CROSS RfFCRirNCF. TO RELATED APPLICATIONS [0001] 7h s application claims priority "o U.S. Application No. filed L',n?::h 28, 2C05. which cimn-s the benefit of 60/55/.831 filed March 30. 2CCA and U.S. Application No. 60/5*39.861 filtfd May 11, 20C4, tho ontiro disclosures of which ,ve herein nccporated by reference. f-IEEt t)Or- THF INVENTION [0002] The prosent r.vontion rolatns to phopyiim.fioprcpanol dt>rivatives, compor.itiof.s containing those derivatives, and methods of their uso fur the prevention .ind tre;i'mont of conditions ameliorated by monoamino rcuptako including, inter alia, vascmctcr symptoms (VMS), sexunl dysfunction, yastrcir.teslinal and t;en.:to,,r.r,ary disordes. chronic f.it.gue syndrorre. fibromyfagia syndrome, nervous system disorders. ;;nd combinations thereof, particularly those conditions selected from the group consisting of major depressive disorder, vosomolor symptoms, st.'ess and urge urinary ;ncor*, nenco. fibro-ny.ilQi.-j. pain. di;»be?ic now'opa^y, and CO'" rmations theroof. HACKGF^CJND OF THP. INVFNTION [0003] V.isor^otor symptoms (VN'S). r<;'errec to as hot dishes and nkjht sweats, ore the most common symptoms associated with menopause, occurring in 60% Jo 80% of all women following natLral cr surg.caliy-iriduced menopause. VMS are I kely to be an adaptive; response of the central nervous system (C\S) to defining sex steroids. To date, the most effective therapies '.or VMS are hormone-based treatments, including flstroqers and/or some progestins. Hormonal treatments arc very offeotr/e at alleviating VMS. bu! they arc not appropriate for aii women. It 'S '.veil reccgnzf d that VMS are causeo by fljc'i.'atioris o' sex steroid levels and can bn disruptive and disabling in bot'i males and females. A hot flush can last up to thirty minutes ard vary in ther frequency from several times a week to multiple wo 2005/06956 PCT/US2005/00404 2 cccjrrences per day The patient experie.noes a hct flash as a suddon feolmg of heat that spreads quickly frcn tho face to tho cliest and back and then over the rest o'. the body. I! is usually accompanied by outbreaks of profuse sweating It may sometimes occur several times an hcur, 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, irritab-lity. hsomnia. dopresson. memory loss, headache, anxiety, norvousness or inability to concentrate are considered to !:e caused by tho sleep deprivation following hoi Hush and right sweats (Kramer ct at.. In: Murphy et ,il, $* Int'l Symposium on Recent Advances in Urological Cancer Diagnosis and Treatment-Proceedings. Paris, Franco: SCI: 3-7 (1992)) [0004J Hot flushes may bo even more severe in women treated fcr b'east cancer fcr several reasons: 1) many survivors of breast cancer a.*o given tamoxifon, the most preva!ent Sido effect o' which is hct flush, 2) many women treated for breast cancer uncargo premature menopause from chemotherapy, 3) women with a history cf breast cancer have generally been denied estrogen therapy because of concerns about potential recurrence of breast cancer (Loprinzi, et at. Lancet, 2000, 356(9247): 2059-2063). [0005] Mon nlso experience hot f!jslics follov/ing steroid hormone (nncjrryon) withdrawal. Th.s is truo in cases cf ncjo-associatod nndrcgen deel no (Katovich, et at.. Proceedings of tho Society for Experimental Biology & Medicine. 1990. 193(2): 129-35) as well as in oxl'dne cases of hormone deprivation associated wth treatments fcr prostate cancer (Berendson, et ni, European Journal of Pharmacology. 2001. 419(1) -17-54. As many as one-third of these patents v.iil experience persisiont and frequent symptorrs sovero enough to cause siqrificant tJiscomfort and inconvenience. [0006J The precise mechanism of these symptoms is urs known but generally is thought to represent disturbances to norriii! homeostat:c mechanisms ccntrc'mg the'morog:.laticn and vasomotor activity (Kronenbery et oreg!.;latory Prysiology of Menopaysa! Hot flashes: A Review." Q>n. J. Physio!. Pharmacol., i 1987,651312-1324) [0007] Tho fact that estnxjen treatment (e.g. estrogen -epiaco'nent tlwnapy) relieves the symptoms establishes tho link between these symptoms and an estrogen deficiency. For example, the nenopausal stage of lifo is associated with a v/ide range of other acute symptoms as described above and these symptoms are generally estrogen responsive, [0008] It has been suggested that es!rogens may stimulate tho activity of bcth tho norepinephr.no (NE) ani'or serotonin (5-HT) systems (J. Pharmacology & Experimental Therapeutics. 1986. ?36{3) 646-652) It is hypothes-ze;! that estrogens modulate NC and 5-HT levels providing homeostasis in the therrnoregulatory center of tho hypothalamus. The descending pathways from the hypothalamus via bra nstern/spinal cord and the adrenals to the skin are involved in maintaining normal skin temperature. The action cf N'E and 5-HT reuplako inh-bitors is known to imp.'ngo on both tho CNS and peripheral nervous systom (PNSi. The pathophysblogy of VMS is mediated by both cenlral and peripheral mechanisms and, therefore, the inte'plny between the CNS and PNS may account for the officacy of dual acting SRI/NR!s in the treatment of themoregulatory dysfunction. In fact, the physiological aspects and tho CNS'PNS involvement in VMS may account for the lower doses proposed tc troa* VMS (Loprinzi. el nl., Lincot, 2000. 356:2059-2063; Stearns et nl. JAMA, 2003. 389:2827-2834) comparod to doses used to treat the behavioral aspects of depression. The inierplay of iho CNS/PNS in the pathophysioiogy of VMS and tho presented data within this document were used !o support the dairrs t."iat the norepinepnrine system could be targeted to treat VMS. [0009] Al'hourjh VMS are most commonly treated by hormone therapy (crally, transdermally. or via an irrp.'ant), sorro patents cannot tolerate estrogen treatment (Berer.dser, Maturitas, 2000. 36(3): 155-164, Fink ct nn!'esr» WO ?nnMW-fci P( I,is:nn5 .unMft x irKonthence or urge urinary incontinence, in a suhjixM in need thoroot, comprising the stop of: administering to said subject an effective nmouni of a! least one compound of formula I or pharwaccutically acceoiablo salt tr-ereof. [0021] In another embodinen', the present invention is d rected to rrolhods for treating or preventing chronic fatigue syndrome in a subject in need thereof, comprising !ho step of: administering lo said subject an effective amount of at least one compound of formula I or pharmnceutically acceptable salt thereof. [0022] In another embodiment, tho present invention is directed to methods for treating or preventing fibromylayia syndrone in a subject in need thereof, comprising Ihe stop of: administering tc said subject an effective amount of at loast cno compound of formula I or pnarmaceut caly acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS [0023] Tho invention ten t>e more fully understood from ihe following cJota«lnri description and the accompafiyirig drawings that form a part of this application [0024] Figure 1 is an overview cf estrogen action on norepinophrinesorotonin mediated tr*r?rmoroc)ulation. [0025] Figure 2 is a schematic representation of the interactions of norepinephrine and serotcn-n and their respective receptors (5-HT?!1. cti and a;-ndronorcjic). DETAILED DESCRIPTION OF THH INVENTION [0026] "he present invention is directed lo phenylamincpropanol derivatives. cr>mpcsilionr. containing these derivatives, and methods of their use lor the? WO inns.i9"i.i P('Tts:m5'OioMn provont;on and treatment of conditions ameliorated by monoamine reupiako including, inter alia, vanor~otor symptoms (VMS), sexual dysfunction, gastrointestinal anti genitourinary disorders, chronic fatigue syndrome, libromyljigia syndrome, nervous system disorders, and combinations thoroof. particularly thoso conditions selected from tho group consisting of major depressive cJiso'ricr, vasomctor symptoms, stress and urge urinary incontinence, fibromyalgia. pan, diabetic neuropathy, and combinations thereof [0027] Tho following definitions aro provided for tM© full understanding cf 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 ono or more compounds and equivalents thereof known to those skilled in the art, and so forth. [0029] "The abbreviations in ihe specification correspond to units of measure, techniques, properties, or compounds as follo-.vs: "min' means minutes, "h* means hcur(s), "ViL" means microl:tor(s). "mL" means nrillili!er(s). "mM" means mi'lin-iolar, *M" means molar, "mmoirf rr.eans m=ili'no!e(s). "cm" means centirreters. 'SFM" neans standard error of tho mean and "IU" means International Un'ts. A°C^ and A "ED..- value" moans dose which results in 50% alleviation cf the observed condition or effect (50% mean maximum endpoint). [0030] "Norepinophrine transporter' is abbreviated NET. '"Hunan rorepinephrino transporter' Is abbreviated hNET "Serotonin transporter" is abbreviated SERT. "Human serotonin transporter" is abbreviated hSERT. "Norepirmphrre reuptake inhibitor" is abbreviated NRI. "SokJctivo noropinephrino rejptake :nh;bitor" is abbreviated SNRI. "Serotonin reuptake inhibitor" is abbreviated SRI. "Selective scotonin reuptake inhibitor is abbreviated SSRI. \VO!«ir*n9"M PCMSI^H^I,, in "Norcpinophrino" is abbreviated NF. "Serctonin is abbreviated 5-HT. "Subcutaneous" is abbreviated sc. "Intraoonionoar is abbreviated ip. "Orar is abbreviated po. [0031] In tho context ol this disclosure, a number of terms shall be utilized. The term "troalrrent" as used herein includes preventatrve [eg . prophylactic), curatrve or palliative treatment and 'treating' as used herein also includes preventative, curative and palliative treatment. [0032] Tho term "effective anoint.* as used herein, refers to an anount effective, at dosages, and for periods of time nocossary, to achieve the desired result with respect to prevention or treatment of vascmctor symptoms, depression disorders, sexual dys'unction, or pain. In particular, with respect to vasomotor symptoms, "effective amount" refers to the amojnt of compound or composition of corrpourds that would increase norepinephrine fovels to compensate in part or total for the lack of stero;d availabiity in subjects subject atticted with a vasomcior symotom. Varying hcrrrcne levels will influence the amour* of compound required in the present inveniion. For example, the pro-mcropausal s'ato may require a lowor level of compound due to higher hormone levels than the pen-menopausai slate [0033] it will be appreciated that tho effective amount of components of the present invent.on will vary from patiert to patient not only with the particular compound, component or composition selected, tho route of administration, and the ahHily of tne components (alone cr in combination with one or mo.-e combination drugs) to e'icit a desired response in the individual, but also with factors such as the disease state or sevority of tho condition to be alleviated, hormono levels, age. sex. weight of the individual, the state of bomy cf the patient, and tho soverity of the pathological condition being treated, concurrent medication or special diets then being follcweti by tho particular pat'ont, and other facto's which those skilled in tho art will recognise, with tho appropriate dosaye ultimately being at the ciiscrei'on of the attendant physician. Dosage regimens may be adjusted to provide tho improved wo i«nviT*Ai |.(-F,( s;iMMnr»5in M therapeutic rosponsc An eMcctivo amount is also ono in which any tcxic or detrimental effects of the components arc outweighed by the iherapeuticaily beneficial effects. [0034] Preferably, the compounds of the present nvontion are administered at a dosage and for a time such that the number of hot (lushes is reduced as compared to the number of hot flushes prior to tho start of treatment Such treatment can also be beneficial to reduce the overall seventy or intensity distribution of any hot f'ushes still experienced, as compared to the seventy of hot flushes prior to the start of the iroatmont. With respect to repression disorders, sexual dysfunction, and pam, tre compounds of the present invention are administered at a dosage and for a time such that there is tho prevention, alleviation, or elimination of the symptom cr condition. [0035] For example. for an afflicted nationt, compounds of formula I. or a pharmacoi.'tically acceptable salt thereof, may be administered, proferab'y. at a dosage of from about 0.1 mg/day to about 500 mg/day. dosed cne or two times daily, more pre'erably from about 1 mg-'riay Jo about 200 mg'day and most preferably frorr aix)u! 1 mg'day to 1C0 rrg.'day for a time sufficient io reduce and/cr substantial e:irrhate the number ard'or severity cf hot flushes or symptom or condition cf tne depressior disorder, sexual dysfunction, or pnin. [0036] The te'ms "component." "composition of compounds," compound," drjg,* or "pharmacologically achve agent or "active agent" or 'medicament" arc used interchangeably herein to '©for to a conpou'id or compounds or composition of matter which, when administered to a subject (human or anirr.a1) induces a desired pharmacological and/or physiologic offec! by local and/or systemic action. [0037] The terms "corr.poner.r, "drug" or "pharmacologically active agent* or "active agent" or "medicament" are used interchangeably herein to refer to a compound cr compounds or composition of matter which, when administered to an oryaf.ir.rii (human cr animal) induces a desired prarmncologic anrt'or physiology effect by local and'er systemic action. WO :nrtMV>"M P<-T-|-s;on5.iHosin i: [0038] The term ""noduintion* reiors to the capacity to either enhance or inhibit a functional property cf 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 transduclion pathway and/or may bo man fest only in particular cell types. The modulator is intended to comprise a'iy compound, eg, antibody, small molecule, peptide, oligopeptido, polypoptide. or protein, preferably small rrolocule, or pepikJo. [0039] As used herein, the to^n "inhibitor refers to any agort that inhibits, suppresses, represses, or decreases a specific activity, such as serotonin rouptake activity or the norepinephrine reuptake activity. [0040] Trie term "inhibitor" ;s intended to comprise any compound, eg., antibody, small molecule, peptide. oligcpeptido, polypeptido, or protein, preferably s:rall molecule or peptide. thai exhibits a partial, complete, competitive and'or inhibitory otfoct on marnrral:an, preferably the human norepinophrme reuptake or both serotonin reup*ake and the norepinephrine reup:ake, ihus diminishing or blocking, preferably diminishing, some or all cf the biological effects of endogenous noreoincphrine reuptake cr of both seroion:i reuptake and the noropinephrine rouptako [0041] Within the present invention, tho compounds of forrrvjla I may bo orepared in the form cf pharmaceutcally acceptable salts. As used herein, the term "phirmacouticalty acceptable salts' refers to salts prepared from pharmaceijtically acceptable non-toxic acids, including inorganic salts, and organic salts. Su:lablo non-organic salts include inorganic and organic acids such as acetic, benzenosi/fonic, ben/oic. camphorsulfonic. cit'ic. ethenesulforvc. fumaric. gluconic, gluiamic, hydrobrotnic, hyd'ochloric, isothion-c, lactic, malic, maloic, mnrdelic. methar.esLlfonic, rr.'