WO 2005/037283 PCT/US2004/033671
FUSED-ARYL AND HETEROARYL DERIVATIVES AND METHODS OF THEIR USE
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Application No. 10/ filed
October 12, 2004, which claims the benefit of U.S. Application Nos. 60/510,811 filed October 14, 2003, 60/561,447 filed April 12, 2004, and 60/570,056 filed May 11, 2004, the entire disclosures of which are herein incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to fused-aryl and heteroaryl derivatives, 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, vasomotcr symptoms, stress and urge urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and combinations thereof.
E5ACKGROUND OF THE INVENTION
[0003] Vasomotor symptoms (VMS), referred to as hot flushes and night sweats, are the most common symptoms associated with menopause, occurring in 60% to 80% of all women following natural or surgically-induced menopause. VMS are likely to be an adaptive response of the central nervous system (CNS) to declining sax steroids. To date, the most effective therapies for VMS are hormone-based treatments, including estrogens and/or some progestins. Hormonal treatments are very effective at alleviating VMS, but they are not appropriate for all women. It is well recognized that VMS are caused by fluctuations of sex steroid levels and can be disruptive and disabling in both males and females. A hot flush can last up to thirty

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minute- and vary in their frequency from several times a week to multiple occurrences per day. The patient experiences a hot flash as a sudden feeling of heat that spreads quickly from the face to the chest and back and then over the rest of the body. It is usually accompanied by outbreaks of profuse sweating. It may sometimes occur several times an hour, and it often occurs at night. Hot flushes and outbreaks of sweats occurring during the night can cause sleep deprivation. 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 sleep deprivation following hot flush and 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)).
[0004] Hot flushes may be even more severe in women treated for breast cancer for several reasons: 1) many survivors of breast cancer are given tamoxifen, the most prevalent side effect of which is hot flush, 2) many women treated for breast cancer undergo premature rrienopause from chemotherapy, 3) women with a history of breast cancer have generally been denied estrogen therapy because of concerns about potential recurrence of breast cancer (Loprinzi, et al., Lancet, 2000, 356(9247): 2059-2063).
[0005] Men also experience hot flushes following steroid hormone (androgen) withdrawal. This is true in cases of age-associated androgen decline (Katovich, et al., Proceedings of the Society for Experimental Biology & Medicine, 1990, 193(2): 129-35) as well as in extreme cases of hormone deprivation 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 significant-discomfort and inconvenience.
[0006] The precise mechanism of these symptoms is unknown but generally is thought to represent disturbances to normal homeostatic mechanisms controlling thermoregulation and vasomotor activity (Kronenberg et al., "Thermoregulatory

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Physiology of Menopausal Hot Flashes: A Review," Can. J. Physiol. Pharmacol., 1987,65:1312-1324).
10007] The fact that estrogen treatment (e.g. estrogen replacement therapy) relieves the symptoms establishes the 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 estrogen responsive.
[0008] It has been suggested that estrogens may stimulate the activity of both the norepinephrine (NE) and/or serotonin (5-HT) systems (J. Pharmacology & Experimental Therapeutics, 1986, 236(3) 646-652). It is hypothesized that estrogens modulate NE and 5-HT levels providing homeostasis in the thermoregulatory center of the hypothalamus. The descending pathways from the hypothaiamus via brainstem/spinal cord and the adrenals to the skin are involved in maintaining normal skin temperature. The action of NE and 5-HT reuptake inhibitors is known to impinge on both the CNS and peripheral nervous system (PNS). The pathophysiology of VMS is mediated by both central and peripheral mechanisms and, therefore, the interplay between the CNS and PNS may account for the efficacy of dual acting SRI/NRIs in the treatment of thermoregulatory dysfunction. In fact, the physiological aspects and the CNS/PNS involvement in VMS may account for the lower doses proposed to treat VMS (Loprinzi, et al. Lancet, 2000, 356:2059-2063; Stearns et al., JAMA, 2003, 289:2827-2834) compared to doses used to treat the behavioral aspects of depression. The interplay of the CNS/PNS in the pathophysiology of VMS and the presented data within this document were used to support the claims that the norepinephrine system could be targeted to treat VMS.
[0009] Although VMS are most commonly treated by hormone therapy (orally, transdermally, or via an implant), some patients cannot tolerate estrogen treatment (Berendsen, Maturitas, 2000, 36(3): 155-164, Fink et al., Nature, 1996, 383(6598): 306). In addition, hormone replacement therapy is usually not recommended for women or men with or at risk for hormonally sensitive cancers (e.g. breast or prostate cancer). Thus, non-hormonal therapies (e.g. fluoxetine, paroxetine [SRIs]

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and clcnidine) are being evaluated clinically. WO9944601 discloses a method for decreasing hot flushes in a human female by administering fluoxetine. Other options have been studied for the treatment of hot flashes, including steroids, alpha-adrenergic agonists, and beta-blockers, with varying degree of success (Waldinger et al., Maturitas, 2000, 36(3): 165-168).
[0010] It has been reported that a2.adrenergic receptors play a role in
thermoregulatory dysfunctions (Freedman etal., 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 distinct subtypes of the adrenergica2 receptors, i.e., are ?2A, ?2B) ?2C and ?2D (Mackinnon et a!., TIPS, 1994, 15: 119; French, Pharmacol. Ther., 1995, 68: 175). It has been reported that a non-select oc2-adrenoceptor antagonist, yohimbine, induces a flush and an a2-adrenergic receptor agonist, clonidine, alleviates the yohimbine effect (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 flush. However, using such treatment is associated with a number of undesired side effects caused by high doses necessary to abate hot flash described herein and known in the related arts.
[0011] Given the complex multifaceted nature of thermoregulation and the interplay between the CNS and PNS in maintaining thermoregulatory homeostasis, multiple therapies and approaches can be developed to target vasomotor symptoms. The present invention focuses on novel compounds and compositions containing these compounds directed to these and other important uses.
SUMMARY OF THE INVENTION
[0012] The present invention is directed to fused-aryl and heteroaryl derivatives, 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,

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gastroir estinal 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.
[0013] In one embodiment, the present invention is directed to compounds of
formula I:

or a pharmaceutically acceptable salt thereof;
wherein:
A is naphthyl, thiophenyl, pyridinyi, furanyl, benzofuranyl, isobenzofuranyl, xanthenyl, pyrrolyl, indolizinyl, isoindolyl, indolyl, benzothiophenyi, wherein any 1 to 3 carbon atom(s) of said A can be optionally replaced with a nitrogen atom, and wherein said A is optionally substituted with one or more R1;
W is H or OR9;
R1 is, independently, H, OH, alkyl, alkoxy, halo, trifluoromethyl, alkanoyloxy, methylenedioxy, benzyloxy (optionally substituted with one or more R1), phenyloxy (optionally substituted with one or more R1), naphthyloxy (optionally substituted with one or more R1), nitro, trifluoromethoxy, nitrile, alkenyl, alkynyl, sulfoxide, sulfonyl, sulfonamido, phenyl (optionally substituted with one or more R1), heteroaryl (optionally substituted with one or more R1), heteroaryloxy (optionally substituted with one or more R1), heteroaryl methyloxy (optionally substituted with one or more R1), alkanoyl, alkoxycarbonyl, alkylaminocarbonyl, oramino; R5 is H, (C1-C6)alkyl, or trifluoromethyl;

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P6 and R7 are, independently, (C1-C6)a!kyl or (C3-C6)cycloalkyl;
or R6 and R' can together form a ring of 4 to 8 carbon atoms;
where any carbon atom of said R6 and R7 may be optionally replaced with N, S, orO;
where R6 and R7 may be optionally substituted with R5 or OH; or
where R6 and R7 can form a ring with 4 to 8 carbons fused onto a cycloalkyl ring of 4 to 6 carbon atoms;
R8 is H, (C1-C6)alkyl, benzyl (optionally substituted with benzyloxy or phenyloxy), naphthylmethyl (optionally substituted with one or more R1), phenyl(C2-C6)alkyl (optionally substituted with one or more R1), heteroarylmethyl (optionally substituted with R1), cycloalkyl, cycloalkenyl, cycloalkylmethyl (where any carbon atom can be optionally replaced with N, S, or O and where said cycloalkylmethyl can be optionally substituted with OH, CF3, halo, alkoxy, alkyl, benzyloxy, or alkanoyloxy), cycloalkenylmethyl (where any carbon atom can be optionally replaced with N, S, or O and where said cycloalkylmethyl can be optionally substituted with OH, CF3, halo, alkoxy, alkyl, benzyloxy, or alkanoyloxy);
or R5 and R8, together with the nitrogen atom to which Ra is attached, form a ring optionally substituted with R5;
R9 is H, (C1-C4)alkyl, or (C1-C4)alkyl-C(=O); t is 1, 2, or 3; and xisO, 1, or 2.
[0014] In yet 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.
[0015] In another embodiment, the present invention is directed to methods for treating or preventing a condition ameliorated by monoamine reuptake in a subject in need thereof, comprising the step of:
administering to said subject an effective amount of a compound of formula I or pharmaceutically acceptable salt thereof.

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The conditions ameliorated by monoamine reuptake include those selected from the group consisting of vasomotor symptoms, 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.
[0016] In another embodiment, the present invention is directed to methods for treating or preventing vasomotor symptoms in a subject in need thereof, comprising the step of:
administering to said subject an effective amount of at least one compound of formula I or pharmaceutically acceptable salt thereof.
[0017] In yet 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 said subject an effective amount of at least one compound of formula I or pharmaceutically acceptable salt thereof.
[0018] In yet other embodiments, the present invention is directed to methods
for treating or preventing sexual dysfunction in a subject in need thereof, comprising the step of:
administering to said subject an effective amount of at least one compound of Formula I or pharmaceutically acceptable salt thereof.
[0019] In further embodiments, the present invention is directed to methods
for treating or preventing pain in a subject in need thereof, comprising the step of:
administering to said subject an effective amount of at least one compound of formula 1 or pharmaceutically acceptable salt thereof.
[0020] In another embodiment, the present invention is directed to methods for treating or preventing gastrointestinal or genitourinary disorder, particularly stress

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incontinence or urge urinary incontinence, in a subject in need thereof, comprising the step of:
administering to said subject an effective amount of a compound of formula I or pharmaceutically acceptable salt thereof.
[0021] 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 said subject an effective amount of a compound of formula I or pharmaceutically acceptable salt thereof.
[0022] In another embodiment, the present invention is directed to methods for treating or preventing fibromylagia syndrome in a subject in need thereof, comprising the step of:
administering to said subject an effective amount of a compound of formula I or pharmaceutically acceptable salt thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] The invention can be more fully understood from the following detailed
description and the accompanying drawings that form a part of this application.
[0024] Figure 1 is an overview of estrogen action on norepinephrine/serotonin
mediated thermoregulation.
[0025] Figure 2 is a schematic representation of the interactions of
norepinephrine and serotonin and their respective receptors (5-HT2a, a1 and a2-adrenergic).
DETAILED DESCRIPTION OF THE INVENTION
[0026] The present invention is directed to fused-aryl and heteroaryl derivatives, compositions containing these derivatives, and methods of their use for the

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preven'lon 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.
[0027] The following definitions are provided for the full understanding of terms and abbreviations used in this specification.
[0028] 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 forth.
[0029] The abbreviations in the specification correspond to units of measure, techniques, properties, or compounds as follows: "min" means minutes, "h" means hour(s), "uL" means microliter(s), "mL" means milliliter(s), "mM" means millimolar, "M" means molar, "mmole" means millimole(s), "cm" means centimeters, "SEM" means standard error of the mean and "IU" means International Units. "A°C" and A "ED50 value" means dose which results in 50% alleviation of the observed condition or effect (50% mean maximum endpoint).
[0030] "Norepinephrine transporter" is abbreviated NET.
"Human norepinephrine transporter" is abbreviated hNET. "Serotonin transporter" is abbreviated SERT. "Human serotonin transporter" is abbreviated hSERT. "Norepinephrine reuptake inhibitor" is abbreviated NRI. "Selective norepinephrine reuptake inhibitor" is abbreviated SNR1. "Serotonin reuptake inhibitor" is abbreviated SRI. "Selective serotonin reuptake inhibitor" is abbreviated SSRI.

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"Norepinephrine" is abbreviated NE. "Serotonin is abbreviated 5-HT. "Subcutaneous" is abbreviated sc. "Intraperitoneal" is abbreviated ip. "Oral" is abbreviated po.
[0031] In the context of this disclosure, a number of terms shall be utilized. The term "treatment" as used herein includes preventative (e.g., prophylactic), curative or palliative treatment and "treating" as used herein also includes preventative, curative and palliative treatment.
[0032] The term "effective amount," as used herein, refers to an amount effective, at dosages, and for periods of time necessary, to achieve the desired result with respect to 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 compound or composition of compounds that would increase norepinephrine levels to compensate in part or total for the lack of steroid availability in subjects subject afflicted with a vasomotor symptom. Varying hormone levels will influence the amount of compound required in the present invention. For example, the pre-menopausal state may require a lower level of compound due to higher hormone levels than the peri-menopausal state.
[0033] 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 combination drugs) to elicit a desired response in the individual, but also with factors such as the disease state or severity of the condition to be alleviated, hormone levels, age, sex, weight of the individual, the state of being of the patient, and the severity of the pathological condition being treated, concurrent medication or special diets then being followed by the particular patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician. Dosage regimens may be adjusted to provide the improved

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therapautic response. An effective amount is also one in which any toxic or detrimental effects of the components are outweighed by the therapeutically beneficial effects.
[0034] Preferably, the compounds of the present invention are administered at a dosage and for a time such that the number of hot flushes is reduced as compared to the number of hot flushes prior to the start of treatment. Such treatment can also be beneficial to reduce the overall severity or intensity distribution of any hot flushes still experienced, as compared to the severity of hot flushes prior to the start of the treatment. With respect to depression disorders, sexual dysfunction, and pain, the compounds of the present invention are administered at a dosage and for a time such that there is the prevention, alleviation, or elimination of the symptom or condition.
[0035] For example, for an afflicted patient, compounds of formula I may be administered, preferably, at a dosage of from about 0.1 mg/day to about 200 mg/day, more preferably from about 1 mg/day to about 100 mg/day and most preferably from about 1 mg/day to 50 mg/day for a time sufficient to reduce and/or substantially eliminate the number and/or severity of hot flushes or symptom or condition of the depression disorder, sexual dysfunction, or pain.
[0036] 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 physiologic effect by local and/or systemic action.
[0037] ' The terms "component", "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 pharmacologic and/or physiologic effect by local and/or systemic action.

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[0038] The term "modulation" refers to the capacity to either enhance or inhibit a functional property of a biological activity or process, for example, receptor binding or signaling activity. Such enhancement or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway and/or may be manifest only in particular cell types. The modulator is intended to comprise any compound, e.g., antibody, small molecule, peptide, oligopeptide, polypeptide, or protein, preferably small molecule, or peptide.
[0039] As used herein, the term "inhibitor" refers to any agent that inhibits, suppresses, represses, or decreases a specific activity, such as serotonin reuptake activity or the norepinephrine reuptake activity.
[0040] The term "inhibitor" is intended to comprise any compound, e.g., antibody, small molecule, peptide, oligopeptide, polypeptide, or protein, preferably small molecule or peptide, that exhibits a partial, complete, competitive and/or inhibitory effect on mammalian, preferably the human norepinephrine reuptake or both serotonin reuptake and the norepinephrine reuptake, thus diminishing or blocking, preferably diminishing, some or all of the biological effects of endogenous norepinephrine reuptake or of both serotonin reuptake and the norepinephrine reuptake.
[0041] Within the present invention, the compounds of formula I may be prepared in the form of pharmaceutically acceptable salts. 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 inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, malic, maleic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic and the like. Particularly preferred are hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most preferably is the hydrochloride salt.

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[0042] "Administering," as used herein, means either directly administering a compound or composition of the present invention, or administering a prodrug, derivative or analog which will form an equivalent amount of the active compound or substance within the body.
[0043] The term "subject" or "patient" refers to an animal including the human species that is treatable with the compositions, and/or methods of the present invention. The term "subject" or "subjects" is intended to refer to both the male and female gender unless one gender is specifically indicated. Accordingly, the term "patient" comprises any mammal which may benefit from 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-rnenopausal, or post-menopausal period. Furthermore, the term patient includes female animals including humans and, among humans, not only women of advanced age who have passed through menopause but also women who have undergone hysterectomy or for some other reason have suppressed estrogen production, such as those who have undergone long-term administration of corticosteroids, suffer from Cushing's syndrome or have gonadal dysgenesis. However, the term "patient" is not intended to be limited to a woman.
[0044] The terms "premature menopause" or "artificial menopause" refer to ovarian failure of unknown cause that may occur before age 40. It may be associated with smoking, living at high altitude, or poor nutritional status. Artificial menopause may result from oophorectomy, chemotherapy, radiation of the pelvis, or any process that impairs ovarian blood supply.
[0045] The term "pre-menopausal" means before the menopause, the term "peri-menopausal" means during the menopause and the term "post-menopausal" means after the menopause. "Ovariectomy" means removal of an ovary or ovaries and can be effected according to Merchenthaler et al., Maturitas, 1998, 30(3): 307-316.
[0046] "Side effect" refers to a consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on

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a tissue or organ system other then the one sought to be benefited by its administration. In the case, for example, of high doses of NRIs or NRI/SRI compounds alone, the term "side effect" may refer to such conditions as, for example, vomiting, nausea, sweating, and flushes (Janowsky, et al.. Journal of Clinical Psychiatry, 1984, 45(10 Pt 2): 3-9).
[0047] "AlkyI," as used herein, refers to an aliphatic hydrocarbon chain of 1 to about 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably, 1 to 6 carbon atoms, and even more preferably, 1 to 4 carbon atoms and includes straight and branched chains such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and isohexyl. Lower alkyl refers to alkyl having 1 to 4 carbon atoms.
[0048] "Alkoxy," as used herein, refers to the group R-O- where R is an alkyl group of 1 to 6 carbon atoms.
[0049] "Alkoxycarbonyl," as used herein, refers to the group R-O-C(=O)- where R is an alkyl group of 1 to 6 carbon atoms.
[0050] "Alkanoyl," as used herein, refers to the group R-C(=O)- where R is an alkyl group of 1 to 6 carbon atoms.
[0051] "Alkanoyloxy," as used herein, refers to the group R-C(=O)-O- where R is an alkyl group of 1 to 6 carbon atoms.
[0052] "Alkylaminocarbonyl," as used herein, refers to the group R-NH-C(=O)-where R is an alkyl group of 1 to 6 carbon atoms.
[0053] "Alkylcarbonylamino," as used herein, refers to the group R-C(=O)-NH where R is an alkyl group of 1 to 6 carbon atoms.

