Varenicline-related compounds and methods for treating diseases and conditions including disorders in use of tobacco

Abstract

Provided herein are compounds, pharmaceutically acceptable salts, pharmaceutical compositions comprising such compounds or pharmaceutically acceptable salts thereof, kits comprising such compounds or pharmaceutically acceptable salts thereof, and methods for preparing such compounds. Methods of making these compounds, or pharmaceutically acceptable salts thereof, and methods of treating and preventing diseases and conditions using these compounds, or pharmaceutically acceptable salts thereof.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 403,529, filed on September 2, 2022, the entire content of which is incorporated herein by reference.

[0003] Overview

[0004] In some embodiments, provided herein is a pharmaceutically acceptable salt of Formula I:

[0005]

[0006] wherein, independently, X - can be a pharmaceutically acceptable anion, A can be a C1 - C10 alkyl or branched alkyl group with a hydroxy group or any amino acid side chain, and Z can be hydrogen or a pharmaceutically acceptable cation or the following fragment of a pharmaceutically acceptable salt of a compound of Formula I:

[0007]

[0008] and can be D, L, or racemic or achiral; for example, the fragment can be a fragment of any of the following amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or selenocysteine; or a salt of any of these.

[0009] In some embodiments, provided is a pharmaceutically acceptable salt of Formula 1A:

[0010]

[0011] wherein A is a C1 - C10 alkyl or branched alkyl group with a hydroxy group or a C1 - C10 straight - chain or branched alkyl group with a carboxylic acid group or a pharmaceutically acceptable salt thereof.

[0012] Consistent with the above, a pharmaceutically acceptable salt of a compound of Formula I can be a pharmaceutically acceptable salt of Formula IB:

[0013]

[0014] In some embodiments, in the pharmaceutically acceptable salt of Formula I or Formula IB, X -may be an anion selected from the group consisting of: chloride, bromide, sulfate, phosphate, acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, and benzenesulfonate. In some embodiments, in a pharmaceutically acceptable salt of a compound of formula I, Z may be hydrogen (H). In some embodiments, in a pharmaceutically acceptable salt of a compound of formula I, Z may be a pharmaceutically acceptable organic or inorganic cation.

[0015] In some embodiments, a pharmaceutically acceptable salt of formula I may have the structure of formula II:

[0016]

[0017] In some embodiments, a pharmaceutically acceptable salt of formula I may have the structure of formula III:

[0018]

[0019] In some embodiments, there is provided a pharmaceutically acceptable salt of formula IV:

[0020]

[0021] wherein, independently, X may be a pharmaceutically acceptable anion, Y may be a C1-C10 straight or branched chain alkyl group with a carboxylic acid group or a pharmaceutically acceptable salt thereof, and Z may be hydrogen or a pharmaceutically acceptable cation.

[0022] In some embodiments, in a pharmaceutically acceptable salt of formula IV, X - may be an anion selected from the group consisting of: chloride, bromide, sulfate, phosphate, acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, and benzenesulfonate. In some embodiments, in a pharmaceutically acceptable salt of a compound of formula IV, Z may be hydrogen (H). In some embodiments, in a pharmaceutically acceptable salt of a compound of formula IV, Z may be a pharmaceutically acceptable organic or inorganic cation.

[0023] In some embodiments, a pharmaceutically acceptable salt of formula IV may have the structure of formula V:

[0024]

[0025] In some embodiments, a pharmaceutically acceptable salt of formula VI may have the structure of formula VI:

[0026]

[0027] In some embodiments, a compound of Formula VII or a pharmaceutically acceptable salt thereof is provided:

[0028]

[0029] wherein each A can independently be a C1-C5 straight or branched alkyl group.

[0030] In some embodiments, in the compound of Formula VII or a pharmaceutically acceptable salt thereof, each A can independently be methyl.

[0031] In some embodiments, a compound of Formula VIII or a pharmaceutically acceptable salt thereof is provided:

[0032]

[0033] wherein R 1 and R 2 can independently be hydrogen (H) or a C1-C5 branched or straight alkyl,

[0034] or R 1 and R 2 together with the nitrogen atom to which they are attached can form a 5-, 6- or 7-membered ring, and Z can be hydrogen (H) or a pharmaceutically acceptable cation.

[0035] In some embodiments, in the compound of Formula VIII or a pharmaceutically acceptable salt thereof, R 1 and R 2 and Z can be hydrogen.

[0036] In some embodiments, a pharmaceutical composition is provided that comprises a pharmaceutically acceptable salt or compound of Formulas I to VIII and a pharmaceutically acceptable excipient, diluent, carrier, or any combination thereof. In some embodiments, the pharmaceutical composition can be in unit dose form.

[0037] In some embodiments, provided are methods of treating or preventing a disease or condition in a subject or a subject in need thereof, which subject or subject in need thereof can be a human subject or a human subject in need thereof, which human subject or human subject in need thereof can be a human subject in need thereof, the method comprising administering to the subject, human subject, subject in need thereof or human subject in need thereof a pharmaceutically acceptable salt or compound of Formula I to Formula VIII, or a pharmaceutical composition comprising one or more of these and a pharmaceutically acceptable carrier, excipient, diluent or any combination of these, in an effective amount or a therapeutically effective amount sufficient to treat the disease or condition; the pharmaceutical composition can be in unit dosage form. In some embodiments, the disease or condition can be tobacco use disorder, nicotine use disorder, smoking, Parkinson's disease or any combination thereof. In some embodiments, the disease or condition includes tobacco use disorder. In some embodiments, the administration can be once, twice or three times a day; or once every other day; or once every three days. In some embodiments, the administration can be carried out for a period of one day, one week, one month, 6 months, one year, two years, three years, four years, five years, for life or as needed. In some embodiments, the human or human in need thereof can be male or female. In some embodiments, the human or human in need thereof can be 18 years of age or older. In some embodiments, the administration can be oral administration or inhalation administration or intranasal administration or subcutaneous administration or intramuscular administration or intravenous administration. In some embodiments, any pharmaceutically acceptable salt or compound herein, including a pharmaceutically acceptable salt or compound of Formula I to Formula VIII, can be administered in a dosage amount in the range of from about 1 mg to about 20 mg, or about 1 mg to about 15 mg, or about 1 mg to about 10 mg, or about 1 mg to about 5 mg, or about 1 mg to about 3 mg. In some embodiments, any pharmaceutically acceptable salt or compound herein, including a pharmaceutically acceptable salt or compound of Formula I to Formula VIII, can be administered in a dosage amount in the range of from about 0.00001 mg / kg to about 10,000 mg / kg, wherein mg is the mg of the pharmaceutically acceptable salt or compound and kg is the body weight of the subject. For example, these can be administered at about 0.001 mg / kg, about 0.01 mg / kg, about 0.1 mg / kg, about 1 mg / kg, about 10 mg / kg, about 100 mg / kg.

