1-ium bromide (compound 23, 0.06 g, 0.1 mmol, 1 equiv.) in DCM (2 mL) was added boron tribromide (1 M in DCM) (2 mL) at 0° C. and the reaction mixture was stirred at room temperature for 16 h and the progress was monitored by TLC (mobile phase: 10% MeOH in DCM, UV visualization). The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by reversed-phase preparative HPLC (mobile phase (A): 10 mM ammonium bicarbonate (aq.); mobile phase (B): 100% CAN; column: X-select C18 (19*250) 5u, method: 0 / 35, 2 / 40, 20 / 40; flow rate: 18ml / min. The combined pure fractions were lyophilized to give the product 1-(1-((2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)-1-(3-hydroxybenzyl)piperidin-1-ium carbonate (0.02g). MS (ESI): m / z 381.38 [M] + . 1 H NMR (500 MHz, DMSO-d6) δ ppm 1.11 (3 H, br s), 1.31 - 1.62 (2 H, m), 1.76 - 2.25 (12 H, m), 2.93 - 3.13 (1 H, m), 3.43 - 3.54 (3 H, m), 3.60 - 3.76 (1 H, m), 3.92 - 4.17 (2 H, m), 4.21 - 4.39 (1 H, m), 5.29 - 5.63 (1 H, m), 6.67 - 6.85 (4 H, m), 6.91 (2 H, br s), 7.19 (1 H, br t, J=7.78 Hz).

[0216] 30. Synthesis of 1-benzyl-1-(1-((2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)azepan-1-ium bromide: [ka] ·Synthesis of intermediate 2-(azepan-1-yl)-N-(2,6-dimethylphenyl)butanamide. The synthesis of intermediate 2-bromo-N-(2,6-dimethylphenyl)butanamide was as described above for compound 6. To a stirred solution of 2-bromo-N-(2,6-dimethylphenyl)butanamide (0.5 g, 1.9 mmol, 1.0 equiv) in ACN (10 mL) was added K2CO3 (0.393 g, 2.85 mmol, 1.5 equiv) and azepane (0.376 g, 3.8 mmol, 2.0 equiv), the reaction mixture was stirred at 75 °C for 16 h, and the reaction progress was monitored by TLC (mobile phase: 10% MeOH in DCM, UV visualization). The crude reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give intermediate 2-(azepan-1-yl)-N-(2,6-dimethylphenyl)butanamide (0.20 g). MS (ESI): m / z 289.33 [M + H] + . 1 H NMR (400 MHz, CDCl3-d) δ ppm 1.00 - 1.16 (3 H, m), 1.57 - 1.86 (12 H, m), 1.95 - 2.13 (2 H, m), 2.18 - 2.29 (8 H, m), 2.72 - 2.97 (4 H, m), 3.24 (1 H, br t, J=6.72 Hz), 3.46 - 3.55 (2 H, m), 7.03 - 7.15 (4 H, m), 8.75 (1 H, br s).

[0217] Synthesis of 1-benzyl-1-(1-((2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)azepan-1-ium bromide. To a stirred solution of 2-(azepan-1-yl)-N-(2,6-dimethylphenyl)butanamide (0.2 g, 0.7 mmol, 1.0 equiv) in ACN (5 mL) was added benzyl bromide (0.459 g, 2.85 mmol, 1.5 equiv) and the reaction was stirred at 75° C. for 16 h and progress was monitored by TLC (mobile phase: 10% MeOH in DCM, UV visualization). The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product, which was triturated with EtOAc (20 mL) and dried under vacuum to give 1-benzyl-1-(1-((2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)azepan-1-ium bromide (0.118 g). MS (ESI): m / z 379.52 [M] +. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.16 (3 H, t, J=7.32 Hz), 1.26 - 1.51 (4 H, m), 1.60 (2 H, br s), 1.77 - 1.94 (2 H, m), 2.10 - 2.31 (7 H, m), 2.34 - 2.48 (1 H, m), 3.56 - 3.81 (4 H, m), 4.26 (1 H, br d, J=10.68 Hz), 4.66 (1 H, d, J=13.12 Hz), 5.21 (1 H, d, J=13.12 Hz), 7.06 - 7.22 (3 H, m), 7.45 - 7.61 (3 H, m), 7.61 - 7.69 (2 H, m), 10.42 (1 H, s).

[0218] 31. Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)azocan-1-ium bromide [ka] Synthesis of intermediate 2-(azocan-1-yl)-N-(2,6-dimethylphenyl)acetamide: To a stirred solution of 2-bromo-N-(2,6-dimethylphenyl)acetamide (500 mg, 2.065 mmol) in ACN (5.0 mL) was added K2CO3 (713 mg, 5.159 mmol) followed by azocane (467 mg, 4.125 mmol), and the resulting reaction mixture was stirred at 80 °C for 16 h, and the reaction progress was monitored by TLC (5% MeOH in DCM, UV visualization). The crude reaction mixture was poured into ice-cold water (40 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na2SO4, and subsequently concentrated under reduced pressure to give 2-(azocan-1-yl)-N-(2,6-dimethylphenyl)acetamide (480 mg) as an off-white solid. Mass (ESI): m / z 275.1 [M + H] +. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (br s, 1 H), 7.02 - 7.16 (m, 3 H), 3.34 (s, 2 H), 2.74 - 2.88 (m, 4 H), 2.25 (s, 6 H), 1.53 - 1.80 (m, 10 H).

[0219] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)azocane-1-ium bromide: To a stirred solution of 2-(azocane-1-yl)-N-(2,6-dimethylphenyl)acetamide (200 mg, 0.728 mmol) in ACN (2.0 mL) was added benzyl bromide (240 mg, 1.403 mmol) and the resulting reaction mixture was stirred at 90° C. for 16 h and the reaction progress was monitored by TLC (5% MeOH in DCM, UV visualization). The reaction mixture was concentrated under reduced pressure to give the crude product, which was triturated with a 1:1 mixture of EtOAc:Et2O (3×50 mL) to give 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)azocane-1-ium bromide as a light brown solid. Mass (ESI): m / z 365.54 [M] +. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.02 (s, 1 H), 7.46 - 7.70 (m, 5 H), 7.05 - 7.22 (m, 3 H), 4.89 (s, 2 H), 4.07 (s, 2 H), 3.64 - 3.76 (m, 2 H), 3.48 - 3.62 (m, 2 H), 2.23 (s, 6 H), 1.94 - 2.14 (m, 4 H), 1.50 - 1.83 (m, 6 H).

[0220] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-3,3-difluoropiperidine-1-ium bromide: [ka] Synthesis of 2-(3,3-difluoropiperidin-1-yl)-N-(2,6-dimethylphenyl)acetamide: To a stirred solution of 3,3-difluoropiperidine hydrochloride (0.371 g, 0.309 mmol) in ACN (25 mL) at 0 °C was added TEA (0.626 g, 6.195 mmol) at 0 °C. After stirring at 0 °C for 10 min, 2-bromo-N-(2,6-dimethylphenyl)acetamide (0.5 g, 2.065 mmol) was added at 0 °C. The resulting reaction mixture was stirred at room temperature for 16 h and the progress of the reaction was monitored by TLC (30% EtOAc in Pet ether, UV visualization). The reaction mixture was diluted with water (10 mL) and extracted with ETOAc (2x 25 mL). The combined organic layers were concentrated under reduced pressure to give the crude product, which was purified by normal phase flash chromatography (5% MeOH in DCM) to give 2-(3,3-difluoropiperidin-1-yl)-N-(2,6-dimethylphenyl)acetamide (0.4 g) as a white solid. MS (ESI): m / z 283.24 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ ppm 8.58 (s, 1 H),7.07-7.13 (m, 3H),3.27 (s, 2 H), 2.86(t, 2 H), 2.50 (d, 2H),2.23 (s, 6 H), 1.86-2.04 (m,4H).

[0221] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-3,3-difluoropiperidin-1-ium bromide: To a solution of 2-(3,3-difluoropiperidin-1-yl)-N-(2,6-dimethylphenyl)acetamide (0.2 g, 0.708 mmol) in ACN (10 mL) was added benzyl bromide (0.145 g, 0.850 mmol) at room temperature in a sealed tube. The resulting reaction mixture was heated to 75° C. for 16 h and the progress of the reaction was monitored by TLC (5% MeOH in DCM, UV visualization). The reaction mixture was diluted with water (25 mL) and extracted with 10% methanol in DCM (2×100 mL). The combined organic layers were concentrated under reduced pressure to give the crude product, which was triturated with ethyl acetate (10 mL) to give 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-3,3-difluoropiperidin-1-ium bromide (0.060 g) as an off-white solid. MS (ESI): m / z 373.1 [M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.10(s, 1 H),7.56-7.62 (m, 5H),7.07 - 7.18(m, 3 H),5.16 (d, 1H),5.01 (d, 1H),4.31-4.40 (m, 2H), 3.98-4.18(m, 2H), 3.61-3.68(m, 2H), 2.11-2.48(m, 10H).

[0222] Synthesis of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-1-((phenyl-d5)methyl)azepan-1-ium chloride: [ka] Synthesis of 1-(chloromethyl)benzene-2,3,4,5,6-d5: To a stirred solution of benzene-d6 (5 g, 59.41 mmol) in conc. HCl (15 mL) was added paraformaldehyde (5.3522 g, 178.23 mmol) at room temperature, and the reaction mixture was stirred in a sealed tube at 80 °C for 48 h, and the progress of the reaction was monitored by 1H NMR. The reaction mixture was extracted with Et2O (2 x 25 mL), and the combined organic extracts were washed with saturated sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 25 °C to give 1-(chloromethyl)benzene-2,3,4,5,6-d5 (1.6 g) as a colorless liquid. 1 H NMR (400 MHz, CDCl3) δ ppm 4.6 (s, 2 H).

[0223] Synthesis of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-1-((phenyl-d5)methyl)azepan-1-ium chloride To a stirred solution of 2-(azepan-1-yl)-N-(2,6-dimethylphenyl)acetamide (1.5 g, 5.76 mmol) in ACN (15 mL) was added 1-(chloromethyl)benzene-2,3,4,5,6-d5 (1.592 g, 12.1 mmol), and the resulting reaction mixture was stirred in a sealed tube at 80° C. for 16 h, and the progress of the reaction was monitored by TLC (10% MeOH in DCM, UV visualization). The reaction mixture was cooled to room temperature, filtered, and the precipitated solid was washed with EtOAc to give 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-1-((phenyl-d5)methyl)azepan-1-ium chloride (1.67 g) as a white solid. MS (ESI): m / z 356.36[M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.55 (s, 1 H), 7.1 - 7.18 (m, 3 H), 4.95 (s, 2 H), 4.2 (s, 2 H), 3.72 - 3.81 (m, 1 H), 3.5 - 3.6 (m, 1 H), 2.25 (s, 6 H), 1.9 - 2.1 (m, 4 H), 1.1 - 1.2 (m, 4 H).

[0224] Synthesis of 1-(1-((2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)-1-((1-methyl-1H-pyrazol-4-yl)methyl)piperidin-1-ium bromide: [ka] Synthesis of 4-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide: To a stirred solution of (1-methyl-1H-pyrazol-4-yl)methanol (1.0 g, 8.918 mmol) in AcOH (5 mL) was added 33% HBr in AcOH (12 mL) at rt. The reaction mixture was heated at 100° C. for 16 h and the progress of the reaction was monitored by TLC (10% MeOH in DCM, UV visualization). The reaction mixture was concentrated under reduced pressure to give 4-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide (1.5 g) as a light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (s, 1 H), 7.50 (s, 1H), 5.51(s, 2 H), 3.81 (s, 3 H).

[0225] Synthesis of 1-(1-((2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)-1-((1-methyl-1H-pyrazol-4-yl)methyl)piperidin-1-ium bromide: To a solution of 4-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide (0.5 g, 1.953 mmol) in DMF (5 mL) was added N-(2,6-dimethylphenyl)-2-(piperidin-1-yl)butanamide (0.783 g, 2.853 mmol) and potassium carbonate (0.473 g, 3.427 mmol). The resulting reaction mixture was heated in a sealed tube at 100° C. for 24 h and the progress of the reaction was monitored by TLC (5% MeOH in DCM, UV visualization). The reaction mixture was diluted with water (25 mL) and extracted with 10% methanol in DCM (2×100 ml). The combined organic layers were concentrated under reduced pressure to give the crude product, which was purified by normal phase flash chromatography (5% MeOH in DCM) to give 1-(1-((2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)-1-((1-methyl-1H-pyrazol-4-yl)methyl)piperidin-1-ium bromide (0.120 g) as an off-white solid. MS (ESI): m / z 369.48 [M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm10.4 (s, 1 H),8.01 (s, 1 H), 7.64(s, 1 H),7.10- 7.14 (m, 3H),5.17 (d, 1 H), 4.48 (d, 1H),4.1-4.3 (m, 1 H),3.90 (s, 3 H),3.8-3.9 (m, 1 H),3.20-3.45 (m,2 H), 2.30-2.36 (m, 1 H), 2.16 (s, 6 H), 1.92-2.08 (m, 6H), 1.54 (d, 2H), 1.11-1.17 (m, 3H).

[0226] Synthesis of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-1-(3-(methoxycarbonyl)benzyl)piperidin-1-ium bromide: [ka] Synthesis of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-1-(3-(methoxycarbonyl)benzyl)piperidin-1-ium bromide: To a solution of N-(2,6-dimethylphenyl)-2-(piperidin-1-yl)acetamide (200 mg, 0.812 mmol) in ACN (3 mL) was added methyl 3-(bromomethyl)benzoate (241.6 mg, 1.055 mmol) at room temperature. The resulting reaction mixture was stirred at 90° C. for 16 h and the progress of the reaction was monitored by TLC (5% MeOH in DCM, visualization: UV). The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product, which was triturated with EtOAc (3×10 mL) to give pure 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-1-(3-(methoxycarbonyl)benzyl)piperidin-1-ium bromide (57.5 mg) as an off-white solid. MS (ESI): m / z 395.2[M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.09(s, 1 H),8.18(s, 1 H),8.13 (d, 1 H), 7.83-7.85 (m,1H),7.69-7.72 (m, 1 H), 7.12-7.17(m,3H),5.06 (s, 2 H), 4.22 (s,2H), 3.88 (s, 3H), 3.52-3.65 (m, 2 H), 3.47-3.50(m, 2 H), 2.21 (s, 6 H), 1.90-1.96 (m, 4 H), 1.71-1.74 (m, 1 H),1.56-1.57(m, 1 H).

[0227] Synthesis of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-1-(4-(methoxycarbonyl)benzyl)piperidin-1-ium bromide: [ka] Synthesis of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-1-(4-(methoxycarbonyl)benzyl)piperidin-1-ium bromide: To a stirred solution of N-(2,6-dimethylphenyl)-2-(piperidin-1-yl)acetamide (0.4 g, 1.623 mmol) in ACN (5 mL) was added methyl 4-(bromomethyl)benzoate (0.743 g, 3.247 mmol) and the resulting reaction mixture was stirred at 80° C. for 16 h and the progress of the reaction was monitored by TLC (10% methanol in DCM, visualization: UV). The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product, which was purified by refluxing with EtOAc (30 mL) at 70° C. for 2 h. The refluxed product was filtered and washed with warm ethyl acetate (30 mL) to give (1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-1-(4-(methoxycarbonyl)benzyl)piperidin-1-ium bromide (43 mg) as a white solid. Mass (ESI): m / z 395.3 [M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.06(s, 1 H), 8.09 (d, 2 H), 7.72 (d, 2 H), 7.17-7.12 (m, 3 H), 5.03 (s, 2 H), 4.22 (s, 2H), 3.89 (s, 3 H), 3.67-3.64 (m, 2 H), 3.54-3.49 (m, 2 H), 2.20 (s, 6 H), 2.0-1.97(m, 4 H), 1.72-1.69 (m, 1 H), 1.58-1.53 ​​(m, 1 H).

[0228] Synthesis of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-1-(2-(methoxycarbonyl)benzyl)piperidin-1-ium bromide: [ka] Synthesis of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-1-(2-(methoxycarbonyl)benzyl)piperidin-1-ium bromide: To a solution of N-(2,6-dimethylphenyl)-2-(piperidin-1-yl)acetamide (0.500 g, 2.0296 mmol) in ACN (5.0 mL) was added methyl 2-(bromomethyl)benzoate (0.929 g, 4.0592 mmol) and the resulting reaction mixture was heated to 80° C. for 16 h and the progress of the reaction was monitored by TLC (10% MeOH, visualization: UV). The reaction mixture was concentrated under reduced pressure to give the crude compound, which was triturated with 3×10 mL of ethyl acetate followed by 2×10 mL of diethyl ether to give pure 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-1-(2-(methoxycarbonyl)benzyl)piperidin-1-ium bromide (250 mg) as an off-white solid. MS (ESI): m / z 395.2[M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.11 (s, 1H),8.01 (d, 1 H),7.69-7.76 (m, 3H),7.11-7.17 (m, 3 H),5.37 (s, 2H), 4.43-4.46 (m, 2 H), 3.85 (s, 3 H), 3.75 (d, 2 H), 3.17 (t, 2 H), 2.20 (s, 6 H),1.96-2.07 (m, 2 H), 1.79-1.83 (m, 2 H), 1.66-1.70 (m, 1H), 1.37-1.40 (m, 1H).

[0229] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)(methyl)amino)-2-oxoethyl)azepan-1-ium formate: [ka] Synthesis of 2-iodo-N-(2,6-dimethylphenyl)-N-methylacetamide: To a stirred solution of 2-chloro-N-(2,6-dimethylphenyl)acetamide (2.0 g, 10.118 mmol) in THF (16 mL), NaH (60%) (0.607 g, 25.295 mmol) was added at 0 °C and the mixture was stirred at 0 °C for 20 min. Methyl iodide (0.5 ml, 8.031 mmol) was added at 0 °C and the resulting reaction mixture was stirred at room temperature for 16 h and the progress of the reaction was monitored by TLC (10% EtOAc in Pet, visualized by UV). The reaction mixture was poured into ice water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with brine solution (25 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (eluted with 20-30% ethyl acetate in pet ether). The collected pure fractions were concentrated under reduced pressure to give N-(2,6-dimethylphenyl)-2-iodo-N-methylacetamide (0.55 g) as a yellow liquid. Mass (ESI): m / z 304.03 [M+H] + .

[0230] Synthesis of 2-(azepan-1-yl)-N-(2,6-dimethylphenyl)-N-methylacetamide: To a stirred solution of N-(2,6-dimethylphenyl)-2-iodo-N-methylacetamide (0.5 g, 1.649 mmol) in ACN (5.0 mL) was added K2CO3 (0.569 g, 4.123 mmol) and azepane (0.327 ml, 3.298 mmol) at room temperature. The resulting reaction mixture was stirred at 90 °C for 16 h and the progress of the reaction was monitored by TLC (50% EtOAc in pet ether, visualized by UV). The reaction mixture was poured into ice water (25 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic extracts were washed with brine solution (25 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude compound, which was purified by normal phase flash chromatography (eluted with 10% to 50% EtOAc in pet ether). The collected pure fractions were concentrated under reduced pressure to give 2-(azepan-1-yl)-N-(2,6-dimethylphenyl)-N-methylacetamide (0.23 g). MS (ESI): m / z 275.49[M+H] + .

