Title of Invention	4-PHENYL-SUBSTITUTED TETRAHYDROISOQUINOLINE OF THE FORMULA IA-IF
Abstract	Provided herein are compounds of formulae IA-IF. These compounds are tetrahydroisoquinolines of structure (A) wherein R?1¿-R?8¿ for compounds of each of the formulae IA, IB, IC, ID, IE and IF are as described herein. Said compounds are particularly useful in the treatment of various neurological and psychiatric disorders, e.g., ADHD.

Full Text

4-PHENYL-SUBSTITUTED TETRAHYDROISOQUINOLINES AND USE THEREOF TO BLOCK REUPTAKE OF NOREPINEPHRINE, DOPAMINE AND SEROTONIN Field of the Invention The present invention relates to compounds, compositions, methods for the trearment of various neurological and psychological disorders, and the use of the compounds in combination therapy. In particular, the present invention relates to such compounds, compositions and methods wherein the compounds are novel 4-phenyl substituted tetrahydroisoquinolines derivatives. Background of the Invention Serotonin, dopamine and norepinephrine are known to be important chemical messengers participating in the transmission of nerve impulses in the brain. These messengers are liberated at specific sites on pre-synaptic cells and received, to complete transmission of the impulse, at specific sites on post-synaptic cells. Their effect is then terminated by metabolism or by uptake into the pre-synaptic cells. Drugs capable of blocking the pre-synaptosomal uptake of either of these chemical messengers in the brain, are useful in alleviating disorders associated with decreased levels of these chemical messengers. For example, duloxetine and fluoxetine which arc known serotonin reuptake inhibitors have been found to be useful in the treatment of depression, obesity and obsessive-compulsive disease (Wong, et al., U.S. Patent No. 5,532,244). Also. Moldi. et al., U.S. Patent No. 5,444,070. discloses the use of dopamine reuptake inhibitors in the treatment of depression. Parkinsonism, drug addiction and/or abuse, cocaine and/or amphetamine addiction and/or abuse. Freedman, et al., U.S. Patent No. 6,136.803 also discloses synaptic norepinephrine or serotonin uptake inhibitors which are useful in treating depression in a patient. Furthermore, Norden, U.S. Patent No. 5.789,449 discloses the use of serotonin re-uptake inhibitors in treating psychiatric symptoms consisting of anger, rejection sensitivity, and lack of mental or physical energy. Also, Foster, et al., U.S. Patent No. 4.902,710. discloses the use of serotonin and norepinephrine uptake inhibitors in suppressing the desire of humans to smoke or consume alcohol. Thus, there continues to remain a need to develop novel compounds which block reuptake of norephinephrine, dopamine or serotonin. Compounds which inhibit the reuptake of serotonin or norephinephrine. have also been used in combination therapy. For example. Glatt. ei al., U.S. Patent no. 6,121,261 discloses the use of selective serotonin reuptake Inhibitors or norephinephrine uptake inhibitiors. in combination with neurokinin-1 receptor antagonist for treating attention deficit disorder in a patient. Also, Hohenwarter, U.S. Patent No. 4.843,071 discloses the use of a norepinephrine re-uptakc inhibitor and a norepinephrine precursor in the treatment of obesity, drug abuse, or narcolepsy in a patient. Furthermore. Wong, et al., U.S. Patent No. 5,532.244, discloses the use of serotonin reuptake inhibitors in combination with a serotonin IA receptor antagonist, to increase the availability of serotonin, norepinephrine and dopamine in the brain. The treatment of a variety of neurological and psychiatric disorders is characterized by a number of side effects believed to be due to the compounds' inability to selectvely block certain neurochemicals, and not others. ADHD, for example, is a disease affecting 3-6% of school age children, and is also recognized in percentage of adults. Aside from hampering performance at school, and at work, ADHD is a significant risk factor for the subsequent development of anxiety disorders, depression, conduct disorder and drug abuse. Since current treatment regimes require psychostimulants, and since a substantial number of patients (30%) are resistant to stimulants or cannot tolerate their side effects, there is a need for a new drug or class of drugs which treats ADHD and does not have resistance or side effect problems. In addition, methylphenidate, the current drug of choice for the treatment of ADHD, induces a number of side effects; these include anorexia, insomnia and jittery feelings, tics, as well as increased blood pressure and heart rate secondary to the activation of the sympathetic nervous system. However, Methylphenidate also has a high selectivity for the dopamine transporter protein over the norepinephrine transporter protein (DAT/NET Ki ratio of 0.1), which can lead to addiction liability and requires multiple doses per day for optimal efficacy. Thus, there continues to remain a need to develop novel compounds which block reuptake of norephinephrine, dopamine, and serotonin with particular selectivity ratios. U.S. Patent No. 3,947,456, discloses tetrahydroisoquinolines which are said to have utility as anti-depressants. U.S. Patent No. 3,666,763, describes the use of phenyl tetrahydroisoquinoline derivatives as antidepressants and antihypotensives. Canadian Patent Application No. 2,015J 14, discloses the use of phenyl tetrahydroisoquinoline derivatives as antidepressants; moreover, described therein are apparently nonselective as to norepinephrine, serotonin and dopamine uptake. UK Patent Application No. 2.271,566 , discloses the use of phenyl tetrahydroisoquinoline derivatives as anti-HIV agents. PCT International Application No. WO98/40358 discloses the use of phenyl tetrahydroisoquinoline derivatives to be useful in the treatment of disorders of glucose metabolic pathways. W097/36876 discloses the use of phenyl tetrahydroisoquinoline derivatives as anticancer agents. W097/23458 also describes 4 phenyl-substiiuted tetrahydroisoquinolines as NMDA receptor ligands useful for conditions associated with neuronal loss. Phenyl-substituted tetrahydroisoquinolines are also described in Mondeshka et al I] Farmaco, 1994,49 pp. 475-481. Nomofensine® which is a 4 phenyl-substituted tetrahydroisoquinoline derivative is known to inhibit the neuronal uptake of dopamine and other catecholamines and has shown clinical efficacy for ADHD. However, long term administration of Nomofensine® results in fatal immune hemolytic anemia. Thus, there continues to remain a need to develop novel compounds which treat ADHD but do not have the serious side effects associated with Nomifensine® or the currently prescribed psychostimulants. The present invention discloses novel arvl and heteroaryl substituted tetrahydroisoquinoline derivatives compounds which block reuptake of norephinephrine. dopamine, or serotonin, and are useful as alternatives to methylphenidate, and known psychostimulants, in the treatment of ADHD and other neurological and psychiatric disorders. The present inventors have discovered that the claimed compounds which block reuptake of norephinephrine, dopamine, and serotonin with particular selectivity ratios, e.g., being more selective for the norepinephrine transporter (NET) protein than dopamine transporter (DAT) protein or serotonin transporter (SERT) protein (lower Ki for NET than for DAT and SERT). It is postulated that the compounds would therefore be effective as an ADHD treatment with reduced addictive liability profiles. In particular, someof the compounds of this invention are surprisingly and particularly selective for NET over the SERT protein, thus also affording compounds without the known side effect profiles of the selective serotonin reuptake inhibitor (SSRI) class of compounds. Summary of the Invention This invention is directed to a compound of formulae (lA-F): provided that for compounds of formula IE at least one of R1 or R2 is fluoro, chloro. or methyl; DETAILED DESCRIPTION OF THE INVENTION As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:- The term "Alkyl" means an aliphatic hvdrocarbon group which may be straight or branched having about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alky! chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl, ;7-pentyl, and 3-pentyl. The term "Alkenyl" means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. Exemplary alkenyl groups include ethenyl, propenyl, /i-butenyl, and /-buienyl. The term "Alkynyi" means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Preferred alkynyi groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkynyi chain. Exemplary alkynyi groups include ethynyl, propynyl, /7-butynyl, 2-butynyK 3-methylbutynyl, and n-pentynyl. The term "Aryl" means an aromatic monocyclic or multicyclic ring system of 6 to about 14 carbon atoms, preferably of 6 to about 10 carbon atoms. Representative aryl groups include phenyl and naphthyl. The term "Heieroaryl" means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example, nitrogen, oxygen or sulfur. Preferred heteroaryls contain about 5 to 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. A nitrogen atom of a heieroaryl is optionally oxidized to the corresponding N-oxide. Representative heteroaryls include pyrazinyl: furanyl; thienyl; pyridyl; pyrimidinyl; isoxazolyl; isothiazolyl; oxazolyl; thiazolyl; pyrazolyh furazanyl; pyrrolyl; pyrazolyl; triazolyl; 1.2,4-thiadiazolyl; pyrazinyl; pyridazinyl; quinoxalinyl; phthalazinyl; l(2H)-phthalazinonyl; imidazo[l,2-a]pyridine; imidazo[2,l-b]thiazolyl; benzofurazanyl; indolyl: azaindolyl; benzimidazolyl: benzoihienyl; quinolinyl: imidazolyl; thienopyridyl; quinazolinyl: thienopyrimidyl; pyrrolopyridyl; imidazopyridyl: isoquinolinyl; benzoazaindolyl; azabenzimidazolyl. 1,2,4-triazinyl; benzothiazolyi and the like. The term "Alkoxy" means an alkyl-0- group wherein the alkyl group is as herein described. Exemplary alkoxy groups include methoxy. ethoxy. n-propoxy. /-propoxy. /7-butoxy and heptoxy. The term 'Compounds of the invention", and equivalent expressions, are meant to embrace compounds of general formulae (lA-F) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. Similariy, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits. The term "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system of about 3 to about 7 carbon atoms, preferably of about 5 to about 7 carbon atoms. Exemplary monccyclic cycloalkvl include cyclopentyl, cyclohexyl, cycloheptyl and the like. The term "Cycloalkylalkyl" means an cycloalkyl-alkyl- group in which the cycloalkyl and alkyi are as defined herein. Exemplary cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylmethyl. The term "Halo" or "halogen" means fluoro, chloro, bromo, or iodo. The term "Haloalkyl" means both branched and straight-chain alkyl substituted with 1 or more halogen, wherein the alkyl group is as herein described. The term "Haloalkoxy" means a C, alkoxy group substituted by at least one halogen atom, wherein the alkoxy group is as herein described. The term "Substituted" or "substitution" of an atom means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded. "Unsubstiiuted" atoms bear all of the hydrogen atoms dictated by their valency. When a subslituenl is keio (i.e., =0), then 2 hydrogens on the atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds; by "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The term "Pharmaceutically acceptable salts" means the relatively non-toxic, inorganic and organic acid addition salts, and base addition salts, of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds. In particular, acid addition salts can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Exemplary acid addition salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate. stearate, laurate, borate, benzoate, lactate, phosphate, tosylate. citrate, maleate. fumarate, succinate, tartrate, naphthylate. mesylate, glucoheptonaie, lactiobionate, sulphamates. malonates. salicylates, propionates, methylene-bis-b-hydroxynaphihoates. gentisates, iseihionaies, di-p-toluoyltartrates. methane-sulphonates. ethanesulphonates, benzenesulphonates, p-toluenesulphonales, cyclohexylsulphamates and quinateslaurylsulphonate salts, and the like. (See, for example S. M. Berge, et al., "Pharmaceutical Salts,' J. Pharm. Sci., 66: p.1-19 (1977) and Remington's Pharmaceutical Sciences, 17th ed.. Mack Publishing Company. Easton, PA, 1985, p. 1418. which are incorporated herein by reference.) Base addition salts can also be prepared by separately reacting the purified compound in its acid form with a suitable organic or inorganic base and isolating the salt thus formed. Base addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal sails include the sodium, potassium, calcium, barium, zinc, magnesium, and aluminum salts. The sodium and potassium salts are preferred. Suitable inorganic base addition salts are prepared from metal bases which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide. Suitable amine base addition salts are prepared from amines which have sufficient basicity to form a stable salt, and preferably include those amines which are frequently used in medicinal chemistry because of their low toxicity and acceptability for medical use. ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, iris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine. dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, eihylamine, basic amino acids, e.g., lysine and arginine, and dicyclohexyiamine, and the like. The term "Pharmaceutically acceptable prodrugs" as used herein means those prodrugs of the compounds useful according to the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate wMth a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitierionic forms, where possible, of the compounds of the invention. The term "prodrug" means compounds that are rapidly transformed //; vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. Functional groups which may be rapidly transformed, by metabolic cleavage, in vivo form a class of groups reactive with the carboxyl group of the compounds of this invention. They include, but are not limited to such groups as alkanoyl (such as acetyl, propionyl, butyryl. and the like), unsubstituted and substituted aroyl (such as benzoyl and substituted benzoyl), alkoxycarbonyl (such as ethoxycarbonyl). trialkylsilyl (such as trimethyl- and triethysilyl), monoesters formed with dicarboxylic acids (such as succinyl), and the like. Because of the ease with which the metabolically cleavable groups of the compounds useful according to this invention are cleaved in vivo, the compounds bearing such groups act as pro-drugs. The compounds bearing the metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group. A thorough discussion of prodrugs is provided in the following: Design of Prodrugs, H. Bundgaard, ed., Elsevier. 1985; Methods in Enzymology, K. Widder et al, Ed., Academic Press. 42, p.309-396, 1985; A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard. ed.. Chapter 5; 'Design and Applications of Prodrugs" p. 113-191. 1991; Advanced Drug Delivery Reviews, H. Bundgard, 8, p. I-38, 1992; Journal of Pharmaceutical Sciences, 77, p. 285, 1988; Chem. Pharm. Bull., N. Nakeya et al, 32, p. 692, 1984; Pro-drugs as Novel Delivery Systems, T. Higuchi and V. Stella. Vol. 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference. Examples of prodrugs include, but are not limited to. acetate, fonnaie and benzoaie derivatives of alcohol and amine functional groups in the compounds of the invention. The term "Therapeutically effective amounts" is meant to describe an amount of compound of the present invention effective in increasing the levels of serotonin, norepinephrine or dopamine at the synapse and thus producing the desired therapeutic effect. Such amounts generally vary according to a number of factors well within the purview of ordinarily skilled artisans given the description provided herein to determine and account for. These include, without limitation: the particular subject, as well as its age, weight, height, general physical condition and medical history; the particular compound used, as well as the carrier in which it is formulated and the route of administration selected for it; and. the nature and severity of the condition being treated. The term "Pharmaceutical composition" means a composition comprising a compound of formulae (lA-F) and at least one component selected from the group comprising pharmaceutically acceptable carriers, diluents, adjuvants, excipients. or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. Examples of suspending agents include elhoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide. bentonile, agar-agar and tragacanth, or mixtures of these substances. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens. chlorobutanol. phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monosterate and gelatin. Examples of suitable carriers, diluents, solvents or vehicles include water, eihanol. polvols, suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Examples of excipients include lactose, milk sugar, sodium citrate, calcium carbonate, dicaicium phosphate phosphate. Examples of disintegrating agents include starch, alginic acids and certain complex silicates. Examples of lubricants include magnesium stearate, sodium lauryl sulphate, talc, as well as high molecular weight polyethylene glycols. The term "Pharmaceuiically acceptable" means it is, within the scope of sound medical judgement, suitable for use in contact with the cells of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. The term "Pharmaceutically acceptable dosage forms" means dosage forms of the compound of the invention, and includes, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations, including suspensions, sprays, inhalants tablets, lozenges, emulsions, solutions, granules, capsules and suppositories, as well as liquid preparations for injections, including liposome preparations. Techniques and formulations generally may be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest edition. cycloalkylalkyl is optionally substituted with from 1 to 3 substituents selected independently at each group is optionally substituted with from 1 to 3 substituents selected independently at each occurrence Another embodiment of the invention is a compound of formulae lA-F, wherein: substituents R'-R' are as set forth in the following table: Preferred embodiments of this invention are compounds of formulae lA, IC, ID, IE and IF, wherein: wherein: Preferred embodiments of this invention are compounds of formulae lA, IB, IC, ID and IE, wherein: R4 is H or halogen. Preferred embodiments of this invention are compounds of formula IF, wherein: R3 is halogen. Preferred embodiments of this invention are compounds of formulae lA, IB, IC, ID, IE and IF, wherein: the substituents R'-R" are as set fonh in the following table B: More preferred embodiments of this invention are compounds wherein: R' is C,-C, alkyl; R2 is H or C,-C,alkyl; Furthermore preferred compound of this invention include those (+) enantiomers of compounds of formulae lA-IF, selected from table D: Another preferred aspect of the invention is a mixture of compounds of formulae (lA-F) wherein the compound of formulae (lA-F) is radiolabeled, i.e., wherein one or more of the atoms described are replaced by a radioactive isotope of that atom (e.g.. C replaced by 14C and H replaced by 'H). Such compounds have a variety of potential uses, e.g., as standards and reagents in determining the ability of a potential pharmaceutical to bind to neurotransmitter proteins. Another aspect of the invention is a therapeutically effective amount of the compound of formulae (lA-F) and a pharmaceutically acceptable carrier. Another aspect of the invention is a method of treating a disorder which is created by or is dependent upon decreased availability of serotonin, norepinephrine or dopamine, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formulae (lA-F), or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a method of treating a disorder which is created by or is dependent upon decreased availability of serotonin, norepinephrine or dopamine, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formulae (lA-F), or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a serotonin 1A receptor antagonist, or pharmaceutically acceptable salt thereof. Another aspect of the invention is a method of treating a disorder which is created by or is dependent upon decreased availability of serotonin, norepinephrine or dopamine, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formulae (lA-F), or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a compound selected from the group consisting of WAY 100135 and spiperone, or pharmaceutically acceptable salt thereof. WAY 100135 (N-(t-butyl)-3-[a-(2-methoxyphenyl)piperazin-l-yl]-2-phenylpropanamide) is disclosed in Abou-Gharbia et al., U.S. Pat. No. 4,988.814,as having an affinity for the 5-HT,^ receptor. Also, Cliffe et al., J. Med. Chem. 36, 1509-10 (1993) showed that the compound is a 5-HT,^ antagonist. Spiperone (8-[4-(4-nuorophenyl)-4-oxobuiyl]-l-phenyl-1,3.8-triazaspiro[4,5]decan-4- one) is a well-known compound, and is diclosed in U.S. Pat. Nos. 3,155,669 and 3,155.670. The activity of Spiperone as a 5-HT,, antagonist is shown in Middlemiss et al., Neurosci. and Biobehav. Rev. 16, 75-82 (1992). Another aspect of the invention is a method of treating a disorder which is created by or is dependent upon decreased availability of serotonin, norepinephrine or dopamine, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formulae (lA-F), or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a selective neurokinin-] receptor antagonist, or pharmaceutically acceptable salt thereof. Neurokinin-] receptor antagonists of use in combination a compound of fonnulae (lA-F) in the present invention, are fully described, for example, in U.S. Pat. Nos. 5,373.003, 5.387,595, 5,459!270. 5.494,926, 5,162,339. 5,232,929, 5.242,930. 5,496.833, 5.637,699: PCT International Patent Publication Nos. WO 90/05525. 90/05729, 94/0246]. 94/02595, 94/03429,94/03445. 94/04494, 94/04496, 94/05625, 94/07843. 94/08997. 94/10165. 94/10167. 94/10168, 94/10170, 94/11368. 94/13639. 94/13663. 94/14767.94/15903, 94/19320. 94/19323. 94/20500, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151,92/15585, 92/17449. 92/20661. 92/20676, 92/21677, 92/22569, 93/00330, 93/00331. 93/01159, 93/01165, 93/01169, 93/01170, 93/06099. 93/09116,93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181, 93/23380. 93/24465. 94/00440, 94/01402, 94/26735, 94/26740, 94/29309. 95/02595. 95/04040, 95/04042. 95/0664.\ 95/07886. 95/07908, 95/08549,95/11880, 95/14017. 95/153] 1, 95/16679, 95/17382. 95/18]24,95/18129. 95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418, 95/30674. 95/30687. 95/33744, 96/05181, 96/05193, 96/05203, 96/06094. 96/07649, 96/10562, 96/16939, 96/18643. 96/20197, 96/21661, 96/29304,96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489. 97/01553. 97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084,97/19942. 97/21702. and 97/49710; and in U.K. Patent Application Nos. 2 266 529, 2 268 931,2 269 170,2 269 590.2 27] 774.2 292 144,2 293168,2 293 169, and 2 302 689: European Patent Publication Nos. EP 0 360 390. 0517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478. 0 558 156, 0 577 394. 0 585 913. 0 590 152, 0 599 538, 0610 793, 0 634 402, 0 686 629, 0 693 489. 0 694 535. 