MXPA06011028A - Heterocyclic phenylaminopropanol derivatives as modulators of the monoamine reuptake for the treatment of vasomotor symptoms (vms) - Google Patents

Abstract

The present invention is directed to phenylaminopropanol derivatives of formula I:or a pharmaceutically acceptable salt thereof, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions ameliorated by monoamine reuptake including, inter alia, vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromylagia syndrome, nervous system disorders, and combinations thereof, particularly those conditions selected from the group consisting of major depressive disorder, vasomotor symptoms, stress and urge urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and combinations thereof.

Description

DERIVATIVES OF HETEROCYCLIC PHENYLAMINOPROPANOL AS MODULATORS OF MONOAMINE REABSORATION FOR THE TREATMENT OF VASOMOTOR S NTOMAS (VMS) Field of the Invention The present invention relates to phenylaminopropanol derivatives, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions relieved by the reabsorption of monoamine including, inter alia, vasomotor symptoms (VMS for short) in English), sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders and combinations thereof, particularly those conditions selected from the group consisting of major depressive disorder, vasomotor symptoms, urinary incontinence of impulse and tension, fibromyalgia, pain, diabetic neuropathy and combinations thereof.

Background of the Invention Vasomotor symptoms (VMS), referred to as hot flashes and night sweats, are the most common symptoms associated with menopause that occurs in 60% to 80% of all women after menopause. natural or induced Ref.: '175938 surgically. VMS is likely to be an adaptive response of the central nervous system (CNS) to the decline of sex steroids. To date, the most effective therapies for VMS are hormone-based treatments, including estrogens and / or some progestins. Hormone treatments are very effective in relieving VMS, but they are not suitable for all women. It is well recognized that VMS are caused by fluctuations in sex steroid levels and can be disruptive and generate disability in both male and female individuals. A hot flash can last up to thirty minutes and vary in frequency from several times a week to multiple events per day. The patient experiences a hot flash as a sudden feeling of heat that spreads rapidly from the face to the chest and back, and then over the rest of the body. It is usually accompanied by bursts of heavy sweat. It can happen, often several times in an hour, and often happens at night. Hot flushes and bursts of sweat that happen at night can cause sleep suppression. Psychological and emotional symptoms observed such as nervousness, fatigue, irritability, insomnia, depression, memory loss, headache, anxiety, nervousness, or inability to concentrate, are considered to be caused by the suppression of sleep following the embarrassment and the night sweats. (Kramer et al., In: Murphy et al., 3rd Int'l Symposium on Recent Advances in Urological Cancer Diagnosis and Treatment-Proceedings, Paris France: SCI: 3-7 (1992)). Hot flushes can be even more severe in women treated for breast cancer for several reasons: 1) many breast cancer survivors are given tamoxifen, the most common side effect is hot flashes, 2) many women treated for breast cancer, undergo premature menopause from chemotherapy; 3) women with a history of breast cancer have generally been denied estrogen therapy because of concerns about the potential recurrence of breast cancer (Loprinzi, et al. , Lancet, 2000, 356 (9247): 2059-2063). Men also experience hot flushes after the withdrawal of the steroid hormone (androgen). This is true in cases of an androgen decline associated with age (Katovich, et al., Proceedings of the Society for Experimental Biology &Medicine, 1990, 193 (2): 129-35), as well as in extreme cases of hormone suppression associated with treatments for prostate cancer (Berendsen, et al., European Journal of Pharmacology, 2001, 419 (1): 47-54.) As many as one third of these patients will experience persistent and frequent symptoms severe enough to cause inconvenience and discomfort ayors.The precise mechanism of these symptoms is unknown, but is generally believed to represent disturbances to normal homeostatic mechanisms that control thermoregulation and vasomotor activity (Kronenberg et al., "Thermoregulatory Physiology of Menopausal Hot Flashes: A Review, "Can. J. Physiol. Pharmacol., 1987, 65: 1312-1324).

The fact that estrogen treatment (for example, estrogen replacement therapy) relieves symptoms, establishes a link between these symptoms and an estrogen deficiency. For example, the menopausal stage of life is associated with a wide range of other acute symptoms as described above and these symptoms are generally responsive to estrogen. It has been suggested that estrogens can stimulate the activity of both the norepinephrine (NE) and / or serotonin (5-HT) systems (J. Pharmacology &Experimental Therapeutics, 1986, 236 (3) 646-652). There is a hypothesis that estrogen modulates the levels of NE and 5-HT by providing homeostasis in the thermoregulatory center of the hypothalamus. The descending trajectories from the hypothalamus via the spine / brainstem, and the adrenals to the skin are involved in the conservation of the normal temperature of the skin. The action of the NE and 5-HT resorption inhibitors is known to affect both the C? S and the peripheral nervous system (P? S, for its acronym in English). The pathophysiology of the VMS is mediated by central and peripheral mechanisms and therefore, the interaction between the CNS and P? S can mean by the efficacy of the dual action of the SRI /? RI in the treatment of thermoregulatory dysfunction. In fact, the physiological aspects and the involvement of C? S / P? S in VMS may mean lower doses proposed to treat VMS (Loprinzi, et al., Lancet., 2000, 356: 2059-2063; Stearns et al., JAMA, 2003, 289: 2827-2834) compared to the doses used to treat the behavioral aspects of depression. The interaction of the C? S / P? S in the pathophysiology of VMS, and the data presented within this document were used to support the claims that the norepinephrine system could be dissected to treat VMS. Although VMS are most commonly treated by hormone therapy (orally, transdermally or by means of an implant), some patients can not tolerate the treatment of estrogen (Berendsen, Maturitas, 2000, 36 (3): 155-164, Fink et al. .,? ature, 1996, 383 (6598): 306). In addition, hormone replacement therapy is not usually recommended for women or men with or at risk for hormonally sensitive cancers (eg, prostate, or breast cancer). Thus, non-hormonal therapies (eg, fluoxetine, paroxetine, [SRI] and clonidine) are being evaluated clinically. WO09944601 describes a method for reducing hot flashes in human female individuals when administering fluoxetine. Other options have been studied for the treatment of hot flushes including steroids, alpha adrenergic agonists and beta blockers with varying degrees of success (Waldinger et al., Maturitas, 2000, 36 (3): 165-168). It has been reported that a2-adrenergic receptors play a role in thermoregulatory dysfunctions (Freedman et al., Fertility &Sterility, 2000, 74 (1): 20-3).

These receptors are located both pre- and post-synaptically and mediate an inhibitory role in the central and peripheral nervous system. There are four different subtypes of the adrenergic receptors 2, that is, a2A /? 2B, Otee, and a2D (Mackinnon et al., TIPS, 1994, 15: 119, French, Pharmacol. Ther., 1995, 68: 175). It has been reported that a non-selective adrenoreceptor antagonist a2, yohimbine, induces a flushing and an a2 adrenergic receptor agonist, clonidine, improves the effect of yohimbine (Katovich, et al., Proceedings of the Society for Experimental Biology & Medicine, 1990, 193 (2): 129-35, Freedman et al., Fertility & Sterility, 2000, 74 (1): 20-3).

Clonidine has been used to treat hot flashes. However, by using such treatment it is associated with various undesirable side effects caused by the high doses necessary to abate the embarrassment described herein and known in the related arts. Given the complex and multifaceted nature of thermoregulation and the interaction between CNS and PNS in preserving thermoregulatory homeostasis, multiple therapies and methods can be developed to direct vasomotor symptoms. The present invention focuses on novel compounds and compositions containing these targeted compounds for these and other major uses.

Brief Description of the Invention The present invention relates to phenylaminopropanol derivatives, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions relieved by the reabsorption of monoamine including, inter alia, vasomotor symptoms (VMS for its acronyms in English), sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders and combinations thereof, particularly those conditions selected from the group consisting of major depressive disorder, vasomotor symptoms, urinary incontinence of impulse and tension, fibromyalgia, pain, diabetic neuropathy and combinations thereof. In one embodiment, the invention is directed to compounds of formula I: 1 or a pharmaceutically acceptable salt thereof; where: the dotted line represents an optional double bond between U and V or V and W; U is independently, O, S, SO, S02, C = 0, N, NR3, or C (R8) 2; W is CH, CH2, or C = 0; with the proviso that when it is CH2, U is not C (R8) 2; V is C (R8), C (R8) 2, O, U N (R8); Ri is independently each occurring, alkyl, alkoxy, halo, CF3, 0CF3, arylalkyloxy substituted with 0-3 R9, aryloxy substituted with 0-3 R9, aryl substituted with 0-3 R9, heteroaryl substituted with 0-3 R9, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 R9, alkylsulfone, phenylsulfone substituted with 0-3 Rg, alkylsulfonamide, phenylsulfonamide substituted with 0-3 Rg, heteroaryloxy substituted with 0-3 Rg, heteroarylmethyloxy substituted with 0-3 Rg, alkylamido, or phenylamido substituted with 0-3 Rg; or two adjacent R1 representing methylenedioxy; R2 is aryl substituted with 0-3 Ri or heteroaryl substituted with 0-3 Ri; R 3 is H, C 1 -C 4 alkyl substituted with 0-3 Ri, C 3 -C 6 cycloalkyl, or phenyl substituted with 0-3 R x; R4 is each independently occurring, H, C? -C4 alkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl, or both R4 groups, together with the nitrogen through which they are bonded form a heterocyclic ring of 4? up to 6 atoms in the ring, where a carbon can be optionally replaced with N, O, S, or S02, and where any atom in the carbon ring or atom? additional may optionally be substituted with C? -C, F, or CF3 alkyl; Rs is H or C1-C4 alkyl; Re is H or C? -C alkyl; R7 is independently each occurring, H, or C? -C alkyl, or R7 and R4 together with the nitrogen to which R4 is bonded form a nitrogen-containing ring containing 3-6 carbon atoms; R8 is independently each occurrence, H, C? -C4 alkyl, C3-Cg heteroalkyl, or aryl substituted with 0-3 Ra; R9 is independently each occurring, alkyl, alkoxy, halo, CF3, 0CF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two adjacent Rgs also represent methylenedioxy; n is an integer from 0 to 4; x is an integer from 1 to 2; and wherein 1-3 carbon atoms in ring A can optionally be replaced with N. Still in other embodiments, the present invention is directed to compositions comprising: a.- at least one compound of formula I; and b. at least one pharmaceutically acceptable carrier. In another embodiment, the present invention is directed to methods for the treatment or prevention of a condition ameliorated by the reabsorption of monoamine in a subject in need thereof comprising the steps of: administering to the subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. Conditions relieved by monoamine reabsorption include those selected from the group consisting of vasomotor symptoms, sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders and combinations thereof, particularly those conditions selected from the group consisting of major depressive disorder, vasomotor symptoms, impulse and tension urinary incontinence, fibromyalgia, pain, diabetic neuropathy and combinations thereof. In another embodiment, the present invention is directed to methods for the treatment or prevention of vasomotor symptoms in a subject in need thereof comprising the step of: administering to the subject an effective amount of at least one compound of formula I or a pharmaceutically salt acceptable of it. In still another embodiment, the present invention is directed to methods for the treatment or prevention of a depression disorder in a subject in need thereof comprising the step of administering to the subject an effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof. In still other embodiments, the present invention is directed to methods for the treatment or prevention of sexual dysfunction in a subject in need thereof, comprising the step of: administering to the subject an effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof. In further embodiments, the present invention is directed to methods for the treatment or prevention of pain in a subject in need thereof comprising the step of: administering to the subject an effective amount of at least one compound of formula I or a pharmaceutically salt acceptable of it. In another embodiment, the present invention is directed to methods for the treatment or prevention of a gastrointestinal or genitourinary disorder, particularly stress incontinence or impulse urinary incontinence in a subject in need thereof, comprising the steps of: administering to the subject a effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to methods for the treatment or prevention of chronic fatigue syndrome in a subject in need thereof comprising the step of: administering to the subject an effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention is directed to methods for the treatment or prevention of fibromyalgia syndrome in a subject in need thereof comprising the step of: administering to the subject an effective amount of at least one compound of formula I or a salt pharmaceutically acceptable thereof.

BRIEF DESCRIPTION OF THE DRAWINGS The invention can be understood more fully from the following detailed description and the appended figures forming part of this application. Figure 1 is a panorama of the action of estrogens in thermoregulation mediated by norepinephrine / serotonin. Figure 2 is a schematic representation of the interactions of norepinephrine and serotonin and their respective receptors (5-HT2a / «i and a2-adrenergic).

