PROPIOPHENONE DERIVATIVES

RELATED APPLICATIONS

[1] This application claims the benefit of U.S. Provisional Application No. 61/066,615, filed February 21, 2008, the entire contents of which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

[2] Bupropion also known as (±)-2-(tert-butylamino)l-(3-chlorophenyl)propan- 1-one hydrochloride, Wellbutrin®, and Zyban® is a weak inhibitor of the neuronal uptake of norepinephrine and dopamine. It does not inhibit monoamine oxidase or the re-uptake of serotonin.

[3] Bupropion is currently approved for the treatment of depression, major depression, for the cessation of smoking, and for prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder. It is currently in clinical trials for the treatment of female orgasmic disorders, Crohn's disease, treatment of marijuana dependence, treatment of methamphetamine dependence, seasonal affective disorder, depressive disorders, cocaine-related disorders, and treatment of pathological gambling. Bupropion is also being investigated as an agent for causing weight loss and for the treatment of attention deficit-hyperactivity (ADHD).

[4] Bupropion is extensively metabolized and several of its metabolites are active. One such metabolite is radafaxine. Radafaxine is in phase I clinical trials for the treatment of obesity, fibromyalgia and neuropathic pain. It has also been studied for the treatment of bipolar disorder and was in phase II clinical trials for the treatment of depression. Radafaxine is also being investigated as a treatment for obesity.

[5] Other active metabolites of bupropion are hydroxybupropion, formed by hydroxylation of the t-butyl moiety; and ery//zro-hydrobupropion and threo-

hydrobupropion, diastereomeric forms of the metabolite formed by reduction of the carbonyl moiety to a hydroxyl.

[6] Bupropion is associated with seizures in approximately 0.4% (4/1,000) of patients treated at doses up to 450 mg/day. Adverse events commonly encountered in patients treated with bupropion are agitation, dry mouth, insomnia, headache/migraine, nausea/vomiting, constipation, and tremor. It is unknown what, if any, contribution the metabolites of bupropion make to the adverse event profile. Because cytochrome P450IIB6 (CYP2B6) is the principle isoenzyme responsible for formation of the metabolite, hydroxybupropion, there is potential for drug-drug interactions, particularly with drugs metabolized by the CYP2B6 isoenzyme. (See the FDA label for Wellbutrin at fda.gov/cder).

[7] Despite the beneficial activities of bupropion, there is a continuing need for new compounds to treat the aforementioned diseases and conditions.

SUMMARY OF THE INVENTION

[8] This invention relates to novel compounds that are propiophenones derivatives and pharmaceutically acceptable salts thereof. More specifically, this invention relates to novel propiophenones derivatives that are derivatives of bupropion. This invention also provides compositions comprising one or more compounds of this invention and a carrier and use of the disclosed compounds and compositions in methods of treating diseases and conditions that are beneficially treated by administering a norepinephrine dopamine reuptake inhibitor, such as bupropion.

DETAILED DESCRIPTION OF THE INVENTION

[9] The terms "ameliorate" and "treat" are used interchangeably and include both therapeutic treatment and prophylactic treatment (reducing the likelihood of development). Both terms mean decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.

[10] "Disease" means any condition or disorder that damages or interferes with

the normal function of a cell, tissue, or organ.

[11] It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. Thus, a preparation of bupropion will inherently contain small amounts of deuterated isotopologues. The concentration of naturally abundant stable hydrogen and carbon isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of compounds of this invention. See, for instance, Wada, E et al., Seikagaku, 1994, 66: 15; Gannes, LZ et al., Comp Biochem Physiol MoI Integr Physiol, 1998, 119: 725. [12] In the compounds of the invention, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom unless otherwise stated. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. Also unless otherwise stated, when a position is designated specifically as "D" or "deuterium", the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium).

[13] The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. [14] In other embodiments, a compound of this invention has an isotopic enrichment factor for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[15] The term "isotopologue" refers to a species that differs from a specific compound of this invention only in the isotopic composition of its molecules and ions. Isotopologues can differ in the level of isotopic enrichment at one or more

- A -

positions and/or in the position(s) of isotopic enrichment. [16] The term "compound," when referring to a compound of this invention, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this invention will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound. However, as set forth above the relative amount of such isotopologues in toto will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[17] The invention also provides salts, solvates or hydrates of the compounds of the invention.

[18] A salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt. [19] The term "pharmaceutically acceptable," as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient. [20] Acids commonly employed to form pharmaceutically acceptable salts

include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 - sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.

[21] As used herein, the term "hydrate" means a compound which further includes a stoichiometric or non-stoichiometric amount of water bound by non- covalent intermolecular forces.

[22] As used herein, the term "solvate" means a compound which further includes a stoichiometric or non-stoichiometric amount of solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces.

[23] The compounds of the present invention (e.g., compounds of Formula I, Ha, lib and III) contain one or more asymmetric carbon atoms, for example, as the result of deuterium substitution or otherwise. As such, compounds of this invention can exist as either individual enantiomers, or mixtures of multiple enantiomers.

Accordingly, a compound of the present invention will include both racemic mixtures, and also individual specific stereoisomers that are substantially free from another possible stereoisomer. The term "substantially free of other stereoisomers" as used herein means less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers and most preferably less than 2% of other stereoisomers, or less than "X"% of other stereoisomers (wherein X is a number between 0 and 100, inclusive) are present. Methods of obtaining or synthesizing an individual enantiomer for a given compound are well known in the art and may be applied as practicable to final compounds or to starting material or intermediates.

[24] The term "stable compounds," as used herein, refers to compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents). [25] "D" refers to deuterium.

[26] "Stereoisomer" refers to both enantiomers and diastereomers. [27] "Tert", " ^l ", and "t-" each refer to tertiary. [28] "US" refers to the United States of America. [29] "FDA" refers to Food and Drug Administration. [30] Throughout this specification, a variable may be referred to generally (e.g., "each R") or may be referred to specifically (e.g., R ¹ , R ² , R ³ , etc.). Unless otherwise indicated, when a variable is referred to generally, it is meant to include all specific embodiments of that particular variable.