0 699 655, 0 394 989, 0 428 434, 0 429 366, 0 430 771, 0 436 334, 0 443 132,0 482 539,0 498 069,0 499 313.0 512 901,0 512 902,0 514 273,0 514 274,0 514 275,0 514 276, 0 515 681,0 699 674,0 707 006,0 708 101, 0 709 375, 0 709 376, 0 714 891, 0 723 959, 0733 632 and 0 776 893. The preparation of such compounds are fully described in the aforementioned patents and publications. Another aspect of the invention is a method of treating a disorder which is created by or is dependent upon decreased availability of serotonin, norepinephrine or dopamine, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formulae (lA-F), or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a norepinephrine precursor, or pharmaceutically acceptable salt thereof. Another aspect of the invention is a method of treating a disorder which is created by or is dependent upon decreased availability of serotonin, norepinephrine or dopamine, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formulae (lA-F), or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a compound selected from L-tyrosine and L-phenylalanine, or pharmaceutically acceptable salt thereof. Another aspect of the invention is a method of treating a disorder referred to in the above-mentioned embodiments, wherein the disorder is selected from the group: attention deficit disorder, hyperactivity disorder, anxiety, depression, post-traumatic stress disorder, supranuclear palsy, eating disorders, obsessive compulsive disorder, analgesia, nicotine addiction, panic attacks, Parkinsonism and phobia, obesity, late luteal phase syndrome or narcolepsy, cocaine addiction, amphetamine addiction, and psychiatric symptoms anger such as. rejection sensitivity, and lack of mental or physical energy. Another aspect of the invention is a method of inhibiting synaptic norepinephrine uptake in a patient in need thereof comprising administering a therapeutically effective inhibitory amount of a compound of formulae (lA-F). Another aspect of the invention is a method of inhibiting synaptic serotonin uptake in a patient in need thereof comprising administering a therapeutically effective inhibitory amount of a compound of formulae (lA-F). Another aspect of the invention is a method of inhibiting synaptic dopamine uptake in a patient in need thereof comprising administering a therapeutically effective inhibitory amount of a compound of formulae (lA-F). Another aspect of the invention is a therapeutic method described herein wherein the (+)-stereoisomer of the compound of formulae (lA-F) is employed. Another aspect of the invention is a therapeutic method described herein wherein the (-)-stereoisomer of the compound of formulae (lA-F) is employed. Another aspect of the invention is a kit comprising a compound of formulae (lA-F) and at least one compound selected from the group consisting of: a serotonin 1A receptor antagonist compound, a selective neurokinin-1 receptor antagonist compound, and a norepinephrine precursor compound. Another aspect of the invention is a method of treating depression in a patient in need thereof comprising inhibiting synaptic serotonin and norepinephrine uptake by administering a therapeutically effective inhibitory amount of a compound of formulae (lA-F) which functions as both a serotonin and norepinephrine uptake inhibitor. Another aspect of the invention is a method of treating depression in a patient in need thereof comprising inhibiting synaptic serotonin and dopamine uptake by administering a therapeutically effective inhibitory amount of a compound of formulae (lA-F) which functions as both a serotonin and dopamine uptake inhibitor. Another aspect of the invention is a method of treating depression in a patient in need thereof comprising inhibiting synaptic dopamine and norepinephrine uptake by administering a therapeutically effective inhibitory amount of a compound of formulae (lA-F) which functions as both a dopamine and norepinephrine uptake inhibitor. Another aspect of the invention is a method for inhibiting serotonin uptake in mammals which comprises administering to a mammal requiring increased neurotransmission of serotonin a pharmaceutically effective amount of a compound of formulae (lA-F) . Another aspect of the invention is a method for inhibiting dopamine uptake in patients which comprises administering to a mammal requinng increased neurotransmission of dopamine a pharmaceutically effective amount of a compound of formulae (lA-F) . Another aspect of the invention is a method for inhibiting norepinephrine uptake in patients which comprises administering to a mamma! requiring increased neurotransmission of norepinephrine a pharmaceutically effective amount of a compound of formulae (lA-F). Another aspect of the invention is a method of suppressing the desire of humans to smoke comprising administering to a human in need of such suppression an effective dose, to relieve the desire to smoke, of a compound of formulae (lA-F). Another aspect of the invention is a method of suppressing the desire of humans to consume alcohol comprising administering to a human in need of such suppression an effective dose, to relieve the desire to consume alcohol, of a compound of formulae (lA-F) . It is appreciated that certain feactures of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various feactures of the invention which are, for brevity, described in the context of a single embodiment, may also be provided seperaiely or in any suitable subcombination. Preparation of Compounds of the Invention Compounds according to the invention, for example, starting materials, intermediates or products, are prepared as described herein or by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature. Compounds useful according to the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example those described by R. C. Larock in Comprehensive Organic Transformations, VCH publishers. 1989. A compound of formulae (1A-F) including a group containing one or more nitrogen ring atoms. may be converted to the coiresponding compound wherein one or more nitrogen ring atom of the group is oxidized to an N-oxide, preferably by reacting with a peracid, for example peracetic acid in acetic acid or m-chloroperoxybenzoic acid in an inert solvent such as dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature. In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted panicipation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T.W. Green and P.G.M.Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991; J. F. W. McOmie in "Protective Groups in Organic Chemistry" Plenum Press, 1973. Compounds provided herein are synthesized, for example, using the methods described below (see Schemes 1-4), together with methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those methods described below. Compounds of formulae (lA-F) of this invention are. for example, prepared according to Scheme ]. Treatment of an optionally substituted acetophenone of formula (II) with common brominating agents such as, but not limited to, bromine, NBS, or tetrabuiylammonium tribromide readily affords the desired bromoacetophenones of formula (III, X=Br). These reactions are optimally conducted in acetic acid or methylene chloride with methanol used as a co-solvent for the tribromide reagent with reaction temperatures at or below room temperature. Another embodiment of this methodology would include compounds of formula (IIT X=C1). The acetophenones of formula (Ilj are available from commercial sources or are conveniently obtained via several well known methods, including the treatment of the corresponding benzoic acid intermediates with two stoichiometric equivalents of methyllithium as thoroughly described in the review of Jorgenson, M.J. (Organic Reactions. 1970, 18, pg. 1). Alternatively, one may treat the corresponding benzaldehydes with an alkyl-Grignard (for example, MeMgBr) or alkyl-lithium (for example, MeLi) nucleophile foUwed by routine oxidation to the ketone as well demonstrated by Larock, R.C. (Comprehensive Organic Transformations. VCH Publishers, New York, 1989, p. 604). Treatment of intermediates of formula (III) with intermediates of formula (R3,R4.ph)-CH(R2)- NHR* cleanly generates the alkylation products of formula (V)- The alkylation reactions may be run under a wide variety of conditions familiar to one skilled in the an of organic synthesis. Typical solvents include acetonitrile, toluene, diethyl ether, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, methylene chloride, and lower alkyl alcohols including eihanol. The reactions may be successfully rim at temperatures ranging from 0oC up to the boiling point of the solvent employed. Reaction progress is conventionally determined by standard chromatographic and spectroscopic methods. The alkylation reaction is optionally run with the addition of a non-nucleophilic organic base such as, but not limited to. pyridine, triethylamine and diisopropyl eihylamine. The R'-substituted N-benzvl amines of formula (R3.R4-Ph)-CH(R2)-NHRl may be purchased from commercial sources, or alternatively, obtained from a simple reductive amination protocol. Thus, carbonyl containing compounds of Formulae (IV, Scheme I) may be treated with H2N-R^ in lower alkyl alcoholic solvents (preferably methanol) at temperatures at or below room temperature. The resulting imine may be reduced most commonly with alkaline eanh borohvdrides (preferably sodium borohydnde) to provide the desired amine intermediate. Reductions of compounds of formula (V) to the benzyl alcohols of formula (VI) proceeds with many reducing agents including, as example, sodium borohydride, lithium borohydride. borane, diisobutylaluminum hydride, and lithium aluminum hvdride. The reductions are carried out for a period of time between 1 hour to 3 days at room temperature or elevated temperature up to the reflux point of the solvent employed. If borane is used, it may be employed as a complex for example, but not limited to, borane-methyl sulfide complex, borane-piperidine complex, borane-tetrahydrofuran complex. One skilled in the art will understand the optimal combination of reducing agents and reaction conditions needed or may seek guidance from the text of Larock, R.C. {Comprehensive Organic Transformations, VCH Publishers, New York, 1989, p. 527). Compounds of formula (VI) may be cyclized to the target compounds of formulae lA-IF of this invention by brief treatment with a strong acid. Suitable acids include, but are not limited to, concentrated sulfuric acid, polyphosphoric acid, methanesulfonic acid and trifluoroacetic acid. The reactions are run neat or in the optional presence of a co-solvent such as, for example, methylene chloride and 1,2-dichloroethane. The cyclizations may be conducted at temperatures ranging from 0oC up to the reflux point of the solvent employed. One skilled in the art of heterocyclic chemistry will readily understand these conditions or may consult the teachings of Mondeshka, et aL (II Fannaco. 1994, 49, 475-480) or Venkov, et al. {Synthesis, 1990, 253-255). Cyclizations may also be effected by treatment of compounds of formula (VI) with strong Lewis Acids, such as for example, aluminum trichloride typically in halogenated solvents such as methylene chloride. One skilled in the art will be familiar with the precedent taught by Kaiser, et al. (J, Med. Chem., 1984, 27, 28-35) and Wyrick, et al. (J. Med. Chem,, 1981, 24, 1013-1015). Compounds of formulae lA-IF may be obtained in enantiomerically pure (R) and (S) form by crystallization with chiral salts as well known to one skilled in the art. or alternatively, may be isolated through chiral HPLC employing commercially available chiral columns. Alternatively, compounds of formulae (V) and (VI) may be arrived at as described in Scheme 2. Thus, the haloacetophenones of formula may be treated with simple amines of formula H2N-R' under alkylaiion conditions as described above {vide supra) to provide compounds of formulae (VII). A second alkylation may then be performed utilizing reagents of formula (VIII) where X represents a leaving group, such as for example, but not limited to, halogen, mesylate, or tosylate to afford the common intermediate of formula (V). Reagents of formula (VIII) are in turn available from the appropriately substituted carbonyl compound of formula (IV) via reduction {vide supra) and activation. Activation to leaving group X is effected by treatment of the alcohol with methanesulfonyl chloride or p-toluenesulfonyl chloride in the presence of a non-nucieophiiic base such as. but not limited to, L5-diazabicyclo[4.3.0]non-5-ene (DBN). pyridine or triethylamine. The reaction is commonly performed in halogenated organic solvent, for example, methylene chloride, and at temperatures from - 78oC up to the boiling point of the solvent employed. Benzylic activation to Leaving Group X may also be effected by treatment with halogenating agents such as, but not limited to, SO2CI2, Cb. PCI5. Bro. CuBr2, NBS, and CBr4. The various conditions necessary to accomplish this transformation will be readily apparent to those skilled in the art of organic chemistry and additional reference on benzylic activiation may be sought from Larock, R.C. (Comprehensive Organic Transformations. VCH Publishers, New York, 1989, p. 313). The flexibility of the synthesis is funher demonstrated by an alternative sequence of reaction*^, wherein (VII) may be reduced (vide supra) and either i) alkylated as above with (VIII) to afford (VI) or ii) condensed with (IV) followed by in-sim imine reduction to also afford (VI). Where R5=R6=R7_H and the (methylaminomethyl)benzyl alcohol derivative may be obtained from commercial sources. Compounds of formulae lA-IF of this invention may also be prepared according to Scheme 3. Treatment of an appropriately substituted 2-iodobenzaldehyde (or a 2-bromobenzaldehyde) (X) with an amine H2N-R' in lower alkyl alcohol solvents followed by reduction of the resultant imine as described above in Scheme 1 {vide supra) affords an intermediate (2-1 or Br),R2.R3-PhCH2-NH-R' which, when treated with an optionally substituted bromoacetophenone (as described for the synthesis of (V), Scheme 1) provides the alkylation product (XI). Compounds of formula (XI) may be treated with strong bases, such as, but not limited to lower alkyl (C]_5) lithium bases (preferably t-BuLi or n-BuLi) to afford the anticipated halogen-metal exchange followed by intramolecular Barbier cyclization to generate compounds of formulae (lA-IE, R8=0H). Inert solvents such as dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), etc. are necessar)', and reaction temperatures are kept low (-78^C to - 25^G) to avoid by-products. Alternatively, halogen-metal exchange may also be effected in the presence of zerovalent nickel, in which case N,N-dialkylformamides (preferably dimethylformamide) serve as ideal solvents. One skilled in the art of organic synthesis will understand the optimal combination of conditions and may seek further reference from Kihara, et al. {Tetrahedron. 