[0231] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)(methyl)amino)-2-oxoethyl)azepan-1-ium formate To a stirred solution of 2-(azepan-1-yl)-N-(2,6-dimethylphenyl)-N-methylacetamide (0.1 g, 0.364 mmol) in acetonitrile (1.0 mL) was added (bromomethyl)benzene (0.124 g, 0.728 mmol). The resulting reaction mixture was stirred at 90° C. for 16 h and the progress of the reaction was monitored by TLC (10% MeOH in DCM, visualization: UV). The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by reversed phase Prep HPLC. (Column: X-select C18 (250*19) mm, 5u, Mobile phase A: 0.1% FA in water, Mobile phase B: ACN:MeOH, Flow rate; 13ml / min, Solubility: Water+THF+ACN, Method (T% of B): 0 / 10, 2 / 10, 10 / 50, 13 / 50, 13.2 / 98, 17 / 98, 17.2 / 10, 20 / 10, Temperature: Room temperature). The collected pure fractions were lyophilized to give the product (1-benzyl-1-(2-((2,6-dimethylphenyl)(methyl)amino)-2-oxoethyl)azepan-1-ium formate (70mg) as a white gum. MS (ESI): m / z 365.3[M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (s, 1 H), 7.56-7.42 (m, 5 H), 7.26-7.17(m, 3 H), 4.95(s, 2 H), 4.41(s, 1 H), 3.91-3.85(m, 1 H), 3.62-3.50 (m, 3 H), 3.36(s, 1 H), 3.14 (d, 3 H), 2.32-2.05 (s, 7 H), 1.95-1.65 (m, 2 H), 1.46-1.23(m, 5 H).

[0232] Synthesis of 1-benzyl-1-(1-(mesitylamino)-1-oxobutan-2-yl)piperidin-1-ium bromide: [ka] Synthesis of 2-bromo-N-mesitylbutanamide: To a stirred solution of 2,4,6-trimethylaniline (2.0 g, 14.791 mmol) in DCM (20 mL) was added DIPEA (5.735 g, 44.373 mmol) at room temperature, followed by dropwise addition of 2-bromobutanoyl chloride (3.291 g, 17.749 mmol) at 0 °C, and the resulting reaction mixture was stirred for 3 h and the progress of the reaction was monitored by TLC (20% ethyl acetate in Pet ether. Visualization: UV). The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (eluted with 10% to 50% ethyl acetate in Pet ether). The pure fractions were combined and concentrated to give the desired product 2-bromo-N-mesitylbutanamide (1.5 g). MS (ESI): m / z 286.11[M+2] + . 1 H NMR(400 MHz, CDCl3) δ ppm 7.60 (s, 1 H), 6.95 (s, 2 H), 4.45(t, 1 H), 2.25(s,3 H), 2.2(s,6H),1.60-1.40(m, 2 H), 1.10 (t, 3 H).

[0233] Synthesis of N-mesityl-2-(piperidin-1-yl)butanamide: To a stirred solution of 2-bromo-N-mesitylbutanamide (1.5 g, 5.278 mmol) in acetonitrile (30 ml) was added potassium carbonate (2.18 g, 15.834 mmol) and piperdine (0.943 g, 11.083 mmol) at room temperature. The resulting reaction was refluxed for 16 h and the progress of the reaction was monitored by TLC (50% EtOAc / Hexane, visualization: UV). The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure to give the crude product, which was triturated with ethyl acetate (40 mL) to give pure N-mesityl-2-(piperidin-1-yl)butanamide (760 mg). MS (ESI): m / z 289.43 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.07(s, 1 H), 6.86 (s, 2 H), 3.06-3.01 (t, 1 H), 2.60-2.48(m, 4H), 2.21(s,3H), 2.06 (s, 6H), 1.80-1.25 (t,8H), 0.95 (t, 3H).

[0234] Synthesis of 1-benzyl-1-(1-(mesitylamino)-1-oxobutan-2-yl)piperidin-1-ium bromide: To a stirred solution of N-mesityl-2-(piperidin-1-yl)butanamide (0.15 g, 0.52 mmol) in acetonitrile (1 mL) was added benzyl bromide (0.177 g, 1.04 mmol). The resulting reaction mixture was stirred at 80° C. for 20 h and the progress of the reaction was monitored by TLC (10% methanol in DCM, visualization: UV). The reaction mixture was concentrated under reduced pressure to give the crude product, which was triturated with EtOAc (20 mL) to give the desired product 1-benzyl-1-(1-(mesitylamino)-1-oxobutan-2-yl)piperidin-1-ium bromide (194 mg) as a white solid. Mass (ESI): m / z 379.3 [M] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 10.31 (s, 1 H), 7.62-7.50(m, 5 H), 6.93 (s, 2 H), 5.42-5.39 (m, 1 H), 4.63-4.20 (m, 2 H), 4.05-3.55 (m, 2H), 3.30-3.10(m, 2H), 2.41-2.31 (m, 1H), 2.23 (s,9H), 2.15-2.06(m,2H),2.05-1.80 (m, 3H), 1.57-1.43(m, 2H), 1.23-1.07(m, 3 H).

[0235] Synthesis of 1-benzyl-1-(2-((4-((tert-butoxycarbonyl)(butyl)amino)phenyl)amino)-2-oxoethyl)azepan-1-ium bromide: [ka] Synthesis of 2-bromo-N-(4-nitrophenyl)acetamide: Bromoacetyl bromide (29.226 g, 144.790 mmol) was added to a stirred suspension of 4-nitroaniline (10 g, 72.395 mmol) in H2O (100 mL) at 0 °C, the reaction mixture was stirred at room temperature for 16 h, and the progress of the reaction was monitored by TLC (50% EtOAc in Pet-ether, visualization: UV). The reaction mixture was basified with sat.Na2CO3 solution (100 mL) and the precipitated solid was filtered and dried. The crude product was triturated with diethyl ether (2 x 100 mL) to give 2-bromo-N-(4-nitrophenyl)acetamide (8 g) as a yellow solid. Mass (ESI): m / z 259.17 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.97 (s, 1 H), 8.25(d, 2 H), 7.83 (d, 2H),4.11(s, 2 H).

[0236] Synthesis of 2-(azepan-1-yl)-N-(4-nitrophenyl)acetamide: To a stirred solution of 2-bromo-N-(4-nitrophenyl)acetamide (5 g, 19.300 mmol) in ACN (50 ml) was added K2CO3 (8 g, 57.900 mmol) followed by azepane (3.8 g, 38.600 mmol, 2 eq.) and the reaction mixture was heated to 90° C. in a sealed tube for 16 h and the progress of the reaction was monitored by TLC (50% EtOAc in Pet ether, visualization: UV). The reaction mixture was allowed to cool to room temperature and then diluted with water (200 mL) and extracted with EtOAc (2×200 mL). The combined organic extracts were washed with brine solution (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was triturated with diethyl ether (2×50 mL) to give pure 2-(azepan-1-yl)-N-(4-nitrophenyl)acetamide (2.5 g). Mass (ESI): m / z 278.27 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.26 (s, 1 H), 8.21 (d, 1 H), 7.91(d,2 H), 3.33-3.4(m, 2 H), 2.72-2.81 (m, 4 H), 1.56-1.62 (m, 8 H).

[0237] Synthesis of N-(4-aminophenyl)-2-(azepan-1-yl)acetamide: To a stirred solution of 2-(azepan-1-yl)-N-(4-nitrophenyl)acetamide (2.5 g, 9.014 mmol) in MeOH (25 mL) was added 10% Pd / C (2.5 g) at room temperature and the reaction mixture was stirred at RT for 16 h under H2 gas (Balloon pressure) and the progress of the reaction was monitored by TLC (50% EtOAc / pet-ether, visualization: UV). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give pure N-(4-aminophenyl)-2-(azepan-1-yl)acetamide (1.5 g). Mass (ESI): m / z 248.30 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.20 (s, 1 H), 7.22(d,2H),6.49(d,2 H), 4.85 (s, 1 H),3.16-3.19 (m,2 H), 2.68-2.72 (m, 4 H), 1.57 - 1.62 (m, 8 H).

[0238] Synthesis of 2-(azepan-1-yl)-N-(4-(butylamino)phenyl)acetamide: To a stirred solution of N-(4-aminophenyl)-2-(azepan-1-yl)acetamide (1.8 g, 7.277 mmol) and butyronitrile (2.51 g, 36.385 mmol) in methanol (20 mL) was added 10% Pd / C (1.8 g) and the reaction mixture was stirred at room temperature under H2 gas atmosphere (balloon) for 16 h and the progress of the reaction was monitored by TLC (50% EtOAc in Pet ether, visualization: UV). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the desired product 2-(azepan-1-yl)-N-(4-(butylamino)phenyl)acetamide (1 g). Mass (ESI): m / z 304.43[M+1] + .

[0239] Synthesis of tert-butyl (4-(2-(azepan-1-yl)acetamido)phenyl)(butyl)carbamate To a stirred solution of 2-(azepan-1-yl)-N-(4-(butylamino)phenyl)acetamide (1.4 g, 4.613 mmol) in ACN (20 mL) was added triethylamine (1.39 g, 13.839 mmol) followed by di-tert-butyl dicarbonate (1.5 g, 6.919 mmol), the reaction mixture was stirred at rt for 16 h, and the progress of the reaction was monitored by TLC (50% EtOAc in Pet-ether, visualization: UV). After completion of starting material on TLC, the crude compound was diluted with water (100 mL) and extracted with EtOAc (2×120 mL), the combined organic extracts were washed with brine solution (70 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (eluted with 10%-20% EtOAc in pet-ether) to give the product tert-butyl (4-(2-(azepan-1-yl)acetamido)phenyl)(butyl)carbamate (1g). Mass (ESI): m / z 404.58[M+H]. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.65(s, 1 H),7.59(d,2H),7.13(d,2H),3.53(t,2H),3.24(s, 2 H),2.70-2.75(m, 4H),1.61-1.86 (m, 8 H), 1.35-1.44 (m,9H), 1.24 -1.32 (m, 3H), 1.17 - 1.22 (m, 3H).

[0240] Synthesis of 1-benzyl-1-(2-((4-((tert-butoxycarbonyl)(butyl)amino)phenyl)amino)-2-oxoethyl)azepan-1-ium bromide: To a stirred solution of tert-butyl (4-(2-(azepan-1-yl)acetamido)phenyl)(butyl)carbamate (200 mg, 0.495 mmol) in ACN (2 mL) was added benzyl bromide (127 mg, 0.742 mmol) at room temperature and the reaction mixture was stirred at 90° C. for 16 h and the progress of the reaction was monitored by TLC (10% MeOH in DCM, visualization: UV). The reaction was concentrated under reduced pressure and the crude compound was triturated with diethyl ether (2 x 20 mL) and EtOAc (2 x 20 mL) to give 1-benzyl-1-(2-((4-((tert-butoxycarbonyl)(butyl)amino)phenyl)amino)-2-oxoethyl)azepan-1-ium bromide (80 mg). Mass (ESI): m / z 494.56 [M] + . 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.63(s, 1 H), 7.66 (d,2H),7.50-7.60 (m,5 H), 7.24 (d, 2 H),4.91 (s,2 H), 4.00 (s, 2H), 3.52-3.76 (m, 6 H), 1.90-1.98 (m, 4 H), 1.63-1.76 (m, 4 H), 1.37-1.41 (m, 13H),0.85(t,3 H).

[0241] Synthesis of 1-benzyl-1-(2-((4-(butylamino)phenyl)amino)-2-oxoethyl)azepan-1-ium formate: [ka] Synthesis of 1-benzyl-1-(2-((4-(butylamino)phenyl)amino)-2-oxoethyl)azepan-1-ium formate: A reaction mixture of 1-benzyl-1-(2-((4-((tert-butoxycarbonyl)(butyl)amino)phenyl)amino)-2-oxoethyl)azepan-1-ium bromide (50 mg, 0.087 mmol) in 47% Aq. HBr (1 mL) was stirred at 80° C. for 16 h and the progress of the reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by reversed phase Prep. HPLC (Column: X-Select C18 (19X250) mm 5u, Mobile phase: 0.1% formic acid in H2O; CAN, Flow rate: 18 ml / min, Gradient method: 0 / 51, 7.1 / 50, 7.2 / 99, 9.2 / 99, 9.3 / 5, 12 / 5). Pure fractions were collected and lyophilized to give 1-benzyl-1-(2-((4-(butylamino)phenyl)amino)-2-oxoethyl)azepan-1-ium formate (25 mg). Mass (ESI): m / z 394.53 [M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.95 (s, 1 H), 8.56 (s,1 H), 7.68(d,2 H), 7.49-7.54 (m, 3 H), 7.36 (d, 2 H), 6.54 (d, 2 H),5.52 (t, 1H),4.89 (s, 2H),4.01 (s, 2H),3.67-3.69 (m, 2H),3.51-3.53 (m, 2H),2.97 (t, 2H),1.91-2.01 (m,4H),1.49-1.62 (m,2H), 1.35-1.40 (m, 2 H), 1.36 (t, 3 H).

[0242] Synthesis of 1-benzyl-1-(2-((4-(butylamino)phenyl)amino)-2-oxoethyl)piperidin-1-ium carbonate: [ka] Synthesis of N-(4-nitrophenyl)-2-(piperidin-1-yl)acetamide: To a stirred solution of 2-bromo-N-(4-nitrophenyl)acetamide (3.0 g, 11.580 mmol) in ACN (30.0 mL) was added potassium carbonate (4.801 g, 34.74 mmol) and piperidine (1.972 g, 23.16 mmol), and the resulting reaction mixture was stirred at 85° C. for 1 h and the reaction progress was monitored by TLC (50% ethyl acetate in Pet ether, UV visualization). The reaction mixture was cooled to rt and concentrated under reduced pressure to give the crude residue. The crude residue was diluted with water (150 mL) and extracted with EtOAc (3 x 100 mL), and the combined organic extracts were washed with brine solution (1 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (eluted with 5% EtOAc in Pet ethyl) to give the product N-(4-nitrophenyl)-2-(piperidin-1-yl)acetamide (1.40 g) as a pale yellow solid. MS (ESI): m / z 264.26 [M + H + ] .1 H NMR (400 MHz, DMSO-d6) δ ppm 10.28(s, 1H),8.20-8.23(m,2H),7.89-7.93(m,2H),3.14 (s, 2H), 2.44-2.51 (m,4H), 1.53-1.59 (m,4H), 1.40 (t, 2H).

[0243] Synthesis of N-(4-aminophenyl)-2-(piperidin-1-yl)acetamide: To a solution of N-(4-nitrophenyl)-2-(piperidin-1-yl)acetamide (1.4 g, 5.3171 mmol) in MeOH (15.0 ml) was added 10% Pd / C (1.4 g) and the resulting reaction mixture was stirred at RT for 16 h under hydrogen gas atmosphere (balloon pressure) and the progress of the reaction was monitored by TLC (50% EtOAc in Pet ether, visualization: UV). The reaction mixture was filtered through Celite, washed with excess methanol (2 x 20 ml) and the combined filtrate was concentrated under reduced pressure to give the crude product, which was triturated with diethyl ether (3 x 20 mL) to give N-(4-aminophenyl)-2-(piperidin-1-yl)acetamide (1.20 g). MS (ESI): m / z 234.29 [M+] 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.25 (s, 1 H), 8.22 (d,2H), 7.92 (t,2H), 3.32 (d, 2H), 2.72-2.85(m, 4H), 1.52-1.62(m,8H). Analytical data included.

[0244] Synthesis of N-(4-(butylamino)phenyl)-2-(piperidin-1-yl)acetamide: To a solution of N-(4-aminophenyl)-2-(piperidin-1-yl)acetamide (1.2 g, 5.1431 mmol) in methanol (15.0 mL) was added butyronitrile (1.777 g, 25.7157 mmol) and 10% Pd / C (1.2 g) under nitrogen atmosphere. The resulting reaction mixture was stirred at rt for 16 h under hydrogen gas atmosphere (balloon pressure) and the progress of the reaction was monitored by TLC (ethyl acetate in Pet ether, UV visualization). The reaction mixture was filtered through Celite, washed with excess methanol (2 x 20 mL) and concentrated to give the crude product, which was purified by column chromatography (eluted with 20% EtOAc in Pet ether) to give pure N-(4-(butylamino)phenyl)-2-(piperidin-1-yl)acetamide (1.10 g). MS (ESI): m / z 290.42 [M+H] .1H NMR (400 MHz, DMSO-d6) δ ppm9.21(s, 1 H), 7.27 (d, 2H),6.48(d, 2H),5.33 (t,2H),2.88-2.95(m,4H),2.49-2.51(m,4H), 1.47-1.58 (m, 6H), 1.34-1.41 (m, 4H), 0.90 (t, 3H).

[0245] Synthesis of tert-butyl butyl (4-(2-(piperidin-1-yl)acetamido)phenyl)carbamate: To a stirred solution of N-(4-(butylamino)phenyl)-2-(piperidin-1-yl)acetamide (0.956 g, 3.30 mmol) in DCM (10.0 mL) at 0° C. was added TEA (1.672 g, 16.527 mmol) and di-tert-butyl dicarbonate (1.803 g, 8.2635 mmol), and the resulting reaction mixture was stirred at rt for 16 h, and the progress of the reaction was monitored by TLC (100% EtOAc, visualization: UV). The reaction mixture was concentrated under reduced pressure, diluted with water (50 mL), and extracted with DCM (3×50 mL). The combined organic extracts were washed with brine solution (1×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by normal phase flash chromatography (eluted with 30% in Pet ether). The collected pure fractions were concentrated under reduced pressure to give the product tert-butyl butyl(4-(2-(piperidin-1-yl)acetamido)phenyl)carbamate (1.15 g). MS (ESI): m / z 390.57[M+H] + .

[0246] Synthesis of 1-benzyl-1-(2-((4-((tert-butoxycarbonyl)(butyl)amino)phenyl)amino)-2-oxoethyl)piperidin-1-ium bromide: To a stirred solution of tert-butylbutyl(4-(2-(piperidin-1-yl)acetamido)phenyl)carbamate (0.225 g, 0.5776 mmol) in acetonitrile (3 mL) in a microwave vial was added benzyl bromide (0.197 g, 1.1552 mmol). The reaction mixture was stirred at 100° C. for 1 h in a microwave (CEM instrument) and the progress of the reaction was monitored by LCMS and TLC (5% MeOH in DCM, detection: UV). The reaction mixture was cooled to rt and concentrated under reduced pressure to give the crude product which was triturated with diethyl ether (5×5 ml) to give the product 1-benzyl-1-(2-((4-((tert-butoxycarbonyl)(butyl)amino)phenyl)amino)-2-oxoethyl)piperidin-1-ium bromide (110 mg). MS (ESI): m / z 480.58 [M]+.