[0038] In some embodiments, provided is a kit comprising a pharmaceutically acceptable salt or compound of Formula I to Formula VIII, or a pharmaceutical composition comprising one or more of these, and a container.

[0039] In some embodiments, provided is a method of preparing a kit, the method comprising placing a pharmaceutically acceptable salt or compound of Formula I to Formula VIII or any pharmaceutical composition comprising these in a container.

[0040] In some embodiments, provided are methods of preparing compounds of Formula I to Formula VIII or pharmaceutically acceptable salts thereof, and also provided are intermediate compounds and salts thereof useful for preparing these and methods of preparing these intermediate compounds and salts thereof.

[0041] This summary is intended to provide exemplary embodiments herein and is in no way intended to be restrictive otherwise.

[0042] Incorporation by reference

[0043] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent, or patent application is specifically and individually indicated to be incorporated by reference. Brief Description of the Drawings

[0045] The features of the present disclosure are particularly set forth in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description of illustrative embodiments that utilize the principles of the present disclosure and the accompanying drawings, in which:

[0046] Figures 1A - 1B are schematic diagrams and response curves illustrating the monitoring of striatal dopamine in awake, behaviorally normal animals in response to varenicline. Figure 1A shows a fiber photometry system and fiber placement for monitoring DA-induced fluorescence changes in awake, behaviorally normal mice, and representative images show striatal GPCR-activated DA (GRAB-DA) and fiber placement. Scale bar 200 μm. Figure 1B shows striatal dopamine responses before and after intraperitoneal (IP) administration of nicotine.

[0047] Figures 2A - 2C are bar graphs and response curves illustrating the striatal dopamine response to nicotine. Figure 2A shows dopamine responses (average at 30 minutes after nicotine administration) in animals pretreated with vehicle, varenicline (1.5 mg / kg (mpk) and 4.5 mg / kg (mpk)), Servarenicline chloride, varenicline-Enacarbil, varenicline-CBT, or varenicline glycinamide. Figures 2B - 2C show exemplary traces and quantification of striatal dopamine responses before and after IP administration of nicotine. Mice were pretreated with varenicline (light gray) or varenicline-Enacarbil (dark gray).

[0048] Figures 3A - 3B are bar graphs and response curves showing the striatal dopamine responses to oral compound administration. Figure 3A shows the dopamine responses (average at 30 minutes after compound administration) in animals given vehicle, varenicline (1.5 mpk and 4.5 mpk), Servarenicline chloride, varenicline - Enacarbil, varenicline - CBT, or varenicline glycinamide. Figure 3B shows the time kinetics of the dopamine responses in animals given vehicle, varenicline (1.5 mpk and 4.5 mpk), Servarenicline chloride, varenicline - Enacarbil, varenicline - CBT, or varenicline glycinamide.

[0049] Figure 4 is a schematic diagram showing a method for stabilizing dopamine responses. Figure 4 shows the dopamine responses to treatment with a smoking cessation product or vehicle and subsequent dopamine responses to nicotine doses. Note how the ideal "prodrug" stabilizes dopamine responses throughout the day.

[0050] Figure 5 is a bar graph showing the open field responses to orally administered compounds. Figure 5 shows the time spent in the open field test center in animals given vehicle, varenicline (1.5 mpk and 4.5 mpk), Servarenicline chloride, varenicline - Enacarbil, varenicline - CBT, or varenicline glycinamide. DETAILED DESCRIPTION OF THE INVENTION

[0052] DEFINITIONS

[0053] Unless otherwise defined, all technical terms, symbols, and other technical and scientific terms or terminology used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be construed as indicating a substantial difference from what is commonly understood in the art.

[0054] In this document, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an immutable limitation on the scope of the present disclosure. Thus, the description of a range should be considered to have specifically disclosed all possible sub-ranges as well as individual numerical values within that range. For example, a description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as individual numbers within that range such as 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the range.

[0055] As used in the specification or claims, unless the context clearly indicates otherwise, the singular forms "a", "an", and "the" include plural referents. For example, the term "sample" includes more than one sample, including mixtures thereof.

[0056] The terms "determine", "measure", "evaluate", "assess", "assay", and "analyze" are often used interchangeably herein to refer to forms of measurement and include determining whether an element may be present (e.g., detecting). These terms can include quantitative determinations, qualitative determinations, or both quantitative and qualitative determinations. An assessment can optionally be relative or absolute. "Detect the presence of..." includes determining the amount of something present, as well as determining whether it may be present or absent.

[0057] The terms "subject", "individual", or "patient" are often used interchangeably herein. A "subject" can be a biological entity containing expressed genetic material. The biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa. A subject can be a tissue, cell, and progeny thereof of a biological entity obtained in vivo or cultured in vitro. A subject can be a mammal. The mammal can be a human. A subject can be diagnosed or suspected of being at high risk of a disease. The disease can be endometriosis, tobacco use disorder, nicotine use disorder, or smoking. In some cases, a subject may not necessarily be diagnosed or suspected of being at high risk of a disease.

[0058] The term "in vivo" can be used to describe an event that occurs within a subject.

[0059] The term "ex vivo" can be used to describe an event that occurs outside of a subject. An "ex vivo" assay may not be performed on a subject. Instead, it can be performed on a sample that is separate from the subject. Examples of "ex vivo" assays performed on a sample can be "in vitro" assays.

[0060] The term "in vitro" can be used to describe events that occur in a container used to hold laboratory reagents such that they can be separated from the living biological source organisms from which the materials can be obtained. In vitro assays can encompass cell-based assays in which live or dead cells are employed. In vitro assays can also encompass cell-free assays in which intact cells are not employed.

[0061] As used herein, the term 'about' a number can mean that number plus or minus 10% of that number. The term 'about' a range can mean the range minus 10% of its lowest value and plus 10% of its highest value.