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[0054] "Alkenyl" or "olefinic," as used herein, refers to an aikyl group of at least two carbon atoms having one or more double bonds, wherein alkyl is as defined herein. Alkenyl groups can be optionally substituted with one or more R1, as defined herein.
[0055] "Alkynyl," as used herein, refers to an alkyl group of at least two carbon atoms having one or more triple bonds, wherein alkyl is as defined herein. Alkynyl groups can be optionally substituted with one or more R1, as defined herein.
[0056] "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 therein), with from about 6 to about 10 carbons being preferred. Non-limiting examples include, for example, phenyl, naphthyl, anthracenyl, and phenanthrenyl. Aryl groups can be optionally substituted with one or with one or more R1, as defined herein.
[0057] "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 sulfur, oxygen, or nitrogen heteroatom ring members. Heteroaryl groups can have, for example, from about 3 to about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 4 to about 10 carbons being preferred. Non-limiting examples of heteroaryl groups include, for example, pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyi, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl. Heteroaryl groups can be optionally substituted with one or with one or more R1, as defined herein.
[0058] "Heterocyclic ring," as used herein, refers to a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring that is saturated, partially unsaturated or unsaturated (aromatic), and which contains 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 above

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defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen atom in the heterocycle may optionally be quaternized. It is preferred that when the lotal 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 is not more than one. Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazo!e, 4H-quinolizlnyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4-H-carbazoiyl, a-, (3-, or y-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H.6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H-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, oxazolidinylpyrimidinyl, 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, quinolinyl, 4H-quinoIizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, Ihienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1 H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl,

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oxindoiyl, benzoxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
[0059] "Heteroarylmethyi," as used herein, refers to the group R-CH2- where R is a heteroaryl group, as defined herein.
[0060] "Heteroarylmethyloxy," as used herein, refers to the group R-CH2-O- where R is a heteroaryl group, as defined herein.
[0061] "Heteroaryloxy," as used herein, refers to the group R-O- where R is a heteroaryl group, as defined herein.
[0062] "Heteroarylmethyioxy," as used herein, refers to the group R-CH2-O- where R is a heteroaryl group, as defined herein.
[0063] "Cycloalkyl," as used herein, refers to an optionally substituted, alkyl group having one or more rings in their structures having from 3 to about 20 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from 3 to about 10 carbon atoms being preferred. Multi-ring structures may be bridged or fused ring structures. Groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, 2-[4-isopropyl-1-methyl-7-oxa-bicyclo[2.2.1]heptanyl], 2-[1,2,3,4-tetrahydro-naphthalenyl], and adamantyl.
[0064] "Cycloalkylmethyl," as used herein, refers to the group R-CH2- where R is a cycloalkyl group, as defined herein.
|0065] "Cycloalkenyl," as used herein, refers to an optionally substituted, alkene group having one or more rings in their structures having from 3 to about 20 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from 3 to about 10 carbon atoms being preferred. Multi-ling structures may be bridged or fused ring structures. Groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclooctenyl.

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[0066] "Cycloalkenylmethyl," as used herein, refers to the group R-CH2- where R is a cycloalkenyl group, as defined herein.
[0067] "Sulfoxide," as used herein, refers to a compound or moiety containing the group -S(=O)-.
[0068] "Sulfonamido," as used herein, refers to a moiety containing the group -S(O)2-NH-.
[0069] "Sulfonyl," as used herein, refers to a moiety containing the group -S(O)2-.
[0070] "Halo" or "halogen," as used herein, refers to chloro, bromo, fluoro, and iodo.
[0071] In one embodiment, the present invention is directed to compounds of formula I:


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or a pharmaceutically acceptable salt thereof; wherein:
A is naphthyl, thiophenyl, pyridinyl, furanyl, benzofuranyl, isobenzofuranyl, xanthenyl, pyrrolyl, indolizinyl, isoindolyl, indolyl, benzothiophenyl, wherein any 1 to 3 carbon atom(s) of said A can be optionally replaced with a nitrogen atom, and wherein said A is optionally substituted with one or more R1; W is H or OR9;
R1 is, independently, H, OH, alkyl, alkoxy, halo, trifluoromethyl, alkanoyloxy, methylenedioxy, benzyloxy (optionally substituted with one or more R1), phenyloxy (optionally substituted with one or more R1), naphthyloxy (optionally substituted with one or more R1), nitro, trifluoromethoxy, nitrile, alkenyl, alkynyl, sulfoxide, sulfonyl, sulfonamido, phenyl (optionally substituted with one or more R1), heteroaryl (optionally substituted with one or more R1), heteroaryloxy (optionally substituted with one or more R1), heteroaryl methyloxy (optionally substituted with one or more R1), alkanoyl, alkoxycarbonyl, alkylaminocarbonyl, or amino; R5 is H, (C1-C6)alkyl, or trifluoromethyl; R6 and R7 are, independently, (C1-C6)alkyl or (C3-C6)cycloalkyl; or R6 and R7 can together form a ring of 4 to 8 carbon atoms; where any carbon atom of said R6 and R7 may be optionally replaced with N, S, orO;
where R6 and R7 may be optionally substituted with R5 or OH; or where R6 and R7 can form a ring with 4 to 8 carbons fused onto a cycloalkyl ring of 4 to 6 carbon atoms;
R8 is H, (C1-C6)alkyl, benzyl (optionally substituted with benzyloxy or phenyloxy), naphthylmethyl (optionally substituted with one or more R1), phenyl(C2-C6)alkyl (optionally substituted with one or more R1), heteroarylmethyl (optionally substituted with R1), cycloalkyl, cycloalkenyl, cycloalkylmethyl (where any carbon atom can be optionally replaced with N, S, or O and where said cycloalkylmethyl can be optionally substituted with OH, CF3, halo, alkoxy, alkyl, benzyloxy, or alkanoyloxy), cycloalkenylmethyl (where any carbon atom can be optionally replaced with N, S, or O and where said cycloalkylmethyl can be optionally substituted with OH, CF3, halo, alkoxy, alkyl, benzyloxy, or alkanoyloxy);

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or R5 and R8, together with the nitrogen atom to which R8 is attached, form a ring optionally substituted with R5;
R9 is H, (C1-C4)alkyl, or (C1-C4)alkyl-C(=O); t is 1 , 2, or 3; and xis O, 1, or 2.
[0072] In certain preferred embodiments,
A is naphthyl, thiophenyl, pyridinyl, furanyl, benzofuranyl, isobenzofuranyl, xanthenyl, pyrrolyl, indolizinyl, isoindolyl, indolyl, benzothiophenyl, wherein any 1 to 3 carbon atom(s) of said A can be optionally replaced with a nitrogen atom, and wherein said A is optionally substituted with one or more R1;
W is H or OR9;
R1 is, independently, H, OH, alkyl, alkoxy, halo, trifluoromethyl, alkanoyloxy, methylenedioxy, benzyloxy (optionally substituted with one or more R1), phenyloxy (optionally substituted with one or more R1), naphthyloxy (optionally substituted with one or more R1), nitro, trifluoromethoxy, nitrile, alkenyl, alkynyl, sulfoxide, sulfonyl, sulfonamido, phenyl (optionally substituted with one or more R1), heteroaryl (optionally substituted with one or more R1), heteroaryloxy (optionally substituted with one or more R1), heteroaryl methyloxy (optionally substituted with one or more R1), alkanoyl, alkoxycarbonyl, alkylaminocarbonyl, or amino;
R5 is H, (C1-C6)alkyl, or trifluoromethyl;
R6 and R7 together form a ring of 4 to 8 carbon atoms;
R8 is H, (C1-C6)alkyl, benzyl (optionally substituted with benzyloxy or phenyloxy), naphthylmethyl (optionally substituted with one or more R1), phenyl(C2-C6)alkyl (optionally substituted with one or more R1), heteroarylmethyl (optionally substituted with R1), cycloalkyl, cycloalkenyl, cycloalkylmethyl (where any carbon atom can be optionally replaced with N, S, orO and where said cycloalkylmethyl can be optionally substituted with OH, CF3, halo, alkoxy, alkyl, benzyloxy, or alkanoyloxy), cycloalkenylmethyl (where any carbon atom can be optionally replaced with N, S, or O and where said cycloalkylmethyl can be optionally substituted with OH, CF3, halo, alkoxy, alkyl, benzyloxy, or alkanoyloxy);
or R5 and R8, together with the nitrogen atom to which R8 is attached, form a ring optionally substituted with R5;

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R9 is H;
t is 1, or 2; and
x is 1, or 2.
[0073] In certain preferred embodiments, A is naphthyl, thiophenyl, pyridinyl, furanyl, benzofuranyl, isobenzofuranyl, xanthenyl, pyrrolyl, indolizinyl, isoindolyl, indolyl, benzothiophenyl.
[0074] In certain preferred embodiments, W is H. In certain other preferred embodiments, W is OR9.
[0075] In certain preferred embodiments, R1 is, independently, H, OH, alkyl (especially methyl, ethyl, propyl, and butyl), alkoxy (especially methoxy and ethoxy), halo (especially chloro, fluoro, and bromo), trifluoromethyl, alkanoyloxy, methylenedioxy, benzyloxy, phenyloxy, naphthyloxy, nitro, trifluoromethoxy, nitrile, alkenyl, alkynyl, sulfoxide, suifonyl, sulfonamido, phenyl, heteroaryl, heteroaryloxy, heteroaryl methyloxy, alkanoyl, alkoxycarbonyl, alkylaminocarbonyl, or amino;
[0076] In certain preferred embodiments, R5 is H or (C1-C6)alkyl (especially methyl, ethyl, propyl, and butyl.
[0077] In certain preferred embodiments, R6 and R7 are, independently, (C1-C6)alkyl (especially methyl, ethyl, propyl, and butyl) or (C3-C6)cycloalkyl (especially cyclopropyl, cyclobutyl, and cyclohexyl)
[0078] In certain preferred embodiments, R6 and R7 can together form a ring of 4 to 3 carbon atoms.
[0079] In certain preferred embodiments, R8 is H, (C1-C6)alkyl (especially methyl, ethyl, propyl, and butyl), benzyl, naphthylmethyl, phenyl(C2-C6)alkyl, heteroarylmethyl, or cycloalkyl (especially cyclopropyl, cyclobutyl, and cyclohexyl), cycloalkenyl, cycloalkylmethyl, cycloalkenylmethyl.

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[0080] In certain preferred embodiments, R5 and R8, together with the nitrogen atom to which R8 is attached, form a ring optionally substituted with R5.
[0081] In certain preferred embodiments, R9 is H or (C1-C4)alkyl (especially methyl or ethyl).
|0082] In certain preferred embodiments, t is 1. In certain other preferred embodiments, t is 2. In yet certain other preferred embodiments, t is 3.
|0083] In certain preferred embodiments, x is 0. In certain other preferred embodiments, x is 1. In yet certain other preferred embodiments, x is 2.
[0084] In certain preferred embodiments, A is naphthyl, benzothienyl, thienyl, quinolinyl or indolyl.
[0085] In certain preferred embodiments, R1 is hydrogen, OH, halogen, C1-C6alkyl and CrCealkoxy.
[0086] In certain preferred embodiments, R6 and R7 for example may form a 4, 5, 6, 7 or 8 membered ring; ,e.g., a cyclohexyl ring, one carbon of which is optionally nitrogen. The ring formed by R6 and R7 may be for example substituted by H or Ci-C6 alkyl.
[0087] (n certain preferred embodiments, when alkyl, R6 and R7 are,
independently, methyl or ethyl.
[0088] In certain preferred embodiments, W is OH.
[0089] In certain preferred embodiments, t is 1 or 2.
[0090] In certain preferred embodiments, x is 1.
[0091] In certain preferred embodiments, R8 is H, (C1-C6)alkyl (especially methyl,

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ethyl, propyl, and butyl), benzyl, naphthylmethyl, phenyl(C2-C6)a!kyl, heteroarylmethyl, cycloalkyl (especially cyclopropyl, cyclobutyl, and cyclohexyl), cycloalkenyl, cycloalkylmethyl, or cycJoalkenylmethyl.
[0092] Preferred compounds of formula I include:
1 -[1 -(2-naphthyl)-2-piperazin-1 -ylethyl]cyclobutanol dihydrochloride; 1 -[1 -(1 -naphthyl)-2-piperazin-1 -ylethyljcyclohexanol dihydrochloride; 1-[1-(1-naphthyl)-2-piperazin-1-ylethyl]cyclopentanol dihydrochloride; 3-ethyl-2-(1 -naphthyl)-1 -piperazin-1 -ylpentan-3-ol dihydrochloride; 1 -[2-(4-methylpiperazin-1 -yl)-1 -(1 -naphthyl)ethyl]cyclopentanol dihydrochloride;
1 -methyl-4-[1 -(2-naphthyl)-2-piperazin-1 -ylethyl]piperidin-4-ol dihydrochloride; 1 -[1 -(2-naphthyl)-2-piperazin-1 -ylethyljcyclohexanol dihydrochloride; 1 -[2-(4-methy]piperazin-1 -yl)-1 -(2-naphthyl)ethyl]cyclohexanol dihydrochloride;
1-[1-(1-naphthyl)-2-piperazin-1-ylethyl]cyclobutanoI dihydrochloride; 1 -[2-(4-methylpiperazin-1 -y!)-1 -(1 -naphthyl)ethyl]cyclobutanol dihydrochloride; 4-tert-butyl-1 -[1 -(1 -naphthyl)-2-piperazin-1 -ylethyl]cyc!ohexanol dihydrochloride;
3-ethyl-1 -(4-methylpiperazin-1 -yl)-2-(1 -naphthyl)pentan-3-oi dihydrochloride; 4-ethyI-1 -[1 -(1 -naphthyl)-2-piperazin-1 -ylethyl]cyclohexanol dihydrochloride; 4-methyl-1 -[1 -(1 -naphthyl)-2-piperazin-1 -ylethyl]cyclohexanol dihydrochloride; 4-tert-butyl-1 -[2-(4-methylpiperazin-1 -yl)-1 -(1 -naphthyl)ethyl]cyclohexano! dihydrochloride;
1 -[1 -(2,5-dichlorothien-3-yl)-2-piperazine-1 -ylethyl]cyclohexanol dihydrochloride;
1 -[1 -(5-ch!orothien-2-yl)-2-piperazin-1 -ylethyl]cyclohexanol dihydrochloride; 1 -[1 -(5-bromothien-2-yl)-2-piperazin-1 -ylethyljcyclohexanol dihydrochloride; 1 -[1 -(5-chlorothien-3-yl)-2-piperazin-1 -ylethyljcyclohexanol dihydrochloride; 1 -[2-(4-aminopiperidin-1 -yl)-1 -(5-ch!orothien-3-yl)ethyl]cyclohexanol dihydrochloride;
1-[1-(1-benzothien-3-yI)-2-piperazin-1-ylethyljcyclohexanol dihydrochloride;

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1. [1 -(1 -methyl-1 H-indol-3-yl)-2-piperazin-1 -ylethyl]cyclohexanol dihydrochloride;
1 -[1 -(1 H-indol-3-yl)-2-piperazin-1 -ylethyl]cyclohexanol dihydrochloride; 1 -[1 -(2-chlorothien-3-yl)-2-piperazin-1 -ylethyl]cyc!ohexano! dihydrochloride; 1 -[1 -(5-chlorothien-3-yl)-2-(4-methylpiperazin-1 -yl)ethyl]cyclohexanol dihydrochloride;
[(1R)-1-(5-chIorothien-3-yl)-2-(4-methylpiperazin-1-yl)ethyl]cyclohexanol dihydrochloride;
1 -[(1 S)-1 -(5-chlorothien-3-yl)-2-(4-methy!piperazin-1 -yl)ethyl]cyclohexanol dihydrochloride;
1 -[1 -(5-chloro-1 -benzothien-3-yl)-2-piperazin-1 -ylethy!]cyclohexanol dihydrochloride;
1 -[1 -(1 -benzothien-2-yl)-2-piperazin-1 -ylethyl]cyclohexanol dihydrochloride; 1-(2-piperazin-1-yl-1-quinolin-3-yIethyl)cyclohexanol dihydrochloride; 1 -[1 -(1 -naphthyl)-2-piperazin-1 -ylethyl]cyclooctanol dihydrochloride; 1 -[2-(4~methylpiperazin-1 -yl)-1 -(1 -naphthyl)ethyl]cyclooctanol dihydrochloride;
1 -[1 -(1 -naphthy!)-2-piperazin-1 -y!ethyl]cycloheptanol dihydrochloride; 1 -[2-(4-methylpiperazin-1 -yl)-1 -(1 -naphthyl)ethyl]cycloheptanol dihydrochloride;
1 -[1 -(5-methoxy-1 -benzothien-3-yl)-2-piperazin-1 -ylethyl]cyclohexanol dihydrochloride;
1 -[1 -(4-bromothien-2-yl)-2-piperazin-1 -ylethyl]cyclohexanol dihydrochloride; 4-ethyl-1 -[2-(4-methylpiperazin-1 -yl)-1 -(1 -naphthyl)ethyl]cyclohexanol dihydrochloride;
4-methyl-1-[2-(4-methylpiperazin-1-yl)-1-(1-naphthyl)ethyl]cyclohexanol dihydrochloride;
1 -(2-piperazin-1 -yl-1 -pyridin-3-ylethyl)cyclohexanol trihydrochloride; 1 -(2-piperazin-1 -yl-1 -pyridin-3-ylethyl)cyclohexanol trihydrochloride; 1 -[1 -(6-methoxy-2-naphthyl)-2-piperazin-1 -ylethyl]cyclohexanol; 1 -[1 -(S-methoxy-2-naphthyl)-2-(4-methylpiperazin-1 -yl)ethyl] cyclohexanol; and
pharmaceutically acceptable salts thereof.

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[0093] Some of the compounds of the present invention may contain chiral centers and such compounds may exist in the form of stereoisomers (i.e. enantiomers). The present invention includes ail such stereoisomers and any mixtures thereof 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 mole %, more preferably at least about 95 mole %, and most preferably at least about 98 mole % of the desired stereoisomer is present relative to other possible stereoisomers. Preferred enantiomers may 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., ef al., Tetrahedron, 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds, (McGraw-Hill, NY, 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).
[0094] The present invention includes prodrugs of the compounds of formula I. "Prodrug," as used herein, means a compound which is convertible in vivo by metabolic means (e.g. 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 Drug Design and Development, Chapter 5, 113-191 (1991), Bundgaard, et al., Journal of Drug Deliver Reviews, 1992, 8:1-38, Bundgaard, J. of Pharmaceutical Sciences, 1988, 77:285 et seq.; and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975).
[0095] Further, the compounds of formula I may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like In general the snlvatpd forms are considered eauivalent to the

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unsolvated forms for the purpose of the present invention.
[0096] The compounds of the present invention may be prepared in a number of ways well known to those skilled in the art. The compounds can be synthesized, for example, by the methods described below, or variations thereon as appreciated by the skilled artisan. All processes disclosed in association with the present invention are contemplated to be practiced on any scale, including milligram, gram, multigram, kilogram, multikilogram or commercial industrial scale.
[0097] As will be readily understood, functional groups present may contain protecting groups during the course of synthesis. Protecting groups are known per se as chemical functional groups that can be selectively appended to 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 of a variety of protecting groups may be employed with the present invention. Protecting groups that may be employed in accordance with the present invention may be described in Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis 2d. Ed., Wiley & Sons, 1991.
[0098] This invention also provides processes for preparing a compound of formula I, which processes include one of the following: a) reducing a compound of formula


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wherein R5"8, x, t, A and W are as defined herein, to give a compound of formula I; if necessary any reactive groups or sites being protected during the reaction by protecting group(s) and removed thereafter; or
b) alkylating a compound of formula I wherein R8 is hydrogen with an alkylating
agent to give a compound of formula 1 wherein R8 is as defined herein
excepting hydrogen;
or
c) converting a compound of formula I having a reactive substituent group to a
compound of formula I having a different substituent group;
or .
d) converting a basic compound of formula I to a pharmaceutically acceptable
salt or vice versa.
[0099] For example, compounds of the present invention are suitably prepared in accordance with the following general description and specific examples. Variables used are as defined for formula I, unless otherwise noted. 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 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. In accordance with this invention, compounds of formula I are produced by the following reaction schemes (Scheme 1-5).