Detailed Description of the Invention The present invention relates to phenylaminopropanol derivatives, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions relieved by the reabsorption of monoamine including inter alia, vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders and combinations thereof, particularly those conditions selected from the group consisting of major depressive disorder, vasomotor symptoms, impulse and stress urinary incontinence , fibromyalgia, pain, diabetic neuropathy and combinations thereof. The following definitions are provided for a complete understanding of the terms and abbreviations used in this specification. As used herein and in the appended claims, the singular forms "a", "an" and "the" include the plural reference unless the context clearly indicates otherwise. Thus, for example, a reference to "an antagonist" includes a plurality of such antagonists, and a reference to "a compound" is a reference to one or more compounds and equivalents thereof known to those skilled in the art and so on. . The abbreviations in the specification correspond to units of measure, techniques, properties or compounds as follows: "min" means minutes, "h" means Hours, "μL" means microliters, "L" means milliliters, "mM" means millimolar, " M "means molar," mmol "millimoles," cm "means centimeters," SEM "means standard error of the mean, and" IU "means International Units. The value of "? 2C" and? "ED50 value" means doses which result in an improvement of 50% of the observed condition or effect (average of 50% of the maximum end point). "Norepinephrine transporter" is abbreviated NET. "Human Norepinephrine Transporter" is abbreviated hNET. "Serotonin transporter" is abbreviated SERT. "Human serotonin transporter" is abbreviated hSERT. "Orepinephrine Reuptake Inhibitor" is abbreviated RI. "Selective Orepinephrine Reuptake Inhibitor" is abbreviated S? RI. "Serotonin reuptake inhibitor" is abbreviated SRI. "Selective Serotonin Reuptake Inhibitor" is abbreviated SSRI. "? orepinefrina" is abbreviated? "Serotonin" is abbreviated 5-HT. "Subcutaneous" is abbreviated. "Intraperitoneal" is abbreviated ip. "Oral is abbreviated po In the context of this description, a number of terms should be used.The term" treatment "as used herein, includes preventive (eg, prophylactic), curative or palliative treatment and" treating " as used herein also includes preventive, curative and palliative treatment The term "effective amount" as used herein, refers to an effective amount in doses and for periods of time necessary to achieve the desired result with respect to the prevention or treatment of vasomotor symptoms, depression disorders, sexual dysfunction or pain. In particular with respect to vasomotor symptoms, "effective amount" refers to the amount of compounds or composition of compounds that would increase norepinephrine levels to partially or totally compensate for the lack of steroid availability in subjects suffering from a symptom. vasomotor. The varying levels of hormones will influence the amount of compounds required in the present invention. For example, the pre-menopausal state may require a lower level of compound due to higher levels of the hormone than in the peri-menopausal state. It will be appreciated that the effective amount of components of the present invention will vary from patient to patient not only with the particular compound, component or composition selected, the route of administration and the ability of the components (alone or in combination with one or more drugs combination) to produce a desired response in the individual, but also with factors such as the state of disease or severity of the condition to be alleviated, hormone levels, age, sex, weight of the individual, the state of the patient's welfare and the severity of the pathological condition to be treated, medication in parallel or special diets that are then followed by the patient the particular, and other factors which will recognize those experts in the art with the appropriate dose finally being at the discretion of the attending physician. Dosage regimens can be adjusted to provide the improved therapeutic response. An effective amount is also one in which any deleterious or toxic effects of the components are overcome by the therapeutically beneficial effects. Preferably, the compounds of the present invention are administered at a dose and for a time such that various hot flashes are reduced compared to the number of hot flashes prior to the start of treatment. Such treatment may also be beneficial in reducing the overall severity or intensity distribution of any of the hot flashes still experienced compared to the severity of the hot flashes prior to the start of treatment. With respect to disorders of depression, sexual dysfunction and pain, the compounds of the present invention are administered at a dose and for a time such that there is prevention, alleviation or elimination of the symptom or condition. For example, for a patient with the condition, the compounds of formula I, or a pharmaceutically acceptable salt thereof, can be administered preferably at a dose from about 0.1 mg / day to about 500 mg / day, one dose or twice a day, more preferably from about 1 mg / day to about 200 mg / day and more preferably from about 1 mg / day to 100 mg / day for a sufficient time to reduce and / or substantially eliminate the number and / or severity of hot flashes or symptom or condition of depression, sexual dysfunction or pain disorder. The terms "component", "composition of compounds", "compound", "drug", or "pharmacologically active agent" or "active agent" or "medicament", are used interchangeably herein to refer to a compound or compounds or composition of matter which when administered to a subject (human or animal) induces a desired pharmacological and / or physiological effect by local and / or systemic action. The terms "components", "drug" or "pharmacologically active agent", or "active agent" or "medicament", are used interchangeably herein to refer to a compound or compounds or. composition of matter which when administered to an organism (human or animal) induces a desired pharmacological and / or physiological effect by local and / or systemic action. The term "modulation", refers to the ability to either improve or inhibit a functional property of a biological activity or process e.g., receptor binding or signaling activity. Such improvement or inhibition may be contingent in the presence of a specific event such as the activation of a signal transduction path and / or may be manifest only in particular types of cells. The modulator is intended to comprise any compound - for example, antibody, small molecule, peptide, oligopeptide, polypeptide, or protein, preferably small molecule or peptide. As used herein, the term "inhibitor" refers to any agent that inhibits, suppresses, suppresses or diminishes a specific activity such as serotonin reuptake activity or norepinephrine reuptake activity. The term "inhibitor" is intended to comprise any compound, for example, antibody, small molecule, peptide, oligopeptide, polypeptide or protein, preferably, molecule or small peptide that exhibits a partial, complete, competitive and / or inhibitory effect in a mammal, preferably the resorption of human norepinephrine or the reuptake of serotonin and the reuptake of norepinephrine, thereby decreasing or blocking, preferably decreasing, some or all of the biological effects of endogenous norepinephrine reuptake or both serotonin reuptake and norepinephrine reuptake .- Within the present invention, the compounds of formula I can be prepared in pharmaceutically acceptable salt forms. As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic salts and organic salts. Suitable non-organic salts include organic and inorganic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ether sulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, malic, maleic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic and the like. Hydrochloric, hydrobromic, phosphoric and sulfuric acids and more preferably the hydrochloride salt are particularly preferred. "Administration" as used herein, means either directly administering a compound or composition of the present invention, or administering a derivative or analog prodrug which will form an equivalent amount of the active compound or substance within the body. The term "subject" or "patient" refers to an animal that includes the human species that is treated with the compositions and / or methods of the present invention. The term "subject" or "subjects" is intended to refer to the male and female gender unless a gender is specifically indicated. Thus, the term "patient" includes any mammal that can benefit from the treatment or prevention of vasomotor symptoms, depression disorders, sexual dysfunction, or pain such as a human, especially if the mammal is female, either in the pre-menopausal, peri-menopausal, post-menopausal period. Additionally, the term patient includes female animals including humans and humans, not only older women who have passed through menopause but also women who have undergone hysterectomy or for some other reason have been suppressed. the production of estrogens, such as those that have undergone a long-term administration of corticosteroids, that suffer from Cushing's syndrome or that have gonadal dysgenesis. However, the term "patient" is not intended to be limited to women. The terms "premature menopause" or "artificial menopause" refer to ovarian insufficiency of unknown cause that can happen before the age of 40. It can be associated with smoking, live at high altitude or a poor nutritional situation. Artificial menopause can result from oophorectomy, chemotherapy, radiation from the pelvis or any process that impairs the blood supply to the ovaries. The term "pre-menopausal" means before menopause, the term "peri-menopausal" means during menopause and the term "post-menopausal" means after menopause. "Ovarioectomy" means the removal of an ovary or ovaries and can be done according to Merchenthaler et al., Maturitas, 1998, 30 (3): - 307-316. "Collateral effect" refers to a consequence other than one for which an agent or measure is used, in terms of the adverse effects produced by a drug, especially in a different tissue or organ system that is sought to benefit from its administration In the case, for example, of high doses of NRI or NRI / SRI compounds alone, the term "side effect" can refer to conditions such as for example vomiting, nausea, sweating and embarrassment (Janowsky, et al., Journal of Clinical Psychiatry, 1984, 45 (10Pt2): 3-9). "Alkyl" as used herein, refers to an aliphatic hydrocarbon chain of 1 to about 20 carbon atoms (and all combinations and subcombinations of specific ranges and numbers of carbon atoms herein), with about 1 to 8 carbon atoms are preferred, and with from about 1 to 4 carbon atoms, referred to herein as "lower alkyl" is more preferred. Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, cyclopentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclohexyl, cyclooctyl. , adamantyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl. "Heteroalkyl" as used herein, refers to a substituent of the general formula (alkyl-X) n-alkyl-, wherein each "alkyl" is independently as defined above, "X" is sulfur, oxygen, or a portion containing heteroatom N and n is 1-4, preferably one. Heteroalkyl groups include, but are not limited to, methoxymethyl, ethoxyethyl, methoxyethyl, methylsulfanylmethyl, ethylsulfanylethyl, methylsulfanylethyl, methylaminoethyl, ethylaminoethyl, and methylaminoethyl. "Perfluorinated alkyl" as used herein, refers to an alkyl as defined above, in which the hydrogen is bonded directly to the carbon atoms, is completely replaced by fluorine. "Alkenyl" as used herein, refers to an alkyl group of at least two carbon atoms having one or more double bonds, wherein alkyl is as defined herein. The alkenyl groups may be optionally substituted. "Alkynyl" as used herein, refers to an alkyl group of at least two carbon atoms having one or more triple bonds, wherein the alkyl is as defined herein. The alkynyl groups may be optionally substituted. "Aryl" as used herein, refers to an optionally substituted mono, di, tri or other multicyclic aromatic ring system having from about 5 to about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms in the) with from about 6 to about 10 carbons being preferred. Non-limiting examples include, for example, phenyl, naphthyl, anthracenyl, and phenanthrenyl. "Heteroaryl" as used herein, refers to an optionally substituted mono, di, tri or other multicyclic aromatic ring system that includes at least one and preferably from 1 to about 4 ring members of sulfur heteroatoms, oxygen or nitrogen. Heteroaryl groups can have, for example, from about 3 to about 50 carbon atoms (and all combinations and subcombinations of specific ranges and numbers of carbon atoms in them), with from about 4 to about 10 preferred carbons. Nonlimiting examples of heteroaryl groups include for example pyrryl, furyl, pyridyl, 1, 2, 4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl and isoxazolyl. The "heterocyclic ring" as used herein, refers to a bicyclic heterocyclic ring of 5 to 7-membered monocyclic or stable or bicyclic 7 to 10 which is saturated partially unsaturated or unsaturated (aromatic) and containing carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the heterocyclic rings defined above is fused to a benzene ring. The nitrogen and sulfur heteroatoms can optionally be oxidized. The heterocyclic ring can be placed in its pendant group on any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein can be substituted on a carbon atom or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen atom in the heterocyclic may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds one, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle be not more than one. Examples of heterocycles include, but are not limited to, lH-indazole, 2-pyrrolidonyl, 2H, 6H-1, 5, 2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H -quinolizinyl, 6H-1, 2, 5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4H-carbazolyl, a-, β- or? -carbolinilo, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1, 5, 2-dithiazinyl, dihydrofuro [2, 3-b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, iH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1, 3, 4 -oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinilpirimidinilo, phenanthridinyl, phenanthrolinyl, phenoxazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl , pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinilinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinylinyl, tetrahydroquinolinyl, 6H1, 2,5-thiadiazinyl, , 2,3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1, 2 , 3-triazolyl, 1, 2,4-triazolyl, 1,2,5-triazolyl, 1,3-triazolyl, xanthenyl. Preferred heterocycles include, but are not limited to pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, indazolyl iH-oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Spiro and fused ring compounds containing, for example, the above heterocycles are also included. "Alkoxy", as used in this, refers to the group R ~ 0- where R is an alkyl group as defined herein. "Aryloxy" as used herein, refers to the group R-O- wherein R is an aryl group, as defined herein. "Heteroaryloxy" as used herein, refers to the group R-O- wherein R is a heteroaryl group, as defined herein. "Alkoxyloxy" as used herein, refers to the group R-C (= 0) -0- wherein R is an alkyl group of 1 to 5 carbon atoms. "Alkylsulfoxide" as used herein, as used herein, refers to -S (= 0) -R, wherein R is alkyl, as defined above. "Alkylsulfone" as used herein, refers to -S (= 0) 2-R, wherein R is alkyl, as defined above. "Alkylsulfonamide" as used herein, refers to -NR-S (= 0) 2- / wherein each R is independently alkyl, as defined above or the part NR may also be NH. "Phenylsulfonamide" as used herein, refers to -NR-S (= 0) 2-phenyl, wherein R is H or alkyl, as defined above. "Heteroarylmethyloxy" as used herein, refers to -0CH2-R, wherein R is heteroaryl, as defined above. "Alkylamido" as used herein, refers to -NR-C (= 0) -R, wherein each R is independently alkyl, as defined above, or the part NR may also be NH. "Phenylamido" as used herein, refers to -NR-C (= 0) -phenyl, wherein R is H or alkyl, as defined above. "Halo" as used herein, refers to chlorine, bromine, fluorine, and iodine. In one embodiment, the invention is directed to compounds of formula I: or a pharmaceutically acceptable salt thereof; where: the dotted line represents an optional double bond between U and V or V and W; U is independently, O, S, SO, S02, C = 0, N, NR3, or C (R8) 2; W is CH, CH2, or C = 0; with the proviso that when it is CH2, U is not C (R8) 2; V is C (R8), C (R8) 2, O, u N (R8); i is independently each occurring, alkyl, alkoxy, halo, CF3, 0CF3, arylalkyloxy substituted with 0-3 Rg, aryloxy substituted with 0-3 R9, aryl substituted with 0-3 Rg, heteroaryl substituted with 0-3 Rg, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 Rg, alkylsulfone, phenylsulfone substituted with 0-3 R9, alkylsulfonamide, phenylsulfonamide substituted with 0-3 R9, heteroaryloxy substituted with 0-3 R9, heteroarylmethyloxy substituted with 0-3 R9, alkylamido, or phenylamido substituted with 0-3 R9; or two adjacent R1 representing methylenedioxy; R2 is aryl substituted with 0-3 Ri or heteroaryl substituted with 0-3 Ri; R3 is H, C1-C4 alkyl substituted with 0-3 Ri, C3-C6 cycloalkyl, or phenyl substituted with 0-3 R; R4 is independently each occurrence, H, C? -C4 alkyl / arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl, or both R4 groups, together with the nitrogen through which they bond form a heterocyclic ring of 4? up to 6 atoms in the ring, where a carbon can be optionally replaced with N, 0, S, or S02, and where any atom in the carbon ring or atom? additional may optionally be substituted with C 1 -C 4 alkyl, F, or CF 3; Rs is H or C? -C alkyl; Re is H or C? -C4 alkyl; R7 is independently each occurring, H, or C1-C4 alkyl, or R7 and R4 together with the nitrogen to which R4 is bonded form a nitrogen-containing ring containing 3-6 carbon atoms; R8 is independently each occurring, H, C1-C4 alkyl, C3-C6 heteroalkyl, or aryl substituted with 0-3 Ri; Rg is independently each occurring, alkyl, alkoxy, halo, CF3, 0CF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two adjacent R9 also represent methylenedioxy; n is an integer from 0 to 4; x is an integer from 1 to 2; and wherein 1-3 carbon atoms in ring A can optionally be replaced with N. The dotted line in the ring is fused to ring A representing either an optional double bond between U and V or between V and W. The dotted line between the two groups R4 represents an optional heterocyclic ring of 4 to 6 ring atoms which can be formed between the two R groups, together with the nitrogen to which they are bound. In certain preferred embodiments of the compounds of formula I, U is O. In certain other preferred embodiments, U is S. In certain other preferred embodiments, U is SO. In certain other preferred embodiments, U is S02. In certain other preferred embodiments, U is C = 0. In certain other preferred embodiments, U is? H. In certain other preferred embodiments, U is? R3. In certain other preferred embodiments, U is CH2. In certain preferred embodiments of the compounds of the formula I, W is CH. In certain other preferred embodiments, W is CH2. In certain other preferred embodiments, it is C = 0. In certain preferred embodiments of the compounds of the formula I, V is C (R8), especially CH. In certain other preferred embodiments, V is C (R8) 2 / especially CH2. In certain other preferred embodiments, V is 0. In certain other preferred embodiments, V is N (R8), especially NH. ' In certain preferred embodiments of the compounds of the formula I, Ri is independently each occurring, alkyl, preferably C-C alkyl, more preferably methyl. In certain other preferred embodiments, R1 is independently each occurrence, alkoxy. In certain other preferred embodiments of the compounds, Ri is independently every one that occurs, halo, preferably F or Cl. In certain other preferred embodiments, Ri is independently every occurrence, CF3. In certain other preferred embodiments, Ri is independently every occurrence, 0CF3. In certain other preferred embodiments, Ri is independently each occurrence, benzyloxy substituted with 0-3 Ri. In certain other preferred embodiments, Ri is independently each occurrence, aryloxy substituted with 0-3 Ri. In certain other preferred embodiments, Ri is independently every occurrence, aryl substituted with 0-3 Ra. In certain other preferred embodiments, Ri is independently each occurring, heteroaryl substituted with 0-3 Ri. In certain other preferred embodiments, Ri is independently occurring, hydroxy. In certain other preferred embodiments, Ri is independently occurring, alkanoyloxy. In certain other preferred embodiments, i is independently each occurring, methylenedioxy. In certain other preferred embodiments, Ri is independently each occurring, nitro. In certain other preferred embodiments, Ri is independently each occurring, nitrile. In certain other preferred embodiments, Ri is independently every occurrence, alkenyl. In certain other preferred embodiments, Ri is independently each occurring, alkynyl. In certain other preferred embodiments, Ri is independently each occurrence, alkylsulfoxide. In certain other preferred embodiments, Ri is independently each occurring, phenylsulphoxide substituted with 0-3 Ri. In certain other preferred embodiments, Ri is independently each occurrence, alkylsulfone. In certain other preferred embodiments, Ri is independently each occurring, phenylsulfone substituted with 0-3 Ri. In certain other preferred embodiments, Ri is independently occurring, alkylsulfonamide. In certain other preferred embodiments, Ri is independently each occurring, phenylsulfonamide substituted with 0-3 Ri. In certain other preferred embodiments, Ri is independently each occurring, heteroaryloxy substituted with 0-3 Ri. In certain other preferred embodiments, i is independently each occurring, heteroarylmethyloxy substituted with 0-3 Ri.

In certain other preferred embodiments, Ri is independently each occurring, alkylamido. In certain other preferred embodiments, Ri is independently each occurring, phenylamido substituted with 0-3 Ri. In certain preferred embodiments of the compounds of formula I, R2 is aryl substituted with 0-3 Ra, preferably substituted with non-Rx. In certain preferred embodiments, R2 is naphthyl substituted with 0-3 Rx, preferably 'substituted with non-Rx. In certain preferred embodiments, R 2 is heteroaryl substituted with 0-3 RX 1 preferably substituted with non Ri. In certain preferred embodiments of the compounds of formula I, R 3 is H. In certain other preferred embodiments, R 3 is C 1 -C alkyl. , preferably Ci. In certain other preferred embodiments, R3 is C3-Ce alkyl, preferably Cs-Cs alkyl. In certain other preferred embodiments, R3- is phenyl substituted with 0-3 Ri, especially phenyl. In certain preferred embodiments of the compounds of the formula I, R4 is independently each occurring, H. In certain preferred embodiments, R is independently each occurring, LC alkyl, preferably L-C3 alkyl, more preferably methyl, ethyl, or isopropyl. In certain preferred embodiments of the compounds of the formula I, R 4 is independently occurring, benzyl. In certain preferred embodiments, R is independently each, heteroarylmethyl. In certain preferred embodiments, R4 is independently occurring, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl. In certain preferred embodiments of the compounds of the formula I, both R4 groups, together with the nitrogen to which they are attached, form a heterocyclic ring of 4 to 6 ring atoms, where a carbon can optionally be replaced with N, O, S, or S02, and wherein any atom in the carbon ring can be optionally substituted with C 1 -C 4 alkyl, F, or CF 3. In certain more preferred embodiments, both R4 groups, together with the nitrogen to which they are linked, form a pyridine, piperidine, piperazine or morpholine ring. In certain preferred embodiments of the compounds of the formula I, Rs is independently each occurring, H. In certain preferred embodiments, R5 is independently each occurring, C1-C4 alkyl, preferably C?-C3 alkyl, more preferably methyl , ethyl, or isopropyl. In certain preferred embodiments of the compounds of the formula I, R8 is independently each occurring, H. In certain preferred embodiments, R? is independently each occurrence, C? -C alkyl, preferably C? -C3 alkyl, more preferably methyl, ethyl, or isopropyl. In certain preferred embodiments of the compounds of the formula I, R7 is independently each occurring, H. In certain preferred embodiments, R7 is independently each occurrence, C? -C4 alkyl, preferably C? -C3 alkyl, more preferably methyl, ethyl, or isopropyl. In certain preferred embodiments of the compounds of the formula I, R7 and R4 together with the nitrogen to which R is linked forms a nitrogen-containing ring containing 3-6 carbon atoms, especially pyrrolidinyl, pyrrolyl, piperidinyl, pyridinyl, azepanyl , and azepinyl.