.;cic. nitrk:, pa-noic. panio:ienic. phosphoric, succinic, sulfuric. tartaric actd. p-tc!uenesu!fonic and tho like. Particularfy preferred are hydrochloric, hydrobromc, phosphoric. ann sulfuric ac:ds. and most preferably is the hydrochlorkie tiit WO ?nnMi?Vfti rci.'l.'s?nn used herein, moans either directly administering a compound or composition of the present invention, or administering a prodrug, (Jo'ivative or analog which v.\ill form an equivalent amount of the active compound or substance within the body. [0043] The term rsubject" or 'patient" refers to an animal including the human specios thai 'S treatable with the compos lions, and'or methods of the present invenvon. The term "subject" or 'subjects' is intended to refer to both the rraie and female gender unless one gender is specifically indicated. Accordingly, the term "patent" comprises any mammal which may benefit from treatment or prevonton of vaso-notor symptoms, depression disorders, sexual dysfunction, or pain, such as a human, especially if Iho rrammal is female, either in the pre-menocausaJ, pc't-menopausal. or post-menopausal period. Furthermore, the term patient includes female arvmals inc udirg humans and. among humans, not only women of advanced age who have passed through rnencpause but also women who have undergone hysterectomy or for some other reason have suppressed estrcgen production, such as those who have undergone long-term administration of cort'icosteroids. suffer from Cushing's syndrome c have gonadal dysgenesis. However, the term "patent' is not interded to bo limited to a woman. [0044] The terms "pre.-natu'O rnonopause" or "artificial monopauso" refer to ovarian failure of unknown ca-jso mat may occur before aye 40. It may be associated with smoking, living at high altitude, or poor nutritional status. Artificial menopause may r«sul! from oophoryctomy, chemotherapy, radiation of the polvis. or any process lhat impairs ovarian b ood s-jpply. [0045] The term 'pro-monupausai" means before ihe menopause, the term "peri-menopausai* means during the menopause and the term "post-menopausar means a'ter the menopause. "Ovanoctony" means removal of an ovary or ovaries ard can be effected accord ng to t/erchen:ha"er at nt., Mnturitas. 1998. 30(3): 307-316. WO ;rM)Mi^-M lTM'S2nriv.iiii*|ii li [0046] "Side effect" refers to a consequence other than the one(s) for wh.ch an agent or rreasuro is used, as the adverse* effects produced by a drug, especially on a tissue or organ system ether then the on© sought io he benefited by its administrates. In the case, for oxample. of hkjh doses of NRIs or NRI/SRI compounds alone, the term "sidu effect" rray refer to such conditions as, for example, vomiting, nausea, sweating, and flushes (Janowsky, ot al, Journal of Clinical Psychiatry, 1984, 4S(1O Pt ?.): 3-0). 10047] HA!kyl." as used herein, rofers to an optionally substituted, saturated straight, branched, or cyclic hydrocarbon having from about 1 to about 20 carben atoms (and all combinations and subconvjinatiens of ranges and speal.c numbers of carton atoms therein), with from about 1 to about 8 carbon atoms being preforrod, and with from about 1 to about 4 carbcr atoms, herein referred to as "lower alkyP, being more preferred. Alkyl groups include, but are not limited to, rne'.hyl, ethyl, n-propyl, isocropyl, n-buty1. ir.obutyl, t-butyl n-ponty!, cyclopontyl, iscpentyl. necpontyl. n-hexyl. isohoxyl, cyclohexyi, cyclooclyl. ndanantyl. 3-methylpenryl, 2,2-dimethylt)i.iy:. and 2.3-dimethy'butyl. [0048] "Hetoroa'kyl." as used herein, refers to a subsMuen! of the general fcrrruia (a:kyl-X)1-a'kyl-, v/.nero each 'alkyr is independently as def.necl above. "X" is or of S and O atoms in 'ho hotorocycle oxcoeds one, !hon those heterontoms aro not adjacent to one anoner. It is preferred that the total rujrnhor of S and O atoms in the hete-ocycle is not noro than ore. Examples of heterccycles include, hut are not limited to, 1H-:ndn/olo. 2-pyrrolidonyl. 2H,6H-1.5.2-dithia/inyl, 2H-pyrrolyl, 3H irxJolyl, 4-piperidonyt, 4aH-carba/ole, 4H-quinoJi/inyi. 6H-1,2.5-th:adia?inyl, acndinyl. azecinyl, benzimidazcryl, bonzof-jranyl. bon7Othioft.'ranyl. ben7othiop"ionyl, bo-i7oxazoiyl, bonzthiazolyl, ben/triazolyl. bon/tetrazclyl, benzisoxazolyl, bfinzisothinzotyl, ben^irr.idazalonyl. carta^olyl. 4H-carbazoryl, a-, {\-. or yca'bolinyl. chromanyl, chrcmcnyl. cinrKJiinyl. docahydroouinolinyl. 2H.6H-1,5.2-dithiazinyl, dihydrofuro(2.3-/?Jtetrahydrc'ura.n. furanyl, furazanyl. irnidazolidinyl. i-nlda/olinyl, imidazolyl. 1H-inda/olyl, indole.nyl, indolinyl, ind^l^inyl, indolyl, isobonroturnnyl. isochro-nanyl. isoinda^otyl. isoindoinyl, isoinJinyl. pyrazohny1. pyrazolyl, pyridaz'nyl. pyndooxnzc'o, pyridoim;c!n7olo, pyridotha/olo, pyidinyl, pyidyl. pyrimidry!. pyriolidinyi. pyrrolinyl. pyrrclyl. quinazol:nyl, quinohnyl, 4 H-q jinoli/inyl, qu:nuxal:nyl. ciuinjc'idinyl. carbolinyl. totrahydrofi:ranyl. totruhydroisoQumolinyl, touahydroqu nolinyl. 6//-1,2.5thiadia7nyi. 1,2.3-thiadia/olyl, 1.2,4-thiad'a7oryl. 1.2,5-thiadia/olyi 1.3.4'thladia/olyl. Ihianlhrenyl, thi«-i/olyt, thionyl, tf'.ier!Othia7olyl, thior.ooxa^o'yi. thio'ioimidnzoiyl, Ihiophonyl. triazinyi. 1,2,3-tria/olyl, 1.2.4-tria7clyl, 1,2.5-triazolyf, 1,3/.-triazoly!, xanlhenyl. Preferred hotorocycles include, t:jt aro not lirrited to, pyndinyl, fjranyl, thionyl, pyrrclyl, pya^olyl, imidazolyl, irdoly!, bon7:T*iiJ(T7clyl. 1/7-indtU0ly!, oxa/ol'dinyl, t;enzt>tr.a/olyl. benzisoxnzolyl, oxindolyl. bonzoxazolinyl, or isatiiyl. Also inc'-jderi are fused ring .'ind spiro cempounds contain1 ig, for exp.mplo. i\-o above heteroc^-cles. (0055] "Akoxy," as used horyin. rofcrs to tho group R-O- where R is an n!ky! croup ns def-.ned heroin. WO 2nn*ivrv.i PCI.TSlmivninMn [0056] 'Aryloxy.* as uscc: heroin, rofers to the group R-O- where- R is an aryl tjroup, as defined herein [00571 'Heteroaryioxy," as used heroin, refers lo the group R-O- where R is a hcteroaryl group, as defined herein [0058] "Alkanoyloxy," as used here-n, refers to the group R-C(-O)O- whom R is an alkyl group o( 1 to 5 carbon atoms. [0059] "Alkylsijifoxide." as used herein, refers to as used heroin, refers to -S( O)-R, where R is alkyl, as defined a*x»ve [0060] "Alkylsulfcne.' as used herein, refers lo -S(-O)?-R, where R is afcyl. as defined above. [0061] "Alkylsultonmnido." as used horo-n. refers to -NR-S(-O)rR. where each R is indoponcontly. alkyl, as defined nt>ovo or ihe NR part may also bo NH. [0062] 'Phenytsuifonamicje.1* as used hcreip, refers lo -NR-S(-O),->-pheny!, whore R ir, H or n kyl, as dcf:ned al«>ve. [0063] *Heteroary!nr:e!hyioxy," as jsed herein, refers to -OCH;-R. whew R is hetcroaryl, as defined above. [0064] 'Alkylamido.' as used heroin, rofors to -NR-C(-O)-R. where eacT R is independently, aikyi, as dofineMi|.iMn m I or a pharmaceuticalty acceptable salt thereof; wherein: the dotted line represents an optional double bond between U and V or V and W; U is. independently. O. S. SO. SO?. C-O, N. NR^, cr C(RB)?; WisCH. CH2. orC-O; provided that whon W is; CH? U is not C(Rfi;;>; VisC(Rft). C(R»)?.O. orN(Rfi;; R. is, independently at eac'i occurrence, nlkyl. nlkoxy. hao, CF3, OCF3, ary'alkyioxy substituted with 0-3 R'loxy substituted with 0-3 R<>. heteroarylmethyloxy r,uhstitute(J with C-3 R3. alkylamido, or phonyl.imicfo subsMuted with 0-3 R9; or tv;o adjacent H! also represent mo(hyk>nedioxy: R? is aryl subslitjtec v;i:h 0-3 Ri or he'eroaryl substituted with 0-3 Ri; R3 is H, CvC4 alkyl substituted vnth 0-3 R., CrCi cycloalkyi. or phenyl substituted with 0-3 Ri; R* is. independently at each occurrence, H, C,-C< aikyl, arylaikyl. hetercarylmethyl, cyclohepiyme'ihyl. f>/cloh«xylme',hyl. cyLlopontylr*:ethyl, or cyclobutylrr.e'hyl, or bo'h R.i groups. :e<;e!her with the n-:'ogen i^.rough which they are atinchec. form a he!erocyc!:C ring of 4 lo 6 ring atoms, where one carbon may he optional!'/ ttC>:rms««i"M PC-rrs:nn5-nin5in replaced with N. 0. S, or SO;>. and whoro any carbon ring ntctn or additional N atom may he optionally substituted wr.h C1-C4 alkyl. F, cr CF3; R* isHor C1-C4 alkyl; Re is H or Ci-C4 aikyl; R7 is. independently at each occurrence. H. or C1-C4 aikyl. or R/ and R« together with the nitrogen lo which R* is attached form a nitrogen-containing frig containing 3-6 carbon atoms; R« is. independently nt each occurrence. H, C1-C4 alkyl, C.vCe heteroaikyl, or aryl substituted with 0-3 R-; n» is. independently at each occurrence, alkyl, alkoxy. halo, CF3, CCF(, hydroxy. akanoyioxy. nitro. nitrile, alkenyl, alkynyl, alkylsulfoxido, alkylsulfone, alkylsuMonamidc. or nlkylarnido; or two adjacent R* also represent methylenedioxy; n is an intoyor from 0 to 4; x is an integer Irom 1 to 2; and wherein 1-3 carbon atoms in ring A may optionally be replacod with N. The dotted line in the ring fused to ring A represents either an optional double bond between U and V or betweon V and W. The dotted line between the two Rx g*oups represents an optional hetorocyclic ring of 4 to 6 ring atoms that may be formed between the two R< groups, together with tho nitrogen through which they are attached [0068] h certain preferred embodimer's o' compounds of formula I. U is O In certain other preferred embodiments. LJ is S. In certain other preferred embodirr.or.ts, U is SO. In certain other preferred embodiments. U is SO?. In certain other preferred embodiments, U is C -O. In certain other preferred embodiments, U is NH. In certain other preferred embodiments. U is NR3 'n certain ether preferred embodiments, U is CH?. [0069] In certain preferred embodiments of compounds of formula I. W is CH. In certain other preferred embodiments, W ir» CH2 In certain other preferred embodimefits, W ir» C=O. \w> jniiMra-M !•< it s:nn< nmnin .'0 [0070] In certain preferred embodiments cl corrpounds of formula I, V is C(R8). especially CH. In certain other preferred embodiments, V is C(Re)?. especially CH2. In certain ether preferred embodiments. V is O. In certan other prefer-ed embodiments. V is N(nft). especially NH. [0071] In certain preferred embodiments of compounds of formula I, R, is, independently a! each occurrence, alky], preferably (VC4 alkyl, more preferably methyl, h certain other preferred embodiments, Rs is, independently at each occurrence, alkoxy. !n certain olher preferred embodiments of comfx>unds. R-. is. independently at each occurrence, halo, preferably F or Cl. (n certain other preferred embodiments. R; is. independently at each occurrence. CFV In certain other preferred embodiments, R. is, independently at each occurrence. OCF3. In certain other preferred embodiments, Ri is, independently at each occurrence, ben/yloxy substituted with 0-3 Ri. In certain other preferred embodiments, R. is, independently at each occurrence, nryloxy substituted with 0-3 Ri. In certain other preferred embodiments. R-. is. independently at each occurrence, aryl substituted with 0-3 R-. In certain other preferred embodiments, R: is, independently at each occurrence, hote'oaryl substituted with 0-3 Ri. In certain other preferred embodiments, Ri is, ;ndeponderttty at each occurrence, hydroxy. In certain other preferred embodiments. R. in. indepe'idontly at oach occurrence, aikarx>yloxy. Ir^ certain ott'pr preferred embodiments. R- :s, independently at each occurrence, molhylenodioxy. In ceiaii cthor preferred enbodiments. Ri is. independently nt each occurrence, nitro. Ir ceriain other preferred embodiments. Ri is, independently at each occurrence, nitrlo In certain other p'oferred embcdiments, R- is, independently at each occurrence, alkonyl. In certain other preferred embodiments. R. is. independently at oach occurrence, alkyyt In certain other preferred embodiments. R, is, independently at oach occurrence, nlkylsulfoxide. In cortan other pre'errod embodiments, Ri is. independently at each occurrence phenylsulfoxide substituted with 0-3 Ri. In certain other preferred embodiments. Ri is. independently at oach occurrerx:o, alkyisuifone. In certain o!r-er prefe'red embodiment, R. is, indeppndortly ?.; onch occurrerice. phonyisulfono substituted v/i»^. 0-3 Ri. I ri certain othe- preferred Gmhodimonls, R: is. independently at ench cccur'once. a'kylsulfonarride. In certain other preferred embodiments. ^ is. WO ?nii<7ii"fi| I'Ci 't's;nnvinnMii :i independently at onch occurrence, pheny-suffonamitie substitute:! wilfi 0-3 R-. In certain other preferred embodiments. R, is, independently ai each occurrence. heteroaryloxy substituted wilh 0-3 R,. In certain other preferred embodiments. R, is. independently at each occurrence, heteroarylmethytexy substituted with 0-3 R.. In certain other preferred embodiments, R. is. ndepondontiy at each occurrence, aikylamido. In certain other preferred embodiments. R, is. independently at each occurrence, phenylnmido substituted with 0-3 R|. [0072] In certain preferred embodiments of compounds of formula I, R2 is aryl substituted wth 0-3 Hi. proferably substituted with no Ri. In certain pre'erred embodimcrts, Hs is naphthyl substituted with 0-3 R-, preferably substituted with no Ri. In ceria.n preferred embodiments, R? rs hotoroaryl r>ub5i;tu'.ed with 0-3 R-, preferably substituted with no R-. [0073] In cortain preferred embodiments of compounds of formula I. R} is H. In certain other preferred embodiments, R:t is C--C« alkyl. preferably C, alkyl. In certain other preferred embodiments, R;. is CrCft alkyl, preferably CvCfi alkyl. In certain other preferred enrlxxJifnonts, R:. is p"cnyl substituted with 0-3 R-, er.pecial'y phcnyl. [0074] )n certain preforrod ombodirrents of compounds of formula I, R* is. independently at oach occurrencro, H In certain pre'orrod embodiments. R< is. ndopendentry a: each occurrence. C1-C4 alkyl. preferably Ci-C^ alkyl, more preferably methyl, ethy.'. or isopropyl. In certain preferred emtxxlirnents of compounds of formula I. R4 is, indeporxlently at each occurrence, benzyl. In certan preferrod embodiments. R. is. indeponce"t;y at each occurrence, heteroarylmoS'iyl. In certain preferred ombod ments, R< n:. independently at onch occurrence. cycloheptylmet^lyl. cyciohexylme'.hyl. cyclcpontylmethyt, or cyclobutylmothyl. [0075J In certain preferred embodimon-.s of compounds of formula I, both R^ groups, tocjether with the rilrogen through whT.h they are attached, fcrm a hoterocyclic ring of 4 to G rirg atcms. where one enrbon may be optionally replaced v.ith N. O. S, or SO;, and where any carbon r'ng atom may bo optionally substituted with C.-C4 alkyl, F. or CF3. In certain more preferred embodiments, both R« groups. kxjothor w.ih iho nitrogen through which they aro attached, form a pyrKJine, piporidiro. piporn7ino. or morpholino ring. [0076] In cortan ore'errod embodiments of compounds of formula I, Rs is. independently ai each occurronco, H. In corta;n preferred embodiments. FU is. independently at each occurrence, C1-C4 a'kyl, prefoMbiy C.-Cs alkyl. more preferably methyl. e:hyl. or isopropyl. [0077] In certain preferred embodiments of comjiounds of formula 1, Rfi is. independently at each occurronco, H. In certain preferred embodiments, R-j is. independently at ench occurrence. C-C* alkyl. preferably C1-C3 alkyl. moro preferably meihyi, ethyl, or isopropyl. [0078] In certain preferred emtKxJimcnts of compounds of formula I. R7 ir>. indepondontly at each occurrence, H. Ir certain preferrod orrbodimonts. R; is, indGpendenlry at each occurrence. C1-C4 a'.kyl, preferably C.