WO 2005/037283 PCT/US2004/033671
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where
Y = H, R8, or P.
P is an amine protecting group, preferably but not limited to tert-butoxycarbonyl;
A is as previously defined and can be optionally substituted with one or more Ri; and
R1, R2, R3. R4, R5, Re, R7, R8 and x are as previously defined.
[0100] Compounds of formula I can be prepared from compounds of formula VI via reduction followed by deprotection, where Y = P; otherwise the deprotection step is omitted. Where P = tert-butoxycarbonyl, any conventional method for the deprotection of a carbamate can be utilized for this conversion. In accordance with the preferred embodiment of this invention, deprotection is carried out using a protic acid, i.e., hydrochloric acid. Reduction is performed using any conventional method of reducing an amide to an amine. In accordance with the preferred embodiment of this invention, the compounds of formula VI are treated with a solution of borane in tetrahydrofuran and heated at 70-80°C.
[0101] Compounds of formula VI can be prepared via the coupling of compounds of formula V with an appropriately substituted secondary or primary amine. The

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reaction is carried out by any conventional method for the activation of a carboxylic acid to form an amide. In the preferred embodiment of this invention, the carboxylic acid is treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro phosphate in the presence of an appropriately substituted secondary or primary amine and triethylamine.
[0102] Compounds of formula V are prepared by reacting an appropriately substituted ketone with an aryl or heteroarylacetic acid of formula IV via an aldol reaction. The aryl or heteroarylacetic acids of formula IV can be either commercially obtained or are known compounds that can be prepared by standard procedures described in the literature. Compounds of formula IV represent an organic acid having an alpha carbon atom, so reaction with a ketone occurs at the alpha carbon atom of this carboxylic acid. This reaction is carried out by any conventional means of reacting the alpha carbon atom of a carboxylic acid with a ketone. Generally, in these aldol reactions, a ketone is reacted with the dianion of the acetic acid. The anion can be generated with a strong organic base such as lithium diisopropylamide, as well as other organic lithium bases. This reaction is performed in low boiling point solvents such as tetrahydrofuran at low temperatures from -80°C to about -50°C being preferred.

If it is desired to produce compounds of formula VIII, they can be formed from compounds of formula I, where Y = H, via an alkylation with an alkyl halide or via a reductive amination with an aldehyde or ketone. Any conventional method of alkylating a secondary amine with an alkyl halide can be utilized. In addition, any conventional method of performing a reductive amination can be utilized. In accordance with the preferred embodiment of this invention, when it is desired to form compounds of formula VIII where R8 = methyl, a mixture of the amine and

WO 2005/037283 PCT/US2004/033671
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formaldehyde in formic acid is heated at 60°C-80°C. If is desired to form compounds of formula VIII where R8 = lower alkyl other than methyl, a mixture of the amine and an appropriately substituted aldehyde or ketone in methylene chloride is treated with trisacetoxyborohydride.

[0103] If it is desired to produce compounds of formula X where R1 = nitrile, they can be formed from compounds of formula IX, where P = an amine protecting group, preferably but not limited to tert-butoxycarbonyl. In the case where P = tert-butoxycarbonyl, any conventional method for the deprotection of a carbamate can be utilized for this conversion. In accordance with the preferred embodiment of this invention, deprotection is carried out using a protic acid, i.e., hydrochloric acid.
[0104] Compounds of formula IX can be formed from compounds of formula VII
where R1 = iodine or bromine, and Y = P (See Scheme 1). Any conventional .method
for converting an aryl iodide or aryl bromide to an aryl nitrile can be utilized for this
conversion. According to the preferred embodiment of this invention, the aryl
bromide of formula VII is treated with zinc cyanide, 1, 1'-
bis(diphenylphosphino)ferrocine, zinc dust, and catalytic
tris(dibenzylideneacetone)dipalladium. This reaction is performed in high boiling point solvents such as N, N-dimethylformamide, under nitrogen, at elevated temperatures from 100°C to about 150°C being preferred. Compounds of formula

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VII arc prepared in Scheme 1. If it is desired to form compounds of formula VIII from compounds of formula X, the procedure outlined in Scheme 2 can be followed.

[0105] Compounds of formula VII, where R1 = bromine or iodine and where Y = P
(see Scheme 1), can also be used to form compounds of formula XII, where C =
phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl, if it is desired.
Compounds of formula XII can be formed from compounds of formula VII where R1 =
bromine or iodine via a cross-coupling reaction with either an aryl boronic acid or an
aryl stannane. Any conventional method for the cross coupling of an aryl iodide or
aryl bromide with an aryl boronic acid or aryl stannane can be employed. In
accordance with the preferred embodiment of this invention, the aryl iodide or aryl
bromide of formula VII is treated with an appropriately substituted aryl boronic acid, a
base, i.e. sodium carbonate or potassium phosphate, and catalytic
tetrakis(triphenylphosphine)pa!ladium (0) or [1,4-bis-
(diphenylphosphine)butane]pal!adium (II) dichloride. This reaction is performed in a high boiling point solvent such as N, N-dimethylformamide, 1,4-dioxane, or 1,2-dimethoxyethane in the presence of water, under nitrogen, at elevated temperatures from 70°C to about 100-C being preferred. If it is desired to form compounds of formula VIII from compounds of formula XII, the procedure outlined in Scheme 2 can be followed.

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where B = alkenyl or alkynyl.
[0106] If it is desired to produce compounds of formula XIV, where B = alkynyl or alkenyl, they can be formed from compounds of formula VII, where R1 = bromine or iodine and where Y = P (See Scheme 1). Compounds of formula Xlll can be formed from compounds of formula VII where R1 = bromine or iodine via a cross-coupling reaction with either an appropriately substituted alkenyl or alkynyl stannane. Any conventional method for the cross coupling of an aryl iodide or aryl bromide with an alkenyl or alkynyl stannane can be employed. In accordance with the preferred embodiment of this invention, the aryl iodide or aryl bromide of formula VII is treated with an appropriately substituted alkenyl or alkynyl stannane and catalytic 1etrakis(tripheny!phosphine)pa!ladium (0). This reaction is performed in high boiling point solvents such as N, N-dimethylformamide or toluene, under nitrogen, at elevated temperatures from 9O°C to about 120°C being preferred. Compounds of formula XIV are formed from compounds of formula XIV as described in Scheme 1. If it is desired to form compounds of formula VIII from compounds of formula XIV, the procedure outlined in Scheme 2 can be followed.
[0107] The compounds of formula I have an asymmetric carbon atom. In accordance with this invention the preferred stereoconfiguration is S. If it is desired to produce the R or the S isomer of the compounds of formula I, these compounds can be isolated as the desired isomer by any conventional method. Among the preferred means is to separate the isomers of either the amide of formula VI or

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formula VII, where Y = P, or the amine of formula I or formula VIII via either High Performance Liquid Chromatography (HPLC) or via Supercritical Fluid Chromatography.
[0108] The separation of R and S isomers can also be achieved by forming a lower alkyl ester of phenylacetic acids of formula V. Any conventional method for the formation of an ester from a carboxylic acid can be utilized. Separation is performed using an enzymatic ester hydrolysis of any lower alkyl esters corresponding to the compound of formula V (See, for example, Ahmar, M.; Girard, C; Bloch, R., Tetrahedron Lett, 1989, 7053), which results in the formation of corresponding chiral acid and chiral ester. The ester and the acid can be separated by any conventional method of separating an acid from an ester.
[0109] In other embodiments, the invention is directed to pharmaceutical compositions, comprising:
a. at least 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 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 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. Yet even more preferably, the compound of 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.

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[0110] Such compositions are prepared in accordance with acceptable
pharmaceutical procedures, such as described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985). Pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and biologically acceptable.
[0111] The compounds of this invention may be administered orally or
parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances that may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, 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 shape and size desired. 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, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
[0112] Liquid carriers may be used in preparing 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
fat. The liquid carrier can contain other suitable pharmaceutical additives such as
solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents,
suspending agents, thickening agents, colors, viscosity regulators, stabilizers, or
osmo-reguiators. Suitable examples of liquid carriers for oral and parenteral
administration include water (particularly containing additives as above, e.g.
cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols
(including monohydric alcohols and polyhydric alcohols e.g. glycols) and their
derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral
administration the carrier can also be an oily ester such as ethyl oleate and isopropyl

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myristale. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
[0113] Liquid pharmaceutical compositions, which are sterile solutions or
suspensions, can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
[0114] Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
[0115] In another embodiment of the present invention, the compounds useful in the present invention may be administered to a mammal with one or more other pharmaceutical active agents such as those agents being used to treat any other medical condition present in the mammal. Examples of such pharmaceutical active agents include pain relieving agents, anti-angiogenic agents, anti-neoplastic agents, anti-diabetic agents, anti-infective agents, or gastrointestinal agents, or combinations thereof.
[0116] The one or more other pharmaceutical active agents may be administered in a therapeuticaliy effective amount simultaneously (such as individually at the same time, or together in a pharmaceutical composition), and/or successively with one or more compounds of the present invention.
[0117] 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 flush, sweating,

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thermc regulatory-related condition or disorder, or other. Such administration includes use of each type of therapeutic agent in a concurrent manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
[0118] The route of administration may be any route, which effectively transports the active compound of formula I to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal, such as passive or iontophoretic delivery, or parenteral, e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment. Furthermore, the administration of compound of formula I with other active ingredients may be concurrent or simultaneous.
[0119] It is believed that the present invention described presents a substantial breakthrough in the field of treatment, alleviation, inhibition, and/or prevention 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.
[0120] Accordingly, in one embodiment, the present invention is directed to methods for treating or preventing a condition ameliorated by monoamine reuptake in a subject in need thereof, comprising the step of:
administering to said subject an effective amount of a compound of formula I or pharmaceutically acceptable salt thereof.
The conditions ameliorated by monoamine reuptake include those selected from the group consisting of vasomotor symptoms, 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

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and urge urinary incontinence, fibromyaigia, pain, diabetic neuropathy, and combinations thereof.
[0121] "Vasomotor symptoms," "vasomotor instability symptoms" and "vasomotor disturbances" include, but are not limited to, hot flushes (flashes), insomnia, sleep disturbances, mood disorders, irritability, excessive perspiration, night sweats, fatigue, and the like, caused by, inter alia, thermoregulatory dysfunction.
[0122] The term "hot flush" is an art-recognized term that refers to an episodic
disturbance in body temperature typically consisting of a sudden skin flushing, usually accompanied by perspiration in a subject.
[0123] The term "sexual dysfunction" includes, but is not limited to, condition relating to desire and/or arousal.
[0124] As used herein, "gastrointestinal and genitourinary disorders" includes irritable bowel syndrome, symptomatic GERD, hypersensitive esophagus, nonulcer dyspepsia, noncardiac chest pain, biliary dyskinesia, sphincter of Oddi dysfunction, incontinence (i.e., urge incontinence, stress incontinence, genuine stress incontinence, and mixed incontinence)(including the involuntary voiding of feces or urine, and dribbling or leakage or feces or urine which may be due to one or more causes including but not limited to pathology altering sphincter control, loss of cognitive function, overdistention of the bladder, hyperreflexia and/or involuntary urethral relaxation, weakness of the muscles associated with the bladder or neurologic abnormalities), interstitial cystitis (irritable bladder), and chronic pelvic pain (including, but not limited to vulvodynia, prostatodynia, and proctalgia).
[0125] As used herein, "chronic fatigue syndrome" (CFS) is a condition characterized by physiological symptoms selected from weakness, muscle aches and pains, excessive sleep, malaise, fever, sore throat, tender lymph nodes, impaired memory and/or mental concentration, insomnia, disordered sleep, localized tenderness, diffuse pain and fatigue, and combinations thereof.

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[0126] As used herein, "fibromyalgia syndrome" (FMS) includes FMS and other somatoform disorders, including FMS associated with depression, somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysrnorphic disorder, undifferentiated somatoform disorder, and somatoform NOS. FMS and other somatoform disorders are accompanied by physiological symptoms selected from a generalized heightened perception of sensory stimuli, abnormalities in pain perception in the form of allodynia (pain with innocuous stimulation), abnormalities in pain perception in the form of hyperalgesia (increased sensitivity to painful stimuli), and combinations thereof.
[0127] As used herein, "nervous system disorders," includes addictive disorders (including those due to alcohol, nicotine, and other psychoactive substances) and withdrawal syndrome, age-associated learning and mental disorders (including Alzheimer's disease), anorexia nervosa, bulimia nervosa, attention-deficit disorder with or without hyperactivity disorder bipolar disorder, pain (including chronic pain selected from the group consisting of lower back pain, atypical chest pain, headache such as cluster headache, migraine, herpes neuralgia, phantom limb pain, pelvic pain, myofascial face pain, abdominal pain, neck pain, central pain, dental pain, opioid resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, post partum pain, angina pain, neuropathic pain such as peripheral neuropathy and diabetic neuropathy, post-operative pain, and pain which is co-morbid with nervous system disorders described herein), cyclothymic disorder, depression disorder (including major depressive disorder, refractory depression adolescent depression and minor depression), dysthymic disorder, generalized anxiety disorder (GAD), obesity (i.e., reducing the weight of obese or overweight patients), obsessive compulsive disorders and related spectrum disorders, oppositional defiant disorder, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (i.e., premenstrual syndrome and late luteal phase dysphoric disorder), psychotic disorders (including schizophrenia, schizoaffective and schizophreniform disorders), seasonal affective disorder, sleep disorders (such as narcolepsy and enuresis), social phobia (including social anxiety disorder), selective serotonin reuptake inhibition (SSRl) "poop out" syndrome (i.e.,

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wherein a patient who fails to maintain a satisfactory response to SSRI therapy after an initial period of satisfactory response).
[0128] In one embodiment, the present invention is directed to methods for treating or preventing vasomotor symptoms in a subject in need thereof, comprising the step of:
administering to said subject an effective amount of at least one compound of formula I or pharmaceutically acceptable salt thereof.
[0129] When estrogen levels are low or estrogen is absent, the normal levels between NE and 5-HT is altered and this altered change in neurotransmitter levels may result in changes in the sensitivity of the thermoreguiatory center. The altered chemical levels may be translated in the thermoreguiatory center as heat sensation and as a response, the hypothalamus may activate the descending autonomic pathways and result in heat dissipation via vasodilation and sweating (hot flush) (Figure 1). Accordingly, the estrogen deprivation may result in altered norepinephrine activity.
[0130] Norepinephrine synthesized in perikarya of the brainstem is released at the nerve terminals in the hypothalamus and brainstem. In the hypothalamus, NE regulates the activity of neurons residing in the thermoreguiatory center. In the brainstem, NE innervates serotoninergic neurons (5HT), and acting via adrenergica1 and adrenergiC?2 postsynaptic receptors, it stimulates the activity of the serotoninergic system. In response, 5-HT neurons also modulate the activity the mermoregulatory center and feedback to NE neurons. Via this feedback connection, 5-HT, acting via 5-HT2a receptors, inhibit the activity of NE neurons. Norepinephrine in the synaptic cleft is also taken up by NE transporter (NET) located in NE neurons. The transporter recycles NE and makes it available for multiple neurotransmission (Figure 2).
[0131] The present invention provides a treatment for vasomotor symptoms by methods of recovering the reduced activity of norepinephrine. Norepinephrine activity in the hypothalamus or in the brainstem can be elevated by (i) blocking the

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activity of the NE transporter, (ii) blocking the activity of the presynaptic adrenergic ?2 receptor with an antagonist, or (iii) blocking the activity of 5-HT on NE neurons with a 5-HT2a antagonist.
[0132] 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 said subject an effective amount of at least one compound of formula I or pharmaceutically acceptable salt thereof.
[0133]. In yet other embodiments, the present invention is directed to methods
for treating or preventing sexual dysfunction in a subject in need thereof, comprising the step of:
administering to said subject an effective amount of at least one compound of formula I or pharmaceutically acceptable salt thereof.
[0134] In another embodiment, the present invention is directed to methods for treating or preventing gastrointestinal or genitourinary disorder, particularly stress incontinence or urge urinary incontinence, in a subject in need thereof, comprising the step of:
administering to said subject an effective amount of a compound of formula I or pharmaceutically acceptable salt thereof.
[0135] 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 said subject an effective amount of a compound of formula I or pharmaceutically acceptable salt thereof.
[0136] In another embodiment, the present invention is directed to methods for treating or preventing fibromylagia syndrome in a subject in need thereof, comprising the step of:

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administering to said subject an effective amount of a compound of formula 1 or pharmaceutically acceptable salt thereof.
[0137] In further embodiments, the present invention is directed to methods
for treating or preventing pain in a subject in need thereof, comprising the step of:
administering to said subject an effective amount of at least one compound of formula I or pharmaceutically acceptable salt thereof.
[0138] The pain may be, for example, acute pain (short duration) or chronic pain (regularly reoccurring or persistent). The pain may also be centralized or peripheral.
[0139] 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, bony pain, lumbosacral pain, neck or upper back pain, visceral pain, somatic pain, neuropathic pain, cancer pain, pain caused by injury or surgery such as burn pain or dental pain, or headaches such as migraines or tension headaches, or combinations of these pains. One skilled in the art will recognize that these pains may overlap one another. For example, a pain caused by inflammation may also be visceral or musculoskeletal in nature.
[0140] 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, Fibromylagia, temporomandibular joint, or myofascial pain syndrome; bony pain associated with for example bone or joint degenerating disorders such as osteoarthritis, rheumatoid arthritis, or spinal stenosis; headaches such migraine or tension headaches; or pain associated with infections such as HIV, sickle cell anemia, autoimmune disorders, multiple sclerosis, or inflammation such as osteoarthritis or rheumatoid arthritis.

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[0141] In a more preferred embodiment, the compounds useful in this invention are
used to treat chronic pain that is neuropathic pain, viscera! pain, musculoskeletal
pain, bony pain, cancer pain or inflammatory pain or combinations thereof, in
accordance with the methods described herein. 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 for example
diabetic neuropathy, peripheral neuropathy, post-herpetic neuralgia, trigeminal
neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal
neuralgia, reflex sympathetic dystrophy, casualgia, thalamic syndrome, nerve root
avulsion, or nerve damage cause by injury resulting in peripheral and/or central
sensitization such as phantom limb pain, reflex sympathetic dystrophy or
postthoracotomy pain, cancer, chemical injury, toxins, nutritional deficiencies, or viral
or bacterial infections such as shingles or HIV, or combinations thereof. The
methods of use for compounds of this invention further include treatments in which
the neuropathic pain is a condition secondary to metastatic infiltration, adiposis
dolorosa, bums, or central pain conditions related to thalamic conditions.
[0142] As mentioned previously, the methods of the present invention may 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 include pains associated with structural or soft tissue injury experienced during surgery, dental procedures, burns, or traumatic body injuries. 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 maladies of the internal organs such as ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn's disease, rheumatologic (arthralgias), tumors, gastritis, pancreatitis, infections of the organs, or biliary tract disorders, or combinations thereof. One skilled in the art will also recognize that the pain treated according to the methods of the present invention may also be related to conditions of hyperalgesia, allodynia, or both. Additionally, the chronic pain may be with or without peripheral or central sensitization.