1992, 48. 67-78), and Blomberg. ei aL {Synthesis, 1977, p. 18-30). Additionally, compounds of formulae (lA-E. R'=OH) may be readily alkylated (vide supra) to afford compounds formulae (lA-E, R^==OR^ ')• Finally, funher treatment of compounds of formulae (lA-E, RS=:OH) with a halogenating reagent or specifically a fluorinating reagent such as, but not limited to, diethylaminosulfur irifluoride (DAST), readily provides compounds of formulae (lA-F. R^=F). Funher reference may be gained from the review of Hudlicky (Organic Reaciions, 1985, 35, p. 513-637j. Compounds of formulae lA-F of this invention may also be prepared according to Scheme 4. 4-Bromoisoquinolines (XII) may be treated with an aryl boronic acid or aryl boronic acid ester where Y is equivalent to B(OH)2 or B(ORA)(ORB) (where Ra and Rb are lower alkyl, ie. C1-C6. or taken together, Ra and Rb are lower alkylene. ie. C2-C ] -)) in the presence of a metal catalyst with or without a base in an inert solvent to give isoquinoline compounds of formula (XIII). Metal catalysts include, but are not limited to, salts or phosphine complexes of Cu, Pd, or Ni (eg. Cu(OAc)2, PdCl2(PPh3)2, NiCl2(PPh3)2). Bases may include, but are not limited to, alkaline earth metal carbonates, alkaline earth metal bicarbonates, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably diisopropylethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to acetonitrile, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylaceiamides (preferably dimethylacetamide), N,N-dialkylformamides (preferably dimethylformamide), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloaalkanes (preferably methylene chloride). Prefered reaction temperatures range from room temperature up to the boiling point of the solvent employed. The reactions may be run in conventional glassware or in one of many commercially available parallel synthesizer units. Non-commercially available boronic acids or boronic acid esters may be obtained from the corresponding optionally substituted aryl halide as described by Gao, et al. {Tetrahedron, 1994, 50. 979-988). Compounds of formula (XIII) are converted into the target tetrahydroisoquinolines of formula via a two-step procedure employing first amine quaicmization with a reagent R'-LG, where LG represents a suitable leaving group such as I. Br, O-triflate. 0-tosylate, 0-methanesulfonate, etc. The reactions are optimally conducted in haloaalkanes (preferably methylene chloride), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane) or other inert solvent. The reactions are optimally conducted at or below room temperature and reaction times vary from 10 minutes to 24 hours. The second step of the sequence involves reduction to the tetrahydroisoquinolines of formulae lA-F. Optimally, a mild reducing agent is employed, such as for example, sodium cyanoborohydride in the presence of acid catalyst to facilitate the reaction. Additional guidance for effectively conducting this chemistry may be located from the works of Miller, et al. {Synthetic Communications, 1994, 24. 1187-1193) and Terashima. ei at. (Heterocvcles, 1987, 26, 1603-1610). ptosis if its eyelids are at least 50% closed. Greater than 95% of the control (vehicle-treated) mice are expected to exhibit exploratory loss and ptosis; compound-related activity is then calculated as the percentage of mice failing to respond to the tetrabenazine challenge dose, with therapeutically more effective compounds expected to better at reducing loss of exploratory behavior and ptosis. Accordingly, this invention provides methods of treating subjects afflicted with various neurological and psychiatric disorders by administering to said subjects a dose of a pharmaceutical composition provided herein. Said disorders include, without limitation, attention deficit-hyperactivity disorder, anxiety, depression, post-traumatic stress disorder, supranuclear palsy, feeding disorders, obsessive compulsive disorder, analgesia, smoking cessation, panic attacks, Parkinson's and phobia. The compounds provided herein are particularly useful in the treatment of these and other disorders due, at least in part, to their ability to selectively bind to the transporter proteins for certain neurochemicals with a greater affinity than to the transporter proteins for other neurochemicals. The compounds of the invention, their methods or preparation and their biological activity will appear more clearly from the examination of the following examples which are presented as an illustration only and are not to be considered as limiting the invention in its scope. Examples The compounds listed in the following Table 1 were made by the processes described above. Step A: A solution of/n-tolualdehyde (500 mg, 4.16 mmol), i -(melhylaminomethyl)benzyl alcohol (630 mg, 4.16 mmol) and acetic acid (0.5 ml) was stirred in methanol (16 ml) at O^C under nitrogen as sodium cyanoborohydride (784 mg, 12.5 mmol) was added in small ponions. The reaction mixture was stirred for 5 minutes at 0oC and two days at ambient temperature. The reaction mixture was brought to pH 12 with 2N sodium hydroxide, diluted with water, and extracted with diethyl ether (3X). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and the solvent removed /// vacuo to provide the desired intermediate (1.24 g): 'H NMR (300 MHz, CDCI3) 5 7.08-7.35 (m,9H), 4.73-4.77 (m, IH), 3.71 (dJ=13.0Hz, IH), 3.50 (dj=13,0 Hz, IH), 2.46-2.67 (m, 2H), 2.36 (s, 3H), 2.32 (s, 3H); CI MS m/z = 256 [C]7H2iNO+H]+. Step B: The product from Step A (1.24 g, 4,90 mmol) was stirred in methylene chloride (208 ml) and treated dropwise with concentrated sulfuric acid (98%, 10 ml) over 3 minutes. After stirring for 20 minutes, the reaction was diluted with ice chips and made basic with 25% aqueous ammonium hydroxide. The reaction mixture was extracted with methylene chloride (3X) and the organic extracts combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography, eluting with hexanes / ethyl acetate (5/1). afforded the desired letrahydroisoquinoline (0.23 g): 'H NMR f300 MHz, CDCI3) 5 7.17-7.31 (m, 5H), 6.87-6.89 (m, 2H), 6.75 (d, J=7.8 Hz, IH), 4.20-4.26 (m, IH), 3.72 (d, J=14.8 Hz. IH). 3.57 (d. J=14.8 Hz, IH), 2.96-3.10 (m, IH), 2.51-2.58 (m. IH), 2.42 (s, 3H). 2.29 (s, 3H). Step C: The product from Step B (0.23 g) was treated with ethereal HCl in methanol (5 ml) to afford a precipitate. The solvents and excess HCl were removed in vacuo and the resultant solid recrystallized from ethanol /diethyl ether to provide the HCl salt of the target (0,21 g) as a white solid: mp245-250OC; 'H NMR (CD3OD) 6 6.86-7.40 (m, 7H). 6.74 (d. J-7.8 Hz, IH), 4.52-4.64 (m, 3H), 3.72-3.88 (m, IH), 3.45-3.55 (m. IH), 3.08 (s, 3H). 2.32 (s. 3H); '^c NMR (75 MHz, CD3OD) : 130.6, 130.3, 129.1, 127.8.59.3,56.8.44.5,44.0,21.1: IR (KBr) 2937. 2474, 1454.701 cm'^ CI MS m/: = 238[C]7H]9N+H]+. Anal. Calcd. for CnHi9N-HCl: C, 74,57; H,7.36; N,5.12. Found: C, 74.20; H,7.34; N, 4.82. Example 4 Preparation of 2.7-dimethv]-4-(3-fluorophenvn-K23,4--tetrahydroi.soquinoline Step A: /n-Tolualdehyde (1.66 g, 14.0 mmol) was treated with methyl amine (40% aqueous, 1.39 ml, 18.0 mmol) in methanol (20 ml) at room temperature. The reaction was stirred 20 minutes and treated with sodium borohydride (0.26 g, 7.0 mmol) portionwise. The reaction was stirred 1 hour and treated with 3'-fluoro-2-bromoacetophenone (3.0 g, 14.0 mmol) followed by stirring for 45 minutes at room temperature. The reaction was finally treated with sodium borohydride (0.52 g, 14.0 mmol) portionwise and stirring continued overnight. The reaction was diluted with water (100 ml) and extracted with methylene chloride (3 X 100 ml). The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate, followed by filtration and concentration in vacuo. Purification by column chromatography on silica gel eluting with hexanes /ethyl acetate (3/1) provided the amino alcohol (4.3 g) as a yellow oil; 1H NMR (300 MHz, CDCI3) 5 7.08-7.30 (m, 7H), 4.73 (i, J=6.0 Hz, IH), 3.60 (ABq, JAB==14.0 HZ, 2H), 2.55 (d, J=8,0 Hz, 2H), 2.36 (s, 3H), 2.31 (s, 3H); CI MS ni/z ^ 214 [C]7H2oNFO+H]+. Step B: The product from Step A (1.0 g, 4.0 mmol) was stirred in methylene chloride (100 ml) and treated dropwise with concentrated sulfuric acid (98%, 7.0 ml) over 3 minutes. After stirring for 1 hour, the reaction was diluted with ice chips and and made basic with 25% aqueous ammonium hydroxide. The reactions mixture was extracted with methylene chloride (3 X 100 ml) and the organic extracts combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography, eluting with hexanes / ethyl acetate (3/1), afforded the desired tetrahydroisoquinoline as a yellow oil: 'H NMR (300 MHz, CDCI3) 5 6,89-7.00 (m, 5H), 6.75 (d, j=8.0 Hz, IH), 4.21 (t.J=7.0Hz, IH), 3.64 (ABq, 3^5=15.0 Hz, 2H), 3.02 (m. IH), 2.56(m, IH), 2.41 (s, 3H), 2.29 (s, 3H); CI MS ni/z = 256 [C]7H ] gNF-fH]+. Step C: The product from Step B was subjected to chiral HPLC separation employing a Chiral Technologies Chiracel® AD column (5 cm X 50 cm) eluting with hexanes / isopropanol (9/1) to afford the (R), [a]-j^ -16.3 (c=0.498, MeOH) and (S), [a]'-^ +16.3 (c=0.476, MeOH) enantiomers in order of elution. The (S)-(+) enantiomer was treated with majeic acid (1.0 equilvalent) and the resultant maleate salt filtered and dried to constant weight. (S)-(+)-2,7-dimethyI-4-(3-nuorophenyl)-1,2,3,4- tetrahydroisoquinoline, maleate salt: mp 172-173.5oC. Example 6 Preparation of 2,7-dimethyl-4-(4-nuoro-3-methylphenyl)-1.23.4-tetrahvdroisoquinoline Step A: m-Tolualdehyde (4.0 g, 33.0 mmol) was treated with methyl amine (40% aqueous, 3.36 ml, 43.0 mmol) in methanol (40 ml) at room temperature. The reaction was stirred 20 minutes and treated with sodium borohydride (0.64 g, 33.0 mmol) ponionvvise. The reaction was stirred 1 hour and treated with 4'-fluoro-3'-methyl-2-bromoacetophenone (7.69 g, 33.0 mmol) followed by stirring for 45 minutes at room temperature. The reaction was finally treated with sodium borohydride (1.0 g, 33 mmol) ponionwise and stirring continued overnight. The reaction was diluted with water (100 ml) and extracted with methylene chloride (3 X 100 ml). The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate, followed by filtration and concentration in vacuo. Purification by column chromatography on silica gel eluting with hexanes / ethyl acetate (2/1) provided the amino alcohol (65.3 g) as a yellow oil; CI MS ni/z = 286 [Ci8H22NFO+H]+. Step B: The product from Step A (0.52 g, 2.0 mmol) was dissolved in methylene chloride (20 ml) and treated dropwise with concentrated sulfuric acid (98%, 3 ml). The reaction was stirred ovemight at room temperature, then diluted with ice chips and and made basic with 25% aqueous ammonium hydroxide. The reaction mixture was extracted with methylene chloride (3 X 50 ml) and the organic extracts combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography, eluting with hexanes / ethyl acetate (3/1) afforded the desired tetrahydroisoquinoline (0.08 g): 'H NMR (300 MHz, CDCI3) 5 6.87-7.00 (m, 5H), 6.74 (d, J=8.0 Hz, IH), 4.17 (t, J=7.0 Hz, IH), 3.64 (ABq, JAB^'^.O HZ, 2H), 3.01 (m, IH), 2.53 (m, IH), 2.40 (s, 3H), 2.29 (s, 3H), 2.23 (s, 3H); CI MS ni/z = 270 [C ] 8H2oNF+H]+. Example 28 Preparation of 2.7-dimethvl-8-fluoro-4-phenvl-1,2,3.4-tetrahvdroisoquinoline Step A: A solution of -(methylaminomethyDbenzyl alcohol (745 mg, 4.9 mmol) and triethylamine (0.79 ml, 5.66 mmol) in aceionitrile (45 ml) at O˚C under nitrogen was treated dropwise with 2-fluoro-3-methylbenzyl bromide (1.0 g. 4.9 mmol) as a solution in acetonitrile (25 ml). The reaction was stirred at O˚C for 1 hour and at room temperature for ] .5 hours, followed by dilution with water and extraction with methylene chloride (3X), The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo 10 provide the alkylation product (1.35 g): ^H NMR (CDCI3) 8 7.23 (m. 5H), 7.08-7.17 (m. 2H), 6.97-7.06 (m, IH), 4.71-4.82 (m, IH). 3.79 (d, J=13.1 Hz, IH), 3.62 (d, J=13.2 Hz, IH), 2.33 (s, 3H), 2.29 (s, 3H). Step B: The product from Step A (0.5 g, 1.8 mmol) was treated with sulfuric acid (3.7 m!) and purified by column chromatography as described for Example 1. Step B to afford the desired product (0.33 g) as an oil: 'H NMR (CDCI3) 5 7.06-7.37 (m, 5H). 