Indian Patents. 218978:PIPERAZINYL AND DIAZAPANYL BENZAMIDES AND BENZTHIOAMIDES

Title of Invention	PIPERAZINYL AND DIAZAPANYL BENZAMIDES AND BENZTHIOAMIDES
Abstract	Substituted piperazinyl and diazapanyl benzamides and benzohipemides of fomula (I). compositions containing them, and methods or making and using them to treal histimine-mediated conditions.

Full Text	More recently, several publications have described histamine H3 ligands that do not contain an imidazole moiety, for example: Ganellin. C-R. et al.; 5 Walczynski, K. et al., Arch. Pharm. Pharm. Med. Chem. (Weinheim, Ger.) 1999, 332:389-398, Walczynski, K. et at., farmeco 1999, 54:584-694; Linney, I.D. et al., J. Med Chem. 2000, 43:2362-2370; Tozer, M.J, and Kafindjian, S.B., Exp, Opin. Ther. Pafents 2000, 10:1045-1055; U.S. Patent 5,352,707; PCT Application WO 98/42458, Aug. 26, 1999; PCT Applfcatron WO 10 02/076925; and European Patent Application 0978512, Feb. 9, 2000. The compounds of the present invention do not contain the imidazole moiety, and its inherent liabilities, and yet maintain potency at the human H3 receptor as determined by receptor binding to the human histamine H3 receptor (see Lovenberg, T.W. et al., Mol. Pharmacol 1999, 55:1101-1107). Screening 15 using the human receptor is particularly important for the identification of new therapies for the treatment of human disease. Conventional binding assays are determined using rat synaptosomas (Garbarg, M. et al., J. Pharmacol. Exp. Ther. 1992, 263 (1):304-310), rat cortical membranes (West, R.E. et al., Mol. Pharmacol. 1990, 33:610-613), and guinea pig brain (Korte, A. et al., Biochem. 20 Biophys, Res. Commun, 1990, I68(3):979-986). Only limited studies have been performed previously using human tissue but these allude to significant differences in the pharmacology of rodent and primate receptors (West, R.E. et al., Eur. J. Pharmacol 1999,377:233-239). We now descride a series of piperazinyl and diazepanyl benzamides and 25 benzthioamides with the ability to modulate the activity of the histamine receptor, specifically the H3 receptor, without the inherent problems associated with the presence of an imidazolyl moiety. SUMMARY OF THE INVENTION 30 The present invention is directed to pharmaceutically active piperazinyl and diazepanyl benzamides and benzthioamides, methods of making them, and methods of using them. The invention features compounds of formula (I): 4 WO 2004/037801 PCT/US2003/033343 wherein R1 is C1-10 alkyl, C3-8 atkenyl, C3-8 cycloalkyl, (C3-8 cycloaSkyl)C3-8 alkyl, (C3-8 5 cycloalkyl)C3-8 alkenyl, or (C1-8 afkylcarbonyl)C1-8 alkyl; n is 1 or 2; X is O or S; one of R2, R3 and R4 is G and the other two independency are hydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl, methyl, or C1-3 alkoxy; 10 G is LQ; L is unbranehed -(CH2)m- wherein in is an integer from 1 to 7 (preferably m is 1 to 4, more preferably m is 1); Q is NR8R9 wherein R8 is Independently selected from hydrogen, C1-6 alkyl, C3-8 alkenyl, 3-9 membered carbocyclyl, 3-12 membered heterocyclyl 15 (preferably 5-9 or 5-8-membered heterocyctyl). phenyl, (6-9-mernbered heterocyclyl)C1-5 alKylene, and (phenyl)C1-6 alkylene; and R9 is Independently selected from C1-8 alkyl, C3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl (preferably 5-9 or 5-8- membered heterocyclyl), phenyl, (6-9-rnembered heterocyclyl)C1-5 20 alkylene, and (phenyl)C1-5 alkylene; or Q is a saturated 3-12 rnembered N-linked heterocyclyl, wherein, in addition to the N-Iinking nitrogen, the 3-12 membered heterocyclyl may optionally contain between 1 and 3 additional hetenoafoms independently selected from O, S.and NH; 5 WO 2004/037801 PCT/US2003/033343 wherein Q is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halo, carboxamide, C1-6 alkyl, 5-9 membered or 6-9 membered heterocyclyl, -N(C1-6 alkyl)(5-9 membered or 6-9 membered heteracyclyl), -NH(5-9 membered or 6-9 membered 5 heterocydyl), -O(5-9 or 6-9 membered heterocydyl), (5-9 membered or 6-9 membered heterocyclyl)C1-3 alkylene, C1-6 alkoxy. (C3-6 cycloalkyl)- O-. phenyl, (phenyl)C1-3 alkylene, and (phenyl)C1-3 alkylene-O-, where each of above heterocyclyl, phenyl, and alkyl groups rnay be optionally substituted with fnom 1 to 3 substituents Independently selected from 10 trifluoromethyl, methoxy, halo, nitro, cyano, hydroxy, and C1-3 alkyI; provided however that when R1 is methyl, G is not piperidin-1-ylmethyl; and wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and aryl groups may each be independently and optionally substituted with between 1 and 3 substrtuents independently selected 15 from trifluonomethyl, methoxy, halo, amino, nitro, hydroxy, and C1-3 alkyl; or a pharmaceutically acceptable salt, esterT tautomer, solvate or amide thereof. The invention also features a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier; and 20 methods of preparing or formulating such compositions. A composition of the invention may further include more than one compound of the invention, or a combination therapy (combination formulation or combination of differently formulated active agents). The invention also provides methods of treating certain conditions and 25 diseases, each of which methods includes administering a therapeutically effective (or jointly effective) amount of a compound or composition of the invention to a subject in need of such treatment. The disclosed compounds are useful in methods for treating or preventing neurologic disorders including sleep/wake and arousal/vigitance disorders (e.g. insomnia and jet lag), 30 attention deficit hyperactivity disorders (ADHD), learning and memory disorders, cognitive dysfunction, migraine, neurogenic inflammation, dementia. mild cognitive impairment (pro-dementia), Alzheimer's disease, epilepsy, narcolepsy, eating disorders, obesity, motion sickness, vertigo, schizophrenia, 6 WO 2004/037801 PCT/US2003/033343 substance abuse, bipolar disorders, manic disorders and depression, as well as other histamine H3 receptor mediated disorders such as upper airway allergic response, asthma, itch, nasal congestion and allergic chinitis in a subject in need thereof. For example, the invention features methods for 5 preventing, inhibiting the progression of, or treating upper airway allergic response, asthma, itch, nasal congestion and allergic rhinitis. In yet another embodiment, the disclosed compounds may be used in a combination therapy method including administering a Jointly effective dose of an Ha antagonist and administering a Jointly effective dose of a histarnine H1 10 antagonist, such as loratidine (C LARI Tl N™), desloratidine (C LARINEXTM), fexofenadine (ALLEGRA™) and cetirizine (ZYRTEC™), for the treatment of allergic rhintis, nasal consestion, and altergie congestion. In yet another embodiment, the disclosed compounds may be used in a combination therapy method, including administering a jointly effective dose of 15 an H3 antagonist and administering a jointly effective dose of a neurotransmitter re-uptake blocker, such as a selective serotonin re-uptake inhibitor (SSRI) or a non-selective serotonin, dopamine or norepinephrine re- uptake inhibitor, including fluoxetine (PROZAC™), sertraline (ZOLOFT™), paroxeline (PAXIL™) and amitryptyline, for the treatment of depression, mood 20 disorders or schizophrenia. Additional features and advantages of the invention will become apparent from the detailed description and examples betow, and the appended claims. 25 DETAILED DESCRIPTION OF THE INVENTION The present invention provides phenylpiperidine compounds useful for the treatment of disorders and conditions modulated by a histamine receptor, A, Terms 30 Certain terms are defined below and by their usage throughout this disclosure. 7 WO 2004/037801 PCT/US2003/033343 examples include cydopropyl. cydobutyl, cyclopentyl, cyclohexyl, cyclohepfyl and cyclooctyl. As used herein, unless otherwise noted. "cycloalkenyl" shall denote a three- to eight-membered, partially unsaturated, monocyclic, carbocyclic ring 5 structure, wherein the ring structure contains at least one double bond. Suitable examples include cyclohexenyl, cyclopentenyl, cycloheptenyl, cydooctenyl, cyclohex-1.3-dienyl and the like. As used herein, unless otherwise noted, "aryl" shall refer to carbocyclic aromatic groups such as phenyl, naphthyl, and the like. Divalent radicals include 10 phenylene (-C6H4-) which is preferably phen-1,4-dlyl, but may also be phen-1.3- diyl. As used herein, unless otherwise noted, "aralkyl" shall mean any alkyl group substituted with an aryl group such as phenyl, naphthyl, and the like. Examples of aralkyls include benzyl, phenethyl, and phenylprapyl 15 As used herein, unless otherwise noted, "carbocyclyl shall mean any cyclic group consisting of 3-12 carbon atoms, and preferably 6-9 carbon atoms, in the skeleton ring or rings, if the carbacycle is a fused or spiro bicyclic or tricyclic group. A carbocycle may be saturated, unsaturated, partially unsaturated, or aromatic. Examples include cycioalkyl, cycloalkenyl, 20 cycloalkynyl: specific examples include phenyl, benzyl. indanyl, and biphenyl. A carbocycle may have substituents that are not carbon or hydrogen, such as hydroxy, halo, halomethyl, and so on as provided elsewhere herein. As used herein, unless otherwise noted, the terms 'heterecycle", "heteracyclyl" and "heterocyclo" shall denote any three-, four-r five-, six-, seven-, 25 or eight-membered monocyclic, nine- or ten-membered bicyclic, or thirteen- or fourteen-membered lricyclic ring structure containing at least one heteroatom moiely selected from the group consisting of NH, O, SO, SO2, (C=O), and S, and preferably NH, O, or S, optionally containing one to four additional heteroatoms in each ring. In some embodiments, the heterocyclyl contains between 1 and 3 30 or between 1 and 2 additional heteroatoms. Unless otherwise specified, a heteracyclyl may be saturated, partially unsaturated, aromatic or partially aromatic. The heterocyclyl group may be attached at any hetenoatom or carbon atom that results in the creation of a stable structure. 