[0062] As used herein, the term "treatment" or "treating" can mean a pharmaceutical or other intervention regimen used to obtain a beneficial or desired result in a recipient. Beneficial or desired results can include, but are not limited to, therapeutic benefits and / or prophylactic benefits. A therapeutic benefit can mean the eradication or alleviation of one or more symptoms of the underlying disorder being treated or the underlying disorder being treated. Moreover, a therapeutic benefit can be achieved by eradicating or alleviating one or more of the physiological symptoms associated with the underlying disorder such that an improvement can be observed in the subject, even though the subject may still be afflicted with the underlying disorder. A prophylactic effect can include delaying, preventing, or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefits, a subject at risk of developing a particular disease or reporting one or more physiological symptoms of a disease can undergo treatment even though a diagnosis of the disease may not have been made.

[0063] As used herein, the terms "unit dose" or "dosage form" can be used interchangeably and can mean a pharmaceutical product in the form in which it is sold, having a specific configuration of active ingredients and a specific mixture of inactive components or excipients, and being dispensed in a specific dose to be delivered. The term "unit dose" can sometimes also encompass a non-reusable package, although the U.S. Food and Drug Administration (FDA) differentiates between unit dose "packaging" or "dispensing". More than one unit dose can mean different pharmaceutical products packaged together or a single pharmaceutical product containing multiple drugs and / or doses. The term "unit dose" can sometimes also mean a granule containing a pharmaceutical composition and any mixtures involved. The type of unit dose can vary with the route of administration used for drug delivery and the substance being delivered. A solid unit dose can be the solid form of a dose of a compound that is a pharmaceutically acceptable drug or intended for administration or consumption.

[0064] As used herein, "dose" can mean the measured amount of a therapeutic agent to be taken at one time.

[0065] As used herein, "pharmaceutically acceptable salts" can refer to drug molecules that can be formed as weak acids or weak bases and chemically made into their salt forms, such as hydrochloride, sodium salt, or sulfate. Pharmaceutical products synthesized as salts can enhance drug solubility, facilitate absorption into the bloodstream, promote therapeutic effects, and increase their effectiveness. Pharmaceutically acceptable salts can also facilitate the development of controlled-release dosage forms, improve drug stability, extend the shelf life, enhance targeted drug delivery, and increase drug effectiveness.

[0066] As used herein, the term "effective amount" or "therapeutically effective amount" of a drug for treating a disease can be an amount that is capable of reducing the severity of the disease, reducing the severity of one or more symptoms associated with the disease or its treatment, or delaying the onset of more severe symptoms or a more severe disease that may occur at a certain frequency after the condition being treated. The "effective amount" can be determined empirically and in a conventional manner according to the stated purpose.

[0067] The term "substantially" or "essentially" can refer to a qualitative condition that exhibits all or nearly all of the range or degree of an interesting characteristic or property. In some cases, substantially can refer to a pain or dopamine response level that differs from the average or median pain or dopamine response level by approximately plus or minus: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%. For example, substantially can refer to: 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% reduced pain or dopamine response. In some cases, substantially can refer to at least about 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% of the total range or degree of an interesting characteristic or property.

[0068] Review

[0069] Diseases or conditions such as tobacco use disorder, nicotine use disorder, smoking, and Parkinson's disease are impairing individuals suffering from these diseases. Because they (e.g., tobacco use disorder and nicotine use disorder) involve drug-seeking or addictive behavior, the molecule or a pharmaceutically acceptable salt thereof can be used to help an individual reduce or stop using any and all forms of tobacco or nicotine, including but not limited to smoking and snuff.

[0070] In some embodiments, provided herein is a pharmaceutically acceptable salt of Formula I:

[0071]

[0072] wherein, independently, X - can be a pharmaceutically acceptable anion, A can be a C1-C10 alkyl or branched alkyl group bearing a hydroxy group, and Z can be hydrogen or a pharmaceutically acceptable cation.

[0073] In any compound or pharmaceutically acceptable salt herein containing one or more alkyl or branched alkyl groups, each alkyl or branched alkyl group can independently be, for example, a methyl group and an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, an isobutyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, or a decyl group.

[0074] In some embodiments, in any salt herein, including the pharmaceutically acceptable salt of Formula I, the anion and / or X - can be an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, and benzenesulfonate. In some embodiments, in the pharmaceutically acceptable salt of a compound of Formula I, Z can be hydrogen (H). In some embodiments, in the pharmaceutically acceptable salt of Formula I, Z can be a pharmaceutically acceptable organic or inorganic cation. In some embodiments, the inorganic cation can be a sodium cation, a lithium cation, or a potassium cation. A magnesium cation (in some cases, when the cation is a magnesium cation or a calcium cation and bears a positive two charge, the inorganic cation associates with two molecules or pharmaceutically acceptable salts herein), a lithium cation, a calcium cation (in some cases, when the calcium cation bears a positive two charge, it associates with two molecules or pharmaceutically acceptable salts herein), or a potassium cation.

[0075] In some embodiments, provided is a pharmaceutically acceptable salt of Formula 1A:

[0076]

[0077] Wherein A is a C1-C10 alkyl or branched alkyl group with a hydroxyl group or a C1-C10 straight or branched alkyl group with a carboxylic acid group or a pharmaceutically acceptable salt thereof.

[0078] Consistent with the above, the pharmaceutically acceptable salt of the compound of formula I can be the pharmaceutically acceptable salt of formula IB:

[0079]

[0080] In some embodiments, in the pharmaceutically acceptable salt of formula I or formula IB, X - can be an anion selected from the group consisting of: chloride, bromide, sulfate, phosphate, acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, and benzenesulfonate. In some embodiments, in the pharmaceutically acceptable salt of formula I, Z can be hydrogen (H). In some embodiments, in the pharmaceutically acceptable salt of formula I, Z can be a pharmaceutically acceptable organic or inorganic cation.

[0081] In some embodiments, the pharmaceutically acceptable salt of formula I can have the structure of formula II:

[0082]

[0083] In some embodiments, the pharmaceutically acceptable salt of formula I can have the structure of formula III:

[0084]

[0085] In some embodiments, there is provided a pharmaceutically acceptable salt of formula IV:

[0086]

[0087] Wherein, independently, X can be a pharmaceutically acceptable anion, Y can be a C1-C10 straight or branched alkyl group with a carboxylic acid group or a pharmaceutically acceptable salt thereof, and Z can be hydrogen or a pharmaceutically acceptable cation.