6.88 (t. J-7.8 Hz. IH), 6.54 (d. J=7.8 Hz, IH), 4.18-4.27 (m, IH), 3.86 (d, J=15.6 Hz, IH), 2.94-3.04 (m, IH), 2.49-2.59 (m, IH), 2.45 (s, 3H), 2.22 (s, 3H). Step C: The product from Step B (0.33 g. 1.3 mmol) was treated with ethereal HCl as described in Example 1, Step C to provide the anticipated hydrochloride salt (0.30 g): mp 215-216˚C; 1 H NMR (300 MHz, CD3OD) 5 7.31-7.44 (m, 2H). 7.21-7.28 (m, 2H), 7.15 (t, J=7.9 Hz, IH), 6,61 (d, J-8.0 hz, IH), 4.67-4.78 (m, !H), 4.42-4.62 (m, 2H). 3.77-3.88 (m, IH). 3.55 (l, 3=12.0 Hz, IH), 3.11 (s, 3H), 2.26 (s, 3H); IR (KBr) 3432, 2954, 2376, 1497. 1457,1216, 1043,704 cm-'; CI MS ni/z = 256 [Ci7H|8NF+H]+. Anal.Calcd. for C17H]8NF-HCl: C, 69.98; H, 6.56; N,4.80. Found: C, 69.64; H, 6.49; N,4.65. Example 70 Preparation of 4-(4-chloro-3-fluorophenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline Step A: Methylmagnesium bromide was added dropwise over 5 minutes to a stirred solution of 4-chloro-3-nuorobenzaldehyde (10.86 g, 68.5 mmol) in anhydrous tetrahydrofuran (100 ml) at -78^C under nitrogen. After stirring for 15 minutes, the cooling bath was removed, and the solution allowed to warm to room temperature. After stirring 3 hours, the solution was poured slowly with stirring into saturated ammonium chloride (100 ml), then diluted with water (50 ml) and extracted with diethyl ether. The organic extracts were washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to provide the benzylic alcohol (11.89 g) as a clear, yellow oil: 'H NMR (300 MHz. CDCI3) 5 7.35 (i. J-7.8 Hz, IH), 7.18 (dd, J=2.0, 10.0 Hz, IH), 7.07(dd,J=1.7, 8.1 Hz. IH), 4.83-4.92 (m. IH), 2.01 (d.J=3.6Hz, IH). 1.47 (d. J=6.3 Hz. 3H). CI MS m/z= 175(C8H8CIFO+H]+, Step B: The product from Step A (9.0 g, 52.0 mmol) in anyhdrous methylene chloride (60 ml) under nitrogen was added by cannula to a stirred suspension of pyridinium chlorochromate (16.7 g, 77.0 mmol) and diatomaceous earth (15 e) in anhvdrous methylene chloride (150 ml) at 0*^C under nitrogen. After stirring for 26 hours, the heterogeneous mixture was diluted w^ith diethyl ether (300 ml), stirred for 1 hour, and filtered. The filtrate was concentrated in vacuo and the volatile product purified by column chromatography on silica gel (60 g) eluting with hexanes / ethyl acetate (9/1) to provide the desired acetophenone in quantitative crude yield:1 H NMR (300 MHz, CDCI3) 5 7.65-7.75 (m. 2H). 7.51 (i, J=7.6 Hz, IH). 2.60 (s. 3H), CI MS m/z =- 173 [C8H6C1FO+H]+. Step C: The product from Step B (52 mmol) was treated with tetrabutylammonium tribromide (25,5 g. 52.9 mmol) in methanol / methylene chloride (1/3. 240 ml) under nitrogen. After stirring 3 days at room temperature, the solvents were removed in vacuo, and the residue dissolved in diethyl ether (200 ml), washed with water (4 X 50 ml), dried over anhvdrous sodium sulfate, filtered and concentrated //? vacuo. Purification by column chromatography on silica gel (120 g) eluting with hexanes / ethyl acetate (30/1) afforded the desired n-bromoacetophenone (6.23 g) as a crystalline solid: ^H NMR (300 MHz, CDCI3) 6 7.70-7,81 (m, 2H), 7.55 (t. J=7.7 Hz, IH). 4.39 (s, 2H); CI MS ni/z = 251 [C8H5BrClFO+H]+. Step D: Methylamine (40 wt9c aqueous, 18.0 mmol) was added to a stirred solution of benzaldehyde (1.8 g, 17 mmol) in methanol (20 ml) under nitrogen. After stirring 10 minutes at room temperature, the solution was cooled to O˚C and treated with sodium borohydride (0.32 g, 8.5 mmol) ponionwise. The reaction was stirred for 15 minutes, warmed to room temperature and stirred an additional 1 hour, whereupon the product from Step C (4.3 g, 17 mmol) was added. The reaction was stirred I hour, cooled to O˚C and treated again with sodium borohydride (0.32 g, 8.5 mmol) and allowed 10 stir overnight with warming 10 room temperature. The solution was diluted with water (100 ml) and extracted with methylene chloride (3 X 50 ml). The organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide the desired product as a clear yellow oil (1.77 g): 1H NMR (300 MHz, CDCI3) 8 7.25-7.39 (m, 6H), 7.17 (dd, J=1.8, 10.0 Hz, IH), 7.04 (d, J=8.3 Hz, IH), 4.69 (dd, 3=5.8, 8.2 Hz, IH), 3.74 (d. J=:13.0 Hz, !H), 3.52 (d. J=:!3.0 Hz, IH), 2.45-2.57 (m, 2H), 2.32 (s, 3H), CI MS m/z = 294 [C]6H17ClFNO+H]+. Step E: The product from Step D (1.77 g. 6.0 mmol) was stirred in concentrated sulfuric acid (4.0 ml) and methylene chloride (40 ml) for 15 minutes at room temperature. The reaction was poured on ice, made alkaline with concentrated ammonium hydroxide, and extracted with diethyl ether. The combined ether extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product as a cloudy yellow oil (1.7 g): 1H NMR (300 MHz. CDCI3) 5 7.30 (t, J=7.9 Hz. 1H), 7.06-7.22 (m, 3H), 6.92-7,03 (m, 2H), 6.85 (d, J=7.4 Hz, IH), 4.28 (t, J=6,7 Hz, IH), 3.77 (d, J=15.1 Hz, IH), 3.70(d,J=15,l Hz, IH), 3.05 (dd, J=5.6, 11.9 Hz, IH), 2.62 (dd, J=8.0, 11.5 Hz, IH), 2.46 (s, 3H). Step F: The product from Step E (1.7 g. 6.0 mmol) was treated with ethereal HCl (1.0 M, 12.0 ml, 12.0 mmol) in methanol (20 ml) to afford a precipitate. The solvents and excess HCl were removed in vacuo and the resultant solid recrystallized from methanol / diethyl ether to provide the HCl salt of the targetd.l g) as a white solid: mp230-235OC; 1H NMR fCD30D) 5 7.51 (t,J=8.0Hz, IH), 7.26-7.39 (m, 3H), 7.18 (dd. J-2.0, 10.2 Hz, IH), 7.11 (dd. J=l.S. 8.3 Hz. IH). 6.92 (d, J=7.9 Hz, IH), 4.68 (dd. J=6.3, 11.3 Hz, IH). 4.59 (bs. 2H), 3.87 (dd. J=6.2, 12.4 Hz, IH). 3.56 (t, J-11.8 Hz, IH), 3.08 (s, 3H); IR (Kbr) 3448, 2928, 2365. 1491. 1060, 747 cm-'; CI MS ni/z = 276 [C|1H15NClF+H]+; Anal. Calcd. for C16H]5NClF-HCl: C.61.55: H,5.17; N. 4.49. Found: C.61.20; H, 5.07; N,4.32. Step G: The product from Step E was subjected lo chiral HPLC separation employing a Chiral Technologies Chiracel® OD column (2 cm X 20 cm) eluting with hexanes / isopropanol (9/1) to afford the (S) and (R) enantiomers in order of elution. Each enantiomer was treated with maleic acid (1.0 equilvalent) and the resultant maleate salts filtered and dried to constant weight. (S)-(+)-4-(4-chloro-3- fluorophenyl)-2-methy]-l,2,3.4-tetrahydroisoquinoline, maleate salt: mp 171-172^C; [a] j) +16.0 (c=0,200, MeOH).(R)-(-)-4-(4-chloro-3-fluorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline, maleate salt: mp171-1720C;[α]25 -15.5 (c=0.200. MeOH), Example 78 Preparation of 4-(3.4-difluorophenvl)-2-methyl-1,2,3,4-tetrahydroisoquinoline Step A: 3,4-Difluoroacetophenone (25.0 g, 160.0 mmol) was treated with acetic acid (250 ml) and bromine (8.23 ml, 160.0 mmol, solution in 13 ml acetic acid) at room temperature under nitrogen. The reaction was stirred at room temperature for 1 hour and concentrated in vacuo to remove acetic acid. The residue was suspended in saturated sodium carbonate and extracted with methylene chloride several times. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the desired bromoacclophenone derivative (37.0 g) as a yellow cr>'staliine solid: 'H NMR (300 MHz, CDCI3) 5 7.81 (m. 2H), 7.32 (m, IH), 4.39 (s, 2H). Step B: The product from Step A (37.0 g, 158.0 mmol) was dissolved in methylene chloride (290 ml) and added dropwise to a solution of N-benzyl-N-methylamine (20.3 ml, 158.0 mmol) and triethylamine (22.0 ml, 158.0 mmol) in methylene chloride (312 ml). The addition was carried out over 45 minutes at 0˚C. warmed to room temperature and allowed to stir an additional 4 hours. The reaction was diluted with water (300 ml) and extracted with methylene chloride. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The product was purifed by column chromatography on silica gel (600 g) eluting with hexanes / ethyl acetate (7/3) to afford the desired alkylation-product as a clear, light brown oil (30.2 g): *H NMR (300 MHz, CDCI3) 5 7.87-7.73 (m, 2H), 7.35-7.15 (m, 6H), 3.68 (s, 2H), 3.64 (s. 2H), 2.34 (s, 3H). Step C: The product from Step B f 15.0 g, 54.0 mmol) was dissolved in methanol (65 ml), chilled in an ice bath and treated with sodium borohydride (1.38 g. 36.0 mmol). The reaction was stirred at O˚C for 1 hour and at room temperature for 1 hour, followed by quenching with water and extraction with methylene chloride. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to directly provide the pure benzylic alcohol (14.4 g) as a yellow oil: ^H NMR (300 MHz, CDCI3) 5 7.38-7.00 (m, 8H), 4.67 (t, J-7.0 Hz, IH), 3.74 and 3.35 (ABq, JAB^I3-2 HZ, 2H), 2,50 (d,J=7.0 Hz. 2H). 2-31 (s,3H). Anal. Calcd. for C15H17N1O1F2: C, 69.30; H,6.19; N, 5.05. Found: C. 68.94; H.6,2]; N,4.94. Step D: The product from Step C (14.4 g, 52.0 mmol) was stirred in concentrated sulfuric acid (27.0 ml) and methylene chloride (333 ml) for 15 minutes at room temperature. The reaction was poured on ice, made alkaline with concentrated ammonium hydroxide, and extracted with diethyl ether. The combined ether extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The product was purified by column chromatography on silica gel eluting with hexanes/ethyl acetate (1/1) to provide the pure tetrahydroisoquinoline (11.4 g): 'H NMR (300 MHz, CDCI3) 5 7.29-7.36 (m, IH), 6.83-7.20 (m, 6H), 4.20 (t, J=6.3 Hz, 1H), 3.66 (s. 2H), 2.95 (dd, J=5.4, 11.5 Hz, 1H), 2.58 (dd, J=7.4, 11.3 Hz, 1H),2.41 (s, 3H). Step E: The product from Step D (0.8 g, 3.0 mmol) was treated with ethereal HCl as described in Example 1, Step F 10 provide the anticipated hydrochloride salt (0.6 g): mp 200^C (sublimed); ' H NMR (300 MHz, CD3OD) 5 7.24-7.39 (m, 4H), 7.14-7.23 (m, IH), 7.06-7.13 (m, IH), 6.92 (d, J=7-8 Hz, lH),4.65(ddJ=6.1. 11.4 Hz), 4.58 (s, 2H), 3.85 (ddj=6.2, 12.4 Hz, IH), 3.54 (t, J=] 1.8 Hz, IH), 3.07 (s,3H): IR (KBr) 3448, 2932, 2549, 1512, 1465, 1276, 742 cm"'; CI MS m/^ = 260 [C]6H15NF2+H]+, Anal. Calcd. for C16H15NF2-Ha-0.25 H2O: C, 64.00, H, 5.54; N,4.66. Found: C, 64.11; H, 5.30; N, 4.62. Step F: The product from Step D was subjected to chiral HPLC separation employing a Chiral Technologies Chiracel® OD column (2 cm X 20 cm) eluting with hexanes / isopropanol (9/1) to afford the (S) and (R) enantiomers in order of elution. Each enantiomer was treated with maleic acid (1.0 equilvalent) and the resultant maleate salts filtered and dried to constant weight. (S)-(-)-4-(3,4- difluorophenyl)-2-methyl-1.2,3.4-teirahydroisoquinoline, maleate salt: mp ]38-139˚C; [a]~[) -2.6 (c=0.366, MeOH). (R)-(+)-4-(3.4-dinuorophenyl)-2-methyl-l,2,3.4-ietrahydroisoquinoline, maleate salt: 138-139^0; [a]^ +2.5 (c=0.386, MeOH). Example 80 Preparation of 4-(3.5-dif]uorophenvl)-2-methv1-1,2.3,4-tetrahvdroisoquinoline Step A: Tetrabutylammonium tribromide (18.6 g. 38.6 mmol) was added to a stirred solution of 3.5-difluoroacetophenone (6.0 g, 38.6 mmol) in methanol / methylene chloride (1/3, 180 ml) under nitrogen. After stirring at room temperature for 72 hours, the solvents were removed in vacuo. The residue was dissolved in diethyl ether (200 ml), washed with water (4 X 50 ml), dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to give a mixture of the a-bromoacetophenone and the corresponding dimethyl ketal (9.0 g): ' H NMR (300 MHz. CDCI3) 5 7.50 (dd, J-2.0, 4.0 Hz, 2H),7.08(m, IH), 4.39 (s, 2H). Step B: To the product mixture from Step A (3.5 g. 14.7 mmol) and N-methyl-N-benzylamine (1.8 g. 14.7 mmol) in methylene chloride (15 ml) was added diisopropyl ethyl amine (3.0 ml, 17 mmol). The reaction was stirred at room temperature for 5.5 hours, then washed with water and dried over anhydrous sodium sulfate. After filtration and concentration in vacuo, the material was purified by column chromatography on silica gel (140 g) eluting with hexanes / ethyl acetate / triethylamine (9/1/0.1) to provide the desired alkylation product (1.2g) as an orange oil: 'H NMR (300 MHz. CDCI3) 5 7.48 (dd, J=:2.0, 4.0 Hz, 2H), 7.33 (m, 5H), 7.00 (m. 1H). 3.69 (s, 2H), 3.66 (s, 2H), 2.36 (s, 3H)- StepC: The product from Step B (1.1 g, 4.0 mmol) was dissolved in methanol, chilled in an ice bath and treated with sodium borohydride (0.1 g, 2.7 mmol). The reaction was stirred at O^C for 1 hour and at room temperature for 1 hour, followed by quenching with water and extraction with methylene chloride. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to provide the benzylic alcohol (0.8 g) as an orange oil: 'H NMR (300 MHz, CDCI3) 5 7.40-7.30 (m, 5H), 6.90-6.82 (m, IH), 6.70-6.60 (m. IH), 4.70 (m. IH), 3.73 (d, J=14,0 Hz, IH), 3.52 (d. J=14.0 Hz, IH), 2.55-2.40 (m. 2H), 2.29 (s, 3H). Step D: The product from Step C (0.4 g, 1.4 mmol) was stirred in concentrated sulfuric acid (1.5 ml) and methylene chloride (10 ml) for 15 minutes at room temperature. The reaction was poured on ice, made alkaline with concentrated ammonium hydroxide, and extracted with diethyl ether. The combined ether extracts were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography on silica gel (15 g) eluting with hexanes /ethyl acetate / triethylamine (9/1/0.1) afforded the target (70 mg): ^ H NMR (300 MHz, CDCI3) 5 7.40-7.07 (m, 4H), 6.87 (d, J=7.0 Hz, IH), 6.77-6.62 (m, 2H), 4.21 (t, J=6.0 Hz, IH). 