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[0143] The compounds useful in this invention may also be used to treat acute and/or chronic pains associated with female conditions, which may also be referred to as female-specific pain. Such groups of pain include those that are encountered solely or predominately by females, including pain associated with menstruation, ovulation, pregnancy or childbirth, miscarriage, ectopic pregnancy, retrograde menstruation, rupture of a follicular or corpus luteum cyst, irritation of the pelvic viscera, uterine fibroids, adenomyosis, endometriosis, infection and inflammation, pelvic organ ischemia, obstruction, intra-abdominal adhesions, anatomic distortion of the pelvic viscera, ovarian abscess, loss of pelvic support, tumors, pelvic congestion or referred pain from non-gynecological causes.
EXAMPLES .
[0144] The present invention is further defined in the following Examples, in which all parts and percentages are by weight and degrees are Celsius, unless otherwise stated. It should be understood that these examples, while indicating preferred embodiments of the invention, are given by way of illustration only. From the above discussion and these examples, one skilled in the art can ascertain 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 usages and conditions.
Reference Example 1-a: Aldol Reaction: Preparation of Acid Intermediates
[0145] A solution of diisopropylamine (7.87 ml_, 56.2 mmol) in dry tetrahydrofuran (50 mL) under nitrogen was cooled to -78 °C and treated dropwise with a solution of n-butyllithium (2.5 M in hexanes, 22 mL, 55.0 mmol). The resulting solution was warmed to 0 °C and stirred for 15 min. The solution was re-cooled to -78 °C and treated, via cannula, with a solution of 3-chlorophenylacetic acid (4.0 g, 23.4 mmol) in tetrahydrofuran (20 mL). The reaction was then allowed to warm to 25 °C where it was stirred for 45 minutes and was then re-cooled to -78 °C. A solution of cyclohexanone (3.65 mL, 35.3 mL) in tetrahydrofuran (10 mL) was then added via cannula, and the

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resulting mixture was stirred at -78 °C for 1.5 h. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium chloride, and the tetrahydrofuran was removed in vacuo. The resulting residue was dissolved in a 2N aqueous solution of sodium hydroxide (30 mL) and washed with ethyl acetate (1 x 30 mL). The aqueous layer was then acidified to pH = 1 with the addition of a 2 N aqueous solution of hydrochloric acid. The product was extracted with ethyl acetate (3 x 30 mL), and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to yield 6.05 g (96%) of pure (3-chlorophenvl)(1-hydroxvcyclohexvPacetic acid as a white solid. HRMS: calcd for C14H17CIO3, 268.0866; found (ESLFT), 291.0748.
b) In an analogous manner, (3-bromophenyl)(1 -hydroxycvclohexvDacetic acid was
prepared from 3-bromophenylacetic acid and cyciohexanone. HRMS: calcd for
C14H17BrO3, 312.0361; found (ESLFT), 350.99924.
c) In an analogous manner, (1 -hydroxycvclobutyl)(2-naphthvl)acetic acid was
prepared from 2-napthylacetic acid and cyclobutanone. HRMS: calcd for
C16H16O3, 256.1099; found (ESLFT), 279.09927.
d) In an analogous manner, 3,4-dichloro-alpha-(1-hvdroxvcyclohexyl)benzeneacetic
acid was prepared from 3, 4-dichlorophenylacetic acid and cyciohexanone. MS
(ESI) m/z 301/303/305 ([M-H]"); Anal. Calcd for C14H15CI2O3: C, 55.46; H, 5.32; N,
0.00. Found: C, 55.42; H, 5.30; N, 0.00.
e) In an analogous manner, (1-hydroxvcvclohexvl)(1-naphthyl)acetic acid was
prepared from 1-napthylacetic acid and cyciohexanone. MS (ESI) m/z 283 ([M-
H]'); HRMS: calcd for C18H2oO3, 284.1412; found (ESI_FT), 307.13001.
f) In an analogous manner, (1-hvdroxvcyclohexyl)[3-(trifluoromethoxy)phenvHacetic
acid was prepared from 3-trifluoromethoxyphenylacetic acid and cyciohexanone.
HRMS: calcd for C15H17F3O4, 318.1079; found (ESI), 317.1013.
g) In an analogous manner, (1-hvdroxvcvclohexvl)[4-(trifluoromethoxv)phenynacetic
acid was prepared from 4-trifluoromethoxyphenylacetic acid and cyclohexanone.
MS(ESI)m/z317([M-H]).
h) In an analogous manner, (4-bromophenvPf 1 -hydroxycyclohexyl)acetic acid was prepared from 4-bromophenylacetic acid and cyciohexanone. MS (ESI) m/z 313/315 ([M+H]+); Anal. Calcd for C14H17BrO3: C, 53.69; H, 5.47; N, 0.00. Found: C, 53.87; H, 5.42; N, 0.00.

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i) !;, an analogous manner, (3,4-dichlorophenyl)(4-hvdroxy-1-methvlpiperidin-4-vDacetic acid was prepared from 3,4-dichlorophenylacetic acid and 1-methyl-4-piperidone. HRMS: calcd for C14H17CI2MO3 • HCI, 353.0352; found (ESLFT), 318.0653.
j) In an analogous manner, (3-bromophenyl)(1 -hydroxycyclobutyl)acetic acid was prepared from 3-bromophenylacetic acid and cyctobutanone. HRMS: calcd for C12H13BrO3, 284.0048; found (ESLFT), 306.99337.
k) In an analogous manner, (1-hydroxvcyclobutyl)|"3-(trifluoromethoxy)phenyl1acetic acid was prepared from 3-trifluoromethoxyphenyIacetic acid and cyclobutanone. HRMS: calcd for C13H13F3O4 290.0766; found (ESI), 289.0686.
I) In an analogous manner, (3-bromo-4-methoxyphenvl)(1-hydroxycvclohexvl)acetic acid was prepared from 3-bromo-4-methoxyphenylacetic acid and cyciohexanone. MS (ESI) m/z 341/343 ([M-H]"); HRMS: calcd for C15H19BrO4, • . 342.0467; found (ESLFT), 341.03897.
m) In an analogous manner, (1-hvdroxvcvclohexyl)r3-(trifluoromethyl)phenvnacetic
acid was prepared from 3-trifluoromethylphenylacetic acid and cyciohexanone.
MS (ESI) m/z 301 ([M-H]"); HRMS: calcd for C15H17F3O3, 302.1130; found
(ESLFT), 325.1024.
n) In an analogous manner, (4-benzyloxyphenyl)(1 -hydroxvcyclohexypacetic acid
was prepared from 4-benzyloxyphenylacetic acid and cyclohexanone. o) In an analogous manner, (1 -hydroxvcyclobutyl)(1 -naphthyl)acetic acid was
prepared from 1 -napthylacetic acid and cyclobutanone.
p) In an analogous manner, (3,4-dichlorophenyl)(1 -hydroxycyclobutyl)acetic acid was prepared from 3, 4-dichlorophenylacetic acid and cyclobutanone. HRMS: calcd for C12H12Cl2O3, 274.0163; found (ESLFT), 273.00881.
q) In an analogous manner, (1 -hydroxvcvclohexyl)(2-naphthvDacetic acid was prepared from 2-napthyIacetic acid and cyciohexanone. HRMS: calcd for C18H20O3, 284.1412; found (ESLFT), 323.10414.
r) In an analogous manner, (3-bromophenyl)(4-hvdroxv-1-methylpiperidin-4-vl)acetic acid was prepared from 3-bromophenylacetic acid and 1-methyl-4-piperidone. HRMS: calcd for C14H18BrNO3 . HCI, 363.0237; found (ESI_FT), 328.05356.

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s) :n an analogous manner, (1 -hydroxvcvclopentyl)(1-naphthyl)acetic acid was prepared from 1-napthylacetic acid and cyclopentanone. MS (ESI) m/z 269 ([M-H]"); HRMS: calcd for C17H18O3, 270.1256; found (ESLFT), 293.11485. t) In an analogous manner, 2-(3-bromophenyl)-3-ethyl-3-hydroxvpentanoic acid was prepared from 3-bromophenylacetic acid and 3-pentanone. MS (ESI) m/z 299/301 ([M-H]); HRMS: calcd for C13H17BrO3, 300.0361; found (ESLFT), 323.02505. u) In an analogous manner, 2-(3-chlorophenyl)-3-hvdroxv-3-propvlhexanoic acid
was prepared from 3-bromophenylacetic acid and 4-heptanone. MS (ESI) m/z
283/285 ([M+H]+); HRMS: calcd for C15H21CIO3, 284.1179; found (ESI_FT),
307.1074. v) In an analogous manner, 2-(3-chlorophenvl)-3-ethyl-3-hvdroxypentanoic acid was
prepared from 3-chlorophenylacetic acid and 3-pentanone. MS (ESI) m/z
255/257 ([M+H]+). w) In an analogous manner, 3-ethyl-3-hydroxv-2-(1 -naphthyl)pentanoic acid was
prepared from 1-napthylacetic acid and 3-pentanone. MS (ESI) m/z 271 ([M-H]"). x) In an analogous manner, (4-hvdroxv-1-methvlpiperidin-4-yl)(2-naphthvl)acetic
acid was prepared from 2-napthylacetic acid and 1-methyl-4-piperidone. HRMS:
calcd for C18H21NO3, 299.1521; found (ESI_FT), 300.15911. y) In an analogous manner, 2-(3-bromo-4-methoxyphenvO-3-ethvl-3-
hydroxypentanoic acid was prepared from 3-bromo-4-methoxyphenylacetic acid
and 3-pentanone. MS (ESI) m/z329/331 ([M+H]+). z) In an analogous manner, (4-benzyloxyphenvl)(1 -hydroxycyclobutvl)acetic acid
was prepared from 4-benzyloxyphenylacetic acid and cyclobutanone. aa) In an analogous manner, (3-chlorophenvl)(1-hvdroxydecahydronapthyl)acetic
acid was prepared from 3-ch!oropheny!acetic acid and decahydronapthiene-1-
one. MS (ESI) m/z321/323 ([M-H]"). bb) In an analogous manner, (3-bromo-4-methoxvphenvD(4-fe/t-butvl-1-
hydroxycyclohexvOacetic acid was prepared from 3-bromo-4-
methoxyphenylacetic acid and 4- ferf-butylcyclohexanone. MS (ESI) m/z397/399
([M-H]"); HRMS: calcd for C19H27Br04, 398.1093; found (ESLFT), 421.09875.

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cc) In an analogous manner, (3-chlorophenvn(2-hvdroxvdecahvdronapthyl)acetic acid was prepared from 3-chlorophenylacetic acid and decahydronapthlene-2-one. MS (ESI) m/z 321/323 ([M-H]").
dd) In an analogous manner, (4-tert-butyl-1 -hydraxycyclohexyl) -naphthyl)acetic acid was prepared from 1-napthylacetic acid and 4- te/t-butylcyclohexanone. MS (ESI) m/z 339 ([M-H]"); HRMS: calcd for C22H28O3, 340.2038; found (ESI_FT), 363.19309.
ee) In an analogous manner, (3-cblorophenyl)(4-hydroxytetrahydro-2H-pyran-4-yl)acetic acid was prepared from 3-chlorophenylacetic acid and tetrahydro~2H-pyran-4-one. MS (ESI) m/z 269 ([M-H]"); HRMS: calcd for C13H15C1O4, 270.0659; found (ESLFT), 293.05499.
ff) In an analogous manner, (3-bromophenvO(4-tert-butvl-1-hvdroxvcyclohexyl)acetic acid was prepared from 3-bromophenylacetic acid and 4- tert-butylcyclohexanone. MS (ESI) m/z 367/369 ([M-H]"); HRMS: calcd for C18H25BrO3; 368.0987; found (ESLFT), 391.0878.
gg) In an analogous manner, 2-(3-bromophenyl)-3-hvdroxv-3-propylhexanoic acid was prepared from 3-bromophenylacetic acid and 4-heptanone. MS (ESI) m/z 327/329 ([M+H]+).
hh) In an analogous manner, 2-(3-chlorophenyl)-3,3-dicvclopropvl-3-hydroxypropanoic acid was prepared from 3-chlorophenylacetic acid and dicyclopropyl ketone. MS (ESI) m/z 279.0801 ([M-H]"); HRMS: calcd for C15H17CIO3, 280.0866; found (ESI), 279.0801; Anal. Calcd for C15H17CIO3: C, 64.17; H, 6.10; N, 0.00. Found: C, 64.05; H, 6.31; N, 0.00.
ii) In an analogous manner, (3-bromophenyQ(1-hydroxv-3,3,5,5-tetramethylcyclohexvDacetic acid was prepared from 3-bromophenylacetic acid and 3,3,5,5-tetramethylcyclohexanone. MS (ESI) m/z 367/369 ([M-H]"). ii) In an analogous manner, (4-ethyl-1-hydroxycyclohexyl) -(1-naphthyl) acetic acid was prepared from 1-napthylacetic acid and 4-ethylcyclohexanone. MS (ESI) m/z 311 ([M-H]").
kk) In an analogous manner, (3-chlorophenvl)(4-tert-butyl-1-hydroxycyclohexyl)acetic acid was prepared from 3-chlorophenylacetic acid and 4- tert-butylcyciohexanone.

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II) In an analogous manner, (4-methy)-1-hvdroxvcyclohexvl) -(1-naphthyl) acetic acid was prepared from 1-napthylacetic acid and 4-methylcyclohexanone. MS (ESI) m/z297 ([M-Hp.
mm) In an analogous manner, (3-bromophenyl)(4-hydroxvtetrahvdro-2H-pyran-4-
yl)acetic acid was prepared from 3-bromophenylacetic acid and tetrahydro-2H-
pyran-4-one. MS (ESI) m/z 313/315 ([M+H]+); HRMS: calcd for C13H15BrO4,
314.0154; found (ESI_FT), 315.02244.
nn) In an analogous manner, (3-benzvloxvphenyl)(1 -hydroxvcvclohexyl)acetic acid
was prepared from 3-benzyloxyphenylacetic acid and cyclohexanone. oo) In an analogous manner, (3-bromophenvl)(2-hydroxy-2-adamantyl)acetic acid was prepared from 3-bromophenylacetic acid and adamantanone. MS (ESI) m/z 363/365 ([M-H]").
pp) In an analogous manner, (3-bromo-4-methoxvphenyl)(4-hvdroxvtetrahvdro-2H-
pyran-4-vDacetic acid was prepared from 3-bromo-4-methoxyphenylacetic acid
and tetrahydro-2H-pyran-4-one. MS (ESI) m/z 343/345 ([M-H]'); HRMS: calcd for
C14H17BrO5) 344.0259; found (ESI_FT), 367.01582.
qq) In an analogous manner, (3-benzyloxyphenyl)(1 -hydroxycyclobutyDacetic acid
was prepared from 3-benzyloxyphenylacetic acid and cyclobutanone. rr) In an analogous manner,(5-chlorothien-2-yl)(1 -hydroxycyclohexyl)acetic acid was prepared from 5-chloro-2-thiophene-3-acetic acid (Example 142) and cyclohexanone. MS (ESI) m/z 273/275 ([M-H]-).
ss) In an analogous manner, (5-bromothien-2-yl)(1 -hydroxycyclohexyl)acetic acid was prepared from 5-bromo-2-thiophene acetic acid (Example 143) and cyclohexanone. MS (ESI) m/z 317/319 ([M+H]+)
tt) In an analogous manner, 1 -benzothien-3-yl(1 -hydroxycyclohexyl)acetic acid was prepared from 1-benzothien-3-yl acetic acid and cyclohexanol. MS (ESI) m/z 289 ([M-H]-)
uu) In an analogous manner, (2-bromophenvl)(1-hvdroxvcyclohexvl)acetic acid was prepared from 2-bromophenylacetic acid and cyclohexanol. MS (ESI) m/z 311/313 ([M-H]-)
vv) In an analogous manner, (4-bromophenvyl) 1 -hydroxycyclohexvl)acetic acid was prepared from 4-bromophenylacetic acid and cyclohexanone. MS (ESI) m/z

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313/315 ([M+H]+); Anal. Calcd for C14H17BrO3: C, 53.69; H, 5.47; N, 0.00. Found: C, 53.87; H, 5.42; N, 0.00. ww) In an analogous manner, (4-bromophenyl)(1 -hydroxycyclobutyl)acetic acid was
prepared from 4-bromophenylacetic acid and cyclobutanone. xx) In an analogous manner, (1-methyl-1H-indol-3-yl) (1-hydroxvcylclohexyl) acetic
acid was prepared from N-Methy!-3-indole acetic acid and cyclohexanone. yy) In an analogous manner, (1 -(tert-butyl-dirnethvl-silanyl)-1 H-indol-3-yl) (1 -hydroxycylclohexyl) acetic acid was prepared from [1~(tert-butyl-dimethyl-silanyl)-1 H-indol-3-yl]-acetic acid1 and cyclohexanone.
zz) In an analogous manner, (1-hydroxvcyclohexyl)(1,1 '-biphenyl-4-yl)acetic acid was prepared from 4-biphenylacetic acid and cyclohexanone. MS (ESI) m/z 309 ([M-H]-) aaa) In an analogous manner(1-hydoxycvclobutyl)[4-trifluoromethoxv)phenyl1 acetic
acid was prepared from 4-trifluoromethoxyphenyl acetic acid and cyclobutanone. MS (ESI) m/z 289 ([M-H]').
bbb) In an analogous manner (1-hvdoxvcvclohexyl)[4-phenoxyphenyll acetic acid was prepared from 4-phenoxyphenylacetic acid and cyclohexanone. MS (ESI) m/z 325 ([M-H]").
ccc) In an analogous manner (1-hvdoxvcvclohexvl)f3-phenoxyphenvn acetic acid was prepared from 3-phenoxypheny(acetic acid and cyclohexanone. MS (ESI) m/z 325 ([M-H]"). Anal. Calcd for C20H22O4O.I H2O: C,73.19; H, 6.82. Found: C, 73.04; H, 6.88. ddd) In an analogous manner, (1 -naphthyl){1 -hydroxycyclooctvPacetic acid was
prepared from 1-naphthy! acetic acid acid and cyclooctanone.
eee) In an analogous manner, [4-(benzyloxy)-3-chlorophenyn(1-hydroxycyclohexvPacetic acid was prepared from [4-(benzyloxy)-3-ch!orophenyl]acetic acid (DE 2556474, 1976, M.Kucher; B.Brunova; J. Grimova; N. Oldrich) and cyclohexanone. MS (ESI) m/z373;
fff) In an analogous manner, (1 -naphthvl)(1 -hydroxvcycloheptyl)acetic acid was prepared from 1-napthylacetic acid and cycioheptanone.
Solid-phase synthesis of polyamine spider toxins and correlation with the natural products by HPLOMS/MS. Manov, Nikolay; Tzouros, Manuel; Chesnov, Sergiy; Bigler, Laurent; Bienz, Stefan. Institute of Organic Chemistry, University of Zurich, Zurich, Swttz. Helvetica Chimica Acta (2002), 85(9), 2827-2846

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ggg) In an analogous manner, 2-(3-chlorophenvl)-3-hvdroxv-3-methylbutanoic acid was prepared from 3-chlorophenylacetic acid and acetone. MS (ES) m/z 226.9.
hhh) In an analogous manner, (3-chIorophenvl)(1-hydroxv-3,3,5,5-tetramethylcyclohexyOacetic acid was prepared from 3-chlorophenylacetic acid and 3,3,5,5-tetramethylcyclohexanone. MS (ES) m/z 323.2.
iii) In an analogous manner, (1-hvdroxv-cyclohexyl)-(5-methoxv-benzo[b1thiophen-3-yl)-acetic acid was prepared from 5-methoxy benzo[b]thiophene acetic acid (Campaigne, E.; Kim, C.S.; Pinza, M.; Pifferi, G. J. Heterocyclic Chem. 1983, 20, 1697-1703) and cyclohexanone. HRMS: calcd for C15H17F3O4, 318.1079; found (ESI), 317.1013.
jjj) In an analogous manner, (2-hydroxydecahydronapthyl)(1-napthyl)acetic acid was prepared from 1-napthylacetic acid and decahydronapthlene-2-one. MS (ESI) m/z337([M-H]-).
kkk) In an analogous manner, (3-chlorophenyl)(4-methvl-1-hydroxycyclohexyl) acetic acid was prepared from 3-chlorophenylacetic acid and 4-methylcyclohexanone. MS (ESI) m/z 281/283 ([M-H]").
Ill) Step 1: A mixture of 4-(chIoromethyl)dibenzyl (0.92 g, 4 mmol) and potassium cyanide (.039 g, 6 mmol) in N,N'-dimethylformamide (20 mL) was heated at 80 °C for 16 hours. At the end of this time the solution was poured into water and extracted 2 times with ethyl acetate. 7he extracts were combined and filtered through a plug of silica gel. The filtrate was concentrated to yield 4; (phenethylphenvl)acetonitrile as an oil which was used in the next step without further purification.
Step 2: 4-(Phenethy!phenyl)acetonitrile from the above reaction was treated with a 6 N aqueous solution of hydrochloric acid (10 mL) and heated at 95 °C for 4 h. The reaction was cooled to 0 °C and solid potassium hydroxide was added until pH 14 was achieved. The solution was washed twice with diethyl ether and the resulting aqueous layer was then acidified to pH 1 with concentrated hydrochloric acid. The product was extracted with diethyl ether (2 X 50 mL) and the combined ethereal extracts were dried over magnesium sulfate and concentrated. Trituration with hexane and fitration of the resulting solid afforded 0.64 g of 4-(2-phenylethyl)phenyl]acetic acid as an off white solid. MS (ESI) m/z 239.