-C3 alkyl. more preferably methyl, ethyl, cr isoprooyl. In certain preferred embodiments ct compoundr. of formula I, R; and R4 lecjethor with ihe nitrogen to which Rt is n!t«->chod form a nitrogen-containing nnc; containing 3-6 carbon atoms, especially, pyrrohdir.yl, pyrrolyl. piperidnyi. pyridiryl, p.zopany'. and azepiny1. [0079] In certain preferred embodiments of compounds of formula I. RB is. independently at each occurrence, H. In certain preferred embodiments. R« is. iridepondently at each occurrence. Ci-C* alkyl. preferably CI-CJ alky!, more preferably methyl, othyl, or isopropyl. In cetain preferred embodiments of compoumis oi formula I, R8 is, independently at each occj'ronco, CrC0 heteroalkyl, preferably methoxymeihyl, ethoxyethyi, nethoxyethy!, mR'.hylS'jI'anylrreihy!. othy'su'fnnylethyl, rrothylsulfanylothyl. msthylaminoethyl. ethylaminoothyl. and methyiamhoethyl In curtain preferred embodiments of compounds of fcrmu'a I, R« is. indopofciontly at each occur-ence. an/1 s-.jbs'.itu!ed v.i'h 0-3 Ri, especially phenyl. tolyl. and xylyl. [0080] In certain profe.-ro:! embodimonts of compounds of formula I. Rj is. P(.T.t."S:onv»io<|n M mrJopendently at each occurrence, alkyl. p-eferably C--C6 nlkyl. C-.-d alkyl. preferably C1-C3 nky!. moro preferably methyl, ethyl, or isopropy!. In certain preferred embodiments of compounds of formula I, R,, is, independent^ at each occurrence, alkoxy, l:i certain preferred embodiments of compounds of formula I. R9 is, independently at each occurrence, ha o. In certain preforrod embodiments of compounds of formula I, RfJ is, independently at each occurrence, CFn. In certain preferred embodiments cf compounds of formula I. R5 is, independently at each occurrence, OCF5 In certain preferred embodiments of compounds of formula I, R<> is. independency ai each occurrence, hydroxy. In certain preferred embodiments of compounds o' formula I, Ra ;s, independently at oach occurrence, alkanoyloxy. In certain preferred embodiments of compounds of formula I. Ru is, independently at each occurrence, me'hyleredicxy. In certain preferred «;mbodiments of compounds of formula I, Rg is, independently at each occurrefKe, nitro. In cortuin preferred embodiments cf compounds of formula t, R=> is, independently at each occurrence, mtrile. In certain preferred embodiments of compounds of formula I, K3 is, independently at each occurrence, alkenyi In certain proforrod embodiments of compounds of formula I. R^ is. independont'y at each occurrence, alkyryl. In corain preferred embod monts cf compounds of formula I. R» s, independently at each occurrence. a!kylr»u!foxide. In certain preferred embodTronts of compounds cf fcrmu'a I, R5 is. independently at each occurrence, a'kylsulfone. !n cerian pre'er.'cd embodimerts of con^pounds of formula I. R?, is, mdependeritry at each occurrence, alkylsuifonamido. In certain preferred embjdiTents of compounds of formula I. Rn is, independently at each occurrence, alkylamidc. (0081J In certain preferred embodiments of compounds cf formula I, n is an integer from 0 to 3. More preferably, n is 0 to 2. Even more preferably, n is 0 to 1. Yet more preferably, n is 0. [0082] In certain preferred embodiments of ccrrpounds of formula I, x is an :ntt>ger from 1 to 2 More pre'e'abfy, x s 1. [0083] In certa;r> preferred embodiments of compounds of formula I. 1-2 carbon atoms in ring A may optionally be replaced with N. In certain pro'erred WOJIH.MWVM pn.lW0|»<|n OfrbocifTmnis. one carbon atom in ring A may opiionn'.y bo rpplacod with N. In certain preferred embodiments, nc carben atoms ir ring A arc replaced with N. [0084] Preferred compounds of formua 1 include: i-t^.S-dihydro^H-i^-bt'n/ox.-j/in^-y.'j-n-trrothylamrnoJ-i-phonylpropan-^-ol: 3 (methylamino)-i-(4-mo!hyl-3,4-dihydroquinoxalin-1(2H)-yi)-1-phonyipropan-?-ol; 3-(rrethylarrino}-1 -phonyl-1 [4-(2.2.2-trif!iJorc;othyl)-3.4-dihydroquinoxalin-1(2H)-yl]propan-2-ol; 1-(6-chloro-2.3-d;hydro-4H-1.4-bonzDX«izin-4-y!)-1-(3.5-dinuorcphony1)-3-(mothylamino)propan-2ol. 1-(3^rjorcphonyl)-3-{mc(hylarnino)-1-(2-mothyl-2.3-flihyriro-4H-: ,4-bon?oxnzin-4-yl)propan-2-o!: 1 -(6-chloro-2.3-dihydro-4H-1 ^-benzoxaiin^-yO-S-tmethylamino)-! -phenylpropan-2-oi: 3-(moihylamino)-1-(fi-mothyl-2,3-dihydro-4H-1.4-benzoxazin-4-yl)-i-phenylpropan-2-ol; 1-(6-chloro-2.3-dihyd:o-4H-1.4-t>cnzoxa^in-4-yl)-3-Cn(?thyii)mino)-1-phonyipropan-2-of; 1-(6-Chlcro-? 3 d:hy(1ro-4H-1,4 tJon^oxi'./in-^-y'J^l-fmothylarriino^-i-phenylpropan 2-ol; i-te-chloro^.S-cihyd'o-iH-i^-bonzcxazin^-yn-i-fS-fiucrop'ienylJ-S-(me'hylamino)propan-2-ol; 1-(2.2-dimclhyl-2,3-d|hydro 4H-1,4-bon/oxazin-4-yl)-1-(3-fli;orophony')-3-(mothylamno)prop-4H-1 /.-b(?n7Ox;i7in-4-yl)-3-(mothylarTiino)-1 ¦ phenylpropan-2-ol; 1-(2.3-dihydro-4H-1/,-bcnzothiax:n-4-y:)-1-(3-fUorophenyl)-3- (meihylnm:no)prcpan-2-o): 1-(3-{luorophenyl)-3-(mcthylamino)-1-(P-phcnyl-2.3-dihy(;ro-''.H-1.4- ber>.zcxaz;p-4-yi)propan-2-cl; 1 (3-fluorophenyl)-3-(mo:hylanii!X>)-! -;2-phenyl-2.3-cJihyc!ro-4H-1.4-bonzoxa/ir-4-yl]propan-2-ol; 1-(3fluofOphcnyl)-3-(molhyUifr,:no)-l-(2-pht?r.y;-?.3 dihydro-4H-1.4-bonzoxnzir-d-yiJpropnn-S-ol; and phnrmacouticaliy acceptably salts thereof, particularly dihydrochlorido salts thereof. [0085] Particularly preferred compounds of formula I include: (1 RS.2SR) 1 -(2.3 dihydro-4H-1,4-bon/oxazin-4-yl)-3-(mothylam:ro)-1 -phonylpropan-2-ol; (1S'.2R')-3-(rr!Gthyiarr;ino)-1-(4-methyl-3-4-dihydroquinoxal!n-1(2H)-yl)-1-phenylpropan-2-ol; (1S'.2R*)-3-(methyla'nino)-1-phonyl-1-[/.-(2.2,2-t'ifluoroethy1)-3l4-(Jihydroquincxalio-1 (21 l)-yTorcpnn-2-cl; (iS.2R)-1-(6-chloro-2.3 dihydro-4H-i .4-bon/oxa/in-4-y!)-1-(3.5-difluorophenyl)-3-(methylamino)propa'v2-ol; (1 S,2R)-1 -(S-fiuorop^ienyO^trrelhylamirK))-1 -(2-mothyl-2,3-dihydro-4H 1 .•:-bt?nzoxazin-4-yl}propan-2-ci; (1 S'.PfV)-1 -(6-ch!oro-2.3-d hydro-4H ¦ 1,4-t>en2Oxa^in-4-yi)-3-(methyiamino)-1 -nhenylpropan-2-ol; (IS'^R'J-S-tmethylamiroJ-i-'.e-nethyl^^-c'ihydro-^H-i^-bcn/oxa/in^-yl)- 1-phenyipropa*v2-o!; (1S.2n)-1-{6-chloro-2.3-dihydro-4H-1.4-tx)nzoxa7in-4-yl)-3-(moihytamino)-1- phenylprcpan-2-ol; (1R.2S)-1-(6-chloro-2.3-:i!hydro-4H-1 4-bRnroxa7in-4-yl)-3-(rncthyUinr-no)-1- phonylpropan-2-ol; (I S.2H)-1 -(6-chloro-?,3-dihydro-4H-1,4-bonzoxa/in-4-yl)-1 -(3-fluoroi)he.iyi)-3-(mc!hylarm>o)propan-/?-ol; (1S.2R)-1-{2,2-difrethyl-2.3-enzoxa7in-4-yl]proptin-2-ol; (1S.2n)-1-(3flvJOfOphcnyl)-3-(mothy!amino)-1-i(2S)-2-phonyl-2.3-dihydro-''.H-1,4-bcnzoxa/in-4-yfipropan-2-ol; n.id phnrnracouticaly acceptab'o salts thereof, particular^ dihydrochloride salts thereof. [0066] Some of tho compounds cf the present invention may contain chirai centers and SJCII compounds may exist in tho forrr cf sterooiscmors (i.e. enantiomors). The present invention includes all such sterooisomers and any mixtures thereof including rncemic mixtures. Racemic mixturos of Ihe sterooisome.'S as well as the substantially pure stereo.somors are within tno scope of the invontion. 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 storeoisomor is present relative to other possible stereoisomers. Preferred onantiomers may be isolated frcn racemic mixtures by any method known to Nose skilled in the ad, including high performance liquid chromatography (HPLC) and the formaiion and crystallization of chira! salts or prepared by methods der.cnbed herein. See. for example, Jacques, cf al.. Enantiomcrs, Rncemntes and Resolutions (W ley Interscicnce, New York. 1981); Wn'on. S.H.. ct ai, Tetrahedron. 33:2/25 (1977); El:o!. EL. Stereochemistry of (Xirbon Compounds, (McGraw-Hill. NY, 1962); Wilen. S.H. Tabtos cf Resolving Agents and Optical Resolutions, p. 2G0 {fE.L El-nl. Ed.. University of Noire Dame Press, Notre Dame, IN 1972). [0087] The present invention irtdudes prodrugs of the compounds of formu'a I "¦Prcdn;g.* as used herein, means a compound wfrch is ccnvertible in vivo by metabolic moans (e.g. by hydxlysis) lo a compound of formula I. Var oi;s forms of prodrugs are known in the art, fo' oxamole, as discussed in Bundgaard. (e:l.). Design of Prodrugs. Elsovier (1985); WkJdor. et al. (od). Methods in Cnzymoloyy. vol. 4, Asatfe-nic Press (1035); K'ogsganrd-Larsen. et al.. (od). "Design and Application of Pro.irucjs," Textbook of Un:cxyl grojps. These groups are present in a chemical compound to reader such functionality inert to chemical reaction conditions to which the compound is exposed. Any of a variety of protecting groups rray bu employed with tho present invention. Prelecting groups that may be empioyod in accordance wi:h the present invention may be described in Greene. T.W. and Wuts. P.G.M.. Protective Groups in Organic Synthesis 2± Ed., Wiley & Sons, 1991 [0091] Compounds o\ the present invention are suitably prepared in accordance with tho fo'w.m.g general descript on and specific examples. Variab'os used are as defined 'or formula I. unless trhonviso noted. The reagents used in the preparation cf the cempounds of this invention can bo er.her commercia'ly obtained or can be prepared by standard procedures described in the literature. t*cri."S2i>nvnin5io [0092] T.io compounds of this invention conta n chiral centers, providing various r.tcreoisomeric fcms such as enantiomori; mixtures as woll as optica' isomors. The individual cpt.cal isomers can be prepared directly through asymmetric and/or stereospeciic synthesis or hy conventional chiral separation of optical isoners Ucm the enantiomeric mixture. [0093] Compounds of tho present invention nro su tably prepared s dpr.i-ed tc synthesize compounds o! fofmu'a ^a, they can be prepared from compounds o' formula 1J and 19 in three steps beginning with a regio- and stereo-seiectve rng opening of an epoxide of formula ^9 with an appropriately substituted compound of formula J8 to produce compojnds of formula 20 (Scheme I). Any conventional method for the regio- and sicoo-soloctive opening of an opoxde am be utilised for this conversion. In accordance with the preferred omt:odimori! o) this invention, compounds of formula 1.8 are heated with compounds of formula 19 at tyrnperatu'es from about 120X to about 150"C in 'he absence of solvent to afford compound of formula 20. Compound*, of formuia 2J can he formed fron corr.pc.jncs of formula 20 via direct amidation with an appropriate amine. Any WO 2005/097,761 PCT/US20O5/01051O 29 conventional method for direct conversion of an ester to an amide can be utilized for this conversion. In accordance with the preferred embodiment of this invention, compounds of formula 20 are heated in a sealed tube at temperatures between about 50°C to [about 100°C with an excess of alcoholic amine to form compounds of formula 21 which can be reduced to form compounds of formula Na. Any conventional method for reduction of an amide can be utilized for this conversion. In accordance with the preferred embodiment of this invention, compounds of formula 21 are heated; with borane-tetrahydrofuran complex at temperatures between about 50°C and about 90°C to afford compounds of formula Na that can be converted to a pharmaceutically acceptable salt using any conventional method. WO 2005/097761 PCT/US2005/010510 30 Scheme Where: A, R1( n, R2, FU» Re, Rg, U, V and W are as previously described. if = C1-C4 lower alkyl [0096] If it is' desired to produce compounds of formula l-aa. they can be prepared via alkylation of compounds of formula 20 (Scheme III). Any conventional method for the alkylation of secondary alcohols can be employed for this conversion. In accordance with the preferred embodiment of this invention, compounds of formula 20 are treated with an alkyl halide using sodium hydride as base to afford compounds ofl formula 21_. Compounds of Formula 2\_ can be converted in two steps to compounds! of formula l-aa in an identical manner as previously described for the conversion of icompounds of formula 20 to compounds of formula \^a (Scheme f). Compounds of formula Jka can be converted into a pharmaceutically acceptable salt using any conventional method. wo ;im< ci9-~r.i PC I TS2f>nvnin.esulfonato. in tho p'esonce cf a hindered base, eg 2,6-di-fGrtbij:yl-';-methylpyridine. The reaction can be performed either at room temperature or heated !o about 40aC to at>out 80"C. Compounds of formula 25 can br> converted to compounds of formula l-aa as previcus'y coscribnd for the r»ynttrn?is cf compounds of 'ormu'a ^a. Corrpounds of wo 2inivi«r?(.i rci-'fsiini5-«in«irt forrnu'a t-aa can bo converted to a pharrrncmjticnily acceptable sail using any conventional method. Scheme III Where: A. R-. n, R2. Rs, Re. R?, H-c U, V and W aro as previously descbed R? ¦ C1-C3 lower alky!; OTs - para-toluenesu!fcnyla!e or any conventional leaving group [0099] if it is riosircd to form come ouods of formula Mb, they can bo formed from compounds of formula £3 {Scheme IV). Compounds of 'orcnu'a 23 can be converted in four r.teos to compounds of lo'mula Nb. TMs roulft involves tho selective protection of the p'iciary alcohol followed by conversion of the secondary alcohol to a leaving youp. Any conventional method for the selective protection of a primary alcohol, ard any conventional method for converting of a secondary alcohol .nto a loavir.g gro-jp can be utilised for this convnrr.ion. In accordance with tho preferred embodiment of thin invention, compounds of formula 23 are treated with para-nitrot>OM/oyl ch.Iorido in pyrid;ne at low tomporatu'e (preferably below about tfC) to form compounds of formula 26. Compounds of formula 26 can be converted to a secondary mesyiate of formula 27 via reaction with mothanosulfonyl chloride in dichloromethane using trielhylamine as base. The reaction is preferably carried out at tempera'ures between about -15"C and about 10cC. Deprotecticn cf tho pnrrary nicohcl in compounds of formula 27 allows for tho formation cf a primary epoxido through an 3^2 reaction resulting in an inversion of tho steroccontor. Any cc'*-vf?niiopril method for ctcprotec:t>o:i of .1 primary a'cohol. and ary conventional method for epoxido formation onto an alpha leaving group am bo employed (or this conversion In acco'danco with the preferred embodiment of this invention, compounds of formula 27 are treated with an aqueous solution of a s.^table base n organic sovont. preferably, aqueous sori:um hydroxide in dioxnne. Tho resulting epoxide of formula 28 can ba ring opono can bo convcriod to a pharrraceUicaUy acceptable salt usiruj any conventional method. WO :ons..v»-v.i TC 1 I Siring nu.fin Where: A. R|. n, R,->, R,. Rft, R3, U, V and W nro as previously described R? is H PNB - par<7-n:tror>orvoy! or any conventional prelecting group; OMs -mothanesulfonate or any conventional leaving group; T = d-C* lower alkyl [0100] If it is des-red to form compounds of formula Ubb. they can be formed from compounds of formula \jb in three steps {Scheme V) in an identical manner as previously described for the conversion of compounds of formula Ub (o compound:; of formula l-bb {Scheme ///)¦ Compounds of formula i-bb enn bo converted to a pharmncoutica'ly acceptable salt using any conventional method. Scheme V [0101] Compounds of lormJa 23 «re formed via regio- nnd storco-soleclive ring oporvng c' an appropriate?