In certain preferred embodiments of the compounds of the formula I, Rg is independently each occurring, H. In certain preferred embodiments, R8 is independently each occurring, C? -C alkyl, preferably C? -C3 alkyl, more preferably methyl, ethyl, or isopropyl. In certain preferred embodiments of the compounds of the formula I, R8 is independently each occurring, C3-C6 heteroalkyl, preferably methoxymethyl, ethoxyethyl, methoxyethyl, methylsulfanylmethyl, ethylsulfanylethyl, methylsulfanylethyl, methylaminoethyl, ethylaminoethyl and methylaminoethyl. In certain preferred embodiments of the compounds of the formula I, R8 is independently every occurrence, aryl substituted with 0-3 Rx, especially phenyl, tolyl, and xylyl. In certain preferred embodiments of the compounds of the formula I, Rg is independently each occurring, alkyl, preferably C 1 -C 6 alkyl, C 1 -C alkyl, preferably C 1 -C 3 alkyl, more preferably methyl, ethyl, or isopropyl . In certain preferred embodiments of the compounds of the formula I, R9 is independently each occurrence, alkoxy. In certain preferred embodiments of the compounds of formula I, Rg is independently each occurrence, halo. In certain preferred embodiments of the compounds of formula I, Rg is independently each occurrence, CF3. In certain preferred embodiments of the compounds of the formula I, Rg is independently each occurrence, OCF3. In certain preferred embodiments of the compounds of the formula I, Rg is each independently occurring, hydroxy. In certain preferred embodiments of the compounds of the formula I, Rg is each independently occurring, alkanoyloxy. In certain preferred embodiments of the compounds of the formula I, Rg is each independently occurring, methylenedioxy. In certain preferred embodiments of the compounds of the formula i, R9 is independently each occurring, nitro. In certain preferred embodiments of the compounds of the formula I, R9 is independently each occurring, nitrile. In certain preferred embodiments of the compounds of the formula I, R9 is independently each occurrence, alkenyl. In certain preferred embodiments of the compounds of the formula I, Rg is independently each occurrence, alkynyl. In certain preferred embodiments of the compounds of the formula I, R9 is independently each occurrence, alkylsulfoxide. In certain preferred embodiments of the compounds of the formula I, R9 is independently each occurrence, alkylsulfone. In certain preferred embodiments of the compounds of the formula I, Rg is independently each occurrence, alkylsulfonamido. In certain preferred embodiments of the compounds of the formula I, R9 is independently each occurring, alkylamido. In certain preferred embodiments of the compounds of the formula I, n is an integer from 0 to 3. More preferably, n is 0 to 2. Even more preferably, n is 0 to 1. Still more preferably, n is 0. In certain preferred embodiments of the compounds of the formula I, x is an integer from 1 to 2. More preferably, x is 1. In certain preferred embodiments of the compounds of the formula I, 1-2 carbon atoms in the A ring can be optionally replaced with N. In certain preferred embodiments, a carbon atom in ring A may optionally be replaced with N. In certain preferred embodiments, no carbon atom in ring A is replaced with N. Preferred compounds of formula I include: 1- (2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -1- phenylpropan-2-ol; 3- (methylamino) -1- (4-methyl-3, 4-dihydroquinoxalin-1 (2H) -yl) -1-phenylpropan-2-ol; 3- (methylamino) -1-phenyl-1- [4- (2, 2, 2-trifluoroethyl) -3,4-dihydroquinoxalin-1 (2H) -yl] propan-2-ol; 1- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -1- (3, 5-difluorophenyl) -3-. { methylamino) propan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1- (2-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl) propan-2-ol; 1- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -1-phenylpropan-2-ol; 3- (methylamino) -1- (6-methyl-2, 3-dihydro-4H-l, 4-benzoxazin-4-yl) -l-phenylpropan-2-ol; 1- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3- (methylamino) -l-phenylpropan-2-ol; 1- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -1-phenylpropan-2-ol; 1- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (2,2-dimethyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (2,2-dimethyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (ethylamino) -l-phenylpropan-2-ol; l- (2,3-dihydro-4H-l, 4-benzothiazin-4-yl) -l- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1- (2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl) propan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1- [2-phenyl-2,3-dihydro-4H-1, -benzoxazin-4-yl] propan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1- [2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl] propan-2-ol; and pharmaceutically acceptable salts thereof, particularly dichlorohydrate salts thereof. Particularly preferred compounds of formula I include: (1RS, 2SR) -1- (2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -l-phenylpropan-2- ol; (lS *, 2R *) - 3- (methylamino) -1- (4-methyl-3,4-dihydroquinoxalin-1 (2H) -yl) -1-phenylpropan-2-ol; (ÍS *, 2R *) -3- (methylamino) -1-phenyl-1- [4- (2, 2, 2-trifluoroethyl) -3,4-dihydroquinoxalin-l (2H) -yl] propan-2 ol; (SS, 2R) -1- (6-chloro-2,3-dihydro-4H-l, -benzoxazin-4-yl) -1- (3, 5-difluorophenyl) -3- (methylamino) propan-2- ol; (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (2-methyl-2, 3-dihydro-4H-1, 4-benzoxazin-4-yl) propan-2-ol; (SS *, 2R *) -1- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -l-phenylpropan-2-ol; (1S *, 2R *) -3- (methylamino) -1- (6-methyl-2, 3-dihydro-4H-l, 4-benzoxazin-4-yl) -l-phenylpropan-2-ol; (1S, 2R) -l- (6-chloro-2,3-dihydro-4H-1, 4-benzoxazin-4-yl) -3- (methylamino) -l-phenylpropan-2-ol; (IR, 2S) -1- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -l-phenylpropan-2-ol; (SS, 2R) -1- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; (SS, 2R) -1- (2,2-dimethyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2 -ol; (1S, 2R) -1- (2,2-dimethyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -l-phenylpropan-2-ol; (SS, 2R) -1- (2,3-dihydro-4H-l, 4-benzothiazin-4-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; (SS, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (2-phenyl-2,3-dihydro-4H-1, -benzoxazin-4-yl) propan-2-ol; (SS, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- [(2R) -2-phenyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl] propan -2-ol; (SS, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- [(2S) -2-phenyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl] propan -2-ol; and pharmaceutically acceptable salts thereof, particularly dichlorohydrate salts thereof. Some of the compounds of the present invention may contain chiral centers and such compounds may exist in the form of stereoisomers (ie, enantiomers). The present invention includes all those stereoisomers and some mixtures of the mimes including racemic mixtures. Racemic mixtures of the stereoisomers as well as the substantially pure stereoisomers are within the scope of the invention. The term "substantially pure" as used herein, refers to at least about 90 mol%, more preferably at least about 95 mol% and more preferably at least about 98 mol% of the desired stereoisomer that is present in relation to to other possible stereoisomers. Preferred enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by methods described herein. See for example Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron, 33: 2725 (1977); Eliel, E. L. Stereochemistry of Coal Compounds (McGraw-Hill,? Y, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions, p. 268 (E. L.

Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present invention includes prodrugs of the compounds of formula I. "Prodrug" as used herein, means a compound that is converted in vivo by metabolic means (eg, by hydrolysis) to a compound of formula I. Various forms of prodrugs are known in the art for example as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al., (Ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (Ed.). "Design and Application of Prodrugs", Textbook of Durg Design and Development, chapter 5, 113-191 (1991), Bundgaard, et al., Journal of Durg Deliver Reviews, 1992, 8: 1-38, Bundgaard, J. Pharmaceutical Sciences, 1988, 77: 285 et seq .; and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975). In addition, the compounds of formula I can exist in unsolvated form as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solvated forms are considered equivalent to unsolvated forms for the purpose of the present invention. The compounds of the present invention can be prepared in various forms well known to those skilled in the art. The compounds can be synthesized for example by the methods described below or variations therein as appreciated by the skilled artisan. All the processes described in association with the present invention are contemplated to be practiced at any scale, including milligram, gram, multigram, kilogram, multikilogram or commercial industrial scale. As will be readily understood, the present functional groups may contain protecting groups during the course of the synthesis. Protecting groups are known per se as chemical functional groups that can be selectively appended and removed from functionalities such as hydroxyl groups and carboxyl groups. These groups are present in a chemical compound to render such functionality inert to chemical reaction conditions to which the compound is exposed. Any variety of protecting groups can be employed with the present invention. Protecting groups that can be employed in accordance with the present invention can be described in Greene, T. W. And Wuts, P.M., Protective Groups in Organic Synthesis 2d. Ed. Wiley & Sons, 1991. The compounds of the present invention are suitably prepared in accordance with the following general description and specific examples. The variables used are as defined by formula I, unless indicated otherwise. The reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature. The compounds of the invention contain chiral centers, provide various stereoisomeric forms such as enantiomeric mixtures as well as optical isomers. The individual optical isomers can be prepared directly through asymmetric and / or stereospecific synthesis or by conventional chiral separation of optical isomers from the enantiomeric mixture. The compounds of the present invention are suitably prepared in accordance with the following general description and specific examples. The variables used are as defined by formula I, unless indicated otherwise. The reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature. The compounds of this invention contain chiral centers, provide various stereoisomeric forms such as enantiomeric mixtures as well as optical isomers. The individual optical isomers can be prepared directly through asymmetric and / or stereospecific synthesis or by conventional chiral separation of optical isomers from the enantiomeric mixture. In accordance with this invention, the compounds of the formula I are produced by the following reaction schemes (reaction schemes I to VII). Depending on the desired diastereomer, the compounds are prepared by means of different synthetic routes (diastereomer A - reaction schemes I and III, and diastereomer B - reaction scheme IV). If it is desired to synthesize compounds of the formula I-a, these can be prepared from the compounds of formula 18 and 19 in three steps starting with an opening in the regio and stereo selective ring of an epoxide of formula 19 with an appropriately substituted compound of formula 18 to produce the compounds of Formula 20 (Reaction Scheme I). Any conventional method for the selective regio and stereo opening of an epoxide can be used for this conversion. In accordance with the preferred embodiment of this invention, the compounds of the formula 18 are heated with the compounds of the formula 19 at temperatures from about 120 ° C to about 150 ° C in the absence of the solvent to provide the compounds of the formula 20. The compounds of formula 21 can be formed from the compounds of formula 20 by means of direct amidation with an appropriate amine. Any conventional method for direct conversion of an ester to an amide can be used by this conversion. In accordance with the preferred embodiment of this invention, the compounds of formula 20 are heated in a test tube at temperatures between about 50 ° C to about 100 ° C with an excess of alcoholic amine to form the compounds of the formula 21 which compounds for the formula Ia can be reduced to forms. Any conventional method for reducing an amide can be used for this conversion. In accordance with the preferred embodiment of this invention, the compounds of formula 21 are heated with borane-tetrahydrofuran complex at temperatures between about 50 ° C and up to about 90 ° C to provide compounds of formula Ia which can be converted to a pharmaceutically acceptable salt using any conventional method.

Reaction Scheme I you Where: A, Ri, n, R2, R, R8, Rg, U, V and W are as previously described. T = lower alkyl? - C4 If desired to produce compounds of the formula I-aa, which can be prepared by alkylation of the compounds of the formula 20 (Reaction Scheme III). Any conventional method for the alkylation of secondary alcohols can be employed for this conversion. In accordance with the preferred embodiment of this invention, the compounds of the formula 20 are treated with an alkyl halide using sodium hydride as a base to provide the compounds of the formula 21. The compounds of the formula 21 can be converted into 2 stages for the compounds of the formula I-aa in an identical manner as previously described for the conversion of the compounds of the formula 20 to the compounds of the formula Ia (Reaction Scheme I). The compounds of the formula I-a can be converted to a pharmaceutically acceptable salt using any conventional method.

Reaction scheme II Where: A, Ri, n, R2, R4, R8, Rg, U, V and W are as previously described R3 = lower alkyl C? -C3; T = C 1 -C 4 lower alkyl Alternatively, the compounds of the formula I-a and I-aa can be formed from the compounds of the formula 23 (Reaction Scheme III). The compounds of the formula I-a can be formed from the compounds of the formula 23 to selectively convert the primary alcohol to a starting group and displace with a desired amine. Any conventional method for the selective conversion of a primary alcohol to a starting group is displaced with an amine which can be used for this conversion. In accordance with the preferred embodiment of this invention, the diol of the formula 23 is treated with para-toluenesulfonyl chloride in pyridine to form the tosylate of the formula 24, which is converted to the compound of the formula Ia by means of treatment with a Excess of an alcoholic amine solution, either at room temperature or heated to about 40 ° C to around 802C in a sealed tube. The compounds of the formula I-a can be converted to a pharmaceutically acceptable salt using any conventional method. If it is desired to form the compounds of the formula I-aa, they can be prepared from the compounds of the formula 24 by means of alkylation followed by amination. Any conventional method of alkylating a hydroxyl group in the presence of a tosyl group can be used for this conversion. In accordance with the preferred embodiment of this invention, the compounds of the formula 24 are treated with an alkyl trifluoromethanesulfonate, for example methyl trifluoromethanesulfonate, in the presence of a hindered base, for example 2,6-di-tert-butyl-4 -methylpyridine. The reaction can be carried out either at room temperature or heated to about 40 ° C to about 80 ° C. The compounds of the formula 25 can be converted to the compounds of the formula I-aa as previously described for the synthesis of the compounds of the formula I-a. The compounds of formula I-aa can be converted to a pharmaceutically acceptable salt using any conventional method.

Reaction scheme III Where: A, Ri, n, R2, R4, R8, Rg, I, U, V and W are as previously described R3 = lower alkyl C1-C3; OTs = para-toluenesulfonilate or any conventional starting group If it is desired to form the compounds of the formula I-b, they can be formed from the compounds of the formula (Reaction scheme IV). The compounds of the formula 23 can be converted in four stages to the compounds of the formula I-b. This route involves the selective protection of the primary alcohol followed by the conversion of the secondary alcohol to a starting group. Any conventional method for the selective protection of a primary alcohol, and any conventional method for converting a secondary alcohol into a starting group that can be used for this conversion. In accordance with the preferred embodiment of this invention, the compounds of the formula 23 are treated with para-nitrobenzoyl chloride in pyridine at a lower temperature (preferably below about 0 ° C) to form the compounds of the formula 26. The compounds of the formula 26 can be converted to a mesylate secondary of formula 27 by reaction with methanesulfonyl chloride in dichloromethane using triethylamine as the base. The reaction is preferably carried out at temperatures between about -15 ° C and about 10 ° C. The deprotection of the primary alcohol in the compounds of the formula 27 is allowed for the formation of a primary epoxide through a SN2 reaction which results in an inversion of the stereocenter. Any conventional method for the deprotection of a primary alcohol, and any conventional method for the formation of epoxide in an alpha starting group can be employed for this conversion. In accordance with the preferred embodiment of this invention, the compounds of formula 27 are treated with an aqueous solution of a suitable base in organic solvent, preferably, aqueous sodium hydroxide in dioxane. The resulting epoxide of formula 28 can be a regioselectively opened ring with an amine to produce the desired aminoalcohol of formula I-b. Any conventional method for the open regioselective ring of a primary epoxide can be used for this conversion. In accordance with the preferred embodiment of this invention, the compounds of formula 28 are treated with an excess of an alcoholic amine solution in a sealed flask, either at room temperature or heated to about 40 ° C to about 90 ° C. ° C. The compounds of formula I-b can be converted to a pharmaceutically acceptable salt using any conventional method.

Reaction scheme IV Where: A, Ri, n, R2, R4, R8, Rio, U, V and W are as previously described R9 is H PNB = para-nitrobenzoyl or any conventional protecting group; OMs = methanesulfonate or any conventional starting group; T = lower alkyl C? -C4. If it is desired to form the compounds of the formula I-bb, they can be formed from the compounds of the formula Ib in 3 steps (Reaction Scheme V) in an identical manner as previously described for the conversion of the compounds of the formula Ib for the compounds of the formula I-bb (Reaction scheme III). The compounds of the formula I-bb can be converted to a pharmaceutically acceptable salt using any conventional method.

Reaction scheme V Where: A, Rx, n, R2, R4, R8, R9, Rio, U, V and W are as previously described R3 = lower alkyl C? -C3, P == protective group, preferably tert-butoxycarbonyl The compounds of Formula 23 are formed by means of a regio- and stereo-selective ring opening of an appropriately substituted epoxide of formula 17 (formed by means of an epoxidation of an appropriately substituted allyl alcohol) with an appropriately substituted compound of formula (Reaction scheme VI). Any conventional method for the regio- and stereo-selective ring opening of an epoxide can be used for this conversion. According to the preferred embodiment of this invention, the compounds of formula 18 are treated with a base, for example sodium hydride, sodium tert-butoxide, potassium hydroxide, potassium tert-butoxide or potassium hydroxide, then it is treated with the epoxide of the formula 17. The epoxide of the formula 17 can be pretreated with a Lewis acid, for example titanium iso-propoxide, boron trifluoride, etc. to ensure the regio-selective ring opening. The reaction occurs at room temperature for a duration of about 2 to about 72 hours. Alternatively, compounds of formula 18 which are suitably nucleophilic can be heated with the epoxide of formula 17 at temperatures from about 50 ° C to about 170 ° C to form the compounds of formula 23. The epoxidation of transboundary alcohols Allylic can be carried out either racemically or asymmetrically using methods described in the literature. In accordance with the preferred embodiment of this invention, the racemic epoxidation is conducted with either peracetic acid or meta-chloroperbenzoic acid. If it is desired to produce a simple enantiomer of the compounds of formula I, the asymmetric epoxidation of an allyl alcohol can be carried out with tert-butylhydroperoxide or eumenohydroperoxide in the presence of the appropriate tartrate ester, titanium (IV) isopropoxide, and molecular sieves. This method is well established in the literature (eg K. B. Sharpless, et al, J. Org. Chem. 1986, 51, 3710). The compounds of the formula 18 and the starting allyl alcohols are either available from commercial sources or are accessible through well-established methods in the literature.

Reaction scheme VI Where: A, Ri, n, R2, R8, R9, Rio, U, V and W are as previously described Compounds of formula 19 can be formed either racemically or asymmetrically using methods described in the literature starting with either esters trans-allylic or trans-allylic alcohols (Reaction Scheme VII). In accordance with the preferred embodiment of this invention, the racemic epoxidation of the trans-allyl ester is conducted using di- (trifluoromethyl) dioxirane formed in-situ of trifluoroacetone and oxone (Yang, D .; Wong, M.-; Yip J Org Chem. 1995, 60, 3887-3889). If it is desired to produce a simple enantiomer of the compounds of formula I, the asymmetric epoxidation of an allyl ester can be carried out with oxone and a chiral ketone as reported in the literature (WY, Wu, X. She, Y. Shi , J. Am. Chem. Soc. 2002, 124, 8792). Alternatively, the compounds of the formula 19 can be formed by means of the oxidation and esterification of the compounds of the formula 17 (described in Reaction Scheme VI). Any conventional method for the oxidation of an epoxy alcohol and any conventional method for the esterification of an epoxy acid that can be used for this conversion. In accordance with the preferred embodiment of this invention, the epoxy alcohol 17 is oxidized with sodium periodate and catalytic ruthenium trichloride in carbon tetrachloride, buffer solution with sodium bicarbonate. The resulting acid can be esterified with diazomethane or with catalytic sulfuric acid in ethanol to form the compounds of formula 19.

Reaction scheme VII Where: R2, R8 and R9 are as previously described and where: T = C? -C4 lower alkyl? In other embodiments, the invention is directed to pharmaceutical compositions, comprising: a. at least one compound of formula I, or pharmaceutically acceptable salt thereof; and b. at least one pharmaceutically acceptable carrier.