THERAPEUTIC COMPOUNDS

[31] The present invention provides a compound of Formula I:

or a salt thereof, wherein:

R ¹ is selected from CH ₃ , CH ₂ D, CHD ₂ and CD ₃ ;

R ² is t-butyl, wherein 1 to 9 hydrogen atoms are optionally replaced with deuterium; and

"*" represents a stereocenter. [32] In certain embodiments of a compound of Formula I: a) R ¹ is selected from CH ₃ and CD ₃ ; b) R ² is selected from -C(CH ₃ ) ₃ and -C(CD ₃ ) ₃ ; or c) The stereochemistry at * is not racemic

[33] In a more specific embodiment, a compound of Formula I has the features set forth in at least two of a) - c) (e.g, a and b, a and c, and b and c). [34] In yet another embodiment, the compound of Formula I is selected from any one of:

Compound 103, or a pharmaceutically acceptable salt of any of the foregoing, wherein the stereochemistry at each * in any of compounds 100-103 is not racemic.

[35] In still another embodiment, the invention provides a compound of Formula I

selected from: Compound 101a,

Compound 102a, and

Compound 102b, or a pharmaceutically acceptable salt of any foregoing. [36] In another embodiment, the invention provides a compound of

Formula Ha:

, or a pharmaceutically acceptable salt of either of the forgoing, wherein: each R is independently selected from CH ₃ , CH ₂ D, CHD ₂ and CD ₃ ; and each Y is independently selected from hydrogen and deuterium.

[37] In certain embodiments of a compound of Formula Ha or lib: a) each R is independently selected from CH ₃ and CD ₃ ; b) R ³ and R ⁴ are the same; or c) each Y is the same.

[38] In a more specific embodiment, a compound of Formula I has the features set forth in at least two of a) - c) (e.g., a and b, b and c, and a and c).

[39] In a more specific embodiment of Formula Ha or Hb, R ³ and R ⁴ are CH ₃ ; and each Y is hydrogen. In one aspect of this embodiment, R ¹ is selected from CH ₃ and

CD ₃ ; R ³ and R ⁴ are CH ₃ ; and each Y is hydrogen.

[40] In another specific embodiment of Formula Ha or Hb, R ³ and R ⁴ are CD ₃ and each Y is deuterium. In one aspect of this embodiment, R ¹ is selected from CH ₃ and

CD ₃ ; R ³ and R ⁴ are CD ₃ and each Y is deuterium.

[41] In yet another embodiment, the compound of Formula Ha is selected from any one of:

Compound 104;

Compound 105;

Compound 106; and

Compound 107, or a pharmaceutically acceptable salt of any of the foregoing.

[42] In still another embodiment, the compound of Formula lib is selected from any one of:

Compound 111 , or a pharmaceutically acceptable salt of any of the foregoing.

[43] In another embodiment, the invention provides a compound of Formula III:

or a salt thereof, wherein: R ¹ is selected from CH ₃ , CH ₂ D, CHD ₂ and CD ₃ ;

R ² is t-butyl, wherein 1 to 9 hydrogen atoms are optionally replaced with deuterium;

Y ³ is selected from hydrogen and deuterium; and each "*" represents a stereocenter.

[44] In certain embodiment of a compound of Formula III; a) R ¹ is selected from CH ₃ and CD ₃ ; b) R ² is selected from -C(CH ₃ ) ₃ and -C(CD ₃ ) ₃ ; or c) the stereochemistry at each * is the same.

[45] In a more specific embodiment, a compound of Formula III has the features set forth in at least two of a) - c) (e.g., a and b, a and c, b and c). [46] In another specific embodiment of a compound of Formula III, the compound is a mixture of enantiomers in which the stereochemistry at each * is the same (i.e., a mixture of (S ₁ S) and (R, R) enantiomers, also known as a "threo pair"). In another specific embodiment of a compound of Formula III, the compound is a mixture of enantiomers in which the stereochemistry at each * is different (i.e., a mixture of (S ₁ R) and (R ₁ S) enantiomers, also known as an "erythro pair"). In yet another specific embodiment of a compound of Formula III, the compound is a single enantiomer substantially free of all other enantiomers. In a more specific embodiment, each enantiomer of a compound of Formula III whether substantially free of other enantiomers or part of a threo pair or an erythro pair also has the properties of at least one of a) or b), above.

[47] In yet another embodiment, the compound of Formula III is selected from any one of:

Compound 112;

Compound 1 13;

Compound 1 14;

Compound 1 15;

Compound 1 16;

Compound 117;

Compound 118; and

Compound 1 19, or a pharmaceutically acceptable salt of any of the foregoing, wherein the stereochemistry at each * is not racemic. Thus, each one of compounds 1 1 1-1 19 may exist as threo pairs, erythro pairs, or specific enantiomers.

[48] In another set of embodiments, any atom not designated as deuterium in any of the embodiments of Formulae I, Ha, lib and III set forth above is present at its natural isotopic abundance.

[49] The synthesis of compounds described herein can be readily achieved by synthetic chemists of ordinary skill. Relevant procedures and intermediates are disclosed, for instance in Fang, QK et al., Tetrahedron: Asymmetry, 2000, 11 : 3659- 3663; and US Patent 6,337,328.

[50] Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.

EXEMPLARY SYNTHESIS

[51] Scheme 1. Synthesis of Compounds of Formula I.

Formula I

[52] Scheme 1 above depicts a convenient method for synthesizing compounds of Formula I. A deuterated m-chloropropiophenone 10 may be converted to the silyl enol ether 11 (Z:E 99: 1) by treatment with LDA at -78° C followed by reaction with

TBDMS-Cl. Sharpless asymmetric dihydroxylation (Hashiyama, et al., J Org Chem, 1992, 57: 5067-5068) with commercially available AD-mix α or AD-mix β catalyst provides the (S) 12 or (R) 13 α-hydroxyketones, respectively. The α- hydroxyketones 12 and 13 may be converted to the corresponding triflates 12a and 13a with triflic anhydride followed by reaction with a deuterated t-butylamine (such as commercially available c/p-t-butylamine) to provide single enantiomer compounds of Formula I. [53] Scheme 2. Synthesis of Deuterated m-Chloropropiophenone 10.

[54] Scheme 2 above depicts the synthesis of a deuterated m- chloropropiophenone 10. A deuterated propiophenone 15 may be converted to the m-choro derivative 10 as disclosed by Su, W et al., Org Lett, 2007, 9: 993-996 by reaction with triphosgene and aluminum chloride in chloroform. Commercially

available 6? ₂ -propiophenone or commercially available d$-

propiophenone may be used as starting material 15 to produce m-chloropropiophenones 10, wherein R ¹ is CH ₃ , or CD ₃ , respectively. [55] Scheme 3. Synthesis of Compounds of Formula Ha and Hb.