*/ substituted epcxido of formula |7 (formed va an cpoxidatio.-i of an appropriately sub&liiutod aliylic alcof-.ol) with an appropriately substtuted compound of formula 18 [Scheme Vf) Any conventional methocf for rogio- and nteroo-selective ring opening of an epox-do can be employed for :his WO ?nnCT-TS:nn> iimMO conversion. In accordance with the preferred embodiment of this invention, compounds cf formula 1_8 aro Iroalod wit i a baso, e.g. sodium hydride, sodium tert-hutox.de. potassium hydroxide, potassium fe»rf-butoxide or potassium hydroxide, then treated with the epoxido ol formula 17 The opoxtde of formula t7 can be pro-treated with a Lewis acid, e.g. titanium /sopropoxido. boron-tnfluorido, etc. !o ensure regio-seleotive ring-opening. The reaction occurs at room temperature over a duration of about 2 to about 72 hours. Alternatively, compounds of formula .18 that are suitabty nucleophilic can bo heated with the opoxide of formu.'a 17 at temperatures from about 50°C to about 17OaC !o form compounds of formula 23. [0102] EDoxidation of trans-a'lylic alcohols can be poriorrred either racemicaNy or asymmet'icnlly using methods described in 'ho literature. In accordance with the pretorrod embodiment of this invention, racom c epoxidation is conducted with either peracetic acid or c7efa-chlorcperJ>en/oic acid. If ii is desired to produco a single enantiomer cf compounds of formjia I. asymrr-otric epoxidation of an aliyiic alcohol can be performed w:1h tort-bjtyihydrop-erox'do or cumene hydroperoxide in the presence cf the appropriate tartrato ester, titanum (IV) isopropoxido. and mo'ecular sieves. This method is well estnb ished m (ho 'rteraturo {e.g. K B Sharpless. et. nl.. J. Org. Chcm. 1986. 51, 3710). Compounds of formula !8 and the starling allyhc alcohols are either available fron commercial soj'ces c are accessible Ihrough metJicK.'s well establisried in the literature. u, Scheme VI Whore: A, R.. n. R,-.. Re. R-j. R.;, U. V and W are as previous'y described ¦0103] Compounds cf formula 19 can bo formed either racemrca'ly or asymmetrically using methods desc-ibec in Ihe lile'aturo starting with either trans- ilfylic esters or trans-n-'lylic alcohols (Schema Vlf) In accordance with iho preferred embodiment of this invention, racemic upoxidation of the :rans-allylic este' is ;onductod using di-(tr.fluoromethyl)d)oxi'ano formed in-situ from trifluoroacotcw aid ;xcne (Yang. D.; Wong, M.-K.; Yip J. Orq. Chem. 1995, 60. 3337-3389). If it is Jesired 1o produce a single cnanticmer of compourKis of fcrmjia I, asymmetric ?()oxidati«n oi an aliylic es:or can bo po'lomned with oxene and a chira! kolone as eponed in the I teraturo {VJ-Y. Wu. X. She. Y. Shi, J. Am. Chem. Soc. 2002, 124, ?792). Alternatively, compounds of formula 19 can he formed via the oxidation and jsterifiention of compounds of fomula 17 (doscribed :n Schema Vf), A*iy :onvontioral method tor the oxidation cf an epoxy alcohol and any conventual inethcd for the ostenfication of an epoxy acid enn be utili7ed for this conversion. In iccordanco with the preferred embedment cf this invention, opcxy alcoho. V7 is ixidizod with sodium perioda'e and catalytic ruthenium trichloride in carbon otracMoiide, bulferod with sodium bicarbonate. Tfie resulting acid can be eslenfied vith ciia^crnetnane or with catalytic su'furic acid in etharol to form compounds of ormu'a 19. WO >nnVr><>--M 1'CT'I S2(MH n|f,Mn Scheme VII Whore: H;. R* and R<» are as previously described And where" T - CiC< lower alkyl [0104] In other ombedimonts, tho invention is diroctod to pharmaceutical compositions, comprising: a at least compound of formula I. or pharmnceutically acceptable salt thereof; and b at least one pharmaceu!ic;nlly acceptable carrier Generally, tho compound cf formula I, or a phartnaceuticalry acceptable salt th?.rt?of. will be present at a level of fron about 0.1%, by weight, :o about 90% by v.o.gfit. based on !hr> total weight of the pharmaceutical composition, based on the total weight of tho pharmaceutical composition. Prftferab;y. the compound of formula I, or a pharmaccuticaily acceptable salt thereof, will be present at a level cf at least about Ixo, by weight, based on tho total weight of tho pharmacoutica1 composition. More p'e'orably, tho compound of formula I. or a pharrnacoUicaily acceptable sa't thereof, will be present at a level cf at loast about 5%. by weight, based on the total weight of thu pharmaceutical composition. Even more preferably, the norcpincphrine rouptake inhibitor or a pharmaceutcally acceptable salt thereof wil bo present at a level of at least about 10%, by wo-ght, based on tho total weight of the pharmaceutical composition. Yot oven more preferably, the compound c> formula I, or a pharmaceutical^ acceptable salt 'hereof, will ho present at a 'evel of a: least about 25%. by weight, based en tho total weight of the pharmaceutical composition. [0105] Such compositions aro prepared in accordance w-th accoptablo pharrnaceut.cal procedures, such as described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro. Mack Publishing Company. WOMO^-V.1 l-CI-liSinoS-nin-i,,, 3s Easton, PA (1985). Pharmaceutical^ acceptable camp's are these th?ii are coinpatib'o with the other ingredients in the formulation and biologically acceptable. [0106] Tho cornpountJs of this invention may bo administered orally or parentoralry, neat or in combination with conventional pharmaceutical carters. Applicable solid carriers can include one or more substances that may also act as flavoring agents, lubricants, sciubilizors, suspending agents, fillers, glkjants. 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, tho active ingredient is mixed with a carrier having tho necessary comp'ossion properties in suitable proportions and compacted in the shape and si2o desired The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magresium stearate, talc, sugars, lactose, dextrin, starch, gelatin. col!i,!ose. methyl cellulose, sodium carboxymothyl co'.kjioso, potyvinylpyrrolidine. lew molting waxes and ion exchange resins. [0107] Liqu'd carriers may te used in preparing solutions, suspensions, emulsions, syrups, and elixirs. The active irgred:ent of this invont:on can bo dissolved or suspended in a pharmacouticnlly acceptable l:quid carrier sixh as water, an organc solvent, a mixture of both or pha'rr-aceuticaHy acceptable oils or fat. Tho Ik^uid earner can contain otho* r>-j;1ar>lo pharmaceutical additives such as solubilizers. emulsifiors, bu'fers. preservatives, swoetoncrs, flavoring agents, suspending agents, thickening agents, ct;'ors. viscosity regulators, stabilisers, or osmo-reg-lators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g. cellulose derivatives, preferably sccfi.jm carboxymethy! cellulose solution), a'cohols (including monohydric alcohols and polyhydric aicohols. e.g. glycols) and their derivatives, and oils {e.g. fractionated coconut o>l and arachis oHV For parenteral administration, tho carrier can also bo an o !y ester siK:h as ethyl oloato ar-.d isopropyl myrista'.e. Sterile l:cu;d carriers are .;se:i in sterile liquid form composttiors for parenteral administration. wo iihivno—M rn.rsjiws ftiniio 3-) [0108] Liquid pharmaceutical comnos'iions. which are sterile soiulioos or suspensions, can be administered by, for (ixmiplo, intramuscular, intraporitonoal or subcutaneous injection. Sterile solutions can also bo administered intravenously. Oral administration may be either liquid or sold composition form. [0109] Preferably the pharmaceutical composition is in unit dosage form. eg. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such fcm. the composition is subdivided in unit doso containing appropriate quantises of the active ngiedient; the unit dosage forms can be packaged compositions, for examplo pacH unit dosage form can be, for exarrple, a capsule or -ablet ilself, or it can b© the appropriate numbor of any such compositions in package form. [0110] In another embedment of the per.ert 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 ccncition present in the rrammal. Examples of such pharmaceutical active agents include pain relieving acjenir,. anii-arg;cgenic agents, anti-neoplastic agents. anti-diabot" a;jcrts. an!; ir'cc::vo agents, or gast'ointestina1 agents, or combinations thereof. [0111] The one or more ether pharmaceutical active agents Tiay be admin;stered in a therapoi;!icniiy effr>ctive amount simultaneously (such as individually at the same l-rne. or together in a pharmaceuticai composilion). and/or successively with one or more compounds of '.he pror.ent iventicn. [0112] The te'm "comlvnalion therapy" refers to the administration cf hvo or more therapeutic agents or compounds to treat a therapeutc conclit.Dn or disorder described n the present disclosure, *o' example hot flush, s-.veat.ng. thermoregulatory-roiated ccnoition or disorder, or other. Such administration includes use of each typo of iherapeut'c agent in a concurrent manrer. In eithor caso, the treatme'it regimen will provide ^ono'cinl effects o* tho drug ccribination in \vo :mi*r.o-v.i PCI I "S?nlo salt thereof. The conditions ameliorated by moncc'i.-mhe reuptake include those selected from the group consisting of vasomotc symrtonr.s, sexual dysfuncton, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromylagia syndrome, nervous system disorders, and combinations thereof, pa.'ticuiarly those conditions selected from the group consisting of rraior degressive disordor, vasomotor symptoms, stress and urge urinary incontinorco, firromyalga, pn;n, diabetic neuropathy, and c;;rT't)tn<-»tio'ir> thpreof. wo :nn >i* fv-i.i 'Tit "S:nfl5 'omsm U resistant pain. visceral pain, surgical pain. bore iti|ury pain, pain daring labor and delivery, pnin resulting from buns, post partum pain, angina pain, nouropathic pain such as peripheral neuropathy and diabetic neuropathy, post-oporativo pain, and pam which is co-morbid with nervous system, disorders described heron. [0124] As used heroin, '.he term "acute pain' refers to centralized or peripheral pain that is intense, localized, sharp, or stinging, and/cr dull, achirg, diffuse, or burning in nature and that occurs for short periods of time. [0125] As used heroin, the term "chronic pain" refers to centralized or penohcal pain that is intense, locali/cd, sharp, or slinging, and/or dull, aching, diffuse, or burning in nature and that occurs for extended periods of time (i.e., persistent and/or regu'arly reoccurrino). including, for the purpose1 of the present invention, neuropathic pain and cancor pain. Chronic pain includes neuropathic pain, hyperalgesia. and/or allodynia. [0126] As used herein, tho term "neuropath.c pam" refers to chronic pain caused by damage to or pathological changes in tho peripheral or central nervous syslems. Examples of pathclogical changes related to neuropathic pain include prolonged peripheral or central neuronal sensiti/aticn. crrfal sens;ti7ation related damage to nervous system inhibitory and/or oxhihitory functions and abnormal interactions between tho parasympathotic and sympathetic nervous systems. A wide range of clinical corditionr, may be associated with or form the bas-s for neuropathic pain including, for example, diabetes, posl traumatic pain of amputation (nerve damage cause by injury resulting in peripheral and'c contra.1 r.ensitization such as phantom limb pain), lower hack pain, cancer, chemical in;ury, toxins, other ma;or surgeries, por;phernl rervo damage duo to traumatic injury compression, posl-herpetic: neuralgia, trigeminal neuralgia, iumhar or cervical radiculopathies. fibrcrrya!gia, glossopharyngea! neuralgia, reflex sympathetic dysirophy. casuifgia, thalamic syndrcmo, nerve root avUS'on. reflex sympathetic dystrophy or post thoracotomy pain, nutnlicnnl (Joficioncios, or viral or bacterial infections such as shindies or human imrruncdefioioncy vrus (HIV), ard ccMbinatsons thereof. Aiso included in tho definition of neuropathic pah is a conditicn secondary to metastaiic infiltration, 44 adiposis dolorosa, burns, cmv.ral pnin co-uiitions related to thaiarr.ic conditions, and combinations thereof. [0127] As used he-rein, tho term "hyperalgesa" refers to pan wheo them is an incrooco in sensitivity to a typically noxious stimulus. [0128] As used heroin, tho term "aiiodynia" refers to an :ncroase in sensitivity to a typically non-nox:ous stimulus. [0129] As usod here;n. the term "visceral pain" refers to pa n associated with cr resulting from maladies of the internal organs, such as, for exa-nplo, ulcerative colitis, irritable bowol syndrome, irritable bladder, Crohn's disease, rheumatolcxjic (arttualytas), tumors, gasf tis, pancreatitis, infections of the organs, biliary tract disorders, and combinations thereof. [0130] As used heroin, '.ho '.erm "female-specific pain" refers to pain that may he acute and/or chronic pain assoc ated .vitr- female cond-lions. Such groups of pain include those that arc encountered solely or p'odominately by females, ii^cluciing pain assoc nted with -menstruation, ovu alion, pregnancy or c'li'dbrrth, miscarriage, ectopic pregnancy, retrograck? rneoslruation, rcottre cf a follicular or corpus luteum cyst. irri;a!on of the pelvic viscera, utenno fibrc-ds. adenomyosis, enrtorrotrioSiS, infection nnd inflammation, pelvic organ iRchomia. obstruction, intra-abdomnal adhesions, anatomic dstolon of the oe'vic viscera, ovarian abscess, loss of pelvic support, tumors, pelvic congcst.cn cr referred pain from non-gynecological causes, and comb nations thereof. [0131] h one embodiment, the present invention is dirGcted to methods for t/enting or preventing vascrrctor symptcms in a subject in need thereof, comp'is'ng the stop cf: administering to said subjoct an elective amount of a*, least cno corrpcunc: ot formula I or pharmaceutical y acceptable salt thorec'. [0132] When estrogon levels a-e low cr estrogen is absent, the noTnal levels between Nf and 5-HT is altered and tnis altered change in nouro'.ransmiKor levels may result in ctinngos in the sensitivity of the thermoregulatory center. The a'tered chomical levels may be translated in We thormorogulatory center as heat sensation and as a -esponso, the hypoihalnnr.js mny activate tho descending autonomic pathways and result in heat dissipation vin vaso(Jilation and sweating (hot (lush) (Figure 1). Accordingly, the estrogen deprivation may result in altered noropinephrine activity. [0133] Norepinephrino synthesized m perikarya of the brainstem ;s released at the rorvo terminate in the hypotha'amus and brainstem. In the hypotftalnmus, NE regulates the activity of neurons residing in tho thormoregulatory centor. In the brainstem, NE innervates sorotcninercic neurons (5HT), and acting via adronergic«i and adrenergic-vi postsynaptic receptors, it stimulates tho activity of the serotoninergic system In response. 5-HT neurons also modulate tho activity the thenmorogLilaiory contor and feedback to NE neurons Via this feedback connection, 5-HT, acting via 5-HT?Jl receptors, inh:bit tho activity of NE neurons. Norep-nephrhe in Ihe synaotic cleit is also taken up by NE transporter (NET) located in NE neurons. Tho transporter recycles NF ard maker, n available for multiple neurolransmiss on (Figure 2) [0134] The present invention provides a treatment for vasomotor symptoms by meihods of recovering tho reduced act-vity of noropi.