Generally, the compound of formula I, or a pharmaceutically acceptable salt thereof, will be present at a level of from about 0.1%, by weight, to about 90% by weight, based on the total weight of the pharmaceutical composition, based on the total weight of the pharmaceutical composition. Preferably, the compound of the formula I, or a pharmaceutically acceptable salt thereof, will be present at a level of at least about 1%, by weight, based on the total weight of the pharmaceutical composition. More preferably, the compound of the formula I, or a pharmaceutically acceptable salt thereof, will be present at a level of at least about 5%, by weight, based on the total weight of the pharmaceutical composition. Even more preferably, the norepinephrine reuptake inhibitor or a pharmaceutically acceptable salt thereof will be present at a level of at least about 10%, by weight, based on the total weight of the pharmaceutical composition. Still more preferably, the compound of the formula I, or a pharmaceutically acceptable salt thereof, will be present at a level of at least about 25%, by weight, based on the total weight of the pharmaceutical composition. Such compositions are prepared according to pharmaceutically acceptable methods, such as are described in Remington's Pharmaceutical Sciences, I7th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985). The pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable. The compounds of this invention can be administered orally or parenterally, either pure or in combination with conventional pharmaceutical carriers. Applicable solid carriers may include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, flow improvers, compression aids, binders or tablet disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid that is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, low melting waxes, and ion exchange resins. Liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical liquid additives such as solubilizers, emulsifiers, buffer solutions, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives, such as the above, for example cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, for example glycols) and their derivatives and oils (for example fractionated coconut oil and peanut oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. Liquid pharmaceutical compositions which are sterile solutions or suspensions may be administered by for example intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration can be a liquid or solid form of composition. Preferably, the pharmaceutical composition is in a unit dosage form for example as tablets, capsules, powders, solutions, suspensions, emulsions, granules or suppositories. In such form, the composition is divided into unit doses containing suitable amounts of the active ingredient; the unit dosage forms can be packaged compositions for example packaged powders, vials, ampoules, pre-filled syringes or sachets containing liquids. The unit dosage form may be for example a capsule or tablet itself or may be the appropriate number of any such compositions in the form of a pack. In another embodiment of the present invention, the compounds useful in the present invention can be administered to a mammal with one or more other active pharmaceutical agents such as those agents that are used to treat any other medical condition present in the mammal. Examples of such active pharmaceutical agents include pain-releasing agents, anti-angiogenic agents, anti-neoplastic agents, antidiabetic agents, anti-infective agents, gastrointestinal agents or combinations thereof. The one or more other active pharmaceutical agents can be administered in a therapeutically effective amount simultaneously (such as individually at the same time or together in a pharmaceutical composition), and / or successively with one or more of the compounds of the present invention. . The term "combination therapy" refers to the administration of two or more therapeutic agents or compounds to treat a therapeutic condition or disorder described in the present disclosure, for example, hot flashes, sweating, thermoregulatory related condition or disorders, or others. Such administration includes the use of each type of therapeutic agent in a parallel manner. In any case, the treatment regimen will provide beneficial effects of the drug combination in the treatment of the conditions and disorders described herein. The route of administration can be any route, which effectively transports the active compound of the formula I, or a pharmaceutically acceptable salt thereof, to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal, such as passive or iontophoretic, or parenteral, for example, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or ointment. Additionally, administration of the compounds of formula I, or pharmaceutically acceptable salt thereof, with other active ingredients may be parallel or simultaneous. It is believed that the present invention described, presents a substantial advance in the field of treatment, alleviation, inhibition and / or prevention of conditions relieved by the reabsorption of monoamine including, inter alia, vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal disorders or genitourinary, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders and combinations thereof, particularly those conditions selected from the group consisting of major depressive disorder, vasomotor symptoms, impulse and stress urinary incontinence, fibromyalgia, pain, neuropathy diabetic, and combinations thereof. Thus in one embodiment, the present invention is directed to methods of treating or preventing a condition ameliorated by the reabsorption of monoamine in a subject in need thereof, comprising the step of: administering to the subject an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

Conditions relieved by monoamine reabsorption include those selected from the group consisting of vasomotor symptoms, sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders and combinations thereof, particularly those conditions selected. of the group consisting of major depressive disorder, vasomotor symptoms, impulse and stress urinary incontinence, fibromyalgia, pain, diabetic nephropathy, and combinations thereof. "Vasomotor symptoms", "symptoms of vasomotor instability" and "vasomotor disturbances" include but are not limited to, hot flashes (hot flashes), insomnia, sleep disturbances, mood disorders, irritability, excessive perspiration, night sweats, fatigue and the like , caused by, inter alia, thermoregulatory dysfunction. The term "embarrassment" is a term recognized in the art, which refers to an episode disturbance in body temperature, which typically consists of a sudden flushing of the skin, usually accompanied by perspiration in a subject. The term "sexual dysfunction" includes, but is not limited to, condition related to desire and / or excitement.

As used herein, "gastrointestinal or genitourinary disorders" include irritable bowel syndrome, symptomatic GERD, hypersensitive esophagus, non-ulcer dyspepsia, non-cardiac chest pain, biliary dyskinesia, sphincter of Oddi dysfunction, incontinence ( that is, impulse incontinence, stress incontinence, genuine tension incontinence, and mixed incontinence) (which includes emptying stool or urine, and leaking or leaking stool or urine that may be due to one or more causes including but not are not limited to sphincter control that alters pathology, loss of cognitive function, overdistention of the bladder, hyperreflexia and / or involuntary relaxation of the ureter, weakness of the muscles associated with the bladder or neurological abnormalities), interstitial cystitis (bladder) irritable) and chronic pelvic pain (which includes but is not limited to vulvodynia, prostatodynia and proctalgia). As used herein, "chronic fatigue syndrome" (CFS) is a condition characterized by selected physiological symptoms of muscle weakness, pain and discomfort, excessive sleepiness, malaise, fever, sore throat, lymph nodes. firm lymphatics, impaired mental memory and / or concentration, insomnia, disordered sleep, localized sensitivity, diffuse pain and fatigue and combinations thereof. As used herein, "fibromyalgia syndrome" (FMS) includes FMS and other somatoform disorders, including FMS associated with depression, somatization disorder, conversion disorder, pain disorder, hypochondriasis, dysmorphic disorder of the body, somatofor or undifferentiated disorder, and somatoform NOS. FMS and other somatoform disorders are accompanied by physiological symptoms selected from a generalized increased perception of sensory stimuli, abnormalities in the perception of pain in the form of allodynia (pain with innocuous stimulation), abnormalities in the perception of pain in the form of hyperalgesia (sensitivity increasing to painful stimuli) and combinations thereof. As used herein, "nervous system disorders" include addictive disorders (including those due to alcohol, nicotine and other psychoactive substances) and withdrawal syndrome, learning associated with age and mental disorders (including Alzheimer's disease). , anorexia nervosa, bulimia nervosa, attention deficit disorder with or without hyperactivity disorder, bipolar disorder, pain, cyclothymic disorder, depression disorder (including major depressive disorder, refractory depression, depression in adolescents and minor depression), dysthymic disorder, generalized anxiety disorder (GAD), obesity (that is, weight reduction of obese or overweight patients), obsessive-compulsive disorders and spectrum-related disorders, oppositional provocative disorder, panic disorders, post-tension disorder -traumatic, premenstrual dysphoric disorder (ie, premenstrual syndrome and luteal phase dysphoric disorder), psychotic disorders (including schizophrenia, schizoaffective and schizophrenic disorders), seasonal affective disorder, sleep disorders (such as narcolepsy and enuresis), social phobia (including social anxiety disorder), selective inhibition of serotonin reuptake (SSRI), "burnout" syndrome (ie, where a patient fails to maintain a satisfactory response to SSRI therapy after an initial period of satisfactory response) . As used herein, "pain" includes both acute pain and chronic pain, which may be centralized pain, peripheral pain or combination thereof. The term includes many different types of pain including, but not limited to, neuropathic pain, visceral pain, bone pain, cancer pain, inflammatory pain, and combinations thereof, such as low back pain, atypical chest pain , headache such as group headache, migraine, herpes neuralgia, phantom hip pain, pelvic pain, myofascial face pain, abdominal pain, neck pain, central pain, dental pain, opioid resistant pain, visceral pain, pain from surgery, pain due to bone injury, pain during delivery and delivery, pain resulting from burns, postpartum pain, angina pain, neuropathic pain such as peripheral neuropathy and diabetic neuropathy, post-operative pain , and pain that is co-morbid with nervous system disorders described herein. As used herein, the term "acute pain" refers to centralized or peripheral pain that is intense, localized, sharp, or stabbing, and / or deaf, aching, diffuse, or burning by nature and that occurs during periods of time. short of time. As used herein, the term "chronic pain" refers to centralized and peripheral pain that is intense, localized, sharp, or throbbing, and / or deaf, painful, diffuse, or burning by nature and that occurs during periods of time. extended time (ie, persistent and / or recurring regularly), including, for the purposes of the present invention, neuropathic pain and cancer pain. Chronic pain includes neuropathic pain, hyperalgesia, and / or allodynia.

As used herein, the term "neuropathic pain" refers to chronic pain caused by damage to or pathological changes in the peripheral or central nervous systems. Examples of pathological changes related to neuropathic pain include prolonged peripheral or central neuronal sensitization, central sensitization related to damage to the inhibitory and / or exhibiting functions of the nervous system and annal interactions between the parasympathetic and sympathetic nervous systems. A wide range of clinical conditions may be associated with or form the basis for neuropathic pain including, for example, diabetes, post-traumatic amputation pain (damage to the nerve caused by injury resulting in peripheral and / or central sensitization such as ghost chain), lower back pain, cancer, chemical injury, toxins, other major surgeries, damage to the peripheral nerve due to compression due to traumatic injury, post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal neuralgia, dystrophy sympathetic reflex, casualgia, thalamic syndrome, nerve root alvusion, reflex sympathetic dystrophy or post thoracotomy pain, nutritional deficiencies, or viral or bacterial infections such as herpes zoster or human immunodeficiency virus (HIV), and combinations thereof . Also included in the definition of neuropathic pain is a condition secondary to metastatic infiltration, painful adiposis, burns, central pain conditions related to thalamic conditions, and combinations thereof. As used herein, the term "hyperalgesia" refers to pain that increases in sensitivity to typically noxious stimuli. As used herein, the term "allodynia" refers to an increase in sensitivity to typically non-harmful stimuli. As used herein, the term "visceral pain" refers to pain associated with or resulting from malignancies of internal organs, such as, for example, ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn's disease, rheumatological (atralgia), tumors, gastritis, pancreatitis, organ infections, disorders of the biliary tract, and combinations thereof.

As used herein, the term "specific pain of a female subject" refers to pain that may be acute and / or chronic associated with female conditions. Such pain groups include those that are found only and predominantly in female subjects, including pain associated with menstruation, ovulation, pregnancy or delivery, abortion, ectopic pregnancy, retrograde menstruation, rupture of a follicular or corporeal luteal cyst, irritation of the pelvic viscera, uterine fibroids, adenomyosis, endometriosis, infection and inflammation, pelvic organ ischemia, obstruction, intra-abdominal adhesions, anatomical distortion of the pelvic viscera, abscesses in the ovaries, loss of pelvic support, tumors, pelvic congestion or pain referred to non-gynecological causes, and combinations thereof. In one embodiment, the present invention is directed to methods of treating or preventing vasomotor symptoms in a subject in need thereof, comprising the step of: administering to the subject an effective amount of at least one compounds of formula I or a salt pharmaceutically acceptable thereof. When estrogen levels are low or estrogen is absent, normal levels between NE and 5-HT are altered, and this altered change in neurotransmitter levels can result in changes in the sensitivity of the thermoregulatory center. The altered chemical levels can be translated into the thermoregulatory center as a sensation of heat as a response, the hypothalamus can activate the descending autonomous trajectories and result in the dissipation of heat through vasodilatation and sweating (Figure 1). In this way, the elimination of estrogen can result in altered norepinephrine activity. Norepinephrine synthesized in the brainstem pericaria is released at the nerve terminals in the hypothalamus and brainstem. In the hypothalamus, the NE regulates the activity of the neurons that reside in the thermoregulatory center. In the brainstem, NE enervates serotonergic neurons (5HT) and acts through post-synaptic adrenergic receptors? and adrenergic 2 stimulates the activity of the serotonin system. In response, 5-HT neurons also modulate the thermoregulatory center activity and feed NE neurons. By means of this feedback connection, 5-HT, which acts by means of 5-HT2ai receptors, inhibits the activity of NE neurons. Norepinephrine in the synaptic cleft is also taken by the NE transporter (NET) located in the NE neurons. The transporter recycles NE and makes it available for multiple neurotransmission (Figure 2). The present invention provides a treatment for vasomotor symptoms by methods for recovering reduced norepinephrine activity. Norepinephrine activity in the hypothalamus or brainstem may be elevated by (i) blocking the activity of the NE transporter, (ii) blocking the activity of the a2 presynaptic adrenergic receptor with an antagonist, or (iii) blocking the activity of 5-HT in NE neurons with a 5-HT2a antagonist. In another embodiment, the present invention is directed to methods for treating or preventing a depression disorder in a subject in need thereof, comprising the step of: administering to the subject an effective amount of at least one compound of the formula I or a pharmaceutically acceptable salt thereof. In still other embodiments, the present invention is directed to methods of treating or preventing sexual dysfunction in a subject in need thereof, comprising the step of: administering to the subject an effective amount of at least one compound of the formula I or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention is directed to methods for treating or preventing a gastrointestinal or genitourinary disorder, particularly stress incontinence or urge urinary incontinence, in a subject in need thereof, comprising the step of: administering to the subject a effective amount of a compound of the formula I or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to methods for treating or preventing chronic fatigue syndrome in a subject in need thereof, comprising the step of: administering to the subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention is directed to methods for treating or preventing fibromyalgia syndrome in a subject in need thereof, comprising the step of: administering to the subject an effective amount of a compound of formula I or a salt pharmaceutically acceptable thereof. In additional embodiments, the present invention is directed to methods of treating or preventing pain in a subject in need thereof, comprising the step of: administering to the subject an effective amount of at least one compound of the formula I or a salt pharmaceutically acceptable thereof. The pain may be, for example, acute pain (of short duration) or chronic pain (regularly recurrent or persistent). The pain can also be centralized or peripheral.

Examples of pain that can be acute or chronic and that can be treated in accordance with the methods of the present invention include inflammatory pain, musculoskeletal pain, bone pain, lumbosacral pain, neck or upper back pain, visceral pain, somatic pain, neuropathic pain, cancer pain, pain caused by injury or surgery such as pain from burning or dental pain, or headaches such as migraines or tension headaches, or combinations of these pains. Someone with experience in art will recognize that these pains can overlap with each other. For example, pain caused by inflammation can also be visceral or musculoskeletal in nature. In a preferred embodiment of the present invention the compounds useful in the present invention are administered in mammals to treat chronic pain such as neuropathic pain associated for example with damage to or pathological changes in the peripheral or central nervous systems; cancer pain; visceral pain associated with for example the abdominal, pelvic, and / or perineal regions or pancreatitis; musculoskeletal pain associated with for example the lower or upper back, spine, fibromyalgia, temporomandibular joint, or myofascial pain syndrome; bone pain associated with for example, bone or joint degenerative disorders such as osteoarthritis, rheumatoid arthritis, or spinal stenosis; headaches such as migraine or tension headaches; or pain associated with infections such as HIV, sick cell anemia, autoimmune disorders, multiple sclerosis, or inflammation such as osteoarthritis or rheumatoid arthritis. In a more preferred embodiment, the compounds useful in this invention are used to treat chronic pain which is neuropathic pain, visceral pain, musculoskeletal pain, bone pain, cancer pain or inflammatory pain or combinations thereof, in accordance with the methods described in the present. Inflammatory pain can be associated with a variety of medical conditions such as osteoarthritis, rheumatoid arthritis, surgery, or injury. Neuropathic pain may be associated with eg diabetic neuropathy, peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, casualgia, talami syndrome, avulsion of the nerve root, or nerve damage caused by injury resulting in peripheral and / or central sensitization such as phantom limb pain, reflex sympathetic dystrophy or post-toractomic pain, cancer, chemical lesions, toxins, nutritional deficiencies, or viral or bacterial infections such as herpes zoster or HIV, or combinations thereof. The methods of use for the compounds of this invention also include treatments in which neuropathic pain is a secondary condition to metastatic infiltration, painful adiposis, burns, or central pain conditions related to thalamic conditions. As mentioned previously, the methods of the present invention can be used to treat pain that is somatic and / or visceral in nature. For example, somatic pain that can be treated in accordance with the methods of the present invention including pain associated with structural or soft tissue injury experienced during surgery, dental procedures, burns, or traumatic bodily injury. Examples of visceral pain that can be treated in accordance with the methods of the present invention include those types of pain associated with or resulting from malignancies of internal organs such as ulcerative colitis, irritable bowel syndrome, irritable bowel, Crohn's disease, rheumatologic (arthralgias), tumors, gastritis, pancreatitis, organ infections, or disorders of the biliary tract, or combinations thereof. One skilled in the art will also recognize that pain treated in accordance with the methods of the present invention may also relate to conditions of hyperalgesia, allodynia, or both. Additionally, chronic pain can be with or without central sensitization.

The compounds useful in this invention may also be used to treat acute and / or chronic pain associated with female conditions, which may also be referred to as female specific pain. Such pain groups include those that are found only or predominantly in female subjects, including pain associated with menstruation, ovulation, pregnancy or childbirth, abortion, ectopic pregnancy, retrograde menstruation, rupture of a follicular corpus or body cyst , pelvic viscera irritation, uterine fibriudes, adenomyosis, endometriosis, infection and inflammation, pelvic organ ischemia, obstruction, intra-abdominal adhesions, anatomical distortion of the pelvic viscera, ovarian abscesses, loss of pelvic support, tumors, pelvic congestion or referenced pain of non-gynecological causes. The present invention is further defined in the following Examples, in which all parts and percentages are by weight the degrees are centigrade, unless stated otherwise. It should be understood that these examples, while indicating preferred embodiments of the invention, are given by way of illustration only. From the foregoing discussion and these examples, one skilled in the art can discern the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various uses and conditions. .

EXAMPLES EXAMPLE 1: (1RS, 2SR) -1- (lH-indol-1-yl) -3- (4-methyl-piperazin-1-yl) -1-phenyl-propan-2-ol dichlorohydrate Step 1: A mixture of indole (2.34 g, 20 mmol) and powdered solid potassium hydroxide (1.12 g, 20 mmol) was stirred for 30 minutes under nitrogen at room temperature. The trans-3-phenylglycidol (3.0 g, 20 mmol) in dimethyl sulfoxide (1 L) was then added and the mixture was stirred at 70 ° C for 2 hours until no epoxide remained. The mixture was then cooled and partitioned between water and dichloromethane. The organic layer was separated, washed with water several times, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by means of Biotage chromatography (FlasH40i, silica, 10%, 20%, 30% ethyl acetate / hexane) to yield 1.92 g (36%) of (2RS, 3RS) -3-indol-l-yl-3-phenyl-propan-l, 2-diol as an oil. 1 H NMR (DMSO): d 3.27 (m, 2H, CH2OH), d4.45 (m, 1 H, CHOH), 54.80 (t, ÍH, CH2OH), 55.20 (d, ÍH, CHOH), d5.60 (d, 1 H, CHPh); MS (ESI) m / z 268 ([M + H] +).