12a Formula Ha

13a Formula lib

[56] ^~ Scheme 3 above depicts a convenient method for synthesizing compounds of Formula Ha and Hb. Coupling of the trifiate intermediates 12a and 13a from Scheme 1 with the deuterated amino alcohol 14 yields compounds of Formula Ha and lib as single diastereomers. [57] Scheme 4. Synthesis of Deuterated Amino Alcohol 14.

[58] Scheme 4 above depicts a convenient method for the synthesis of deuterated amino alcohol 14. Commercially available ck-2-nitropropane (16) may be reacted with deuterated formaldehyde in the presence of base as disclosed in Kambe, S et al., Bull Chem Soc Jap, 1968, 41 : 1444-1446; and Dornow, A et al., Chem Ber, 1960, 93: 41-44 to provide nitro alcohol 17. The nitro group may be reduced to the amine in the presence of iron under acidic conditions as disclosed by Senkus, M, J Industrial Eng Chem, 1948, 40: 506-508 to provide the desired amino alcohol 14. [59] Scheme 5a. Synthesis of Ervthro Pair of Formula HI.

Formula I (racemic) Formula III (racemic erythro pair)

Formula I (racemic) Formula III (racemic threo pair)

[61] The syntheses of the deuterated racemic erythro or threo pairs of enantiomers of compounds of Formula III are shown in Schemes 5a and 5b. The deuterated analogs may be prepared according to the methods disclosed in United States Patent No. 6,337,328 for the synthesis of the corresponding undeuterated compounds. As shown in Scheme 5a, a racemic compound of Formula I may be reduced with a metal hydride (or metal deuteride) reagent, such as Red-Al, to provide compounds of Formula III that are enriched in the racemic erythro pair. The purified racemic erythro pair may be obtained by conversion to the HCl salt followed by recrystallization from IPA.

[62] As shown in Scheme 5b, the racemic threo pair may be obtained by reduction of a racemic compound of Formula I with borane (or deuteroborane) to provide compounds of Formula III that are enriched in the racemic threo pair. Again, the purified racemic threo pair may be obtained by conversion to the HCl salt followed by recrystallization from IPA. [63] Scheme 6a. Synthesis of a Single Ervthro Enantiomer of Formula HI.

Formula I (single enantiomer) Formula III (single erythro enantiomer)

Scheme 6b. Synthesis of a Single Threo Enantiomer of Formula HI.

Formula I (single enantiomer) Formula III (single threo enantiomer)

The chemistry shown in Schemes 5a and 5b, may also be used to prepare single erythro or threo enantiomers as shown in Schemes 6a and 6b. As shown in Schemes 6a and 6b, a single enantiomer of Formula I prepared according to Scheme 1 may be selectively reduced to produce a compound of Formula III enriched in the corresponding erythro or threo enantiomer, which then may be further purified by conversion to the HCl salts and recrystallization from IPA.

[65] The specific approaches and compounds shown above are not intended to be limiting. The chemical structures in the schemes herein depict variables that are hereby defined commensurately with chemical group definitions (moieties, atoms, etc.) of the corresponding position in the compound formulae herein, whether identified by the same variable name (i.e., R ¹ , R ² , R ³ , etc.) or not. The suitability of a chemical group in a compound structure for use in the synthesis of another compound is within the knowledge of one of ordinary skill in the art. [66] Additional methods of synthesizing compounds of Formula I and their synthetic precursors, including those within routes not explicitly shown in schemes herein, are within the means of chemists of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the applicable compounds are known in the art and include, for example, those described in Larock R, Comprehensive Organic Transformations, VCH Publishers (1989); Greene TW et al., Protective Groups in Organic Synthesis, 3 ^rd Ed., John Wiley and Sons (1999); Fieser L et al., Fieser and Fieser 's Reagents for Organic Synthesis, John Wiley and Sons (1994); and Paquette L, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.

[67] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds.

COMPOSITIONS

[68] The invention also provides pyrogen-free compositions comprising an effective amount of a compound of any of the formulae described herein (e.g., Formula I, Ha, lib or III), or a pharmaceutically acceptable salt of said compound; and an acceptable carrier. Preferably, a composition of this invention is formulated for pharmaceutical use ("a pharmaceutical composition"), wherein the carrier is a pharmaceutically acceptable carrier. The carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.

[69] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. [70] If required, the solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions may be enhanced by methods well-known in the art. One method includes the use of lipid excipients in the formulation. See "Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water- Soluble Drugs (Drugs and the Pharmaceutical Sciences)," David J. Hauss, ed. Informa Healthcare, 2007; and "Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples," Kishor M. Wasan, ed. Wiley-Interscience, 2006.

[71] Another known method of enhancing bioavailability is the use of an amorphous form of a compound of this invention optionally formulated with a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See United States patent

7,014,866; and United States patent publications 20060094744 and 20060079502. [72] The pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In certain embodiments, the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch or iontophoretic techniques). Other formulations may conveniently be presented in unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985).

[73] Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[74] In certain embodiments, the compound is administered orally. Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.

[75] In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

[76] Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

[77] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) 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.

[78] Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1 ,3- butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

[79] The pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating

excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols. [80] The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, e.g.: Rabinowitz JD and Zaffaroni AC, US Patent 6,803,031, assigned to Alexza Molecular Delivery Corporation.

[81] Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For topical application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.

[82] Application of the subject therapeutics may be local, so as to be administered at the site of interest. Various techniques can be used for providing the subject compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access.

[83] Thus, according to yet another embodiment, the compounds of this invention may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters. Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein.

[84] According to another embodiment, the invention provides a method of coating an implantable medical device comprising the step of contacting said device with the coating composition described above. It will be obvious to those skilled in the art that the coating of the device will occur prior to implantation into a mammal. [85] According to another embodiment, the invention provides a method of impregnating an implantable drug release device comprising the step of contacting said drug release device with a compound or composition of this invention. Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafers.

[86] According to another embodiment, the invention provides an implantable medical device coated with a compound or a composition comprising a compound of this invention, such that said compound is therapeutically active. [87] According to another embodiment, the invention provides an implantable drug release device impregnated with or containing a compound or a composition comprising a compound of this invention, such that said compound is released from said device and is therapeutically active.