9 WO 2004/037803 PCT/US2003/033343 As used herein, "Ca-b," (where a and b are integers) refers to a radical containing from a to 6 carbon atoms inclusive. For example, C1-3 denotes a radical containing 1, 2 or 3 carbon atoms. As used herein, "halo" or "halogen" shall mean monovalent radicals of 5 chlorine, bramine, fluorine and iodine. As used herein, the term "alkyi", whether used alone or as part of a substituent group, shall include straight and branched saturated carbon chains. For example, alkyl radicate include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like. Unless otherwise noted, "lower" 10 when used with alkyl means a carbon chain composition of 1-4 carbon atoms. "Alkylene" refers to a bivalent hydrocarbyl group, such as methylene (-CH2-), elhylene (-CH3-CH2") or propylene (-CH2CH2CH2-), and so on. As used herein, unless otherwise noted, "alkenyl" shall mean an alkylene group with at least two hydrogen atoms replaced with a pi bond to 15 form a carbon-carbon double bond, such as properlyl, butenyl, pentenyl, and so on. Where the alkenyl group is R8 or R9, the open radical (point of attachment to the rest of the molecule) is on sp3 carbon, as illustrated by allyl, and the double bond or bonds is therefore at feast alpha (if not befa, gamma, etc) to the open radical. 20 As used herein, "alkylidene" refers to a saturated or unsaturated, branched, straight-Chain or cyclic divalent hydrocarbon radical derived by removal of two hydrogen atoms from the same carbon atom of a parent alkane, alkene or alkyne. The divalent radical center forms a double bond with a single atom on the rest of the motecule. Typical alkylidene radicals include, but are 25 not limited to, ethanylidene; propylidenes such as propan-1-ylidene, proparn-2- ylidene, cyclopropan-1-yliden; butylidenes such as butan-1-ylidene, butan-2- ylidene, 2-methyl-propan-1 -ylidene, cyclobutan-1-ylidene; and ths like. As used herein, unless otherwise noted, "alkoxy" shall denote an oxygen ether radical of the above-described straight or branched chain alkyl groups. For 30 example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like. As used herein, unless otherwise noted, "cycloalkyl" shall denote a three- to eight-membered, saturated monocyclic cartracyclic ring structure. Suitable 8 WO 2004/037801 PCT/US2003/03334 Exemplary monocyclic heterocyclic groups can Include pymolidlnyl, pyrrolyl, indoiyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazoly!, Smidazolinyl imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolmyl, isoxazolyl, thiazaolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetraftydrofuryl, 5 thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopymotidinyl, 2-oxazepinyl, azepinyl, hexahydroazepinyl, 4-piperidinyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dixolane 10 and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl. thietanyl, thiiranyl. triazinyl, triazolyl, tetrazolyl, azefidinyl and the like. For example, where O is a saturated 3-12 membered N-linked heterocyclyl, Q necessarily contains at least one nitrogen, and the carbon atoms are sp3 hybridzed. Where Q is a fused bicyclic heterocyclyl, the carbon 15 atoms of the ring linked to U is sp3 hybridized, provided the adjacent ring (and the common carbon atoms) may be sp2, such as an indanyl where one of the carbon atoms has been replaced with nitrogen. In general, exemplary bicyclic heterocyclyls include benzthiazolyl. benzoxazolyl, benzaxazinyl, benzothienyl, quinuclidinyl, quinolinyl. quinolinyl-N- 20 oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzirmidazolyl, benzopyranyl, indolizinyl, benzofuryl, chronnonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pynrolopridyl, furopyridinyl (such as furo{2r3-c}pyridinyl, furo{3,1- b}pyridinyl), or furo{2,3-b}pyridinyl}, dihydroisoindolyl, dihydroquinasolinyl (such as 3.4-dihydro-4-oxo-quinszolinyl), tetrahydroquinolinyl (such as 1,2,3,4- 25 tetrahydroqurnolinyl), tetrahydroisoquinolinyl(such as 1,2,3,4- tetrahydraisoquiunolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl,dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothlopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isoindolyl, 30 tetrahydroincloazolyl (such as 4,5,6,7-tetrahydroindazolyl), isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, 10 WO 2004/037801 PCT/US2003/033343 quinazotinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl. Exemplary tricyclic heterocylclic groups include acridinyl, phenaxazinyl, phenazinyl, phenothiazinyl, carbozolyl, perminidinyl, phenanthrolinyl, carbolinyl, 5 naphthothlenyI, thianthrenyl, and the like. Preferred heterocyclyl groups Include morpholinyl, thlomorpholinyl. piperidinyl, piperazinyl, pyrrolidinyl, pyrimidinyl, pyridyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, acridinyl, azepinyl, hexahydroazepinyl, azatidinyl, indolyl, isoindolyl, thiazolyl, thiadiazolyl, quinollnyl, isoquinolinyl, 1,2,3,4- 10 tetrahydroquinolinyl, 1,3,4-trihydrolsoquinoIinyl, 4,5,6,7-tetrahydroindadolyl, benzoxazinyl, benzoaxzolyl, benzthiazolyl, benzimidazoly], tetrazolyl, oxadiazolyl, As used herein, unless otherwise noted, the term "heterocyclyl-alkyl" or "heterocyclyl-alkylene" shall denote any alkyl group substituted with a 15 heterocyclyl group, wherein the heterocycyl-alkyl group is bound through the alkyI portion to the central part of the motecule. Suitable examples of heterocyclyl-alkyl groups include, but are not limited to piperidinyl methyl, pyrrolidinylmelhyl, piperidinylethyl, piperazinylmethyl, pyrrolyibutyl, piperidinylisobutyl pyridylmethyl, pyrimidylethyl, and the like. 20 When a particular group is "substituted" (e.g., aIkyl. alkylene, cycloaIkyl. aryi, heterocyclyl, heteroaryl), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents. 25 It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the 11 WO 2004/037801 PCT/US2003/03343 art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein. Under standard nomenclature used throughout this disclosure, the 5 terminaI portion of the designated side chain is described first, followed by the adjacant functionality toward the point of attachment. Thus, for example, a "phenyl(alkyl)amido(alkyl)" substituent refers to a group of the formula 10 The term 'sufcsject" as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment observation or experiment. The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or 15 medicinal response in a tissue system, animal or human that is being sought by a researcher, voterinarian, medical doctor or other clinician, which includes prevention, inhibition of onset, or alteviation of the symptoms of the disease or disorder being treated. As used herein, the term "composilion" is intended to encompass a 20 product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified Ingredients in the specified amounts. Abbreviations used in the specification, particularly in the Schemes and Examples, are as follows: 25 12 WO 2004/037801 PCT/US2003/033343 B. Compounds Ths invention features compounds of formula (1): 5 wherein R1 is C1-10 alkyl, C3-8 alkenyl, C3-8 cydoalkyl, (C3-8 cycloalkyl)C1-6 alkyl, (C3-8 cycloalkyl)C3-8 alkenyl, or (C1-8 alkytcarbonyl)C1-8 alkyl, n is 1 or 2; 10 X is O or S; one of R2, R3 and R4 is G and the other two independently are hydrogen, fluoro, chioro, bromo, nitro, trifluoromethyl, methyl, or C1-3 alkoxy; G is LQ; 13 WO 2004/037801 PCT/US2003/033343 L is unbranched -(CH2)m- wherein m is an integer from 1 to 7; Q is NR8R9 wherein R6 is independently selected from hydrogen, C1-5 alkyI, C3-6 alkenyl, 3-9 membered carbocyclyl, 3-12 membered heterocyclyl (preferably 5-9 or 5-3-membered heterocyelyl), phenyl, (B-9-membered 5 heteracyclyl)C1-8 alkylene, and (phenyl )C1-6 alkylene; and R9 is independently selected from C1-5 alkyI, C3-8 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl (preferably 5-9 or 5-8- membered heterocyclyl), phenyl, (6 9-membered heterocyclyl)C1-6 alkylene, and (phenyl)C1-5 alkylene; or 10 Q is a saturated 3-12 membered N-linked hetenocyclyl, wherein, in addition to the N-linking nitrogen, the 3-12 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms independently selected from O,S, and NH; wherein Q is optionally substituted with 1-3 substituents