Step 2: A solution of (2RS, 3RS) -3-indol-l-yl-3-phenyl-propane-1,2-diol (1.83 g, 6.8 mmol) and p-toluenesulfonyl chloride (1.31 g, 6.8 mmol ) in anhydrous pyridine (10 L) was stirred at room temperature under nitrogen for 15 hours. The mixture was then diluted with water (10 L), quenched with a 2N aqueous solution of hydrochloric acid in a water / ice bath until the solution was pH = 3, and extracted with dichloromethane. The organic layer was washed with water again, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by means of Biotage chromatography (FlasH40i, silica, 10%, 25% EtOAc / hexane) to yield 1.98 g (69%) of 2-hydroxy-3-indol-1-yl-3-phenyl ester. propyl of the acid (2RS, 3RS) -toluene-4-sulfonic acid as a white solid. ^ NMR (DMSO): d3.70 and d3.85 (dd and dd, 2H, CH2OTs), d4.80 (, 1 H, CHOH), d5.52 (d, 1H, CHPh), d5.82 (d , ÍH, CHOH); MS (ESI) m / z 422 ([M + H] +).

Step 3: A mixture of 2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester of (2RS, 3RS) -toluene-4-sulfonic acid (0.185 g, 0.4 mmol), 1-methyl piperazine (0.05 L, 0.4 mmol) and potassium carbonate (0.07 g, 0.44 mmol) in acetonitrile (10 mL) was stirred under reflux under nitrogen for 24 hours. After cooling, the mixture was filtered and the filtrate was concentrated and purified by means of Biotage chromatography (5% methanol / dichloromethane) to give a white solid of (1RS, 2SR) -1- (1H-indol-1-yl) -3- (4-methylpiperazin-1-yl) -1- phenylpropan-2-ol. The free base was dissolved in a minimum amount of ethanol and treated with a 1N etheral solution of hydrochloric acid until the solution was pH = 3 followed by diethyl ether. The product was then crystallized by adding a minimum amount of hexane to provide the title compound, (1RS, 2SR) -1- (1H-indol-1-yl) -3- (4-methylpiperazin-1-yl) dichlorohydrate. -1-phenylpropan-2-ol as an off white solid. MS m / z 350 ([M + H] +); HRMS: calculated for C22H2 N3o + H +, 350.22269; found (ESI, [M + H] +), 350.2228.

EXAMPLE 2: Dichlorohydrate of (1RS, 2SR) -1- (2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3- (methylamino) -1-phenylpropan-2-ol A mixture of 3,4-dihydro-2H-benzo [1,4] oxazine (2027 g 15.00 mmol) and trans-ethyl-3-phenylglycidate (2883 g, 15.00 mmol) was stirred at 135 ° C for 12 hours. After cooling, the viscous liquid was purified by Biotage Horizon medium (FLASH 40 M, silica, 10%, 20%, 30% EtOAc / hexane) and recrystallized (minimum chloroform / hexane / -20 ° C heating) to produce 4.261 g (87%) (2RS, 3RS) -3- (2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -2-hydroxy-3-phenylpropanoic acid ethyl ester as a white solid. MS (ESI) m / z 328.0 ([M + H] +). A mixture of ethyl (2RS, 3RS) -3- (2, 3-dihydro-4H-1, 4-benzoxazin-4-yl) -2-hydroxy-3-phenylpropanoate (283 mg, 0.864 mmol) and Methanolic methylamine (5 mL, 33% in ethanol) was stirred at 70 ° C in a sealed tube for 5 hours. After cooling, all volatiles were removed under reduced pressure. The resulting yellow solid was purified by means of Biotage Horizon (FLASH 12 S, silica, 20%, 35%, 50% EtOAc / hexane) to produce 235 mg (87%) (2RS, 3RS) -3- (2,3-Dihydro-4H-l, 4-benzoxazin-4-yl) -2-hydroxy-N-methyl-3-phenylpropanamide as a white solid. EM (ESI) m / z 311.0 ([M-H] -). A solution of (2RS, 3RS) -3- (2, 3-dihydro-4H-l, 4-benzoxazin-4-yl) -2-hydroxy-N-methyl-3-phenylpropanamide (216 mg, 0.692 mmol) in tetrahydrofuran dry (3 mL) under nitrogen was treated dropwise with a borane solution (1.0 M in tetrahydrofuran, 3.50 mL, 3.50 mmol), and the resulting solution was stirred at 70 ° C for 2 hours. After cooling in an ice bath, the reaction mixture was treated with a 2N aqueous solution of hydrochloric acid (1 mL), and the resulting mixture was heated at 50 ° C for 30 minutes. The tetrahydrofuran was removed under reduced pressure, and the aqueous residue was dissolved in water (5 L) and washed with diethyl ether (10 mL). The aqueous layer was made alkaline with solid potassium carbonate and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated under reduced pressure to yield 202 mg (98%) (1RS, 2SR) -1- (2,3-dihydro-4H-1, - benzoxazin-4-yl) -3- (methylamino) -1-phenylpropan-2-ol as a colorless oil. This oil was dissolved in ethanol (1 mL) and treated with a solution of hydrochloric acid (0.5 mL, 4M in 1,4-dioxane). All volatiles were removed again under reduced pressure. The resulting white solid was recrystallized (minimum ethanol / ethyl ether / -20 ° C heating) to yield 105 mg (41%) (1RS, 2SR) -1- (2,3-dihydro-4H-l, -benzoxazin-4-yl) dichlorohydrate) -3- (methylamino) -1-phenylpropan-2-ol as a white solid. MS (ESI) m / z 299.0 ([M + H] +); HRMS: calculated for C? 8H22 202 + H +, 299.17540; found (ESI, [M + H] +), 299.1755.

EXAMPLE 3: (ÍS, 2R) -1- (3-chlorophenyl) -1- (IH-indol-1-yl) -3- (methylamino) propan-2-ol hydrochloride Step 1: A suspension of sodium hydride (60% in mineral oil, 4.0 g, 100 mmol) in tetrahydrofuran (600 mL) was treated dropwise with diethyl ethoxycarbonylmethylphosphonate (20 mL, 100 mmol) at 23 ° C. After 1 hour s, 3-chlorobenzaldehyde (9.3 mL, 82 mmol) was added. After an additional 1 hour, the reaction was quenched with water (20 L) and concentrated in vacuo to remove tetrahydrofuran. The residue was taken up in ethyl acetate (300 mL), washed with water (5 x 300 mL) and brine (1 x 300 L), dried (magnesium sulfate) and concentrated in vacuo to give ethyl ester of ethyl acetate. (2E) -3- (3-chlorophenyl) -acrylic acid (18 g, quantitative) as a pale yellow, clear oil. MS (ESI) m / z 210 ([M + H] +).

Step 2: Ethyl ester of (2E) -3- (3-Chlorophenyl) -acrylic acid (17.6 g, 82 mmol) was dissolved in dry dichloromethane (300 mL), cooled to -78 ° C and treated with a solution of di-isobutylaluminum hydride (1.0 M solution in hexane, 250 mL, 250 mmol) for 20 minutes. After 1.5 total hoursThe reaction was quenched with methanol (75 mL) at -78 ° C, warmed to 23 ° C and treated with a saturated aqueous solution of sodium potassium tartrate (300 mL). The aqueous phase was separated and extracted with dichloromethane (2 x 300 mL). The combined extracts were washed with a saturated aqueous solution of sodium tartrate (450 mL), dried (sodium sulfate) and concentrated under vacuum to give a cloudy yellow oil (14.6 g) which was pre-absorbed on silica gel ( 25 g). Instant column chromatography (silica 250 g, 10%, 20% ethyl acetate / hexanes) provided (2E) -3- (3-chlorophenyl) prop-2-en-l-ol (12.4 g, 90%) as a colorless, clear oil. MS (ESI) m / z 151 ([M + H-H20] +).

Step 3: In a manner analogous to EXAMPLE 10, step 4, [(2R, 3R) -3- (3-chlorophenyl) oxirane-2-yl] methanol was prepared from (2E) -3- (3-chlorophenyl) prop -2-in-l-ol. MS (ESI) m / z 167 ([M + H-H20] +).

Step 4 (Method A): In a manner analogous to EXAMPLE 10, step 5, (2S, 3S) -3- (3-chlorophenyl) -3- (lH-indol-l-yl) propane-1,2-diol was prepared from lH-indole and [(2R, 3R) -3- (3-chlorophenyl) oxiran-2-yl] methanol. MS (ES) m / z 302 ([M + H] +).

Step 4a (Method B): [(2R, 3R) -3- (3-chlorophenyl) oxirane-2-yl] methanol (4.8 g, 26 mmol) and indoline (d 1063, 2.9 L, 26 mmol) were heated pure at 135 ° C in a sealed flask. After 1.5 hours, the cold mixture was pre-absorbed on silica gel (25 g). Flash column chromatography (silica 375 g, 20%, 40%, 80% ethyl acetate / hexanes) provided (2S, 3S) -3- (3-chlorophenyl) -3- (2,3-dihydro-lH- indole-1-yl) propane-l, 2-diol (5.8 g, 73%) as a white solid. MS (ES) m / z 304 ([M + H] +).

Step 4b (Method B): A solution of (2S, 3S) -3- (3-chlorophenyl) -3- (2, 3-dihydro-lH-indol-1-yl) propane-l, 2-diol (5.8 g, 19 mmol) in ca. 1: 1 (v / v) toluene-dichloromethane (200 mL) was treated with a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (4.4 g, 19 mmol) in toluene (100 mL). ) at 0 ° C.

After 30 minutes, the mixture was diluted with ethyl acetate (1 L) and washed with 5% aqueous sodium carbonate (4 x 1 L), water (1 L) and brine (1 L), dried (magnesium sulfate) and concentrated in vacuo to give a dark oil (5.4 g) which was pre-absorbed on silica gel (15 g). Flash column chromatography (silica 235 g, 20%, 40% ethyl acetate / hexanes) provided (2S, 3S) -3- (3-chlorophenyl) -3- (lH-indol-1-yl) propane-1 , 2-diol, (4.7 g, 82%) as a turbid yellow oil. MS (ES) m / z 302 ([M + H] +).

Step 5: In a manner analogous to EXAMPLE 1, step 2, 3- (3-chlorophenyl) -2-hydroxy-3-indol-1-yl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid was prepared from (2S, 3S) -3- (3-chlorophenyl) -3- (lH-indol-l-yl) propane-l, 2-diol. MS (ES) m / z 456 ([M + H] +).

Step 6: 3- (3-Chlorophenyl) -2-hydroxy-3-indol-1-yl-propyl ester of (2S, 3S) -toluene-4-sulfonic acid (0.60 g, 1.2 mmol) was treated with a Methylamine in methanol solution (2.0 M, 3 mL, 6 mmol) and the solution was stirred at 23 ° C for 18 hours. At this time, the solution was concentrated under vacuum and dissolved in diethyl ether (50 L). The organic solution was washed with a 1 N aqueous solution of sodium hydroxide (50 mL), water (50 L) and brine (50 mL), dried (sodium sulfate) and concentrated under vacuum to provide an orange foam ( 0.30 g) which was purified by reverse phase HPLC (90:10 water-acetonitrile at 50:50 water-acetonitrile containing 0.1% trifluoroacetic acid @ 20 mL / min). The product fractions were concentrated under vacuum to remove acetonitrile and the aqueous solution was made basic with an aqueous solution 2? of ammonium hydroxide. The resulting milky suspension was extracted with ethyl acetate (200 mL) and the organic phase was washed with water (200 mL) and brine (100 mL), dried (sodium sulfate) and concentrated under vacuum. The residue was dissolved in absolute ethanol (4 mL), treated with a 4 M hydrochloric acid in 1,4-dioxane (1.3 eq) and stirred for 10 minutes. The solution was concentrated under vacuum, then dissolved in absolute ethanol (3 mL) and allowed to stand at 23 ° C overnight. Vacuum filtration afforded (I S, 2R) -1- (3-chlorophenyl) -1- (1 H -indol-1-yl) -3- (methylamino) propan-2-ol hydrochloride (62 mg, 5% 3 stages) as a white crystalline solid. HRMS calculated for C? 8H? GCIN20 + H +, 315.12587; found (ESI) 315.1267 ([M + H] +).

EXAMPLE 4: (1SR, 2RS) -3- (methylamino) -1- (4-methyl-3, -dihydroquinoxalin-l (2H) -yl) -1-phenylpropan-2-ol hydrochloride Step 1: In a manner analogous to EXAMPLE 7, step 3, 3-phenylglycidol was prepared from the cinnamyl alcohol as a white solid. MS (ES) m / z 151.1 ([M + H] +).

Step 2: In a manner analogous to EXAMPLE 6, step 4, (2SR, 3SR) -3- (4-methyl-3, -dihydroquinoxalin-1 (2H) -yl) -3-phenylpropane-1,2-diol is prepared 1-methyl-1, 2, 3, 4-tetrahydroquinoxaline (ref: Cavagnol, J.C. Wiselogle, FYJ Am. Chem. Soc. 1947, 69, 795-799.) and 3-phenylglycidol as a colorless oil viscous. MS (ES) m / z 299.0 ([M + H] "1"); HRMS: calculated for C? 8H22N2? 2 + H +, 299.1760; found (ESI, [M + H] +), 299.1739.

Step 3: In a manner analogous to EXAMPLE 6, step 6, hydrochloride of (1SR, 2RS) -3- (methylamino) -1- (4-methyl-3, 4-dihydroquinoxalin-1 (2H) -yl) -1 phenylpropan-2-ol was prepared from (2SR, 3SR) -3- (4-methyl-3,4-dihydroquinoxalin-l (2H) -yl) -3-phenylpropane-1,2-diol as a white powder. EM (ES) m / z 312.0 ([MH + H] +); HRMS: calculated for C? 9H25N30 + H +, 312.2076; found (ESI, [M + H] +), 312.2065.

EXAMPLE 5: (1SR, 2RS) -3- (methylamino) -1- phenyl-1- [4- (2,2, 2-trifluoroethyl) -3,4-dihydroquinoxalin-l (2H) -yl] -propane hydrochloride -2-ol Compound 1- (2,2,2-trifluoroethyl) -1,2,3,4-tetrahydroquinoxaline was obtained as a white powder byproduct of the quinoxaline-1,2,3,4-tetrahydroquinoxaline reduction reaction using borohydride of sodium in trifluoroacetic acid (ref: Bugle, R. C; Osteryoung, RAJ Org Chem. 1979, 44, 1719-1720.) MS (ES) m / z 217.1 ([M + H] +). In a manner analogous to EXAMPLE 6, step 4, (2SR, 3SR) ~ 3- (4- (2, 2, 2-trifluoroethyl) -3,4-dihydroquinoxalin-1 (2H) -yl) -3-phenylpropane 1,2-diol was prepared from 1- (2,2,2-trifluoroethyl) -1,2,3,4-tetrahydroquinoxaline and 3-phenylglycidol (EXAMPLE 4, step 1) as a viscous colorless oil. In a manner analogous to EXAMPLE 6, step 6, hydrochloride of (1SR, 2RS) -3- (methylamino) -1-phenyl-1- [4- (2, 2, 2-trifluoroethyl) -3,4-dihydroquinoxalin- l (2H) -yl] propan-2-ol was prepared from (2SR, 3SR) -3- (4- (2, 2, 2-trifluoroethyl) -3,4-dihydroquinoxalin-1 (2H) -yl) - 3-phenylpropane-1,2-diol as a white powder. MS (ES) m / z 380.0 ([M + H] +); HRMS: calculated for C20H2F3N3O + H +, 380.1950; found (ESI, [M + H] +), 380.1934.

EXAMPLE 6: (1S, 2R) -1- (3-fluorophenyl) -1- (lH-indol-1-yl) -3- (methylamino) propan-ol hydrochloride Step 1: To a mixture of trans-3-fluoro-cinnamic acid (50 g, 300 mmol) and iodomethane (300 mL) in acetone (1 L), cesium carbonate (147 g, 450 mmol, 1.5 equiv. ), and the mixture was heated at 65 ° C for 1.5 hours in a reaction vessel. During cooling to room temperature, the reaction mixture was diluted with ethyl acetate (1 L), filtered through a pad of silica gel, and concentrated to give 47.33 g (87%) of the methyl ester of the ethyl acetate. trans-3-fluorocinnamic acid as a colorless oil. MS (ES) m / z 180.0 (M +).

Step 2: To a solution of trans-3-fluorocynamic acid methyl ester (69.61 g, 386 mmol) in dry dichloromethane (1 L) at -78 ° C under nitrogen was added dropwise diisobutylaluminum hydride (neat, 172 mL, 965 mmol, 2.5 equiv.) By means of an addition funnel. After the addition was complete, the reaction mixture was allowed to warm to -30 ° C and was stirred for an additional 1 hour, then quenched with methanol (150 mL). During heating to room temperature, the reaction mixture was treated with saturated aqueous sodium / potassium tartrate solution (300 mL) and stirred for 30 minutes. The organic layer was washed sequentially with 1N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, brine, and dried (anhydrous sodium sulfate). The crude oil was purified by silica gel chromatography (0-50% ethyl acetate: hexane) to give 53.07 g (90%) of trans-3-fluorocinnamyl alcohol as a colorless oil. MS (ES) m / z 152.1 (M +).