[88] Where an organ or tissue is accessible because of removal from the patient, such organ or tissue may be bathed in a medium containing a composition of this

invention, a composition of this invention may be painted onto the organ, or a composition of this invention may be applied in any other convenient way. [89] In another embodiment, a composition of this invention further comprises a second therapeutic agent. The second therapeutic agent may be selected from any compound or therapeutic agent known to have or that demonstrates advantageous properties when administered with a compound having the same mechanism of action as bupropion. Such agents include those indicated as being useful in combination with bupropion, including but not limited to, those described in PCT patent publications WO 2003097046, WO 2004052461, WO 2006017504, WO 2007016108, WO 2007048080, and WO 2007064586.

[90] Preferably, the second therapeutic agent is an agent useful in the treatment or prevention of a disease or condition selected from depression, major depression, nicotine dependence, seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder, female orgasmic disorders, Crohn's disease, marijuana dependence, methamphetamine dependence, seasonal affective disorder, depressive disorders, cocaine-related disorders, pathological gambling, obesity, attention deficit-hyperactivity (ADHD), obsessive-compulsive disorder (OCD), and restless-legs syndrome.

[91] In one embodiment, the second therapeutic agent is selected from zonisamide, naltrexone, mecamylamine, varenicline, eszopiclone, the transdermal nicotine patch, nefazodone, escitalopram, mirtazapine, and venlafaxine. [92] In another embodiment, the invention provides separate dosage forms of a compound of this invention and one or more of any of the above-described second therapeutic agents, wherein the compound and second therapeutic agent are associated with one another. The term "associated with one another" as used herein means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously).

[93] In the pharmaceutical compositions of the invention, the compound of the present invention is present in an effective amount. As used herein, the term "effective amount" refers to an amount which, when administered in a proper dosing

regimen, is sufficient to treat (therapeutically or prophylactically) the target disorder. For example, and effective amount is sufficient to reduce or ameliorate the severity, duration or progression of the disorder being treated, prevent the advancement of the disorder being treated, cause the regression of the disorder being treated, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy. [94] The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described in Freireich et al., (1966) Cancer Chemother. Rep 50: 219. Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N. Y., 1970, 537.

[95] In one embodiment, an effective amount of a compound of this invention can range from about 2 mg/day to about 3000 mg/day. In more specific embodiments the range is from about 20 mg/day to 1500 mg/day, or from about 40 mg/day to 600 mg/day, or most specifically from about 200 mg/day to 300 mg/day. The dose per day can be administered in a single dose or multiple doses (e.g., 2 or 3 or more). When multiple doses are used, the amounts administered per dose can be the same or different. Treatment typically is administered three times daily. [96] Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the patient, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. For example, guidance for selecting an effective dose can be determined by reference to the prescribing information for bupropion.

[97] For pharmaceutical compositions that comprise a second therapeutic agent, an effective amount of the second therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent. Preferably, an effective amount is between about 70% and 100% of the normal monotherapeutic dose. The normal monotherapeutic dosages of these second therapeutic agents are well known in the art. See, e.g., Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe

Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of which references are incorporated herein by reference in their entirety.

[98] It is expected that some of the second therapeutic agents referenced above will act synergistically with the compounds of this invention. When this occurs, it will allow the effective dosage of the second therapeutic agent and/or the compound of this invention to be reduced from that required in a monotherapy. This has the advantage of minimizing toxic side effects of either the second therapeutic agent of a compound of this invention, synergistic improvements in efficacy, improved ease of administration or use and/or reduced overall expense of compound preparation or formulation.

METHODS OF TREATMENT

[99] In another embodiment, the invention provides a method of inhibiting the uptake of norepinephrine and dopamine in a neuronal cell, comprising contacting such a cell with one or more compounds of any of Formula I, Ha, lib or III herein. [100] According to another embodiment, the invention provides a method of treating a disease that is beneficially treated by bupropion in a patient in need thereof comprising the step of administering to said patient an effective amount of a compound or a composition of this invention. Such diseases are well known in the art and are disclosed in, but not limited to the following patents and published applications: US 3819706, WO 2003097046, WO 2004017951, WO 1999037305 (radafaxine), and WO 2007064586. Such diseases include, but are not limited to, depression, major depression, nicotine dependence, seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder, female orgasmic disorders, Crohn's disease, marijuana dependence, methamphetamine dependence, seasonal affective disorder, depressive disorders, cocaine-related disorders, pathological gambling, obesity, attention deficit-hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and restless-legs syndrome. [101] In one particular embodiment, the method of this invention is used to treat a disease or condition in a patient in need thereof selected from depression, major depression, nicotine dependence, seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder, female orgasmic disorders, Crohn's

disease, marijuana dependence, methamphetamine dependence, seasonal affective disorder, depressive disorders, cocaine-related disorders, pathological gambling, obesity, and attention deficit-hyperactivity disorder (ADHD). [102] In another particular embodiment, the method of this invention is used to treat a disease or condition selected from depression, major depression, nicotine dependence, and seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder in a patient in need thereof.

[103] Methods delineated herein also include those wherein the patient is identified as in need of a particular stated treatment. Identifying a patient in need of such treatment can be in the judgment of a patient or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).

[104] In another embodiment, any of the above methods of treatment comprises the further step of co-administering to the patient one or more second therapeutic agents. The choice of second therapeutic agent may be made from any second therapeutic agent known to be useful for co-administration with bupropion. The choice of second therapeutic agent is also dependent upon the particular disease or condition to be treated. Examples of second therapeutic agents that may be employed in the methods of this invention are those set forth above for use in combination compositions comprising a compound of this invention and a second therapeutic agent.

[105] In particular, the combination therapies of this invention include coadministering a compound of Formula I and a second therapeutic agent for treatment of the following conditions (with the particular second therapeutic agent indicated in parentheses following the indication): depression (escitalopram, mirtazapine, and venlafaxine); obesity (zonisamide and naltrexone); nicotine dependence (mecamylamine, naltrexone, varenicline, eszopiclone, and the transdermal nicotine patch); marijuana dependence (nefazodone).

[106] The term "co-administered" as used herein means that the second therapeutic agent may be administered together with a compound of this invention as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and an second therapeutic agent as described above) or as separate,

multiple dosage forms. Alternatively, the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this invention. In such combination therapy treatment, both the compounds of this invention and the second therapeutic agent(s) are administered by conventional methods. The administration of a composition of this invention, comprising both a compound of the invention and a second therapeutic agent, to a patient does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound of this invention to said patient at another time during a course of treatment.