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Step3: In an analogous manner (as Reference Example l-a), (1-hydroxvcvclohexyl)4-(2-phenvlethyl)phenyl]acetic acid was prepared from [4-(2-phenylethyl)phenyljacetic acid and cyclohexanone. MS (ESI) m/z 337. mmm)Step 1: 3-Fluoro-4-hydroxyphenylacetic acid (0.85 g, 3.62 mmol) and of benzyl bromide (1.30 g, 7.60 mmol) were added to a flask containing N,N'-dimethylformamide (20 mL). Potassium carbonate (1.25 g, 9.00mmol) was then added, and the solution was heated at 50 °C for 4 hours. A 2 N aqueous solution of sodium hydroxide (10 mL) was added and heating was maintained for an additional 16 hours. At the end of this time the solution was poured into water and washed twice with diethyl ether. The ethereal extracts were discarded and the aqueous layer was acidified with concentrated hydrochloric acid until pH 1 was achieved. The product was then extracted with diethyl ether (2 x 50 mL). The combined ethereal layers were dried over magnesium sulfate and concentrated to afford 0.95 g of 4-benzyloxv-3-fluorophenylacetic acid which was used as such in the next step. MS (ESI) m/z 325.
Step 2: In an analogous manner (as Reference Example I-a), [4-(benzyloxy)-3-fluorophenylid-hydroxvcyclohexvPacetic acid was prepared from [4-(benzyloxy)-3-fluorophenyl]acetic acid and cyclohexanone. MS (ESI) m/z 357. nnn) In an analogous manner, [4-(benzyloxy)-3-methoxypheny!](1-
hydroxycyc!ohexyl)acetic acid was prepared from [4-(benzyloxy)-3-methoxyphenyl] acetic acid and cyclohexanone. MS (ES) m/z 369.0. ooo) Step 1: In an analogous manner to Reference Example l-mmm, step 1 {3-chloro-4-r(3-methoxvbenzvl)oxv1phenyl)acetic acid was prepared from {3-chloro-4-hydroxy-phenyl) acetic acid and 3-methoxybenzyl chloride. Step 2: In an analogous manner (as Reference Example l-a), [3-chloro-4-(3-methoxv-benzyloxy)-phenyl](1-hydroxy-cyclohexyl)acetic acid was from {3-chloro-4-[(3-methoxybenzyl)oxy]phenyi}acetic acid and cyclohexanone. PPP) Step 1: In an analogous manner to Reference Example l-mmm, step 1 {3-chloro-4-[(2-methoxvbenzvl)oxyl]phenyl]acetic acid was prepared from {3-chloro-4-hydroxy-phenyl) acetic acid and 2-methoxybenzyl chloride .MS (ES) m/z 304.9. Step 2: In an analogous manner (as Reference Example l-a), [3-chloro-4-(2-methoxy-benzyloxy)-phenylH1 -hydroxy-cyctohexyl)-acetic acid was from {3-ch!oro-4-[(2-methoxybenzyl)oxy]phenyl}acetic acid and cyclohexanone.

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qqq) In an analogous manner, [(3R)-1-hvdroxy-3-methvlcvclopentvl][3-
(trifluoromethoxy)phenvnacetic acid was prepared from (3-trifluoromethoxy-
phenyl)-acetic acid and 3(R)-methyl-cyclopentanone. rrr) In an analogous manner, (1-hvdroxv-2,2-dimethvl-cvclopentyl)-(3-
trifluoromethoxy-phenyl)-acetic acid was prepared from (3-trifluoromethoxy-
phenyl)-acetic acid and 2,2-dimethy!-cyclopentanone. sss) In an analogous manner, (1 -hvdroxycvclohexvl)(6-methoxy-2-naphthyl)acetic acid
was prepared from (6-methoxy-2-naphthyl)acetic acid (Harrison, Ian Thomas;
Lewis, Brian; Nelson, Peter; Rooks, Wendell; Roszkowski, Adolph; Tomolonis,
Albert; Fried, John H. J. Med. Chem. 1970, 13, 203-5) and cyclohexanone. MS
(ES) m/z 313.0; HRMS: calcd for C19H22O4 + H+, 315.15909; found (ESI, • [M+H]+), 315.159. ttt) In an analogous manner, (3-chloro-4-methoxvphenyl)-1 (1 -hydroxycyclohexyl)
acetic acid was prepared from (3-ch!oro-4-methoxyphenyl)acetic acid and
cyclohexanone. MS(ESI) m/z 297 ([M-H]"). uuu) In an analogous manner, (1 -hydroxvcyclohexyl)-(4- phenethyloxyphenyl)
acetic acid was prepared from (4- phenethyloxypheny!) acetic acid and
cyclohexanone. MS(ESI) m/z 353 ([M-H]-). vvv) Step 1: In an analogous manner to Reference Example l-mmm, step 1 {4-[2-(4-
fluoro-phenyl)-ethoxy]-phenyl}-acetic acid was prepared from (4-
hydroxyphenyl)acetic acid and 2-(4-fluorophenyl)ethyl bromide. MS(ESI) m/z 273
([M-H]-).
Step 2: In an analogous manner (as Reference Example l-a), |4-[2-(4-fluoro-phenyl)ethoxy]-phenyl}(1 -hydroxy-cyclohexyl)acetic acid was prepared from {4-[2-(4-fluoro-phenyl)-ethoxy]-phenyl}-acetic acid and cyclohexanone. MS(ESI) m/z 371 ([M-H]")
www) Step 1: In an analogous manner to Reference Example l-mmm, step 1 [4-(2-naphthalen-1 -yl-ethoxy)-phenvll-acetic acid was prepared from (4-hydroxyphenyl)acetic acid and 1-(2~bromoethyl)napthalene. MS(ESI) m/z 305 ([M-H]-).
Step 2: In an analogous manner (as Reference Example l-a), (1-hydroxv-cyclohexylH4-(2-naphthalen-1-yl-ethoxy)-phenyr]-acetic acid was prepared from

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[4-(2-naphthalen-1-yl-ethoxy)-phenyl]-acetic acid and cyclohexanone. MS(ESl) m/z403 ([M-H]")
xxx) Step 1: In an analogous manner to Reference Example l-mmm, step 1 (4-[2-(4-methoxv-phenvO-ethoxvi-phenyll-acetic acid was prepared from (4-hydroxyphenyl)acetic acid and 4-(2-chloroethyl)anisole. MS(ESI) m/z 273 ([M-H]"
)•
Step 2: In an analogous manner (as Reference Example l-a), (1-hvdroxv-cvclohexvl)-{4-[2-(4-methoxv-phenvl)-ethoxv1-phenyl)-acetic acid was prepared from {4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}-acetic acid and cyclohexanone. MS(ESI) m/z 383 ([M-H]-)
yyy) Step 1: In an analogous manner to Reference Example l-mmm, step 1 (4; cyclohexylmethoxy-phenyl)-aceticacid was prepared from (4-hydroxyphenyl)acetic acid and cyclomethyl bromide. MIS(ESI) m/z 247 ([M-H]"). Step 2: In an analogous manner (as Reference Example l-a), (4-cyclohexvlmethoxy-phenyl)-(1 -hydroxy-cyclohexyl)-acetic acid was prepared from (4-cyclohexylmethoxy-pheny!)-acetic acid and cyclohexanone. MS(ESl) m/z 345 ([M-H]-)
zzz) Step 1: To a stirred solution of (4-hydroxyphenyl)acetic acid methyl ester (0.33 g, 0.002 mole), S-(-)-sec-phenethyl alcohol (0.24 g , 0.002 mole) and triphenylphosphine (0.52 g , 0.002 mole) in anhydrous tetrahydrofuran (6 mL) was added dropwise over 15 minutes diisopropyl azodicarboxylate (0.40 g, 0.002 mole) in tetrahydrofuran (16 mL). The reaction solution was stirred for 1 h at room temperature and was then evaporated to dryness in vacuo. To the residue was added methanol (12 mL) and sodium hydroxide (O.44g, 0.011 mole), and the reaction solution was stirred under reflux for 1 h. The methanol was then removed in vacuo, and to the residue was added 12 mL of water. After stirring for 1 h, the precipitated triphenylphosphine oxide was removed by suction filtration. The aqueous filtrate was extracted with 25 mL of ethyl acetate . The ethyl acetate phase was discarded and the aqueous phase was acidified with concentrated hydrochloric acid giving the solid product 4-( (1R)-1-phenvlethoxvphenyl)acetic acid. MS(ESl) m/z 253 ([M-H]"). Step 2: In an analogous manner (as Reference Example l-a), (1-hydroxvcvclohexvl)-4-( (1R)-1-phenvlethoxvphenyl)acetic acid was prepared from

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4-( (1R)-1-phenylethoxyphenyl)acetic acid and cyclohexanone. MS(ESI) m/z 353 ([M-H])
aaaa) Step 1: In an analogous manner to Reference Example l-zzz, step 1 4-(
(1 S)-1 -phenylethoxvphenyl]acetic acid was prepared from (4-hydroxyphenyl)acetic acid and R-(+)-sec-phenethyl alcohol. MS(ESI) m/z 253
([M-H])-
Step 2: In an analogous manner (as Reference Example l-a), (1-
hydroxycyclohexyl)-4-( (1S)-1-phenylethoxyphenvl)acetic acid was prepared from
4-( (1S)-1-phenylethoxyphenyl)acetic acid and cyclohexanone. MS(ESI) m/z 353
([M-H]-)
Example 1: 1-[1-(3-chlorophenyl)-2-piperazin-1-ylethylicyclohexanol dihydrochloride

[0146] Step 1: A solution of (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-a) (5.4 g, 20.1 mmol), benzotriazol-1-yloxytris(dimethy!amino)phosphonium hexafluorophosphate (14.22 g, 32.15 mmol), and tert-butyl 1-piperazinecarboxylate (5.99 g, 32.15 mmol) in methylene chloride (20 ml_) was treated with triethylamine (8.4 mL, 60.3 mmol). The reaction was stirred at 25 °C for 16 h, after which time the solvent was removed in vacuo and the product was purified via Biotage Horizon (FLASH 40 M, silica, gradient from 0% EtOAc/hexane to 30% EtOAc/hexane) to yield 7.10 g (81%) tert-butyl 4-r(3-chlorophenyl](1-hydroxvcyclohexvl)acetyl]piperazine-1-carboxylate as a white foam. HRMS: calcd for C23H33CIN2O4, 436.2129; found (ESI_FT), 437.21996.
[0147] Step 2: A solution of 4-[(3-chlorophenyl)(1-hydroxycyclohexyl)acetyl]piperazine-1 -carboxylate (200 mg, 0.46 mmol) in dry tetrahydrofuran (3 mL) under nitrogen was treated dropwise with a solution of borane (1.0 M in tetrahydrofuran, 1.60 mL, 1.60

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mmol). The resulting solution was heated at 70 °C for 2 h, after which time the reaction was cooled in an ice bath and was treated dropwise with a 2N aqueous solution of hydrochloric acid (1 ml_). The reaction was again heated at 70 °C for 1 h, and was then cooled and treated with methanol (1 mL). After the solvent was removed in vacuo, the resulting residue was dissolved in water (5 rnL) and was washed with ethyl acetate (1 x 4 mL). The aqueous layer was basified with the addition of a 2 N aqueous solution of sodium hydroxide until the pH = 10. The product was extracted with ethyl acetate (4x5 mL) and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to yield 146 mg (99%) 1 -[1 -(3-chlorophenyl)-2-piperazin-1 -vlethyl]cyclohexanol as a colorless oil. HRMS: calcd for C18H27CIN2O, 322.1812; found (ESl_FT), 323.18977. 1-[1-(3-Chlorophenyl)-2-piperazin-1-ylethyl]cyclohexanoI (146 mg) was dissolved in methanol (0.5 mL) and treated with a saturated methanolic solution of hydrochloric acid (0.5 mL) followed by diethyl ether. After crystallizing in the refrigerator for 16 h, the resulting solid was collected, washed with diethyl ether and dried in vacuo to yield 110 mg (60%) 1 -[1 -(3-chlorophenvl)-2-piperazin-1 -vlethvl]cyclohexanol dihydrochloride as a white solid. MS (ESI) m/z 323/325 ([M+H]+); HRMS: calcd for Ci8H27CIN2O • 2.00 HCI, 394.1345; found (ESI_FT), 323.18831.
Example 2: 1 -[2-(1.4'-bipiperidin-1 '-yl)-1 -(3-chlorophenvl)ethyl]cyclohexanol
dihvdrochloride

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[0148] in an analogous manner to Example 1, step 1 1 -[2-(1,4'-bipiperidin-1 '-yl)-1 -(3-chlorophenvl)-2-oxoethyl]cvclohexanol was prepared from (3-chIoropheny!)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-a) and N-(4-piperidine)piperidine. MS (ESI) m/z 419/421 ([M+H]+); HRMS: calcd for C24H35CIN2O2, 418.2387; found (ESI), 419.2451.
[0149] In an analogous manner to Example 1, step 2 1 -[2-(1,4'-bipiperidin-1 '-yl)-1 -(3-chlorophenyl)ethvl]cyclohexanol dihydrochloride was prepared from 1-[2-(1,4'-bipiperidin-1'-yl)-1-(3-chlorophenyl)-2-oxoethyl]cyclohexanol. MS (ESI) m/z405/407 ([M+H]+); HRMS: calcd for C24H37CIN2O 2.00 HCI, 476.2128; found (ESI), 405.2664.
Example 3: 1-ri-(3-chlorophenyl)-2-(4-pvrrolidin-1-vlpiperidin-1-vl)ethvl]cyclohexanol
dihydrochloride

[0150] In an analogous manner to Example 1, step 1 1 -[1 -(3-chlorophenyl)-2-(4-pyrrolidin-1 -vlpiperidin-1 -vl)-2-oxoethvl]cyclohexanol was prepared from (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-a) and 4-(1-pyrrolidinyl)piperidine.

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[0151 ] In an analogous manner to Example 1, step 2 1 -[1 -(3-chlorophenvl)-2-(4-pvrrolidin-1-vlpiperidin-1-vl)ethvncvclohexanoldihydrochloride was prepared from 1 -[1 -(3-ch!orophenyl)-2-(4-pyrrolidin-1 -ylpiperidin-1 -yl)-2-oxoethyl]cyclohexanol. MS (ESI) m/z 391/393 ([M+H]+); HRMS: calcd for C23H35CIN2O • 2.00 HCI, 462.1971; found (ESI), 391.2497.
Example 4:1-[2-(1,4'-bipiperidin-1'-yl)-1-(3-bromophenyl)ethvncyclohexanol
dihydrochloride

[0152] In an analogous manner to Example 1, step 1 1 -[2-(1,4'-bipiperidin-1 '-yl)-1 -(3-bromophenvl)-2-oxoethvncvcloriexanol was prepared from (3-bromophenyl)(1-hydroxycyclohexyI)acetic acid (Reference Example 1-b) and N-(4-piperidine)piperidine. MS (ESI) m/z463 ([M+H]+); HRMS: calcd for C24H35BrN2O2, 462.1882; found (ESI), 463.1975.

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[0153] In an analogous manner to Example 1, step 2 1-[2-(1,4'-bipiperidin-1'-vl)-1-(3-bromophenvDethypcyclohexanol dihvdrochloride was prepared from 1-[2-(1,4'~ bipiperidin-1'-yl)-1-(3-bromophenyl)-2-oxoethyl]cyclohexanol. MS m/z449/451 ([M+H]+); HRMS: calcd for C24H37BrN2O • 2.00 HCI, 520.1623; found (ESI), 449.2149.
Example 5: 1-[1-(2-naphthyl)-2-piperazin-1-ylethyllcyclobutanol dihvdrochloride

[0154] In an analogous manner to Example 1, step 1 tert-butyl 4-[(1-
hvdroxvcvclobutyl)(2-naphthy])acetyl]piperazine-1-carboxylate was prepared from (1-hydroxycyclobutyl)(2-naphthyl)acetic acid (Reference Example 1-c) and tert-butyl 1-piperazinecarboxylate. HRMS: calcd for C25H32N2O4, 424.2362; found (ESI_FT), 425.24337.
[0155] In an analogous manner to Example 1, step 2 1-[1-(2-naphthvl)-2-piperazin-1-vlethvllcyclobutanol dihyrochloride was prepared from tert-butyl 4-[(1-hydroxycyclobutyl)(2-naphthyl)acetyl]piperazine-1-carboxylate. HRMS: calcd for C20H26N2O • 2.00 HCI, 382.1579; found (ESI_FT), 311.21184.
Example 6: 1-[2-(1,4'-bipiperidin-1'-yl)-1-(3,4-dichlorophenvnethvncvclohexanol
dihvdrochloride


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[0156] In an analogous manner to Example 1, step 1 1 -[2-(1.4'-bipiperidin-1 '-yl)-1 -(3.4-dichlorophenvl)-2-oxoethvncyclohexanol was prepared from 3,4-dichloro-alpha-(1-hydroxycyclohexyl)benzeneacetic acid (Reference Example 1-d) and N-(4-piperidine)piperidine.
[0157] In an analogous manner to Example 1, step 2 1 -[2-(1,4'-bipiperidin-1 '-yl)-1 -(3,4-dichlorophenyl]ethvncyclohexanol dihydrochloride was prepared from 1-[2-(1,4'-bipiperidin-1l-yl)-1-(3,4-dichlorophenyl)-2-oxoethyi]cyclohexanol. MS m/z 439/441/443 ([M+H]+); HRMS: calcd for C24H36CI2N2O • 2.00 HCI, 510.1738; found (ESI), 439.2267.
Example 7: 1 -[1 ~(3-bromophenyl)-2-(4-pyrrolidin-1 -ylpiperidin-1 -yl)ethyl]cyclohexanol dihydrochloride

[0158] In an analogous manner to Example 1, step 1 1 -[1 -(3-bromophenvl)-2-oxo-2-(4-pyrrolidin-1 -ylpiperidin-1 -yl)ethyl]cyclohexanol was prepared from (3-bromopheny!)(1-hyd,roxycyc!ohexyl)acetic acid (Reference Example 1-b) and 4-(1-pyrrolidinyl)piperidine. MS (ESI) m/z 449 ([M+H]+); HRMS: calcd for C23H33BrN2O2, 448.1725; found (ESI), 449.1789.
[0159] In an analogous manner to Example 1, step 2 1-[1 -(3-bromophenvl)-2-(4-pyrrolidin-1 -ylpiperidin-1 -yl)ethvl]cyclohexanol dihydrochloride was prepared from 1-[1-(3-bromophenyl)-2-oxo-2-(4-pyrrolidin-1 -ylpiperidin-1 -yl)ethyl]cyclohexanol. MS m/z 435/437 ([M+H]+); HRMS: calcd for C23H35BrN2O • 2.00 HCI, 506.1466; found (ESI), 435.2021.