[0088] Where applicable, any pharmaceutically acceptable salt or compound herein may be in the form of enantiomers, diastereomers, racemic mixtures of enantiomers or mixtures of diastereomers. When any compound or pharmaceutically acceptable salt herein contains one or more stereocenters, each stereocenter may independently be R or S. In some embodiments, any compound or pharmaceutically acceptable salt herein may have an enantiomeric excess or optical purity in the range from about 0% to 100% or about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 79%, 75%, 80%, 85%, 90%, 95% or 100% as determined by the optical rotation of plane-polarized light at the sodium D line. In some embodiments, any compound or pharmaceutically acceptable salt herein may have a diastereomeric excess or diastereomeric purity in the range from about 0% to 100% or about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 79%, 75%, 80%, 85%, 90%, 95% or 100% as determined by the optical rotation of plane-polarized light at the sodium D line.

[0089] In some embodiments, in the pharmaceutically acceptable salts of Formula IV, X - may be an anion selected from the group consisting of chloride, bromide, sulfate, phosphate, acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate and benzenesulfonate. In some embodiments, in the pharmaceutically acceptable salts of Formula IV, Z may be hydrogen (H). In some embodiments, in the pharmaceutically acceptable salts of Formula IV, Z may be a pharmaceutically acceptable organic or inorganic cation.

[0090] In some embodiments, the pharmaceutically acceptable salts of Formula IV may have the structure of Formula V:

[0091]

[0092] In some embodiments, the pharmaceutically acceptable salts of Formula VI may have the structure of Formula VI:

[0093]

[0094] In some embodiments, there is provided a compound of Formula VII or a pharmaceutically acceptable salt thereof:

[0095]

[0096] Each A can independently be a C1-C5 straight-chain or branched alkyl group.

[0097] In some embodiments, in the compound of formula VII or a pharmaceutically acceptable salt thereof, each A can independently be methyl.

[0098] In some embodiments, there is provided a compound of formula VIII or a pharmaceutically acceptable salt thereof:

[0099]

[0100] wherein R 1 and R 2 can independently be hydrogen (H) or a C1-C5 branched or straight-chain alkyl,

[0101] or R 1 and R 2 together with the nitrogen atom to which they are attached can form a 5-, 6- or 7-membered ring, and Z can be hydrogen (H) or a pharmaceutically acceptable cation.

[0102] In some embodiments, in the compound of formula VIII or a pharmaceutically acceptable salt thereof, R 1 and R 2 and Z can be hydrogen.

[0103] In some embodiments, there is provided a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0104]

[0105] wherein X is OR 1 、halogen, fluorine, chlorine, bromine, iodine or NR 2 R 3 wherein R 1 is hydrogen or an organic or inorganic cation or a C1-C10 straight-chain or branched alkyl, and wherein R 2 and R 3 are each independently a C1-C10 straight-chain or branched alkyl, or R 2 and R 3 together with the nitrogen atom to which they are attached form a 5- to 7-membered ring.

[0106] In some embodiments, there is provided a pharmaceutical composition comprising a compound of formula I to formula VIII or a pharmaceutically acceptable salt of formula I to formula VIII and a pharmaceutically acceptable excipient, diluent, carrier or any combination thereof.

[0107] In some embodiments, a pharmaceutically acceptable carrier, diluent, or excipient may include a pharmaceutically acceptable excipient. As used herein, "excipient" may refer to a substance formulated with the active ingredient of a drug, including substances for long-term stability, filling solid formulations containing a small amount of a potent active ingredient, and / or for the purpose of conferring therapeutic enhancement to the active ingredient in the final dosage form. Excipients may facilitate drug absorption, reduce viscosity, or enhance solubility. Excipients may also facilitate the handling of the active ingredient, improve in vitro stability, and / or extend the shelf life of the drug product. The choice of excipient may vary with the route of administration used for drug delivery, the unit dose, and the composition containing the active ingredient.

[0108] In some embodiments, pharmaceutically acceptable excipients may include anhydrous calcium phosphate, calcium phosphate dihydrate, hydroxypropyl methylcellulose, sodium croscarmellose, sodium croscarmellose free of GMO, carbomer, magnesium aluminum metasilicate, mannitol, polyvinylpyrrolidone (PVP), crospovidone, sorbitol, polydimethylsiloxane, sodium stearyl fumarate, sodium starch glycolate, hydroxypropyl cellulose, natural corn starch, modified corn starch, carrageenan, alginate, silicon dioxide, microcrystalline cellulose, sodium carboxymethylcellulose, carboxymethylcellulose (CMC), sodium carboxymethylcellulose (Na CMC), natural gums, maltitol, glucose syrup, silicone, fatty alcohols, alcohols, carbohydrates, petrolatum derivatives, butters, waxes, DMSO coagulant, esters, fatty acids, oil-in-water (O / W) emulsifiers, water-in-oil (W / O) emulsifiers, silica, fumed silica, polysorbate, isopropyl myristate, cellulose derivatives, xanthan gum, propylene glycol, noveon AA-1 polycarbophil, dimethyl isosorbate, silicone elastomer 1100, silicone elastomer 1148P, preservatives, flavorings, colorants, functional coatings, aesthetic coatings, pharmaceutically acceptable salts of any of these, or any combination thereof.