[0247] Synthesis of 1-benzyl-1-(2-((4-(butylamino)phenyl)amino)-2-oxoethyl)piperidin-1-ium carbonate A reaction mixture of 1-benzyl-1-(2-((4-((tert-butoxycarbonyl)(butyl)amino)phenyl)amino)-2-oxoethyl)piperidin-1-ium bromide (105 mg, 0.2184 mmol) in aqueous hydrogen bromide (48%) (1 mL) was stirred at rt for 16 h and the progress of the reaction was monitored by LCMS and TLC (80% ethyl acetate in pet ether, detection: UV). The reaction mixture was lyophilized to give the crude product, which was purified by reversed phase Prep. HPLC (Column: X-select C18 (19*250) 5u, Mobile phase (A): 10 mM ammonium bicarbonate, Mobile phase (B): 100% ACN Method: 0 / 3, 2 / 40, 20 / 40, 20.50 / 100, 30 / 35, Flow rate: 18 ml / min, Solubility: CAN + THF + MeOH). Pure fractions were combined and lyophilized to give 1-benzyl-1-(2-((4-(butylamino)phenyl)amino)-2-oxoethyl)piperidin-1-ium carbonate (15.1 mg). MS (ESI): m / z 380.2 [M]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.10 (brs, 1 H), 7.54-7.72(m, 5 H), 7.34 (d, 2 H), 6.52 (d, 2 H), 5.44 (t, 1 H), 4.94(s, 2 H), 4.09(s,2H),3.65 (d, 2H), 3.33-3.5(m,2H),2.97-3.01 (m, 2H),1.92-1.97(m, 4H),1.63(q, 1H), 1.48-1.55 (m, 3H), 1.34-1.42 (m, 2 H), 0.91 (t, 3 H).

[0248] Synthesis of 1-benzyl-1-(1-((4-(butylamino)-2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)piperidin-1-ium carbonate: [ka] Synthesis of N-(2,6-dimethylphenyl)-4-methylbenzenesulfonamide: Tosyl chloride (94.396 g, 495.131 mmol) was added to a stirred solution of 2,6-dimethylaniline (50 g, 413 mmol) in pyridine (1.2 L) and the mixture was heated to reflux at 115 °C for 4 h, and the progress of the reaction mixture was monitored by TLC (30% ethyl acetate in pet ether, visualization: UV). The reaction mixture was concentrated under reduced pressure to give a crude residue, which was diluted with water (500 mL), adjusted to pH 6 with 2N HCl (500 mL), and extracted with ethyl acetate (2 x 1 L). The combined organic extracts were washed with brine solution (1.0 L), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was triturated with pet ether to give N-(2,6-dimethylphenyl)-4-methylbenzenesulfonamide (90 g) as an off-white solid. MS (ESI): m / z 276.23 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 9.231 (s, 1 H), 7.530-7.551(d, 2 H), 7.354-7.375(d, 2 H), 6.985-7.069(m, 3H), 2.384 (s, 3 H), 1.940 (s, 6 H).

[0249] Synthesis of N-(2,6-dimethyl-4-nitrophenyl)-4-methylbenzenesulfonamide: To a solution of N-(2,6-dimethylphenyl)-4-methylbenzenesulfonamide (90 g, 326.8 mmol) in AcOH (675 mL) and water (450 mL) was added NaNO2 (45.103 g, 653.666 mmol) followed by dropwise addition of conc. HNO3 (41.181 g, 653.666 mmol) over 15 min at room temperature. The resulting reaction mixture was heated to 110° C. for 5 h and the progress of the reaction mixture was monitored by TLC (30% ethyl acetate in pet ether, visualization: UV). The reaction mixture was diluted with ice-cold water (500 mL), basified with 1N NaOH solution (800 mL) and extracted with ethyl acetate (2 x 1 L). The combined organic extracts were washed with brine solution (1 L), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was triturated with pet ether (500 mL) to give the product N-(2,6-dimethyl-4-nitrophenyl)-4-methylbenzenesulfonamide (40 g) as an off-white solid. MS (ESI): m / z 321.18[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ ppm9.72 (s, 1 H), 7.925(s, 2 H), 7.562-7.583(d, 2 H), 7.390-7.409(d, 2H), 2.400 (s, 3 H), 2.073 (s, 6 H).

[0250] Synthesis of 2,6-dimethyl-4-nitroaniline: To a stirred solution of N-(2,6-dimethyl-4-nitrophenyl)-4-methylbenzenesulfonamide (25 g, 78.037 mmol) in AcOH (125 ml) was added HClO4 (250 ml) at rt and the mixture was heated to 100° C. for 3 h and the progress of the reaction mixture was monitored by TLC (30% ethyl acetate in pet ether, visualization: UV). The reaction mixture was poured onto crushed ice, basified with aqueous ammonium chloride (pH approx. 11) and extracted with ethyl acetate (2×1 L). The combined organic extracts were washed with brine solution (300 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (eluted with 20% ethyl acetate in pet ether) to give 2,6-dimethyl-4-nitroaniline (10 g) as a yellow solid. MS (ESI): m / z 167.03[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.787 (s, 2 H), 6.142 (s, 2 H), 2.155 (s,6 H).

[0251] Synthesis of 2-bromo-N-(2,6-dimethyl-4-nitrophenyl)butanamide: To a cooled solution (0° C.) of 2,6-dimethyl-4-nitroaniline (3 g, 18.05 mmol) in DCM (45 mL) was added pyridine (1.713 g, 21.66 mmol) followed by 2-bromobutanoyl chloride (4.017 g, 21.66 mmol). The resulting reaction mixture was allowed to stir at rt for 16 h and the progress of the reaction mixture was monitored by TLC (50% ethyl acetate in pet ether, visualization: UV). The reaction mixture was filtered and the isolated solid was washed with DCM (20 mL) and dried under high vacuum to give 2-bromo-N-(2,6-dimethyl-4-nitrophenyl)butanamide (2 g) as an off-white solid. MS (ESI): m / z 315.26 [M] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 10.05 (s, 1H), 8.0(s, 2 H),4.55(t, 1 H), 2.279 (s, 6 H), 1.940-2.143 (m, 2H), 0.99(t, 3 H).

[0252] Synthesis of N-(2,6-dimethyl-4-nitrophenyl)-2-(piperidin-1-yl)butanamide: To a stirred solution of 2-bromo-N-(2,6-dimethyl-4-nitrophenyl)butanamide (2 g, 6.345 mmol) in ACN (30 mL) was added K2CO3 (2.627 g, 19.03 mmol) and piperidine (1.080 g, 12.690 mmol). The resulting mixture was heated to 80 °C for 16 h and the progress of the reaction mixture was monitored by TLC (50% ethyl acetate in pet ether, visualization: UV). The reaction mixture was concentrated, diluted with ethyl acetate (150 mL) and washed with water (50 mL X 3) and brine solution (60 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (eluted with 50% ethyl acetate in pet ether) to give N-(2,6-dimethyl-4-nitrophenyl)-2-(piperidin-1-yl)butanamide (1.70 g). MS (ESI): m / z 320.42[M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.578 (s, 1 H), 7.992 (s, 2H), 3.12 (t, 1 H),2.55-2.62 (m, 4 H), 2.28(s, 6 H),1.60-1.81(m, 2H), 1.35-1.56(m, 6H), 0.93(t, 3H).

[0253] Synthesis of N-(4-amino-2,6-dimethylphenyl)-2-(piperidin-1-yl)butanamide: To a stirred solution of N-(2,6-dimethyl-4-nitrophenyl)-2-(piperidin-1-yl)butanamide (1.7 g, 5.322 mmol) in EtOH (40 mL) was added 10% Pd-C (0.900 g) and the mixture was stirred at rt for 16 h under H2 gas (balloon pressure) and the progress of the reaction mixture was monitored by TLC (100% ethyl acetate, visualization: UV). The mixture was filtered through Celite, the filter bed was washed with MeOH (200 ml) and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by normal phase flash chromatography (eluting with EtOAc) to give N-(4-amino-2,6-dimethylphenyl)-2-(piperidin-1-yl)butanamide (1.0 g). MS (ESI): m / z 290.46 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (s,1 H), 6.23 (s, 2H), 4.82 (s, 2H),2.95 (t, 1 H),2.45-2.6(m, 4H), 1.2-1.6 (m,8H), 0.910(t, 3 H).

[0254] Synthesis of N-(4-(butylamino)-2,6-dimethylphenyl)-2-(piperidin-1-yl)butanamide: To a solution of N-(4-amino-2,6-dimethylphenyl)-2-(piperidin-1-yl)butanamide (1.0 g, 3.455 mmol) in MeOH (20 mL) was added butyronitrile (2.387 g, 34.551 mmol) and 10% Pd / C (1 g), the mixture was stirred at rt for 16 h under H2 gas (balloon pressure), and the progress of the reaction mixture was monitored by TLC (ethyl acetate, visualization: UV). The reaction mixture was filtered through a bed of Celite, the filter bed was washed with MeOH (150 ml), and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by normal phase flash chromatography (eluting with ethyl acetate) to give N-(4-(butylamino)-2,6-dimethylphenyl)-2-(piperidin-1-yl)butanamide (0.500 g). MS (ESI): m / z 346.51 [M+H] + .1 H NMR (500 MHz, DMSO-d6) δ ppm 8.789 (s, 1 H), 6.242 (s, 2H), 2.96 (t, 3 H), 2.50-2.57 (m, 3H), 2.027 (s, 6 H), 1.498-1.518(m,2 H), 1.475-1.488(m, 6H),1.22-1.387 (m, 6H),0.885-0.918 (m, 6H).

[0255] Synthesis of tert-butylbutyl(3,5-dimethyl-4-(2-(piperidin-1-yl)butanamido)phenyl)carbamate: To a stirred solution of N-(4-(butylamino)-2,6-dimethylphenyl)-2-(piperidin-1-yl)butanamide (0.400 g, 1.157 mmol) in EtOH (10 mL) was added DIPEA (0.179 g, 1.389 mmol) and di-tert-butyl dicarbonate (0.758 g, 3.473 mmol) at 0° C. The reaction mixture was stirred at rt for 16 h and the progress of the reaction mixture was monitored by TLC (50% ethyl acetate in pet ether, visualization: UV). The mixture was concentrated under vacuum to give a crude residue which was diluted with ethyl acetate (80 ml) and washed with water (40 ml), brine solution (40 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by normal phase flash chromatography (eluted with 40% ethyl acetate in pet ether) to give tert-butyl butyl (3,5-dimethyl-4-(2-(piperidin-1-yl)butanamido)phenyl)carbamate (0.300 g). MS (ESI): m / z 446.66[M+H] + . 1 H NMR data shows the product with aliphatic impurities. Analytical data is included.

[0256] Synthesis of 1-benzyl-1-(1-((4-((tert-butoxycarbonyl)(butyl)amino)-2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)piperidin-1-ium bromide: To a stirred solution of tert-butyl butyl (3,5-dimethyl-4-(2-(piperidin-1-yl)butanamido)phenyl)carbamate (0.250 g, 0.561 mmol) in ACN (5 mL) was added benzyl bromide (0.191 g, 1.116 mmol) and the mixture was heated to 85° C. for 24 h and the progress of the reaction mixture was monitored by TLC (10% methanol in DCM, visualization: UV). The reaction mixture was concentrated under vacuum to give the crude product which was triturated with a mixture of diethyl ether (20 ml) and ethyl acetate (10 ml) to give 1-benzyl-1-(1-((4-((tert-butoxycarbonyl)(butyl)amino)-2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)piperidin-1-ium bromide (0.200 g). MS (ESI): m / z 536.61[M] + . 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.317 (s, 1 H), 7.547(s, 5 H), 7.002 (s, 2H), 5.41 (d, 1 H), 4.62(d, 1 H), 3.6-3.9 (m, 3H), 3.1-3.4(m, 2 H),2.4-2.5(m, 2 H), 1.953-2.184 (m, 12 H), 1.163-1.620 (m, 18 H), 0.857 (s, 3 H).

[0257] Synthesis of 1-benzyl-1-(1-((4-(butylamino)-2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)piperidin-1-ium carbonate: 47% HBr aqueous solution (8 ml) was added to 1-benzyl-1-(1-((4-((tert-butoxycarbonyl)(butyl)amino)-2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)piperidin-1-ium bromide (0.150 g, 0.243 mmol) at 0° C. and the resulting mixture was allowed to stir at rt for 16 h and the progress of the reaction mixture was monitored by TLC (10% methanol in DCM, visualization: UV). The reaction mixture was concentrated under reduced pressure and the residue was washed with diethyl ether (5 ml) to give the crude product, which was purified by reversed-phase prep-HPLC (column: kromasil C18 (25X150) mm 10u, mobile phase- 10 mM ammonium bicarbonate in H2O:CAN, flow rate; 25 ml / min, gradient method: 0 / 40, 10 / 82, 10.1 / 99, 12 / 99, 12.1 / 40, 14 / 40). Pure fractions were collected and lyophilized to give 1-benzyl-1-(1-((4-(butylamino)-2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)piperidin-1-ium carbonate salt (0.050 g). MS (ESI): m / z 436.61[M] + . 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.826 (s, 1H), 7.54(t, 5H), 6.271 (s, 2H), 5.44(t, 2 H), 4.60(d, 2 H), 3.708 (s, 2H), 2.96(q, 2 H), 2.362(s, 2H).2.027-2.066(m, 8 H), 1.838-1.99 (m, 2 H), 1.492-1.549 (m,6 H), 1.32-1.45(m, 3 H), 1.12-1.25(m, 3H),0.922(t, 3 H).

[0258] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-4-(methoxycarbonyl)piperidin-1-ium bromide: [ka] Synthesis of methyl 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidine-4-carboxylate: To a stirred solution of 2-bromo-N-(2,6-dimethylphenyl)acetamide (0.500 g, 2.065 mmol) and methyl piperidine-4-carboxylate (0.443 g, 3.097 mmol) in ACN (10 ml) was added K2CO3 (0.712 g, 5.162 mmol). The mixture was heated to 90 °C for 16 h and the progress of the reaction mixture was monitored by TLC (50% ethyl acetate in pet ether, visualization: UV). The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (100 ml) and washed with water (50 ml x 3) and brine solution (50 ml). The organic extract was dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by normal phase flash chromatography (eluted with a gradient of 10% to 30% ethyl acetate in pet ether). The collected pure fractions were concentrated under reduced pressure to give the desired product methyl 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidine-4-carboxylate (0.400 g). MS (ESI): m / z 305.36 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.171 (s, 1 H), 7.060-7.09(m, 3H), 3.607(s, 3 H), 3.089 (s, 2 H), 2.879-2.908 (m, 2 H), 2.316-2.371 (m, 1 H), 2.198-2.261 (m, 2 H), 2.129 (s, 6H), 1.816-1.856(m, 2 H).1.680-1.778 (m, 2 H).

[0259] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-4-(methoxycarbonyl)piperidine-1-ium bromide: To a stirred solution of methyl 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidine-4-carboxylate (0.200 g, 0.657 mmol) in ACN (5 ml) was added benzyl bromide (0.224 g, 1.314 mmol) and the mixture was heated to 90° C. for 24 h and the reaction progress was monitored by TLC (10% MeOH in DCM, visualization: UV). The reaction mixture was concentrated to give the crude product which was triturated with ethyl acetate (30 ml) and n-pentane (20 ml) to give pure 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-4-(methoxycarbonyl)piperidin-1-ium bromide (0.080 g) as a white solid. MS (ESI): m / z 395.3[M] + . 1 H NMR(400 MHz, DMSO-d6) δ ppm 10.048 (s, 1 H), 7.551-7.591 (m, 5 H), 7.144-7.159 (m,3H), 4.947 (s, 2 H), 4.237 (s, 2 H), 3.671-3.766(m,5 H), 3.541-3.549 (m, 2 H), 2.732-2.788 (m,1H),2.128-2.212 (m, 10 H).

[0260] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-3-(ethoxycarbonyl)piperidin-1-ium bromide: [ka] Synthesis of ethyl 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidine-3-carboxylate To a stirred solution of 2-chloro-N-(2,6-dimethylphenyl)acetamide (5 g, 25.295 mmol) in ACN (100 ml) was added K2CO3 (8.726 g, 63.237 mmol) and ethyl piperidine-3-carboxylate (5.964 g, 37.942 mmol) at RT. The resulting reaction mixture was stirred at RT for 16 h and the progress of the reaction mixture was monitored by TLC (30% ethyl acetate in pet ether, visualization: UV). The reaction mixture was filtered to remove inorganic salts and the filtrate was concentrated under reduced pressure to give the crude product, which was diluted with ethyl acetate (250 ml) and washed with water (80 ml x 3) and brine solution (80 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give ethyl 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidine-3-carboxylate (6.5 g). MS (ESI): m / z319.01 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.751 (s, 1 H), 7.066-7.101 (m, 3H), 4.075-4.168 (m, 2H), 3.154-3.249 (m, 2 H), 2.927-2.949 (m, 1 H), 2.761-2.817 (m, 2H), 2.613-2.664 (m, 1H), 2.45-2.49 (m, 1H),2.23 (s, 6H), 1.506-2.045(m,4H), 1.209-1.277 (m, 3H).

[0261] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-3-(ethoxycarbonyl)piperidin-1-ium bromide: To a stirred solution of ethyl 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidine-3-carboxylate (0.300 g, 0.942 mmol) in ACN (10 ml) was added benzyl bromide (0.322 g, 1.884 mmol) and the mixture was heated to 90° C. in a sealed tube for 16 h and the reaction progress was monitored by TLC (10% MeOH in DCM, visualization: UV). The reaction mixture was concentrated under reduced pressure to give the crude product which was purified by normal phase flash chromatography (eluted with 2% methanol in DCM). The collected pure fractions were concentrated under reduced pressure to give the desired product as a colourless gum (LCMS-85%). The compound was diluted with ethyl acetate (15 ml) and stirred for 1 h, then filtered and washed with ethyl acetate (15 ml x 3) to give pure 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-3-(ethoxycarbonyl)piperidin-1-ium bromide (70 mg) as an off-white solid. MS (ESI): m / z 409.2[M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm10.05 (s, 1H),7.545-7.585 (m, 5H), 7.125- 7.178(m, 3 H), 4.945-5.060 (m,2 H), 4.109-4.342 (m, 4H), 3.904-3.934 (m, 1H), 3.644-3.677(m, 1H),3.433-3.569 (m, 2 H),3.230-3.262 (m, 1H), 2.213 (s, 6H),1.948-2.195(m, 3 H), 1.553-1.620 (m, 1 H), 1.24(t, 3 H).

[0262] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-3-(isopropoxycarbonyl)piperidin-1-ium trifluoroacetate [ka] Synthesis of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidine-3-carboxylic acid: A mixture of ethyl 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidine-3-carboxylate (5 g, 15.702 mmol) in conc. HCl (100 ml) was heated to 100° C. for 16 h and the progress of the reaction was monitored by TLC (50% EtOAc in pet ether, visualization: UV). The reaction mixture was concentrated under reduced pressure to give 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidine-3-carboxylic acid (4.2 g). MS (ESI): m / z 291.13 [M+H] + .