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Example 8:1-[2-(1,4'-bipiperidin-1'-yl)-1-(3-bromo-4-methoxyphenyl)ethyl]cyclohexanol dihydrochloride

[0160] In an analogous manner to Example 1, step 1 1 -F2-(1,4'-bipiperidin-1 '-vl)-1 -(3-bromo-4-methoxyphenyl)-2-oxoethyl]cvclohexanol was prepared from (3-bromo-4-methoxyphenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-1) and N-(4-piperidine)piperidine.
[0161] In an analogous manner to Example 1, step 2 1 -[2-(1,4'-bipiperidin-1 '-yl)-1 -(3-bromo-4-methoxyphenvl)ethyl]cyclohexanol dihydrochloride was prepared from 1-[2-(1,4'-bipiperidin-r-yl)-1-(3,4-dichlorophenyl)-2-oxoethyl]cyclohexanol. MS m/z 479/481 ([M+H]+); HRMS: calcd for C25H39BrN2O2 ' 2.00 HCI, 550.1728; found (ESI), 479.2269.
Example 9:1 -[1 -(3-bromo-4-methoxyphenyl)-2-(4-pyrrolidin-1 -ylpiperidin-1 -yt)ethyl]cyclohexanol dihydrochloride

[0162] In an analogous manner to Example 1, step 1 1-[1 -(3-bromo-4-methoxvphenyl)-2-(4-pyrrolidin-1 -ylpiperidin-1 -yl)-2-oxoethvncyclohexanol was prepared from (3-brorno-4-methoxyphenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-1) and 4-(1-pyrrolidinyl)piperidine.

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[0163] In an analogous manner to Example 1, step 2 1 -[1 -(3-bromo-4-methoxyphenvD-2-(4-pvrrolidin-1 -ylpiperidin-1 -yl)ethvl]cyclohexanol dihydrochloride was prepared from 1 -[1 -(3-bromo-4-methoxyphenyl)-2-(4-pyrrolidin-1 -ylpiperidin-1 -yl)-2-oxoethyl]cyclohexanol. MS m/z465/467 ([M+H]+); HRMS: calcd for C24H37BrN2O2 • 2.00 HCI, 536.1572; found (ESI), 465.2096.
Example 10: 1-[2-(benzylamino)-1-(3,4-dichlorophenvl)ethyl]cyclobutanol hydrochloride

[0164] in an analogous manner to Example 1, step 1 N-benzyl-2-(3,4-dichlorophenyl)-2-(1-hydroxycyclobutvl)acetarnide was prepared from (3,4-dichlorophenyl)(1-hydroxycyclobutyl)acetic acid (Reference Example 1-p) and benzylamine. HRMS: calcd for C19H19CI2NO2, 363.0793; found (ESI_FT), 364.08658.
[0165] In an analogous manner to Example 1, step 2 1 -[2-(benzylamino)-1 -(3,4-dichlorophenyl)ethyl]cyclobutanol hydrochloride was prepared from N-benzyl-2-(3,4~ dichlorophenyl)-2-(1-hydroxycyclobutyl)acetamide. HRMS: calcd for C19H21Cl2NO HCI, 385.0767; found (ESI_FT), 350.10832.
Example 11:1-[1-(3,4-dichlorophenyl)-2-(4-pvrrolidin-1-vlpiperidin-1-yl)ethvncyclohexanol dihydrochloride


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[0166] In an analogous manner to Example 1, step 1 1 -[1 -(3,4-dichlorophenyl)-2-(4-pvrrolidin-1-ylpiperidin-1-vl)-2-oxoethvncyclohexanol was prepared from 3,4-dichloro-alpha-(1-hydroxycyclohexyl)benzeneacetic acid (Reference Example 1-d) and 4-(1-pyrrolidinyl)piperidine.
[0167] In an analogous manner to Example 1, step 2 1 -[1 -(3.4-dichlorophenyl)-2-(4-pyrrolidin-1-vlpiperidin-1-vl)ethyl]cyclohexanol dihvdrochloride was prepared from 1-[1-(3,4-dichlorophenyl)-2-(4-pyrroIidin-1 -ylpiperidin-1 -yl)-2-oxoethyl]cyclohexanol. MS m/z 425/427/429 ([M+H]+); HRMS: calcd for C23H34CI2N2O 2.00 HCI, 496.1582; found (ESI), 425.2129.
Example 12: 1-[2-(benzvlamino)-1-(2-naphthyl)ethyl]icvclobutanol hydrochloride

[0168] In an analogous manner to Example 1, step 1 N-benzv)-2-(1-
hydroxycyclobutyl)-2-(2-naphthyl)acetamide was prepared from (1-hydroxycyclobutyl)(2-naphthyl)acetic acid (Reference Example 1-c) and benzylamine. HRMS: calcd for C23H23NO2, 345.1729; found (ESI_FT), 346.17885.
[0169] In an analogous manner to Example 1, step 2 1 -[2-(benzylamino)-1 -(2-naphthvPethvncyclobutanol hydrochloride was prepared from N-benzyl-2-(1-hydroxycyclobutyl)-2-(2-naphthyl)acetamide. HRMS: calcd for C23H25NO . HCI, 367.1703; found (ESI_FT), 332.20146.
Example 13:1 -{1 -(3,4-dichlorophenyl)-2-[4-(methylamino)piperidin-1 -yl]ethyl}cyclohexanol dihydrochloride

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[0170] Step 1: In an analogous manner to Example 1, step 1 tert-butyl (1-[(3.4-dichlorophenyl)(1-hvdroxvcvclohexvl)acetvPpiperidin-4-yl)carbamate was prepared from 3,4-dichloro-alpha-(1-hydroxycyclohexyl)benzeneacetic acid (Reference Example 1-d) and 4-N-boc-aminopiperidine. MS (ES) m/z 485.2 ([M+H]+); HRMS: calcd for C24H34CI2N2O4, 484.1896; found (ESI), 485.1987.
[0171] Step 2: A solution of tert-butyl {1-[(3,4-dichlorophenyl)(1-
hydroxycyciohexyl)acetyl]piperidin-4-yl}carbamate (364 mg, 0.75 mmol) in dry
tetrahydrofuran (1 mL), under nitrogen, was treated with a solution of borane (1.0 M in
tetrahydrofuran, 2.62 mL, 2.62 mmol). The reaction was heated at 74 °C for 2 h, after
which time the reaction was cooled and quenched by the addition of methanol (4 mL).
The solvents were removed in vacuo, and the products were purified via Biotage
Horizon (FLASH 25 M, silica, gradient from 10% EtOAc/hexane to 90% EtOAc/hexane)
to yield 187 mg (53%) tert-butyl {1-[2-(3,4-dichlorophenyl)-2-(1-
hydroxycyclohexyl)ethyl]piperidin-4-yl}carbamate as a white foam which eluted first and
88 mg (31%) 1-{1~(3,4-dich!orophenyl)-2-[4-(methylamino)piperidin-1-
y!]ethyl}cyclohexanol as a colorless oil which eluted second, tert-butyl (1-[2-(3,4-dichlorophenvl)-2-(1-hvdroxycvclohexvl)ethvnpiperidin-4-vl)carbamate: MS (ES) m/z 471.3 ([M+H]+); HRMS: calcd for C24H36Cl2NzO3 470.2103; found (ESI), 471.2165. 1-{1-(3,4-dichlorophenvlV2-[4-(methvlamino')piperidin-1-vnethvl)cvclohexanol: MS m/z 385/387/389 ([M+H]+). 1 -{1 -(3,4-dich!orophenyl)-2-[4-(methylamino)piperidin-1 -yl]ethyl}cyclohexanol was converted to the dihydrochloride salt with a methanolic solution of hydrochloric acid and diethyl ether to yield 45 mg (41%) 1-(1-(3,4-dichlorophenvD^-^-fmethylamino^piperidin-i-vnethvUcvclohexanol dihydrochloride as a white solid. HRMS: calcd for C20H30CI2N2O • 2.00 HCI, 456.1269; found (ESI), 385.183.

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Example 14: 1 -[2-(4-aminopiperidin-1 -y|)-1 -(3,4-dichlorophenvl)ethyncyclohexanol
dihydrochloride

[0172] A solution of tert-butyl {1-[2-(3,4-dichlorophenyl)-2-(1-
hydroxycyclohexyl)ethyl]piperidin-4-yl}carbamate (130 mg, 0.28 mmol) (Example 13), in diethyl ether (2 mL) was treated with a 4 N solution of hydrogen chloride in dioxane (1 mL). The resulting solution was stored at 25 °C for 16 h, during which time crystals began to form. The mixture was transferred to the refrigerator where ft was stored for an additional 16 h. The resulting crystals were collected, washed with diethyl ether, and dried in vacuo to yield 101 mg (82%) 1 -[2-(4-aminopiperidin-1 -vl)-1 -(3.4-dichlorophenyl)ethvl]cyclohexanol dihydrochloride as a white solid. MS m/z 371/373/375 ([M+H]+);HRMS: calcd for dghfeaCfeNaO • 2.00 HCI, 442.1112; found (ESI), 371.1642.
Example 15: 4-[2-(benzyIamino)-1 -(3,4-dichlorophenyl)ethyl]-1 -methylpiperidin-4-ol dihydrochloride

[0173] In an analogous manner to Example 1, step 1 N-benzyl-2-(3,4-dichlorophenyl)-2~(4-hydroxy-1-methylpiperidin-4-yl)acetamide was prepared from (3,4-dichlorophenyl)(4-hydroxy-1-methylpiperidin-4-yl)acetic acid (Reference Example 1-i)

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and berizylamine. HRMS: calcd for C21H24CI2N2O2, 406.1215; found (ESI_FT), 407.12885.
[0174] In an analogous manner to Example 1, step 2 4-[2-(benzylamino)-1 -(3,4-dichlorophenyl)ethvP-1 -methvlpiperidin-4-ol dihydrochloride was prepared from N-benzyl-2-(3,4-dichloropheny!)-2-(4-hydroxy-1-methylpiperidin-4-yl)acetamide. HRMS: calcd for C21H26CI2N2O • 2.00 HCI, 464.0956; found (ESI_FT), 393.14924.
Example 16: 1 -[2-[(3S)-3-aminopyrrolidtn-1 -yl]-1 -(3-chlorophenyl)ethvl]cyclohexanol
dihydrochloride

[0175] In an analogous manner to Example 1, step 1 ((S)-1 -[2-(3-Chloro-phenyQ-2-(1 -hvdroxy-cyclohexvl)-acetvn-pyrrolidin-3-yl|-carbamic acid tert-butyl ester was prepared from (3-chiorophenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-a) and (3S)-(-)-3-(tert-butoxycarbonylamino)pyrroiodine.
[0176] In an analogous manner to Example 1, step 2 1 -[2-[(3S)-3-aminopyrrolidin-1 -yl]-1 -(3-chlorophenyl)ethvricvclohexanol dihydrochloride was prepared from {(S)-1-[2-(3-Chloro-phenyi)-2-(1 -hydroxy-cyc!ohexyl)-acetyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester. HRMS: calcd for C18H27CIN2O • 2.00 HCI, 394.1345; found (ESI), 323.1884.
Example 17:1 -{1 -(3-chlorophenyl)-2-[4-(methylamino)piperidin-1 -yl]ethyl}cyclohexanol dihydrochloride

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[0177] In an analogous manner to Example 1, step 1 .tert-butyl (1-[(3-chlorophenyl)(1-hvdroxvcvclohexyl)acetvnpiperidin-4-vl)carbamate was prepared from (3-ch!orophenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-a) and 4-N-boc-aminopiperidine. MS m/z 451/453 ([M+H]+); HRMS: calcd for C24H35CIN2O4, 450.2285; found (ESI), 451.2353.
[0178] In an analogous manner to Example 13, step 2 1 -{1 -(3-chlorophenyl)-2-[4-(methylamino)piperidin-i-ynethyl}cyclohexanol dihydrochloride was prepared from tert-butyl {1-[(3-chlorophenyl)(1-hydroxycycIohexyl)acetyl]piperidin-4-yl}carbamate. MS m/z 351/353 ([M-+-H]+); HRMS: calcd for C20H31CIN2O • 2.00 HCI, 422.1658; found (ESI), 351.2208.
Example 18:1 -[2-(4-aminopiperidin-1 -yl)-1 -(3-bromophenyf)ethyl]cyc!ohexanol dihydrochloride

[0179] In an analogous manner to Example 1, step 1 tert-butyl (1-[(3-bromophenyl)(1-hydroxvcyclohexyl)acetyl]piperidin-4-yl)carbamate was prepared from (3-bromophenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-b) and 4-N-boc-aminopiperidine. MS (ES) m/z 495.2 ([M+H]+); HRMS: calcd for C24H35BrN2O4, 494.1780; found (ESI), 495.1864.

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[0180] In an analogous manner to Example 13, step 2 tert-butvl {1-[2-(3-
bromophenvl)-2-(1-hvdroxvcvclohexyl)ethyllpiperidin-4-vl)carbamate was prepared from
tert-butyl {1 -[(3-bromophenylphenyl)(1 -hydroxycyclohexyl)acetyl]piperidin-4-
yl}carbamate. MS (ES) m/z 481.3 ([M+H]+); HRMS: calcd for C24H37BrN2O3! 480.1988; found (ESI), 481.2081.
[0181] In an analogous manner to Example 14, 1-r2-(4-aminopiperidin-1-yl)-1-(3-bromophenvOethyl]cvclohexanol dihydrochloride was prepared from terf-butyl {1-[2-(3-bromophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperidin-4-yl}carbamate. HRMS: calcd for C19H29BrN2O 2.00 HCl, 452.0997; found (ESI), 381.1525.
Example 19: 1 -{1 -(3-bromophenyl)-2-[4-(methylamino)piperidin-1 -yi]ethyl}cyclohexanol dihydrochloride

[0182] In an analogous manner to Example 1, step 1 ferf-butyl (1-[(3-bromophenyl)(1-hydroxvcvclohexvl)acetvnpiperid)'n-4-vl)carbamate was prepared from (3-bromophenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-b) and 4-N-boc-aminopiperidine. MS (ES) m/z 495.2 ([M+H]+); HRMS: calcd for C24H35BrN2O4, 494.1780; found (ESI), 495.1864.
[0183] In an analogous manner to Example 13, step 2 1 -{1 -(3-bromophenyl)-2-[4-(methylamino)piperidin-1-yl]ethyl}cyclohexanol dihydrochloride was prepared from tert-butyl {1 -[(3-bromophenylpheny!)(1 -hydroxycyclohexyl)acetyl]piperidin-4-yl}carbamate. MS (ESI) m/z 395 ([M+H]+); HRMS: calcd for C2oH3iBrN20 " 2.00 HCl, 466.1153; found (ESI), 395.1708.

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Example 20: 1-{2-(1,4'-bipiperidin-1 '-yl)-1-[3-(trifluoromethyl)phenyl]ethyl}cyc!ohexanol dihydrochloride

[0184] In an analogous manner to Example 1, step 1 1-(2-(1,4'-bipiperidin-1'-yl)-1-f3-(tnfluoromethvnphenvl1-2-oxoethyl]cyclohexanol was prepared from (1-hydroxycyclohexyl)[3-(trifluoromethoxy)phenyl]acetic acid (Reference Example 1-f) and N-(4-piperidine)piperidine.
[0185] In an analogous manner to Example 1, step 2 1 -{2-(1,4'-bipiperidin-1 '-yl)-1 -[3-(trifluoromethyl)phenvnethyl}cyclohexanol dihydrochloride was prepared from (1-hydroxycyclohexyl)[3-(trifluoromethoxy)phenyl]acetic acid. m/z 439 ([M+H]+); HRMS: calcd for C25H37F3N2O • 2.00 HCI, 510.2392; found (ESI), 439.2928.
Example 21: 1-[1-(1-naphthyl)-2-piperazin-1-ylethyl]cvclohexanol dihydrochloride

[0186] In an analogous manner to Example 1, step 1 fe/t-butyl 4-1Y1-
hydroxycyclohexvl)(1-naphthvl)acetvllpiperazine-1-carboxylate was prepared from (1-hydroxycyclohexyl)(1-naphthyl)acetic acid (Reference Example 1-e) and tert-butyl 1-

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piperazirecarboxylate. MS (ESI) m/z 453 ([M+H]+); HRMS: calcd for C27H36N2O4, 452.2675; found (ESI_FT), 453.27518.
[0187] In an analogous manner to Example 1, step 2 1 -[1 -(1 -naphthvl)-2-piperazin-1 -ylethyl]cyclohexanol dihydrochloride was prepared from tert-butyl 4-[(1-hydroxycyclohexyl)(1-naphthyl)acetyl]piperazine-1-carboxylate. MS (ESI) m/z 339 ([M+H]+); HRMS: calcd for C22H30N20 " HCI, 374.2125; found (ESI_FT), 339.24268.
Example 22:1-[2-(1,4'-bipiperidin-1'-yI)-1-(2-naphthyl)ethyl]cyclohexanol dihydrochloride

[0188] In an analogous manner to Example 1, step 1 1 -[2-(1,4'-bipiperidin-1 '-yl)-1 -(2-naphthyl)-2-oxoethyncyclohexanol was prepared from (1-hydroxycyclohexyl)(2-naphthyl)acetic acid (Reference Example 1-q) and N-(4-piperidine)piperidine.
[0189] In an analogous manner to Example 1, step 2 1-[2-(1,4'-bipiperidin-1'-yl)-1-(2-naphthyl)ethyl]cyclohexanol dihydrochloride was prepared from 1-[2-(1,4'-bipiperidin-1'-yl)-1-(2-naphthyl)-2-oxoethy!]cyciohexanol. MS m/z 421 ([M+H]+); HRMS: calcd for C28H40N2O • 2.00 HCI, 492.2674; found (ESI), 421.3224.
Example 23:1 -{2-piperazin-1 -yl-1 -[3-(trif luoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride


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[0190] In an analogous manner to Example 1, step 1 tert-butyl 4-{(1-
hydroxycyclohexvl)[3-(trifluoromethoxy)phenynacetyl)piperazine-1-carboxvlate was prepared from (1-hydroxycyclohexyl)[3-(trifluoromethoxy)phenyl]acetic acid (Reference Example 1-f) and tert-butyl 1-piperazinecarboxylate. HRMS: calcd for C24H33F3N2O5, 486.2342; found (ESI), 487.2398.
[0191] In an analogous manner to Example 1, step 2 1 -{2-piperazin-1 -yl-1 -f3-(trifluoromethoxv)phenyliethyllcyclohexanol dihydrochloride was prepared from tert-butyl 4-{(1-hydroxycyclohexyl)[3-(trifluoromethoxy)phenyl]acetyl}piperazine-1-carboxylate. HRMS: calcd for C19H27F3N2O2 . 2.00 HCI, 444.1558; found (ESI), 373.2095.
Example 24: 1-{2-(4-methylpiperazin-1-yl)-1-[3-(trifluoromethoxy)phenyl]ethy!}cyclohexanol dihydrochloride

[0192] A solution of 1-{2-piperazin-1-yl-1-[3-
(trifluoromethoxy)phenyl]ethyl}cyclohexanol (590 mg, 1.59 mmol) (see Example 23), in formic acid (3.1 mL) at 50 °C, was treated with an aqueous solution of formaldehyde (37% in water, 1.3 mL, 1.94 mmol). The reaction was heated at 70 °C for 1.5 h, after which time the reaction was poured into water (50 mL) and basified to pH = 10 with the addition of a 2 N aqueous solution of sodium hydroxide. The product was then extracted with ethyl acetate (3 x 20 mL), and the combined organic extracts were dried over magnesium sulfate and concentrated to yield 442 mg (72%) 1-{2-(4-rnethylpiperazin-1-yl)-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol as a colorless oil. The product was dissolved in methanol (0.5 mL) and the resulting solution was treated with a saturated methanolic solution of hydrochloric acid (0.5 mL) followed by diethyl

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ether (2 TIL). The solution was stored in the refrigerator for 16 h. The resulting precipitate was filtered and washed with diethyl ether to yield 299 mg (57%) 1-{2-(4-methylpiperazin-1 -yl)-1 -[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride as a white solid. HRMS: calcd for C20H29F3N2O2 . 2.00 HCI, 458.1715; found (ESI), 387.2263.
Example 25: 1-[2-(4-aminopiperidin-1-yl)-1-(3-bromo-4-methoxyphenyl)ethyl]cyclohexanol dihydrochloride

[0193] In an analogous manner to Example 1, step 1 fert-butyl {1-[(3-bromo-4-methoxvphenvnd-hvdroxvcvclohexvDacetv^piperidin^-vDcarbamate was prepared from .(3-bromo-4-methoxyphenyl)(1-hydroxycyc!ohexyl)acetic acid (Reference Example 1-1) and 4-N-boc-aminopiperidine. MS (ES) m/z 525.2 ([M+H]+); HRMS: caicd for C25H37BrN2O5, 524.1886; found (ESI), 525.1971.
[0194] In an analogous manner to Example 13, step 2 tert-butyl {1-[2-(3-bromo-4-methoxyphenyl)-2-(1 -hydroxycyc!ohexyl)ethyl]piperidin-4-yl}carbamate was prepared from tert-butyl {1 -[(3-bromo-4-methoxyphenyl)(1 -hydroxycyclohexyl)acetyl]piperidin-4-yljcarbamate. MS (ES) m/z 511.4 ([M+H]+); HRMS: calcd for C25H39BrN2O4, 510.2093; Iound (ESI), 511.2147.
[0195] In an analogous manner to Example 14, 1-[2-(4-aminopiperidin-1-yl)-1-(3-bromo-4-methoxyphenyl)ethyl]cyclohexanol dihydrochloride was prepared from tert-butyl {1 -[2-(3-bromophenyl)-2-(1 -hydroxycyclohexyl)ethyl]piperidin-4-yl}carbamate. MS m/z 411/413 ([M+H]+); HRMS: calcd for C2oH31BrN202 ' 2.00 HCI, 482.1102; found (ESI), 411.1656.