independently selected 15 from the group consisting of hydroxy, halo, carboxamide, C1-6 alkyl, 5-9 membered or 6-9 membered heterocyclyl, -N(C1-6alkyl)(5-9 membered or 6-9 membered heterocyclyl), -NH(5-9 membered or 6-9 membered heterocyclyl), -O(5-9 or 6-9 membered heterocyclyl), (5-9 membered or 6-9 membered heterocyclyt)C1-3 alkylene, C1-6 alkoxy, (C3-6cycloalkyl)- 20 O-, phenyl, (phenyl)C1-3 alkylene, and (phenyl)C1-3 alkylene-O-, where each of above heteracyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from trifluoromethyl, methoxy, halo, nitro, cyano, hydroxy, and C1-3 alkyl; provided however that when R1 is methyl, G is not piperidin-1-ylmethyl; and 25 wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and aryl groups may each be independently and optionally substituted with between 1 and 3 substituents independently selected from trifluoromethyl, methoxy, halo, amino, nitro, hydroxyl, and C1-3 alkyl; 30 or a pharmaceutically acceptable salt, ester, tautomer, solvate or amide thereof. Preferred compounds of formula (1) include those wherein; 14 WO 2004/037801 PCT/US2003/033343 (a)n is 1: (b) R1 is C1-10 alkyl (preferably branched); (c) R1 is branched C3-5 alkyl; (d) one of R2, R3 and R4 is G; (preferably one of R3 and R4 is G) 5 (e) R4 is G; (f) L is unbranched -(CH2)m-, wherein m is an integer from 1 to 4; g) is -CH2-; h) Q is a saturated N-linked nitrogen-containing heterocyclyl; (i) Q is substituted or unsubstituted piperidinyl, diazepanyl, azepanyl, 10 decahydroisoquinolin-2-yl, piperazinyl, pyrrolinyl, pymolidinyl, thiomorpholinyl, or morpholirtyl; (j) Q is unsubstituted diazepanyl, azepanyl, morpholinyl, decahydroisoquinolin 2-yl, piperldinyl, or pyrrolidinayl; (k) substituted Q are selected from N-(C1-6 alkyl)piperazinyl, N-phenyl- 15 piperazinyl, 1,3,8-triaza-spiro{4.5}decyl, and 1,4-dioxa-B-aza-spiro{4.5}decyl; (I) Q is a monovalent radical of an amine selected from aziridine, 1,4,7- trioxa-10-aza-cyclododecane, thiazolidine, 1-phenyl-1,3,8-triaza- spiro{4.5}decan-4-one, piperidins-3-carboxylic acid diethylarnide, 1,2,3,4,5,6- hexahydro-{2.3}bipyridinyl, 4-(3 -trifluoromelhyl-phenyl)-piperazine, 2-piperazin- 20 1-yl-pyrimidine, piperidine-4-carboxylic acid amide, methyl-(2-pyridin-2-yl- ethyl )-amine. {2-(3.4-dimethoxy-phenyl)-ethyl methyl-amine. thiomorpholinyl, allyl-cydopenlyl-amine, {2(1 H-indol-3-yl)-ethyl}-methyl-amine, 1-piperidin-4-yl- 1,3-dihydro-benzoimidazol-2-one, 2-(piperidin-4-yloxy)-pyrimidine, piperidin-4- yl-pyridin-2-yl-amine, phenylamine, and pyridin-2-ylamine; 25 (m) Q is selected from diazepanyl, azepanyl, morpholinyl, piperidinyl, and pymolidinyl, optionally substituted with between 1 and 3 substituente independently selected from hydroxy, halo, carboxamide, C1-6 alkyl, 5-9 membered or 6-9 membered heterocyclyl, -N(C1-6 aIkyl) (5-9 membered or 6-9 membered heterocyclyl), -NH(5-9 membered or 6-9 membered heterocyclyl), 30 -O(5-9 or 6-9 membered heterocyclyl), (5-9 membered or 6-9 membered heterocyclyl)C1-3 alkylene, C1-6 alkoxy, (C3-6 cycloalkyl)-O-, phenyl. (phenyl)C1-3 alkylene, and (phenyl)C1-3 alkylene-O-, where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 15 WO 2004/03780l PCT/US2003/033343 substituents independently selected from trifluoromethyl, methoxy, halo, nitro, cyano, hydroxy, and C1-3 alkyl; (n) Q is substituted with a substituent comprising a 5-9 membered or 6-9 membered heterocyclyl group selected from: pyridyl, pyrimldyl, furyl, thiofuryl, 5 imidazolyl, (imkiazolyl)C1-6 alkylene, oxazolyl, thiazolyl, 2.3 dihydro indolyl, benzimidazolyl, 2-oxobenzimidazalyl, (ietrazolyI)C1-6 alkylene, tetrazolyl, (triazolyl)C1-6 alkylene, triazolyl, (pyrrolyl)C1-6 alkylene, pyrrolidinyl, and pyrrolyl; (o) Q is piperidinyl; (p) R8 is hydrogen; 10 (q)R9 is C1-6 alkyl; (r) R9 is unsubstituted or substituted phenyl; (s) R6 and R9 independently are C1-8 alkyl; (t) R8 and R9 are methyl; (u) R8 and R9 are ethyl; 15 (v) R9 is selected from phenyl or 5-8 membered aromatic heterocyclyl, wherein said phenyl or aromatic hetenocyclyl is optionally substituted with 1-3. substituents selected from methoxy, hydroxy, halo, nitro, cyano, trifluoromethyl, and C1-8 alkyI; (w) R9 is selected from substituted or unsubstituted phenyl, pyridyl, 20 pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C1-6 alkylene, oxazolyl. thlazolyl, 2,3-dihydro-indolyl, benzimidazlyl, 2-oxobenzimidazolyl, (tetrazolyl)C1-6 alkylene, tetrazolyl, (triazolyl)C1-6 alkylene,1 triazolyl, (pymolyl)C1-6 alkylene, pyrrolidinyl, and pyrrolyl; (x) R9 is substituted or unsubstituted pyridyl; 25 (y) X is O; and (z) combinations of (a)} through (z) above. Examples of compounds of the invention include: (4-{( Ethyl-(2-methoxy-ethyl)-amino]-methyl}-phenyl)-(4-isopropyl-piperazin-1- 30 yl)-methanone; (4-Azepan-1 -ylmethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone dihydrochlonde: {4-Azepan-1-yImethyl-pheny)-(4-see-butyl-piperazin-1 -yl)-methanone; 16 WO 2004/03780l PCT/US2003/033343 (4-Azepan-1 -ylmethyI-phenyl)-{4-(1-ethyl- p ropyI)-piperszin-1-yl}-methanone; (4-Butyl-piperazin-1-yl)- {4-dimethylaminomethyl)-phernyl-methanone; (4 -Butyl)-piperazin-1 -yl )-(4-morpholin-4-ylmethyl -phenyl)-methanone; (4-Butyl-piperazin-1 -yl) {4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}- 5 methanone; (4-Butyl-piperazin-1-yl)-{4-{(4-trifluonamethyl-phenylamlno)-methyl}-phenyI) - methanone; (4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-yImethyl-phenyl)-methanone: (4-Diethylamimethyl-phenyl)-(4-isopropyl-piparazin-1-yl)-methanone 10 dihydrachloride; (4 -Dimethylaminomethyl-phenyl)-(4-isopropy)-piperazi n-1-yl)- methanone dihydrochforide; (4-Dimethylaminomethyl -phenyl)-{4-{1-ethyl-propyl )-piperazin-1-yl}-methanone dinydrocinloride; 15 (4-Isoprapyl-piperazin-1-yl)-(3-morpholin-4-yI methyl-phenyl)-methanone; (4-IsopropyI-piperazin-1-yl-(3-Piperidin-1-ylmethyl-phenyl-methanone; (4-isopropyl-piperazin-1 -yl)-(4-{[{2-methoxy-ethyI)-propy-amino)-methyl}- phenyl)-methgnone; {4-Isopropyl-pi0perazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone; 20 (4-isopropyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone dihydrochforide; (4 - Isopropyl-piparazin-1-yl)-(4-piperidin-1-yl methyl- phenyl)-methanone; (4-Isopropyl-piperazin-1-yl}-(4-pyrralidin-1-ylmethyl-phenyI)- methanone dihydrochforide; 25 (4-Isopropyl-piperazin-1-yl)- (4-thiomorpholin -4-ylmethyI-phenyl)-methanone; (4- Isopropyl-piperazin-1-yl )-{4-(3-trifluoromethyl-piperidin-1-yl) methyI)- phenyl}- methanone dihydrochforide; (4- Isapcopyl-piperazin-1-yl)-(4-(4-isoprapyl-piperzin-1-ylmethyl phenyl)- methanone; 30 (4-Isopropyl-piperazin-1-yl)-(4-[(2-methoxy-ethylamino)-methyl]-phenyl)- methanone; (4- Isopropyl- piperazin-1 -yl )-[4-( pyridin-2-ylamirometh yl)-phenyl] -methanone; 17 WO 2004/037801 PCT/US2003/0333801 (4-lsopropyl -piperazin-1 -yl)-(4-(2 -methoxy- 1 -methyl-ethylamino)-methyl)- phenyl}-methanone; (4-lsopropyl -piperazin-1 -yl)-{4-{(4-trifluoromethyl-phenylamlno)-methyl}- phenyl}-methanone; 5 (4-lsopropyl -piperazin-1 -yl)-(4-{(4-trifluoromithyl-pyridin-2-ylamino)-methyI}- phenyl}-methanone dihydrochloride; (4-lsopropyl -piperazin-1 -yl)-{4-{(5-trifluoromethyl-pyridin-2-ylamino)-methyl}- phenyl)-methanone dihydroohioride; (4-lsopropyl -piperazin-1 -yl)-{4-{(6-trifIuoromethyl-pyridin-3-ylsmino)-methyl)- 10 phenyl}-methanone dihydrochlorids; (4-lsopropyl -piperazin-1 -yl)-(4-morphoiln-4-ylmethyl-phenyl)-methanone dihydrochloride; (4-lsopropyl -piperazin-1 -yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone dihydrochloride; 15 (4-lsopropyl -piperazin-1 -yl)-{4 -dimethylaminomethyl-phenyl)-methanone; (4-sec-Butyl-piperazin-1-yl)-{4-morpholln-4-ylmethyl-phenyl)-methanone dihydrochloride; (4-lsopropyl -piperazin-1 -yl)-(4-phenylaminomethyl-phenyl)-methanone: (4-lsopropyl -piperazin-1 -yl)-(4-pipendin-1 -ylmethyl-phenyl )-methanone; 20 (4-lsopropyl -piperazin-1 -yl)-(4-pyrrolidin-1 -ylmethyl-pheriyl)-methanone; (4-lsopropyl -piperazin-1 -yl)-[4-(3-trifluoromethyl-piperidin-1-ylmethyl )-phenyl}- methanone dihydrocfiloride; {3-(4-Benzyl-pipendin-1 -yImethyl)-phenyl)-(4-methyl-piperazin-1-yl)- methanone; (4-(1 -Ethyl-propyl)-piperazin-1 -yl)-(4-morpholin-ylmethyl-phenyl)-methanone 25 dihydnochloride; (4-lsopropyl -piperazin-1 -yl)-{4-phenylaminamethyl-phenyl)- methanone dihydrochlonde; (4-lsopropyl -piperazin-1 -yl)-(4-piperidin-1-ylmethyl-phenyl)- methanone; (4-lsopropyl -piperazin-1 -yl)-(4-pyrrolidin-1 -ylmethyl-phenyl)-methanone; 30 (4-lsopropyl -piperazin-1 -yl)-(4-(3-trifluoromethyl-piperrodin-1-ylmethyl)- phenyl}-methanone dihydrochloride; (4-lsopropyl -piperazin-1 -yl)-{4-(decahydro-isoquInolin-2-ylmethyl)- phenyl)-methanone; 18 WO 2004/037801 PCT/US2003/0333801 (4-(1-Ethyl-propyl)-piperazin)-{4-{[4-trifluoromethyJ-phenylamino)-methyl} phenyl}-methanone dihydrochloride; {4-{1 -Methyl-heptyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)- methanone: 5 (4-(1-Methyl-heptyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone; (4 -(Benzylamino-methyl)-phenyl}-{4-isopropyl-piperazin-1-yl)- methanone dihydrochloride; {4-(Benzylamino-methyl)phenyl}-{4-{1 -ethyl-propyl)-piperazin-1-yl}- methanone; and 10 {4-{(5-Chloro-pyridin-2-ylamino)-methyl}-phenyl}- (4-isopropyl -piperazin-1 -yl)- methanone dihydrochloride. Preferred example compounds include: (4-{[EthyI-(2-methoxy-ethyl)-annino]-methyl}-p henyl)-(4-isopropyl-piperazin-1- 15 yl)-methanone; {4-Azepan-1 -ylmethyl-phenyl)-(4-isopropyl-piperazin-1 -yl)-methanone dihydrochloride: (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1 -yl)-methanone; (4-Azepan -1 -yimethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl} methanone; 20 (4-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone; (4-Butyl-piperazin-1-yl}-(4-morphollin-4-ylmethyl-phenyl)-methanone; (4-Butyl-piperazin-1-yl)-(4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl)- methanone; (4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone; 25 (4-Diethylaminomethyl-phenyl)-(4-Isopropyl-piperazin-1-yl)-Methanone dihydrocholoride; (4-Dimethyl aminamethyl-phenyl)-(4-isopropyhpiperazin-1-yl)-methanone dihydrochloride; (4-Dimethyiaminomethyl-phenyl)-{4-(1-ethyl-propyl)-prperazin-1-yl}-methanone 30 dihydrochloride; (4-Isopropyl-pipenazin-1-yl)-(3-piperidin-1 -ylmethyl- phenyl)-methanone; (4-lsopropy-1-piperazin-1-yl)-(4-{[(2-methoxy-ethyl)-propyl-aminol-methyl}- phenyl)-methanone; 19 WO 2004/037801 PCT/US2003/033343 {4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-yI methyl-phenyl)-methanone; (4-Isopropyl-pipenazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone dihydnochloride; (4-lsopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phanyl)-methanone; 5 (4-lsopnapyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone dihydrochloride; (4-Isopropyl-piperazin-1-yl)-(4-thiomorphoIin-4 -ylmethyl-phenyl)-methanone; (4-Isopnopyl-piperazin-1-yl)-{4-(3-trifluoroinethyl-piperidin-1-ylmethyl}-phenyl}- methanone dihydrochioride; 10 {4-Isopropyl-piperazin-1-yl)-{4-(4-isopropyl-piperazin-1-ylmethyl)-phenyl}- methanone; (4 -Isopropyl-piperazin-1-yl)-(4-[(2-methoxy-ethylamino)-methl]-phenyl}- methsnone; (4-Isopropyl-piperazin-1-yl)-(4-(pyridin-2-ylaminomethyI)-phenyl)-methanone; 15 (4-Isopropyl-pipenazin-1-yl)-{4-[(2-metho5xy-1-methyl-ethylamino)-methyl]- phenyl)-methanone; (4-lsopropyl-piperazin-1-yI)-{4-{(5-trifIuoromethyl-pyildin-2-ylamino)-methyl}- phenyl)-methanone dihydrochloride; (4-Isopropyl-piperazin-1-yl)-{4-{(6-trifluoromethyl-pyridin-3-ylamino)-methyl}- 20 phenyl}-methanone dihydrochloride; (4-Methyl-piperazin-1-yl)- (4-morpholin-4-ylmethyl- phenyl)-methanone dihydrochloride; (4-Methyl-piperazin-1-yl)-(4 -piperidin-1-yImethyl-phenyI}-methanone dihydrochloride; 25 (4 -sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone- (4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone dihydrochloride; (4-sec-Butyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone: (4-sec-Butyl-piperazin-1-yl)-{4-piperidin-1-ylmethyl-phenyl)-methanone; 30 (4-sec-Butyl-piperazin-1-yl)-(4-pyrrolid in-1-ylmethyl-phennyl)-methanone; (4-sec-Butyl-piperazin-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}- methanone dihydnochloricle; 20 WO 2004/037801 PCT/US2003/033343 {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone dihydrochloride, {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-piperidin--ylmethyl- phenyI)-methanone; {4-(1-ElhyI-propyl)-piperazin-1yl}-(4-pynrolidin-1-ylmethyl-phenyl)-methanone; 5 {4-(1-Ethyl-propyl)-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl) phenyl)-methanoae dihydrachloride; {4-(1-Ethyl-propyl)-piperazin-1-yl)-(4-{decahydro-Isoquinolin-2-ylmethyl)- phenyl}-methanone; {4-(Benzylanrtino-methyl)-phenyl}-(4-isopropyl-piperazin-1-yl)- methanone 10 dihydrachloride; {4-(Benzytanino-methyl)-phsnyl}-(4-(1-ethyl-propyl)-piperzin-1-yl}-methanone; and {4-{(5-Chloro-pyridin-2-ylamino)-methyl}-phenyl}-(4-isopropyl-piperazin-1-yl)- methanone dihydoachloride. 15 More preferred example compounds include: (4-{[Ethyl-(2-methoxy-ethyI)-amino]-methyl}-phenyl)-(4-isopropyl-piperazin-1- yl)-methanone. (4-Azepan-1-ylmethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone 20 dihydrochloride; (4-Azepan-1 -ylmethyl-phenyl)-(4-sec-butyl-piperazin-1 -yl)-methanone; (4- Azepan-1 -ylmethyl-phenyl)-(4-(1-ethyl-propyl)-piperzin-1-yl}- methanone; (4-Butyl -piperazin-1-yl)-(4-inorpholin-4 -yImethyl-phenyl}-methanone; (4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone; 25 (4- Diethylaminomethyl-phenyl)-(44-isopropyl-piperazin-1-yl)-methanone dihydrochloride; (4-Dimethylaminanrtethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride; (4- Dirmethylaminomethyl-phenyl)-{4 -(1 -ethyl-prapyl)-piperazin-1-yl}-methanone 30 dihydrochloride, (4-Isopropyl-piperazin-1-yl)-(4-{[{2-methoxy-ethyI)-propyl-amino)-methyl}- phenyl)-methanone; (4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl- phenyl)-methanone; 21 WO 2004/037801 PCT/US2003/033343 {4-Isoprapyl-pipenazin-1-yl)-(4-piperdin-1-ylmethyl-phenyl)- methanone; (4-lsopropylpiperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone dihydrochloride; {4-lsoppyl-piperazin-1-yl)-(4-thiomorpholin-4-ylmethal-phenyl)-methanone 5 (4-Isopropyl-piperazin-1-yl)-(4-(3-trifluoromethyl-piperidin-1-ylmethyl}-phenyl}- methanone dihydrochloride; (4-Isopropyl-piperazin-1-yl }-{4-[(2-methoxy-ethylamino)-methyl]-phenyl}- methanons; (4-Isopropyl-piperazin-1-yl)-[4-(pyridin-2-ylaminometnyl)-phenyl}-methanonne 10 (4-Isopropyl-piperazin-1-yl)-(4-[(2-methoxy-1-methyl-ethylamino)-methyl]- phenyl]-metrianone; (4 -sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone; (4-sec- Butyl-piperazin-1-yI)- (4-morpholin-4-ylmethyl- phenyl)-methanone dihydrochloride; 15 (4-sec-Butyl-plperazin-1-yl)-{4-piperidin-1-ylmethyl-phenyl)-methanone; (4-sec-Butyl-piperazin-1-yl }-{4-pymolidin-1-ylmethyl-phenyl)-methanone; {4- (1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)- methanone dihydrachloride; {4-(1-Ethyl-propyl)-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone; 20 {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone; {4-(1-Ethyl-propyl)- piperazin-1-yl]-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)- phenyl}-methanone dihydrochloride; {4-{1- Ethyl-propyl)- piperazin-1-yl}-{4(decahydro-isoquinolin-Z-ylmethyl)- phenyl)-methanone; 25 {4-{Bentzylamino-methyl)-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride: and {4-(Benzylamino-methyl)-phenyl}-{4-(1-ethyl-propyl)-piperazin-1-yl} methanone. Even more preferred example compounds include: 30 (4-Azepan-1-ylmethyl-phenyl)-(4-Isopropyl-piperazin-1-yl)-methanone dihydrochloride; (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone; (4-Cyclohexyl-piperazin-1-yl)-(4-pipendin-1-ylmethyl-phenyl)-methanone: 22 WO 2004/037801 PCT/US2003/033343 (4-lsopropyl-piperrazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone; {4-lsopropyl-piperazin-1-yl)-(4-pyrrolidin-1-yImethyl-phenyl)-methanone dihydrochloride; (4-Isopropyl-piperazin-1-yl)-{4-(3-trifluoromethyl -piperidin-1-ylmethyl)-phenyl}- 5 methanonedihydrpchloride; (4-sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl)-phenyl)-methanone; (4-seo-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl}-methanone; (4-sec-ButyIpiperazin-1-yl)-(4-pyttolidin-1-ylmethyl-phenyl)-methanone; (4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-pheayl)-methanone 10 dihydrochloride; {4-(1-Etnyl-propyl)-piperazin-yl)-{4-piperidin-1-ylmthyl-phenyl)-methanone; and {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone, 15 Yet even more preferred example compounds include: (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone; (4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone; (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone; {4«(1-Ethyl-propyl)-piperazin-1-yl}-(4-piperdin-1-ylmethyl-phenyl)-methahone; 20 {4-(1-Elhyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone; (4-lsopropyl-piperazin-1-yl)-{4-morpholin-4-ylmethyl-phenyl)-methanone; (4-sec-Butyl-piperazin-1-yl)-[4-morpholin-4-ylmethyl-phenyl)-methanone dihydrochoride; and {4-(1- Ethyl-propyI)-piperazin-1-yl)-(4-morpholin-4-yImethyl-phenyI)- methanone 25 dihydrochoride; The invention also provides compounds that are useful as synthetic intermediates of the compounds of the invention. Such compounds, which themselves may or may not have pharmaceutical activity, include those 30 provided in the schemes and synthetic examples. The invention also conternplates compounds isotopically-labelled to be detectable by positron emission tomography (PET) or single-photon emission computed tomography (SPECT) useful for studying H3-mediated disorders. 23 WO 2004/037801 PCT/US2003/033343 During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. In addition, compounds of the invention may be modified by using protecting groups; such compounds, 5 precursors, of prodrugs are also within the scope of the invention. This may be achieved by means of conventional protecting groups, such as those described in "Protective Groups, in Organic Chemistry", ed, J.F.W. McOmie, Plenum Press, 1973: and T.W. Greene & P.G.M. Wuts, "Protective Groups in Organic Synthesis". 