3.66 (d. J-2.0 Hz. 2H), 2.95 (dd, J=5.0, 6.0 Hz, IH), 2.61 (dd,J=6.0Hz,7.0Hz, IH). 2.41 (s, 3H). Step E: The product from Step D (70 mg, 0.27 mmol) was treated with ethereal HCl (1.0 M. 0.6 ml. 0.6 mmol) in methanol (1.4 ml) to afford a precipitate. The solvents and excess HCl were removed in vacuo and the resultant solid recrystallized from methanol / diethyl ether to provide the HCl salt of the target (53 mg) as a white solid: mp 230-233OC; 12 H NMR (300 MHz, CD3OD) 5 7.36-7.28 (m, 3H), 6.99-6.90 (m, 4H), 4.67 (dd. J=6.0. 6.0 Hz, IH), 4.58 (bs. IH). 3.87 (dd, J=6.0. 6.0 Hz, IH), 3.57 (m. IH), 3.08(s,3H): IR (KBr) 2931. 2473, 1625. 159S, 1462. ll!9cm-l; ClMSn2/z = 260 [C]5Hi5F2N+H]+; Anal. Calcd. for C]6H|5F2N-HC!-0.]H20: C, 64.58: H, 5.49: N,4.7l. Found: C. 64.45; H, 5.43; N. 4.49. Example 85 Preparation of (3,5-difluoro)-4-phenvF 1,2,7-trimethvl-1,2.3.4-tetrahvdroisoquinoiine Step A: Nitromethane (1.6 mL, 30 mmol) was added dropwise to an ice-cold solution of letrabutylammonium fluoride (7.5 mmolj in dry THF (20 mL). A solution of 3,5-difluorobenzaldehyde (2.85 g, 20.1 mmol) in dry THF (5 mL) was added dropwise. Triethylamine (2.8 mL. 20 mmol) was then added dropwise. A solution of tert-butyldimethylsilyl chloride (4.54 g, 30.1 mmol) in dry THF (15 mL) was added dropwise, causing a white precipitate to form. The reaction was stirred at 0˚C for 30 min and then was filtered. The solid was washed with ether/hexanes. The filtrate was washed (2 x) with water. The organic layer was dried over MgSO,, filtered, and concentrated under reduced pressure leaving a yellow oil. The yellow oil was purified by column chromatography on silica gel (300 g) eluting with 30% EtOAc/hexanes to give compound the product (2.65 g. 65%) as a colorless oil: 'H NMR (300 MHz, CDCi;) 5 6,98-6.95 (m, 2H), 6.80 (tt, J = 8.8. 2.3 Hz, 1H), 5.49-5.44 (m, 1H), 4.56-4.53 (m,2H),3.0O(d,7 = 2.9Hz, IH). ' Step B: A slurry of the product from Step A (2.35 g, 11.6 mmol) and platinum oxide (0.20 g) in absolute ethanol (20 mL) was hydrogenated at 40 psig for 4 h. The reaction was filtered throgh a plug of Celite, which was washed with additional absolute ethanol. The solvent was removed in vacuo leaving the amine product (1.97 g, 98%) as a while solid: mp 54-58 ˚C; 1H NMR (300 MHz, CDpD) 5 7.01-6.98 (m,2H), 6.87-6.81 (m, ]H),4.70 (dd,y = 8.2. 3.8 Hz, 1H),2.90 {6dJ= 13.0, 3.8 Hz, ]H),2.76 (dd,J= 13.0, 8.2 Hz, IH). Step C: A solution of 3-methylacetophenone (L36 g, 10.1 mmol) and the product from Step B (1.75 g, 10.1 mmol) in toluene (20 mL) was healed at reflux with azeotropic removal of water for 4 h under nitrogen. The toluene was removed in vacuo leaving an orange oil. To an ice-cold solution of the orange oil in methanol (10 mL), was added NaBH3 (0.44 g, 12 mmol). The reaction was stirred for 1 h at 0˚C and then slowly allowed to warm to room temperature over 4 h. The reaction was concentrated under reduced pressure. The residue was taken up in water and extracted (3 x) with ether. The combined organic extracts were dried over Na,SO4. filtered, and concentrated in vacuo to give the product as a mixture of diastereomers (3.00 g, > 100%) as a yellow oil: 'H NMR (300 MHz, CDCI,) 5 7.22-7.18(m,2H), 7.08-7.06 (m,2H), 6.91-6.81 (m. 2H), 6.70-6.64 (m, IH), 4.69-4.45 (m, IH), 3.81-3.67 (m, IH), 2.83-2.75 (m, ]H), 2.58-2.40 (m. 1H).2.34 (s. 3H), 1.39-1.36 (m, 3H). Step D: Concentrated H2SO4 (12.0 mL) was added to a stirred, ice-cold solution of the crude product from Step C (3.00 g, 10.3 mmol) in CH.Cl, (105 mL). After stirring 15 min, the mixture was poured onto ice, made strongly alkaline with excess cone. NH^OH. and extracted (2 x) with Et,0. The combined organic extracts were dried over Na.SO,. filtered, and the solvent was removed in vacuo. The residue (1.75 g) was purified by column chromatography on silica gel (145 g) eluting with 107c EtOAc/hexanes containing 1 % Et.N and then 20% EtOAc/hexanes containing 1 % Et,N to afford the product, a mixture of diastereomers, (426 mg. 157c) as a yellow oil: 'H NMR (300 MHz, CDCI J 5 7.04-6.61 (m, 6H), 4.22-3.99 (m, 2H), 3.49-3.29 (m, IH), 3.19-2.92 (m, IH), 2.34-2.32 (m, 3H), 1.52-1.47 (m. 3H). Step E: Formaldehyde (37 wt7c, 0.70 mL. 9.4 mmol) was added to a solution of the product from Step D (426 mg, 1.56 mmol) in methanol (16 mL). After ! .5 h, Raney nickel (0.51 g) was added. and the reaction was hydrogenated at 35 psig for 21 h. The reaction was filtered through a pad of Celite, which was washed with methanol. The filtrate was evaporated in vacuo, leaving a milky liquid, which was extracted with ether. The ether extract was dried over iNa2SO4, filtered, and the solvent was removed in vacuo. The residue (392 mg) was purified by column chromatography on silica gel (150 g) elating with 10% EtOAc/hexanes containing 1% Et,N to give the desired compound (82 mg, 18%) as a colorless oil-: 'HNMR(300MHz,CDC10 5 6.97 (s, IH), 6.92 (d, 7 = 7.7 Hz, IH), 6.78-6.61 (m,4H),4.11 {uJ = 6.4 Hz, 1H), 3.65 (q, J = 6.6 Hz, IH), 3,04-2.86 (m, 2H), 2.45 (s, 3H), 2.32 (s, 3H), 1.45 (d, J ^ 6.6 Hz, 3H). Step F : A 1 M HCl solution in ether (1.0 mL, 1.0 mmol) was added dropwise to a stirred solution of of the product from Step E (82 mg, 0.28 mmol) in methanol (3 mL). After 30 min, the solvents and excess HCl were removed in vacuo, and the residue precipitated from ether and sonicated for 30 min. The off-white solid was isolated by filtration and then dried at room temperature under vacuum for 24 h to give the product (78 mg, 83%) as an off-white solid: mp 194-197˚C (with decomposition); 'H NMR (300 MHz, CD3OD 5 7.14-7.12 (m, 2H), 7.00-6.81 (m, 4H), 4.65-4.59 (m, 2H), 3.66-3.64 (m, 2H), 3.03 (s, 3H), 2.35 (s, 3H), 1.75 (d, J = 6.5 Hz, 3H); IR (KBr) 2928, 2480. 1624, 1599, 1464, 1119, 975, 859 cm'; CI MS n^z = 288 [C,,H,,F.N+H]^ HPLC >99%, /^ = 16.96 min; Anal. Calcd. forC,,H„F.N-HCL0.25Hp: C, 65.85; H, 6.29; N, 4.27. Found: C, 65.98; H, 6.12; N, 4.16. Example 89 Preparation of (8-fluoro-2-methyl-4-phenvl-L2.3,4-tetrahydro-7-isoquinolinyl)-N-methvlmethanamine Step A: Methylamine (15.3 mL, 407o aq. solution, 177 mmol) was added to a stirred solution of 3-fluorobenzaldehyde (20.0 g, 161 mmol) in MeOH (150 mL) at room temperature. After stirring for 6 h, the reaction was cooled to 0 °C and then NaBH, (6.10 g, 161 mmol) was added portionwise. The cooling bath was removed and the reaction was warmed lo room temperature and stirred for 16.5 h. The reaction was quenched with H,0, and cautiously acidified with 2 N HCL and then extracted (3 x) with CH2CL2. The aq. phase was then basified using 6 N NaOH and then extracted (4 x) with CH.CK. The latter organic extracts were combined, dried over Na2SO4, filtered, and concentrated in vacuo to afford the product (21.51 g. 96%), as a clear oil: 'H NMR (300 MHz, CDCl,) 5 7.32 (td. J = 7.5, 1.7 Hz. IH). 7.28-7.19 (m, IH). 7.14-6.98 (m. 2H). 3.80 (s. 2H). 2.45 (s, 3H), 1.47 (br s, IH). Step B: Trieihylamine (8.40 mL, 60.0 mmol) was added lo a stirred solution of the product from Step A (8.35 g, 60.0 mmo!) and phenacyl bromide (11.94 g, 60.0 mmol) in CH,CK (200 mL) at room temperature under N2, After stirring for 18 h, the reaction was quenched with a mixture 10:1 mixture of H.0/6 N NaOH (33 mL) and organic layer was dried over Na,SO,, filtered, and the solvent evaporated in vacuo, affording crude product (17.08 g. theoretical = 15.44 g). as a yellow oil: 1H NMR (300 MHz, CDC10 5 8.00-7.94(m,2H), 7.59-7.52 (m, IH), 7.48-7.37 (m. 3H), 7.30-7.21 (m, IH), 7.15-7.10 (m, 2H).3.85(s. 2H). 3.79 (S.2H). 2.39(8, 3H): IR (CH.CK solution) 3055, 2925, 2850. 1682. 1598. 1490. 1450, 1266, 1225, 738, 703 cm-1'; CI MS m/z = 258 [C,,H,,FNO+H]\ This material was used without further manipulation. Step C: Sodium borohydride (4.54 g, 120 mmol) was added portionwise to a stirred solution of the product from Step B (17.1 g, --60.0 mmol) in MeOH (150 mL), cooled to 0 °C under R. After stirring for 4.5 h at room temperature, the reaction was diluted with H2O (300 mL) and extracted (4 x) with CH,CL. The organic extracts were combined, washed with sat. NaCl, dried over Na2SO4,. filtered, and the solvent evaporated in vacuo. Chromatography of the residual yellow oil (15.81 g) using silicc (200 g) and elution with 50% EtOAc/hexanes afforded the product (14.81 g, 95% over 2 steps), as a yellow oil: 'H NMR (300 MHz, CDCl,) 5 7.39-7.22 (m, 7H), 7.15-7.01 (m, 2H), 4.75 (dd, 7 = 8.3, 5.6 Hz, lH),3.79(d,J= 13.3 Hz, IH), 3.64 (d.7 = 13.3 Hz, IH), 2.65-2.53 (m, 2H), 2.33 (s, 3H): IR (CH.CU solution) 3062, 2849, 1587, 1491, 1455, 1333, 1266. 1228, 1094, 1062, 1023,897,877,758, 738, 701 cm-'; CI MS n^Jz = 260 [C„H,,FNO+H]Step D: Cone, sulfuric acid (24 mL) was added dropwise to a stirred solution of the product from Step C (14.8 g, 57.1 mmol) in CH.Cl, (280 mL), cooled to 0 °C, using an ice-water bath. The cooling bath was removed after addition was complete and the reaction was vigorously stirred at room temperature for 20 min. The reaction was then poured into an ice / water mixture (400 mL) and the resultant mixture basified with cone. NH3,OH solution to pH - 10. The aq. layer was extracted (3 x) with CH.Cl,. The organic extracts were combined, washed with a 2:1 mixture of sal. NaCI/I N NaOH, dried over Na,SO„ filtered and concentrated in vacuo. Chromatography of the residue (13.91 g) on silica (450 g) and elution with 33% EtOAc/hexanes afforded the product (12.66 g, 92%). as a yellow oil: 'H NMR (300 MHz, CDCl,) 5 7.33-7.15 (m, 5H), 7.08-6.98 (m, IH), 6.90-6.82 (m. IH), 6.66 (d, J = 7.7 Hz, IH), 4.30-4.22(m. IH), 3.86 (d, 7 := 15.6 Hz, IH), 3.53 (d, 7 = 15.6 Hz, IH), 3.02 (dd, J= 11.4,5.6, 1.1 Hz, IH), 2.57(dd,J= 11.6,8.7 Hz, IH), 2.47 (s. 3H); IR (CH,CL solution) 2941, 2782, 1583, 1494, 1468. 1457, 1378, 1248, 1139, 1040,887,792,764,736,701 cm'; CI MS ;7z/c = 242 [C„H,,FN+Hr. Step E: r-Butyl lithium (30 mL, 1.7 M in pentane, 50.5 mmol) was added dropwise to a stirred solution of the product from Step D (5.50 g, 22.8 mmol) and TMEDA (7.6 mL, 50.2 mmol) in Et,0 (120 mL) cooled to -60˚C under N.. After stirring for 45 min, DMF (7.0 mL, 91.2 mmol) was added and the reaction mixture was stirred at -60˚C for 1.5 h. The reaction was quenched with MeOH (10 mL), warmed to room temperature, and then diluted with H,0 (200 mL) and the aqueous layer was extracted (4 x) with CH2Cl2. The combined CH2Cl. extract was dried over Na.SO,, filtered and concentrated in vacuo. Chromatography of the residue (9.05 g) on silica (350 g) and elution with 33% EtOAc/hexanes afforded the product (1.21 g, 20%), as a brown oil: 'H NMR (300 MHz, CDCl,) 5 10,32 (s, IH), 7.56 (t. J = 7.6 Hz, IH), 7.34-7.21 (m, 3H). 7,19-7.10 (m, 2H), 6.79 (d. J = 8.2 Hz, IH), 4.31-4.23 (m, IH), 3.90 (d, 7 =15.8 Hz, lH),3.58(d.J= 15.8 Hz, IH). 3.04 (dd. J = 11.9, 5.6, 1.0 Hz, 1H),2.6] (dd, 7 = 11.7, 8.3 Hz, IH), 2.49 (s. 3H); CI MS ni/z = 270 [C1210FNO+H]' Step F: Methylamine (0.05 mL, 40% aq. solution, 0.62nnmol) was added to a stirred solution of impure aldehyde 147 (0.15 g, -0.57 mmol) in MeOH (3 mL) at room temperature. After stirring for 6 h, the reaction was cooled to 0 °C and then NaBH^ (0.022 g, 0.57 mmol) was added. The cooling bath was removed and the reaction was warmed to room temperature and stirred for 18 h. The reaction was quenched with H,0 extracted (4 x) with CH.CL. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography of the residue (0.18 g) using silica (10 g) and elution with 88:12:1 CHCl,:MeOH:conc, NH4OH afforded methylamine 147 (0.10 g), as a brown oil: 'H NMR (300 MHz, CDCI,) 5 7.32-7.12 (m, 5H), 7.02 (t, 7 = 7.8 Hz, IH), 6.63 (d, J = 7.9 Hz, IH), 4.28- 4.20 (m, IH), 3.86 (d, 7 = 15.6 Hz, IH), 3.75 (s, 2H), 3.52 (d, 7 = 15.6 Hz, IH), 3.00 (dd, 7 = 11.3, 5.6, 0.9 Hz, 1H), 2.55 (dd, 7 = 11.5, 8.7 Hz, 1H). 2.46 (s, 3H), 2.43 (s, 3H); CI MS m/z = 285 [C„H3,FN,+H]Step G: An ethereal HCl solution (1.80 mL, 1 N, 1.80 mmol) was added to a solution of the product from Step F (O.IO g, 0.35 mmol) in MeOH (0.5 mL) and Et,0 (5 mL) at room temperature, resulting in the formation of a off-white solid. The solid was isolated and then recrystallizcd from MeOH/Etp (3x) and the solid was dried in vacuo (54 ˚C) to afford the salt (0.083 g, 66%) as a light green solid: mp 185-205 X; 'H NMR (300 MHz, CD.OD) 5 7.50-7.24 (m, 6H), 6.86-6.78 (m, IH), 4.80-4.50 (m, 3H), 4.29 (s, 2H), 3.92-3.83 (m, IH), 3.70-3.55 (m, IH), 3.15 (s, 3H), 2,76 (s, 3H); IR (KBr) 3422,2956,2698. 