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Example 26:1-{2-(4-pyrrolidin-1-ylpiperidin-1-yl)-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol dihydrochloride

[0196] In an analogous manner to Example 1, step 1 1-{2-(4-pyrrolidin-1-vlpiperidin-1-vl)-1-[3-(trifluorometlwl)phenvl1-2-oxoethvl)cyclohexanol was prepared from (1-hydroxycyclohexyl)[3-(trifluoromethyl)phenyl]acetic acid (Reference Example 1-m) and 4-(1 -pyrro!idinyl)piperidine.
[0197] In an analogous manner to Example 1, step 2 1-{2-(4-pyrrolldin-1-ylpiperidin-1-yl)-1-[3-(trif!uoromethyl)phenyl]ethyl}cyclohexano! dihydrochloride was prepared from 1-{2-(4-pyrroiidin-1-ylpiperidin-1-yl)-1-[3-(trifluoromethyi)phenyi]-2-oxoethyl}cyclohexanol. MS m/z 425 ([M+H]+); HRMS: calcd for C24H35F3N2O • 2.00 HCl, 496.2235; found (ESI), 425.2789.
Example 27:1 -{1 -[4-(benzyloxy)phenyi]-2-piperazin-1 -ylethyl}cyclohexano! dihydrochloride

[0198] In an analogous manner to Example 1, step 1 tert-butyl 4-[[4-
(b_enzvloxv)phenvl|(1-hvdroxvcvclohexvl)acetyl]pipera2)'ne-1-carboxylate was prepared from (4-benzyloxyphenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-n) and

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tert-butyi 1-piperazinecarboxylate. MS (ESI) m/z 509 ([M+H]+); HRMS: calcd for C30H40N2O5, 508.2937; found (ESI), 509.3027.
[0199] In an analogous manner to Example 1, step 1-{1-[4-(benzyloxy)phenyl]-2-piperazin-1-ylethyl}cyclohexano! dihydrochloride was prepared from tert-butyi 4-[[4-(benzyloxy)phenyl](1 -hydroxycyclohexyl)acetyl]piperazine-1 -carboxylate. HRMS: calcd for C25H34N2O2 • 2.00 HCI, 466.2154; found (ESI), 395.2683.
Example 28:1-{2-piperazin-1-yl-1 -[4-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride

[0200] In an analogous manner to Example 1, step 1 tert-butyl 4-1(1-
hvdroxvcvclohexvl)[4-(trifluoromethoxv)phenvnacetvl|piperazine-1-carboxviate was prepared from (1-hydroxycyclohexy!)[4-(trifluoromethoxy)phenyl]acetic acid (Reference Example 1-g) and tert-butyl 1-piperazinecarboxylate. MS (ESI) m/z 487 ([M+H]+).
i0201] In an analogous manner to Example 1, step 2 1-{2-piperazin-1-yi-1-[4-(trifluoromethoxy)phenyl]ethyl}cyc!ohexanol dihydrochloride was prepared from tert-butyl 4-{(1-hydroxycyclohexyl)[4-(trifluoromethoxy)phenyl]acetyl}piperazine-1-carboxylate. MS m/z 373 ([M+H]+); Anal. Calcd for C19H27F3N2O2 . 2.00 HCI '2.10 H2O: C, 47.23; H, 6.93; N, 5.80. Found: C, 46.93; H, 6.80.
Example 29:1 -{1 -(3-bromo-4-methoxyphenyl)-2-[4-(methylamino)piperidin-1 -yl]ethyl}cyclohexanol dihydrochloride

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|0202] In an analogous manner to Example 1, step 1 tert-butyl {1 -[(3-bromo-4-methoxvphenvn(1-hvdroxvcvclohexvl)acetvnpiperidin-4-vl|carbamate was prepared from (3-bromo-4-methoxyphenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-1) and 4-N-boc-aminopiperidine. MS (ES) m/z 525.2 ([M+H]+); HRMS: calcd for C25H37BrN2O5, 524.1886; found (ESI), 525.1971.
[0203] In an analogous manner to Example 13, step 2 1-{1-(3-bromo-4-
methoxyphenyl)-2-[4-(methylamino)piperidin-1-yl]ethyl}cyclohexanol dihydrochioride
was prepared from tert-butyl {1-[(3-bromo-4-methoxyphenyl)(1-
hydroxycyclohexyl)acetyl]piperidin-4-yl}carbamate. MS (ESI) m/z 425 ([M+H]+); HRMS: calcd for C21H33BrN2O2 " 2.00 HCl, 496.1259; found (ESI), 425.1793.
Example 30: 1-{2-[4-(methylamino)piperidin-1-yl]-1-[3-(trif!uoromethyl)phenyl]ethyi}cyclohexanol dihydrochioride

|0204] In an analogous manner to Example 1, step 1 tert-butyl (1-1(1-
livdroxycyclohexyn[3-(trifluoromethyl)phenyl"|acetyl|piperidin-4-yl)carbamate was
prepared from (1-hydroxycyc!ohexyl)[3-(trifluoromethyl)phenyl]acetic acid (Reference Example 1-m) and 4-N-boc-aminopiperidine. MS (ES) m/z485.3 ([M+H]+); HRMS: calcd for C25H35F3N2O4, 484.2549; found (ESI), 485.2612.

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[0205] In an analogous manner to Example 13, step 2 1-{2-[4-(methylamino)piperidin-
1-yl]-1-[3-(trifIuoromethyl)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from
terf-butyl (1 -{(1 -hydroxycyclohexyl)[3-(trifluoromethyl)phenyljacetyl}piperidin-4-
y!)carbamate. MS m/z 385 ([M+H]+); HRMS: calcd for C21H31F3N2O • 2.00 HCI, 456.1922; found (ESI), 385.2454.
Example 31:1 -[1 -(2-naphthyl)-2-(4-pyrrolidin-1 -ylpiperidin-1 -yl)ethyl]cyclohexanol dihydrochloride

[0206] In an analogous manner to Example 1, step 1 1 -[1 -(2-naphthyl)-2-(4-pyrrolidin-1 -ylpiperidin-1 -vl)-2-oxoethvl]cyclohexanol was prepared from (1-hydroxycyclohexyl)(2-naphthyl)acetic acid (Reference Example 1-q) and 4-(1-pyrrolidinyl)piperidine.
[0207] In an analogous manner to Example 1, step 2 1-[1-(2-naphthyl)-2-(4-pyrrolidin-1 -ylpiperidin-1 -yl)ethyl]cyclohexanol dihydrochloride was prepared from 1-[1-(2-naphthyl)-2-(4-pyrrolidin-1 -ylpiperidin-1 -y!)-2-oxoethyl]cyc!ohexanol. MS m/z 407 ([M+H]+); HRMS: calcd for C27H38N2O • 2.00 HCI, 478.2518; found (ESI), 407.3055.
Example 32: 1 -[2-(4-aminopiperidin-1 -yl)-1 -(2-naphthyl)ethyl]cyclohexanol dihydrochloride


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[0208] In an analogous manner to Example 1, step 1 tert-butyl (1-[(1-
hvdroxvcvclohexvl)(2-naphthv0acetvl]piperidin-4-vl)carbamate was prepared from (1-hydroxycyclohexyl)(2-naphthyl)acetic acid (Reference Example 1-q) and 4-N-boc-aminopiperidine. MS (ES) m/z467.3 ([M+H]+); HRMS: calcd for C28H38N2O4, 466.2832; found (ESI), 467.2902.
[0209] In an analogous manner to Example 13, step 2 tert-butyl (142-0-
hvdroxvcvclohexyl)-2-(2-naphthvl)ethvnpiperidin-4-vl)carbamate was prepared from tert-butyl {1-[(1-hydroxycyclohexyl)(2-naphthyl)acetyl]piperidin-4-yl}carbamate. MS (ES) m/z 453.4 ([M+H]+); HRMS: calcd for C28H4oN203, 452.3039; found (ESI), 453.3095.
[0210] In an analogous manner to Example 14, 1-[2-(4-aminopiperidin-1-yl)-1-(2-naphthyl)ethyl]cyclohexanol dihydrochloride was prepared from fert-butyl {1-[2-(1-hydroxycyclohexyl)-2-(2-naphthyl)ethyI]piperidin-4-yl}carbamate. MS m/z 353 ([M+H]+); HRMS: calcd for C23H32N2O • 2.00 HCI, 424.2048; found (ESI), 353.2598.
Example 33: 1-[2-[(3-chlorobenzyl)amino]-1-(2-naphthyl)ethyl]cyclohexanol hydrochloride

[0211] In an analogous manner to Example 1, step 1 N-(3-chlorobenzyl)-2-(1 -hydroxycyclohexyl)-2-(2-naphthvl)acetamide was prepared from (1-hydroxycyclohexyl)(2-naphthyl)acetic acid (Reference Example 1-q) and 3-chlorobenzylamine. MS (ESI) m/z408/410 ([M+H]+).
10212] In an analogous manner to Example 1, step 2 1-[2-[(3-chlorobenzyl)amino]-1-(2-naphthyl)ethyl]cyclohexanol hydrochloride was prepared from N-(3-chlorobenzyl)-2-

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(1-hydroxycyclohexyl)-2-(2-naphthyl)acetamide. MS m/z 394/396 ([M+H]+); HRMS: calcd for C25H28CINO HCI, 429.1626; found (ESI), 394.191.
Example 34: 1-[1-(3-chloropheny!)-2-pyrrolidin-1-ylethyl]cyclohexanol hydrochloride

[0213] In an analogous manner to Example 1, step 1 1 -[1 -(3-chlorophenyl)-2-oxo-2-pyrrolidin-1-vlethvHcvclohexanol was prepared from (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-a) and pyrrolidine. MS (ESI) m/z 322/324 ([M+H]+); HRMS: calcd for. C18H24CINO2, 321.1496; found (ESl_FT), 322.15603.
[0214] In an analogous manner to Example 1, step 2 1-[1-(3-chlorophenyl)-2-pyrrolidin-1-y!ethyl]cyclohexanol hydrochloride was prepared from 1-[1-(3-chlorophenyI)-2-oxo-2-pyrrolidin-1-ylethyl]cyclohexanol. HRMS: calcd for C18H26CINO • HCI, 343.1470; found (ESLFT), 308.17736.
Example 35: 1-[2-(4-aminopiperidin-1-yl)-1-(3-chlorophenyl)ethyl]cyclohexanol dihydrochloride

[0215] In an analogous manner to Example 1, step 1 tert-butyl (1 -[ (3-chlorophenvl)(1 -hvdroxvcvclohexvl)acetvllpiperidin-4-vl)carbamate was prepared from (3-

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chlorophenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-a) and 4-N-boc-aminopiperidine. MS m/z 451/453 ([M+H]+); HRMS: calcd for C24H35CIN2O4, 450.2285; found (ESI), 451.2353.
[0216] In an analogous manner to Example 13, step 2 1-[2-(4-aminopiperidin-1-yi)-1-(3-ch!orophenyl)ethy!]cyclohexano! dihydrochloride was prepared from tert-butyl {1-[(3-chlorophenyl)(1-hydroxycyclohexyl)acetyl]piperidin-4-yi}carbamate. MS m/z 337/339 ([M+H]+); HRMS: calcd for C19H29CIN2O • 2.00 HCI, 408.1502; found (ESI), 337.2022
Example 36: 1 -{1 -(3-chlorophenyl)~2-[4-(dimethylamino)piperidin-1 -yl]ethyl}cyclohexanol dihydrochloride

|0217] A solution of 1-[2-(4-aminopiperidin-1-yl)-1-(3-chlorophenyl)ethyl]cyclohexanol (50 mg, 0.15 mmol) (see Example 35), in formic acid (0.28 m!_) was treated with an aqueous solution of formaldehyde (37% in water, 0.12 mL). The reaction was heated at 70 °C for 1 h, after which time the reaction was diluted with water (3 mL) and basified to pH = 10 with a 2 N aqueous solution of sodium hydroxide. The product was extracted with ethyl acetate (4x5 mL), and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The resulting colorless oil was treated with methanolic hydrochloric acid and diethyl ether to yield 32 mg (53%) 1-{1-(3-chlorophenyi)-2-[4-(dimethylamino)piperidin-1-yl]ethyl}cyc!ohexanol dihydrochloride as a white solid. HRMS: calcd for C21H33CIN2O • HCI, 400.2048; found (ESI), 365.2349.
Example 37: 4-[1 -(3,4-dichlorophenyl)-2-piperazin-1 -ylethyl]-1 -methylpiperidin-4-o! trihydrochloride

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[0218] In an analogous manner to Example 1, step 1 tert-butvl 4-[(3,4-
dichlorophenvl)(4-ydroxv-1-methvlpiperidin-4-yl)acetyl]piperazine-1-carboxvlate was prepared from (3,4-dichlorophenyl)(4-hydroxy-1-methylpiperidin-4-yl)acetic acid (Reference Example 1-i) and tert-butyl 1-piperazinecarboxyiate. HRMS: calcd for C23H33CI2N3O4, 485.1848; found (ESI_FT), 486.19305.
[0219] In an analogous manner to Example 1, step 2 4-[1-(3,4-dichIorophenyl)-2-piperazin-1-ylethyl]-1-methylpiperidin-4-ol trihydrochloride was prepared from tert-butyl 4-[(3,4-dichIorophenyl)(4-hydroxy-1-methylpiperidin-4-yl)acetyl]piperazine-1-carboxylate. HRMS: calcd for C18H27CI2N3O • 3.00 HCl, 479.0831; found (ES!_FT), 372.16065.
Example 38: 1-[2-(benzylamino)-1-(3,4-dich!orophenyl)ethy!]cyclohexanol hydrochloride

[0220] In an analogous manner to Example 1, step 1 A/-benzyl-2-(3,4-dichlorophenvO-2-n-hydroxycvclohexvl)acetamide was prepared from 3,4-dich!oro-alpha-(1-hydroxycyclohexyl)benzeneacetic acid (Reference Example 1-d) and benzylamine. HRMS: calcd forC21H23CI2NO2, 391.1106; found (ESI_FT), 392.11598.
[0221] In an analogous manner to Example 1, step 2 4-[1 -(3,4-dichlorophenyl)-2-piperazin-1-ylethyl]-1-methylpiperidin-4-ol hydrochloride was prepared from A/-benzyl-2-(3,4-dichlorophenyl)-2-(1-hydroxycyclohexyl)acetamide. HRMS: calcd for C21H25CI2NO • HCl, 413.1080; found (ESI_FT), 378.13864.

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Example 39: 1-{2-(4-aminopiperidin-1-yl)-1-[3-(trifluoromethyl)phenyl]ethyl}cyc!ohexanol dihydrochloride

[0222] In an analogous manner to Example 1, step 1 tert-butyl (1-((1-
hvdroxvcyclohexvl)r3-(trifluoromethvl)phenvl]acetvl|piperidin-4-yl)carbamate was
prepared from (1-hydroxycyclohexyl)[3-(trif!uoromethyl)phenyl]acetic acid (Reference Example 1-m) and 4-N-boc-aminopiperidine. MS (ES) m/z 485.3 ([M+H]+); HRMS: calcd for C25H35F3N2O4, 484.2549; found (ESI), 485.2612.
[0223] In an analogous manner to Example 13, step 2 tert-butyl (1-(2-(1-
hvdroxvcvclohexvl)-2-[3-(trifluoromethyl)phenvnethvl)piperidin-4-vl)carbamate was
prepared from tert-butyl (1-{(1-hydroxycyclohexyl)[3-
(trifluoromethyl)phenyl]acetyl}piperidin-4-yl)carbamate. MS (ES) m/z 471.4 ([M+H]+); HRMS: calcd for C25H37F3N2O3, 470.2756; found (ESI), 471.2852.
|0224] In an analogous manner to Example 14, 1-{2-(4-aminopiperidin-1-yl)-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from tert-butyl (1-{2-(1-hydroxycyclohexyl)-2-[3-(trifluoromethyl)phenyl]ethyl}piperidin-4-yl)carbamate. MS m/z 371 ([M+H]+); HRMS: calcd for C20H29F3N2O • 2.00 HCI, 442.1766; found (ESI), 371.2309.
Example 40: 1-[2-(benzy!amino)-1-(3-bromophenyi)ethy!]cyclobutanol hydrochloride

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[0225] In an analogous manner to Example 1, step 1 N-benzyl-2-(3-bromophenyl)-2-(1 -hydroxycyclobutvl)acetamide was prepared from (3-bromophenyl)(1-hydroxycyclobutyl)acetic acid (Reference Example 1-j) and benzylamine. HRMS: calcd for C19H20BrNO2) 373.0677; found (ES!_FT), 374.07415.
[0226] In an analogous manner to Example 1, step 2 1-[2-(benzylamino)-1-(3-bromophenyl)ethyl]cyc!obutanol hydrochloride was prepared from N-benzyl-2-(3-bromophenyl)-2-(1-hydroxycyclobutyl)acetamide. HRMS: calcd for C-19H22BrNO . HCI, 395.0652; found (ESl_FT), 360.09546.
Example 41; 1-[2-(benzylamino)-1-(3-chlorophenyl)ethyl]cyclohexanol hydrochloride

[0227] In an analogous manner to Example 1, step 1 N-benzy!-2-(3-chlorophenyl)-2-(1 -hydroxycyclohexvnacetamide was prepared from (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-a) and benzylamine. HRMS: calcd for C21H24ClNO2. 357.1496; found (ESLFT), 358.15607.
[0228] In an analogous manner to Example 1, step 2 1-[2-(benzylamino)-1-(3-chi'orophenyl)ethyl]cyclohexanol hydrochloride was prepared from N-benzyl-2-(3-

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chlorophenyl)-2-(1-hydroxycyclohexyl)acetamide. HRMS: calcd for C21H26CINO • HCI, 379.1470; found (ESI_FT), 344.17761.
Example 42: 1 -[2-(cyclohexyIamino)-1 -(3,4-dichlorophenyl)ethyl]cyclohexanol hydrochloride