3rd ed., John Wlley & Sons, 1999. The protecting groups may be 10 removed at a convenrient subsequent stage using methods known from the art, HYDROXYL PROTECTING GROUPS Protection for the hydroxyl group includes methyl ethers, substituted 15 methyl ethersr substituted ethyl ethers, substitute benzyl ethers, and silyi ethers, Substituted Methyl Ethers Examples of substituted methyl ethers include methyoxymethyl, 20 methylthiomethyl, t-butylthlomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl, f-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2- methoxyethoxymethyl, 2,2,2-trichloroethoxymethyt, bis(2-chloroethoxy)methyl, 2-(trimethylsily)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, 25 tetrahydrothiopyranyl,1-methoxycyclohexyl,4-methoxytetrahydropyranyl, 4- methaxytetrahydrothiopyronyl, 4-methoxytetrahydrothiopyranyl S.S-dioxioide, 1- {(2-chloro-4 - methyl)phenyl}-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and 2,3,3a,4,5,6,7,7a-octahydro-7,8,8- trimethyl-4.7-methanobenzofuran-2-yI. 30 Substituted Ethyl Ethers Examples of substituted ethyl ethers include 1-ethoxyethyl, 1-(2- chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1- benzyloxyethyl, 1- 24 WO 2004/037801 PCT/US2003/033343 methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsitylethyl, 2- (phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4- dinitropbenyl and benzyl 5 Substituted Benzyl Ethers Examples of substituted benzyl ethers include p-methoxybenzyl, 3,4- dimethoxy benzyl, o-ritrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenyl benzyl, 3- and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenyImethyl, a 10 naphthyldiphenylmethyl, p-methoxyphenyldiphen ylmethyl,di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4- bromophenacyloxy)phenyldiphenylmethyl,4,4',4",-tris(4,5- dichlorophthallmidophenyl)methyl,4,4',4"-tris(fevulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyl oxyphenyI)methyl, 3- (imidazol-1-ylmethyl)bis(4',4"- 15 dimethoxyphesnyl)methyl,1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl,9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithioIan 2-yl, and benzisothiazolyl S,S-dioxido. Silyl Ethers 20 Examples of sityl ethers include trimethylsityl, triethyIsilyl, triisopropyIsilyI. dimethylisopropylsilyl, diethylisopropytsilyl, dimethyithexylsilyl, t- butyldimethylsilyl, t-butydiphenylsilyl, tribenzylsily tri-p-xylysilyl, triphenylsilyl, diphenylmethylsilyl, and t-butylmethoxyphenyleylsilyl. 25 Esters In addition to ethers a hydroxyl group may be protected as an ester. Examples of esters include formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, triflueroacetate, methoxyacetate, triphenylmethoxyacetate, phertoxyacetate, p-chiorophenoxyacetate, p-P- 30 phenylacetate, 3-phenylpropionate, 4-oxopertanoate(levulinate),4,4- (ethylenedithia)penfanoate, pivatoate, adamantoate, crotonate, 4- methaxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzolte(mesitoate) 25 WO 2004/037801 PCT/US2003/033343 Carbonates Examples of carbonates include methyl, 9-fluorenytmethyl, ethyl, 2,2,2- trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulforiyl)ethyl, 2- 5 (triphenylphosphonlo)ethyl, Esobutyl, vinyl. anyl, r-nitrophenyl, benzyl, - methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, r-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, and methyl dithiocarbonate. Assisted Cleavage 10 Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate; 4-nitro-4-methylpentanoate, o-tribromomethyl)benzoate, 2- formylbenzenesuffonate, 2-(methylthiomethoxy)ethyl carbonate, 4- (methythromethoxy)butyrate, and 2-(methythiomethylxymethyl)benzoate. 15 Miscellaneous Esters Examples of misoellaneous eaters Include 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichlono-4-(1,1,3,3- tetra methylbutyl)phenoxyacetate, 2,4-bis (1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2- 20 butenoate{figloate), o-(methoxycarbonyl)benzoate, r-P-benzoate, a- naphthoate, nitrate, alkyl N,N,N,N -tetramethylphospborodiamidste, N- phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4- dinitrophenylsulfenate 25 Sulfonates Examples of sulfonates include sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate. PROTECTION FOR 1,2- AND 1,3 DIOLS 30 Cyclic Acetels and Ketals Examples of cyclic acetals and ketals include methylene, ethylidene, 1-t- butylethylidene, 1-phenylethylidene, (4-methoxyphenyl)ethylidene, 2,2,2- 26 WO 2004/037801 PCT/US2003/033343 trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohesxylidene. cycloheptylidene, benzylidene, r-methoxybenzylidene. 2,4- dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and 2-nitrobenzylidene. 5 Cyclic Ortho Esters Examples of cyclic ortho esters include methoKymethylene, ethoxymethvlene, dimsthoxymethylene, 1-methoxyethylidene, 1- ethoxyethylidfne, 1,2-dimethoxyethylidene, a-methoxybenzylidene, 1-(N,N- dimethylamino)ethylidene derivative, a-(N,N-dimethylamino)benzyiIdene 10 derivative, and 2-oxacyclopeatylideae, Silyl Derivatives Examples of silyl derivatives include di- f-butylsilylene group, and 1,3- (1,1,3,3-fetraisopropyldisiloxanylidene)derivative. 15 AMINO PROTECTING GROUPS Protection for the amino group includes carbamatesr amides, and special -NH protective groups. 20 Examples of carbannates include methyl and ethyl carbamates, substituted ethyl carbanates, assisted cleavage carbamates, photolytic cleavage carbarnates, urea-type derivatives, and miscellaneous carbamates. 25 Carbamates Examples of methyl and ethyl carbanates include methyl and ethyl, 9- fluorenylmethyl, 9-(2-sulfo)fluoreriylimethyl, 9-(2,7-dioromo)fluarenylrnethyl, 2,7- methoxyphenacyl. 30 Substituted Ethyl Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl, 2- trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methyl ethyl. 1.1-dimethyl-2- 27 WO 2004/037801 PCT/US2003/033343 haloethyI, 1,1 -dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichforoethyl,1- methyl-1-(4-biphenylyl)ethyl, 1-(3.5-di-butylphertyl)-1-methylethyl, 2-(2'- and 4' -pyridyl)ethyI, 2-{N, N-dicydohexyIcarboxamido)ethyl, f-butyl, 1 -adamantyI. vinyl allyl. 1-Isopropyl allyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N- 5 hydroxypiperidinyl alkyldithio, berreyl, r-methoxybenzyl, r-nitrobsnzyl, r- bromobenzyl, r-chtorobenzyl, 2,4-dichlorobenzyl, 4-meylsorlfonylnylbenzyl, 9- anthrylmethyl and diphenylmethyl. Assisted Cleavage 10 Exampies of asststed cleavage include 2-methylthioethyl, 2- methylsulfonyfelhyl, 2-(r-toluenesulfonyl)ethyl, {2-(1.3-dithianyl)}methyl, 4- methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl, 2- triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl. m-chloro-r- acyloxybenzyl, r-(dihydnaxyboryl)benzyl, 5-benzisoxazolylmethyl, and 2- 15 (trifluotromettyl)-6-chromonyl methyl. Phototytic Cleavage Examples of photolytic cleavage include m-nitrophenyl, 3,5- dimethoxybenzyl, o-nitrobenzyl. 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o- 20 nitrophenyl)methyl, Urea-Type Derivatives Examples of urea-type derivatives include phenothiazinyl-(10)-cartionyl derivative, N'-r-toluenesulfonylaminocanbonyl, and N'- 25 phenylaminothiocarbonyl. Miscellaneous Carbamates Examples of miscellaneous carbamates include f-amyl. S-benzyl thiocarbamate. p-cyanobenzyl. cyclobutyl, cyciohexyl, cyclopentyl, 30 cyclopropytmethyI, p-decyloxybenzyl ,dilsqpropylmethyl 2,2- dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl 1,1-dimethyl-3- (N,N-dimeihylcarboxamido)propyl,1,1-dimethylpropynyl, di{2-pyrldyI)methyl, 2- furanylmethyl, 2-iodoethyl, Isobomyl isobulyl, isonicolinyl, r-{p'- 28 WO 2004/037801 PCT/US2003/033343 methoxyphenyIazo)benzyl, 1-methylcyclobutyI, 1-methyl cyclohexyl, 1-methyl-1- cycloprapylmethyl. 1-methyl-(3,5-dimethoxyphenyl)ethyl, 1-methyl-1-{p- phienylazaphenyl)ethyl, 1-methyl-1-phenytethyl, 1 -methyl- 1-(4-pyridyI) ethyl. phenyl, p-(phenylazo)benzyl, 2,4,6-tri-1-butylphenyl, 4- 5 (trimethytammonim)benzyl, and 2,4,6-trimethylbeneyl- Examples of amides include: Amides 10 N-formy), W-acetyl. M-choroacetyl, N-trichioroacetyl, N-trifluoroacetyl N- phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-pyrldylcarboxamlde, N- benzoylphenylalanyl derivative, N-benzoyl, N-p-phenylbenzoyl. Assisted Cleavage 15 N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl, (N'- dithiobenzyloxycarbonylamino)acetyl, N-3-(r-hydroxyphenyl)propionyI, N-3-(o- nitrophenyl)propionyl, N-2-methyl-2-{o-nitrophenoxy)propionyl,N-2-methyl-2-(o- phenytazophenoxy)propeonyl, N-4-chlorabutyryl, N-3-methyl-a-nitrabutylyl, N-o- nitrocinnamoyl, N-acetylmethionine derivative, N-o-nitrobeneoyl, N-o- 20 (benzoyloxymethyl)benzoyl, and 4,5-diphenyl-3-oxazolin-2-one. Cyclic Imide Derivatives N-phthalimide, N-dithiasuccinoyl. N-2.3-diphenylmaleoyl, N-2,5- dimethyipyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5- 25 subtituted 1,3-dimethyl-1,3,5-triazacyclohrexan-2-one, 5-substituted 1,3- dibenzyl-1,3,5-triazacyclohexan-2-one, and 1-substituted 3,5-dinitro-4- pyridonyl. SPECIAL - NH PROTECTIVE GROUPS 30 Exarnples of special NH protective groups include: N-AlkyI and N-Aryl Amines 29 WO 2004/037801 PCT/US2003/033343 N-methyl, H-allyl, N-(2-{trimethylsllyl)ethoxy)methyl, N-3-acetoxyplopyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N- benzyl N-4-methoxybenzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N-(4-methoxyphenyl)dipheny,methyl, N-9-phenylfluoreny, N- 5 2,7-dichloro-9-fluorenyimethylene, N-ferrocenylmethyl, and N-2-picolylamine N'-oxide. Imine Derivatives N-1.1-dimethythiomethylerie, N-benzylidene, N-p-methoxybenzylidene. 