[107] Effective amounts of these second therapeutic agents are well known to those skilled in the art and guidance for dosing may be found in patents and published patent applications referenced herein, as well as in Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), and other medical texts. However, it is well within the skilled artisan's purview to determine the second therapeutic agent's optimal effective-amount range.

[108] In one embodiment of the invention, where a second therapeutic agent is administered to a subject, the effective amount of the compound of this invention is less than its effective amount would be where the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount would be where the compound of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.

[109] In yet another aspect, the invention provides the use of a compound of Formula I alone or together with one or more of the above-described second therapeutic agents in the manufacture of a medicament, either as a single composition or as separate dosage forms, for treatment or prevention in a patient of a disease, disorder or symptom set forth above. Another aspect of the invention is a compound of Formula I for use in the treatment or prevention in a patient of a

disease, disorder or symptom thereof delineated herein.

PHARMACEUTICAL KITS

[110] The present invention also provides kits for use to treat depression, major depression, nicotine dependence, seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder, female orgasmic disorders, Crohn's disease, marijuana dependence, methamphetamine dependence, seasonal affective disorder, depressive disorders, cocaine-related disorders, pathological gambling, obesity, and attention deficit-hyperactivity disorder (ADHD). These kits comprise (a) a pharmaceutical composition comprising a compound of any of Formula I, Ha, lib or III or a salt thereof, wherein said pharmaceutical composition is in a container; and (b) instructions describing a method of using the pharmaceutical composition to treat depression, major depression, nicotine dependence, and seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder. [Ill] The container may be any vessel or other sealed or sealable apparatus that can hold said pharmaceutical composition. Examples include bottles, ampules, divided or multi-chambered holders bottles, wherein each division or chamber comprises a single dose of said composition, a divided foil packet wherein each division comprises a single dose of said composition, or a dispenser that dispenses single doses of said composition. The container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. The container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle, which is in turn contained within a box. In one embodiment, the container is a blister pack. [112] The kits of this invention may also comprise a device to administer or to measure out a unit dose of the pharmaceutical composition. Such device may

include an inhaler if said composition is an inhalable composition; a syringe and needle if said composition is an injectable composition; a syringe, spoon, pump, or a vessel with or without volume markings if said composition is an oral liquid composition; or any other measuring or delivery device appropriate to the dosage formulation of the composition present in the kit.

[113] In certain embodiment, the kits of this invention may comprise in a separate vessel of container a pharmaceutical composition comprising a second therapeutic agent, such as one of those listed above for use for co-administration with a compound of this invention.

EXAMPLES

[114] Example 1. Synthesis of (RV2-((tert-Butyl-dQ)amino)-l-(3-chlorophenyl)-2- d^-propan-1-one deuterochloride (Compound 101 a). Compound 101a was prepared as outlined in Scheme 7 below. Details of the synthesis follow.

[115] Scheme 7. Preparation of Compound 101a.

[116] Synthesis of l-(3-chlorophenyl)-2-d ₂ -propan-l-one (21). A round-bottom flask was charged with 20 (5 g, 29.7 mmol) and MeOD (200 mL, 99.5 atom % D methan(ol-d) (Sigma-Aldrich)) under N ₂ . D ₂ O (100 mL, 99.9 atom % D deuterium oxide (Cambridge Isotopes)) was added slowly, followed by K ₂ CO ₃ (820 mg, 5.93 mmol). The reaction was stirred at room temperature (rt) for 20 hours (h). The mixture was concentrated in vacuo nearly to dryness and then partitioned between EtOAc and D ₂ O. The organic layer was washed with D ₂ O (IX). The combined aqueous solutions were washed with EtOAc (IX). The combined organic layers

were dried (Na ₂ SO ₄ ) and concentrated in vacuo to dryness to afford 4.32 g (86%) of 21 as a white solid. The percentage of material deuterated at the 2 position was estimated to be 99% by ¹ H NMR analysis. ¹ H NMR (CDCl ₃ ): δ 7.94-7.92 (m, IH), 7.85-7.81 (m, IH), 7.52 (m, IH), 7.40 (m, IH), 1.21 (s, 3H). [117] Synthesis of (Z)-terf-butyl(l-(3-chIorophenyl)-2-di-prop-l- enyloxy)dimethylsilane (22). A round-bottom flask was charged with THF (17.5 mL) and diisopropylamine (2.67 mL, 18.9 mmol) and cooled to -78 ⁰ C. To the solution was added rc-BuLi (2.24 M, 7.86 mL, 0.931 mmol) dropwise via syringe at such a rate that the temperature of the reaction did not rise above -65 °C. When the addition was complete, the reaction was stirred for 30 minutes (min) at -78 °C. 10.4 mL of the LDA solution were removed via syringe and added to a flask containing 9.27 mL of THF cooled to -78 °C. To the resulting mixture was added HMPA (6.38 mL, freshly distilled from CaH ₂ and stored over 4A.MS) dropwise with rapid stirring. Meanwhile, a solution of 21 (1.00 g, 5.86 mmol) in THF (2.30 mL) had been cooled to -78 °C. This solution was transferred via syringe to the LDA/HMPA solution at such a rate that the temperature of the reaction did not rise above -70 ⁰ C during the addition. The resulting mixture was stirred for 45 min, whereupon a solution of TBSCl (973 mg, 6.46 mmol) in hexane (6.45 mL) was added via syringe at such a rate that the temperature did not rise above -69 °C. The reaction was stirred for 5 min at -78 °C and then the bath was removed and the reaction was allowed to warm to rt. After approximately 2 h, the reaction was diluted first with CH ₂ Cl ₂ and then with a solution OfNa ₂ CO ₃ in D ₂ O (0.002 M, 99.9 atom % D deuterium oxide (Cambridge Isotopes)). The organic layer was washed twice with Na ₂ CO ₃ in D ₂ O, and then the combined aqueous solutions were washed once with CH ₂ Cl ₂ . The combined organic solutions were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Two purifications via column chromatography on an ISCO instrument (0.5% triethylamine in hexane) provided 1.09 g (66%) of 22. ¹ H NMR (CD ₂ Cl ₂ ): δ 7.45- 7.13 (m, 4H), 1.70 (s, 3H), 0.97 (s, 9H), -0.44 (s, 6H).