Step 3: A 2-L, 3-neck, oven-dried round bottom flask equipped with two oven-dried addition funnels and a rubber septum was charged with diisopropyl D-tartrate (11.55 g, 49.3 mmol, 0.30 equiv.), 4A powder, activated molecular meshes (40 g) and dry dichloromethane (800 mL) under nitrogen. After being cooled to -25 ° C, titanium isopropoxide (9.6 L, 33 mmol, 0.20 equiv.) Was slowly added to the reaction mixture by means of a hypodermic syringe. After stirring for 10 minutes, anhydrous t-butyl hydroperoxide (5.5 M in decane, 75.0 mL, 413 mmol, 2.5 equiv.) Was added at a moderate ratio by means of an addition funnel. The resulting mixture was stirred at -25 ° C for 30 minutes. Alcohol trans-3-fluorocinnamyl (25.0 g, 164 mmol) in dry dichloromethane (50 mL) was added dropwise by means of an addition funnel while maintaining the temperature at -25 ° C. After the addition, the reaction mixture was stirred at -25 ° C for 1 hour and at -20 ° C for another 3 hours. After the reaction was complete, cooled aqueous sodium hydroxide solution (30%, 20 mL) saturated with sodium chloride was slowly added at -20 ° C. After diethyl ether (150 mL) was added, the cold bath was removed and the mixture allowed to warm to ~5 ° C and stirred for 1 hour. Magnesium sulfate (anhydrous, 50 g) was added and the mixture was stirred for 20 minutes, then filtered through a pad of silica gel, and washed with ether (300 L). The filtrate was concentrated and toluene was used to azeotropically remove excess t-butyl hydroperoxide. The residual oil was purified on silica gel (0-30% ethyl acetate: hexane) to give 24.80 g (90%) of [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol. as a viscous colorless oil. Ee: >percentage; 96.5%. MS (ESI) m / z 169.1 ([M + H] +).

Step 4: A mixture of indoline (1.42 g, 11.89 mmol) and [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (2.0 g, 11.89 mmol) was heated at 125 ° C for 5 hours in a sealed reaction vial. During cooling, the crude product was dissolved in ethyl acetate, absorbed in Fluorocil, and purified by Biotage chromatography (FlasH40i, silica, 0-55% EtOAc / hexane) to give 2.55 g (75%) of (2S, 3S) -3- (2, 3-dihydro-lH-indol-1-yl) -3- (3-fluorophenyl) propane-1,2-diol as a colorless oil. MS (ESI) m / z 288.1 ([MH + H] +).

Step 5: A mixture of (2S, 3S) -3- (2, 3-dihydro-lH-indol-1-yl) -3- (3-fluorophenyl) propane-l, 2-diol (2.00 g, 6.96 mmol ) and activated manganese dioxide (20.0 g, 230 mmol) in dichloromethane (30 L) was stirred at 20 ° C for 3 hours. The mixture was diluted with ethyl acetate (15 L), filtered through a pad of silica gel, and concentrated. The crude product was purified by Biotage chromatography (FlasH40i, silica, 0-70% EtOAc / hexane) to give 1.40 g (71%) of (2S, 3S) -3- (3-fluorophenyl) -3- (1H-indole -l-il) pro? ano-l, 2-diol as a colorless oil. MS (ESI) m / z 286.0 ([M + H] +). HRMS: calculated for C? H? 6FN02 + H +, 286.1238; found (ESI, [M + H] +), 286.1239.

Step 6: To a solution of (2S, 3S) -3- (2, 3-dihydro-lH-indol-1-yl) -3- (3-fluorophenyl) propane-1,2-diol (452 mg, 1.586 mmol) in dichloromethane (3 mL) under nitrogen was added triethylamine (1.1 mL, 7.93 mmol). The mixture was cooled to 0 ° C, and para-toluenesulfonyl chloride (423 mg, 2.22 mmol) was added in portions. The reaction mixture was stirred at 0 ° C for 1 hour and stored at 0 ° C overnight. Methylamine in absolute ethanol (8 M, 5 mL, 40 mmol) was added and the reaction mixture was sealed, and stirred overnight while warming to room temperature. All volatiles were removed under reduced pressure. The oil residue was dissolved in dichloromethane (20 mL), washed with aqueous potassium carbonate (5 L), dried (anhydrous sodium sulfate), and concentrated. Purification by Biotage chromatography (FlasH12i, silica, 0-15% MeOH / dichloromethane / 0.5% triethylamine) gave (ÍS, 2R) -1- (3-fluorophenyl) -1- (lH-indol-1-yl) -3 - (methylamino) propan-2-ol, which was dissolved in dichloromethane (5 mL) and treated with a 1 M ethereal solution of hydrochloric acid (1.9 mL, 1.9 mmol). To the resulting solution hexane was added until it formed white powder, which was collected, washed with hexane, and dried in vacuo to produce 209 mg (44%) of (SS, 2R) -1- (3-fluorophenyl) -1- (lH-indol-1-yl) -3- (methylamino) propan-2-ol hydrochloride as a white powder. M (ES) m / z 299.0 ([M + H] +); HRMS: calculated for C18H? 9FN20 + H +, 299.1554; found (ESI, [M + H] +), 299.1553.

EXAMPLE 7: (1S, 2R) -1- (lH-indol-1-yl) -3- (methylamino) -1- (2-methylphenyl) propan-2-ol hydrochloride Step 1: In a manner analogous to EXAMPLE 6, step 1, methyl ester of trans-2-methylcinnamic acid was prepared from trans-2-methylcinnamic acid.

Step 2: In a manner analogous to EXAMPLE 6, step 2, trans-2-methylcinnamyl alcohol was prepared from the methyl ester of trans-2-methylcinnamic acid as a colorless oil. MS (ES) m / z 146.9 ([M-H] ").

Step 3: To a solution of trans-2-methyl acyl alcohol (1.50 g, 10.14 mmol) in dichloromethane (30 L) was added sodium carbonate (1.50 g, 14.19 mmol). The mixture was cooled to 10 ° C and peracetic acid (32% by weight, 2.56 mL, 12.16 mmol) was added dropwise by means of an addition funnel. The reaction mixture was stirred for 3 hours while warming to room temperature, and quenched with saturated aqueous sodium sulfite solution (15 mL) slowly. More dichloromethane (30 mL) was added and the mixture was extracted. The organic layer was washed with brine, dried (anhydrous sodium sulfate), and concentrated. The oil residue was purified by silica gel chromatography (10-30% EtOAc / hexane) to give 920 mg (55%) of 3- (2-methylphenyl) glycidol as a colorless oil. HRMS: calculated for C? O H? 202 + H +, 165.0916; found (ESI, [M + H] +), 165.0936.

Step 4: In a manner analogous to EXAMPLE 10, step 5, (2SR, 3SR) -3 ~ (lH-indol-l-yl) -3- (2-methylphenyl) propane-l, 2-diol was prepared from indole and 3- (2-methylphenyl) glycidol as a colorless, viscous liquid. MS (ES) m / z 282.2 ([M + H] +); HRMS: calculated for C? 8H? 9N02 + H +, 282.1494; found (ESI, [M + H] +), 282.1499.

Step 5: In a manner analogous to EXAMPLE 6, step 6, (1SR, 2RS) -1- (lH-indol-1-yl) -3- (methylamino) -1- (2-methylphenyl) propan-2-ol was prepared from (2SR, 3SR) -3- (1H-indol-1-yl) -3- (2-methylphenyl) propane-1,2-diol as an oil.

Step 6: (1SR, 2RS) 1- (1H-indol-1-yl) -3- (methylamino) -1- (2-methylphenyl) propan-2-ol racemic was dissolved in ethanol (20 mg / mL). The resulting solution was injected into the column in the Supercritical Fluid Chromatography instrument in 1 mL increments. The enantiomers that resolve the baseline, using the conditions described below, were collected. The enantiomeric purity of each enantiomer was determined under conditions of similar Supercritical Fluid Chromatography using a Chiralcel OJ-H 5u column, 250 mm L x 4.6 mm ID a 1. 2 mL / minute flow ratio using Chromatography of Analytical Supercritical Fluid (Berger Instruments, Inc. Newark, DE USA). SFC Instrument: Berger MultiGram Prep SFC (Berger Instruments, Inc. Newark, DE 19702. Column: Chiralcel OJ-H; 5u; 25Omm L x 2Omm ID (Chiral Technologies, Inc., Exton, PA, USA). Column temperature: 35 ° C SFC modifier :. MeOH 15% with DEA 1.0% / CO2 85% Flow rate: 50 mL / min Exit Pressure: 100 bar Detector: UV at 220 nm Step 7: In a manner analogous to EXAMPLE 13, step 2, hydrochloride of (SS, 2R) -1- (lH-indol-l-yl) -3- (methylamino) -1- (2-methylphenyl) propan-2 -ol was prepared as a white solid, from (1S, 2R) -1- (lH-indol-1-yl) -3- (methylamino) -1- (2-methylphenyl) propan-2-ol, which was isolated as Peak 1 of the chiral separation (step 6). Chiral purity: 100%. MS (ESI) m / z 295.3 ([M + H] +); HRMS: calculated for C? GH22N20 + H +, 295. 1805; found (ESI, [M + H] +), 295.1795.

EXAMPLE 8: (I S, 2 R) -1- (6-Chloro-2,3-dihydro-4 H-l, 4-benzoxazin-4-yl) -1- (3, 5-difluorophenyl) -3- hydrochloride ( methylamino) propan-2-ol Step 1: In a manner analogous to EXAMPLE 16, step 1, 6-chloro-3,4-dihydro-2H-l, 4-benzoxazine was prepared from 6-chloro-2H-l, 4-benzoxazin-3 (4H) -one like a yellow solid. MS (ES) m / z 170.0 ([M + H] +); HRMS: calculated for C8H8CINO + H +, 170.0367; found (ESI, [M + H] +), 170,0365.

Step 2: In a manner analogous to EXAMPLE 6, step 4, (2S, 3S) -3- (6-chloro-2,3-dihydro-4H-1, -benzoxazin-4-yl) -3- (3, 5-difluorophenyl) propane-1,2-diol was prepared from 6-chloro-3,4-dihydro-2H-1, 4-benzoxazine and [(2R, 3R) -3- (3, 5-difluorophenyl) oxirane- 2-yl] methanol (EXAMPLE 157, step 3) as a yellowish, viscous liquid. MS (ES) m / z 356.1 ([M + H] +); HRMS: calculated for C? 7H? 6CIF2N03 + H +, 356.0860; found (ESI, [M + H] +), 356.0869.

Step 3: In a manner analogous to EXAMPLE 6, step 6, hydrochloride of (SS, 2R) -1- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -1- (3, 5-difluorophenyl) -3- (methylamino) propan-2-ol was prepared from (2S, 3S) -3- (6-chloro-2,3-dihydro-4H-1, 4-benzoxazin-4-) il) -3- (3, 5-difluorophenyl) propane-l, 2-diol as a white powder. MS (ES) m / z 369.1 ([M + H] +); HRMS: calculated for C? 8H? GCIF2N202 + H +, 369.1176; found (ESI, [M + H] "1"), 369.1178.

EXAMPLE 9: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (2-methyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) hydrochloride propan-2-ol In a manner analogous to EXAMPLE 16, step 1, 2-methyl-3,4-dihydro-2H-1, 4-benzoxazine was prepared from 2-methyl-2H-1, 4-benzoxazin-3 (4H) -one ( ref: Wheeler, KWJ Med. Pharm.

Chem. 1962, 5, 1378-1383.) As a brown oil. MS (ES) m / z 149. 9 ([M + H] +). In a manner analogous to EXAMPLE 6, step 4, (2S, 3S) -3- (3-fluorophenyl) -3- (2-methyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) propane-l, 2-diol was prepared from 2-methyl-3,4-dihydro-2H-1,4-benzoxazine and [(2R, 3R) -3- (3-fluorophenyl) oxirane-2-yl] methanol ( EXAMPLE 6, step 3) as a brown, viscous liquid. MS (ES) m / z 318.2 ([M + H] "*"); HRMS: calculated for C? 8H20FNO3 + H +, 318.1500; found (ESI, [M + H] +), 318.1513.

In a manner analogous to EXAMPLE 6, step 6, hydrochloride of (SS, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (2-methyl-2,3-dihydro-4H-1, 4-benzoxazin-4-yl) propan-2-ol was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (2-methyl-2,3-dihydro-4H-1,4-benzoxazin) -4-yl) propane-l, 2-diol as a white powder. MS (ES) m / z 331.0 ([M + H] +); HRMS: calculated for C? 9H23FN202 + H +, 331.1816; found (ESI, [M + H] +), 331.1804.

EXAMPLE 10: (1S, 2fl) -1- (5-fluoro-3-methyl-lH-indol-1-yl) -3- (methylamino) -l-phenylpropan-2-ol hydrochloride Step 1: To a mixture of 4-fluoro-phenylamine (9 g, 81 mmol), concentrated hydrochloric acid (20.4 mL), and water (35.1 mL) was added sodium nitrite (6.3 g, 89.1 mmol) was dissolved in water (7.8 mL). In a separating flask ethyl 2-ethylacetoacetate (14.4 g, 89.1 mmol) in ethanol (63.6 mL) at 0 ° C was treated with potassium hydroxide (5.1 g, 89.1 mmol) in water (7.5 mL) and ice and the solution previous was added. The pH of the reaction was adjusted to 5-6 and the reaction was stirred at 0 ° C for 3 hours and then stored in the freezer overnight. The reaction was then extracted with ethyl acetate (100 mL) and the organics were washed with saturated brine solution (100 mL), dried with anhydrous magnesium sulfate. More of the solvent was removed in vacuo before this was added dropwise to a 14.5% ethanolic hydrochloric acid solution (70 mL) at 78 ° C. The heating was continued for 2 hours. The solvent was removed in vacuo and the residue was treated with dichloromethane (300 mL) and water (100 mL). The organic layer was washed with saturated sodium chloride (200 mL), dried over sodium sulfate and concentrated in vacuo. Purification on a short washed column (silica gel, 25% ethyl acetate / hexane) gave ethyl 5-fluoro-3-methyl-lH-indole-2-carboxylate as a white solid. EM (ES) m / z 220.0 Step 2: Ethyl 5-fluoro-3-methyl-lH-indole-2-carboxylate (8.3 g, 37.5 mmol) and potassium hydroxide (6.3 g, 112.5 mmol) in a mixture of ethanol (20 mL) and water ( 15 mL) was heated to reflux for 1 hour. The volume was reduced to 10 mL under reduced pressure and the solution was brought to an acidic pH with a 3N aqueous solution of hydrochloric acid. The resulting precipitate was filtered, washed with water (100 L) and dried in vacuo at 80 ° C overnight to give 5-fluoro-3-methyl-1H-indole-2-carboxylic acid as a white solid. MS (ES) m / z 192.0 Step 3: 5-Fluoro-S-methyl-lH-indole-carboxylic acid (8.49 g, 43.9 mmol) and copper metal (0.35 g, 5.5 mmol) in distilled quinoline (22 mL) was heated to reflux for 3 hours. The copper powder was completely filtered and the filtrate was brought to pH 3 at 0 ° C with a 6N aqueous solution of hydrochloric acid. The solution was extracted with ether (200 mL) and the organics were washed with saturated sodium chloride (200 L), dried over magnesium sulfate and concentrated in vacuo to give 5-fluoro-3-methyl-1H-indole as a solid coffee. MS (ES) m / z 150.0.

Step 4: To a solution of diisopropyl D-tartrate (6 mL, 28 mmol) in methylene chloride (800 L) at -10 ° C under nitrogen was added 4Á molecular meshes (15g), titanium isopropoxide (5.9 mL) , 20 mmol), and cinnamyl alcohol (27 g, 200 mmol). The mixture was allowed to age for 40 minutes at -10 ° C, after which time it was cooled to -20 ° C, and treated in a dropwise fashion with a hydroperoxide solution (TBHP, ~ 450 mmol) in isooctane . After 18 hours at -30 to -15 ° C, the reaction mixture was treated with a 30% aqueous solution of sodium hydroxide (5 mL) and diethyl ether (100 L). The cold bath was removed and the mixture was allowed to warm to ~ 10 ° C. Magnesium sulphate (anhydrous, 15 g) was added and the mixture was stirred for 20 minutes. After the solids were placed, the solution was filtered through a pad of silica gel, and washed with ether (50 mL). The filtrate was concentrated in vacuo and toluene was added to azeotropically remove unreacted TBHP. The residue was then purified using a column of silica gel (hexane: ethyl acetate / 3: 1) and the purified product was crystallized from hexane / ethyl acetate to produce [(2R, 3R) -3-phenyloxyran-2. il] methanol as white crystal (18g, 60%, 98.2% ee). MS (ESI) m / z 151.

Step 5: A mixture of 5-fluoro-3-methyl-1H-indole (2.91 g, 19.5 mmol) and 50% dispersion of potassium hydride in mineral oil (2.8 g, 35.1 mmol) in dichloromethane (40 mL) was added. stirred for 10 minutes under nitrogen at room temperature. A solution of [(2R, 3R) -3-phenyloxyran-2-yl] methanol (2.0 g, 13.0 mmol) and titanium isopropoxide (4.3 mL, 14.3 mmol) in dichloromethane (10 L) was then added and the mixture was added. stirred at room temperature for 12 hours. After the disappearance of the epoxide, the mixture was partitioned between a 1 N aqueous solution of hydrochloric acid (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with saturated sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by means of Biotage chromatography (FlasH40i, silica, 60% ethyl acetate / hexane) to give (2S, 3S) -3- (5-fluoro-3-methyl-lH-indol-1-yl) -3-phenylpropane-1,2-diol . EM (ESI) m / z 300 Step 6: A solution of (2S, 3S) -3- (5-fluoro-3-methyl-lH-indol-1-yl) -3-phenylpropane-1,2-diol (1.03 g, 3.4 mmol) and chloride of p-toluenesulfonyl (0.78 g, 4.1 mmol) in anhydrous pyridine (11 mL) was stirred at room temperature under nitrogen for 12 hours. The reaction was poured into a 1N aqueous solution of hydrochloric acid (50 L) and extracted with ethyl acetate (50 L). The organics were dried over anhydrous sodium sulfate, filtered, and concentrated to give 3- (5-fluoro-3-methyl-indol-1-yl) -2-hydroxy-3-phenyl-propyl (2S) ester. , 3S) -toluene-4-sulphonic. The product was used in the next step without further purification. To a solution of 3- (5-fluoro-3-methyl-indol-1-yl) -2-hydroxy-3-phenyl-propyl ester of toluene-4-sulfonic acid (1.6 g, 3.4 mmol) in methanol ( 10 mL) was added a solution 2? of methylamine in methanol (8.6 mL, 17 mmol) and the reaction was stirred for 12 hours. During the completion, the reaction was divided between saturated sodium bicarbonate (50 mL) and ethyl acetate (50 L). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by means of Biotage chromatography (FlasH40i, silica, 20% MeOH / dichloromethane) to give (1S, 2R) -1- (5-fluoro-3-methyl-1H-indol-1-yl) -3 - (methylamino) -1-phenylpropan-2-ol as a clear oil. The free base was dissolved in a minimum amount of ethanol and treated with a 2N etheral solution of hydrochloric acid and stirred for 1 hour. The ethanol was removed in vacuo and the light oil was triturated with ether / dichloromethane to give (S, 2R) -1- (5-fluoro-3-methyl-1H-indol-1-yl) -3- (methylamino) hydrochloride. ) -1-phenylpropan-2-ol as a white solid. MS (ESI) m / z 313 EXAMPLE 11: (1RS, 2SR) -1- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride In a manner analogous to EXAMPLE 3, step 1, (2RS, 3RS) -3- (6-chloro-2, 3-dihydro-4H-1, -benzoxazin-4-yl) -2-hydroxy-3-phenylpropanoate of ethyl was prepared from 6-chloro-3,4-dihydro-2H-1,4-benzoxazine (EXAMPLE 8, step 1) and trans-ethyl-3-phenylglycidate as a yellow, viscous liquid. MS (ESI) m / z 362.0 ([M + H] +); HRMS: calculated for C? 9H20CINO4 + H +, 362.1154; found (ESI, [M + H] +), 362.1150.