[0109] In some embodiments, pharmaceutically acceptable excipients may include gum arabic, acesulfame potassium, acetic acid, glacial acetic acid, acetone, tributyl acetyl citrate, triethyl acetyl citrate, agar, albumin, alcohol, alginic acid, aliphatic polyesters, alitame, almond oil, alpha-tocopherol, aluminum hydroxide adjuvant, aluminum oxide, aluminum phosphate adjuvant, aluminum stearate, ammonium solution, ammonium alginate, ascorbic acid, ascorbyl palmitate, aspartame, attapulgite, bentonite, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, benzyl benzoate, boric acid, bronopol, butylated hydroxyanisole, butylated hydroxytoluene, butyl paraben, calcium alginate, calcium carbonate, calcium phosphate, dibasic anhydrous, calcium phosphate, dibasic dihydrate, calcium phosphate, tribasic, calcium stearate, calcium sulfate, canola oil, carbomer, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carrageenan, castor oil, hydrogenated castor oil, cellulose (e.g., microcrystalline cellulose, powdered cellulose, siliconized microcrystalline cellulose, cellulose acetate, cellulose acetate phthalate), carob gum, cetearyl alcohol, cetrimonium bromide, cetyl alcohol, cetylpyridinium chloride, chitosan, chlorhexidine, chlorobutanol, chlorocresol, chlorodifluoroethane, chlorofluorocarbon, chloroxylenol, cholesterol, citric acid monohydrate, colloidal silicon dioxide, coloring agents, copovidone, corn oil, cottonseed oil, cresol, croscarmellose sodium, crospovidone, cyclodextrin, cyclomethicone, denatonium benzoate, dextran, dextrin, dextrose, dibutyl phthalate, dibutyl sebacate, diethanolamine, diethyl phthalate, difluoroethane, dimethicone, dimethyl ether, dimethyl phthalate, dimethyl sulfoxide, dimethylacetamide, disodium edetate, sodium docusate, edetic acid, erythorbic acid, erythritol, ethyl acetate, ethyl lactate, ethyl maltol, ethyl oleate, ethyl vanillin, ethylcellulose, ethylene glycol palmitostearate, ethylene vinyl acetate, ethyl paraben, fructose, fumaric acid, gelatin, glucose, glycerin, glyceryl behenate, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, glycofurol, guar gum, lithium montmorillonite, heptafluoropropane, hexetidine, hydrocarbons, hydrochloric acid, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, honey, imidazolidinyl urea, inulin, iron oxide, isomalt, isopropyl alcohol, isopropyl myristate, isopropyl palmitate, kaolin, lactic acid, lactitol, lactose anhydrous, lactose monohydrate, spray-dried lactose,Lanolin, lanolin alcohol, lanolin hydrous, lauric acid, lecithin, leucine, linoleic acid, polyethylene glycol hydroxystearate, magnesium aluminum silicate, magnesium carbonate, magnesium oxide, magnesium silicate, magnesium stearate, magnesium trisilicate, malic acid, maltitol, maltitol solution, maltodextrin, maltol, maltose, mannitol, medium-chain triglycerides, meglumine, menthol, methylcellulose, methylparaben, mineral oil, light mineral oil, monoethanolamine, monosodium glutamate, monothioglycerol, myristic acid, neohesperidin dihydrochalcone, nitrogen, nitrous oxide, octyldodecanol, oleic acid, oleyl alcohol, olive oil, palmitic acid, paraffin, peanut oil, pectin, petrolatum, phenol, phenoxyethanol, phenethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, phosphoric acid, potassium polacrylate, poloxamer, polycarbophil, polydextrose, polyethylene glycol, polyethylene oxide, polymethacrylate, poly(methyl vinyl ether / maleic anhydride), polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, polyvinyl acetate phthalate, polyvinyl alcohol, potassium alginate, potassium benzoate, potassium bicarbonate, potassium chloride, potassium citrate, potassium hydroxide, potassium metabisulfite, potassium sorbate, povidone, propionic acid, propyl gallate, propylene carbonate, propylene glycol, propylene glycol alginate, propylparaben, 2-pyrrolidone, raffinose, saccharin, sodium saccharin, soapstone, sesame oil, shellac, simethicone, sodium acetate, sodium alginate, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium borate, sodium chloride, sodium citrate dihydrate, sodium cyclamate, sodium hyaluronate, sodium hydroxide, sodium lactate, sodium lauryl sulfate, sodium metabisulfite, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium propionate, sodium starch glycolate, sodium stearoyl fumarate, sodium sulfite, sorbic acid, sorbitan esters (sorbitan fatty acid esters), sorbitol, soybean oil, starch, starch (e.g., pregelatinized, sterilizable corn starch), stearic acid, stearyl alcohol, sucralose, sucrose, sugar, compressible sugar, confectionery, sugar balls, sulfobutyl ether β-cyclodextrin, sulfuric acid, sunflower oil, suppository base, stearin, talc, tartaric acid, tetrafluoroethane, thaumatin, thimerosal, thymol, titanium dioxide, tragacanth, trehalose, triacetin, tributyl citrate, triethanolamine, triethyl citrate, vanillin, hydrogenated vegetable oil, water, wax, anionic emulsifier, wax (e.g., carnauba wax, cetyl ester, microcrystalline, nonionic emulsifier, white wax, yellow wax), xanthan gum, xylitol, zein, zinc acetate, zinc stearate or any combination thereof.

[0110] In some embodiments, pharmaceutically acceptable excipients can include carbohydrates, alginates, povidone, carbomers, flavoring agents, natural gums, silicones, alcohols, butters, waxes, fatty acids, preservatives, pharmaceutically acceptable salts of any of these, or any combination thereof. In some embodiments, pharmaceutically acceptable excipients can include carbohydrates. In some embodiments, carbohydrates can include lactose, microcrystalline cellulose, cellulose, mannitol, sorbitol, starch, starch glycolate, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, cyclodextrin, maltodextrin, croscarmellose sodium, corn starch, carrageenan, maltitol, glucose, pharmaceutically acceptable salts of any of these, or any combination thereof.

[0111] Water as a carrier

[0112] In some cases, pharmaceutically acceptable carriers or diluents can include water. In some embodiments, the water can be sterile. In some embodiments, the water can include buffers, carbohydrates, salts, pH regulators, or any combination thereof. Monosaccharides such as mannitol, sucrose, glucose, trehalose can be added in an amount from 1 mg / ml to 50 mg / ml to inhibit peptide or polypeptide aggregation. Citrate can be used as a buffer. In some cases, sodium chloride and phosphate may or may not be employed. Larger polysaccharides can also be used to enhance stability.

[0113] A carrier can refer to a reagent, cell, compound, material, composition, dosage form, or any combination thereof that is compatible with a therapeutically administrable agent. In some cases, the carrier can be suitable for use in contact with the tissues of a subject. In some cases, the carrier can be non-toxic, non-irritating, free of allergic response, or any combination thereof. Carriers that can be suitable for use can include liquids, solid materials (e.g., pills or suppositories), or any combination thereof. In some cases, carriers can be designed to resist degradation in the body (non-biodegradable), or they can be designed to degrade in the body (biodegradable). Biodegradable materials can also be bioresorbable or bioabsorbable. In some cases, biodegradable materials can degrade and be eliminated from the body by being converted into other materials or by breaking down and being eliminated through natural pathways.

[0114] Representative dosage forms

[0115] In some embodiments, the composition or pharmaceutical composition can be in the form of: capsules; tablets; gummies; oils; liquids; inhalation dosage forms, which can be powders or liquids delivered as aerosols; tinctures; lotions; creams; balms; candies; chocolates; foods; beverages; suppositories; injectable liquids, which can be, for example, intravenous liquids, intramuscular liquids, or subcutaneous liquids; syrups; or any combination thereof.