[0263] Synthesis of isopropyl 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidine-3-carboxylate: To a stirred solution of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidine-3-carboxylic acid (0.5 g, 1.722 mmol) in isopropanol (10 mL) was added thionyl chloride (5 mL) dropwise at 0° C. The resulting reaction mixture was allowed to stir at 90° C. for 16 h and the progress of the reaction was monitored by TLC (50% EtOAc in pet ether, visualization: UV). The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a crude residue which was quenched with ice-cold saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by normal phase flash chromatography (eluted with 20%-30% EtOAc / Pet ether). The collected pure fractions were concentrated under reduced pressure to give 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidine-3-carboxylate (0.54 g) as a pale yellow solid. MS (ESI): m / z 332.27 [M+H] + . 1H NMR (400 MHz, CDCl3) δ ppm 8.5 (brs, 1 H),7.06-7.11(m, 3H),4.97 -5.03 (m, 1 H),3.19 -3.24 (m, 2 H), 2.93-2.95 (m, 1 H), 2.59-2.48 (m, 2 H), 2.48-2.40 (m, 2 H), 2.18-2.20 (m, 5 H),1.41-1.65 (m, 3 H),1.18-1.24 (m, 6 H).

[0264] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-3-(isopropoxycarbonyl)piperidin-1-ium trifluoroacetate: To a stirred solution of isopropyl 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidine-3-carboxylate (0.4 g, 1.203 mmol) in ACN (10 mL) was added benzyl bromide (0.6173 g, 3.609 mmol) at room temperature. The resulting reaction mixture was stirred in a sealed tube at 90° C. for 16 h and the progress of the reaction was monitored by TLC (50% EtOAc in Pet ether, visualization: UV). The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to give 430 mg (LCMS 51%) of crude compound, which was further purified by reverse phase Prep. HPLC (Column: X-select csh C18 (250*19) mm, 5u; Mobile phase A: 0.1% TFA in water (Aq.), Mobile phase B: Acetonitrile, Flow rate: 22 ml / min, Method (T / %) of B: 0 / 10, 2 / 10, 10 / 50, 13 / 50, 13.1 / 100, 16 / 100, 16.1 / 10, 19 / 20, Solubility: ACN +H2O+THF, Temperature: Ambient). The combined pure fractions were lyophilized to give pure 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-3-(isopropoxycarbonyl)piperidin-1-ium trifluoroacetate (168 mg). LCMS: 99.37% (77.95% + 21.42%, mixture of isomers), MS (ESI): m / z 423.2, [M] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 10.01-10.05 (m, 1 H),7.57-7.61 (m, 5 H),7.12-7.17(m, 3 H),4.92-5.06 (m, 3H),4.14-4.22 (m, 2 H), 3.87-3.67 (dd, 1 H),3.46-3.55 (m, 3 H),3.15-3.21 (m, 1 H), 2.208 (d, 6 H),1.85-2.07 (m, 3 H),1.19-1.23 (m, 6 H).

[0265] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-3-(propoxycarbonyl)piperidin-1-ium bromide [ka] Synthesis of propyl piperidine-3-carboxylate: To a stirred solution of piperidine-3-carboxylic acid (2.0 g, 15.484 mmol) in propan-1-ol (20.0 ml) was added SOCl2 (11.05 g, 92.908 mmol) at 0-5 °C. The resulting reaction mixture was stirred at 80 °C for 16 h and the progress of the reaction was monitored by TLC (30% ethyl acetate / pet ether. Visualization: ninhydrin). The reaction mixture was concentrated under reduced pressure to give the crude compound, which was dissolved in ethyl acetate (100 ml) and washed with saturated bicarbonate solution (1x100 ml) and brine solution (1x50 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give propyl piperidine-3-carboxylate (2.0 g) as a colorless liquid. This crude product was carried forward to the next step without purification and analysis.

[0266] Synthesis of propyl 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidine-3-carboxylate: To a stirred solution of 2-chloro-N-(2,6-dimethylphenyl)acetamide (2.0 g, 10.15 mmol) in ACN (20 ml) was added K2CO3 (4.14 g, 29.95 mmol) and propyl piperidine-3-carboxylate (3.47 g, 20.28 mmol) at room temperature. The resulting reaction mixture was stirred at 80° C. for 16 h and the progress of the reaction was monitored by TLC (50% ethyl acetate / pet ether, visualization: UV activity). After completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure to give the crude compound, which was diluted with water (30 ml) and extracted with ethyl acetate (2X100 ml). The combined organic extracts were washed with brine (50.0 ml), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography (eluted with 20%-80% ethyl acetate / pet ether). The collected pure fractions were concentrated under reduced pressure to give propyl 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidine-3-carboxylate (1.0 g) as a gummy compound. MS (ESI): m / z 333.10 [M+H] + .

[0267] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-3-(propoxycarbonyl)piperidin-1-ium bromide: To a solution of propyl 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidine-3-carboxylate (0.3 g, 0.9030 mmol) in acetonitrile (10 ml) was added benzyl bromide (0.3113 g, 1.806 mmol) at room temperature. The resulting reaction mixture was stirred at 90 °C for 16 h and the progress of the reaction was monitored by TLC (10% MeOH / DCM, visualization: UV). After consumption of starting material by TLC, the reaction mixture was directly concentrated under reduced pressure to give the crude compound as a pale yellow semi-solid, which was purified by normal phase flash chromatography (eluted with 0%-30% MeOH / DCM). The collected pure fractions were concentrated under reduced pressure to give 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-3-(propoxycarbonyl)piperidin-1-ium bromide (70 mg) as an off-white solid. MS (ESI): m / z 423.3 [M] + . 1 HNMR (400 MHz,DMSO-d6) δ ppm 10.30 (s, 1 H),7.55-7.60 (m, 5H),7.11-7.18 (m,3H),4.97-5.15 (m, 2H),4.33 (dd, 2H)4.05 (t, 2 H), 3.88 (d, 1H), 3.66 (d, 1H), 3.31-3.54 (m, 3H), 2.09-2.21 (m, 8H), 1.96 (d, 2H), 1.55-1.64 (m, 3H), 0.87-0.93 (m, 3H).

[0268] The following example was prepared from piperidine-3-carboxylic acid, 2-chloro-N-(2,6-dimethylphenyl)acetamide and benzyl bromide following the procedure described for the synthesis of compound 47A. [Table 9]

[0269] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-3-(propionyloxy)piperidin-1-ium bromide [ka] Synthesis of tert-butyl 3-(propionyloxy)piperidine-1-carboxylate: To a stirred solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (2 g, 9.936 mmol) and pyridine (2.357 g, 29.808 mmol) in DCM (30 ml) was added propionyl chloride (1.103 g, 11.923 mmol) at 0° C., the resulting reaction mixture was stirred at room temperature for 24 h, and the progress of the reaction was monitored by TLC (20% EtOAc in Pet ether, visualization: UV). The reaction mass was diluted with DCM (120 mL), washed twice with water (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give tert-butyl 3-(propionyloxy)piperidine-1-carboxylate (1.34 g) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ ppm4.85-4.75(m, 1 H), 3.51-3.43 (m, 3 H), 3.3-3.29 (m, 1 H), 2.41-2.39 (m, 2 H), 1.85-1.72 (m, 3 H), 1.45 (s, 9 H), 1.18-1.12 (m, 4 H).

[0270] Synthesis of piperidin-3-yl propionate: To a stirred solution of tert-butyl 3-(propionyloxy)piperidine-1-carboxylate (1.3 g, 5.05 mmol) in DCM (20 ml) was added TFA (5 ml) at 0° C., and the resulting reaction mixture was stirred at room temperature for 16 h, and the progress of the reaction was monitored by TLC (50% EtOAc in Pet ether, visualization: ninhydrin). The reaction mixture was concentrated under reduced pressure to give the crude product, which was co-distilled with toluene (2×15 mL) to give piperidin-3-ylpropionate TFA salt (1.34 g) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm5.16 (s, 1 H), 3.41 (d, 2 H), 3.24(t, 1 H),3.10 (d, 1 H), 2.42-2.36 (m, 2 H),2.13-2.10(m, 2H), 2.02-2.01(m, 2 H), 1.88-1.84 (m, 3 H).

[0271] Synthesis of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidin-3-ylpropionate: To a stirred solution of 2-chloro-N-(2,6-dimethylphenyl)acetamide (0.3 g, 1.517 mmol) in acetonitrile (15 mL) was added DIPEA (0.5884 g, 4.551 mmol) and piperidin-3-ylpropionate TFA salt (0.4937 g, 1.8204 mmol) at room temperature. The resulting reaction mixture was stirred in a sealed tube at 80 °C for 16 h and the progress of the reaction was monitored by TLC (50% EtOAc in pet ether, visualization: UV). The reaction mixture was concentrated under reduced pressure to give a residue which was diluted with water (50 ml) and extracted with ethyl acetate (2 x 25 ml). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by normal phase flash chromatography (eluted with 25%-30% EtOAc / Pet ether). The collected pure fractions were concentrated under reduced pressure to give 2-(azepan-1-yl)-N-(3-methyl-[1,1'-biphenyl]-2-yl)acetamide (310 mg). Mass (ESI): 319.26 m / z, [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm8.67 (s, 1 H), 7.12-7.06 (m, 3 H), 4.95-4.92 (m, 1 H), 3.20 (s, 2 H), 2.95-2.89 (m, 1 H),2.73-2.56 (m, 1 H),2.59-2.54 (m, 2 H), 2.31-2.23(m,8H),1.88-1.84 (m, 2 H), 1.68-1.56 (m, 3H), 1.09 (t, 3 H).

[0272] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-3-(propionyloxy)piperidine(piperdin)-1-ium bromide To a stirred solution of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidin-3-ylpropionate (0.2 g, 0.6281 mmol) in acetonitrile (15 ml) was added benzyl bromide (0.4297 g, 2.5124 mmol) in a sealed tube at room temperature and the resulting reaction mixture was stirred at room temperature for 16 h and the reaction progress was monitored by TLC (10% methanol in DCM. Visualization: UV). The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to give the crude product, which was triturated with 1:1 EtOAc:Et2O (30:30 ml) to give 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-3-(propionyloxy)piperidin-1-ium bromide (90 mg) (mixture of isomers, peak-1: 35.75% + peak-2: 63.34%). Mass (ESI): m / z 409.03 [M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm10.05 (d, 1 H),7.60-7.56 (m, 5 H), 7.15-7.13(m, 3 H),5.45-5.25 (m, 1H),5.05-4.97 (m, 1 H),4.35-4.18(m, 2H), 4.29 (d, 2 H), 3.87-3.52 (m, 4 H), 2.44-2.35 (m,2H),2.21(m, 6H),2.20-1.98(m,3H),1.80-1.6(m,1 H), 1.04 (t, 3H).

[0273] Synthesis of 1-benzyl-3-carbamoyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidin-1-ium bromide: [ka] Synthesis of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidine-3-carboxamide To a stirred solution of 2-chloro-N-(2,6-dimethylphenyl)acetamide (2.0 g, 10.1183 mmol) in ACN (20.0 ml) was added potassium carbonate (4.195 g, 30.3551 mmol) and the resulting mixture was allowed to stir at RT for 10 min. The reaction mixture was treated with piperidine-3-carboxamide (2.6081 g, 20.2366 mmol) at room temperature and then heated at 90° C. with stirring for 16 h and the progress of the reaction was monitored by TLC (10% MeOH in DCM. Visualization: UV). The reaction mixture was allowed to cool to room temperature, diluted with 70 ml of ethyl acetate and washed with 2×50 ml of water followed by 1×30 ml of brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidine-3-carboxamide (2.5 g) as an off-white solid. MS(ESI): m / z 290.25[M+H] + . 1 H NMR (400 MHz, chloroform-d) δ ppm 8.57 (s, 1 H), 7.06-7.09 (m, 3H),5.95 (brs, 1 H), 5.45 (brs, 1H),3.15-3.30 (m, 2H), 2.70-2.90 (m, 3 H),2.45-2.60 (m, 2 H), 2.15-2.30 (m, 6),1.81-1.86 (m, 2 H), 1.60-1.72 (m, 2 H).

[0274] Synthesis of 1-benzyl-3-carbamoyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidin-1-ium bromide: To a stirred solution of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidine-3-carboxamide (0.250 g, 0.865 mmol) in ACN (3.0 ml) was added benzyl bromide (0.295 g, 1.730 mmol) and the resulting reaction mixture was heated at 90° C. for 16 h and the progress of the reaction was monitored by TLC (10% MeOH in DCM, visualization: UV). The reaction mixture was directly concentrated under reduced pressure to give the crude compound which was triturated with 3×10 ml of ethyl acetate to give 1-benzyl-3-carbamoyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)piperidin-1-ium bromide (130 mg) as an off-white solid (33.18% + 65.55%, mixture of isomers). MS(ESI): m / z 380.2[M] + . 1 H NMR (400 MH-DMSO-d6) δ ppm 9.92-10.15(m, 1 H),7.45-7.60 (m, 6H),7.16-7.22 (m, 4H),4.94-5.06 (m, 2H),4.05-4.29 (m, 2H), 3.41-3.83 (m, 4 H), 2.92 (t, 1 H), 2.19-2.21 (m, 6 H), 1.98-2.08 (m, 3 H), 1.50-1.54 (m, 1 H).

[0275] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-3-(ethylcarbamoyl)piperidin-1-ium bromide [ka] Synthesis of 3-(ethylcarbamoyl)piperidine-1-carboxylate To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (2 g, 8.722 mmol) in THF (20 mL) was added Et3N (2.64 g, 26.166 mmol) and ethanamine hydrochloride (1.42 g, 17.444 mmol), followed by HATU (4.97 g, 13.083 mmol), and the reaction mixture was stirred at room temperature for 16 h, and the progress of the reaction was monitored by TLC (50% EtOAc-Pet-ether, visualization: ninhydrin). Upon completion, the reaction mixture was concentrated under reduced pressure, quenched with 2N HCl, and extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound (2.2 g), which was purified by column chromatography (eluted with 40% EtOAc in pet-ether) to give pure tert-butyl 3-(ethylcarbamoyl)piperidine-1-carboxylate (2.1 g) as a light brown liquid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.12 (brs, 1 H), 3.83 (brs, 2 H), 2.80 (S, 5 H), 2.26-2.28(m, 1 H), 2.04-1.05 (m, 2 H), 1.84-1.85 (m, 1 H), 1.46-1.48(m, 11H), 1.13 (t, 3H).

[0276] Synthesis of N-ethylpiperidine-3-carboxamide To a stirred solution of tert-butyl 3-(ethylcarbamoyl)piperidine-1-carboxylate (2.5 g, 9.752 mmol) in DCM (20 mL) was added TFA (10 mL) at 0° C., the reaction mixture was stirred at room temperature for 3 h, and the reaction progress was monitored by TLC (10% MeOH-DCM, visualization: ninhydrin). The reaction mixture was concentrated under reduced pressure to give pure N-ethylpiperidine-3-carboxamide TFA salt (2.4 g) as a light brown liquid. LCMS purity: 99.89%, mass (ESI): m / z 157.09 [M+H] + .

[0277] Synthesis of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-N-ethylpiperidine-3-carboxamide To a solution of N-ethylpiperidine-3-carboxamide TFA salt (1 g, 3.96 mmol) in ACN (10 mL) was added DIPEA (1.53 g, 11.89 mmol) followed by 2-bromo-N-(2,6-dimethylphenyl)acetamide (960 mg, 3.96 mmol), and the reaction mixture was stirred in a sealed tube at 90° C. for 16 h, and the reaction progress was monitored by TLC (10% MeOH-DCM, visualization: UV). The reaction mixture was concentrated under reduced pressure to give the crude compound (1.5 g), which was purified by column chromatography (eluted with 2% MeOH in DCM) to give the product 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-N-ethylpiperidine-3-carboxamide (1 g) as a semi-solid. LCMS purity: 39%, mass (ESI): m / z 318.12 [M+H] + This product was carried onto the next step without further purification.

[0278] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-3-(ethylcarbamoyl)piperidin-1-ium bromide To a stirred solution of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-N-ethylpiperidine-3-carboxamide (0.3 g, 0.945 mmol) in acetonitile (2 ml) was added benzyl bromide (0.808 g, 4.724 mmol) and the resulting reaction mixture was stirred at 90° C. for 16 h and the reaction progress was monitored by TLC (10% methanol in DCM. Visualization: UV). The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to give the crude product, which was purified by normal phase flash chromatography (eluted with 10% to 15% MeOH in DCM) to give 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-3-(ethylcarbamoyl)piperidin-1-ium bromide (100 mg) as a white solid. MS (ESI): m / z 408.19[M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm10.15 (s, 1 H), 7.98 (t, 1 H), 7.60-7.53 (m, 5 H), 7.18-7.12 (m, 3 H), 5.01-5.00 (m, 2 H), 4.22 (s, 2 H), 3.73-3.66 (m, 2 H), 3.51-3.42 (m, 2 H), 3.13-3.04 (m, 2 H), 2.9-2.78 (m, 1 H), 2.21 (s, 6 H), 2.02-1.98 (m, 3 H), 1.54-1.51 (m, 1 H),0.99 (t, 3 H).

[0279] The following examples were prepared from 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid, 2-bromo-N-(2,6-dimethylphenyl)acetamide and benzyl bromide according to the procedure described for the synthesis of compound 54A. The products were purified by normal phase flash chromatography or reverse phase prep. HPLC. [Table 10-1] [Table 10-2] [Table 10-3]

[0280] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-4-(propoxycarbonyl)-1,4-diazepan-1-ium bromide [ka] Synthesis of 1-(tert-butyl) 4-propyl 1,4-diazepane-1,4-dicarboxylate To a stirred solution of tert-butyl 1,4-diazepane-1-carboxylate (0.5 g, 2.496 mmol) in THF (5 ml) was added carbonyldiimidazole (1.21 g, 7.488 mmol, 3.0 equiv.) and TEA (0.758 g, 7.488 mmol), followed by 1-propanol (0.449 g, 7.488 mmol) at 0° C. The resulting reaction mixture was stirred at 80° C. for 16 h and the progress of the reaction was monitored by TLC (30% EtOAc-Hexane, visualization: PMA,). The reaction mixture was concentrated under reduced pressure to give the crude product, which was diluted with EtOAc (150 ml) and washed with water (3×30 ml). The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give 1-(tert-butyl) 4-propyl 1,4-diazepane-1,4-dicarboxylate (0.655 g). MS (ESI): m / z 287.19[M+H] + .