In a manner analogous to EXAMPLE 3, step 2, (2R'S, 3RS) -3- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -2-hydroxy-N-methyl -3-phenylpropanamide was prepared from ethyl (2RS, 3RS) -3- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -2-hydroxy-3-phenyl propanoate as needles white MS (ESI) m / z 344.9 ([MH] "); HRMS: calculated for C? SH? 9CIN203 + H +, 347.1157; found (ESI, [M + H] +), 3471150. In a manner analogous to EXAMPLE 3 , step 3, hydrochloride of (1RS, 2SR) -1- (6-chloro-2,3-dihydro-4H-1, 4-benzoxazin-4-yl) -3- (methylamino) -1-phenylpropan-2 ol was prepared from (2RS, 3RS) -3- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -2-hydroxy-β-methyl-3-phenylpropanamide as a powder white MS (ESI) m / z 333.1 ([M + H] +); HRMS: calculated for C? 8H2? CI? 202 + H +, 333.1370; found (ESI, [M + H] +), 333.1381.

EXAMPLE 12: (1RS, 2SR) -3- (methylamino) -1- (6-methyl-2, 3-dihydro-4H-l, 4-benzoxazin-4-yl) -1-phenylpropan-2-ol hydrochloride In a manner analogous to EXAMPLE 16, step 1, 6-methyl-3, -dihydro-2H-1, -benzoxazine was prepared from 6-methyl-2H-1,4-benzoxazin-3 (4H) -one as an oil yellow. MS (ES) m / z 150.0 ([M + H] +); HRMS: calculated for CgHuNO + H +, 150.0919; found (ESI, [M + H] +), 150.0924. In a manner analogous to EXAMPLE 3, step 1, (2RS, 3RS) -2-hydroxy-3- (6-methyl-2, 3-dihydro-4H-1, -benzoxazin-4-yl) -3-phenylpropanoate of ethyl was prepared from 6-methyl-3,4-dihydro-2H-1,4-benzoxazine and trans-ethyl-3-phenylglycidate as a yellow, viscous liquid. MS (ESI) m / z 342.0 ([M + H] +); HRMS: calculated for C2oH23N? 4 + H +, 342.1700; found (ESI, [M + H] +), 342.1683. In a manner analogous to EXAMPLE 3, step 2, (2RS, 3RS) -2-hydroxy-β-methyl-3- (6-methyl-2,3-dihydro-4H-1, 4-benzoxazin-4-yl) -3-phenylpropanamide was prepared from ethyl (2RS, 3RS) -2-hydroxy-3 ~ (6-methyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3-phenylpropanoate as a white powder. MS (ESI) m / z 325.0 ([MH] "); HRMS: calculated for C? 9H22? 203 + H +, 327.1703; found (ESI, [M + H] +), 327.1703 .In a manner analogous to EXAMPLE 3 , step 3, (1RS, 2SR) -3- (methylamino) -1- (6-methyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -l-phenylpropan-2-hydrochloride ol was prepared from (2RS, 3RS) -2-hydroxy-β-methyl-3- (6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3-phenylpropanamide as a powder MS (ESI) m / z 313.0 ([M + H] +); HRMS: calculated for C? 9H24? 2? 2 + H +, 313.1911; found (ESI, [M + H] +), 313.1908.

EXAMPLE 13: (ÍS, 2R) -1- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -1-phenylpropan-2-ol hydrochloride Stage 1: (1SR, 2SR) -l- (6 ~ Chloro-2,3-dihydro-4H-1, 4-benzoxazin-4-yl) -3- (methylamino) -l-phenylpropan-2-ol racemic ( EXAMPLE 11) was dissolved in methanol. The resulting solution was injected into the Supercritical Fluid Chromatography instrument. The enantiomers that resolve the baseline, using the conditions described below, were collected. The enantiomeric purity of each enantiomer was determined under the same conditions as Supercritical Fluid Chromatography using a Chiralpak AD-H 5u column, 250 mm x 4.6 mm ID at 2.0 mL / minute flow ratio using Analytical Supercritical Fluid Chromatography (Berger Instruments , Inc. Newark, DE USA). SFC instrument: Berger MultiGram Prep SFC (Berger Instruments, Inc. Newark, DE 19702. Column: Chiralpak AD-H; 5u; 25Omm L x 2Omm ID (Chiral Technologies, Inc., Exton, PA, USA) Column temperature: 35 ° C SFC modifier: MeOH 40% with DEA 0.5% Flow rate: 50 mL / min Output pressure: 100 bar Detector: UV at 266 nm Step 2: A solution of (ÍS, 2R) -1- (6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -3- (methylamino) -l-phenylpropan-2- ol, isolated as Pico 1, (58 mg, 0.17 mmol) in dichloromethane (3 mL) was treated with an ethereal solution of hydrochloric acid (1 M, 0.2 mL, 0.2 mmol). To the resulting solution hexane was added until white powder formed, which was collected, washed with hexane, and dried in vacuo to yield 62 mg (45%) of (S, 2R) -1- (6-chloro) hydrochloride -2, 3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -l-phenylpropan-2-ol. Chiral purity: > 99.9%. MS (ESI) m / z 333.0 ([M + H] +); HRMS: calculated for C? 8H2? CIN202 + H +, 333.1370; found (ESI, [M + H] +), 333.1372.

EXAMPLE 14: Hydrochloride of (IR, 2S) -1- (6-chloro-2,3-dihydro-4H-l, -benzoxazin-4-yl) -3- (methylamino) -1-phenylpropan-2-ol In a manner analogous to EXAMPLE 13, step 2, hydrochloride of (IR, 2S) -1- (6-chloro-2,3-dihydro-4H-1, 4-benzoxazin-4-yl) -3- (methylamino) -l-phenylpropan-2-ol was prepared from (lR, 2S) -l- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -1 phenylpropan-2-ol which was isolated as Pico 2 from the chiral separation (EXAMPLE 13, step 1). Chiral purity: > 99.9%. MS (ESI) m / z 333.0 ([MH + H] +); HRMS: calculated for C? 8H2iCIN202 + H +, 333.1370; found (ESI, [MH + H] +), 333.1374.

EXAMPLE 15: (ÍS, 2R) -1- (6-Chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -1- (3-fluorophenyl) -3- (methylamino) hydrochloride propan-2-ol In a manner analogous to EXAMPLE 6, step 4, (2S, 3S) -3- (6-chloro-2,3-dihydro-4H-l, -benzoxazin-4-yl) -3- (3-fluorophenyl) propane -1,2-diol was prepared from 6-chloro-3,4-dihydro-2H-1, 4-benzoxazine (EXAMPLE 8, step 1) and [(2R, 3R) -3- (3-fluorophenyl) oxirane 2-yl] methanol (EXAMPLE 6, step 3) as a yellowish, viscous liquid. MS (ES) m / z 335.8 ([M-H] "); HRMS: calculated for C20H22FNO2 + H +, 338.0959; found (ESI, [MH + H] +), 338.0959.

In a manner analogous to EXAMPLE 6, step 6, hydrochloride of (SS, 2R) -1- (6-chloro-2,3-dihydro-4H-l, -benzoxazin-4-yl) -1- (3-fluorophenyl) ) -3- (methylamino) propan-2-ol was prepared from (2S, 3S) -3- (6-chloro-2,3-dihydro-4H-1, 4-benzoxazin-4-yl) -3- ( 3-fluorophenyl) propane-l, 2-diol as a white powder. MS (ES) m / z 351.0 ([M + H] +); HRMS: calculated for C? 8H20CIFN2? 2 + H +, 351.1276; found (ESI, [MH + H] +), 351.1276.

EXAMPLE 16: (1S, 2R) -1- (2, 2-Dimethyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -1- (3-fluorophenyl) -3- hydrochloride ( methylamino) propan-2-ol Step 1: To a solution of 2,2-dimethyl-2H-l, 4-benzoxazin-3 (4H) -one (ref: Caliendo, G.; Perissutti, E .; Santagada, V .; Fiorino, F .; Severino, B .; Bianca, R.) (2658 g, 15.0 mmol) in tetrahydrofuran (10 mL) under nitrogen was slowly added a solution of borane (1.0 M in tetrahydrofuran, 22.5 mL, 22.5 mmol) by syringe. The resulting mixture was stirred at room temperature for 10 minutes and then at 70 ° C for 1 hour. After cooling, the reaction mixture was quenched with methanol (3 mL) slowly. All volatiles were removed under reduced pressure. A 1N aqueous solution of • hydrochloric acid (10 mL) was added to the liquid residue and the mixture was warmed at 50 ° C for 10 minutes. After cooling, the reaction mixture was made alkaline using saturated sodium bicarbonate solution (15 L), and extracted with ethyl acetate (25 mL). The organic layer was washed with water, brine, dried (anhydrous sodium sulfate), filtered through a pad of silica gel, and concentrated under reduced pressure to yield 2.310 g (94%) of 2-, 2- dimethyl-3, -dihydro-2H-l, 4-benzoxazine as a brown oil. MS (ES) m / z 164.0 ([M + H] +).

Step 2: In a manner analogous to EXAMPLE 6, step 4, (2S, 3S) -3- (2, 2-dimethyl-2,3-dihydro-4H-1, -benzoxazin-4-yl) -3- ( 3-fluorophenyl) propane-1,2-diol was prepared from 2,2-dimethyl-3,4-dihydro-2H-1, 4-benzoxazine and [(2R, 3R) -3- (3-fluorophenyl) oxirane- 2-yl] methanol (EXAMPLE 6, step 3) as a white solid. MS (ES) m / z 332.2 ([M + H] +); HRMS: calculated for C? 9H22FN03 + H +, 332.1657; found (ESI, [M + H] +), 332.1648.

Step 3: In a manner analogous to EXAMPLE 6, step 6, hydrochloride of (SS, 2R) -1- (2,2-dimethyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) - 1- (3-fluorophenyl) -3- (methylamino) propan-2-ol was prepared from (2S, 3S) -3- (2, 2-dimethyl-2,3-dihydro-4H-1, 4-benzoxazin- 4-yl) -3- (3-fluorophenyl) propane-1,2-diol as a white powder. MS (ES) m / z 345.2 ([M + H] +); HRMS: calculated for C20H25FN2O2 + H +, 345.1978; found (ESI, [M + H] "1"), 345.1981.

EXAMPLE 17: (ÍS, 2R) -1- (2, 2-dimethyl-2, 3-dihydro-4H-l, -benzoxazin-4-yl) -3- (methylamino) -1-phenylpropan- 2- hydrochloride ol In a manner analogous to EXAMPLE 6, step 4, (2S, 3S) -3- (2, 2-dimethyl-2, 3-dihydro-4H-l, 4-benzoxazin-4-yl) -3-phenylpropane-1 , 2-diol was prepared from 2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazine (EXAMPLE 16, step 1) and [(2R, 3R) -3-phenyloxyran-2-yl] methanol (EXAMPLE 10, step 4) as a white solid. MS (ES) m / z 314.1 ([M + H] +). In a manner analogous to EXAMPLE 6, step 6, (ÍS, 2R) -1- (2, 2-dimethyl-2,3-dihydro-4H-1, -benzoxazin-4-yl) -3- (methylamino) hydrochloride ) -1-phenylpropan-2-ol was prepared from (2S, 3S) -3- (2, 2-dimethyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3-phenylpropane- 1,2-diol as a white powder. MS (ES) m / z 327 .2. ([M + H] +); EMAR: calculated for • C.2oH26N2? 2 + H + ,. 327..2-073; • found (ESI, { M + H] +), 327.2-082.

EXAMPLE 18: (1S, 2R) -l- > . { 2, 3-dihydro-4-H-5 1,4-benzothiazin-4-yl) -1- (3-f luoro-f-enyl) -3- (methylamino) -phen-2-ol In a manner analogous to EXAMPLE 6, step 4, (2S, 3S) -3- (2, 3 ~ dihydro-4H-l, 4-benzothiazin-4-yl) -3- (3-fluorophenyl) ropano-1 , 2-diol was prepared from 3,4-dlhydro-2H-1,4-benzothiazine (r-ef: El-Subbagh, HI; Abadi, AH; Al-Khawad, IE; Al-Rashood, KA Arch. Pharm 1999, 332, 19-24) and [2R, 3R) -3- (3-fluorof «nil) oxirane-2-yl] methanol - (EXAMPLE 6, step 3) as a yellowish, viscous liquid. MS (ES) m / z 320.1 ([M + H] +); HRMS: calculated for C? 7H18FN02S + H +, 320.1115; found (ESI, { M + H] +), 320.1113. In a manner analogous to EXAMPLE ', step 6, hydrochloride of (SS, 2R) -l- (2, 3 ~ dihydro-4H-l, 4-benzthiazin-4-yl) -1- (3-fluorophenyl) ) -3- (methylamino) propan-2-ol < it was prepared from (2S, 3S) -3- (2, 3-dihydro-4-Hl, 4-benzo-thia2Ín-4-yl) -3- (3-fluorophenyl) -palene-1, 2-diol as a white powder. MS (ES) m / z 333.1 ([M + H] +); HRMS: calculated for C H 8 H 2? FN 2 OS + H +, 333.1431; found (ESI, [M + H] +), 333.1420.

EXAMPLE 19: (I S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (2-phenyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) hydrochloride propan-2-ol In a manner analogous to EXAMPLE 6, step 4, (2S, 3S) -3- (3-fluorophenyl) -3- (2-phenyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) propane-l, 2-diol was prepared from 2-phenyl-3,4-dihydro-2H-1,4-benzoxazine reference: (Olagbemiro, TO; Nyakutse, CA; Lajide, L.; Agho, MO; Chukwu, CE Bull. Soc. Chim. Belg. 1987, 96, 473-480.) And [(2R, 3R) -3- (3-fluorophenyl) oxiran-2-yl] methanol (EXAMPLE 6, step 3) as a solid White. MS (ES) m / z 380.0 ([M + H] +); HRMS: calculated for C23H22FN03 + H +, 380.1662; found (ESI, [MH + H] +), 380.1661. In a manner analogous to EXAMPLE 6, step 6, hydrochloride of (SS, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (2-phenyl-2,3-dihydro-4H-1, 4-benzoxazin-4-yl) propan-2-ol was prepared from (2S, 3S) -3- (3-fluorophenyl) -3- (2-phenyl-2,3-dihydro-4H-1,4-benzoxazin -4-yl) propane-l, 2-diol as a white powder.

MS (ES) m / z 393.2 ([MH + H] +); HRMS: calculated for C 24 H 25 FN 2 O 2 + H +, 393.1978; found (ESI, [M + H] +), 393.1986.

EXAMPLE 20: (ÍS, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- [(2R) -2-phenyl-2,3-dihydro-4H-l, 4-benzoxazine- hydrochloride 4- il] propan-2-ol Step 1: Distereomeric mixture of (SS, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (2-phenyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) ) propan-2-ol (EXAMPLE 19) was dissolved in methanol. The resulting solution was injected into the Supercritical Fluid Chromatography instrument. The diastereomers that resolve the baseline, using the conditions described below, were collected. SFC instrument: Berger MultiGram Prep SFC (Berger Instruments, Inc.? Ewark, DE 19702. Column: ethyl pyridine; 25Omm L x 2Omm ID (Princeton Chromatography Inc. ) Column temperature: 35 ° C SFC modifier: 15% MeOH with C02 85% Flow rate: 50 mL / min Output pressure: 100 bar Detector: UV at 220 nm Step 2: (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- [(2R) -2-phenyl-2,3-dihydro-4H-l, 4-benzoxazin-4- il] propan-2-ol, isolated as Pico 1, was subjected to chlorohydrate salt formation in a manner analogous to EXAMPLE 13, step 2 to give (ÍS, 2R) -1- (3-fluorophenyl) -3 hydrochloride - (methylamino) -1- [(2R) -2-phenyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl] propan-2-ol as a white powder. MS (ES) m / z 393.2 ([MH + H] +); HRMS: calculated for C24H25FN2? 2 + H +, 393.1973; found (ESI, [M + H] +), 393.1992.

EXAMPLE 21: (ÍS, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- [(2S) -2-phenyl-2,3-dihydro-4H-l, -benzoxazin-4-hydrochloride -il] propan-2-ol In a manner analogous to EXAMPLE 20, (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -l- [(2S) -2-phenyl-2,3-dihydro-4H-1 hydrochloride. , 4-benzoxazin-4-yl] propan-2-ol was prepared as a white powder of (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- [(2S) -2- phenyl-2, 3-dihydro-4H-l, 4-benzoxazin-4-yl] propan-2-ol, which was isolated as Pico 2 from the diastereomeric separation (EXAMPLE 20, stage 1). MS (ES) m / z 393.2 ([M + H] +); HRMS: calculated for C24H25FN2? 2 + H +, 393.1973; found (ESI, [M + H] +), 393.1982.