[0116] In some embodiments, the pharmaceutical composition can be in unit dosage form.

[0117] In some embodiments, a method of treating or preventing a disease or condition in a subject, which can be a subject in need thereof, can be a mammal, can be a human subject, can be a human subject in need thereof, the method comprising administering to the human subject a compound of Formula I to Formula VIII or a pharmaceutically acceptable salt or pharmaceutical composition thereof in an amount sufficient to treat the disease or condition. In some embodiments, the disease or condition can be tobacco use disorder, nicotine use disorder, smoking, Parkinson's disease, or any combination thereof. In some embodiments, the disease or condition includes tobacco use disorder.

[0118] Dosing schedule and amount

[0119] In some embodiments, the administration can be once, twice, or three times a day; or once every other day; or once every three days. In some embodiments, the administration can be carried out for a period of one day, one week, one month, 6 months, one year, two years, three years, four years, five years, for life, or as needed. In some embodiments, the human or subject or mammal can be male or female. In some embodiments, the human or subject or mammal can be 18 years of age or older. In some embodiments, the administration can be oral administration, inhalation administration, intranasal administration, subcutaneous administration, intramuscular administration, or intravenous administration. In some embodiments, the compound or pharmaceutically acceptable salt or compound of Formula I to Formula VIII can be administered in a dosage amount in the range of from about 1 mg to about 20 mg, or about 1 mg to about 15 mg, or about 1 mg to about 10 mg, or about 1 mg to about 5 mg, or about 1 mg to about 3 mg.

[0120] In some cases, the amount of the compound or a pharmaceutically acceptable salt thereof may be administered in an amount ranging from about 0.0001 mg / kg of the subject's body weight to about 1000 g / kg or mg / kg of the subject's or the subject in need thereof's body weight; the dose may be, for example, in terms of mg of the pharmaceutically acceptable salt or compound or a derivative thereof per kg of the subject's body weight, and may be about: 0.0001, 0.001, 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 g / kg or mg / kg of the subject's body weight.

[0121] In some cases, the amount of the compound or a pharmaceutically acceptable salt thereof that may be administered to the subject or the subject in need thereof may range from 0.00001 mg to 1000 g; the dose may be, for example, about: 0.0001, 0.001, 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 g or mg.

[0122] Route of administration

[0123] In some embodiments, the pharmaceutical composition or the compound or a pharmaceutically acceptable salt thereof may be administered to the subject by: oral route, injection route, sublingual route, buccal route, rectal route, vaginal route, ocular route, otic route, nasal route, intranasal route, inhalation route, cutaneous route, subcutaneous route, intramuscular route, intravenous route, transdermal route or any combination thereof.

[0124] In some embodiments, the pharmaceutical composition or the compound or a pharmaceutically acceptable salt thereof may be formulated for oral administration. In some embodiments, the pharmaceutical composition may be in the form of a pill or a liquid. In some embodiments, the second therapy may be administered simultaneously or sequentially with the pharmaceutical composition. In some embodiments, the second therapy is administered as part of the pharmaceutical composition. In some embodiments, the second therapy is administered separately from the pharmaceutical composition.

[0125] In some embodiments, a kit is provided that comprises a compound or a pharmaceutically acceptable salt of Formula I to Formula VIII, or a pharmaceutical composition comprising one or more of these, and a container.

[0126] In some embodiments, a method of preparing a kit is provided, the method comprising placing a compound of Formula I to Formula VIII or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising these in a container.

[0127] In some embodiments, methods of preparing a compound of Formula I to Formula VIII or a pharmaceutically acceptable salt thereof, and also intermediate compounds and salts thereof useful for preparing these are provided.

[0128] In some embodiments, when compared to administering a substantially similar amount of varenicline or a pharmaceutically acceptable salt thereof via the same route of administration, a compound of Formula I to Formula VIII or a pharmaceutically acceptable salt thereof can have one or more unexpectedly superior properties, including unexpectedly superior: release profile, peak plasma concentration (Cmax), area under the curve (AUC) at 8 hours, 16 hours, or 24 hours or infinity, or half-life. Examples

[0129] The following examples are included for illustrative purposes only and are not intended to limit the scope of the present disclosure.

[0130] Example 1

[0131]

[0132] Synthesis of Nicotinoyl-Asp(OtBu)-OtBu: 2; To H-Asp(OtBu)-OtBu.HCl (1.0 equivalent) in dichloromethane (DCM) was added Et 3 N (2.0 equivalents). Nicotinoyl chloride hydrochloride (2.0 equivalents) was added in portions (4 times, within 20 min) in an ice bath. After the addition, the mixture was stirred at below 5 °C for 1 h. Water (30 mL) was added to quench the reaction, followed by DCM. The DCM layer was further washed with 5% NaHCO 3 and brine, and dried over Na 2 SO 4 The solvent was evaporated and the residue was purified by silica gel column chromatography (MeOH / DCM).

[0133] Varenicline-N-CO 2 CH 2-Cl,3 Synthesis; Varenicline (1.0 equivalent) was purified and initially synthesized in DCM and cooled in an ice bath. 4-Dimethylaminopyridine (DMAP) (4.0 equivalents) was added and the resulting mixture was stirred for 10 min. Chloroformyl chloride (2.5 equivalents) in DCM was added slowly. The ice bath was removed and the reaction was stirred at room temperature for 5 h. Ethyl acetate was added, followed by water (20 mL) to quench the reaction. The ethyl acetate layer was separated and washed with IN HCl and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography.

[0134] Varenicline-N-CO 2 CH 2 -Nicotinoyl-Asp(OtBu)-OtBu,5 Synthesis; The chloromethyl carbamate of varenicline (1.5 equivalents) in acetonitrile and nicotinoyl-Asp(OtBu)-OtBu,2 (1.0 equivalent) were heated at 70 °C for 24 h. The solvent was evaporated. The residue was purified by silica gel column chromatography.

[0135] 6-Chloride Synthesis; Varenicline-N-CO 2 CH 2 -Nicotinoyl-Asp(OtBu)-OtBu chloride was stirred for 3 h. The solvent was evaporated. The residue was co-evaporated with DCM, then dissolved in DCM (4 mL) and TBME (25 mL) was added. The resulting solid was collected, washed with TBME (4 × 2 mL) and dried in vacuo. The solid 6-chloride was obtained in yield.