[0281] Synthesis of Propyl 1,4-diazepane-1-carboxylate A solution of 4M dioxane.HCl (10 ml) was added to 1-(tert-butyl) 4-propyl 1,4-diazepane-1,4-dicarboxylate (0.65 g, 2.269 mmol, 1.0 equiv) at 0° C., and the resulting reaction mixture was stirred at room temperature for 16 h, and the progress of the reaction was monitored by TLC (10% methanol in DCM, visualization: PMA). The reaction mixture was concentrated under reduced pressure to give propyl 1,4-diazepane-1-carboxylate hydrochloride (0.41 g) as a pale yellow gummy solid. MS (ESI): m / z 187.12 [M+H] + .

[0282] Synthesis of Propyl 4-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-1,4-diazepane-1-carboxylate To a stirred solution of 2-chloro-N-(2,6-dimethylphenyl)acetamide (0.4 g, 2.023 mmol) in ACN (10 ml) was added DIPEA (0.522 g, 4.046 mmol) and propyl 1,4-diazepane-1-carboxylate hydrochloride (0.376 g, 2.023 mmol) at 0° C. The resulting reaction mixture was stirred at 90° C. for 16 h and the progress of the reaction was monitored by TLC (50% EtOAc-Hexane, visualization: UV). The reaction mixture was concentrated under reduced pressure to give a residue which was diluted with EtOAc (100 ml), washed with water (60 ml), dried over Na2SO4 and concentrated under reduced pressure. The resulting crude product was purified by normal phase flash chromatography (eluted with 10% to 50% EtOAc in Pet ether) to give propyl 4-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-1,4-diazepane-1-carboxylate (0.25 g) as a white solid. MS (ESI): m / z 348.69[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 9.19(s, 1 H), 7.00 (s, 3 H), 3.96-3.91 (m, 2 H), 3.50-3.43 (m, 4 H), 3.25(s, 2 H), 2.80-2.65 (m, 4 H), 2.13 (s, 6 H), 1.84-1.81 (m, 2H), 1.60-1.53 ​​(m, 2 H), 0.90-0.85 (m, 3 H).

[0283] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-4-(propoxycarbonyl)-1,4-diazepan-1-ium bromide To a stirred solution of propyl 4-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-1,4-diazepane-1-carboxylate (0.25 g, 0.719 mmol) in ACN (5 ml) was added benzyl bromide (0.419 g, 2.876 mmol) at room temperature and the resulting reaction mass was stirred at 90° C. for 16 h and the progress of the reaction was monitored by TLC (10% methanol in DCM, visualization: UV). The reaction mixture was concentrated under reduced pressure to give the crude product which was triturated with ethyl acetate (40 ml) to give 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-4-(propoxycarbonyl)-1,4-diazepan-1-ium bromide (122.1 mg) as a white solid. Mass (ESI): m / z 438.2 [M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.99 (s, 1 H),7.61-7.53(m, 5 H), 7.18-7.11(m, 3 H), 5.00 (s, 2 H),4.29-4.16(m, 2 H), 4.01-3.56(m, 10 H),2.32-2.30(m,2H),2.21 (s, 6 H),1.62-1.57(m, 2 H), 0.92-0.88(m, 3 H).

[0284] Synthesis of 1-benzyl-1-(2-((2-fluoro-6-methylphenyl)amino)-2-oxoethyl)azepan-1-ium bromide [ka] Synthesis of 2-bromo-N-(2-fluoro-6-methylphenyl)acetamide A solution of 2-fluoro 6-methylaniline (3.0 g, 23.980 mmol) in water (30.0 ml) was cooled to 0° C. and bromoacetyl bromide (29 g, 143.884 mmol) was added. The resulting reaction mixture was stirred at rt for 16 h and the progress of the reaction was monitored by TLC (50% EtOAc in pet ether, visualization: UV). The reaction mixture was basified with NaCO3, stirred for 20 min, filtered, washed with water (100 ml) then pet ether (50 mL) and dried to obtain crude compound 2-bromo-N-(2-fluoro-6-methylphenyl)acetamide (2.8 g) as an off-white solid. MS (ESI): m / z 246.08 [M] + . 1 H NMR (400 MHz, DMSO-d6)δ ppm 9.95(s, 1H), 7.18 (d, 3H),4.15 (s, 2H), 2.20 (s, 3H).

[0285] Synthesis of 2-(azepan-1-yl)-N-(2-fluoro-6-methylphenyl)acetamide To a stirred solution of 2-bromo-N-(2-fluoro-6-methylphenyl)acetamide (4.0 g, 16.254 mmol) in ACN (40 ml) was added potassium carbonate (2.243 g, 48.762 mmol) at room temperature and the mixture was stirred for 10 min. Azepane (3.225 g, 32.509 mmol) was then added and the reaction mixture was stirred at room temperature for 16 h and the progress of the reaction was monitored by TLC (50% EtOAc in pet ether, visualization: UV). The reaction mixture was diluted with ethyl acetate (100 ml), washed with water (2 x 50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was triturated with n-pentane (3 x 30 ml) to give 2-(azepan-1-yl)-N-(2-fluoro-6-methylphenyl)acetamide (2.2 g) as an off-white solid. MS (ESI): m / z 264.34[M] + . 1 H NMR (400 MHz, chloroform-d) δ ppm 8.88 (s, 1 H),7.26(s, 1 H),7.10-7.16 (m, 1H),6.93-7.03 (m, 1H),3.31 (s, 2 H), 2.82( t, 4 H ),2.27 ( s, 3 H ), 1.58-1.73 ( m, 8 H ).

[0286] Synthesis of 1-benzyl-1-(2-((2-fluoro-6-methylphenyl)amino)-2-oxoethyl)azepan-1-ium bromide To a stirred solution of 2-(azepan-1-yl)-N-(2-fluoro-6-methylphenyl)acetamide (0.50 g, 1.89 mmol) in ACN (5.0 mL) was added benzyl bromide (1.9411 g, 11.35 mmol) at room temperature, and the resulting reaction mixture was heated to 80° C. for 16 h, and the progress of the reaction was monitored by TLC (10% MeOH in DCM, visualization: UV). The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude compound, which was triturated with a solution of 1:1 EtOAc / pet ether (3 x 10 mL) to give the product 1-benzyl-1-(2-((2-fluoro-6-methylphenyl)amino)-2-oxoethyl)azepan-1-ium bromide (200 mg). MS (ESI): m / z 355.2[M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.19 (s, 1 H), 7.64 (t, 2 H), 7.51-7.57 (m, 3H),7.27-7.32(m, 1H),7.17 (t, 2H), 4.88 (s, 2 H), 4.11 ( s, 2 H ), 3.78 ( q, 2 H ), 3.51-3.56 ( m, 2 H ),2.27 ( s, 3 H ), 1.96 ( s, 4 H ), 1.66 ( s, 4 H ).

[0287] The following examples were prepared from bromoacetyl bromide, benzyl bromide, azepane and the appropriate aniline following the procedure described for the synthesis of compound 69A. [Table 11-1] [Table 11-2]

[0288] Synthesis of 1-benzyl-1-(2-((2-hydroxy-6-methylphenyl)amino)-2-oxoethyl)azepan-1-ium formate [ka] 1-benzyl-1-(2-((2-hydroxy-6-methylphenyl)amino)-2-oxoethyl)azepan-1-ium To a stirred solution of 1-benzyl-1-(2-((2-methoxy-6-methylphenyl)amino)-2-oxoethyl)azepan-1-ium bromide (1 g, 2.235 mmol) in DCM (25 ml) was added BBr3 (2.239 g, 8.94 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 16 h and the progress of the reaction mixture was monitored by TLC (10% MeOH in DCM, visualization: UV). The reaction mixture was concentrated under reduced pressure to give the crude product which was purified by normal phase flash chromatography (eluted with 6% MeOH in DCM). Gradient. Pure fractions were concentrated under reduced pressure to give 1-benzyl-1-(2-((2-hydroxy-6-methylphenyl)amino)-2-oxoethyl)azepan-1-ium bromide (0.9 g) as an off-white solid. MS (ESI): m / z 353.21[M] + . 1 H NMR (300 MHz, DMSO-d6) δ ppm 9.82 (s, 1 H), 9.59(s, 1 H), 7.73-7.71 (m, 2 H), 7.59-7.49 (m, 3 H), 7.07-7.02(t, 1H), 6.77-6.70(m, 2H), 4.88 (s, 2H), 4.06(s, 2H),3.77-3.72(m, 2H), 3.58-3.53(m, 2H), 2.17(s,3H),2.05-1.9 (m, 4H), 1.66-1.45 (m, 4H).

[0289] Synthesis of 1-benzyl-1-(2-((2-methyl-6-(propionyloxy)phenyl)amino)-2-oxoethyl)azepan-1-ium bromide [ka] Synthesis of 1-benzyl-1-(2-((2-methyl-6-(propionyloxy)phenyl)amino)-2-oxoethyl)azepan-1-ium bromide Propionic anhydride (5 ml) was added to 1-benzyl-1-(2-((2-hydroxy-6-methylphenyl)amino)-2-oxoethyl)azepan-1-ium bromide (0.4 g, 0.922 mmol) at room temperature and the resulting reaction mixture was heated to 80° C. for 16 h and the progress of the reaction mixture was monitored by TLC (10% MeOH in DCM, visualization: UV). The reaction mixture was concentrated under reduced pressure to give the crude product which was purified by normal phase flash chromatography (eluted with 15% MeOH in DCM). Pure fractions were concentrated under reduced pressure to give the product which was again triturated with diethyl ether (45 ml) to give 1-benzyl-1-(2-((2-methyl-6-(propionyloxy)phenyl)amino)-2-oxoethyl)azepan-1-ium bromide (95.6 mg) as an off-white solid. MS (ESI): m / z 409.2[M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm10.16 (s, 1 H), 7.66-7.64(m, 2H), 7.57-7.51 (m, 3 H), 7.31-7.27 (t, 1 H), 7.22-7.21(d, 1H), 7.09-7.07(m, 1 H), 4.89(s, 2 H), 4.08 (s, 2 H),3.75-3.71(m, 2 H), 3.51-3.47(m, 2 H), 2.58(q,2H),2.27(s, 3H), 2.05-1.85(m, 4 H),1.75-1.55 (m, 4 H), 1.12 (t, 3 H).

[0290] Synthesis of 1-benzyl-1-(2-((2-carbamoyl-6-methylphenyl)amino)-2-oxoethyl)azepan-1-ium bromide [ka] Synthesis of N,N,3-trimethyl-2-nitrobenzamide: To a stirred solution of 3-methyl-2-nitrobenzoic acid (3.0 g, 16.56 mmol) in DMF (30 ml) was added DIPEA (6.42 g, 49.68 mmol) and HATU (9.44 g, 24.84 mmol), followed by dimethylamine (2M in THF) (16.56 ml, 33.12 mmol). The resulting reaction mixture was stirred at room temperature for 16 h and the progress of the reaction was monitored by TLC (30% EtOAc / pet ether, visualization: UV). The reaction mixture was poured into ice water and extracted with EtOAc (2 x 50 ml). The combined extracts were washed with brine (30 ml), dried over Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by normal phase flash chromatography (eluted with 20% to 80% EtOAc in pet ether) to give N,N,3-trimethyl-2-nitrobenzamide (2.2 g) as a black liquid. Mass (ESI): m / z 209.09[M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 7.47-7.43(m,1 H), 7.36-7.33(m, 1 H), 7.22-7.19(m, 1 H), 3.09(s, 3 H), 2.93(s, 3 H), 2.80(s,6H),2.33(s, 3 H).

[0291] Synthesis of 2-amino-N,N,3-trimethylbenzamide: To a stirred solution of N,N,3-trimethyl-2-nitrobenzamide (2 g, 9.605 mmol) in ethanol (20 ml) and H2O (20 ml) was added Fe (3.75 g, 67.235 mmol) and NH4Cl (3.59 g, 67.235 mmol) at room temperature. The resulting reaction mixture was stirred at 80 °C for 8 h and the progress of the reaction was monitored by TLC (10% EtOAc in pet ether, visualization: UV). The reaction mixture was filtered through a pad of Celite and washed twice with EtOH (2 x 50 ml). The filtrate was concentrated under reduced pressure to give a residue which was diluted with water (50 ml) and extracted with EtOAc (2 x 50 ml). The combined organic extracts were washed with brine (50 ml), dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (eluted with 10%-40% EtOAc in pet) to give 2-amino-N,N,3-trimethylbenzamide (600 mg). LCMS purity: 98.02%, mass (ESI): m / z 179.12 [M+H]. + . 1 H NMR (400 MHz, CDCl3) δ ppm 7.26(s, 1 H),7.06 (s, 1 H), 6.97(d, 1 H),6.66-6.63(m, 1 H),4.33 (bs, 2 H),3.05(s, 6H),2.17(s, 3H).

[0292] Synthesis of 2-(2-bromoacetamido)-N,N,3-trimethylbenzamide: To a stirred solution of isopropyl 2-amino-N,N,3-trimethylbenzamide (0.6 g, 3.366 mmol) in H2O (6 ml) was added 2-bromoacetyl bromide (5.34 g, 26.928 mmol) at 0°C. The resulting reaction mixture was stirred at room temperature for 16 h and the progress of the reaction was monitored by TLC (10% MeOH in DCM, visualization: UV). The reaction mixture was basified with saturated Na2CO3 at 0°C to give a precipitated solid which was filtered, washed with water and dried to give (2-(2-bromoacetamido)-N,N,3-trimethylbenzamide (650 mg) as a white solid. LCMS purity: 93.98%, mass (ESI): m / z 301.12 [M+2] + . 1 H NMR (400 MHz, CDCl3) δ ppm8.84 (s, 1 H), 7.26-7.07 (m, 3 H), 3.93 (s, 2 H) 3.09 (s, 3 H), 2.93(s, 3 H), 2.21(s, 3 H).

[0293] Synthesis of 2-(2-(azepan-1-yl)acetamido)-N,N,3-trimethylbenzamide To a stirred solution of 2-(2-bromoacetamido)-N,N,3-trimethylbenzamide (0.6 g, 2.005 mmol) in acetonitrile (6 ml) was added K2CO3 (0.692 g, 5.012 mmol) and azepane (0.397 g, 4.01 mmol) at room temperature. The resulting reaction mixture was stirred at 80° C. for 16 h and the progress of the reaction was monitored by TLC (10% MeOH in DCM, visualization: UV). After completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure to give a residue which was poured into ice water and extracted with EtOAc (2 x 25 ml). The combined organic extracts were washed with brine (50 ml), dried over Na2SO4 and concentrated under reduced pressure to give (2-(2-(azepan-1-yl)acetamido)-N,N,3-trimethylbenzamide (600 mg). MS (ESI): m / z 318.27 [M+H] + . 1H NMR (400 MHz, CDCl3) δ ppm 9.19(s, 1 H) 7.27-7.25 (m, 1H), 7.20-7.17 (m, 1 H), 7.09-7.07 (m, 1 H), 3.24 (s, 2 H) 3.04 (s, 3 H), 2.91 (s, 3 H),2.79-2.76(t, 4 H),2.26(s, 3 H) 1.71 - 1.62 (m, 8 H).

[0294] Synthesis of 1-benzyl-1-(2-((2-(dimethylcarbamoyl)-6-methylphenyl)amino)-2-oxoethyl)azepan-1-ium bromide To a stirred solution of 2-(2-(azepan-1-yl)acetamido)-N,N,3-trimethylbenzamide (0.5 g, 1.575 mmol) in acetonitrile (5 ml) was added benzyl bromide (0.538 g, 3.15 mmol) at room temperature. The resulting reaction mixture was stirred at 80° C. for 48 h and the progress of the reaction was monitored by TLC (mobile phase: -10% MeOH in DCM, Rf: 0.47, visualization: UV). After consumption of starting material by TLC, the reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (eluted with 4%-8% MeOH in DCM) to give (1-benzyl-1-(2-((2-(dimethylcarbamoyl)-6-methylphenyl)amino)-2-oxoethyl)azepan-1-ium bromide (100 mg) as a brown solid. Mass (ESI): m / z 408.2 [M] + . 1H NMR (400 MHz, DMSO-d6) δ ppm10.31 (s, 1 H), 7.70-7.68 (m, 2 H), 7.56 - 7.51 (m, 3 H), 7.38-7.36(m,1 H), 7.32-7.28 (m, 1 H),7.19-7.16 (m, 1 H),4.85 (s, 2 H), 4.03(s, 2 H), 3.70-3.66(m, 2 H),3.47-3.43(m, 2 H), 2.95(s, 3 H), 2.87 (s,3 H), 2.27 (s, 3 H), 1.94-1.90 (s, 4 H), 1.70-1.65(s, 4 H).

[0295] Synthesis of 1-benzyl-1-(2-((2,6-dimethylbenzoyl)oxy)ethyl)azepan-1-ium bromide [ka] Synthesis of intermediate 2-bromoethyl 2,6-dimethylbenzoate: To a stirred solution of 2,6-dimethylbenzoic acid (5 g, 33.29 mmol) in toluene (40 mL) was added 2-bromoethan-1-ol (4.16 g, 33.29 mmol) and catalytic amount of concentrated H2SO4 (0.2 ml). The resulting reaction mixture was refluxed for 16 h using a Dean-Stark condenser and the progress of the reaction was monitored by TLC (30% EtOAc in Pet ether, visualization: UV). After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to give a residue which was diluted with ice water (250 ml) and extracted with EtOAc (3 x 150 ml). The combined organic extracts were washed with saturated sodium bicarbonate solution (50 ml) and brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-bromoethyl 2,6-dimethylbenzoate (5.52 g). MS (ESI): m / z 258.82 [M+H+2] +. 1H NMR (400 MHz, CDCl3) δ ppm 7.22-7.18 (m, 1 H), 7.0-7.02 (m, 2 H), 4.64 (t, 2 H), 3.63(t, 2H), 2.33(s,6H).

[0296] Synthesis of intermediate 2-(azepan-1-yl)ethyl 2,6-dimethylbenzoate: To a stirred solution of 2-bromoethyl 2,6-dimethylbenzoate (2.0 g, 7.778 mmol) in ACN (30 ml) was added K2CO3 (3.224 g, 23.334 mmol) and azepane (1.157 g, 11.667 mmol). The resulting mixture was stirred at 90 °C for 16 h and the progress of the reaction was monitored by TLC (30% EtOAc in pet ether, visualization: UV). The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to give a residue which was diluted with cold water (100 ml) and extracted with EtOAc (3 x 50 ml). The combined organic extracts were washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-(azepan-1-yl)ethyl 2,6-dimethylbenzoate (1.80 g) as a brown liquid. MS (ESI): m / z 276.35 [M + H] +.1 H NMR (400 MHz,CDCl3) δ ppm7.19-7.15(m, 1 H), 7.03-7.01(m, 2H),4.41 (t, 2 H),2.86(t, 2H), 2.72-2.69(mt, 4 H), 2.33(s, 6 H),1.65-1.56(m,8H).