[118] Synthesis of (5)-l-(3-chlorophenyl)-2-di-2-hydroxypropan-l-one (23a). A 3 -neck round-bottom flask cooled to 0 °C was charged with AD-mix-α (6.7 g, Sigma-Aldrich) and methanesulfonamide (336 mg, 3.53 mmol). D ₂ O (18.4 mL, 99.9 atom % D (Cambridge Isotopes)) and /-BuOD (18.4 mL, 99 atom % D t-BuOD

(Cambridge Isotopes)) were added. The mixture was stirred for 25 min and then 22 (0.490 mL, 1.77 mmol) was added. After stirring overnight, the reaction was partitioned between CH ₂ Cl ₂ and 0.002 M Na ₂ CO ₃ in D ₂ O. The organic layer was washed twice with 0.002 M Na ₂ CO ₃ in D ₂ O, and then the combined aqueous solutions were washed once with CH ₂ Cl ₂ . The combined organic solutions were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification via column chromatography on an ISCO instrument (0 to 20% EtOAc in hexane) provided 197 mg (60%) of 23a. ¹ H NMR (CDCl ₃ ): δ 7.91 (s, IH), 7.79 (d, J= 6.8, IH), 7.60 (d, J = 7.8, IH), 7.46 (t, J= 7.8, IH), 3.64 (s, IH), 1.44 (s, 3H). Chiral HPLC (Chiralcel OD-H, hexane/IPA/TFA (99/1/0.1)): 97.4% ee.

[119] Synthesis of (R)-2-((tert-butyl-d ₉ )amino)-l-(3-chlorophenyl)-2-di- propan-1-one, deuterium chloride salt (Compound 101a). To a solution of 23a (187 mg, 1.01 mmol) in CH ₂ Cl ₂ (3.53 mL) at -78 °C was added trifluoromethanesulfonic anhydride (0.258 mL, 1.53 mmol) followed by 2,4,6-tri- te/Y-butylpyridine (604 mg, 2.44 mmol). The reaction was stirred for 5 min and then the flask was removed from the bath and allowed to warm to 0 ⁰ C. After stirring for 1 h, the reaction was cooled to -40 ⁰ C and d9-t-butylamine (0.333 mL, 3.03 mmol) was added. The reaction was stirred for 30 min at -40 ⁰ C, warmed to 0 °C, and then stirred at 0 °C for 30 min. The reaction was quenched with 0.002 M Na ₂ CO ₃ in D ₂ O (99.9 atom % D deuterium oxide (Cambridge Isotopes)) and diluted with CH ₂ Cl ₂ . The organic layer was washed twice with 0.002 M Na ₂ CO ₃ in D ₂ O, and then the combined aqueous solutions were washed once with CH ₂ Cl ₂ . The combined organic solutions were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude material was purified by chromatography on a silica plug (0 to 10 to 30 to 80 to 100% EtOAc in heptane). Concentration of the desired fractions afforded a residue which was dissolved in MTBE (2.4 mL) and cooled to 0 °C. DCl (2.02 mL, 1 M in Et ₂ O, 98 atom % D DCl in Et ₂ O (Sigma-Aldrich)) was added and the resulting slurry was stirred for 45 min. Stirring was stopped, and the solvent was carefully removed with a pipet. The residue was rinsed once with cold (0 °C) MTBE and then the flask was placed under high vacuum overnight. Compound 101a (87 mg, 30%) was obtained as a white solid. ¹ H NMR (DMSO): δ 9.23 (br s, IH), 8.70-8.55 (m, IH), 8.28 (s, IH), 8.16 (d, J= 7.5, IH), 7.87 (d, J= 7.5, IH), 7.68 (t, J= 8.5, IH),

1.49 (s, 3H). MS (M+H): 250.2. Chiral HPLC (Chiralcel OD-H, hexane/IPA (99:1)): 96% ee.

[120] Example 2. Synthesis of (S)-2-(ftert-butyl-dQ)aminoVl-(3-chlorophenylV2- d-propan- 1 -one deuterochloride (Compound 101b). Compound 101b was prepared as outlined in Scheme 7 above using AD-mix-β in place of AD-mix-α for the conversion of intermediate 22 to intermediate 23b (R enantiomer of 23a). Details of the synthesis are as follows.

[121] Synthesis of (R)-l-(3-chlorophenyl)-2-di-2-hydroxy-propan-l-one (23b). Intermediate 23b was prepared following the same procedure employed for the synthesis of 23a (see Example 1), using AD-mix-β in place of than AD-mix-α. ¹ H NMR (CDCl ₃ ): δ 7.91 (s, IH), 7.79 (d, J- 6.8, IH), 7.60 (d, J= 7.8, IH), 7.46 (t, J = 7.8, IH), 3.64 (s, IH), 1.44 (s, 3H). Chiral HPLC (Chiralcel OD-H, hexane/IPA/TFA (99/1/0.1)): 98% ee.

[122] Synthesis of (S)-2-((tert-butyl-d ₉ )amino)-l-(3-chlorophenyl)-2-di- propan-1-one, deuterium chloride salt (Compound 101b). Compound 101b was prepared using the same procedure as for Compound 101a (see Example 1), except that ketone 23b was used in place of 23a. ¹ H NMR (DMSO): δ 9.23 (br s, IH), 8.70-8.55 (m, IH), 8.28 (s, IH), 8.16 (d, J = 7.5, IH), 7.87 (d, J= 7.5, IH), 7.68 (t, J = 8.5, IH), 1.49 (s, 3H). MS (M+H): 250.2. Chiral HPLC (Chiralcel OD-H, hexane/IPA (99: 1)): 96% ee.

[123] Example 3. Synthesis of (R)-2-(tert-butylamino)- 1 -(3-chlorophenyQ- 2,3,3,3-d4-propan-l-one deuterochloride (Compound 102a). Compound 102a was prepared as outlined in Scheme 8 below. Details of the synthesis are as follows.

[124] Scheme 8. Preparation of Compound 102a.