Cell Lines, Culture Reagents, and Assays MDCK-? Etd cells, stably transfected with human hNET (Pacholczyk, T., RD Blakely, and SG Amara, Nature, 1991, 350 (6316): p.350-4) are cultured in growth medium containing high glucose DMEM (Gibco, Cat. No. 11995), 10% FBS (dialysed, heat inactivated, US Bio-Technologies, Lot FBD1129HI) and 500 Dg / ml G418 (Gibco, Cat. No. 10131). The cells were seeded at 300,000 / T75 flask and the cells were split twice a week. The JAR cell line (human placental choriocarcinoma) was purchased from the ATCC (Cat.? O. HTB-144). Cells were cultured in growth medium containing RPMl 1640 (Gibco, Cat.? Or 72400), 10% FBS (Irvine, Cat. 3000), 1% sodium pyruvate (Gibco, Cat. o. 1136) and 0.25% glucose. Cells were seeded at 250,000 cells / T75 flask and plated twice weekly. For all assays, the cells were seeded in 96-well sterile plates' Wallac (PerkinElmer, Cat.? Or 3983498).

Norepinephrine Reuptake Assay (NE) On day 1, cells were seeded at 3,000 cells / well in growth medium and maintained in a cell incubator (37 ° C, C02 5%). On day 2, the growth medium was placed with 200 μl of assay buffer (25 mM HEPES, 120 mM NaCl, 5 mM KCl, 2.5 mM CaCl2, 1.2 mM MgSO4, glucose 2 mg / ml (pH 7.4, 37 ° C)) containing 0.2 mg / ml 10 μM ascorbic acid and pargyline. Plates containing cells with 200 μl of assay buffer were equilibrated for 10 minutes at 37 ° C before the addition of compounds. A stored solution of desipramine was prepared in DMSO (10 mM) and administered to triplicate wells containing cells for a final test concentration of 1 μM. The data from those wells were used to define the non-specific resorption Ne (minimum Ne reabsorption). The test compounds were prepared in DMSO (10 mM) and diluted in assay buffer according to the test range (1 to 10,000 nM). Twenty-five microliters of assay buffer (maximum Ne-resorption) or test compound were added directly to triplicate wells containing cells in 200 μl of assay buffer. The cells in assay buffer with the test compounds were incubated for 20 minutes at 37 ° C. Upon initiation of NE resorption, [3H] NE diluted in assay buffer (final assay concentration 120 nM) was administered in 25 μl aliquots to each well and plates were incubated for 5 minutes (37 ° C). The reaction was terminated by decanting the supernatant from the plate. The plates containing cells were washed twice with 200 μl (37 ° C) assay buffer to remove the free radioligand. The plates were then inverted, allowed to dry for 2 minutes, then reinvested and air-dried for an additional 10 minutes. The cells were lysed in 25 μl of solution? AOH 0.25? (4 ° C), they were placed on a shake board and shaken vigorously for 5 minutes. After cell lysate, 75 μl of scytization cocktail was added to each well and the plates were sealed with adhesive film. The plates were returned to the shaking table and shaken vigorously for a minimum of 10 minutes to ensure proper division of organic and aqueous solutions. The plates were counted in a Wallac Microbeta counter (PerkinElmer) to collect the raw cpm data.

Serotonin (5-HT) Reabsorption Assay Methods for 5-HT functional reabsorption using the JAR cell line were modified using a previous report from the literature (Prasad, et al., Placenta, 1996. 17 (4): 201 -7). On day 1, cells were seeded at 15,000 cells / well in 96-well plates containing growth medium (RPMl 1640 with 10% FBS) and kept in a cell incubator (37 ° C), CO2 5%). On day 2, the cells were stimulated with staurosporine (40 nM) to increase the expression of the 5-HT transporter [17]. On day 3, the cells were removed from the cell incubator two hours before the test and kept at room temperature to balance the growth medium to ambient oxygen concentration. Subsequently, the growth medium was replaced with 200 μl of assay buffer (25 mM HEPES; 120 mM NaCl; 5 mM KCl; 2.5 mM CaCl2; MgSO4 1.2 mM; glucose 2 mg / ml (pH 7.4, 37 ° C)) containing 0.2 mg / ml ascorbic acid and 10 μM pargyline. A stored solution of paroxetine (AHR-4389-1) was prepared in DMSO (10 mM) and administered to triplicate wells containing cells for a final test concentration of 1 μM. The data from those wells were used to define the non-specific 5-HT reabsorption (minimal 5-HT reabsorption). The test compounds were prepared in DMSO (10 mM) and diluted in assay buffer according to the test range (1 to 1,000 nM). Twenty-five microliters of assay buffer (maximum 5-HT reabsorption) or test compound were added directly to triplicate wells containing cells in 200 μl of assay buffer. The cells were incubated with the compound for 10 minutes (37 ° C). To initiate the reaction, [3 H] idroxytryptamine creatinine sulfate diluted in assay buffer was administered in 25 μl aliquots to each well for a final test concentration of 15 nM. The cells were incubated with the reaction mixture for 5 minutes at 37 ° C. The 5-HT reabsorption reaction was terminated by decanting the assay buffer. The cells were washed twice with 200 μl (37 ° C) assay buffer to remove the free radioligand. The plates were inverted and allowed to dry for 2 minutes, then reinvested and air dried for an additional 10 minutes. Subsequently, the cells were lysed in 25 μl of 0.25 N NaOH (4 ° C) then placed on a shaking table and shaken vigorously for 5 minutes. After lysing the cell, 75 μl of scintillation cocktail was added to the wells, the plates were sealed with adhesive film and placed on the shaking table for a minimum of 10 minutes. The plates were counted in a Wallac Microbeta counter (PerkinElmer) to collect the raw cpm data.

Evaluation of Results For each experiment, a data stream of cpm values collected from the Wallac Microbeta counter was downloaded to a Microsoft Excel statistical application program. Calculations of the EC50 values were made using the logic dose response program of both sides written by Wyeth Biometrics Department. -The statistical program uses mean cpm values of the wells representing the maximum binding or reabsorption (assay buffer) and mean cpm values of the wells that represent minimal binding or reabsorption ((1 μM desipramine (hNET) or 1 μM paroxetine ( hSERT)) The estimate of the EC50 value was completed on a log scale and the line was placed between the maximum and minimum link or resorption values, all the representation of the graphic data was generated by normalizing each of the data points to an average percentage based on the maximum and minimum binding or reabsorption values The EC50 values reported from the multiple experiments were calculated by collecting the raw data from each of the experiments and analyzing the data collected as an experiment. Table 1 Table 1 When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, it is intended to encompass all combinations and subcombinations of specific ranges at present.

The descriptions of each patent, patent application and publication cited or described in this document are hereby incorporated by reference in their entirety. Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention. This is, therefore, provided that the amended claims cover all equivalent variations as provided within the true spirit and scope of the invention. It is noted that with this date, the best method known to the applicant to carry out the practice of said invention, is that which is clear from the present description of the invention.

Claims (49)

1. Claims Having described the invention as above, the content of the following claims is claimed as property. 1. A compound of the formula I: ) or a pharmaceutically acceptable salt thereof; characterized in that: the dotted line represents an optional double bond between U and V or V and W; U is independently O, S, SO, SO2, C = 0, N, NR3, or C (R8) 2; W is CH, CH2, O C = 0; with the proviso that when W is CH, U is not C (R8) 2; V is C (R8), C (R8) 2, O, u (R8); Ri is independently each occurrence, alkyl, alkoxy, halo, CF3, OCF3, arylalkyloxy substituted with 0-3 Rg, aryloxy substituted with 0-3 R9, aryl substituted with 0-3 R9, heteroaryl substituted with 0-3 Rg, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 Rg, alkylsulfone, phenylsulfone substituted with 0-3 Rg, alkylsulfonamide, phenylsulfonamide substituted with 0-3 R9, heteroaryloxy substituted with 0-3 Rg, heteroarylmethyloxy substituted with 0-3 Rg, alkylamido, or phenylamido substituted with 0-3 Rg; or two adjacent R1 also represent methylenedioxy; R2 is aryl substituted with 0-3 Ri or heteroaryl substituted with 0-3 Ri; R 3 is H, C 1 -C 4 alkyl substituted with 0-3 R x, C 3 -C 6 cycloalkyl, or phenyl substituted with 0-3 Ri; R4 is each independently occurring, H, C? -C alkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl, or both R4 groups, together with the nitrogen through which they are bonded form a heterocyclic ring of 4. up to 6 atoms in the ring, where a carbon can be optionally replaced with N, O, S, or S02, and where any atom in the carbon ring or additional N atom can be optionally substituted with C1-C4 alkyl, F, or CF3; R5 is H or C1-C4 alkyl; R6 is H or C1-C4 alkyl; R7 is independently each occurrence, H, or C?-C4 alkyl, or R-7 and R-4 together with the nitrogen to which R4 is bonded form a nitrogen-containing ring containing 3-6 carbon atoms; R8 is independently each occurring, H, C? -C4 alkyl, C3-C6 heteroalkyl, or aryl substituted with 0-3 Ri; R9 is independently each occurring, alkyl, alkoxy, halo, CF3, 0CF3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two adjacent R9 also represent methylenedioxy; n is an integer from 0 to 4; x is an integer from 1 to 2; and wherein 1-3 carbon atoms in ring A can optionally be replaced with N.
2. 2. The compound according to claim 1, characterized in that: U is 0.
3. 3. The compound according to claim 1 or 2. , characterized in that: W is CH2.
4. 4. The compound according to any of claims 1 to 3, characterized in that: Ri is halo.
5. 5. The compound according to claim 4, characterized in that: Ri is fluoro or chloro.
6. 6. The compound according to any of claims 1 to 5, characterized in that: R2 is aryl substituted with 0-3 Rx.
7. 7. The compound according to claim 6, characterized in that: aryl is phenyl.
8. 8. The compound according to any of claims 1 to 7, characterized in that: R3 is H or C1 alkyl.
9. 9. The compound according to any of claims 1 to 8, characterized in that: R4 is H or C? -C alkyl.
10. 10. The compound according to claim 9, characterized in that: R is H, methyl, ethyl or isopropyl.
11. 11. The compound according to any of claims 1 to 8, characterized in that: both R4 groups, together with the nitrogen to which they are bound, form a ring of pyridine, piperidine, piperazine or morpholine.
12. 12. The compound according to any of claims 1 to 11, characterized in that: R5 is independently each that is present, H or C1 alkyl.
13. 13. The compound according to any of claims 1 to 12, characterized in that n is 0 or 1.
14. 14. The compound according to claim 1, characterized in that it is one of the following: 1- (2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -1- phenylpropan-2 -ol; 3- (methylamino) -1- (4-methyl-3,4-dihydroquinoxalin-l (2H) -yl) -1-phenylpropan-2-ol; 3- (methylamino) -1-phenyl-1- [4- (2, 2, 2-trifluoroethyl) -3,4-dihydroquinoxalin-1 (2H) -yl] propan-2-ol; 1- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -1- (3, 5-difluorophenyl) -3- (methylamino) propan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1- (2-methyl-2,3-dihydro-4H-1, -benzoxazin-4-yl) propan-2-ol; 1- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -l-phenylpropan-2-ol; 3- (methylamino) -1- (6-methyl-2, 3-dihydro-4H-1, -benzoxazin-4-yl) -1-phenylpropan-2-ol; 1- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -1-phenylpropan-2-ol; 1- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -1-phenylpropan-2-ol; 1- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (2,2-dimethyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; 1- (2,2-dimethyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -1-phenylpropan-2-ol; l- (2,3-dihydro-4H-l, 4-benzothiazin-4-yl) -l- (3-fluorophenyl) -3- (methylamino) ropan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1- (2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl) propan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1- [2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl] propan-2-ol; 1- (3-fluorophenyl) -3- (methylamino) -1- [2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl] propan-2-ol; or a pharmaceutically acceptable salt thereof.
15. 15. The compound according to claim 1, characterized in that it is one of the following: (1RS, 2SR) -1- (2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- ( methylamino) -l-phenylpropan-2-ol; (ÍS *, 2R *) -3- (methylamino) -1- (4-methyl-3, 4-dihydroquinoxalin-1 (2H) -yl) -l-phenylpropan-2-ol; (1S *, 2R *) -3- (methylamino) -1-phenyl-1- [4- (2, 2, 2-trifluoroethyl) -3,4-dihydroquinoxalin-1 (2H) -yl] propan-2 ol; (SS, 2R) -1- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -1- (3, 5-difluorophenyl) -3- (methylamino) propan-2 -ol; (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (2-methyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) propan-2-ol; (ISA, 2R *) -1- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -l-phenylpropan-2-ol; (SS *, 2R *) -3- (methylamino) -1- (6-methyl-2, 3-dihydro-4H-l, 4-benzoxazin-4-yl) -1-phenylpropan-2-ol; (SS, 2R) -1- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -1-phenylpropan-2-ol; (IR, 2S) -1- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -l-phenylpropan-2-ol; (1S, 2R) -1- (6-chloro-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2-ol; (SS, 2R) -1- (2,2-dimethyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -1- (3-fluorophenyl) -3- (methylamino) propan-2 -ol; (SS, 2R) -1- (2,2-dimethyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) -3- (methylamino) -1-phenylpropan-2-ol; (1S, 2R) -l- (2,3-dihydro-4H-l, 4-benzothiazin-4-yl) -l- (3-fluorophenyl) -3- (methylamino) propan-2-ol; (SS, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- (2-phenyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl) propan-2-ol; (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- [(2R) -2-phenyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl] propan -2-ol; (1S, 2R) -1- (3-fluorophenyl) -3- (methylamino) -1- [(2S) -2-phenyl-2,3-dihydro-4H-l, 4-benzoxazin-4-yl] propan -2-ol; or a pharmaceutically acceptable salt thereof.
16. 16. A composition, characterized in that it comprises: a. at least one compound according to any of claims 1 to 15; and b. at least one pharmaceutically acceptable carrier.
17. 17. A method for treating or preventing a condition alleviated by the reabsorption of monoamine in a subject in need thereof, characterized in that it comprises the step of: administering to the subject an effective amount of a compound according to any of claims 1 to 15 or a pharmaceutically acceptable salt thereof.
18. 18. The method according to claim 17, characterized in that the condition alleviated by monoamine reabsorption is selected from the group consisting of vasomotor symptoms, sexual dysfunction, gastrointestinal or genitourinary disorders, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders and combinations thereof.
19. The method according to claim 18, characterized in that the condition alleviated by the reabsorption of monoamine is selected from the group consisting of major depressive disorder, vasomotor symptoms, impulse and stress urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and combinations thereof.
20. A method for treating or preventing at least one vasomotor symptom in a subject in need thereof, characterized in that it comprises the step of: administering to the subject an effective amount of a compound according to any one of claims 1 to 15 or a salt pharmaceutically acceptable thereof.
21. 21. The od according to claim 20, characterized in that the vasomotor symptom is a hot flash.
22. 22. The od according to claim 21, characterized in that the subject is a human.
23. 23. The od according to claim 22, characterized in that the human is a subject of the female sex.
24. 24. The od according to claim 23, characterized in that the subject of the female sex is pre-menopausal.
25. 25. The od according to claim 23, characterized in that the subject of female sex is peri-menopausal.
26. 26. The od according to claim 23, characterized in that the subject of female sex is post-menopausal.
27. 27. The od according to claim 22, characterized in that the human is a male subject.
28. 28. The od according to claim 27, characterized by the subject of male sex is naturally, chemically or surgically andropramatically.
29. A od for treating or preventing at least one depression disorder in a subject in need thereof, characterized in that it comprises the step of: administering to the subject an effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.
30. 30. The od according to claim 29, characterized in that the depression disorder is a major depressive disorder, anxiety, sleep disturbances, or social phobia.
31. 31. The od according to claim 30, characterized in that the subject is human.
32. 32. A od for treating or preventing at least one sexual dysfunction in a subject in need thereof, characterized in that it comprises the step of: administering to the subject an effective amount of a compound according to any of claims 1 to 15 or a salt pharmaceutically acceptable thereof.
33. 33. The od according to claim 32, characterized in that sexual dysfunction is a condition related to desire and / or excitation.
34. 34. The od according to claim 33, characterized in that the subject is human.
35. 35. A od for treating or preventing pain in a subject in need thereof, characterized in that it comprises the step of: administering to the subject an effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt of the same .
36. 36. The od according to claim 35, characterized in that the pain is acute centralized pain, acute peripheral pain, or a combination thereof.
37. 37. The od according to claim 35, characterized in that the pain is chronic centralized pain, chronic peripheral pain, or a combination thereof.
38. 38. The od according to claim 35, characterized in that the pain is neuropathic pain, visceral pain, musculoskeletal pain, bone pain, cancer pain, inflammatory pain, or a combination thereof.
39. 39. The od according to claim 38, characterized in that neuropathic pain is associated with diabetes, post-traumatic pain of amputation, low back pain, cancer, chemical injury, toxins, major surgery, peripheral nerve damage due to compression due to traumatic injury , post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, causalgia, thalamic syndrome, nerve root alvusion, reflex sympathetic dystrophy or post-thoracotomy pain, nutritional deficiencies, viral infection, bacterial infection matastatic infiltration, painful adiposis, burns, central pain conditions related to thalamic conditions, and combinations thereof.
40. 40. The od according to claim 38, characterized in that the visceral pain is associated with ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn's disease, rheumatological (arthralgias), tumors, gastritis, pancreatitis, organ infections, disorders of the biliary tract, and combinations thereof.
41. 41. The method according to claim 35, characterized in that the pain is a specific female pain.
42. 42. The method according to claim 35, characterized in that the subject is human.
43. 43. A method for treating or preventing gastrointestinal or genitourinary disorder in a subject in need thereof, characterized in that it comprises the step of: administering to the subject an effective amount of a compound according to any of claims 1 to 15 or a pharmaceutically salt acceptable of them.
44. 44. The method according to claim 43, characterized in that the disorder is impulse and tension urinary incontinence.
45. 45. The method according to claim 44, characterized in that the subject is human.
46. 46. A method for treating or preventing chronic fatigue syndrome in a subject in need thereof, characterized in that it comprises the step of: administering to the subject an effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt of the same.
47. 47. The method according to claim 46, characterized in that the subject is human.
48. 48. A method for treating or preventing fibromyalgia syndrome in a subject in need thereof, characterized in that it comprises the step of: administering to the subject an effective amount of a compound according to any of claims 1 to 15 or a pharmaceutically salt acceptable of them.
49. 49. The method according to claim 48, characterized in that the subject is human.