10 N-diphenyltnethylene, N-[(2-pyridyl)mesityl}methylene, and N-{N' ,N'- dimethylammornethylene). PROTECTION FOR THE CARBONYL GROUP 15 Acyclic Acetals and Ketals Examples of acyclic acetals and ketals include dimethyl, bis(2,2,2 trichloroethyl). dibenzyl, bis{2-nitnobenzyl) and diacetyl Cyclic Acetals and Ketals 20 Examples of cyclic acetals and ketals include1,3-dioxanes,5- inethylene-1,3-dioxane, 5,6-dibromo-1,3-dioxane, 5-{2-pyridyl}-1,3-dioxane, 1,3 dioxolanes, 4-bromomethyl 1, 3-dioxolane, 4-(3-butenyl)-1,3-dioxolane, 4- phenyl-1,3-dioxolane, 4-(2-nitrophenyl)-1,3-dioxolane, 4,5-dimethoxymethyl 1,3-dioxolane; O,O'-phenylenadioxy and 1,5-dihydro-3H-2,4-benzodioxepin. 25 Acyclic Dithio Acetals and Ketals Examples of acycilc dithio acetals and ketals include S,S'-dimethyl. S,S'-diethyl, S,S'-dipropyl, S,S'-dibutyl, S,S'-dipentyl, S.S'-diphenyl, S,S'- dibenzyl and S,S'-diacetyl. 30 Cyclic Dithio Acetals and Ketals Examples of cyclic dithio acetals and ketals include 1,3-dithiane. 1,3- dithiolane and 1,5-dihydro-3H-2,4-benzodithiepin. 30 WO 2004/037801 PCT/US2003/033343 Acyclic Monothio Acetals and Ketals Examples of acyclic monothio acetals and ketals include O-trimethylsilyI- S-alkyl. O-methyl-S-alkyl or -S-phenyl and G-methyl-S-2 (methylthio)ethyl 5 Cyclic Monothio Acetals and Ketals Examples of cyclic monothio acetals and ketals include 1,3- oxathiolanes. MISCELLANEOUS DERIVATIVES 10 O-Substituted Cyanohydrins Examples of O-substituted cyanohydnins include O-acetyl, O- trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl. 15 Substituted Hydrazanes Examples of substituted hydra zones indude N,N-dimethyl and 2,4- dinitrophenyl. Oxime Derivatives 20 Examples of oxime derivatives include O-methyl. O-benzyl and O- phenylthiomethyl. Imines Substituted Methylene Derivatives, Cyclic Derivatives 25 Examples of substituted methylene and cyclic derivatives include oxazolidines, 1-methyl-2(1-hydroxyalkyl)imidazoles. N,N'- and methyIaluminum bis{2,6-di-t-butyl-4-methytphenoxide)(MAD)complex. 30 MONOPROTECTION OF DlCARBOMYL COMPOUMDS Setective Protection Of a-and b-Diketones 31 WO 2004/037801 PCT/US2003/03343 Examples of selective prortection of a-and b-diketones include enarmines, enol acetates, enol ethers, methyl, ethyl, i-butyl, piperidinyl, morpholinyl. 4-methyl-1,3-dioxolanyl, pyrrolidiny), benzyl, S-butyl, and trimethylsilyl. 5 Cyclic Ketals, Monothio and Dithio Ketals Examples of cyclic ketals, monothio and dithio Ketals include bismethylenedioxy derivatives and teframethylbismethylenedioxy derivatives- 10 PROTECTION FOR THE CARBOXYL GROUP Esters Substituted Methyl Esters Examples of substituted methyl esters include 9-fluorenylmethyl, 15 methoxymethyl, methylthiamethyl, tetrahydropyranyl. tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsily)ethoxymethyl, benzyloxymethyl, phenacyl, r-bromophenacyl, a-methylphenacyl, r-methoxyphenacyl, carboxamidomethyl, and N-phthalimidomethyl. 20 2-Substituted Ethyl Esters Examples of 2-substituted ethyl esters include 2,2,2-trichloraethyl, 2-haloethyl, wchloroalkyl., 2-(trimethylsilyl)ethyl, 2-methylthioethyl, 1,3- dithianyl-2-methyl, 2-(r-nitrophenylsulfenyl)ethyl, 2-(r-toluenesutfonyl)ethyl. 2-(2'-pyridyl)ethyl, 2-(diphenylphosphno)ethhyl, 1-methyl-1-phenylethyl, t- 25 butyl, cyclopenrtyl, cyclohexyl. allyl, 3-buten-1-yl, A-(trimethylsityl)-2-buten-1-yl cinnamyl, a-methylcinnamyl, phemyl,r-(methylmercapto)phenyl and benzyl. Substituted Berzyl Esters Examples of substituted benzyl esters in dude triphenyl methyl, 30 diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2(9,10- dioxo)anthrymethyl, 5-dibenzosuberyl, 1-pyrenyImethyl, 2-(trifluoromethyl)-6- chromylmethyl, 2,4,6-trimethylbenzyl, r-bromobenzyl. o-nitrobenzyl, r- 32 WO 2004/037801 PCT/US2003/033343 nitrobenzyl, r-methaxybenzyl, 2,6-dimethaxybenzyl, 4-(methylsulfuytryl)beozyl, 4- sulfobenzyl, plperonyl, 4-picoyl and p-P-benzyl. Silyl Esters 5 Examples of silyl esters include trimethylsilyl, triethylsilyl. t- butyldimethylsilyl, i-propyldimethylsilyl, phertyldimethylsrlyl and di-t- butylmethylsilyi. Activated Esters 10 Examples of activated esters include thiols. Miscellaneous Derivatives Examples of miscellaneous derivatives include oxazoles, 2-alkyl-1,3- oxazolines, 4-alky-5-oxo-1,3-oxazolidines. 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group and pentaaminooobatt(Ill) complex. 15 Stannyl Estesrs Examples of stannyl esters include triethylstannyl and tri-n-butylstannyl. AMIDES AND HYDRA21DE5 20 Amides Examples of amides include N,N-dimethyl. pyrrolidinyl, piperidmyl, 5,6- dihydrophenanthridinyl, o-nitroanllides, N-7-nitroindolyl, N-8-Nitro-1,2,3,4- tetrahydroquinolyl, and r-P-benzenesulfonamides. 25 Hydrazides Examples of hydrozides Include N-phenyl and N,N'-disopropyl- The compounds of the invention can be prepared according to the 30 methods described in the next section. 33 WO 2004/037801 PCT/US2003/03343 C. Synthesis The compounds of the invention can be prepared according to traditional synthetic organic methods and matrix or combinatorial chemistry methods, as shown in Scheme 1 below and in Examples 1-72. A person of 5 ordinary skill will be aware of variations and adaptations of the schemes and examples provided to achieve the compounds of the invention. One skilled in the art will recognize that synthesis of the compounds of the present invention may be effected by purchasing intermediate or protected intermediate compounds described in any of the Schemes disclosed herein. 10 Throughout the schemes when the reacting functionality is located at R4, one skilled to the art will recognize that the choice of R4 is illustrative only and that the reacting functionality could also be located at.R3 or R2 also. One skilled in the art will further recognize that during any of the processes for preparation of the compounds of the present invention, it may be 15 necessary and/or desirabIe to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in "Protective Groups in Organic Chemistry", ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wute, "Protective Groups in Organic Synthesis". John Wiley & Sons, 20 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Compounds of formula (XIII) may be prepared according to the processes outlined in Scheme 1. One skilled in the art will recognize that the location of formyl functionality at R4 is for illustrative purposes only and that the 25 formyl group may also be located at R2 or R3. 34 WO 2004/037801 PCT/US2003/033343 A compound of formula (Xlll) is prepared as outlined in Scheme 1 from a 15 compound of formula (V), in which the group M2 represents a nitrogen- protecting group. One skilled in the art will be capable of selecting a protecting group that is compatible with the transformations in Scheme 1. In a particularly 35 WO 2004/037801 PCT/US2003/033343 preferred embodiment, the group M1 is tert-butyl-cartiamoyl. A compound of formula (VI) is obtained from a compound of formula (V) by reacting a compound of formula (V) with an aldehyde or ketone under reductive amination conditions in the presence of a reductant such as sodium 5 triacetoxyboro hydride, sodium cyanoborohydride, or phenylsilane in a solvent such as THF, DCE, DCM, methanol, ethanol, or ether at a temperature between 0 and 30 °C, One skilled in the art will recognize that the use of a promoter or catalyst with acidic character such as organometallie complexes or carboxylic acids may increase the rate of the reaction and/or reduce the 10 formation of by-products, in a particularly preferred embodiment, a compound of formula (V) is reacted with an aldehyde or ketone, acetic acid, and sodium trracetoxyhorohyrdide in DCE at room temperature. A compound of formula (VII) is obtained from a compound of formula (VI) by reacting a compound of formula (VI) with a reagent capable of removing the protecting group M1 under 15 nitrogen-deprotection conditions. In a preferred embodiment a compound of formula (VI), in which the protecting group M1 is tert-butyl carbamoyl, is reacted with an acid such as anhydrous hydrogen chloride in a solvent such as dioxane or etherat room temparature. A compound of fovmula (IX) is obtained by reacting a compound of formula (VlI) with a compound of formula (VIll) under 20 amide-formation conditions. In a preferred embodiment, a compound of formula (VIII), either as a free base or as s mineral acid salt, is reacted with a compound of formula (VIII) in the presence of a dehydrating agent and a base in a solvent at a temperature between 0 °C and 60 °C. In a particularly preferred embodiment, a compound of formula (VII) as a hydrochloride salt is 25 used, the dehydrating agent is 143-(dimethylamino)propyl]-3-ethylcarbodlimide hydrochloride and 1-hydroxybenzotriazole hydrate, and the base is N- methylmarpholine. A compound of formula (XIII) is obtained by reacting a compound of formula (IX) with a compound of formula (XI) in the presence of a reducing agent under reductive amination conditions, as outfined in step A. A 30 compound of formula (X) is