[125] Synthesis of N-methoxy-N-methyl-(propion-d ₅ )amide (25). To a solution of 24 (4.0 g, 41.0 mmol, 98 atom % D d5-propionyl chloride (CDN Isotopes)) in CH ₂ Cl ₂ (82.1 mL) was added N-methoxy-N-methyl amine hydrochloride (4.0 g, 41.0 mmol) followed by triethylamine (12.0 mL, 86.2 mmol). The reaction was allowed to warm to rt. After stirring for 21 h, the reaction was quenched with D ₂ O (99.9 atom % D deuterium oxide (Cambridge Isotopes)) and diluted with CH ₂ Cl ₂ . The organic layer was washed twice with D ₂ O. The combined aqueous solutions were washed once with CH ₂ Cl ₂ , and then the combined organic solutions were dried (MgSO ₄ ), filtered and concentrated in vacuo to give a slurry. The slurry was diluted with Et ₂ O and filtered through a cotton plug. After concentrating, the material was still heterogeneous and further filtrations as a solution in Et ₂ O through Celite and silica gel did not entirely remove the solid. Final removal of the Et ₂ O in vacuo afforded 5.32 g of crude 25. ¹ H NMR (CDCl ₃ ): δ 3.68 (s, 3H), 3.18 (s, 3H). [126] Synthesis of l-(3-chlorophenyl)-(propan-ds)-l-one (26). A solution of 1- bromo-3-chlorobenzene (5.36 mL, 45.63 mmol) in Et ₂ O (150 mL) was cooled to -40 °C. «-BuLi (20.6 mL of a 2.16 M solution in hexanes, 44.5 mmol) was added dropwise via syringe. The reaction was stirred for 15 min and then cooled to -78 °C. A solution of 25 (2.708 g, 22.2 mmol) in Et ₂ O (44.6 mL) was added. After stirring for 5 min, the solution was warmed to -40 °C. After stirring for aproximately 1.5 h, the reaction was quenched with D ₂ O (99.9 atom % D (Cambridge Isotopes)), diluted with Et ₂ O and warmed to rt. The mixture was partitioned between 1 N DCl in D ₂ O and Et ₂ O. The organic layer was washed with 1 N DCl (99 atom % D in D ₂ O (35 wt. %, Sigma-Aldrich)) in D ₂ O (2X) and 0.002 M Na ₂ CO ₃ in D ₂ O (IX), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification via column

chromatography on an ISCO instrument (0 to 5% EtOAc in hexane) provided 2.19 g (57%) of 26 contaminated (15%) with material undeuterated at the 2 position. This material was combined with other batches to afford 3.86 g (22.2 mmol) of 26 which was dissolved in MeOD (154 mL, 99.5 atom % D (Sigma-Aldrich)). D ₂ O (77 mL) and then K ₂ CO ₃ (632 mg, 4.58 mmol) were added and the reaction was stirred overnight. The mixture was then concentrated under reduced pressure to near dryness and then partitioned between EtOAc and D ₂ O. The organic layer was washed with D ₂ O (IX). The combined aqueous solutions were washed with EtOAc (IX). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to dryness to afford 3.69 g (96%) of 26 as a white solid. The percentage of material undeuterated at the 2 position was estimated to be 2% by ¹ H NMR analysis. ¹ H NMR (CDCl ₃ ): δ 8.57 (s, IH), 8.40 (s, IH), 8.27 (s, IH), 7.35 (s, IH). [127] Synthesis of (R)-l-(3-chlorophenyl)-2,3 _> 3 _» 3-d-r2-hydroxypropan-l-one (27a). Intermediate 27a was prepared following the same procedure as was employed for the synthesis of 23a, starting from ketone 26 and using AD- mix-β instead of AD-mix-α.

[128] Synthesis of (R)-2-(tert-butylamino)-l-(3-chlorophenyl)-2,3,3,3-d ₄ - propan-1-one deuterochloride (Compound 102a). Compound 102a was prepared following the same procedure as for 101a, except that ketone 27a was used instead of ketone 23a. ¹ H NMR (DMSO): δ 9.03 (d, J= 12.3, IH), 8.59 (d, J= 13.3, IH), 8.28 (s, IH), 8.16 (d, J= 8.1, IH), 7.88 (app dd, J= 8.0, 1.4, IH), 7.68 (t, J= 7.8, IH), 1.49 (s, 3H). MS (M+H): 244.1. For the synthesis of this compound, 99.9 atom % D deuterium oxide (Cambridge Isotopes) and 98 atom % D DCl in Et ₂ O (Sigma-Aldrich) were employed.

[129] Example 4. Synthesis of (SV2-( ^" tert-butylamino)-l-(3-chlorophenyl)- 2,3,3,3-d4-propan-l-one deuterochloride (Compound 102b). Compound 102b was prepared as outlined in Scheme 8 above with the exception that AD-mix-α was used in place of AD-mix-β for the conversion of intermediate 26 to intermediate 27b (S enantiomer of 27a). Details of the synthesis are as follows.

[130] Synthesis of (.S)-l-(3-chlorophenyl)-2,3 ₅ 3 ₅ 3-d4-2-hydroxypropaii-l-one

(27b). Intermediate 27b was prepared following the same procedure as was employed for the synthesis of 23a, starting from ketone 26. ¹ H NMR (CDCl ₃ ): δ 7.91 (s, IH), 7.79 (d, J= 7.8, IH), 7.60 (d, J= 8.3, IH), 7.46 (t, J= 7.8, IH), 3.63 (s, IH).

[131] Synthesis of (S)-2-(tert-butylamino)-l-(3-chlorophenyl)-2,3,3,3-d ₄ - propan-1-one deuterochloride (Compound 102b). Compound 102b was prepared following the same procedure as for Compound 101a, except that ketone 27b was used instead of ketone 23a. ¹ H NMR (DMSO): δ 9.03 (d, J= 12.3, IH), 8.59 (d, J = 13.3, IH), 8.28 (s, IH), 8.16 (d, J= 8.1, IH), 7.88 (app dd, J= 8.0, 1.4, IH), 7.68 (t, J= 7.8, IH), 1.49 (s, 3H). MS (M+H): 244.1. For the synthesis of this compound, 99.9 atom % D deuterium oxide (Cambridge Isotopes) and 98 atom % D DCl in Et ₂ O (Sigma-Aldrich) were employed.

[132] Example 5. Synthesis of (2S.3SV2-(3-chlorophenvn-3-d ₁ -3-(methyl-d ₃ V 5,5-trimethylmorpholin-2-ol (Compound 105). Compound 105 was prepared as outlined in Scheme 9 below with synthetic details following.

Scheme 9. Preparation of Compound 105.