1635, 1497, 1456, 1218. 1032, 895, 770, 703, 560 cm'; CI MS m/:: = 285 [C,,H3,FN,+Hr; HPLC 95.5%, /^ = 10.96 min; Anal. Calcd. for C,,H.,FN,-2HC1.0.5Hp: C, 59.02; H, 6.60; R 7.65. Found: C, 59.13; H, 6,73; N, 7.42. Example 90 Preparation of (2-methyl-4-phenyl-7-isoquinolinyl)-N-methvlmethanamine Step A: Methylamine (40 wt% aqueous, 2.6 mL. 30 mmol) was added to a stirred solution of 3-bromobenzaldehyde (5.44 g, 29.4 mmol) in MeOH (30 mL) under N,. After stirring 1 h, the colodess solution was cooled to 0 °C and then NaBH^ (0.60 g, 16 mmol) was added portionwise. After stirring 1 h, the cooling bath was removed. After stirring for 90 min, the reaction was cooled to 0 °C and then phenacyl bromide (5.90 g, 29.6 mmol) was added portionvvise over 30 min. The reaction was allowed to warm to room temperature. After stirring for 2 h at room temperature, the solution was cooled to 0 °C and then NaBH4 (1.20 g, 31.7 mmol) was added portionwise over 10 min. The solution was stirred for 24 h. during which time the temperature rose from 0 ° to 25 °C. The solution was diluted with H.O (400 mL), extracted (4 x) with ether. The ether extracts were dried over Na.SO4, filtered, and the solvent removed in vacuo to give the product (9.21 g. 98%) as a yellow oil: 'H NMR (300 MHz, CDCl,) 5 7.47- 7.21 (m, 9H),4.77(dd,J= 10.0,4.0 Hz, IH), 3.71 i± J = 13.3 Hz, 1H),3.51 (d, 7 = 13.3 Hz, 1H),2.6]- 2.49(m, 2H), 2.32(s. 3H). Step B: Cone. H2SO4 (40.0 mL) was added dropwise over 15 min to a stirred solution of the product from Step A (9.18 g, 28.7 mmol) in CH.Cl, (300 mL). After stirring 45 min, the mixture was poured onto ice, made strongly alkaline with excess cone. NHpH. extracted (3 x) with Et,0. The ether extracts were dried over Na.SO^, filtered, the solvent was removed in vacuo, and the residue (7.29 g) was purified by column chromatography on silica gel (300 g) eluting with 10% EtOAc/hexanes containing 1% Et,N the product (2.05,g, 24%) as an orange oil; 'H NMR (300 MHz, CDCl,) 6 7.32-7.27 (m, 4H), 7.25-7.14 (m,3H),6.74(d,y= 8.3 Hz, IH), 4.22-4.17 (m, 1H),3.71 {dj= 15.1 Hz, IH), 3.57 (d, 7 = 15.1 Hz, IH), 3.05-2.99 (m, IH), 2.54 (dd,7= 11.5,8.7Hz, IH), 2.42 (s, 3H). Step C: A slurry of bromide the product from Step B (1.15 g, 3.81 mmol), zinc cyanide (271 mg. 2.31 mmol), and tetrakis(triphenylphosphine)palladium(0) (266 mg, 0.230 mmol) in dry DMF (5 mL) was heated at 83 °C for 24 h. After allowing the reaction to cool to room temperature, the reaction was diluted with toluene and washed with 2 N NaOH. The toluene extract was dried over Na,SO^. filtered, and concentrated in vacuo. The residue (1.20 g) was purified by column chromatography on silica gel (95 g) eluting with 20% EtOAc/hexanes containing 1% Et,N to give the product (673 mg, 71%) as a yellow solid: mp 103-104 13C; 'H NMR (500 MHz, CDCl,) 5 7.38 (s, IH), 7.34-7.23 (m, 4H), 7.16-7.14 (m,2H),6.98(d,y = 8.0Hz, IH), 4.27 (t,7 = 7.0 Hz, IH), 3.75 (d, 7 = 15.2 Hz, IH), 3.61 (d, 7 = 15.2 Hz, IH), 3.07-3.03 (m, IH), 2.59 (dd, 7 = 11.7, 8.4 Hz. IH), 2.44 (s, 3H); CI MS ni/z - 249 [C,H,,N,+Hr. Step D: A solution of the product from Step C (201 mg, 0.809 mmol) in dry THF (4 mL) was added dropwise to an ice-cold slurry of lithium aluminum hydride (61 mg, 1.6 mmol) in dr>' THF (2 mL). The reaction was stirred for 90 min with cooling and then was allowed to warm to room temperature. The reaction was stirred for 5 h and then was quenched with EtOAc and then a saturated Na2SO4_, solution. The reaction was diluted with ether, dried over solid Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (26 g) eluting with 12% methanol/chioroform containing 1% cone. NH.OH to give the product (134 mg, 66%) as a colorless oil; 'H NMR (300 MHz, CDCl,) 5 7.31-7.18 (m. 5H). 7.04 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.83 (d. 7-8.0 Hz, IH), 4.25 (t, 7 = 7.0 Hz, 1H),3.8] (s. 2H), 3.75 (d, 7 = 14.9 Hz, IH), 3.60 (d,7 = 14.9 Hz. 1H),3.06-3.00(m, IH), 2.56(dd,7=: ll,4,8.7Hz. IH). 2.43 (s, 3H). Step E: A slurry of the product from Step D (53 mg. 0.2 i mmol) and maleic acid (25 mg. 0.22 mmol) in absolute EtOH (10 mL) was heated in a 40 °C water bath until all of the solid had dissolved. After 1 h, the reaction was concentrated in vacuo. The residue was recrystallized from ethanol/ether producing the bis maleate salt (43 mg, 42%) as a green solid: mp 176-177 °C (with decomposition): 'H NMR (300 MHz, CD.OD) 5 7.40-7.30 (m. 5H), 7.22 (dd. 7 - 8.0, 1.3 Hz. 2H), 6.97 (d, 7 = 8.0 Hz, 1H). 6.24(s,4H),4.58(dd.7= 11.3,6.1 Hz. IH), 4.52 (s, 2H). 4.12 (s, 2H). 3.78 (dd, 7 =: 12.3,6.2 Hz. IH). 345j= li.htiz, IH), 3.U2(s,3H);HPLC 95.8%, t,= 10.81 min; Anal. Calcd. for C,,H,,R-2(C,Hp,): C61.98; H, 5.82; N, 5.78. Found: C 61.86; H, 5.82; N, 5.60. Example 91 Preparation of N-methyl-2-methyl-4-phenyl-7-isoquinolinyl)'N-methvymethanamine 5 Step A: A 1 M HCI solution in ether (3.0 mL, 3.0 mmol) was added dropwise to a solution of the product from Step C. Example 90 (82 mg, 0.32 mmol) in methanol (6 mL). The solvents and excess HCl were removed in vacuo leaving a green solid. A slurry of this green solid, potassium carbonate (199 mg, 1.44 mmol), and ethyl chlorofonmate (0.20 mL, 2.1 mmol) in methanol (1 mL) and acetone (6 mL) was heated at 50 °C for 20 h. After allowing the reaction to cool to room temperature, the reaction was ) diluted with brine and extracted (4 x) with EtOAc. The combined organic extracts were dried over solid Na2SO4, filtered, and concentrated in vacuo leaving the carbamate product (99 mg, 88%) as an orange oil: 'H NMR (300 MHz, CDCl,) 5 7.31-7.14 (m, 5H), 6.98-6.93 (m, 2H), 6.83-6.76 (m. IH), 4.30-4.10 (m, 5H), 3.77-3.58 (m, 2H), 3.07-3.01 (m, IH), 2.61-2.54 (m, IH), 2.43 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H); CI MS m/z = 325 [C22H24N2O2+H]. Step B: Lithium aluminum hydride (60 mg, 1.6 mmol) was added in portions to a solution of the product from Step A (99 mg, 0.30 mmol) in dry THF (5 mL). The reaction was heated at reflux for 6 h and then allowed to cool to room temperature. The reaction was quenched with EtOAc and then a saturated Na2SO4 solution. The reaction was diluted with ether, dried over solid Na2SO4,, filtered, and concentrated in vacuo. The residue (81 mg) was purified by column chromatography on silica gel (8 g) eluting with 12% methanol/chloroform containing 1% cone. NH^OH to give compound the product (49 mg, 61%) as a colorless oil: 'H NMR (300 MHz. CDCl,) 5 7.32-7.17 (m, 5H), 7.04 (s, IH), 7.00 (d, J -8.0 Hz, IH), 6.82 (d, 7 = 8.0 Hz. IH). 4.26 {t, 7 = 7.1 Hz. IH). 3.83-3.57 (m, 4H), 3.0.7-3.01 (m, IH). 2.54 (dd, y = 11.4, 8.9 Hz, IH), 2.45 (s, 3H). 2.43 (s, 3H): CI MS ni/~ = 267 [C12H22N.+H] Step C: A slurry of the product from Step B (20 mg, 0.075 mmol) and maleic acid (9 mg, 0.08 mmol) in absolute EtOH (5 mL) was heated in a 40 °C water bath until all of the solid had dissolved. After 2 h, the reaction was concentrated in vacuo. The residue was recrystallized from ethanoi/ether producing the bis maleate product (13 mg. 35%) as a tan solid: mp 160-163 ""C (with decomposition): 'H NMR(300MHz,CD,OD)5 7.41-7.31 (m. 5H). 7.24-7.21 (m. 2H), 6.99 (d. J - 8.0 Hz, IH). 6.24{s, 4H), 4.57 (dd, J = 10.9, 5.7 Hz. IH). 4.50 (s. 2H). 4.1 8 (s. 2H), 3.76 (dd, J = 12.3, 6.2 Hz, IH). 3.50-3.38 (m. 1H), 3.00 (s, 3H), 2.72 (s, 3H); HPLC 95.8%, i, - 11.09 min. Example 92 Preparation of 8-hvdroxy-2-methvl-4-phenyl-1.2.3.4-tetrahydro-7-isoquinolinecarbonitrile Step A: A solution of n-methyI-2-methoxy amine (8.00 g, 52.9 mmol) and triethylamine (5.40 g. 53.0 mmol) in dichloromethane (100 mL) was cooled in an ice water bath. The 2-bromoacetophenone (10.5 H. 53.0 mmol) was added, and the reaction was allowed to warm to room temperature. The V. reaction mixture was diluted with water (200 mL) and MTBJE (200 mL). Layers were separated, and the organic layer was washed with H2O and brine. The organic layer was dried over MgSO,, filtered, and concentrated to yield a red oil which was chromatographed (SiO., 20% EtOAc/hexanes) to yield the desired amino ketone as ayellow oil (12.6 g, 89%); 'H NMR (300MHz, CDCIJ 5 7.97 (d, 7 = 7.4 Hz, 2H), 7.53-7.50 (m, IH). 7.41 (t, J=1.5 Hz. 2H), 7.32 (d, J ^ 7.4 Hz, IH), 7.28-7.21 (m, IH), 6.92 (t,./ = 7.5 Hz, IH), 6.85 (d, J = 8.1 Hz, IH), 3.81 (s, 2H), 3.77 (s, 3H), 3.73 (s, 2H), 2.39 (s, 3H). Step B: The product from Step A (12.6 g, 46.8 mmol) was taken up in methanol (120 mL) and cooled in an ice-water bath. Sodium borohydride (1.76 g, 46.8 mmol) was added portionwise. The reaction was stirred for 1 h at ambient temperature. The reaction mixture was concentrated to half of the original volume. Water (100 mL) was added, and the mixture was extracted (3 x) with dichloromethane. The combined organic layers were dried over MgSO4,, filtered, and concentrated to provide the desired amino alcohol as a light yellow oil (10.0 g, 79%): 'H NMR (300 MHz, CDCl,) 5 7.39-7.21 (m, 6H), 6.94-6.85 (m, 3H), 4.78 (dd, J=4.3, 9.6 Hz, IH), 3.85 (s, 3H), 3.82 (d, 7=12.8 Hz, IH), 3.47 (d. 7=12.8 Hz, IH), 2.62-2.57 (m, 2H), 2.28 (s, 3H). Step C: Methanesulfonic acid (47.7 mL, 735 mmol) was added at ambient temperature to a solution of the product from Step B (4.20 g, 13.7 mmol) in dichloromethane (250 mL). The reaction mixture was stirred at room temperature under nitrogen for 24 h. After the reaction was complete, the reaction was made basic (pH -11) with 2 N NaOH, and extracted (3 x) with methylene chloride. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (SiO„ EtOAc/hexanes, 2/3) to give the desired product as a yellow oil (5.67 g, 61%): 'H NMR (300 MHz, CDCl,) 5 7.30-7.15 (m, 5H), 7.02 (t. 7=8.0 Hz, IH), 6.65 (d, 7=8.1 Hz, 1H), 6.47 (d, 7 = 7.6 Hz, IH), 4.25 (t. 7=6.8 Hz, IH), 3.82 (s, 3H), 3.81 (d, 7=16.2 Hz, IH), 3.36 (d, 7= 16.2 Hz, IH). 2.96 (dd, 7 = 4.1, 15.3 Hz, IH), 2.58 (dd, 7=8.5, 11.4 Hz, IH), 2.43 (s. 3H). Step D: A solution of the product from Step C (5.60 g, 22.1 mmol) in 48% hydrobromic acid (60 mL) was refluxed at 100 °C for 3 h. The reaction mixture was concentrated in vacuo and recrystallized from ethanol to yield the desired product (4.74 g, 67): 'H NMR (300 MHz, DMS0-(7,) 5 9.92 (s, IH), 7.48-7.25 (m, 3H), 7.21 (d. 7=7.8 Hz. 1H), 6.98 (t, 7=7.7 Hz, 1H), 6.67 (d. 7=7.8 Hz. 1 Hj, 6.24 (d, 7=7.7 Hz, IH). 4.26 (t. 7 = 6.0 Hz, IH), 3.80 (d, 7 = 15.8 Hz, IH), 3.32 (d, 7 = 15.8 Hz. IH). 2.99 (dd, 7 = 5.2, 11.3 Hz, 1H), 2.66 (dd, 7 = 7.1, 11.4 Hz, 1H). 2.39 (s, 3H). Step E: A mixture of the product from step D (4.70 g, 14.7 mmol) and hexamethylenetetramine (2.06 g. 14.7 mmol) in trifluoroacetic acid (50 mL) was heated to 80 °C for 7 h. The reaction mixture was concentrated in vacuo then diluted with water (100 mL). The solution was made basic with solid Na2CO3.. The resulting solution was extracted with ethyl ether (3 x), and the combined organic layers were concentrated in vacuo. The residue was purified by chromatography (SiO2„ EtOAc/hexanes. 4/1) to afford the desired product as an off-white solid (2.47 mg. 49%:): 'H NMR (500 MHz. CDCI,) 5 n.42 (bs, IH), 9.82 (s, IH). 7.28 (d. 7=8.1 Hz, IH), 7.12-6.90 (m. 3H), 6.54 (d. 7=8.1 Hz, IH), 4.19 (t. 7=6.1 Hz, IH), 3.72 (d,7= 16.1 Hz. IH). 3.62 (d,7=16.2 Hz. IH), 2.93 (dd.7=11.9. 6.28 Hz, IH), 2.60(dd, 7=11.4,7.0 Hz. lH),2.47(s,3H). Step F: The product from Step E (1.00 g, 2.87 mmol) was dissolved in water (20 mL) before treatment with sodium sulfate (100 mg) and hydroxy! amine sulfonate (0.32 mg 2.87 mmo!). Reaction was stirred for 2 h. Reaction was cooled in an ice-water bath and treated with CH.Cl, (20 mL). Sodium bicarbonate (600 mg) was added and the reaction was allowed to warm to ambient temperature. The solids were filtered off and combined with the organic layer. The mixture was concentrated and chromatographed (SiO,, EtOAc/hexanes, 1/1). Two compounds eluted simultaneously. The mixture was treated with ethanol (5 mL) and filtered. The filtrate was concentrated to yield the desired nitrile as an off-white powder (130 mg, 17%): mp 234-238 °C (decomposed);'H NMR (300 MHz, CD.OD) 5 7.31-7.14 (m,6H), 6.40 (d, 7=8.1 Hz, 1H),4.2] (t, 7=6.1 Hz. IH), 4.12(bs, IH), 3.61-3.50 (m, 2H), 2.72 (dd, 7=5.4, \\n Hz, IH), 2.58 (dd. 7=7.1, 1 1.5 Hz, IH), 2.38 (s. 3H). IR (KBr) 3427, 3026, 2940, 2207, 1590, 1454cm1:ESIMS/7i/c = 265[C„H,,N,0+Hr;HPLC96.3%,/^= 13.54 min. Example 93 Preparation of (2-methyl-4-phenvl-1.2,3,4-teIrahydro-7-isoquinolinyl)methanol Step A: A solution of Step C, Example 90 (127 mg, 0.51 1 mmol) in dry toluene (13 mL) was cooled to -16 °C and then 1 M DIBAL-H in toluene (1.7 mL, 1.7 mmol) was added dropwise. The reaction was stirred for 45 min with cooling and then EtOAc (1.1 mL) was added. The reaction was allowed to warm to room temperature. The reaction was stirred for 45 min and then 1 N H,S0,(12 mL) was added. The reaction was heated at reflux for 30 min. After allowing the reaction to cool to room temperature, the reaction was diluted with water, made basic with 2 N NaOH, and extracted (2 x) with CH.Cl,. The CH,C1, extracts were dried over Na,SO_,, filtered, and concentrated in vacuo to give the desired product (112 mg, 87%) as a yellow oil: 'H NMR (300 MHz. CDC),) 5 9.95 (s, IH). 