-wphrine. Ncrepinentirino activity in tho hypothalamus or in the brainstem can bo elevated Dy 0) blocking tho activity of iho N'E transpoMor. (ii) blocking the activity of the prosynap'ic adronergic o2 receptor wth an antagonist, or (iii) blocking the nct.vity of f>-HT on N'E neurons with a 5-HT?a antagonist. [0135] In another embodiment, ihe present invention is cj.recied to methods for treating or preventing a depression disorder in a subject in need thereof, comprising the step of: administering to said subject an ef'ective amount of at least one co-npcjnr) of ?crmula I cr pr-armacoutically acceptable salt tnoroof. XMiMi.s-.w-r. I rn;i:s:iir.MHnHii [0136] In yot other embodiments, tr.o present invention is directed to methods for treating or preventing sexual dysfunction in a subject in need thereof, comprising the step o* adrr nistering to said subject an effective amount of at least one compound of formula I or pharmaceuticaily acceptab'o salt '.hereof. [0137] In aneffrcr embodiment, the present invention is directed to melhods for treating or preventing gastrointestinal or genitourinary disorder, particular:1/ stress incontinence or urge urinary incontinence, in a subject in need theroof. comprising the step of: acrrnJstonng to said subject an effective amount of a compound of formula I or pharmaceutical^ acceptable salt tnoroof. [0138] in another embodiment, the present invention is directed to melhods for treating or preventing chronic fatigue syndrome in a subject in reed thereof, comprising the step of: administering to said subject an effective amount of a compound of formula I or pharmaceu'caliy acceptable salt thereof [0139] In another embodimont. the present invention is directed to rrtothods for treating or preveni ng fibromylag'a syr drome in a subject in -ieed thereof. cor--prir,ing the step of: administering to said subject an effective amount of a compound of fcmula I or pharmaceutically acceptable salt thereof. [0140] In further ornbod merts. the present invention is directed to methods for treating or preventing pain in a subject in need thereof, comprising the step of: adrrinistenrg to said subject an effective anrcount cf at least one compound of formula I or phamaceutically nccoptnblo salt thereof. [0141] The pair may bo, for exampie, acute pa:n (short duration) or chron-c pain (regularly 'eoccurnng cr persistent). fhe pam may also te centralized cr peripheral. WO ?nos n<)"r,i racral pain, nock or upper back pain, visceral pain, somatic pain, neuropathic pain, cancer pain, pain caused by injury or surgery such as burn pain cr dental pain, or headaches such as migraires or tension headaches, or combinations of these pains. One skilled in tho an w;ll recogni7e that these pains may overlap one another For example, a pain caused by inflammation may also bo viscera' or musculoskeleta! in nature. [0143] In a preferred embodiment of tho 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 cr pathological changes in tho peripheral or central nervous systems; cancer pain; viscerai pain associated with for example the abdominal, pelvic, and'or perinoal regions or pancreatitis, musctjlor.keletal pain associated wish for oxample the lower or upper back, spine, fibrcrrylayia. tempcromandibular joint, or myofascial pam syndrome; bony pain associated with tor exanple bono or joint degenerating disorders such as osteoarthritis, rheumatoid arthritis, or spinal stencsis; headaches such migraine or tension headaches; or pain associated with irfec'ions sucn as HIV. sickle cell ar.err.ia, autoirrn'jno diso'des, m-jltiple sclerosis, cr inflammation such as osteoarihnlis or rheumatoid arthritis. [0144] in n mom preferred embodiment, the compounds useful in this invention aro used to treat chronic pam that is neuropathic pain. v;scoral pain, rrusculoskoletal pain, bony pain, cancer pan or inflammatory pain or combinations thereof, in accordance wiih tho methods described herein. Inflammatory pain can be associated with a variety of medical cotxiitions such as osteoarthntis, rheumatoid arthritis, surgery, or injury. Neuropathic pain may be associated with for example diabetic neuropathy, peripheral neuropathy, post herpotic neuralgia, triyeminal neuralgia, lumbar or cervical radiculopalNas, iibrortiyalgia. glessopharyngoal noi:ra'i;ia. reflex sympathetic dystrophy. cas»algia, thalamic syndrome, ne-rve root avulsion, or ncrvo darr.ago cause by injury resulting in peripheral and'o: central sonr.iti/ation such as phaniom limb pan, reflex sympathet:c dystrcohy or wo :M<.*-r~(>\ rrt.rsifMiMnnMn postihoracctomy pan, cancer, chemical injury, toxins, nutritional deficiencies, cr viral or bacterial infections such as shingles or HIV, or combinations thereof. Tho methods of use for compounds of 'his invention further include treatments in ¦.vhirrh the neuropathic pain is a condition secondary to metastalic infiltration, adposis dolorosa. bums, or central pain conditions related to lhalamic ccnditions. [0145] As nentioned previously, the methods cf the present invention may bo used to treat pain :hat is somatic anc/or visceral in nature. Fcr example, somatic pain that can bo treated in accordance with tho 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 h accordance with the methods of the present invention include those types o' pain associntec with cr resulting from maladies of the internal organs such as ulceraiive colitis, irritable bowel syndrome, irritable bladder, Crohn's disease, rheurr.atologic (arthralgias). lumors, gastritis, pancreatitis, infections of tho organs, or biliary tract disorders, or combinations thereof. One skilled in the art will also recognize that ihe pain treated according to the methods of the present invention rray also be related to conditions of hyperalgesia. aliodynia. or both. Additionally, the chronic pain nay be with or without peripheral or central sens Ii7ntio'i. [0146] Tvie compounds useful !n His invention may also bo used to treat acute and'or chronic pains associate:! with ferna.'e conditions, which may also be referred to as ffc?mnlo-soecif(C pam. Such groups of pain include those that are encountered soie!y or predominately by fema'es. including pain associated wj'n menstruation, ovulation. pregnancy or childbfth. mir.ca'.-iagc, ectopic pregnancy, retrograde menstruation, rupiure of a follicular or corpus luteum cyst, -rritaiion of the peivic viscera, uie'ine fibroids, ndenomyosis. ondometriosis, infection and inflammation, pelvic organ ischemia, obstruction, intra-abriomina' adhesions, anatom'c distortion cf the polvic viscora, ovarian abscess, loss of pelvic support, timers, pelvic congestion or referred pan from ncn-gynocological causes. [0147] The present invention is furiher defined in the following Fxamples, in which r) all parts and percentages arc t>y weight anil dogrcos aro Ce'.s.us. unless otherwise stated. It should bo understood that these examples, while indicating pre'erred embodiments of tho inversion, are cjiven by way of illustration cnty. From tho above discussion and theso examples, one skillod in the art can ascertain tho essential chnrnctorir.tinr, of ihir, invontion. and without (iepart-ng Irom the spirit and scooo thoreot. car, make various changes and modifications of tho invention to adapt it to various usaqos and conditicrs. EXAMPLES [0148] EXAMPLE 1: (iRS^SRj-i-C.H-indcl-i-y.J-S^-mothy'piperazin-VyO-V phonyl propan-2-ol dihydrocNoride [0149] Step 1: A mixture of indoie (2 34 g, 20 mmol) and pulve.'i/od solid potassium nydroxide (1.12 g, 20 mmol) was stirred for 30 minutes under nitrogen at room terrpcraturo. Trans-3-phonylglycidoi (3.0 y, 20 mmol) in dimethylsuHox-de (1 mL) was then addod and the mixture was stirred at 70"C for 2 hours until no opox;de romamod. The mixture was ihen cooled and pariinonod between v.ater and dichlorome'.hane. The organic layer was sepnrated, washed with water soveral times, dried ever anhydrous r>cdium sjlfate, filtered, and concentrated in vocuo. The crude product was purified via Biolage chromatography (FtasH40i. silica, 10%, 20%, 30% ethyl acetate/hexane) to yield 1.92 g (36%) of (2RS.3RS)-3-irxlol-1-yI-3-phcnyl-propanfi-i.2-d:ol as an oil :HNMR (DMSO) o3 27 (m. 2H. CM7OH). 64.45 (TI, 'H, CHOH), 64.80 (t, 1H. CKjOH), 55.20 (d. 1H. CHOH). 65.60 (d. 1H. CHPh); MS (ESI) m/z 268 CI/I+H]-). [0150] Slop 2 A solution of (2RS.3RS)-3-indo!-1-y1-3-phenyl propane-',2-diol (1.83 t). 6 8 mmel) and p-1oluonosul!ony! chloride (1.31 g. 6.8 rrmol) in anhydrous pyridino ('0 mL) was stirred at room temperature urder nitrogen for 15 hours. Tho mixture- was tiien diluted with water (1C mL). quenched with a 2N aqueous soluton of hydrochloric acid in an ice'waler batfi until tho sc'ution was pH - 3 and extracted WO :nns no'Th, !'CTTS:.v.::h diothyl othor (10 :nL). The aqueous layer was made alkaline- win solid potassium carbonate an-J oxfactod with ethyl acotnto (? x 10 ml.). Tho combined organic exiracts were wasned \vi:h brine, dried (sod-um sulfate) and concentrated under reduced pressure to yield 202 mg (98%) {1RS,2Sn)-1-(2.3-d;hydro-4H-1.4-ben7Oxa/in-4-yl)-3-(methyiarr.ino)-1-p.h(?rylpropnr-2-ol ac a colorless o.l. This oil was dissolved m othanol (1 mL) nrxJ treated with a solution cf hydrochloric acid (0.5 mL. 4M m 1,4-dioxano). All volatiios were ayain removed under reduced pressure The resulting white solic! was recrys!all:zod (ninimal warm ethano'-'othyl ether/-20C) to y.old 105 mg (41 %) (1 RS.2SK}- 1-(2.3-dihydro-4H-1,4-benzoxaz.-n-4-yl)-3-(mcthylamino)-: ¦ phenyloropan-2-ol di hydrochloric as a while solid. MS (RSI) ni//_ 299.0 ((M-»-HJ*); f IRMS: cnlcd for C.fiH^N::O.. ¦¦ Hf, 2S9.17540; found (ESI, |M+H;+). 299.1755. WO ;i.fi5 -Y>"(,\ *'C T rs;nriS-n|ftMii *; [0155] EXAMPLE 3: (iS.2H)-1-(3-ctiloroptieryl)-1-(1H-indoM-yl)-3-(rnelhylamino)pfOpan-2-ol hydrochloride [0156] S'.ep 1: A suspension o( sodium hydride (60 % in mineral oil, 4.0 g. 100 mmol) in totrahydrofuran (600 mL) was treated dropwise with diethyl othoxycarbonyimethyiphosphonato (20 mL. 100 m-nol) at 23°C After 1 hour s.3-chlorobon/aldehycte (9 3 mL. 82 mmol) was added. After an additional 1 hour, tho reaction was quenched with water (20 mL) and concentrated under vacuum to remove tol'ahydrofuran. Tho residue was taken up in ethyl acetate (300 mL). washed with water (5 x 300 mL) and brine (1 x 300 mL). dried (magnesium sjlfa'o) and concentrated under vacuurr 'o provide (2E)-3-(3-chloropheny!)-acrylic ac;d ethyl esior (18 g, quantitative) as a clear, pale yellow oil MS (ESI) m/7 210 ([M*Hj'). [0157] Step 2: (2£)-3-(3-C"ilorophonyl) acry'.c acid ethyl ester (17.6 g. 82 mfrcl) was dissolved in dry dichioronethane (300 mL), cooied to -78*C and treated with a solutio'i ol di-/so-hutylaluminum hydrijo (1.0 M solution m hexano. 250 -nL, 250 rr.mol) over 20 m-nutes. Af'.or 1.5 hours total, the reaction was quenched with mothar.ol (75 mL) at - 78'C. warmed to 23OC and treated with a saturated aqueous Go'ution of potassium sodium tartrato (300 mL). Tho aqueous phase v/as separated arid extracted with dich.'oromethnno [2 x 3C0 rrL) The combined extracts wore washed wi:h a saturatec aqueows solution of sodiun tart rate (450 ml), dried (sod-Lm sulfate) and concentrated uifisr vacuum to provide a cloudy yel.'ow oil (14.G g) that was pro-adsorbed on silica gel (25 g). Flash column chrciatography (silica 250 g. 10 %. 20 % ethyl acotale.liexanes) provided (2fJ)-3-(3-chlorophenyl)prop-?-cn-1-ol (12.4 g. 9C %) as a clear, cc'orioss oil. MS (F.SI) irj? 151 QA* H-HjOJ'). WO ?rHiSn9--f.1 f( T.tS:iviN '«|fMO [0158] Step 3: In an analogous manner to fcXAMPLE 10, step 4, [(2/?.3fl!-3-(3-chlorophenyl)oxiran-2-yl!rrethanol was prepared from (2E)-3-(3-chlorophenyl)prop-2-en-1-ol. MS (ESI) m/7 167 [(M+H-H-Ol *). [0159] Step 4 (Method A): In an analogous manner to EXAMPLE 10. step 5. (2S,3S)-3-(3-chlorophonyl)-3-(1H-indo!-1-yl)propano-i.2-fJiol was prepared from 1H-incole and ;(2fl.3/7)-3-(3-chloropheny;)oxiran-2-yli*no'.hanol. MS (ES) m'z 302 [0160] S'ep 4a (Method B): [(2fi.3H)-3-(3-ch1orophenyi)oxiran-2-yllmcthanol (4.8 (j. ?6 mmol) ami indoline [d 1.063. 2.9 mL, 26 mmol) were heated neat at 135SC in a sealed llnsk. Aftor 1 5 hours, the cooled mixture was pre-ndsorbed on silica (jel [?.5 g). F!ash eclumn chrcmatogrnphy (silica 375 g. 20 %. 40 %. 80 % ethyl aceiate/hexanes) provided (2S.3S)-3-(3-chlorcphenyl)-3-{2.3-dihydro-1 H-:ndol-1 -ynpropnro-1.2-diol (5.8 g. 73 n'o) as a whito solid. MS (ES) /n/,-304 ([Mi H]*). [0161] Slop 4b (Method B): A solution of (2S.35)-3-(3-chlorcphonyl) 3-(2.3-dihydro-1H-indol-1-yl)prcpano-1.2-d;ol (:i 8 g, 19 fnmcl) in ca. 1:1 (v/v) toluone-dichloromethane (200 mL) was treated with a solution of 2,3-dichi1oro-5,6-dicyano-1.4-bon/oqjinone (4,4 g, 19 mmol) in toluene (100 mL) at 0"C. After 30 minutes, the mixture was diluted with ethyl acetate (1 I.) and washed with 5 % aqueous sodium carbonate {4 x 1 L). water (1 L) and brine (1 L). dried (magnesium r.ulfate) and concentrated under vacuum to give a dark oil (5.4 y) that was pre-adsorbed on s'lica c;el (15 g). Flash column chromatography (S'Lca 235 g. 20 %, 40 c'» ethyl acotatetioxanes) provided (2S.3S)-3-(3-chloropheny!)-3-( 1 H-irdol-1 -yl)prop;ir.e-1 ,?.-diol, (4.7 g. 82 %) as a clcudy yellow oil- MS (ES) m,'/302 ([M^H]'). [0162] Stop 5: In an analogous manror to EXAMPLE 1. step 2. (?5 3S)-tclueno-4-sulfon-c acd a-fS-chloropher.ylJ^-hyd'Oxy-a-ndc'-i-yl-propyl ester was prepared from (2S.36>3-(3-chlorophony.l)-3-(iH-inctol-1-yl)propano-1.2 diol. MS (ES) n/^4S6 CM*HJ*). [0163] Slep 6: (2S.2S --ilfonic acid 3-(3 chlo:ophcnyl)-2-hydroxy-3- indol-1-yl-propyl ester (0.60 9. ^-ited with a sc'ution of me'.hylamino WO ;rxif ¦)<)'-(.I P(T"rSMn«.(ilO5iO in meihanoi (?.O M. 3 ml.. 6 nrnol) and the solution was stirred at 236C for 18 hours At this lime. the solution was concentrated under vacuum and dissolved in d'ethyl ether (50 mL). The organic so"ution v.as washed with a 1 N aqueous solution of sodium hydroxide (bO ml.), water (50 mL) and brine (50 ml_). dried (soJium sulfate) and concent rated under vacuum to provide an orange foam (0.30 g) that was purified by reverse phase HPLC (90:10 water-acetonitrile to 50:50 water-acetonitnlo containing 0.1 % tnfluoroacetic acid ?D 20 mU'min). The product fractions were concenfaied under vacuum to removo acetonitrile and the aqueous solution was basified with a 2N aqueous solution of ammonium hydroxide. The resulting milky suspensior was extracted w:th ethyl acetate (200 rr.L) and the organic phase was washed wi!h water (200 mL) and brine (100 mL), dried (sodium sulfate) and concentrated under vacuum The rpsklue was dissolved in absolulo ethanol (4 ml.). treated with a 4 M hydrochloric acid in 1,4-dioxare (1.3 eq) and stirred for 10 minutes The solution was concentrated under vacuum, then dissolved in aoso!uto ethanol (3 mL) and left standing at 23°C overnight. Vacuum filtra'on provided (iS.^^-i^^-chloropheiyJ-i-fiH-indoM-ylJ-a-tmethyiaminoJpropan^-o! hydrochloric (62 mcj. 5 % e^ylp'Opan¦2-cl hydroch'o-tdo was prepared from (2SR.3SR)-3-{4-meihyl-314-d;hydroquir.oxa!in-1 (2H)-yl)-3-ph(-r.ylprcpano-1,2-diol as a white powder. MS (ES) mv 312.0 ([M*nn; HRMS: calcd (or C,flH;r,N:iO i H*. 312 2076; found (ESI. jM+H]*). 