[0229] In an analogous manner to Example 1, step 1 N-cyclohexyl-2-(3.4-
dichlorophenvl)-2-(1-hvdroxycvclohexvl)acetamide was prepared from 3,4-dichloro-a!pha-(1-hydroxycyclohexyl)benzeneacetic acid (Reference Example 1-d) and cyclohexylamine. MS (ESI) m/z384/386/388 ([M+H]+).
[0230] In an analogous manner to Example 1, step 2 1-[2-(cyclohexylamino)-1-(3,4-
dichlorophenyl)ethyl]cyclohexanol hydrochloride was prepared from N-cyclohexyi-2-(3,4-
dichlorophenyl)-2~(1-hydroxycyclohexyl)acetamide. MS (ESI) m/z [M+H]+
(370/372/374); HRMS: calcd for C20H29CI2NO ' HCI, 405.1393; found (ESI), 370.1687; Anal. Calcd for C20H29CI2NO . HCI: C, 59.05; H, 7.43; N, 3.44. Found: C, 59.00; H, 7.49; N, 3.37.
Example 43: 1-[2-(4-aminopiperidin-1-yl)-1-(1-naphthyl)ethyl]cyc!obutanol dihydrochloride


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[0231] In an analogous manner to Example 1, step 1 tert-butyl (1-[(1-
hvdroxvcvclobutyl)(1-naphthvl)acetvnpiperidin-4-vl)carbamate was prepared from (1-
hydroxycyclobutyl)(1-naphthyl)acetic acid (Reference Example 1-o) and 4-N-boc-
aminopiperidine. MS (ES) m/z 439.3 ([M+H]+).
[0232] In an analogous manner to Example 1, step 2 1-[2-(4-aminopipendin-1-yl)-1-(1-naphthyl)ethy!]cyclobutanol dihydrochloride was prepared from tert-butyl {1-[(1-hydroxycyclobutyl)(1-naphthyl)acetyl]piperidin-4-yl}carbamate. MS (ES) m/z 325.3 ([M+H]+); HRMS: calcd for C21H28N2O . 2.00 HCI, 396.1735; found (ESI), 325.2272.
Example 44: 4-[2-(benzylamino)-1 -(3-bromophenyl)ethyl]-1 -methylpiperidin-4-ol dihydrochloride

[0233] In an analogous manner to Example 1, step 1 N-benzyl-2-(3-bromophenyl)-2-i'4-hydroxv-1-methylpiperidin-4-vl)acetamide was prepared from (3-bromopheny!)(4-hydroxy-1-methylpiperidin-4-yl)acetic acid (Reference Example 1-r) and benzylamine. HRMS: calcd for C21H25BrN2O2, 416.1099; found (ESI_FT), 417.11652.
10234] In an analogous manner to Example 1, step 2 4-[2-(benzyiamino)-1-(3-bromophenyl)ethyl]-1-methylpiperidin-4-ol dihydrochloride was prepared from N-benzyl-2-(3-bi'omophenyl)-2-(4-hydroxy-1-methyIpipendin-4-yl)acetamide. HRMS: calcd for C21H27BrN2O • 2.00 HCI, 474.0840; found (ESI_FT), 403.13802.
Example 45: 1-[1-(1-naphthyl)-2-piperazin-1-y!ethyl]cyclopentanoI dihydrochloride

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[0235] In an analogous manner to Example 1, step 1 tert-butyl 4-[(1-
hvdroxvcvclopentvl)(1-naphthyl)acetvnpiperazine-1-carboxvlate was prepared from (1-hydroxycyclopentyl)(1-naphthyl)acetic acid (Reference Example 1-s) and tert-butyl 1-piperazinecarboxylate. MS (ESI) m/z 439 ([M+H]+); HRMS: calcd for C26H34N2O4, 438.2519; found (ESI), 439.2563.
[0236] In an analogous manner to Example 1, step 2 1-[1-(1-naphthyl)-2-piperazin-1-ylethyl]cyclopentanol dihydrochloride was prepared from tert-butyl 4-[(1-hydroxycyclopentyl)(1-naphthyl)acety!]piperazine-1-carboxylate. MS (ESI) m/z 325 G:M+H]+); HRMS: calcd for C21H28N2O • 2.00 HCI, 396.1735; found (ESI), 325.2267.
Eixample 46:1 -{2-piperazin-1 -yl-1 -[3-(trifluoromethoxy)phenyl]ethyl}cyclobutanol dihydrochloride

[0237] In an analogous manner to Example 1, step 1 tert-butyl 4-((1-
hydroxycyclobuty))|'3-(trifluoromethoxv)phenvl1acetvl}piperazine-1-carboxvlate was
prepared from (1-hydroxycyclobutyl)[3-(trifluoromethoxy)phenyl]acetic acid (Reference Example 1-k) and tert-butyl 1-piperazinecarboxylate. HRMS: calcd for C22H29F3N2O5, 458.2029; found (ESI), 459.2118.

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T)238] In an analogous manner to Example 1, step 2 1-{2-piperazin-1-yl-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclobutanol dihydrochloride was prepared from tert-butyl 4-{(1-hydroxycyclobutyl)[3-(trifluoromethoxy)phenyl]acetyl}piperazine-1-carboxylate. HRMS: calcd for C17H23F3N2O2 . 2.00 HCI, 416.1245; found (ESI), 345.1801.
Example 47: 1 -{2-[(4-fluorobenzyl)amino]-1 -[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol hydrochloride

[0239] In an analogous manner to Example 1, step 1 N-(4-fluorobenzyl)-2-(1 -hydroxvcvclohexvl)-2-[3-(trifluoromethyl)phenvnacetamide was prepared from (1-hydroxycyc!ohexyl)[3-(trif!uoromethyl)pheny!]acetic acid (Reference Example 1-m) and 4-fluorobenzylamine. MS (ESI) m/z410 ([M+H]+).
[0240] In an analogous manner to Example 1, step 2 1-{2-[(4-fluorobenzyl)amino]-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol hydrochloride was prepared from N-(4-f[uorobenzyl)-2-(1 -hydroxycyclohexyl)-2-[3-(trifluoromethyl)phenyl]acetamide. MS (ESI) m/z 396 ([M+H]+); HRMS: calcd for C22H25F4NO • HCI, 431.1639; found (ESI), 396.1931.
EExample 48: 1-[1-(3-bromophenyl)-2-(cyclohexylamino)ethyl]cyclohexanol hydrochloride


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[0241] In an analogous manner to Example 1, step 1 2-(3-bromophenvl)-N-cvclohexyl-2-(1-hvciroxvcvclohexvl)acetamicle was prepared from (3-bromophenyi)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-b) and cyclohexylamine. MS (ESI) m/z 394/396 ([M+H]+).
[0242] In an analogous manner to Example 1, step 2 1-[1-(3-bromophenyl)-2-(cyclohexylamino)ethyl]cyclohexanol hydrochloride was prepared from 2-(3-bromophenyl)-N-cyclohexyl-2-(1-hydroxycyclohexyI)acetamide. MS (ESI) m/z 380/382 ([M+H]+); HRMS: calcd for C20H30BrNO . HCI, 415.1278; found (ESI), 380.1574.
Example 49:1 -[2-[4-(methylamino)piperidin-1 -yl]-1 -(2-naphthyl)ethyl]cyclohexanol dihydrochloride

CLAIMS:
1. A compound of formula I:

or a pharmaceutically acceptable salt thereof; wherein:
A is naphthyl, thiophenyl, pyridiny!, furanyl, benzofuranyl, isobenzofuranyl, xanthenyl, pyrrolyl, indolizinyl, isoindolyl, indolyl, benzothiophenyl, wherein any 1 to 3 carbon atom(s) of said A can be optionally replaced with a nitrogen atom, and wherein said A is optionally substituted with one or more R1; W is H or OR9;
R1 is, independently, H, OH, alky!, alkoxy, halo, trifluoromethyl, alkanoyloxy, methylenedioxy, benzyloxy (optionally substituted with one or more R1), phenyloxy (optionally substituted with one or more R1), naphthyloxy (optionally substituted with one or more R1), nitro, trifiuoromethoxy, nitrile, alkenyl, atkynyl, sulfoxide, sulfonyl, sulfonamido, phenyl (optionally substituted with one or more R1), heteroaryl (optionally substituted with one or more R1), heteroaryloxy (optionally substituted with one or more R1), heteroary! methyloxy (optionally substituted with one or more R1), alkanoyl, alkoxycarbonyl, alkylaminocarbonyl, or amino; R5 is H, (C1-C6)alkyl, or trifluoromethyl; R6 and R7 are, independently, (C1-C6)alkyl or (C3-C6)cycloalkyl; or R6 and R7 can together form a ring of 4 to 8 carbon atoms;
AMENDED PAGE

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where any carbon atom of said R6 and R7 may be optionally replaced with N, S, or O;
where R6 and R7 may be optionally substituted with R5 or OH; or where R6 and R7 can form a ring with 4 to 8 carbons fused onto a cycloalky! ring of 4 to 6 carbon atoms;
R8 is H, (C1-C6)alkyl, benzyl (optionally substituted with benzyloxy or phenyloxy), naphthylmethyl (optionally substituted with one or more R1), phenyl(C2-C6)alkyI (optionally substituted with one or more R1), heteroarylmethyi (optionally substituted with R1), cycloalkyl, cycloalkenyl, cycloalkylmethyl (where any carbon atom can be optionally replaced with N, S, or O and where said cycloalkylmethyl can be optionally substituted with OH, CF3, halo, alkoxy, alky!, benzyloxy, or alkanoyloxy), cycloalkenylmethyl (where any carbon atom can be optionally replaced with N, S, or 0 and where said cycloalkylmethyl can be optionally substituted with OH, CF3, halo, alkoxy, alkyl, benzyloxy, or alkanoyloxy);
or R5 and R8, together with the nitrogen atom to which R8 is attached, form a ring optionally substituted with R5;
R9 is H, (C1-C4)alkyl, or (C1-C4)alkyl-C(=O); t is 1, 2, or 3; and x is O, 1, or 2.
2. A compound of formula I according to claim 1,
wherein A is naphthyl, benzothienyl, thienyl, quinolinyl or indolyl.
3. A compound of formula I according to claim 1 or claim 2,
wherein R1 is hydrogen, OH, halogen, C1-C6alkyl and C1-C6alkoxy.
4. A compound of formula I according to any one of claims 1 to 3,
wherein R6 and R7 form a 4,5,6,7 or 8 membered ring.
5. A compound of formula I according to claim 4,
wherein R6 and R7 form a cyclohexyl ring, one carbon of which is optionally nitrogen.
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6. A compound of formula 1 according to claim 4 or claim 5,
wherein the ring formed by R6 and R7 is substituted by H or C1-C6 alkyl.
7. A compound of formula 1 according to any one of claims 1 to 3,
wherein R6 and R7 are, independently, methyl or ethyl.
8. A compound of formula I according to any one of claims 1 to 7,
wherein W is OH.
9. A compound of formula 1 according to any one of claims 1 to 8,
wherein t is 1 or 2.
10. A compound of formula I according to any one of claims 1 to 9,
wherein x is 1.
11. A compound of formula I according to any one of claims 1 to 10,
wherein R8 is H, (C1-C6)alkyI (especially methyl, ethyl, propyl, and butyl), benzyl, naphthylmethyl, phenyl(C2-C6)aIkyl, heteroarylmethyl, cycloalkyl (especially cyclopropyl, cyclobutyl, and cyclohexyi), cycloalkenyl, cycloalkylmethyl, cycloalkenylmethyl.
12. A compound according to claim 1,
wherein:
A is naphthyl, thiophenyl, pyridinyl, furanyl, benzofuranyl, isobenzofuranyl, xanthenyl, pyrrolyl, indolizinyl, isoindolyl, indolyl, benzothiophenyl, wherein any 1 to 3 carbon atom(s) of said A can be optionally replaced with a nitrogen atom, and wherein said A is optionally substituted with one or more R1;
W is H or OR9;
Rn is, independently, H, OH, alkyl, alkoxy, halo, trifluoromethyl, alkanoyloxy, methylenedioxy, benzyloxy (optionally substituted with one or more R1), phenyloxy (optionally substituted with one or more R1), naphthyloxy
AMENDED PAGE

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(optionally substituted with one or more R1), nitro, trifluoromethoxy, nitrite, alkenyl, alkynyl, sulfoxide, sulfonyl, sulfonamido, phenyl (optionally substituted with one or more R1), heteroaryl (optionally substituted with one or more R1), heteroaryloxy (optionally substituted with one or more R1), heteroaryl methyloxy (optionally substituted with one or more R1), alkanoyl, alkoxycarbonyl, alkylaminocarbonyl, or amino; R5 is H, (C1-C6)alkyl, or trifluoromethyl; R6 and R7 together form a ring of 4 to 8 carbon atoms; R8 is H, (C1-C6)alkyl, benzyl (optionally substituted with benzyloxy or phenyloxy), naphthylmethyl (optionally substituted with one or more R1), pheny!(C2-C6)alkyI (optionally substituted with one or more R1), heteroarylmethyl (optionally substituted with R1), cycloalkyl, cycloalkenyl, cycloalkylmethyl (where any carbon atom can be optionally replaced with N, S, or O and where said cycloalkylmethyl can be optionally substituted with OH, CF3, halo, alkoxy, alkyl, benzyloxy, or alkanoyloxy), cycloalkenylmethyl (where any carbon atom can be optionally replaced with N, S, or O and where said cycioalkylmethyl can be optionally substituted with OH, CF3, halo, alkoxy, alkyl, benzyloxy, or alkanoyloxy);
or R5 and R8, together with the nitrogen atom to which R8 is attached, form a ring optionally substituted with R5; R9 is H;
t is 1, or 2; and x is 1, or 2.
13. A compound according to claim 1, wherein said compound is one of the following:
1 -[1 -(2-naphthyl)-2-piperazin-1 -ylethyi]cyclobutanol;
1-[1-(1-naphthyl)-2-piperazin-1-yIethyl]cyclohexanol;
1 -[1 -(1 -naphthyl)-2-piperazin-1 -ylethyl]cyclopentanol;
3-ethyl-2-(1-naphthyl)-1-piperazin-1-ylpentan-3-ol;
1 -[2-(4-methylpiperazin-1 -yl)-1 -(1 -naphthyl)ethyl]cyclopentanol;
1 -methyl-4-[1 -(2-naphthyl)-2-piperazin-1 -ylethyl]piperidin-4-ol;
1 -[1 -(2-naphthyl)-2-piperazin-1 -ylethyl]cyclohexanol;
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1 -[2-(4-methy!piperazin-1 -yl)-1 -(2-naphthyl)ethyl]cyclohexanol; 1 -[1 -(1 -naphthyl)-2-piperazin-1 -ylethyl]cyclobutanol; 1 -[2-(4-methylpiperazin-1 -yl)-1 -(1 -naphthyl)ethyl]cyclobutanol; 4-tert-butyl-1-[1-(1-naphthyl)-2-piperazin-1-ylethyl]cyclohexano!; 3-ethyl-1-(4-methylpiperazin-1-yl)-2-(1-naphthyl)pentan-3-ol; 4-ethyl-1 -[1 -(1 -naphthyl)-2-piperazin-1 -ylethyl]cyclohexanol; 4-methyl-1 -[1 -(1 -naphthyi)-2-piperazin-1 -ylethyl]cyclohexanol; 4-tert-butyl-1 -[2-(4-methylpiperazin-1 -yl)-1 -(1 -naphthyl)ethyl]cyclohexanol;
1 -[1 -(2,5-dichlorothien-3-yl)-2-piperazine-1 -ylethyl]cyclohexanol; 1 -[1 -(5-chlorothien-2-yl)-2-piperazin-1 -ylethyl]cyclohexanol; 1 -[1 -(5-bromothien-2-yl)-2-piperazin-1 -ylethyljcyclohexanol; 1 -[1 -(5-chlorothien-3-yl)-2-piperazin-1 -y!ethyl]cyclohexanol; 1 -[2-(4-aminopiperidin-1 -y!)-1 -(5-chlorothien-3-yl)ethyl]cyclohexanol; 1 -[1 -(1 -benzothien-3-yl)-2-piperazin-1 -ylethyl]cyclohexano!; 1 -[1 -(1 -methyl-1 H-indoI-3-yl)-2-piperazin-1 -ylethyl]cyclohexanol; 1 -[1 -(1 H-indol-3-yl)-2-piperazin-1-ylethyl]cyclohexanol dihydrochloride; 1 -[1 -(2-chIorothien-3-yl)-2-piperazin-1 -ylethyl]cyclohexano!; 1 -[1 -(5-ch[orothien-3-yl)-2-(4-methyIpiperazin-1 -yl)ethyl]cyclohexanol; [(1 R)-1 -(5-chlorothien-3-y!)-2-(4-methylpiperazin-1 -yl)ethyl]cyclohexanol;
1 -[(1 S)-1 -(5-chlorothien-3-yI)-2-(4-methyipiperazin-1 -yl)ethyl]cyclohexanol;
1 -[1 -(5-chloro-1 -benzothien-3-yl)-2-piperazin-1 -ylethyl]cyclohexanol;
1 -[1 -(1 -benzothien-2-yl)-2-piperazin-1 -ylethyl]cyclohexanol;
1 -(2-piperazin-1-yl-1 -quinolin-3-ylethyl)cyclohexanoI;
1 -[1-(1 -naphthyl)-2-piperazin-1 -ylethyl]cyclooctanol;
1 -[2-(4-methylpiperazin-1 -yl)-1 -(1 -naphthyl)ethyl]cyclooctanol;
1 -[1 -(1 -naphthyl)-2-piperazin-1 -ylethyljcycloheptanol;
1 -[2-(4-methylpiperazin-1 -yl)-1 -(1 -naphthyl)ethyl]cycloheptanol;
1 -[1 -(5-methoxy-1 -benzothien-3-yl)-2-piperazin-1 -ylethyllcyclohexanol;
1 -[1 -(4-bromothien-2-yl)-2-piperazin-1 -ylethyl]cyclohexanol;
4-ethyl-1 -[2-(4-methylpiperazin-1 -yl)-1 -(1 -naphthyl)ethyl]cyclohGxanol;
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4-methyl-1 -[2-(4-methylpiperazin-1 -yl)-1 -(1 -naphthyi)ethyl]cyclohexanol;
1 -(2-piperazin-1 -yl-1 -pyridin-3-ylethyl)cyclohexanol;
1 -(2-piperazin-1 -yl-1 -pyridin-3-y!ethyl)cyc!ohexanoI;
1 -[1 -(6-methoxy-2-naphthyl)-2-piperazin-1 -yiethyl]cyclohexanoi;
1 -[1 -(6-methoxy-2-naphthyl)-2-(4-methylpiperazin-1 -yl)ethyl] cyclohexano!;
or a pharmaceutically acceptable salt thereof, including the dihydrochloride.
14. A composition, comprising:
a. at least one compound according to any one of claims 1 to 13; and
b. at least one pharmaceutically acceptable carrier.
15, A process for preparing a compound of formula I as claimed in claim 1 which comprises one of the following: a) reducing a compound of formula

wherein R5'8, x, t, A and W are as defined in claim 1, to give a compound of formula I; if necessary any reactive groups or sites being protected during the reaction by protecting group(s) and removed thereafter;
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or
b) alkylating a compound of formula 1 herein R8 is hydrogen with an
alkylating agent to give a compound of formula I wherein R8 is as
defined in claim 1 excepting hydrogen ;
or
c) converting a compound of formula I having a reactive substituent group
to a compound of formula I having a different substituent group;
or
d) converting a basic compound of formula I to a pharmaceutically
acceptable salt or vice versa.
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