obtained by reacting a compound of formula (V) with a compound of formula (Vlll) under amide formation conditions as outlined in step C. A compound of formula (XII) is obtained by reacting a campound of formula (X) with a compound of formula (XI) under reductive amination 36 WO 2004/037801 PCT/US2003/033343 conditions, as described in step A. A compound of formula (XIV) is obtained by reacting a compound at formula (XII) with a reagent capable of removing the protecting group M1 under nitrogen-depiotection conditions, as oullined in step B. A compound of formula (XIII) is obtained by reacting a compound of 5 formula (XIV) with an aldehyde or ketone under reductive amination conditions as outlined in step A. Compounds of the present invention may also be conveniently prepared using various other chemical intermediates. For example, variants of aldehyde (VIII) or amide (IX) could be accessed from a corresponding alyl halide, such as an aryl bromide, via a palladium mediated 10 coupling With a tormyl, carbonyl, or nitrile equivalent. D. Formulation. Administration, and Therapy The disclosed compounds, alone or in combination (with, for example, a histamine H1, receptor antagonist), are useful for treating of preventing 15 naurologic disorders induding sleeplwake and arousallviglliance disorders {e.g. insomnia and jet lag), attention deficit hyperactivity disorders (ADHD), teaming and memory disorders, cognitive dysfunction, migraine, neurogenic inflammation, dementia, and cognitive impaiment (pre-dementia), Alzheimer's disease, epilepsy, narcolepsy, eating disorders, obesity, motion sickness, 20 vertigo, schizophrenic sabstance abuse, bipolar disorders, manic disorders and depression, as well as other histamine H3 receptor mediated disorders such as upper airway allergic response, asthma, itch, nasal congestion and allergic rhinitis in a subject in need thereof. 25 1. Formulation and Administration The compounds or compositions of the invention may be formulated and administered to a subject by any conventional route of administration. including, but not imited to, intravenous, oral, subcutaneous, intrarnuscular, intradermal and parenteral admsnistration. The quantity of the compound 30 which is effective for treating each condition may vary, and can be determined by one of ordinary skil0l in the art. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically aocepteble salts". Other salts may, however, be 37 WO 2004/037801 PCT/US2003/033343 useful in the preparation of compounds according to this, invention or of their pharmaceuticaIIy acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include add addition salts that may, for example, be formed by mixing a solution of the compound with a -solution of a pharmaceutically 5 acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic add, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphorio acid. Furthermore, where the compounds of the invention carry an acidic molety. suitable pharmaceuticlly acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal 10 salts, e.g., calcium or magnesium salts; and salts formed with suitable organic figands, e.g., quaternary ammonium salts. Thus representative pharmaceutically acceptable salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate. carbonate, chloride, 15 clavulanate. citrate. ditiydrochioride, edstate, editsylate, estolate, esytete, fumerate, gluceplate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate. hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactabionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, 20 mucate. napsylate, nitrate, N-methylglucamine ammonium salt oleate, pamoate (embonate), palmitate, panfothanate, phosphate/diphosphate, polygalacturonate, salivate, stearate, sulfate, subaostate, sucinate, tannats, tartrate, teoclate, tosylate, triethiodide and valerate. Tne present invention includes within its scope, prodrugs of the 25 compounds of this invention, in general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a 30 compound that may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard. Elsevier, 38 W0 2004/037801 PCT/US2003/033343 1985. In addition to salts, the invention provides the esters, amides, and other protected or derivatived forms of the described compounds. Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the 5 compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as potymorphs and as such are intended-to be included in the present invention, 10 In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic; solvents, and such solvatee are also intended to be encompassed within the scope of this invention. The present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a 15 phannaceutically acceptable carrier and optionally additional phamaceutical agents such as H1 antagonists or SSRls. Preferably these compositions are in unit dosage forms such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), powders, granules, sterile parenteral solutions or suspensions (including 20 syrups and emulsions), metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternativesy, the composition may be presented in a form suitable for once- weekly or once-monthly administration; for example, an insoluble salt of the 25 active compound, such as the decanoats salt, may be adapted to provide a depot pysparaticin for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g, conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, steatic acid, magnesium, stearate, dicalcium phosphate 30 or gums, and other pharmaceutical diluents, e,g, water, to form a solid pre- formulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these pre-formulation compositions as homogeneous, it is meant 39 W0 2004/037801 PCT/US2003/033343 that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as Eablets, pilis and capsules. This solid pre-formulation composition is then subdivided into unit dosage forme of the type described 5 above containing from 5 to about 1000 mg of the active ingredient of the present invention. Examples include 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, 35 mg, 50 mg, 76 mg, 100 mg, 120 mg, 160 mg, and so on. The tablets or pills of the disclosed compositions can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the 10 tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be 15 used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. The liquid forms in which the compounds and compositions of the present invention may be incorporated for administration orally or by injection 20 include, aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, cocanut oil or peanut oil, as well as elixirs and similar pharmaceutical vehlcles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, 25 acacia, alginate, dextran, sodium carboxymetriylceliulose, methylcellulose, polyvinyl-pymolidone or getelim. Where the processes for the preparetion of the compounds according to the invention give rise to mixture of slereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. 30 The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques., such as the fomation of diaestereomeric pairs by salt 40 WO2004/037801 PCT/US2003/033343 formation With an optically active acid, such as (-)-di-p-tolucyl-d-tartaric acid and/Or (+)-di-p-toluayl-1-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic 5 separation and removal of the chiral auxiliary. Alternatively, the compounds may be resoled using a chiral HPLC column. Advantageously, compounds of the present invention may be administered in a single daily dose, of the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, 10 compounds for the presant invention can be administered in infransal form via topical use of suitable intranasal vehicles, or via trsnsdermal skin patches well known to those of ordinary skill in that art. To be adminstered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. 15 For instance, for oral adminstration to the fom of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders 20 include, without limitation, starch, gelatin, natural sugars such as glucose or beta-actnse, com sweetsners, natural and synthetic gums such as scads, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the 25 like. The compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilannellar vesicles, and multilamellar vesicles. Liposomea can be foimecf from a variety of phospholipids, such as cholesterol, stearylamine or 30 phophatidylcholines. Compounds of the present invention may also be delivered by the use of monoclonal antibodies as Individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with 41 W0 2004/037801 PCT/US2003/033343 soluble polymers as targetable drug carriers. Such polymers can include polyvinylpytrolidone, pyran copotymer, polyhydroxypropylmethacryamidephenot, polyhydroxyethylaspartanmidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention 5 may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. 