[133] Synthesis of (2S,3S)-2-(3-chlorophenyl)- 3-di-3-(methyl-d ₃ )-5,5- dimethylmorpholin-2-ol (Compound 105). To a solution of 27a (185 mg, 0.981 mmol) in CH ₂ Cl ₂ (3.45 mL) at -78 °C was added trifluoromethanesulfonic anhydride (0.252 mL, 1.50 mmol) followed by 2,6-lutidine (0.277 mL, 2.38 mmol). The

reaction was stirred for 5 min and then the flask was removed from the bath and allowed to warm to 0 °C. After stirring for 1 h, the reaction was cooled to -40 ⁰ C and 2-amino-2-methyl-l-propanol (0.294 mL, 3.07 mmol) was added. The reaction was stirred for 30 min at -40 °C, warmed to 0 °C, stirred at 0 °C for 4 h, and then allowed to warm slowly to rt overnight. The reaction was quenched with 0.002 M Na ₂ CO ₃ in D ₂ O (99.9 atom % D (Cambridge Isotopes)), and diluted with EtOAc. The organic layer was washed with the solution OfNa ₂ CO ₃ in D ₂ O (2X), and then the combined aqueous solutions were washed with EtOAc (3X). The combined organic solutions were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude material was purified by chromatography on an ISCO instrument (0 to 100% MeCN in CH ₂ Cl ₂ ). A second purification (50 to 100% EtOAc in heptane) afforded Compound 105 (37 mg, 15%) as a white solid. ¹ H NMR (CDCl ₃ ): δ 7.62-7.59 (m, IH), 7.52-7.46 (m, IH), 7.33-7.27 (m, 2H), 3.83 (dd, J= 0.9, 11.4, IH), 3.41 (d, J = 1 1.2, IH), 1.39 (s, 3H), 1.08 (s, 3H). MS (M+H): 260.2.

[134] Example 6. Synthesis of (2R,3R>2-f3-chlorophenyl>3-d _r 3-fmethyl-d-Q- 5,5-trimethylmorpholin-2-ol (Compound 109). Compound 109 was prepared as outlined in Scheme 8 above starting with reagent 27b in place of 27a. Synthetic details are as follows.

[135] Synthesis of (2R,3R)-2-(3-chlorophenyl)-3-di-3-(methyI-d ₃ )-5,5- trimethylmorpholin-2-ol (Compound 109). Compound 109 was prepared following the same procedure as was used as for the synthesis of Compound 105, except that ketone 27b was used instead of 27a. ¹ H NMR (CD ₂ Cl ₂ ): δ 7.61-7.58 (m, 1 H), 7.52-7.46 (m, 1 H), 7.33-7.29 (m, 2H), 3.79 (d, J = 1 1.4, 1 H), 3.37 (d, J = 1 1.4, IH), 1.37 (s, 3H), 1.07 (s, 3H). MS (M+H): 260.2. For the synthesis of this compound, 99.9 atom % D deuterium oxide (Cambridge Isotopes) was employed. [136] Example 7. Metabolism Studies in Human Liver Microsomes. The metabolic stability of compounds of the invention is tested using pooled liver microsomal incubations. Full scan LC-MS analysis is then performed to detect

major metabolites. Samples of the test compounds, exposed to pooled human liver microsomes, are analyzed using HPLC-MS (or MS/MS) detection. For determining metabolic stability, multiple reaction monitoring (MRM) is used to measure the disappearance of the test compounds. For metabolite detection, Ql full scans are used as survey scans to detect the major metabolites.

[137] Experimental Procedures. Human liver microsomes ("HLM"; 20 mg/mL) are obtained from Xenotech, LLC (Lenexa, KS). β-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl ₂ ), and dimethyl sulfoxide (DMSO) are purchased from Sigma-Aldrich. [138] Stock solutions of test compounds (7.5 mM) are prepared in DMSO. The 7.5 mM stock solutions are diluted to 50 μM in acetonitrile (ACN). The 20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCl ₂ . The diluted microsomes (375 μL) are added to wells of a 96-well deep-well polypropylene plate in triplicate. Ten μL of the 50 μM test compound solution is added to the microsomes and the mixture is pre- warmed for 10 minutes. Reactions are initiated by addition of 125 μL of pre- warmed NADPH solution (8 mM NADPH in 0. IM potassium phosphate buffer, pH 7.4, containing 3 mM MgCl ₂ ). The final reaction volume is 0.5 mL and contains 0.5 mg/mL human liver microsomes, 1 μM test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCl ₂ . The reaction mixtures are incubated at 37° C, and 50 μL aliquots were removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates which contain 50 μL of ice-cold ACN with internal standard to stop the reactions. The plates are stored at 4° C for 20 minutes after which 100 μL of water is added to the wells of the plate before centrifugation to pellet precipitated proteins. Supernatants are transferred to another 96-well plate and analyzed for amounts of parent remaining by LC-MS/MS using an Applied Bio- systems API 4000 mass spectrometer.

[139] The in vitro ti^s for test compounds are calculated from the slopes of the linear regression of % parent remaining (In) vs incubation time relationship, in vitro t > _/2 = 0.693/k, where k = -[slope of linear regression of % parent remaining(ln) vs incubation time]. Data analysis is performed using Microsoft Excel Software.

[140] SUP ERSOMES™ Assay. Various human cytochrome P450-specific SUPERSOMES™ are purchased from Gentest (Woburn, MA, USA). A l.O mL reaction mixture containing 25 pmole of SUPERSOMES™, 2.OmM NADPH, 3.OmM MgCl, and l μM of a test compound in 10OmM potassium phosphate buffer (pH 7.4) was incubated at 37 ⁰ C in triplicate. Positive controls contain 1 μM of bupropion instead of test compound. Negative controls used Control Insect Cell Cytosol (insect cell microsomes that lacked any human metabolic enzyme) purchased from GenTest (Woburn, MA, USA). Aliquots (50 μL) are removed from each sample and placed in wells of a multi-well plate at various time points (e.g., 0, 2, 5, 7, 12, 20, and 30 minutes) and to each aliquot is added 50μL of ice cold acetonitrile with 3μM haloperidol as an internal standard to stop the reaction. [141] Plates containing the removed aliquots are placed in -20° C freezer for 15 minutes to cool. After cooling, 100 μL of deionized water is added to all wells in the plate. Plates are then spun in the centrifuge for 10 minutes at 3000 rpm. A portion of the supernatant (100 μL) is then removed, placed in a new plate and analyzed using Mass Spectrometry.

[142] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. It should be understood that the foregoing discussion and examples merely present a detailed description of certain preferred embodiments. It will be apparent to those of ordinary skill in the art that various modifications and equivalents can be made without departing from the spirit and scope of the invention. All the patents, journal articles and other documents discussed or cited above are herein incorporated by reference.