[0297] Synthesis of 1-benzyl-1-(2-((2,6-dimethylbenzoyl)oxy)ethyl)azepan-1-ium bromide: To a stirred solution of 2-(azepan-1-yl)ethyl 2,6-dimethylbenzoate (300 mg, 1.089 mmol) in ACN (5 ml) was added benzyl bromide (279.3 mg, 1.633 mmol) and the resulting mixture was stirred at 90° C. for 16 h and the progress of the reaction was monitored by TLC (MeOH in DCM, visualization: UV). After consumption of the starting material, the reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure to give the crude product, which was triturated with a 1:2 mixture of Et2O and EtOAc (60 ml) to give 1-benzyl-1-(2-((2,6-dimethylbenzoyl)oxy)ethyl)azepan-1-ium bromide (117.4 mg) as an off-white solid. Mass (ESI): m / z 366.2 [M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm7.61-7.59(m,2H),7.54-7.48(m, 3 H), 7.29-7.26(m, 1 H),7.13-7.11(d, 2 H), 4.89(t,2H),4.67 (s, 2 H), 3.65-3.45(m, 6H), 2.28 (s, 6H), 1.83-.1.77(d,4H), 1.6-1.5(m,4H).

[0298] Synthesis of 1-benzyl-1-(2-(2,6-dimethylphenoxy)-2-oxoethyl)azepan-1-ium 2,2,2-trifluoroacetate [ka] Synthesis of intermediate 2,6-dimethylphenyl 2-bromoacetate: To a stirred solution of 2,6-dimethylphenol (0.5 g, 4.092 mmol) in ACN (5 ml) was added pyridine (0.647 g, 8.184 mmol) and 2-bromoacetyl bromide (1.23 g, 6.138 mmol) at 0° C., the resulting reaction mixture was stirred at 0° C. for 15 min, and the progress of the reaction was monitored by TLC (10% EtOAc in Pet ether, visualization: UV). After consumption of the starting material, the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (2×25 ml). The combined organic extracts were washed with brine (30 ml), dried over Na2SO4, and concentrated under reduced pressure to give the product 2,6-dimethylphenyl 2-bromoacetate (500 mg) as a pale yellow liquid. 1 H NMR (400 MHz, CDCl3) δ ppm 7.07(s, 3 H), 4.07(s, 2 H), 2.18(s, 6 H).

[0299] Synthesis of intermediate 2,6-dimethylphenyl 2-(azepan-1-yl)acetate: To a stirred solution of 2,6-dimethylphenyl 2-bromoacetate (0.5 g, 2.056 mmol) in ACN (5 ml) was added K2CO3 (0.71 g, 5.14 mmol) and azepane (0.407 g, 4.112 mmol) at room temperature. The resulting reaction mixture was stirred at 90 °C for 16 h and the progress of the reaction was monitored by TLC (mobile phase: ethyl acetate, visualization: UV). After completion of the reaction, the mixture was concentrated under reduced pressure to give a residue which was diluted with ice water (25 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic extracts were washed with brine (50 ml), dried over Na2SO4 and concentrated under reduced pressure to give 2,6-dimethylphenyl 2-(azepan-1-yl)acetate (500 mg) as a red liquid. Mass (ESI): m / z 262.09 [M+H] + .

[0300] Synthesis of 1-benzyl-1-(2-(2,6-dimethylphenoxy)-2-oxoethyl)azepan-1-ium 2,2,2-trifluoroacetate. To a stirred solution of 2,6-dimethylphenyl 2-(azepan-1-yl)acetate (0.45 g, 1.721 mmol) in ACN (4.5 ml) was added benzyl bromide (0.588 g, 3.442 mmol) and the resulting reaction mixture was stirred at 90° C. for 16 h and the reaction progress was monitored by TLC (mobile phase: 10% MeOH in DCM, visualization: UV). After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by reverse phase Prep HPLC (Column: X select Phenylhexyl C18 (19*250), 5um; Mobile phase A: 0.1% TFA (Aq); Mobile phase B-Acetonitrile; Flow rate: 15ml / min; Method: 0 / 20, 2 / 20, 10 / 50, 15 / 75, 15.2 / 98, 19 / 98, 19.2 / 20, 23 / 20; Solubility: ACN + water + THF; Temperature: Ambient). The collected pure fractions were lyophilized to give 1-benzyl-1-(2-(2,6-dimethylphenoxy)-2-oxoethyl)azepan-1-ium 2,2,2-trifluoroacetate (56mg) as a pale yellow solid. MS (ESI): m / z 352.2[M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.60-7.53 (m, 5 H), 7.21-7.16(m, 3 H), 4.87(s, 2 H), 4.71 (s, 2 H), 3.90-3.84 (m, 2 H), 3.66-3.60(m, 3 H), 2.19(s, 6H),2.07-1.91(m,4H), 1.40-1.20(s, 4H).

[0301] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)ethyl)azepan-1-ium trifluoroacetate [ka] Synthesis of intermediate 1-(azepan-1-yl)-2-chloroethan-1-one: To a cooled solution (0° C.) of azepane (10 g, 100.826 mmol) in ACN (100 mL) was added TEA (30.6 g, 302.478 mmol) followed by 2-chloroacetyl chloride (13.6 g, 120.98 mmol). The reaction mixture was stirred at room temperature for 3 h and the progress of the reaction was monitored by TLC (mobile phase: EtOAc, UV and ninhydrin visualization). The reaction was quenched with saturated aq. NaHCO3 and extracted with EtOAc (2×250 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (eluted with 30% EtOAc in pet ether) to give 1-(azepan-1-yl)-2-chloroethan-1-one (8.5 g) as a brown liquid. Mass (ESI): m / z175.89[M+1] + . 1 H NMR (400 MHz,CDCl3) δ ppm4.08(s, 2H),3.49-3.55 (m,4H),1.72-1.79 (m, 4H),1.58-1.63 (d, 4H).

[0302] Synthesis of intermediate 1-(azepan-1-yl)-2-((2,6-dimethylphenyl)amino)ethan-1-one: To a stirred solution of 1-(azepan-1-yl)-2-chloroethan-1-one (5 g, 28.464 mmol) in ACN (40 mL) was added DIPEA (11.03 g, 85.392 mmol) followed by 2,6-dimethylaniline (5.17 g, 42.696 mmol), and the resulting reaction mixture was stirred at 90° C. for 3 days, and the progress of the reaction was monitored by TLC (mobile phase: 30% EtOAc in pet-ether, visualization: UV). The reaction mixture was quenched with saturated aq. NaHCO3 (20 ml) and extracted with EtOAc (2×250 ml). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product (8.5 g), which was purified by column chromatography (eluted with 30% EtOAc in pet-ether) to give 1-(azepan-1-yl)-2-((2,6-dimethylphenyl)amino)ethan-1-one (2.7 g, 36%) as a brown solid. Mass (ESI): m / z 261.18 [M+1] + . 1 H NMR (400 MHz,cdcl3) δ ppm6.97 - 7.99 (m, 2H),6.76 - 6.80 (m,1 H), 4.78 (s, 1 H),3.81 (s, 2 H), 3.33 - 3.58 (m,2 H), 3.30 - 3.32 (m, 2H),2.34 (s, 6H),1.72- 1.73 (m, 4H), 1.55-1.59 (m, 5H).

[0303] Synthesis of intermediate N-(2-(azepan-1-yl)ethyl)-2,6-dimethylaniline A solution of 1-(azepan-1-yl)-2-((2,6-dimethylphenyl)amino)ethan-1-one (1.5 g, 5.760 mmol) in THF (15 mL) was cooled to 0° C. and LAH (2M in THF, 5.76 mL, 11.521 mmol) was added dropwise with stirring. The resulting mixture was then stirred at room temperature for 15 h and the reaction progress was monitored by TLC (mobile phase: 30% EtOAc in pet-ether, visualization: UV). The reaction mixture was quenched with saturated aq. NH4Cl solution at 0° C. and then allowed to stir at RT for 1 h. The precipitated solid was removed by filtration and the filtrate was concentrated under reduced pressure to give N-(2-(azepan-1-yl)ethyl)-2,6-dimethylaniline (1.4 g) as a pale yellow liquid. Mass (ESI): m / z 247.23 [M+1] + .

[0304] Synthesis of intermediate t-butyl(2-(azepan-1-yl)ethyl)(2,6-dimethylphenyl)carbamate: To a stirred solution of N-(2-(azepan-1-yl)ethyl)-2,6-dimethylaniline (800 mg, 3.247 mmol) in a 1:1 mixture of 1,4-dioxane and HO (10 ml) was added NaOH (260 mg, 6.494 mmol), followed by (Boc)2O (2.12 g, 9.741 mmol), and the resulting mixture was stirred at rt for 24 h, and the progress of the reaction was monitored by TLC (mobile phase: 30% EtOAc in pet-ether, detection: ninhydrin). The reaction mixture was diluted with water (75 mL), extracted with EtOAc (2 × 75 mL), and the combined organic extracts were washed with brine (70 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluted with 15% EtOAc in pet-ether) to give tert-butyl (2-(azepan-1-yl)ethyl)(2,6-dimethylphenyl)carbamate (600 mg) as a colorless liquid. Mass (ESI): m / z 347.24 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ ppm7.00-7.26 (m, 3H),3.47-3.57 (m,2 H), 2.60-2.73 (m,6 H), 2.30 (s, 6 H), 2.22(t, 11H),1.57(s,6 H).

[0305] Synthesis of intermediate 1-benzyl-1-(2-((tert-butoxycarbonyl)(2,6-dimethylphenyl)amino)ethyl)azepan-1-ium chloride: To a stirred solution of tert-butyl (2-(azepan-1-yl)ethyl)(2,6-dimethylphenyl)carbamate (300 mg, 0.865 mmol) in ACN (4 mL) was added benzyl chloride (328 mg, 2.595 mmol) and the resulting reaction mixture was stirred at 90° C. for 15 h and the reaction progress was monitored by TLC (mobile phase: 10% MeOH in DCM, visualization: UV). The reaction mixture was concentrated under reduced pressure to give crude 1-benzyl-1-(2-((tert-butoxycarbonyl)(2,6-dimethylphenyl)amino)ethyl)azepan-1-ium chloride salt (400 mg) as a colorless gum. Mass (ESI): m / z 437.30 [M+1] + .

[0306] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)ethyl)azepan-1-ium trifluoroacetate: To a stirred solution of 1-benzyl-1-(2-((tert-butoxycarbonyl)(2,6-dimethylphenyl)amino)ethyl)azepan-1-ium chloride (360 mg, 0.634 mmol) was added 4M HCl in 1,4-dioxane (3.17 mL, 12.680) at 0° C. The resulting reaction mixture was stirred at rt for 15 h and the progress of the reaction was monitored by TLC (mobile phase: 10% MeOH in DCM, visualization: UV). The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by reverse phase Prep. HPLC (Column: X-Bridge C18 (150*25) mm, 10u; Mobile phase A: 0.1% TFA in water (Aq); Mobile phase B: Acetonitrile; Flow rate: 14ml / min; Method (T / %) of B: 0 / 20, 2 / 30, 10 / 40, 19 / 40, 19.2 / 98, 22 / 98, 22.2 / 20, 26 / 20; Solubility: ACN + water + THF; Temperature: ambient). Pure fractions were collected and lyophilized to give 1-benzyl-1-(2-((2,6-dimethylphenyl)amino)ethyl)azepan-1-ium trifluoroacetate (165mg) as a light brown solid. Mass (ESI): m / z 337.30[M] +. LCMS: 99.72%. 1 H NMR (400 MHz, DMSO-d6) δ ppm7.41-7.53 (m, 5 H), 6.96-7.21 (m,2H),6.83 (t,1 H),4.56 (s, 2H),3.31-3.53 (m, 8H),2.27 (s, 6H),1.82- 1.83 (m, 4H),1.58- 1.59 (m, 4H).

[0307] Synthesis of 1-benzyl-1-(2-(2,6-dimethylphenoxy)ethyl)azepan-1-ium bromide [ka] Synthesis of 2-(2-bromoethoxy)-1,3-dimethylbenzene: To a stirred solution of 2,6-dimethylphenol (0.500 g, 4.096 mmol) in acetonitrile (8.0 mL) was added potassium carbonate (1.698 g, 12.288 mmol) and 1,2-dibromoethane (3.847 g, 20.480 mmol). The resulting reaction mixture was stirred at 90° C. for 16 h and the progress of the reaction was monitored by TLC (mobile phase: 5% EtOAc in pet ether, visualization: UV). The reaction mixture was cooled to RT, concentrated under reduced pressure, diluted with water (100 mL) and extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with brine solution (1×50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel chromatography (eluted with pet ether) to obtain pure 2-(2-bromoethoxy)-1,3-dimethylbenzene (0.20 g) as a colorless liquid. 1 H NMR (400 MHz,CDCl3) δ ppm7.00- 7.25(m, 2H),6.91 - 6.95 (m, 1H),4.01 - 4.10(m, 2H),3.65 - 3.68(m, 2H), 2.30 (s, 6H).

[0308] Synthesis of intermediate 1-(2-(2,6-dimethylphenoxy)ethyl)azepane: To a solution of 2-(2-bromoethoxy)-1,3-dimethylbenzene (200 mg, 0.87 mmol) in acetonitrile (3.0 mL) was added DIPEA (451.2 mg, 3.49 mmol) and azepane (120.2 mg, 1.22 mmol). The resulting reaction mixture was stirred at 90° C. for 16 h and the progress of the reaction was monitored by TLC. (Mobile phase: 10% EtOAc in pet ether, visualization: UV). The reaction mixture was cooled to RT, concentrated under reduced pressure, diluted with water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic extracts were washed with brine solution (1×20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-(2-(2,6-dimethylphenoxy)ethyl)azepane (210 mg). 1H NMR (400 MHz,CDCl3) δ ppm6.98- 7.00(m, 2H),6.88 - 6.92(m, 1 H), 3.85 - 3.88(m, 2H), 2.93 - 2.96(m, 2H), 2.75 - 2.77(m, 4H),2.28(s,6H), 1.59-1.68 (m, 8H).

[0309] Synthesis of 1-benzyl-1-(2-(2,6-dimethylphenoxy)ethyl)azepan-1-ium bromide: To a solution of 1-(2-(2,6-dimethylphenoxy)ethyl)azepane (100 mg, 0.404 mmol) in acetonitrile (1.5 mL) was added benzyl bromide (0.072 ml, 0.606 mmol) and the resulting reaction mixture was stirred in a sealed tube at 90° C. for 16 h and the progress of the reaction was monitored by TLC (mobile phase: 50% EtOAc in pet ether, visualization: UV). The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a crude gum which was triturated with ethyl acetate (3×5 ml) to give 1-benzyl-1-(2-(2,6-dimethylphenoxy)ethyl)azepan-1-ium bromide (80.5 mg) as an off-white solid. MS (ESI): m / z 338.41[M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm7.63 - 7.65(m,2H), 7.49-7.57 (m, 3 H), 7.04 - 7.08 (m, 2H), 6.96 - 6.98 (m, 1 H), 4.72 (s, 2 H), 4.29 (t,2H), 3.52-3.69 (m, 6 H), 2.29 (s, 6 H), 1.88 - 1.92 (m, 4 H), 1.59 - 1.62 (m, 4 H).

[0310] Synthesis of N-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-N,N-diethyl-3-phenylpropan-1-aminium bromide [ka] Synthesis of intermediate N,N-diethyl-3-phenylpropan-1-amine: To a stirred solution of (3-bromopropyl)benzene (2 g, 10.04 mmol) in acetonitrile (5 ml) was added diethylamine (1.46 g, 19.96 mmol) at room temperature. The resulting reaction mixture was stirred at 75° C. for 16 h and the progress of the reaction was monitored by TLC (mobile phase: 50% EtOAc in pet ether, UV visualization). The reaction mixture was allowed to cool to room temperature, quenched with water, and extracted with ethyl acetate (2×15 ml). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give N,N-diethyl-3-phenylpropan-1-amine (1.3 g). MS (ESI): m / z 192.25 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 7.3 - 7.25 (m, 2 H), 7.22 - 7.15 (m, 3H), 2.6 - 2.25 (m, 2H), 2.55 - 2.42 (m, 6 H), 1.81 - 1.75 (m, 2 H), 1.0 (t, 6 H).

[0311] Synthesis of N-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-N,N-diethyl-3-phenylpropan-1-aminium bromide: To a solution of N,N-diethyl-3-phenylpropan-1-amine (0.2 g, 1.045 mmol) in toluene (5 ml) was added 2-bromo-N-(2,6-dimethylphenyl)acetamide (0.328 g, 1.354 mmol) and the resulting mixture was heated to reflux for 16 h and the reaction progress was monitored by TLC (mobile phase: 10% MeOH in DCM, visualization: UV). The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product, which was triturated with EtOAc (20 ml) to give N-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-N,N-diethyl-3-phenylpropan-1-aminium bromide (95 mg) as an off-white solid. MS (ESI): m / z 353.45 [M] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 9.9 (s, 1 H), 7.45 - 7.3 (m, 5 H), 7.15 - 7.09 (m, 3 H), 4.28 (s, 2 H), 3.58 (q, 4 H), 3.51 - 3.45 (m, 2 H), 2.68 - 2.51 (m, 2 H), 2.15 (s, 6 H), 2.08 - 2.0 (m, 2 H), 1.28 (t, 6 H).

[0312] Synthesis of N-benzyl-2-((2,6-dimethylphenyl)sulfonyl)-N,N-diethylethane-1-aminium bromide [ka] Synthesis of intermediate (2-chloroethyl)(2,6-dimethylphenyl)sulfane: To a stirred solution of 2,6-dimethylbenzenethiol (2 g, 14.468 mmol, 1 equiv) in ethanol (30 ml) was added NaOH (1.736 g, 43.405 mmol) and 1-bromo-2-chloroethane (4.149 g, 28.937 mmol) at 0° C. The resulting reaction mixture was stirred at RT for 16 h and the progress of the reaction mixture was monitored by TLC (mobile phase: 100% Pet ether, visualization: UV). The reaction mixture was concentrated under reduced pressure to give a crude residue which was diluted with ethyl acetate (80 ml), washed with water (50 ml x 2) and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (eluted with Pet ether). The collected pure fractions were concentrated under reduced pressure to give (2-chloroethyl)(2,6-dimethylphenyl)sulfane (0.500 g) as a colorless liquid. 1 H NMR (400 MHz, CDCl3) δ ppm 7.085-7.163 (m, 3H), 3.502-3.542 (m, 2 H), 2.963-3.003 (m, 2 H), 2.544 (s,6 H).

[0313] Synthesis of intermediate 2-((2-chloroethyl)sulfonyl)-1,3-dimethylbenzene: To a stirred solution of (2-chloroethyl)(2,6-dimethylphenyl)sulfane (0.500 g, 2.491 mmol) in acetic acid (10 ml) was added hydrogen peroxide (33% in H2O) (0.847 g, 24.910 mmol) at RT and the reaction mixture was heated to 110 °C for 16 h and the progress of the reaction was monitored by TLC (mobile phase: 20% ethyl acetate in pet ether, visualization: UV). The reaction mixture was diluted with water (60 ml) and extracted with ethyl acetate (70 ml x 3). The combined organic extracts were washed with aq. sodium thiosulfate (50 ml x 2) and brine solution (50 ml) and then concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (eluted with 10% ethyl acetate in pet). The collected pure fractions were concentrated under reduced pressure to give 2-((2-chloroethyl)sulfonyl)-1,3-dimethylbenzene (0.350 g) as an off-white solid. MS (ESI): m / z 232[M] + . 1 H NMR (400 MHz, CDCl3) δ ppm 7.345-7.383 (m, 1 H), 7.176-7.195 (m, 2H), 3.815-3.854 (m, 2 H), 3.531-3.569 (m, 2 H),2.714 (s, 6H).