312 2065. [0168] EXAMPLE 5: (iSR.2RS)-3-(mothylarr..no)-1-phonyl-1-[4-(2,2,2-trifluc'octhyl)-3t4- dihydrcxiuir.oxalin-i (2H)-yPpropnn-2-ol hydro^hloride 10169] Ccrr.pound 1-(2.2.2-tril uoroetviyl)-1,2.3.4-letrahydroquiroxaiir,c was obtained as a white pwcier sido product o' tho reduction reaction o( quincxa'ine to 1,2,3.4-tetrahydroqumoxalino using sodium borohycride in tnfluoroacetis ac:ri2 MS (ES) m/z217.1 ((M-H'/). [0170] In an nnalogous manner to EXAMPLE 6, step 4. (2SR.3SR>-3-(4-(2.2.2-tr1luoroethyl)-3,4-dihydroquinoxalin-1 (2H)-y'.)-3-phenylpropane-1,2-diol was prepared 'rom 1-(2.2,2-1n'uoro€thyl)-1,2.3.4-tGt:ahydrcK'iu:noxaine and 3-phony1cj!yckic: ¦ (EXAMPLE 4. step 1) as a viscous colorless oil. [0171] In an analogous manner to EXAMPLE 6, step 6. (1SR.2RS)-3- (melhylarnino)-i-phenyl 1-[4-(2,2.2-tril!uoroethyl)-3.4-dihydroquinoxalin-1(2H)-yl]p-opan-2-ol hydrochlorido was proofed from (2SR.3SR)-3-(4-(2,2.2-!r;fluorocthyl)-3.4-d-hydroc,'jinoxa!in-i(2H)-y")-3-phenylpropane-1,?-diol as a while powder. MS (ES) nv'/. 380.0 (II.UHj*); HRMS: cn'cd for C^H^F^.O + H\ 380.1950; found (ESI, [M*H]*"). :^80.1934. 3 ikig C, H C : "6 5% MS (ESI) m/z 1G9.1 ([fv'"-H]*;. [0176] Step 4: A mixture of indo'jo (1.42 g, 11.89 mmol) and [{2R.3H)-3-(3-fliioropheny')oxiran-2-yl]methanol (2.0 c>. it.89 mmo!) was heated at 125-C for 5 hours ;n a sealed reaction via!. Upon cooling. Ine cude product was disr.oh/ed in ethyi acetate. absort>od on Fiuorocii, nnd purifieo by Botago chrornntography (FlasH40i. sica. 0-55% ElOAc/hexano) to give 2.55 (j (75%) of (?S.3S)-3-(2,3-i:.hydro-1H-inc!ol-1-yl)-3-(3-f!iJ0rophonyrprcpcTro-1,2-diol as a colorless oil. MS (ESI) mv 288.1 CMfH"). [0177] Step 5: A mixture of (2S,3S)-3-{2.3-dihydro-1Hindo1-1 yl)-3-(3- flucrophonyl)propane-1.2-diol (2.00 g. 6.96 nmol) and activated manganese dioxide (200 g, 230 nrx>!) in dichloromett'.ane (30 mL) was strred at 20°C for 3 hours. Tho mixture was diluted wi!h elhyl acotato (^5 mL), filtered through a pad of silica gel. and concentrated. The crude product was p:irif:ed by Diotage chromatCKj'aphy (F!asH4Oi. silica, 0-70% EtOAciiexane) to tjive 1.40 g (71%) of (2S.3S)-3-(3-fluorophor.yl)-3-(1H-inc!ol-1-y!)propano-1.2-diol as a colorless oil. *v'S (F.SI) m'z \vo:i»* ¦¦'»—c.t !>< M^-if "in^lii ?«6.0 UM»H]-). HRMS: calcd lor C,.H, FNO> + H\ 286.1238; found (LSI. tM«-H;-). 2801239, (0178) Stop 6: To a solution of (2S.3S)-3-(2.3-tiihy(1ro-1H-:ndcl-1-yh-3-(3- fiuoicphonyl)f>ropane-1,2-diol (4132 mg. 1.58'J mmol) in d.c'iloronethano (3 rr.L) undor nitrogen was added triothylamine (1.1 mL, 7.93 mmol). The mixture was cooled to 0"C, and para-toluinesulfon;! chic rju (423 mC for 1 tiour and stored at 0"C overnight. Methylamine in absolute ethanol (8 M. 5 mL, 40 mmol) was added and Me reaction mixture was seated, and stirred overnight while warming to room '.emperalure. All vclntilos wero removed under reduced pressure. The oil residuo was dissch/ed in d.chloromethane (20 mL), washed w^h aqueous potassium carbonate ',5 ml.), dried (anhydrous sodium su'.fato). and concentrated. Purification by Biotage chromntoyraphy {FlasHi2i. silica, 0-15% MeOK-"dich!orornothcentrated. The cil residue was purified by silica gel chromakxjraphy (10-30% EtOAc^hexarM)) to give 920 mg (55%) of 3-(2-methy1phenyi)glycidol as a colcrlosr, oil. HRMS: calcd for C-oH^O, *¦ H*. 165.0916; found (ESI. (M-iH)'). 165.0936. [0183] Step 4; In an analogous manner lo EXAMPLE 10. step 5. (2SR,3SH)-3-(1H-indol-i-yl)-3-(2-me'hylpher-.y:)pT0pane- 1,2-dio' was prepared from indole and 3-(2-mothylphenyl)glycidol as a viscous, cobr'ess =iquid. MS (ES) m'z282.2 ([MVHj*). 17C.0365. [0189] Step 2: In an anacgous niarnor to EXAMPLE 6, stop <:, (2S,3S)-3-(6-chloro-2,3-dihydro-4M-1/.-benzoxazin 4-yl)-3-(3.5-difl'Jcrcphftnyl)prcpanc-1.2-dio. was prepared 'rom 6ch!cro-3.4-dihydro-2H-i.4-hen7oxa/iro and [{2R.3R)-3-(3.5-d:fluoropt-.ony!)ox!rnn-2-y.';me:.1i;wiol (EXAMPLE 157, step 3) ns a v'scous. yoilcwish WU 21105/(197761 PCTAJS2005/010510 61 liquid. MS (ES) m/z 356.1 ([M+H]+); HRMS: calcd for C17H16CIF2NO3 + H+, 356.0860; found (ESI, [M+H]+), 356.0869. [0190] Step 3: In an analogous manner to EXAMPLE 6, step 6, (1S,2R)-1-(6-chloro-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl)-1 -(3,5-difluorophenyl)-3-(methylamino)propan-2-ol hydrochloride was prepared from (2S,3S)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(3,5-difluorophenyl)propane-1,2-diol as a white powder. MS !(ES) m/z 369.1 ([M+Hf); HRMS: calcd for deHigCIFa^C^ + H+, 369.1176; found (ESI, [M+H]+), 369.1178. [0191] EXAMPLE 9: (1S)2R)-1-(3-fluorophenyl}-3-(methylamino)-1-(2-methyI-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propan-2-ol hydrochloride [0192] In an analogous manner to EXAMPLE 16, step 1, 2-methyl-3,4-dihydro-2H-1,4-benzoxazine was prepared from 2--methyl-2H-1,4-benzoxazin-3(4H)-one3 as a brown oil. MS (ES) m/z 149.9 ([M+H]+). [0193] In an analogous manner to EXAMPLE 6, step 4, (2S,3S)-3-(3-fluorophenyl)-3-(2-methyl-2:3-dihydro-4H-154-benzoxazin-4-yl)propane-1,2-diol was prepared from 2-methyl-3,4-dihydro-2H-1,4-benzoxazine and [(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 6, step 3) as a viscous, brown liquid. MS (ES) m/z 318.2 ([M+H]+); HRMS: calcd for C18H2oFN03 + H+, 318.1500; found (ESI, [M+H]+), 318.1513. [0194] In an analogous manner to EXAMPLE 6, step 6, (1S,2R)-1-(3-fluorophenyl)-3-(methyIamino)-1-(2-methyl-2,3-dihydro-4H-1J4-benzoxazin-4-yl)propan-2-ol hydrochloride was prepared from (2S,3S)-3-(3-fluorophenyl)-3-(2-methyl-2,3-dihydro-4H-1,4-benzdxazin-4-yl)propane-1,2-diol as a white powder. MS (ES) m/z 331:0 . 3 Wheeler, K. W. J. Med. Pharm. Chem. 1962, 5, 1378-1383. WO 2005/0977.61 PCTYUS2005/01(1510 62 ([M+H]+); HRMS: calcd for C19H23FN2O:> + H+, 331.1816; found (ESI, [M+H]+), 331.1804. [0195] EXAMPLE 10: , (1S,2R)-1-(5-fIuoro-3-methy!-1H-indol-1-yl)-3- (methylamino):1 -phenylpropan-2-ol hydrochloride [0196] StepU: To a mixture of 4-fiuoro-phenyIamine (9 g, 81 mmol), concentrated hydrochloric acid (20.4 ml_), and water (35.1 mL) was added sodium nitrite (6.3 g, 89.1 mmolj dissolved in water (7.8 mL). In a separate flask ethyl 2-ethylacetoacetate (14.4 g, 89.1 mmol) in ethano! (63.6 mL) at 0°C was treated with potassium hydroxide (5.1 g, 89.1 mmol) in water (7.5 mL) and ice and the above solution added. The pH of the reaction was adjusted to 5-6 and the reaction stirred at 0°C for 3 hpurs and then stored in the freezer overnight. The reaction was then extracted with; ethyl acetate (100 mL) and the organics washed with saturated brine solution (100 mL), dried with anhydrous magnesium sulfate. Most of the solvent was removed in vacuo before it was added dropwise to a 14,5% ethanolic solution of hydrochloric acid (70 mL) at 78°C. Heating was continued for 2 hours. The solvent was removed: in vacuo and the residue treated with dichloromethane (300 mL) and water (100 mL). The organic layer was washed with saturated sodium chloride (200 mL), dried over sodium sulfate and concentrated in vacuo. Purification on a short wash column :(silica gel, 25% ethyl acetate/hexane) gave ethyl 5-fluoro-3-methy!-1 H-indole-2-carboxylate as awhile solid. MS (ES) m/z220.0 [0197] . Step 2: Ethyl 5-fluoro-3-methyl-1 H-indole-2-carboxylate (8.3 g, 37.5 mmol) and potassium hydroxide (6.3 g, 112.5 mmol) in a mixture of ethanol (20 mL) and water (15 mL) was heated at reflux for 1 hour. The volume was reduced to 10 mL under reduced pressure and the solution brought to an acidic pH with a 3N aqueous solution of hydrochloric acid. The resulting precipitate was filtered, washed with WO 2005/097761 PCT/US2005/010510 63 water (100 mL) and dried in vacuo at 80°C overnight to afford 5-f!uoro-3-methyl-1H-indole-2-carboxvlic acid as a white solid. MS (ES) m/z 192.0 [0198] Step'3: 5-fluoro-3-methyl-1H-indole-2-carboxylic acid (8.49 g, 43.9 mmol) and copper metal (0.35 g, 5.5 mmol) in distilled quinoline (22 mL) was heated to reflux for 3 hours. The copper powder was filtered off and the filtrate was brought to pH 3 at 0°C with a 6N aqueous solution of hydrochloric acid. The solution was extracted with; ether (200 mL) and the organics washed with saturated sodium chloride (200 mL), dried over magnesium sulfate and concentrated in vacuo to give 5-fluoro-3-methyl-1H-indoleasabrown solid. MS (ES) m/z 150.0. [0199] Step 4: To a solution of diisopropy! D-tartrate (6 mL, 28 mmol) in methylene chloride (800 mL) at -10°C under nitrogen was added 4A molecular sieves (15g), titanium isopropoxide (5.9 mL, 20 mmol), and cinnamyl alcohol (27 g, 200 mmol). The mixture was allowed to age for 40 minutes at - 10°C) after which time it was cooled to -20°C, and treated in a dropwise fashion with a solution of tert-butyl hydrbperoxide (TBHP, -450 mmol) in isooctane. After 18 hours at -30 to -15°C, the reaction mixture was treated with a 30% aqueous solution of sodium hydroxide (5 rnL) and diethyl ether (100 mL). The cold bath was removed and the mixture was allowed to warm to ~ 10°C. Magnesium sulfate (anhydrous, 15 g) was added and the mixture was stirred for 20 minutes. After the solids settled, the solution was filtered through a pad of silica gel, and washed with ether (50 mL). The filtrate was concentrated in vacuo and toluene was added to azeotropically remove the unreacted TBHP. The residue was then purified using a silica gel column (hexane:ethyl acetate/3:1) and the purified product was crystallized from hexane/ethyl Acetate to yield [(2R,3R)-3-phenyloxiran-2-yl]methano! as white crystal (18g, 60% 98.2%ee). MS (ESI) m/z 151. [0200] Step 5: A mixture of 5-fluoro-3-methyI-1H-indole (2.91 g, 19.5 mmol) and potassium hydride 50% dispersion in mineral oil (2.8 g, 35.1 mmol) in dichloromethane (40 mL) was. stirred for 10 minutes under nitrogen at room temperature. A solution of [(2R,3R)-3-phenyloxiran-2-yl]methanol (2.0 g, 13.0 mmol) and titanium isopropoxide (4.3 mL, 14.3 mmol) in dichloromethane (10 mL) was then added and the mixture was stirred at: room temperature for 12 hours. After WO 2005/097761 PCT/US20O5/O1051O disappearance of the epoxide, the mixture was partitioned between a 1N aqueous solution of hydrochloric acid (50 ml_) and ethyl acetate (50 mL). The organic layer was separated, washed with saturated sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Biotage chromatography (FlasH40i, silica, 60% ethyl acetate/hexane) to give (2S,3S)-3-(5-fluoro-3-methyl-1 tf-indo!-1-yl)-3-phenylpropane-1,2-diol. MS (ESI) m/z 300 [0201] Sxep 6: A solution of (2S,3S)-3-(5-fluoro-3-methyl-1H-indoI-1-yl)-3- phenylpropane-1,2-diol (1.03 g, 3.4 mmol) and p-toluenesulfonyl chloride (0.78 g, 4.1 mmol) in anhydrous pyridine(11 ml) was stirred at room temperature under nitrogen for 12 hours. The reaction was poured into a 1N aqueous solution of hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL). The organics were dried over anhydrous sodium sulfate, filtered, and concentrated to give (2S,3S)-toluene-4~ sulfonic acid 3-(5-fluoro-3-methy!-indoI-1-yl)-2-hydroxy-3-phenyl-propyl ester. The product was used in the next step without further purification. To a solution of to!uene-4-sulfonic acid 3-(5-f!uoro-3~methyMndol-1-yl)-2-hydroxy-3-phenyI~propyl ester (1.6 g, 3.4 mmol) in methanol (10 mL) was added a 2N solution of methylamine in methanol '(8.6 mL, 17 mmol) and the reaction stirred for 12 hours. Upon completion, the reaction was partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Biotage chromatography (FlasH40i, silica, 20% MeOH/dichloromethane) to give (1 S,2fl)-1 -(5-fluoro-3-methy!-1 H-indol-1 -yl)-3-(methylamino)-1-pheny!propan-2-ol as a clear oil. The free base was dissolved in a minimum amount of ethanol and treated with a 2N ethereal solution of hydrochloric acid and stirred for 1 hour. The ethanol was removed in vacuo and the clear oil was triturated with;ether/dichloromethane to give (1S,2/=?)-1-(5-fluoro-3-methyI-1tf-indol-1-yl)~3-(methylamino)-1-phenylpropan-2-ol hydrochloride as a white solid. MS (ESI) m/z 313 [0202] EXAMPLE 11: (1 RS,2SR)-1 -(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)~1-phenylpropan-2-ol hydrochloride WO 2005/0977(51 PCT/US200S/010510 65 [0203] In an analogous manner to EXAMPLE 3, step 1, ethyl (2RS,3RS)-3-(6-chloro~2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-3-phenylpropanoate was prepared from 6-chloro-3,4~dihydro-2H-1,4-benzoxazine (EXAMPLE 8, step 1) and frans-ethyl-3-phenyIglycidate as a viscous, yellow liquid. MS (ESI) m/z 362.0 ([M+H]+); HRMS: calcd for C19H2oCIN04 + H+, 362.1154; found (ESI, [M+H]+), 362.1150, [0204] In an analogous manner to EXAMPLE 3, step 2, (2RS,3RS)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yI)-2-hydroxy-N-methyl-3-phenylpropanamide was prepared froni ethyl (2RS,3RS)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yI)-2-hydroxy-3-phenyl propanoate as white needles. MS (ESI) m/z 344.9 ([M-H]'); HRMS: caicd ;for C18Hi9CIN2O3 + H+, 347.1157; found (ESI, [M+H]4), 347.1150. [0205] In ah analogous manner to EXAMPLE 3, step 3, (1RS,2SR)-1-(6-ch!oro-2,3-dihydro-4M-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan~2-ol hydrochloride was prepared from (2RS,3RS)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-N-methyl-3-phenylpropanamide as a white powder. MS (ESI) m/z 333.1 ([M+H]+); HRMS: calcd for C18H2iCIN2O2 + H+, 333.1370; found (ESUM+H]+),i333.1381. [0206] EXAMPLE 12: (1RS,2SR)-3-(methylamino)-1-(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)~1 -phenylpropan-2-ol hydrochloride [0207] In an analogous manner to EXAMPLE 16, step 1, 6-methyl-3,4-dihydro-2H-1,4-benzoxazine was prepared from 6-methyl-2H-1,4-benzoxazin-3(4H)-one as a WU Z005/097I761 PCT/US2O05/0105m 66 yellow oil. MS (ES) m/z 150.0 ([M+H]+); HRMS: calcd for C9HnNO + H+, 150.0919; found (ESI, [M+H]4), 150.0924. [0208] Injan analogous manner to EXAMPLE 3, step 1, ethyl (2RS,3RS)-2-hydroxy~3-(6-methyl-2J3-dihydro-4H-1,4-benzoxazin-4-yI)-3-phenyIpropanoate was prepared from 6-methyl-3,4-dihydro-2H-1,4-benzoxazine and frans-ethyl-3-phenylglycidate as a viscous, yellow liquid. MS (ESI) m/z 342.0 ([M+H]+); HRMS: calcd for C20H23NO4+ H+, 342.1700; found (ESI, [M+H]4), 342.1683. [0209] In ah analogous manner to EXAMPLE 3, step 2, (2RS,3RS)-2-hydroxy-N-methyl-3-(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-phenylpropanamide was prepared from ethyl (2RS,3RS)-2-hydroxy-3-(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4jyl)-3-phenyl propanoate as a white powder. MS (ESI) m/z 325.0 ([M-H]'); HRMS: Calcd for Ci9H22N2O3 + H+, 327.1703; found (ESI, [M+H]+), 327.1703. [0210] In an analogous manner to EXAMPLE 3, step 3, (1RS,2SR)-3- (methylamino)-i -(6-methyi-2,3-dihydro-4H-1,4-benzoxazin-4~yl)-1 -phenylpropan-2-ol hydrochloride was prepared from (2RSI3RS)-2-hydroxy-N-methyl-3-(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-phenylpropanamide as a white powder. MS (ESI) m/z 313.0 ([fVI+H]+); HRMS: calcd for C19H24N2O2 + H+, 313.1911; found (ESI, [M+H]+), 313.