[0136] Example 2

[0137]

[0138] Synthesis of Servarenicline Chloride

[0139] Synthesis of Nicotinoyl-Ser(tBu)-OtBu; Et 3 N (2.0 equivalents) was added to H-SER(tBu)-OtBu (1.0 equivalent) in DCM. Nicotinoyl chloride hydrochloride (2.0 equivalents) was added in portions (4 times, within 20 min) in an ice bath. After the addition, the mixture was stirred at below 5 °C for 1 h. Water (30 mL) was added to quench the reaction, followed by DCM. The DCM layer was further washed with 5% NaHCO 3 and brine, and dried over Na 2 SO 4 The solvent was evaporated and the residue was purified by silica gel column chromatography (MeOH / DCM).

[0140] Varenicline - N - CO 2 CH 2 -Cl, Synthesis of 7; Varenicline (1.0 equivalent) was purified and initially synthesized in DCM and cooled in an ice bath. 4 - Dimethylaminopyridine (DMAP) (4.0 equivalents) was added and the resulting mixture was stirred for 10 min. Chloroformyl chloride (2.5 equivalents) in DCM was added slowly. The ice bath was removed and the reaction was stirred at room temperature for 5 h. Ethyl acetate was added, followed by water (20 mL) to quench the reaction. The ethyl acetate layer was separated and washed with IN HCl and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography.

[0141] Varenicline - N - CO 2 CH 2 -Nicotinoyl - Ser(tBu)-OtBu, Synthesis of 8; The chloromethyl carbamate of varenicline (1.5 equivalents) in acetonitrile and nicotinoyl - Ser(tBu)-OtBu (1.0 equivalent) were heated at 70 °C for 24 h. The solvent was evaporated. The residue was purified by silica gel column chromatography.

[0142] Synthesis of Servarenicline chloride; Varenicline - N - CO 2 CH 2 -Nicotinoyl - Ser(tBu)-OtBu chloride was stirred for 3 h. The solvent was evaporated. The residue was co - evaporated with DCM, then dissolved in DCM (4 mL) and TBME (25 mL) was added. The resulting solid was collected, washed with TBME (4×2 mL) and dried in vacuo. The solid was obtained in yield.

[0143] Example 3 Synthesis of Varenicline - Enacarbil

[0144]

[0145] Synthesis of 1 - (Isobutyryloxy)ethyl 4 - nitrophenyl carbonate; Zinc oxide (1 g, 12 mmol) was added to a solution of toluene (40 ml) and isobutyric acid (10 ml) and refluxed for 1 h to remove the water generated in the process through a Dean - Stark apparatus. After the temperature was lowered to 60 °C, 1 - chloroethyl 4 - nitrophenyl carbonate (1 g, 4 mmol) and NaI (1 g, 6.4 mmol) were added to the reaction mixture. The mixture was stirred at 60 °C for 24 h. The next day, the reaction mixture was evaporated to residue, then the residue was dissolved in EtOAc, and the organic solution was washed with saturated NaHCO3 The solution was washed and then washed with brine. The organic layer was separated and dried over MgSO 4 4-Nitrophenyl 1-(isobutyryloxy)ethyl carbonate was obtained by evaporation of the dried organic layer.

[0146] For varenicline enacarbil, 9; To varenicline (1.0 eq., 5.75 g, 0.03 mol) in toluene (50 ml) was added chlorotrimethylsilane (2.0 eq.) and tributylamine (2.0 eq.), and then it was stirred at room temperature to obtain a clear solution. Then 4-nitrophenyl 1-(isobutyryloxy)ethyl carbonate (1.0 eq.) in toluene (20 ml) was added to the reaction mixture, and it was stirred at room temperature for 24 h. After completion of the reaction, the reaction mixture was washed with 1N HCl (150 ml) and water (2 × 100 ml). The organic layer was dried over MgSO 4 dried, evaporated, and purified by silica gel column chromatography to obtain the desired product.

[0147] Example 4 Synthesis of Varenicline-CBT

[0148]

[0149] Synthesis of 4-nitrophenyl Boc-Tyr-OMe; A mixture of Boc-Tyr-OMe, 4-nitrophenyl chloroformate and DIEA in DCM was stirred at room temperature for 18 h. After completion of the reaction, the organic layer was washed with water, dried over MgSO 4 dried and evaporated. The crude product was used as such in the following step.

[0150] Synthesis of varenicline-CBT, 10; A solution of varenicline in DMF was added to a mixture of 4-nitrophenyl Boc-Tyr-OMe and diisopropylethylamine (DIEA) in N,N-dimethylformamide (DMF), and then it was stirred at room temperature for 3 h. After completion of the reaction, EtOAc was added to the reaction mixture, and then it was washed with 1N HCl (150 ml) and water (2 × 100 ml). The organic layer was dried over MgSO 4 dried, evaporated, and purified by silica gel column chromatography to obtain the desired product. The purified product was stirred in 6N HCl / dioxane at 40 °C for 24 h. The solvent was evaporated. The residue was co-evaporated with DCM, then dissolved in DCM (4 mL) and TBME (25 mL) was added. The resulting solid was collected, washed with TBME (4 × 2 mL) and dried in vacuo. A solid was obtained

[0151] Example 5

[0152] Compounds of Formulas I through VIII or pharmaceutically acceptable salts thereof are formulated into a dosage form alone at a therapeutically effective amount and administered to an individual subject alone. The compound or pharmaceutically acceptable salt will optionally exhibit an extended release profile and will show plasma concentrations sufficient to be therapeutically effective.

[0153] Example 6

[0154]

[0155] Synthesis of Varenicline Glycinamide

[0156] Varenicline Chloromethyl Carbamate; A solution of chloroformate chloride in DCM (dichloromethane) was added to a mixture of varenicline, 4-DMAP, and DCM at ice bath temperature, allowed to warm up, and stirred at room temperature for 5 hours. Varenicline-Glycinamide; A mixture of ammonium hydroxide and varenicline chloromethyl carbamate was kept at room temperature for 3 hours.

[0157] Example 7

[0158] The ability of varenicline to reduce nicotine use comes from its ability to block nicotine-induced dopamine signaling in the striatum. Real-time sensing of dopamine levels in awake and behaviorally normal mice was measured using a fluorescent dopamine sensor (GRAB-DA) and fluorescence measurement of this sensor (fiber photometry). Figure 1A shows the experimental placement of the fiber in the striatum and an exemplary fluorescence image generated during the experiment. Figure 1B shows exemplary fluorescence response curves before and after intraperitoneal administration of nicotine.