[0314] Synthesis of intermediate 2-((2,6-dimethylphenyl)sulfonyl)-N,N-diethylethan-1-amine: To a stirred solution of 2-((2-chloroethyl)sulfonyl)-1,3-dimethylbenzene (0.300 g, 1.289 mmol) in acetonitrile (10 ml) was added potassium iodide (0.428 g, 2.578 mmol) and diethylamine (0.283 g, 3.867 mmol) at RT. The resulting reaction mixture was heated to 90° C. for 16 h in a sealed tube and the progress of the reaction mixture was monitored by TLC (mobile phase: 50% ethyl acetate in pet ether, visualization: UV). The reaction mixture was concentrated under reduced pressure to give the crude product, which was diluted with ethyl acetate (60 ml), washed with water (30 ml x 3) and brine (30 ml), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (eluted with 40% ethyl acetate in pet ether) and the collected pure fractions were concentrated under reduced pressure to give the desired product 2-((2,6-dimethylphenyl)sulfonyl)-N,N-diethylethan-1-amine (0.200 g) as an off-white solid. MS (ESI): m / z 270.16[M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 7.308-7.346 (m, 1 H), 7.153-7.172(m, 2H), 3.244-3.283(m, 2 H), 2.947-2.985 (m, 2 H), 2.716 (s, 6 H), 2.437-2.490 (m, 4H), 0.937-0.973 (m, 6H).

[0315] Synthesis of N-benzyl-2-((2,6-dimethylphenyl)sulfonyl)-N,N-diethylethane-1-aminium bromide: Benzyl bromide (0.127 g, 0.742 mmol) was added to a stirred solution of 2-((2,6-dimethylphenyl)sulfonyl)-N,N-diethylethan-1-amine (0.100 g, 0.371 mmol) in acetonitrile (5 ml) and the resulting reaction mixture was heated to 90° C. for 16 h and the progress of the reaction mixture was monitored by TLC (mobile phase: 10% MeOH in DCM, visualization: UV). The reaction mixture was concentrated under reduced pressure to give the crude product which was triturated with EtOAc (20 ml) and n-pentane (10 ml) to give N-benzyl-2-((2,6-dimethylphenyl)sulfonyl)-N,N-diethylethan-1-aminium bromide (0.060 mg) as an off-white solid. MS (ESI): m / z 360.0[M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.475- 7.552 (m, 6 H), 7.347-7.366 (d, 2H), 4.604 (s, 2 H), 3.925-3.965 (m, 2 H), 3.520-3.560 (m, 2 H), 3.243-3.288 (m, 4H), 2.676(s, 6H), 1.235-1.312 (m, 6H).

[0316] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)sulfonyl)ethyl)azepan-1-ium bromide [ka] Synthesis of intermediate (2-((2,6-dimethylphenyl)sulfonyl)ethyl): To a stirred solution of 2-((2-chloroethyl)sulfonyl)-1,3-dimethylbenzene (1.0 g, 4.2970 mmol) in ACN (10.0 ml) was added azepane (0.639 g, 6.4455 mmol) and potassium iodide (1.426 g, 8.5940 mmol). The resulting reaction mixture was heated to reflux for 16 h and the progress of the reaction was monitored by TLC (mobile phase: 30% EtOAc in pet ether, visualization: UV). The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2 x 50 ml) and brine (1 x 50 mL). The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound, which was triturated with 2 x 10 ml of n-pentane to give (2-((2,6-dimethylphenyl)sulfonyl)ethyl)azepane (180 mg) as an off-white solid. MS (ESI): m / z 295.44 [M+H]. 1 H NMR (400 MHz, CDCl3) δ ppm 7.34 (t,1 H), 7.17 (d, 2H),3.1-3.8 (m. 6H),2.71 (d, 6 H),1.57-1.82 (m, 10H),2.71 (d, 6H).

[0317] Synthesis of 1-benzyl-1-(2-((2,6-dimethylphenyl)sulfonyl)ethyl)azepan-1-ium bromide: To a stirred solution of 1-(2-((2,6-dimethylphenyl)sulfonyl)ethyl)azepane (0.550 g, 1.864 mmol) in ACN (6.0 ml) was added benzyl bromide (0.637 g, 3.728 mmol) and the resulting reaction mixture was heated to reflux for 48 h and the reaction progress was monitored by TLC (mobile phase: 10% methanol in DCM, visualization: UV). The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude compound, which was triturated with 3 x 10 ml of ethyl acetate to give 1-benzyl-1-(2-((2,6-dimethylphenyl)sulfonyl)ethyl)azepan-1-ium bromide (80 mg) as an off-white solid. MS (ESI): m / z 386.40[M] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 7.5-7.63 (m, 6H),7.44 (d, 2H),4.59-4.65(d, 2H),4.06-4.15 (m, 2H),3.49-3.55 (m, 6H),2.696 (s,6H), 1.817-1.95(m, 4H), 1.569-1.65(m, 4H).

[0318] Synthesis of 1-benzyl-1-(1-(2,6-dimethylphenyl)-2-oxopyrrolidin-3-yl)piperidin-1-ium bromide [ka] Synthesis of 3-bromo-1-(2,6-dimethylphenyl)pyrrolidin-2-one: A stirred solution of 2,6-dimethylaniline (1.0 g, 8.252 mmol) in ACN (20 ml) was treated with K3PO4 (1.751 g, 8.252 mmol) and 2,4-dibromobutanoyl chloride (2.181 g, 8.252 mmol) at 0° C. and the reaction mixture was stirred at RT for 1 h. After 1 h, the resulting reaction mixture was treated with 50% NaOH aq. solution (1.650 g in 3.32 mL water) and the reaction mixture was stirred at RT for another 1 h and the progress of the reaction mixture was monitored by TLC (mobile phase: 50% ethyl acetate in pet ether, visualization: UV). After completion, the reaction mixture was filtered to remove inorganic salts and the filtrate was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product as a colorless gum. The crude product was triturated with n-pentane (30 ml) to give 3-bromo-1-(2,6-dimethylphenyl)pyrrolidin-2-one (1.5 g). MS (ESI): m / z 268.03 [M+H] + . 1H NMR (400 MHz, CDCl3) δ ppm 7.18-7.14 (m, 1 H), 7.10-7.08 (m, 2 H), 4.56-4.54 (m, 1 H), 3.92-3.86 (m,1 H), 3.51-3.46 (m, 1 H), 2.84-2.78(m, 1H), 2.52-2.47(m, 1H), 2.29 (s, 3H), 2.19 (s, 3H).

[0319] Synthesis of 1-(2,6-dimethylphenyl)-3-(piperidin-1-yl)pyrrolidin-2-one: To a stirred solution of 3-bromo-1-(2,6-dimethylphenyl)pyrrolidin-2-one (0.300 g, 1.118 mmol) in ACN (10 ml) was added piperidine (0.114 g, 1.342 mmol) and DIPEA (0.578 g, 4.475 mmol) at RT, the resulting mixture was heated to 90° C. in a sealed tube for 16 h, and the progress of the reaction mixture was monitored by TLC (mobile phase: 10% methanol in DCM, visualization: UV). The reaction mixture was concentrated under reduced pressure to give the crude product, which was diluted with DCM (70 ml) and washed with water (40 ml x 3) and brine (40 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 1-(2,6-dimethylphenyl)-3-(piperidin-1-yl)pyrrolidin-2-one (0.220 g). MS (ESI): m / z 273.35[M+H] + . 1 HNMR (400 MHz, CDCl3) δ ppm 7.14-7.06 (m, 3 H), 3.70-3.48(m,3 H), 2.80-2.89 (m, 2 H), 2.60-2.65(m, 2 H), 2.35-2.28 (m, 2 H), 2.21 (s, 3 H), 2.15 (s, 3 H), 1.67-1.60 (m, 4 H), 1.50-1.46 (m, 2 H).

[0320] Synthesis of 1-benzyl-1-(1-(2,6-dimethylphenyl)-2-oxopyrrolidin-3-yl)piperidin-1-ium bromide: To a stirred solution of 1-(2,6-dimethylphenyl)-3-(piperidin-1-yl)pyrrolidin-2-one (0.220 g, 0.807 mmol) in ACN (5 ml) was added benzyl bromide (0.276 g, 1.615 mmol) and the resulting mixture was heated in a sealed tube at 90° C. for 16 h and the progress of the reaction mixture was monitored by TLC (mobile phase: 10% methanol in DCM, visualization: UV). The reaction mixture was cooled to RT, diluted with ethyl acetate (20 ml) and stirred for 2 h to give a solid which was filtered, washed with ethyl acetate (40 ml) then n-pentane (20 ml) and dried under high vacuum to give 1-benzyl-1-(1-(2,6-dimethylphenyl)-2-oxopyrrolidin-3-yl)piperidin-1-ium bromide (0.090 g) as an off-white solid. MS (ESI): m / z363.1[M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.60-7.52 (m, 5 H), 7.25-7.16 (m, 3H), 5.58-4.02(m,4 H), 3.65-3.57 (m, 2 H),3.13-2.92(m, 3 H), 2.67-2.66 (m,1 H), 2.21-1.94 (m, 10H), 1.61-1.23 (m, 3 H).

[0321] The following example was prepared from 3-bromo-1-(2,6-dimethylphenyl)pyrrolidin-2-one, azepane and benzyl bromide following the procedure described for the synthesis of compound 89A. [Table 12]

[0322] Synthesis of 1-benzyl-1-(1-(2,6-dimethylphenyl)-2-oxopiperidin-3-yl)pyrrolidin-1-ium bromide [ka] Synthesis of 2,5-dibromopentanoyl chloride: A stirred suspension of 5-bromopentanoyl chloride (5 g, 25.066 mmol) was treated with bromine (2.56 ml, 50.132 mmol) at room temperature, and the resulting reaction mixture was then stirred for 2 h at 100° C. After 2 h, the reaction was cooled to room temperature and concentrated under reduced pressure to give crude 2,5-dibromopentanoyl chloride (7.2 g), which was carried on to the next step without further purification.

[0323] Synthesis of 3-bromo-1-(2,6-dimethylphenyl)piperidin-2-one: A stirred solution of 2,6-dimethylaniline (2.0 g, 16.504 mmol) and potassium phosphate (3.503 g, 16.504 mmol) in acetonitrile (50 ml) was cooled to 0° C. and 2,5-dibromopentanoyl chloride (4.594 g, 16.504 mmol) was added dropwise. The resulting reaction mixture was stirred at room temperature for 1 h. After 1 h, 50% NaOH aq. solution (3.3 g, 6.6 ml water) was added to the reaction mixture and the resulting reaction mixture was stirred at room temperature for 1 h and the progress of the reaction was monitored by TLC (mobile phase: 50% EtOAc:Pet Ether, visualization: UV). The reaction mixture was filtered to remove inorganic salts, and the filtrate was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (eluted with 25%-30% EtOAc in Pet ether) to give 3-bromo-1-(2,6-dimethylphenyl)piperidin-2-one (2.2 g) as an off-white solid. MS (ESI): 282.25 m / z, [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm7.15-7.08 (m, 3 H), 4.87 (t, 1 H), 3.54-3.49 (m, 1 H), 3.37-3.34 (m, 1 H), 2.51-2.45 (m, 1H),2.27-2.21(m, 2H),2.22-2.10 (m, 6H),1.94 (m, 1H).

[0324] Synthesis of 1-(2,6-dimethylphenyl)-3-(pyrrolidin-1-yl)piperidin-2-one: To a solution of 3-bromo-1-(2,6-dimethylphenyl)piperidin-2-one (0.2 g, 0.709 mmol) and DIPEA (0.366 g, 2.83 mmol) in acetonitrile (10 mL) was added pyrrolidine (0.0655 g, 0.921 mmol), and the resulting reaction mixture was stirred in a sealed tube at 90° C. for 16 h, and the reaction progress was monitored by TLC (mobile phase: 50% EtOAc in pet ether, visualization: UV). The reaction was concentrated under reduced pressure to give a crude residue, which was diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by normal phase flash chromatography (eluted with 25%-30% EtOAc in Pet ether) to give 1-(2,6-dimethylphenyl)-3-(pyrrolidin-1-yl)piperidin-2-one (350 mg) as a pale yellow gummy oil. LCMS purity: 75.17%, MS (ESI): 273.43 m / z, [M+H] + .

[0325] Synthesis of 1-benzyl-1-(1-(2,6-dimethylphenyl)-2-oxopiperidin-3-yl)pyrrolidin-1-ium bromide: To a stirred solution of 1-(2,6-dimethylphenyl)-3-(pyrrolidin-1-yl)piperidin-2-one (250 mg, 0.9178 mmol) in acetonitrile (10 mL) was added benzyl bromide (0.2041 g, 1.1931 mmol), and the resulting reaction mixture was stirred in a sealed tube at 90° C. for 16 h, and the reaction progress was monitored by TLC (mobile phase: 10% methanol in DCM, visualization: UV). The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product, which was triturated with EtOAc (20 mL x 2) to give 1-benzyl-1-(1-(2,6-dimethylphenyl)-2-oxopiperidin-3-yl)pyrrolidin-1-ium bromide (105 mg) as an off-white solid. MS (ESI): m / z 363.4[M] + . 1H NMR (400 MHz, DMSO-d6) δ ppm7.64-7.62 (m, 2 H), 7.57-7.48 (m, 3 H), 7.20-7.13 (m, 3 H), 4.78 (m, 3 H), 4.03-4.01 (m, 2H), 3.80 -3.72(m, 2 H), 3.55-3.50 (m, 1 H), 3.41-3.61(m, 1H), 2.51-2.49 (m, 1 H), 2.39-2.35 (m, 1 H), 1.21-1.99(m,10 H), 1.97-1.90 (m, 2H).

[0326] The following examples were prepared from 3-bromo-1-(2,6-dimethylphenyl)piperidin-2-one, benzyl bromide and the appropriate azacycloalkane according to the procedure described for the synthesis of compound 91A. The products were purified by trituration or reverse phase prep. HPLC. [Table 13]

[0327] The following example was prepared according to the procedure for preparing compound 69A from bromoacetyl bromide, benzyl bromide and the appropriate azacycloalkane and substituted aniline. [Table 14-1] [Table 14-2] [Table 14-3]

[0328] Example 2 - Inhibition of Nav1.7 currents Representative compounds of the present invention were synthesized according to the methods described and tested for their ability to inhibit voltage-gated sodium channels.

[0329] Manual patch clamp: cell culture NaV1.7 was expressed in HEK293 cells upon induction with tetracycline. Cells were cultured in DMEM containing 10% dialyzed fetal bovine serum (VWR, Radnor, PA), 1% Glutamax (VWR, Radnor, PA), 1% penicillin-streptomycin (VWR, Radnor, PA), 100 mg / L hygromycin (Thermo Fisher Scientific, Waltham, MA), and 5 mg / L blasticidin (Alfa Aesar, Haverhill, MA). Cells were grown and maintained at 37°C in a humidified environment containing 10% CO2 in air. For passaging, cells were detached from the culture flask and harvested using 0.05% trypsin-EDTA (Thermo Fisher Scientific, Waltham, MA). To induce NaV1.7, cells were induced with tetracycline (0.1–1 μg / mL, IBI Scientific, Peosta, IA) the day before recording and plated on 24-well plates. Cells were incubated in DPBS (VWR, Radnor, The cells were washed with PBS (pH 7.0), trypsinized, and then triturated five times in 10 mL of growth medium to break apart cell aggregates. For one 24-well plate, 2 mL of the cell suspension was mixed with 23 mL of fresh growth medium supplemented with 0.1-1 μg / mL of tetracycline. 1 mL of the medium mixed with the cells was then added to each well of a 24-well plate with a 12 mm cover glass already placed at the bottom of the well. The cells were then incubated overnight at 37°C and 10% CO2.

[0330] Patch clamp solutions and drugs The intracellular solution contained the following (in mM): CsCl 135, NaCl 10, EGTA 10, HEPES 10, MgCl22, adjusted to pH 7.2 with CsOH. The external solution was standard Ringer's solution containing (in mM): NaCl 155, HEPES 10, glucose 10, KCl 3.5, CaCl2 1.5, MgCl21, adjusted to pH 7.4 with NaOH. CsCl was from Alfa Aesar, Haverhill, MA. All other chemicals were from Sigma-Aldrich, St. Louis, MO. To test the degree of internal block by test compounds, compounds were dissolved in the internal solution at the test concentrations indicated. In control experiments, the internal solution did not contain any compound. To test the degree of external block by test compounds, compounds were dissolved in the external solution at the test concentrations indicated.

[0331] Whole-cell patch clamp protocol 18–24 h after cells were induced with tetracycline, coverslips were placed in a chamber filled with standard Ringer's solution at room temperature, and the chamber was placed on the microscope. Pipettes were pulled from borosilicate glass with a P97 puller (Sutter Instrument, Novato, CA) and polished with an MF-830 microforge (Narishige International USA, Inc, Amityville, NY) to have a resistance of 1.5–2.5 MΩ when filled with CsCl internal solution at room temperature. Healthy cells (round, no visible translucent blemishes) were selected for seal formation. A seal was formed between the pipette and cell and "pushed" using a brief pulse of suction to establish whole-cell configuration. Before starting the voltage protocol, the membrane potential was held at -100 mV. Only cells with a continuous resistance of 1.5–5 MΩ were retained for analysis. The voltage protocol was as follows: the cell was held at -100 mV for 12 ms, followed by a hyperpolarization step at -105 mV for 12 ms and monitoring for leakage. The cell was then stepped back to -100 mV for 40 ms. The cell was then depolarized to -20 mV for 10 ms and returned to -100 mV for 26 ms.

[0332] Internal blockade by test compounds Once recording was started, the voltage protocol was performed for 5 min with 30 s intervals to obtain a stable baseline. This was followed by 4 30 s 5 Hz stimulations with the same voltage protocol separated by 1 min rest, followed by 0.33 Hz stimulation after the last step. Currents were recorded using PatchMaster software with a Heka EPC10 (HEKA Electronics, Lambrecht, Germany). Only cells with inward current amplitudes between 400 pA and 4 nA at -20 mV were accepted, and cells with leakage currents higher than 10% of their current amplitude were discarded.