7.62 (s, IH). 7.59-7.56 (m. IH), 7.34-7.16 (m, 5H), 7.05 (d, 7 = 8.0 Hz. IH), 4.32 (t, 7 = 7.1 Hz, IH). 3.84 (d, 7 = 15. i Hz, lH),3.67(d,7= 15.1 Hz, IH), 3.10-3.04 (m, IH), 2.60 (dd, 7 = 11.6. 8.6 Hz. IH), 2.46 (s. 3H). Step B: To an ice-cold solution of the product from Step A (110 mg. 0.438 mmol) in methane! (20 mL) was added NaBH, (36 mg. 0.95 mmol). The reaction was slowly allowed to warm to room temperature overnight. The reaction was quenched with water and bnne and then was extracted (3 x) with CH2cl2. The combined organic extracts were dried oyer Na.SO., filtered, and concentrated under reduced pressure. The residue (106 mg) was purified by column chromatography on silica gel (31 g) eluting with EtOAc to give the desired alcohol (44 mg. 40%) as a yellow oil: 'H NMR (300 MHz. CDCl,) 5 7.32-7.22 (m, 3H). 7.17 (dd, 7 = 6.6. 1.6 Hz, 2H), 7.03 (d, 7 = 7.6 Hz, IH), 7.02 (s, IH). 6.83 (d. 7 = 7.6 Hz, ]H), 4.61 (s. 2H). 4.26 (dd. 7 = 8.6. 6.0 Hz, IH). 3.69 (d, 7 = 14.9 Hz, IH), 3.55 (d, 7 = 14.9 Hz, IH). 3.07-3.01 (m. IH), 2.53 (dd. 7 :z: ] 1.5.9.1 Hz. IH). 2.42 (s, 3H). Step C: A 1 M HCl solution in ether (1.0 mL, 1.0 mmol) was added dropwise to a stirred solution of theproduct from Step B (44 mg, 0.17 mmol) in MeOH (2 mL). The solvents and excess HCl were removed in vacuo, and the residue recrystallized from MeOH-Etp to give the salt (32 mg. 62%) as a green solid: mp 237-240 X (with decomposition); 'H NMR (300 MHz. CD.OD) 6 7.42-7.31 (m, 3H), 7.27-7.23 (m. 4H), 6.88 (d, J = 7.2 Hz, ]H), 4.60 (bs, 5H) 3.84 (dd, J = 12.4 , 6.0 Hz, IH), 3.65-3.45 (m, ]H),3.08(s,3H); IR (KBr) 3356, 2934, 2596, 1495, 1456, 1428, 1049,758,703 cm'; ESIMS m/z = 254 [C,,H,12NO+Hr; HPLC 94.9%, t^ = 12:83 min; Anal. Calcd. for C„H.,NO-HC1-0.33 H^: C,69.C3; H,7.04; N,4.74. Found: C, 68.89; H, 6.87; N, 4.61. Example 94 Preparation of 2-ethvl-4-phenvl-1.2.3.4-tetrahvdroisoquinoline Step A: Ethylene glycol dimethyl ether (20 mL) and 2 N Na.CO, (12.2 mL) were sparged with R and charged to a round bottom flask containing 4-bromoisoquinoline (2 g, 9.6 mmol), phenylboronic acid (1.76 g, 14.4 mmol), and Pd(PPh,)_, (1.11 g. 0.96 mmol). The entire solution was sparged with N,. The resulting reaction mixture was heated to reflux under N, overnight. The solution was cooled, quenched with saturated NaHCO, (230 mL), and extracted five times with ethyl ether. The combined organic was dried over Na^SO^, filtered, and the solvent was removed in vacuo to yield an orange oil. Column chromatography (1:1 ethyl acetate/hexanes) afforded the pure isoquinohne as a yellow oil which crystallized upon refrigeration (2.21 g). 'H NMR (300 MHz, CDCl,) 5 9.29 (s, lH),8.52(s, 1H),8.04 (d, ]H,y=8.4Hz),7.91 (d, lH,y = 8.1 Hz), 7.66 (m, 2H), 7.46 (m, 5H). Step B: Ethyl triflate (383 mg, 2.15 mmol) was added dropwise to a solution of the product from Step A (400 mg, 1.95 mmol) in CRCI, (24 mL) at OC under N,. The solution was stirred for 15 min. at room temperature. The solvent was removed in vacuo to yield the triflale salt of the isoquinohne as a white solid (420 mg, 56% yield). The triflate salt (420 mg. 1.09 mmol) was dissolved in MeOH (16 mL), and NaCNBH, (159 mg, 2.53 mmol) was added to the solution. The resulting reaction mixture was stirred for 5 min., and a few drops of bromocresol green in MeOH were added. Methanolic HCl was added to the solution until a vellow color was observed. The reaction mixture was stirred at room temperature for 30 min, while adding methanolic HCl as needed to maintain a yellow-' color. The reaction mixture was quenched with H.O (100 mL) and basified with 5% NaOH until a blue color was observed. The resulting solution was extracted four times with ethyl ether. The combined organic was washed with brine, dried over MgSO4 filtered, and solvent was removed in vacuo to yield the tetrahydroisoquinoline product as a clear oil (140 mg, 30% yield). Step C: The maleate salt was prepared by adding maleic acid (68 mg, 0.59 mmol) and EtOH (2 mL) to the product from Step B . After refrigeration and removal of EtOH, a white solid was obtained (130 mg),mp=172-174r. Free base: 'H NMR CDCL 5 7.17 (m. 8H). 6.85 (d, IH, 7 = 7.7 Hz). 4.28 (t, iH.y = 7.5 Hz), 3.89 (d, 1H, 7 = 14.65 Hz), 3.62 (d, IH, 7 = 14.65 Hz), 3.15 (dd, IH, J = 5.7, 11.7 Hz), 2.57 (m,2H), 1.16(t,3H,7=:7.2Hz). Binding Assavs Primary binding assays: In order to evaluate the relative affinity of the various compounds at the NE, DA and 5HT transporters, HEK293E cell lines were developed to express each of the three human transporters. cDNAs containing the complete coding regions of each transporter were amplified by PCR from human brain libraries. The cDNAs contained in pCRII vectors were sequenced to verify their identity and then subcloned into an Epsiein-Barr virus based expression plasmid (E. Shen, GM Cooke, RA Horlick, Gene 156:235-239, 1995). This plasmid containing the coding sequence for one of the human transporters was transfected into HEK293E cells. Successful transfection was verified by the ability of known reuptake blockers to inhibit the uptake of tritiated NE, DA or 5HT. For binding, cells were homogenized, centrifuged and then resuspended in incubation buffer (50mM Tris, 120mM NaCl, 5mM KCl, pH 7.4). Then the appropriate radioligand was added. For NET binding, ['H] Nisoxetine (86.0 Ci/mmol, NEN/DuPont) was added to a final concentration of approximately 5 nM. For DAT binding, [H] WIN 35,428 (84,5 Ci/mmol) at 15 nM was added. For 5HTT binding, ['H] Citolapram (85.0 Ci/mmol) at 1 nM was added. Then various concentrations (10^-5 to 10-l 1 M) of the compound of interest were added to displace the radioligand. Incubation was carried out at room temperature for 1 hour in a 96 well plate. Following incubation, the plates were placed on a harvester and washed quickly 4 times with (50mM iris, 0.9% NaCI, pH 7.4) where the cell membranes containing the bound radioactive label were trapped on Whatman GF/B filters. Scintillation cocktail was added to the filters which were then counted in a Packard TopCount. Binding affinities of the compounds of interest were determined by non-linear curve regression using GraphPad Prism 2.01 software. Non-specific binding was determined by displacement with 10 micromolar mazindol. TBZ assay: In order to assess in vivo activity of the compounds at the NE and DA transporters, their ability to prevent the sedative effects of tetrabcnazine (TBZ) was determined (G. Slille, Arzn. Forsch 14:534-537, 1964). MaleCFl mice (Charles River Breeding Laboratories) weighing 18-25 gm at the time of testing, are housed a minimum of06 days under carefully controlled environmental conditions (22.2 + 1.1 C; 50% average humidity; 12 hr lighting cycle/24 hr). Mice are fasted overnight (16-22 hr) prior to testing. Mice are placed into clear polycarbonated "shoe" boxes (17 cm x 28.5 cm x 12 cm). Randomized and coded doses of test compounds are administered p.o. A 45 mg/kg dose of tetrabcnazine is administered i.p. 30 minutes prior to score time. All compounds are administered in a volume of 0.1 ml/10 gm body weight. Animals are evaluated for antagonism of tetrabcnazine induced exploratory loss and ptosis at specified time intervals after drug administration. At the designated time interval, mice are examined for signs of exploratory activity and ptosis. Exploratory activity is evaluated by placing the animal in the center of a 5 inch circle. Fifteen seconds are allowed for the animal to move and intersect the perimeter. This is considered antagonism of tetrabenazine and given a score of 0. Failure to leave the circle is regarded as exploratory loss and given a score of 4. An animal is considered to have ptosis if its eyelids are at least 50% closed and given a score of 4 if completely closed. No closure is given a score of 0. Greater than 95% of the control (vehicle-treated) mice are expected to exhibit exploratorv' loss ai.d ptosis. Drug activity is calculated as the percentage of mice failing to respond to the tetrabenazine challenge dose. Statistical evaluation.: Median effective doses (ED50s) and 95% confidence limits are determined numerically by the methods of Thompson (1947) and Litchfield and Wilcoxon (1949). 1. A compound of the formula lA-IF having the following structure: pyrrolidine, piperazine, N-methyipiperazine. morphoiine, or thiomorpholine; 7. The compound of claim 6. wherein R' is methyl, ethyl, propyl, or isopropyl. 8. The compound of claim 6, wherein R3 is -o(phenyl) or -O-CH2-(Phenyl), each of which is optionally substituted from 1 to 3 times with a substituent selected independently at each 25. The compound of claim 23, wherein R4 is halogen. 26. A compound according to claim K wherein The carbon atom designated * is in the R configuration. 27. ^ A compound according to claim 1, wherein the carbon atom designated * is in the S configuration. 29. A composition comprising a mixture of stereoisomeric compounds of claim 1 wherein the carbon atom designated * is in the S or R configuration. 29. A radiolabelled compound of claim 1. 31. A compound according to claim 1, selected from table C. 32. A compound according to claim 1, wherein the enantiomer is selected from table D. 34. A compound according to claim 30, which is the (+) stereoisomer. 34. A compound according to claim 30, which is the (-) stereoisomer. 35. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 1. 36. A method of treating a disorder which is created by or is dependent upon decreased availability of serotonin, norepinephrine or dopamine, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof. 37. A method according to claim 36, which further comprises administering a therapeutically effective amount of a serotonin lA receptor antagonist, or pharmaceutically acceptable salt thereof. 38. A method according to claim 37 wherein the serotonin 1A receptor antagonist is chosen from the group consisting of WAY 100135 and spiperone. 39. A method according to claim 36, which further comprises administering a therapeutically effective amount of a selective neurokinin-] receptor antagonist, or pharmaceutically acceptable salt thereof. 40. A method according to claim 36, which further comprises administering a therapeutically effective amount of a norepinephrine precursor, or pharmaceutically acceptable salt thereof. 41. A method according to claim 40, wherein the norepinephrine precursor is selected from the group consisting of L-tyrosine and L-phenylalanine. 42. A method according to claim 36, wherein the disorder is selected from the group: attention deficit disorder, hyperactivity disorder, anxiety, depression, post-traumatic stress disorder, supranuclear palsy, eating disorders, obsessive compulsive disorder, analgesia, nicotine addiction, panic attacks, Parkinsonism and phobia, obesity, late luteal phase syndrome or narcolepsy, cocaine addiction, amphetamine addiction, and psychiatric symptoms anger such as, rejection sensitivity, and lack of mental or physical energy. 43. A method of inhibiting synaptic norepinephrine uptake in a patient in need thereof comprising administering a therapeutically effective inhibitory amount of a compound according lo claim 1. 44. A method of inhibiting synaptic serotonin uptake in a patient in need thereof comprising administering a therapeutically effective inhibitory amount of a compound according to claim 1. 45. A method of inhibiting synaptic dopamine uptake in a patient in need thereof comprising administering a therapeutically effective inhibitory amount of a compound according to claim 1. 46. The method of claim 36 wherein the (+)-stereoisomer of the compound is employed. 47. The method of claim 36 wherein the (-)-stereoisomer of the compound is employed. 48. A kit comprising a compound according to claim I and at least one compound selected from the group consisting of: a serotonin 1A receptor antagonist compound, a selective neurokinin-1 receptor antagonist compound, and a norepinephrine precursor compound. 49- The method of claim 36 for treating atteniion deficit/hyperactivity disorder. 50. A compound of fORMULA ia-if, substantially as hereinabove described and exemplified. 51. A pharmaceutical composition, substantially as herienabove described and examplified

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