[0159] It was found that the varenicline derivatives designed herein have the same or higher potency as varenicline in reducing nicotine-induced dopamine release (Figure 2A). These data indicate that the response to nicotine is the same 2 hours later regardless of the dose of varenicline. When directly compared to varenicline, Servarenicline Chloride and Varenicline Enacarbil (Figure 2B - Figure 2C) show better potency, but all derivatives act at least as well as varenicline.

[0160] Varenicline increases striatal dopamine levels after administration. This increase is thought to potentially reduce nicotine craving but may also be related to the unwanted side effects of varenicline. It was found that the varenicline-based molecules described herein have different abilities to induce dopamine after oral administration (Figure 3A - Figure 3B). Some molecules (e.g., Servarenicline Chloride, Varenicline-CBT, or Varenicline Glycinamide) do not cause dopamine release, while other molecules (Varenicline Enacarbil) mimic the action of varenicline.

[0161] This set of compounds offers two new advantages. First, a group of molecules that mimic the response of varenicline but are engineered to last longer. Second, molecules that provide a smooth dopamine response, preventing the dopamine surges typically seen with the partial agonist function of varenicline.

[0162] Varenicline also affects the locomotor activity and anxiety-like behavior of mice. In the open field assay ( Figure 5 ), animals exhibit anxiety-like behavior when avoiding the open area (a significant decrease in the time spent in the middle area). This effect was not observed for servarenicline chloride, varenicline-CBT, or varenicline glycinamide, indicating that these varenicline derivatives may have different side effect profiles.

[0163] Although the preferred embodiments have been shown and described herein, such embodiments are provided by way of example only. Many variations, changes, and alternatives will now occur to those skilled in the art without departing from the disclosure herein. It should be understood that various alternatives to the embodiments described herein may be employed.

Claims

1. A pharmaceutically acceptable salt of formula I: Wherein, Independently, X - is a pharmaceutically acceptable anion, A is a C1-C10 alkyl or branched alkyl group bearing a hydroxy group, and Z is hydrogen or a pharmaceutically acceptable cation.

2. The pharmaceutically acceptable salt of formula I according to claim 1, wherein X - is a pharmaceutically acceptable anion selected from the group consisting of: chloride, bromide, sulfate, phosphate, acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, and benzenesulfonate.

3. The pharmaceutically acceptable salt of formula I according to claim 1 or claim 2, wherein Z is H.

4. The pharmaceutically acceptable salt of formula I according to any one of claims 1 - 3, wherein Z is a pharmaceutically acceptable organic or inorganic cation.

5. The pharmaceutically acceptable salt of formula I according to claim 1, having the structure of formula II:

6. The pharmaceutically acceptable salt of formula I according to claim 1, having the structure of formula III:

7. A pharmaceutically acceptable salt of a compound of formula IV: Wherein, Independently, X - is a pharmaceutically acceptable anion, Y is a C1-C10 straight-chain or branched alkyl group with a carboxylic acid group or a pharmaceutically acceptable salt thereof, and Z is hydrogen or a pharmaceutically acceptable cation.

8. The pharmaceutically acceptable salt of formula IV according to claim 7, wherein X - is a pharmaceutically acceptable anion selected from the group consisting of chloride, bromide, sulfate, phosphate, acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, and benzenesulfonate.

9. The pharmaceutically acceptable salt of formula IV according to claim 7 or claim 8, wherein Z is H.

10. The pharmaceutically acceptable salt of formula IV according to any one of claims 7 - 9, wherein Z is a pharmaceutically acceptable organic or inorganic cation.

11. The pharmaceutically acceptable salt of formula IV according to claim 7, having the structure of formula V:

12. The pharmaceutically acceptable salt of formula IV according to claim 7, having the structure of formula VI:

13. A pharmaceutically acceptable salt of formula IA: Wherein A is a C1 - C10 alkyl or branched alkyl group with a hydroxyl group or a C1 - C10 straight or branched alkyl group with a carboxylic acid group or a pharmaceutically acceptable salt thereof.

14. A compound of formula VII or a pharmaceutically acceptable salt thereof: Wherein each A is independently a C1 - C5 straight or branched alkyl group.

15. The compound of formula VII or a pharmaceutically acceptable salt thereof according to claim 14, wherein each A is independently a methyl group.

16. A compound of formula VIII or a pharmaceutically acceptable salt thereof: wherein R 1 and R 2 are independently hydrogen or a C1-C5 branched or straight-chain alkyl group, or R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered ring, and Z is hydrogen or a pharmaceutically acceptable cation.

17. A compound of formula VIII or a pharmaceutically acceptable salt thereof according to claim 16, wherein R 1 and R 2 are hydrogen and wherein Z is hydrogen.

18. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt according to any one of claims 1 - 17 and a pharmaceutically acceptable excipient, diluent or carrier.

19. The pharmaceutical composition according to claim 18, wherein the pharmaceutical composition is in unit dose form.

20. A method of treating or preventing a disease or condition in a human subject in need thereof, comprising administering to the human subject in an amount sufficient to treat the disease or condition the compound or pharmaceutically acceptable salt according to any one of claims 1 - 17 or the pharmaceutical composition according to claim 18 or claim 19.

21. The method according to claim 20, wherein the disease or condition includes smoking, tobacco use disorder or both.

22. The method according to claim 21, wherein the disease or condition includes tobacco use disorder.

23. The method according to any one of claims 20 - 22, wherein the administration is once, twice or three times a day; or once every other day; or once every three days.

24. The method according to any one of claims 20 - 23, wherein the administration is oral administration or inhalation administration or nasal administration.

25. The method according to any one of claims 20 - 24, wherein the compound or a pharmaceutically acceptable salt thereof is administered in a dosage amount in the range from about 1 mg to about 20 mg, or about 1 mg to about 15 mg, or about 1 mg to about 10 mg, or about 1 mg to about 5 mg, or about 1 mg to about 3 mg.

26. A kit comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 17, or the pharmaceutical composition according to any one of claims 18 - 19, and a container.

27. A method for preparing the kit according to claim 26, comprising placing the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 17 or the pharmaceutical composition according to any one of claims 18 - 19 in the container.

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