[0333] Data Analysis: Internal Blockade Data were plotted using Patchmaster software (HEKA Electronics, Lambrecht, Germany) and analyzed by plotting the minimum current during a voltage step to -20 mV (peak inward current) as a function of time. To determine the degree of decline over the course of the experiment, the mean peak inward current amplitude (2-3 points) before the 5 Hz stimulation was designated as the baseline (I baseline). The mean peak inward current was measured during the last 2 s of the last 5 Hz step (I test). The control fraction current remaining was calculated by dividing I test by I baseline. On each recording day, 3 cells were tested with control internal solution and the mean fraction of the remaining current was calculated (Ctrl fraction current).

[0334] To determine the % block produced by internally applied test compounds, the following was done: the mean peak inward current amplitude (2-3 points) before 5 Hz stimulation was adjusted to 0% block (I 0% To correct for the current changes under control conditions, I 0% The block was multiplied by the remaining mean Ctrl fractional current to obtain the corrected 0% block current. The mean peak inward current during the last 2 seconds of the last 5 Hz procedure was designated as the non-blocking current (Inon-block). The % block was calculated using the following equation: (1-Inon-block / (I 0%Calculated using (block * remaining Ctrl fractional current) x 100).

[0335] Representative examples of the present invention were tested for intracellular inhibition of NaV 1.7. Activity ranges are % inhibition at 10 μM test concentration: "++++" (>95%), "+++" 95-70%, "++" (70-40%) or "+" (<40%). Results are shown in the table below. [Table 15]

[0336] Representative examples of the present invention were tested for intracellular inhibition of NaV 1.7. Activity ranges are % inhibition at 3 μM test concentration: "++++" (>90%), "+++" 90-70%, "++" (70-40%) or "+" (<40%). Results are shown in the table below. [Table 16]

[0337] External blockade by test compounds Once recording was started, the voltage protocol was run for 5 min with 30 s intervals to obtain a stable baseline. This was followed by the same voltage protocol with 5 Hz stimulation until the end of the experiment. Test compounds were added during the 5 Hz stimulation procedure to ensure that cells were allowed to wait until they showed a stable rate of current decrease before adding the test compound. Test compounds were added for 5 min before washing with standard Ringer's solution. Currents were recorded using PatchMaster software with a Heka EPC10 (HEKA Electronics, Lambrecht, Germany). Only cells with inward current amplitudes between 400 pA and 4 nA at -20 mV were accepted. Cells with leakage currents greater than 10% of their current amplitude were discarded.

[0338] Data Analysis: External Blockade Data were plotted using Patchmaster software (HEKA Electronics, Lambrecht, Germany) and analyzed by plotting the minimum current during a voltage step to -20 mV (peak inward current) as a function of time. To determine the % block produced by externally applied test compounds, the following was done: After a stable current decrease rate was established during the 5 Hz stimulation procedure, the rate decrease was calculated as the change in peak current amplitude divided by time. The average peak inward current amplitude before compound addition (2-3 sec) was used to determine the 0% block (I 0% In order to correct the decrease, I 0% Subtract (rate decrease * 5 min) from block to obtain the corrected 0% block current. The average peak inward current during the last 2-3 seconds of the 5 min compound application period before washout is the non-blocking current (Inon-block). The following equation is then used: Fractional Current Block = 1 - Inon-block / (I 0% The % block was calculated using: block-rate reduction*5 min.

[0339] Representative examples of the present invention were tested for extracellular inhibition of NaV 1.7. Activity ranges are % inhibition at 10 μM test concentration: "++++" (>90%), "+++" 90-70%, "++" (70-40%) or "+" (<40%). Results are shown below. [Table 17]

[0340] Automated patch clamp: cell culture NaV1.7 was expressed in HEK293 cells upon induction with tetracycline. Cells were cultured in DMEM containing 10% dialyzed fetal bovine serum (VWR, Radnor, PA), 1% Glutamax (VWR, Radnor, PA), 1% penicillin-streptomycin (VWR, Radnor, PA), 100 mg / L hygromycin (Thermo Fisher Scientific, Waltham, MA), and 5 mg / L blasticidin (Alfa Aesar, Haverhill, MA). Cells were grown and maintained at 37°C in a humidified environment containing 10% CO2 in air. For passaging, cells were detached from the culture flask and harvested using 0.05% trypsin-EDTA (Thermo Fisher Scientific, Waltham, MA). To induce NaV1.7, cells were induced with tetracycline (0.1–1 μg / mL, IBI Scientific, Peosta, IA) the day before recording.

[0341] Prior to the experiment, cells were washed with DPBS (VWR, Radnor, PA), digested with Detachin (VWR Radnor, PA), and then triturated 10 times in CHO serum-free medium (VWR Radnor, PA) to resuspend cells and break up cell aggregates. Cells were counted and the final concentration was set to 2-5 million cells per mL.

[0342] Patch clamp solutions and drugs The intracellular solution contained: 140 mM CsF, 1 mM / 5 mM EGTA / CsOH, 10 mM HEPES, 10 mM NaCl, pH adjusted to 7.3 with CsOH and osmolality adjusted to 320 with OSM solution. The external solution contained: 145 mM NaCl, 4 mM KCl, 1 mM MgCl2, 2 mM CaCl2, 10 mM HEPES, 10 mM glucose, pH adjusted to 7.4 with CsOH and osmolality adjusted to 305 with OSM solution. OSM solution was standard Ringer's solution containing (in mM) NaCl 155, HEPES 10, sucrose, KCl 3.5, CaCl2 1.5, MgCl2 1, adjusted to pH 7.4 with NaOH. All chemicals were from Sigma-Aldrich, St. Louis, MO. To test the degree of internal block by test compounds, the compounds were dissolved in the internal solution at the test concentrations indicated. In control experiments, the internal solution did not contain any compound. To test the degree of external block by test compounds, the compounds were dissolved in the external solution at the test concentrations indicated.

[0343] Automated patch clamp protocol Automated patch clamp was performed on a Qube 384 (Sophion Bioscience, Woburn MA) with a multihole Qchip with a temperature setting of 22 degrees. A whole-cell configuration was formed with default Qube seal and push parameters. Before starting the voltage protocol, the membrane potential was held at -100 mV. The two voltage protocols were as follows: Step 1: The cell was held at -100 mV with a depolarizing pulse to -20 mV for 10 ms, the interval was set at 5 s. Currents were corrected by default leak subtraction from all pulses. The duration was set at 5 min. Step 2: The cell was held at -100 mV with a depolarizing pulse to -20 mV for 10 ms. The frequency was 5 Hz. The current was corrected by leak subtraction calculated before step 2. The duration was set at 4 min.

[0344] Internal blockade by test compounds After step 2, the Qchip was removed from the recording chamber. The internal solution was replaced with a solution containing the test compound. After replacement in the recording chamber, the Qchip was held at -100 mV without pulses. The total solution exchange time was 8 min. After the internal solution exchange, the cell was recorded and step 2 was repeated for 10 min.

[0345] Data analysis was performed with a Sophion Analyzer. Cells were filtered with a minimum 50 MΩ seal resistance and a minimum 5 nA starting current. Current reduction was corrected with control cells (no drug). Residuals were calculated by averaging the last three points at the end of the experiment. Baseline was calculated as the average of the last three points of step 2. IC was calculated by DR-plot / Hill function (dose-response plot with Hill fit). 50 The curves were plotted. Representative examples of the present invention were tested for intracellular inhibition of NaV 1.7 in an automated patch clamp assay. The activity range was IC 50 The results are recorded as "++++" (<0.3μM), "+++" (0.3-1μM), "++" (1-3μM) or "+" (3-10μM). The results are shown below. [Table 18]

[0346] External blockade by test compounds After step 2, the external solution was changed to a solution containing the test compound. The Qchip was held at -100 mV without any pulses. The total solution exchange time was 8 min. After the external solution exchange, the cells were recorded for 10 min using the same procedure as in step 2.

[0347] Data analysis was performed using a Sophion Analyzer. Data were normalized using control cells (no drug). IC 50 Data were plotted by DR-plot / Hill function (dose-response plot with Hill fit). Representative examples of the present invention were tested for extracellular inhibition of NaV 1.7 in an automated patch clamp assay. Activity ranges are given by IC 50: reported as "++++" (<1μM), "+++" (1-3μM), "++" (3-10μM) or "+" (>10μM). The results are shown below. [Table 19]

[0348] Example 3 - Membrane permeability The ability of the compounds of the invention to pass through artificial lipid membranes by passive diffusion was determined using the PAMPA assay (pION, Inc., Woburn MA). Test compounds were dissolved in DMSO (10 mM) and diluted 200-fold in buffer (pION Inc., pH 7.4) to obtain a 50 uM stock solution. Buffer (150 μL) was added to a UV blank plate and stock solution (150 μL) was transferred to a UV reference plate. Blank and reference spectra were read using a spectrophotometer. Stock solution (200 μL) was added to the donor plate of a PAMPA sandwich plate and topped with a recipient plate coated with GIT lipids (pION Inc, 5 μL). Buffer (200 μL) was added to the recipient plate and the PAMPA sandwich plate was incubated for 4 hours. An aliquot (150 μL) from the recipient plate was added to the UV plate to read the recipient spectrum. An aliquot (150 μL) of the donor solution was added to a UV analysis plate and read as a donor spectrum. The permeability coefficient of the test compound was calculated using PAMPA Explorer™ software (version 3.5.0.4) based on the AUC of the reference plate, donor plate and acceptor plate.

[0349] PAMPA permeability results for representative compounds (10 -6 cm / s) is "+" (<0.1 10 -6 cm / s). "++" (0.1-2.0 10 -6 cm / s), "+++" (2.0-10.0 10 -6 cm / s) or "++++" (>10.0 10 -6 The velocity is reported as cm / s. [Table 20]

[0350] The patent and scientific literature referenced herein establishes knowledge available to those of skill in the art. All U.S. patents and published or unpublished U.S. patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are incorporated by reference. All other published references, documents, papers and scientific literature cited herein are incorporated by reference.

[0351] While the present invention has been particularly shown and described with respect to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as encompassed by the appended claims. It is also understood that any of the embodiments described herein are not mutually exclusive and may be combined in various ways without departing from the scope of the invention as encompassed by the appended claims.

[0352] Although the present invention has been particularly shown and described with respect to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as encompassed by the appended claims. It will also be understood that any of the embodiments described herein are not mutually exclusive and may be combined in various ways without departing from the scope of the invention as encompassed by the appended claims. The aspects of the present invention include the following. Item 1 Formula (I) [ka] (In the formula: Y - is a pharma- ceutically acceptable anion; R A 、RB and R C each independently represents H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I , C.N., N.R. J R K , N.R. L C(O)R M , S(O)R N , S(O) 2 R N , S.O. 2 R O R P , S.O. 2 NR Q R R , S.O. 3 R S , CO 2 R T ;C(O)R U and C(O)NR V R W Selected from; R I 、R J 、R K 、R L 、R M 、R N 、R O 、R P 、R Q 、R R 、R S 、R U 、R V and R W each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; or R J and R K Or R V and R W Or R Q and R R can be taken together with the nitrogen to which they are attached to form a substituted or unsubstituted 5-, 6-, 7-, or 8-membered ring; R A 、R B and / or R C can be taken together with the phenyl ring to which they are attached to form a fused bicyclic or tricyclic ring system; X 1 -CR X R Y -, -NR Z C(O)-, -NR Z C(O)CR X R Y --OC(O)-, -SC(O)-, -C(O)NR 1A -, -C(O)O-, -(O)CS-, -NR 1A S(O)-, -S(O)NR 1A -, -NR 1A C(O)NR 1A -, -S(O)- and -S(O) 2 - Selected from; R X 、R Y 、R Z and R 1A each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl; R D and R E each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted cycloalkyl; or R D and R E together with the carbon to which they are attached, form substituted or unsubstituted C 3- C 6 forming a cycloalkyl, substituted or unsubstituted heterocyclic ring; or R D and R Z together with the carbon to which they are attached and -NC(O)-, form an optionally substituted 5- to 8-membered lactam; R F and R G are the N that they bond to+ together with N to form an optionally substituted heterocyclic ring having 0, 1 or more nitrogen atoms in addition to N; or R F and R G each independently represents a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, and a substituted or unsubstituted C 3- C 6 cycloalkyl; R H is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl) The compound represented by: Section 2 Y - The compound according to item 1, wherein is bromide, chloride or iodide. Section 3 X 1 The compound according to item 1, wherein is -NHC(O)-. Section 4 R H However, each is C 1-6 Alkane, C 3 -C 6 C optionally substituted with cycloalkyl, heterocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, hydroxyl, amide, ester, sulfonamide, urea, nitrile, or halogen 6-10 Aryl or C 5-10 Item 2. The compound according to item 1, wherein the compound is selected from heteroaryl. Section 5 R H , each of which is substituted or unsubstituted C 1 -C 6 C optionally substituted with alkyl, halo, nitrile, hydroxyl and alkoxy 6-10 Item 2. The compound according to item 1, wherein the aryl is aryl or 5- to 10-membered heteroaryl. Section 6 R A and R B Each of these independently represents H, halogen, or C. 1-4 Alkyl and NR J R K Selected from; R J and R K each independently represents H or C 1-4 alkyl; R C H, halogen, C 1-4 Alkyl or NR JR K Item 3. The compound according to item 1, Section 7 R A 、R B and R C are each independently H, D, halogen, OR I , substituted or unsubstituted C 1- C 4 Alkyl and NR J R K Selected from; R I 、R J and R K each independently represents H and substituted or unsubstituted C 1- C 4 Item 2. The compound according to item 1, wherein the aryl group is selected from alkyl. Section 8 R A and R B Each of the CH 3 and R C But, H, CH 3 Item 2. The compound according to item 1, wherein the aryl group is selected from the group consisting of halogen, nitrile, methoxy and ethoxy. Section 9 R D But halogens, oxygen, C 3-8 C optionally substituted with cyclic alkyl, aryl or heteroaryl 1-4 is alkyl, R E is H, D or C 1-4 Item 3. The compound according to item 1, wherein the compound is alkyl. Section 10 R D and R E The compound according to item 1, wherein both of are hydrogen. Section 11 R D is hydrogen and R E Item 3. The compound according to item 1, wherein is alkyl. Section 12 RD and R E together with the carbon to which they are attached, C 3 -C 6 The compound according to item 1, which forms a cycloalkyl. Section 13 R F and R G But the N they bond to + The compound according to item 1, which together with Section 14 R F and R G each independently represents an unsubstituted C 1 -C 4 Item 2. The compound according to item 1, wherein the aryl group is selected from alkyl. Item 15 The following table:

Table A-1-1

Table A-1-2

Table A-2-1

Table A-2-2

Claims

1. Formula (I) 【Chemistry 1】 (In the formula: Y - is a pharma- ceutically acceptable anion; R A and R B are each independently selected from substituted or unsubstituted alkyl; R C each independently represents H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I , C.N., N.R. J R K , N.R. L C(O)R M , S(O)R N , S(O) 2 R N , S.O. 2 R O R P , S.O. 2 NR Q R R , S.O. 3 R S , CO 2 R T ;C(O)R U and C(O)NR V R W Selected from: RT is selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl; R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R U , R V and R W each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; or R J and R K Or R V and R W Or R Q and R R may be taken together with the nitrogen to which they are attached to form a substituted or unsubstituted 5-, 6-, 7-, or 8-membered ring; X 1 -NR Z C(O)-; R Z is selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl; R D and R E each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted cycloalkyl; or R D and R E together with the carbon to which they are attached, form substituted or unsubstituted C 3- C 6 cycloalkyl, forming a substituted or unsubstituted heterocycle; R F and R G are the N that they bond to + together with, form a substituted or unsubstituted 5-, 6-, 7-, or 8-membered saturated monocyclic heterocycle having 0, 1, or more nitrogen atoms in addition to N as heteroatoms; and R H is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, The compound represented by:

2. Y - 2. The compound of claim 1, wherein is bromide, chloride or iodide.

3. R H However, each is C 1-6 Alkane, C 3 -C 6 C optionally substituted with cycloalkyl, heterocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, hydroxyl, amide, ester, sulfonamide, urea, nitrile, or halogen 6-10 Aryl or C 5-10 The compound of claim 1 , wherein the heteroaryl is selected from the group consisting of aryl, hetero ...

4. R H are substituted or unsubstituted C 1 -C 6 C optionally substituted with alkyl, halo, nitrile, hydroxyl or alkoxy 6-10 The compound of claim 1, which is aryl or 5- to 10-membered heteroaryl.

5. R A and R B Each of the CH 3 and R C But, H, CH 3 2. The compound of claim 1, wherein the aryl group is selected from the group consisting of halogen, nitrile, methoxy and ethoxy.

6. R D But halogens, oxygen, C 3-8 C optionally substituted with cyclic alkyl, aryl or heteroaryl 1-4 is alkyl, R E is H, D or C 1-4 The compound of claim 1 , which is alkyl.

7. R D and R E The compound of claim 1, wherein both of are hydrogen.

8. R D is hydrogen and R E The compound of claim 1 , wherein is alkyl.

9. R D and R E together with the carbon to which they are attached, C 3 -C 6 The compound of claim 1 which forms a cycloalkyl.

10. The following table: 【Table 1-1】 【Table 1-2】 2. The compound of claim 1, selected from:

11. The following table: 【Table 2-1】 【Table 2-2】 2. The compound of claim 1, selected from:

12. 10. A pharmaceutical composition comprising a compound of claim 1 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

13. 13. The composition of claim 12, formulated for oral, intravenous, intramuscular, rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, inhalation, vaginal, intrathecal, epidural or intraocular administration.

14. 14. A pharmaceutical composition according to claim 12 or 13 for use in a method of treating pain, cough, itch or a neuroinflammatory disorder in a patient, comprising administering to the patient an effective amount of a compound according to claim 1.

15. 15. The pharmaceutical composition of claim 14, wherein the cough is selected from the group consisting of asthma, COPD, asthma-COPD overlap syndrome (ACOS), interstitial pulmonary fibrosis (IPF), idiopathic pulmonary fibrosis, post-viral cough, post-infectious cough, chronic idiopathic cough and cough in patients with lung cancer.

16. 15. The pharmaceutical composition of claim 14, wherein the itch is selected from the group consisting of pruritus, brachioradial pruritus, chronic idiopathic pruritus, genital / anal pruritus, back paresthesia, scalp pruritus, allergic dermatitis, contact dermatitis, atopic dermatitis, hand eczema, poison ivy, infection, parasites, insect bites, pregnancy, metabolic disorders, liver or kidney failure, drug reactions, allergic reactions, eczema, genital and anal itch, hemorrhoidal itch, and itch due to cancer.

17. 15. The pharmaceutical composition of claim 14, wherein the neuroinflammatory disorder is selected from the group consisting of allergic inflammation, asthma, chronic cough, conjunctivitis, rhinitis, psoriasis, inflammatory bowel disease, interstitial cystitis, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, gastritis, migraine, rosacea, sunburn, pancreatitis, chronic rhinosinusitis, traumatic brain injury, polybacterial sepsis, tendinopathy, chronic urticaria, rheumatic disease, acute lung injury, exposure to irritants, inhalation of irritants, pollutants, chemical warfare agents, and atopic dermatitis.

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