-1908. [0211] EXAMPLE 13: (1Sl2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino,)-1-phenylpropan-2-ol hydrochloride [0212] Step 1: Racemic (1RS,2SR)-1-(6-ch!oro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methy[amino)-1-phenyIpropan-2-ol (EXAMPLE 11) was dissolved in methanol. The resulting solution was injected onto the Supercritical Fluid Chromatography instrument, the baseline resolved enantiomers, using the conditions described below, were collected. The enantiomeric purity of each enantiomer was determined WO 20()S/(ty77rtl PCT/US2005/0105V0 67 under the same Supercritical Fluid Chromatography conditions using a Chiralpak AD-H 5u, 250 mm x 4.6 mm ID column at 2.0 mL/minutes flow rate using Analytical Supercritical Fluid Chromatography (Berger Instruments, Inc. Newark, DE USA).. SFC Instrument: Berger MultiGram Prep SFC (Berger Instruments, Inc. Newark, DE 19702. Column: Chiralpak AD-H; 5u; 250mm L x 20mm ID (Chiral Technologies, Inc, Exton, PA, USA) Column temperature: . 35°C SFC Modifier: 40% MeOH with 0.5% DEA Flow rate: 50 mL/min Outlet Pressure: 100 bar Detector: UVat266nm [0213] Step;2: A solution of (1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-ol, isolated as Peak 1, (58 mg, 0.17 mmol) in dichloromethane (3 ml_) was treated with an ethereal solution of hydrochloric acid (1 M, 0.2 ml_, 0:2 mmol). To the resulting solution was added hexane until white powder formed, which was collected, washed with hexane, and dried in vacuo to yield 62 mg.(45%) of (1S,2R)-1-(6-chloro-2,3-dihydro-4H-i,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-ol hydrochloride. Chiral purity: > 99.9%. MS (ESI) m/z 333.0 ([M+H]+); HRMS: calcd for C13H21CIN2O2 + H+, 333.1370; found (ESI, [M+H]+), 333.1372. [0214] EXAMPLE 14: (1 R,2S)-1-{6-chloro-2,3-dihydro-4H-1,4-benzoxa2in-4-yl)-3-(methylaminoi-1 -phenylpropan-2-ol hydrochloride [0215] In an analogous manner to EXAMPLE 13, step 2, (1R,2S)-1-(6-chIoro-2,3-dihydro- 4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropan-2-ol hydrochloride was prepared from (1 R,2S)-1 -(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1 - WO 2005/097761 PCT/US2005/010510 68 phenyIpropan-2-o! which was isolated as Peak 2 of the chiral separation (EXAMPLE 13, step 1). Chiral purity: > 99.9%. MS (ESI) m/z 333.0 ([M+H]+); HRMS: calcd for C18H21CIN2O24- H\ 333.1370; found (ESI, [M+H]4), 333.1374. [0216] EXAMPLE 15: (1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3- • fluorophenyl)-3-(methylamino)propan-2-o! hydrochloride [0217] In an analogous manner to EXAMPLE 6, step 4, (2S,3S)-3-(6-chloro-2,3-dihydro~4H-1.4-benzoxazin-4-yl)-3-(3-fluorophenyl)propane-1,2-diol was prepared from 6-chloro-3,4-dihydro-2H-1,4-benzoxazine (EXAMPLE 8, step 1) and [(2R,3R)-3-(3-fluorophenyI)oxiran-2-yl]methanol (EXAMPLE 6, step 3) as a viscous, yellowish liquid. MS (ES) m/z 335.8 ([M-H]"); HRMS: calcd for C20H22FNO2 + H+, 338.0959; found (ESI, [M+H]4), 338.0959. [0218] In an analogous manner to EXAMPLE 6, step 6, (1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-ol hydrochloride was prepared from (2SJ3S)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(3-fluoropheny!)propane-1,2-diol as a white powder. MS (ES) m/z 351.0 ([M+H]+); HRMS: calcd for C1BH2oCIFN202 + H+,. 351.1276; found (ESI, [M+H]+), 351.1276. [0219] EXAMPLE 16: (1S,2R)-1-(2]2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1 -(3-fluorophenyl)-3-(methylamino)propan-2-ol hydrochloride n\jMi\ianrsu\>i PCT/US2005/010510 . 69 [0220] Step 1: To a solution of 2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one4 (2.658 g, 15.0 mmol)iin tetrahydrofuran (10 mL) under nitrogen was added slowly a solution of borane (1.0 M in tetrahydrofuran, 22.5 mL, 22.5 mmol) via a syringe. The resulting mixture was stirred at room temperature for 10 minutes and then at 70°C for 1 hour. After cooling, the reaction mixture was quenched with methanol (3 mL) slowly. All volatiles were removed under reduced pressure. A 1 N aqueous solution of hydrochloric acid (10 mL) was added to the liquid residue and the mixture was warmed to 50°C for 10 minutes. After cooling, the reaction mixture was made alkaline using saturated sodium bicarbonate solution (15 mL), and extracted with ethyl acetate (25 mL). The organic layer was washed with water, brine, dried (anhydrous sodium sulfate), filtered through a pad of silica gel, and concentrated under reduced pressure to yield 2.310 g (94%) of 2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazine as a brown oil. MS (ES) m/z 164.0 ([M+H]+). [0221] Step 2: In an analogous manner to EXAMPLE 6, step 4, (2S,3S)-3-(2,2-dimethyl^.S-dihydro^H-i^-benzoxazin^-ylJ-S-fS-fluorophenylJpropane-i^-diol :was prepared from 2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazine and [(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 6, step 3) as a white solid. MS (ES) m/z 332.2 ([M+Hf); HRMS: calcd for C-^H^FNOg + H+, 332.1657; found (ESI, [M+H]+), 332.il648. [0222] Step 3: In an analogous manner to EXAMPLE 6, step 6, (1S,2R)-1-(2,2-dimethyI-2,3-dihydro~4H-1,4-benzoxazin-4-yl)-1 -(3-fluorophenyl)-3-(methylamino)propan-2-ol hydrochioride was prepared from (2S,3S)-3-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(3-fiuorophenyl)propane-1,2-diol as a white powder. MS (ES) m/z 345.2 ([M+H]+); HRMS: calcd for C20H25FN2O2 + H+, 345.1978; found (ESI, [M+H]+), 345.1981. [0223] EXAMPLE 17: (1S,2R)-1-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yf)-3-(methylamino)~1 -phenylpropan^-ol hydrochioride 4Caliendo, G.; Perissutti, E.; Santagada, V.; Fiorino, F.; Severino, B.; Bianca, R. WO 2005/097761 PCT/US2005/010510 70 [0224] In an analogous manner to EXAMPLE 8, step 4, (2S,3S)-3-(2,2-dimethyl-2,3-dihydro-4h-1,4-benzoxazin-4-yl)-3-phenylpropane-1,2-diol was prepared from 2,2nfimethyl-3-4-dihydro-2H-1,4-benzoxazine (EXAMPLE 16, step 1) and [(2R.3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 10, step 4) as a white solid. MS (ES) m/z 314.1 ([M+H]+). [0225] In an analogous manner to EXAMPLE 6, step 6, (1S,2R)-1~(2J2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)~3-(methylamino)-1-phenyIpropan-2-ol hydrochloride was prepared from (2S,3S)-3-(2I2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-phenylpropane-1,2-dioI as a white powder. MS (ES) m/z 327.2 ([M+Hf); HRMS: calcd for C2QH26N2O2 + H+, 327.2073; found (ESI, [M+H]+), 327.2082. [0226] EXAMPLE 18: (1 S,2R)-1 -(2,3-dihydro-4H~1,4-benzothiazin-4-yl)-1 -(3-fluorophenyl)-3-(methylamino)propan-2-ol hydrochloride [0227] In an1 analogous manner to EXAMPLE 6, step 4, (2S,3S)-3-(2,3-dihydro-4H-1,4-benzothiazin-4-yl)-3-(3-fluorophenyl)propane-1,2-diol was prepared from 3,4-dihydro-2H-1,4-benzothiazine5 and [(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methano! (EXAMPLE 6,| step 3) as a viscous, yellowish liquid. MS (ES) m/z 320.1 ([M+H]+); HRMS: calcd ifor C17H18FNO2S + H+, 320,1115; found (ESI, [M+H]4), 320.1113. 5EI-Subbagh, H. I.; Abadi, A. R; A!-Khawad, I. E.; Al-Rashoodt K- A. Arch. Pharm. 1999, 332,19-24. WO 2005/097761 PCT/US2005/010510 71 [0228] In an analogous manner to EXAMPLE 6, step 6, (1S,2R)-1-(2,3-dihydro-4H-1,4-benzothiazin-4-yl)-1-(3-fIuoropheny!)-3-(methylamino)propan-2-ol hydrochloride was prepared from (2S,3S)-3-(2,3-dihydro-4H-1,4-benzothiazin-4-yl)-3-(3-fluorophenyl)propane-1,2-dio! as a white powder. MS (ES) m/z 333.1 ([M+H]+); HRMS: calcd for C18H2iFN2OS + H+, 333.1431; found (ESI, [M+Hf), 333.1420. [0229] EXAMPLE 19: (1 S,2R)-1 -(3-f!uorophenyl)-3-(methylamino)-1 -(2-pheny!-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propan-2-ol hydrochloride [0230] In ah analogous manner to EXAMPLE 6, step 4, (2S,3S)-3-(3-fluorophenyl)- i 3-(2-phenyl-2!3-dihydro-4H-1,4-benzoxazin-4-yl)propane-1,2-diol was prepared from 2-phenyl-3,4-dihydro-2H-1,4-benzoxazine6 and [(2R,3R)-3-(3-fluorophenyl)oxtran-2-yl]methanol (EXAMPLE 6, step 3) as a white solid. MS (ES) m/z 380.0 ([M+H]+); HRMS: calcd for C23H22FNO3 + H+, 380.1662; found (ESI, [M+H]+), 380.1661. [0231] In an analogous manner to EXAMPLE 6, step 6, (1S,2R)-1-(3-fluorophenyl)-3-(methylamiho)-1-(2-phenyl-2l3-dihydro--4H-1,4-benzoxazin-4-yl)propan-2-oI hydrochioride was prepared from (2S,3S)-3-(3-fluorophenyl)-3-(2-pheny!-2,3-dihydro-4H-1,4-benzpxazin-4-yl)propane-1,2-dio! as a white powder. MS (ES) m/z 393.2 ([M+Hf); HRMS: calcd for C24H2sFN2O2 + H+, 393.1978; found (ESI, [M+H]+), 393.1986. [0232] EXAMPLE 20: (1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2R)-2- phenyl^^-dihydro^H-i^-benzoxazin^-ylJpropan^-ol hydrochloride 6Olagbemiro, T. O.; Nyakutse, C. A.; Lajide, L.; Agho, M. O.; Chukwu, C. E. Bull. Soc. Chim. Belg. 1987,96,473-480. WO 2005/097761 PCT/US2005/010510 72 [0233] Step 1: Diastereomeric mixture of (1S,2R)-1-(3-f!uorophenyl)-3- (methylamino)-i -(2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propan-2-ol (EXAMPLE 19) was dissolved in methanol. The resulting solution was injected onto the Supercritical Fluid Chromatography instrument. The baseline resolved diastereomers, using the conditions described below, were collected. SFC Instrument: Berger MultiGram Prep SFC (Berger Instruments, Inc. Newark, DE 19702. Column: Ethyl pyridine; 250mm L x 20mm ID (Princeton Chromatography Inc.) Column temperature: 35°C SFC Modifier: 15% MeOH with 85% CO2 Flow rate: 50 mL/min Outlet Pressure: 100 bar Detector: UV at 220 nm [0234] Step 2: (IS^RJ-i-fS-fluorophenyO-S-fmethylaminoJ-i-^RJ^-phenyl^.S-dihydro-4H-1i4-benzoxazin-4-yl]propan-2-ol, isolated as peak 1, was subjected to hydrochloride1 salt formation in an analogous manner to EXAMPLE 13, step 2 to give (1S,2R)-1-(3-fluorophenyl)-3-(methylamirio)-1-[(2R)-2-phenyl-2,3-dihydro-4H-1I4-benzoxazin~4-yl]propan-2-ol hydrochloride as a white powder. MS (ES) m/z 393.2 ([M+H]+); HRMS: calcd for C24H25FN2O2 + H+, 393.1973; found (ESI, [M+Hj+), 393.1992. [0235] EXAMPLE 21: (1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2S)-2-phenyI-2,3-dihydro-4H-1,4-benzoxazrn-4-yl]propan-2-ol hydrochloride VYKJ iinra/wy//Di PCT/US20O5/01051O TS [0236] In an analogous manner to EXAMPLE 20, (1S,2R)-1-(3-fluoropheny])-3-(methylamino):-1-[(2S)-2-phenyl-2J3-dihydro-4H-1,4"benzoxazin-4-yl]propan-2-ol hydrochloride-was prepared as a white powder from (1S,2R)-1-(3-fluorophenyl)-3-(methylaminoV-i-^SJ-S-phenyi^^-dihydro^H-i^-benzoxazin^-yllpropan-a-ol, which was isolated as peak 2 of the diastereomeric separation (EXAMPLE 20, stepi). MS (ES) m/z393.2 ([M+H]+); HRMS: calcd for C24H25FN2O2 + H+, 393.1973; found (ESI, [M+HD, 393.1982. Cell Lines. Culture Reagents, and Assays [0237] MDCK-Net6 cells, stably transfected with human hNET (Pacholczyk, T., R.D. Blakely, and S.G. Amara, Nature, 1991, 350(6316): p. 350-4) were cultured in growth medium containing high glucose DMEM (Gibco, Cat. No. 11995), 10% FBS (dialyzed, heat-inactivated, US Bio-Technologies, Lot FBD1129H1) and 500 Dg/m! G418 (Gibco, Cat. No. 10131). Cells were plated at 300,000/ T75 flask and cells were split twice weekly. The JAR cell line (human placental choriocarcinoma) was purchased from ATCC (Cat. No. HTB-144). The cells were cultured in growth medium containing RPM) 1640 (Gibco, Cat. No. 72400), 10% FBS (Irvine, Cat. No. 3000), 1% so;dium pyruvate (Gibco, Cat. No. 1136) and 0.25% glucose. Cells were plated at 250,000 cells/ T75 flask and split twice weekly. For all assays, cells were plated in Wallac 96-well sterile plates (PerkinElmer, Cat. No. 3983498). Norepinephrine fNE) Uptake Assay [0238] On day 1, cells were plated at 3,000 cells/well in growth medium and maintained in a cell incubator (37°C, 5% CO2). On day 2, growth medium was WU ZUU5/W7761 - PCT/US2O05/0105IO 1A replaced with 200 u.1 of assay buffer (25 mM HEPES; 120 mM NaCI; 5 mM KCI; 2.5 mM CaCI2; 1.2'mM MgSO4; 2 mg/ml glucose (pH 7.4, 37BC)) containing 0.2 mg/ml ascorbic acid and 10 \M pargyline. Plates containing cells with 200 uJ of assay buffer were equilibrated for 10 minutes at 37°C prior to addition of compounds. A stock solution iof desipramine was prepared in DMSO (10 mM) and delivered to triplicate wells containing cells for a final test concentration of 1 uM. Data from these wells were used to define non-specific NE uptake (minimum NE uptake). Test compounds were prepared in DMSO (10 mM) and diluted in assay buffer according to test range (1 to 10,000 nM). Twenty-five microliters of assay buffer (maximum NE uptake) or test compound were added directly to triplicate wells containing cells in 200 u,l of asSay buffer. The cells in assay buffer with test compounds were incubated for 20 minutes at 37°C. To initiate the NE uptake, [3H]NE diluted in assay buffer (120 nM final assay concentration) was delivered in 25 \i\ aliquots to each well and the plates: were incubated for 5 minutes (37°C). The reaction was terminated by decanting the isupernatant from the plate. The plates containing cells were washed twice with 200 uJ assay buffer (37°C) to remove free radioligand. The plates were then inverted,!left to dry for 2 minutes, then reinverted and air-dried for an additional 10 minutes. The cells were lysed in 25 \i\ of 0.25 N NaOH solution (4DC), placed on a shake table and vigorously shaken for 5 minutes. After cell lysis, 75 u.l of scintillation cocktail was added to each well and the plates were sealed with film tape. The plates were returned to the shake table and vigorously shaken for a minimum of 10 minutes to ensure adequate partitioning of organic and aqueous solutions. The plates were counted in a Wallac Microbeta counter (PerkinElmer) to collect the raw cpm data. Serotonin (5-HT) Uptake Assay [0239] The methods for 5-HT functional reuptake using the JAR cell line were modified usirjig a previous literature report (Prasad, et a/., Placenta, 1996. 17(4): 201-7). On day 1, cells were plated at 15,000 ceils/well in 96-well plates containing growth medium (RPM11640 with 10% FBS) and maintained in a cell incubator (37GC, 5% CO2). On day 2, cells were stimulated with staurosporine (40 nM) to increase WO 2005/097761 PCT/US2005/010S10 75 the expression of the 5-HT transporter [17]. On day 3, cells were removed from the cell incubator | two hours prior to assay and maintained at room temperature to equilibrate the; growth medium to ambient oxygen concentration. Subsequently, the growth medium was replaced with 2Q0 \x\ of assay buffer (25 mM HEPES; 120 mM NaCI; 5 mM KCI; 2.5 mM CaCI2; 1.2 mM MgSO4; 2 mg/ml glucose (pH 7.4, 37BC)) containing 0.2 mg/mi ascorbic acid and 10 \M pargyline. A stock solution of paroxetine (ArtR-4389-1) was prepared in DMSO (10 mM) and delivered to triplicate wells containing cells for a final test concentration of 1 uM. Data from these wells were used to define non-specific 5-HT uptake (minimum 5-HT uptake). Test compounds were prepared in DMSO (10 mM) and diluted in assay buffer according to test range (1 to 1,000 nM). Twenty-five microliters of assay buffer (maximum 5- HT uptake) or test compound were added directly to triplicate wells containing cells in 200 nl of assay buffer. The cells were incubated with the compound for 10 minutes (37Ed). To initiate the reaction, [3H]hydroxytryptamine creatinine sulfate diluted in assay buffer was delivered in 25 \i\ aliquots to each well for a final test concentration ;of 15 nM. The cells were incubated with the reaction mixture for 5 minutes at 37BC. The 5-HT uptake reaction was terminated by decanting the assay buffer. The cells were washed twice with 200 u.I assay buffer (37°C) to remove free radioligand. The plates were inverted and left to dry for 2 minutes, then reinverted and air-dried for an additional 10 minutes. Subsequently, the cells were lysed in 25 ixl of 0.25 N N'aOH (4*C) then placed on a shaker table and shaken vigorously for 5 minutes. After cell lysis, 75 [i\ of scintillation cocktail was added to the wells, the plates were sealed with film tape and replaced on the shake table for a minimum of . 10 minutes. The plates were counted in a Wallac Microbeta counter (PerkinElmer) to collect the raw cpm data. Evaluation of Results i [0240] For each experiment, a data stream of cpm values collected from the i Wallac Microbeta counter was downloaded to a Microsoft Excel statistical application program. Calculations of EC5o values were made using the transformed-both-sides logistic dose response program written by Wyeth Biometrics Department. The statistical program uses mean cpm values from wells representing maximum binding WO 2005/097761 PCT/US2005/01051O 76 or uptake (assay buffer) and mean cpm values from wells representing minimum binding or uptake ((1 pM desipramine (hNET) or 1 pM paroxetine (hSERT)). Estimation of the EC50 value was completed on a log scale and the line was fit between the m'aximum and minimum binding or uptake values. All graphic data representation yvas generated by normalizing each data point to a mean percent based on the maximum and minimum binding or uptake values. The EC5o values reported from multiple experiments were calculated by pooling the raw data from each experiment and analyzing the pooled data as one experiment. The resultsare reported in Table 1. Table 1 Example % Inhibition @ 1 pM (hNET) 2 33.7 4 46.2 5 52.9 8 12.5 9 53.9 11 60.6 12 3.4 13 38.6 14 41.5 15 41.4 16 10 17 9.3 18 90.4 19 95 20 97.2 21 51.7 [0241] Wheh ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinatioiiis of ranges specific embodiments therein are intended to be WO 2005/09*761 PCT/US2005/010510 77 included. [0242] The; disclosures of each patent, patent application and publication cited or described in j this document are hereby incorporated herein by reference, in its entirety. [0243] Those skilled in the art will appreciate that numerous changes and modifications' can be made to the preferred embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the invention. WO 2005/097761 PCT/US2005/010510 78 What is claimed is: 1. A compound of formula I: or a pharmaceutically acceptable salt thereof; Wherein: the dotted line represents an optional double bond between U and V or V and W; LI is, independently, O, S, SO, SO2, C=O, N, NR3, or C(R8)2; W is CH, CH2, or C=O; provided that when W is CH2l U is not C(R8)2; VisC(R8),C(R8)2,O,orN(R6); Ri is, independently at each occurrence, alkyl, alkoxy, haloirCF3, OCF3, arylalkyloxy substituted with 0-3 Rg, aryloxy substituted with 0-3 R9, aryl substituted with 0-3 Rg, heteroaryl substituted with 0-3 R9, hydroxy, alkanoi'loxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 R9, alkylsulfone, phenylsulfone substituted with 0-3 R9, alkylsulfonamide, phenylsulfonamide substituted with 0-3 R9, heteroaryloxy substituted with 0-3 Rg, heteroarylmethyloxy substituted with 0-3 R9, alkylamido, or phenylamido substituted with 0-3 Rg; or two adjacent R-t also represent methylenedioxy; R2 is aryl substituted with 0-3 Ri or heteroaryl substituted with 0-3 Ri; R3 is H, C1-C4 alkyl substituted with 0-3 Ri, C3-C6 cycloalkyl, or phenyl substituted with 0-3 R-i; R4 is, independently at each occurrence, H, CrC4 alkyl, arylalkyl, WO 2005/097761 PCT/US2O05/O10510 V) heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl, or both R4 groups, together with the nitrogen through which they are attached,^ form a heterocyclic ring of 4 to 6 ring atoms, where'one carbon may be optionally replaced with N, O, S, or SO2, and where any carbon ring atom or additional N atom may be optionally substituted with C1-C4 alkyl, F, or CF3; R5 is H or C1-C4 alkyl; REUSH or-CrC4 alkyl; Rt is, independently at each occurrence, H, or C1-C4 alkyl, or R7 and R4 together with the nitrogen to which R4 is attached form a nitrogen-icontaining ring containing 3-6 carbon atoms; Hk is, independently at each occurrence, H, C1-C4 alkyl, C3-C6 heteroalkyl, or aryl substituted with 0-3 R1; Rb is, independently at each occurrence, alkyl, alkoxy, halo, CF3) OCF3| ftydroxy, alkanoyloxy, nitro, nitrile, alkeny!, alkynyl, alkylsulfoxide, alkylsulfbne, alkylsulfonamide, or alkylamido; or two adjacent R9 also represent methylenedioxy; n is an integer from 0 to 4; xiis an integer from 1 to 2; and Wherein 1-3 carbon atoms in ring A may optionally be replaced with N. A compound according to claim 1, wherein: liisO. A compound according to claim 1 or claim 2, wherein; W is CH2. A compound according to any one of claims 1 to 3, wherein: R-i is halo. A compound according to claim 4, wherein: Ri isfluoro orchioro. WO 2005/097761 PCT/US2005/010510 80 A comDOund according to any one of claims 1 to 5, wherein: iR2 is aryl substituted with 0-3 Ri. A compound according to claim 6, wherein:, aryl is phenyl. A compound according to any one of claims 1 to 7, wherein: iR3 is H or Ci alkyl. A compound according to any one of claims 1 to 8, wherein: FUisHorCi-C4alkyl. A compound according to claim 9, wherein: FU is H, methyl, ethyl, or isopropyl. A compound according to any one of claims 1 to 8, wherein: both FU groups, together with the nitrogen through.which they are attached, form a pyridine, piperidine, piperazine, or morpholine ring. A compound according to any one of claims 1 to 11, wherein: R5 is, independently at each occurrence, H orCi alkyl. A compound according to any one of claims 1 to 12, wherein: n is Oor 1. A compound according to claim 1, which is one of the following: 1-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1- phenylpropan-2-ol; 3-(methylamino)-1 -(4-methy!-3,4-dihydroquinoxalin-1 (2H)-yl)-1 - phenyjpropan-2-bl; 3-(methylamino)-1 -phenyl-1 -[4-(2,2,2-trifluoroethyl)-3,4- dihydroquinoxalin-1(2H)-yl]propan-2-ol; WU2IMI5/IW7761 PCT/US2005/010510 81 1 -(6-chloro-2,3:.dihydro-4H-1,4-benzoxazin-4-yl)-1 -(3,5-difluorophenyl)-3-(rnethyIarnino)propan-2-ol; 1 -(3-f luorophenyl)-3-(methylamino)-1 -(2-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propan-2-ol; 1 -(6-chloro-2,3-dihydro-4H-1 ,4-benzoxazin-4-yl)-3-(rnethylarnino)-1 -phenylpropan-2-ol; 3-(methylamino)-1 -(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1 -phenyipropan~2-ol; 1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(nnethylamino)-1-phenyIpropan-2-ol; 1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenyipropan-2-ol; 1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-ol; 1 -(2J2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-l -(3-fluorophenyl)-3-(methylaminG)propan-2-ol; 1-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1 -phehylpropan-2-ol; 1 -(2,3-dihydro-4H-1,4-benzothiazin-4-yl)-1 -(3-f!uorophenyl)-3-(methylamino)propan-2-ol; l-(3-fluorophenyl)-3-(methylamino)-1-(2-phenyl-2I3-dihydro-4H-1,4- . benzoxazin-4-yl)propan-2-ol; 1 -(3-f!uorophenyI)-3-(methylamino)-1 -[2-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl]propan-2-ol; or 1 -(3-fIuorophenyl)-3-(methylamino)-1 -[2-phenyl-2,3-dihydrcMH-1,4-benzoxazin-4-yl]propan-2-ol; or ,a pharmaceutically acceptable salt thereof. 15. A comf3ound according to claim 1, which is one of the following:' ;(1RS,2SR)-1-(2)3-dihydro-4H-1J4-benzoxazin-4-yl)-3-(methylamino)-1- phenylpropan-2-ol; (1 S*,2R*)-3-(methylamino)-1 -(4-methyl-3,4-dihydroquinoxalin-1 (2H)- yl)-1-pliienylpropan-2-ol; WO 2005/097761 PCT/US2O05/010510 (1S*,2R*)-3-(methylamino)-1-phenyl-1-[4-(2,2I2-trrfluoroethyl)-3,4-dihydroquinoxa!in-1(2H)-y!]propan-2-ol; (1S)2R)-1-(6-chloro-2l3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3,5-difluorophenyl)-3-(methyIamino)propan-2-ol; (1S,2R)-1-(3-fluorophenyi)-3-(methylamino)-1-(2-methyl-2,3-dihydro~ 4H-1,4-benzoxazin-4-yl)propan-2-ol; 1(1 S*,2R*)-1 -(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(meth\Hamino)-1-phenylpropan-2-ol; (1S*,2R*)-3-(methylamino)-1-(6-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-y!)-i-pheny!propan-2-ol; (1S,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methyiamino)-1-phenyipropan-2-ol; ifiR^SJ-i-ce-chloro^.S-dihydro-^H-i^benzoxazin^-yO-S-(methylamino)-l -phenylpropan-2-ol; (1S,2R)-1-(6-chloro-2l3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3-fluorophenyl)-3-(methyJamino)propan-2-ol; (1S,2R)-1-(2l2-dimethyN2I3-dihydro-4H-1,4-benzoxazin-4-yl)-1-(3-' i fluoronhenyl)-3-(methyIamino)propan-2-ol; (1S,2R)-1-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-i -phenylpropan-2-ol; (1 S,2R)-1 -(2,3-dihydro-4H-1 ^-benzothiazin^-yO-i -(3-fluorophenyl)-3-(methyiamino)propan-2-ol; (1 S,2R)-1 -(3-fluorophenyl)-3-(methylamino)~1 -(2-phenyl-2,3-dihydro-4H-1,4-:benzoxazin-4-yl)propan-2-ol; (iS,2R)-1-(3-f!uorophenyl)-3-(methylamino)-1-[(2R)-2-phenyl-2,3-dihydro^4H-1,4-benzoxazin-4-yl]propan-2-ol; or (j1S,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2S)-2-phenyl-2,3-dihydroMH-i ,4-benzoxazin-4-yl]propan-2-oI; or, a pharmaceuticaily acceptable salt thereof. 6. A composition, comprising: a. at least one compound according to any one of claims 1 to 15; and b. at least one pharmaceutically acceptable carrier. WO 2005/097761 PCT/US2005/010510 83 17. A method 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 according to any one of claims 1 to 15 or pharmaceutically acceptable salt thereof 18. A method according to claim 17, Wherein said condition ameliorated by monoamine reuptake is selected from tfre group consisting of vasomotor symptoms, sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, . fibromyllagia syndrome, nervous system disorders, and combinations thereof. 19. A method according to claim 18, wherein said condition ameliorated by monoamine reuptake is selected from the group consisting of major depressive disorder, vasomotor symptoms, stress and urge urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and cornbinations thereof. 20. A method for treating or preventing at least one vasomotor symptom in a subject in need thereof, comprising the step of: administering to said subject an effective amount of a compound according to any one of claims 1 to 15 or pharmaceutical ly acceptable salt thereof. 21. A method according to claim 20, Wherein said vasomotor symptom is hot flush. 22. A method according to claim 21, wherein said subject is human. 23. A method according to claim 22, wherein said human is a female. TV0 2(105/097761 PCT/US2flO5/01051O 84 24. A m°+!jiod according to claim 23, wherein said female is pre-menopausal. 25. A method according to claim 23, ¦wherein said female is peri-menopausal. 26. A method according to claim 23, wherein said female is post-menopausal. 27. A method according to claim 22, wherein said human is a male. 28. A method according to claim 27, wherein said male is naturally, chemically or surgically andropausal. 29. A method for treating or preventing at least one depression disorder in a subject in need thereof, comprising the step of: administering to said subject an effective amount of a compound accordjnq to any one of claims 1 to 15 or pharmaceuticaiiy acceptable salt thereof 30. A method according to claim 29, therein said depression disorder is major depressive disorder, anxiety, sleep disturbance, or social phobia. . . 31. A method according to claim 30, wherein said subject is human. 32. A metriod for treating or preventing at least one sexual dysfunction in a i subjectjin need thereof, comprising the step of: administering to said subject an effective amount of a compound accordihg to any one of claims 1 to 15 or pharmaceuticaiiy acceptable salt WO 2005/09776! PCT/US2005/01051O 85 thereof. 33. A method according to claim 32, Wherein said sexual dysfunction is desire-related or arousal-related. 34. A method according to claim 33, wherein said subject is human. 35. A method for treating or preventing pain in a subject in need thereof, | comprising the step of: administering to said subject an effective amount of a compound according to any one of claims 1 to 15 or pharmaceutically acceptable salt thereof. 36. A method according to claim 35, wherein said pain is acute centralized pain, acute peripheral pain, or a combination thereof. 37- A methbd according to claim 35, i wherein said pain is chronic centralized pain, chronic peripheral pain, or a combination thereof. 38. A method according to claim 35, Wherein said pain is neuropathic pain, visceral pain, musculoskeletal pain, bony pain, cancer pain, inflammatory pain, or a combination thereof. 39. A method according to claim 38, wherein said neuropathic pain is associated with diabetes, post traumatic pain of amputation, lower back pain, cancer, chemical injury, toxins, major surgery, peripheral nerve damage due to traumatic injury compression, post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngea! neuralgia, reflex sympathetic WO 2005/097761 PCT/US2005/010510 86 dystrophy, casualgia, thaiamic syndrome, nerve root avulsion, reflex sympathetic dystrophy or post thoracotomy pain, nutritional deficiencies, viral infection, bacteriaf infection, metastatic infiltration, adiposis dolorosa, burns, central pain conditions related to thaiamic conditions, and combinations thereof A methud according to claim 38, wherein said visceral pain is associated with ulcerative coiitis, irritable i bowel ! syndrome, irritable bladder, Crohn's disease, rheumatologic (arthral^ias), tumors, gastritis, pancreatitis, infections of the organs, biliary tract disorders, and combinations thereof. A method according to claim 35, wherein said pain is female-specific pain. A method according to claim 35, wherein said subject is human. A method for treating or preventing gastrointestinal or genitourinary disorder in a subject in need thereof, comprising the step of: administering to said subject an effective amount of a compound according to any one of claims 1 to 15 or pharmaceutically acceptable salt thered. A method according to claim 43, wherein said disorder is stress incontinence or urge urinary incontinence. A method according to claim 44, wherein said subject is human. A method for treating or preventing chronic fatigue syndrome in a subject in need thereof, comprising the step of: wu zuuD/uyy/oj . I'ci/uszmwuiuMU 87 administering to said subject an effective amount of a compound according to any one of claims "1 to 15 or pharmaceutical!1/ acceptable salt thereof. A metho'd according to claim 46, i wherein said subject is human. A method for treating or preventing fibromylagia syndrome in a subject in i ¦ ; need thereof, comprising the step of: administering to said subject an effective amount of a compound according to any one of claims 1 to 15 or pharmaceutically acceptable salt thereof. A method according to claim 48, i Wherein said subject is human. The present invention is directed to phenylaminopropanol derivatives of formula 1: or a pharmaceutical ly acceptable salt thereof, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions ameliorated by monoamine reuptake including, inter alia, vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromylagia syndrome, nervous system disorders, and combinations thereof, particularly those conditions selected from the group consisting of major depressive disorder, vasomotor symptoms, stress and urge urinary incontinence, fi-bromyalgia, pain, diabetic neuropathy, and combinations thereof.