10 Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment is required. The daily dosage of the products may be varied over a wide range from 1 to 1,000 mg per adult human per day. For oral administration, the compositions 15 are preferably provided in the form of tablets containing 1.0, 5.0,10.0,15.0, 25.0, 50.0,100, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 20 mg/kg of body weight per day. Preferably, the range is from about 0.02 20 mg/kg to about 10 mg/kg of body weight per day, and especially from about 0.05 mg/kg to about 10 mg/kg of body weight per day. The compounds may be administered an a regjmen of 1 to 4 times per day. Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of 25 administraton, the strength of the preparatron, the mode of administratran, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, inducting patient age, weight, diet and time of administration, with result in the need to adjust dosages, 30 2. Combination Therapy The disclosed compounds are useful in combinallon with other therapeutic agents, Including H1 receptor antagonists. H2 receptor antagonists, 42 WO 2004/037801 PCT/US2003/033343 and neuretransmitter modulators such as SSRIs and non-selective serotonin re-uptake inhibitors (NSSRIs). Methods are known in the art for determining effective doses for therapeutic and prophylactic purposes for the disclosed pharmaceutical 5 compositions or the disclosed, drug cambinations, whether or not formulated in the same composition. For therapeutic purposes, the term "jointly effective amount" as used herein, means that amount of each active compound or pharmaceutical agent, alone or in combination, that elicits the biological or medicinal response in a tissue system, animal or human that is being sought 10 by a nesearcher, veterinarian, medical doctor or other clinicianm, which includes alleviation of the symptoms of the disease or disorder being treated. For prophylactic purposes (i.e., inhibiting the onset or progression of a disorder), the term "jointiy effective amount" refers to that amount of each active compound or pharmaceutical agent, alone or in combination, that inhibits in a 15 subject the onset or progression of a disorder as being sought by a researcher, veterinarian, medical doctor or other clinician, the delaying of which disorder is mediated, at least in part, by the modulation of one or more histamine receptors. Thus, the present invention provides combinations of two or more drugs wherein, for example, (a) each drug is administered in an independently 20 therapeutically or prophylactically effective amount; (b) at least one drug in the combination is administered in an amount that is sub-therapeutic or sub- prophylactic if administered alone, but is therapeutic or prophylactic when administered in combination with the second or additional drugs according to the invention; or (c) both drugs are administered in an amount that is sub- 25 therapeutic or sub-prophylactic if administered alone, but are therapeutic or prophylactic when administered together. Combinations of three or more drugs are analogously possible. Methods of combination therapy include co- administration of a single formulation containing all active agentsl essentially contemporaneous administration of more than one formulation; and 30 administration of two or more active agents separately formulated, 43 WO 2004/037801 PCT/US2003/033343 E. Examples In order to illustrate the invention, the following examples are Included. These examples do not limit the invention. They are only meant to suggest a method of practicing the invention. Those skilled in the art may find other 5 methods of practicing the invention, which are obvious to them. However, those methods are deemed to be within the scope of this invention. Protocol for Preparative Raversed-Phass HPLC Gilson® 10 Column: YMC-Pack ODS-A, 5 mm, 75x30 mm Flow rate: 25 mL/min Detection: l = 220 & 254 nm Gradient (acetonitrile/water, 0.05% trifluaraacetic acid) 1) 0.0 min 15% acetonitrile/85% water 15 2) 20.0 min 99% acelonitrile/1% water Protocol for HPLC (Reversed-Phase) Hewlett Packard Series 1100 Column; Agilent ZORBAX® Bonus RP, 5 mm, 4.6x250 mm Flow rate: 1 mL/min 20 Detection: l = 220 & 254 nm Gradient (acetonitrile/water, 0.05% trifluoroacetic acid) 1) 0.0 min 1% acetonitrile /39% water 2) 20.0 min 99% acetonitrile/1% water 25 Mass spectra were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in either positive or negative modes as indicated. Thin-layer chromatography was perfomred using Merck silica gel 60 F254 2.5 cm x 7.5 cm 250 mm or 5.0 cm x 10.0 cm 250 mm pre-coated silica gel plates. Preparative thin-layer chromatography was performed using EM 30 Science silica gel 60 F254 20 cm x 20 cm 0.5 mm pre-coated plates with a 20 cm x 4 cm concentrating zone. NMR spectra were obtained on either a Bruker model DPX400 (400 MHz) or DPX500 (500 MHz) spectra meter. The format of the 1H NMR data 44 WO 2004/07801 PCT/US/2003/03343 below is: chemical shift in ppm down field of the letra methylsilane reference (multiplicity, coupling constant J in Hz, integration). Example 1 4-sec-Butyl-pjperazine-1-carboxylic_acid tert-butyl ester A mixture of piperazine-l-carboxylic acid tert-butyl ester (7.00 g), 3-pentanone (3,89 g), glacial acetic acid (2.22 mL) and sodium triacetoxyborohydride (11.95 i) in dichloromethane (DCM, 200 mL) was stirred for 18 n at room temparature. 10 The reaction mixture was quenched with 1 N aqueous NaOH (80 mL) and stimed for 2,5 h at room temperature. Additional water (10D mL) was added, and the resulting mixture was extracted with DCM (3 x 100 mL). Extracts were combined and washed with water (2 x 100 mL), dried (Na2SO4), and concentrated under reduced pressure, yielding the title compound (6.28 g). 15 The products of Example 2 through Example 5 were prepared in analogy with the procedure of Example 1 using the specified carbonyl compound and amine. 4-(1-Ethyl-propyl)-piperazine-1-carbogxylic acid tert-butyl ester prepared, from 3-pertanone and piperazine-1 -carboxylic acid tert-butyl ester 45 WO 2004/037801 PCT/US2003/033343 4-_Butyl-piperganezin-1-carboxylic acid tert-butyl ester 5 Prepared from butanal and piperazine-1-carboxylic acid fert-butyl ester. 4-(1-Methyl-heptyl)-piperazine-1-carboxylic acid tert-butyl ester 10 Prepared from 2-oclanone and piperaztne-i-carboxylic acid tert-butyl ester. 15 4-Isopropyl-piperazine-1-carboxylic acid tert-butyl ester Prepared from acetone and piperazine-1-carboxylic acid tert-butyl ester. 46 WO 2004/037801 PCT/US2003/033343 1-sec-Butyl-piperzin dihydrocholoride To a solution of the product of Example 1 (6.28 g) in methanol (120 mL) 5 at 5 °C was added 4 M HCl in dioxane (100 mL). The reaction mixture was stirred at room temperature. After 24 h, the solvent was evaporated under vacuum. Ethyl ether was added and evaporated to dryness under vacuum (2 x 100 mL). The resulting white solid was dried under vacuum for 24 h yielding the title compound as its dihydrochloride salt (4.93 g) as a white solid. 10 The products of Example 7 through Example 10 were prepared in analogy to the procedure of Example 6 from the specified tert-butylcarbamate. 15 1 -(1 -Ethyl-propyl)-piperazine dihyrirochloride Prepared from the product of Example 2. 20 1 -Butyl-piperazine dihyldrochlorids Prepared from the product of Example 3. 47 WO 2004/037801 PCT/US2003/033343 1-(1-Methyl-neotyl)-piperazine dihvdrochloride Prepared from the product of Example 4. 5 1-Isoprgpyl- piperazine dihydrochloride Prepared from the product of Example 5. 10 4-(4-sec-Butyl-piperazine-1-carbonyl)-benzaldehyde The product of Example 6 (3.2 g) and 4-formylbenzoic acid (2.102 g) 15 were suspended in DCM (130 mL) under nitrogen. 1-{3- (Dimethylamino)priopyl-3-ethylcacbodilmide hydrochloride (3.96 g), 1- hydroxybenzotriazole hydrate (3.06 g) and N-methylrpoipholine (9,432 g) were added in sequence to the above suspension. The reaction mixture was stirred under nitrogen for 24 h. DCM (100 mL) was added, the resulting mixture was 20 washed with 10 % aqueous NaOH solution (2 x 50 mL) and water (2 x 100 mL), and the separated organic phase was dried over anhydrous MgSO4, and concentrated under reduced pressure to yield the crude product (3.75 g). Chromatography of the residue on silica gel (2-5% 2 M methanolic ammonia/DCM) yieled the title compound (2.75 g). 48 WO 2004/037801 PCT/US2003/033343 The products of Example 12 through Example 18 were prepared in analogy to the procedure of Example 11 using the specified prperazine derivatives and carboxylic acids. 5 4-{4-(1-Ethyl-propyl)-pipgrazine-1-cabopnyl-benzaldehyde Prepared from the product of Example 7 and 4-formylbenzoic acid. 10 4-(4-Butyl-piperazine-1 -tarbonyl)-benzaldenyde Prepared from the product of Example 8 and 4-formybenzoic acid. 15 4-{4-(1-Methtyl-hepyl)-piperzine-1-carbonyl)-benzaldehyde Prepared from the product of Example 9 and 4-formylbenzoic acid. 20 49 WO 2004/037801 PCT/US2003/033343 4-(4-lsopropyl-piperazine-1-carbonyl-1-benzaIdehyde Prepared from the product of Example 10 and 4-formylbenzolic acid. 5 4-(4-Methyl-piperazine-1-carbonyl)-benaldehyde Prepared from N-methylpiperazine and 4-formylbenzole acid. 10 3-(4-Methy-piperazine-1-carbony)-benzaidehyde Prepared from N-methylpiperazine and 4-formylbenzoic acid. 15 3-(4-lsosropyl-piperazine-1-carbonyl)-benzaldehyde 50 WO 2004/037801 PCT/US2003/033343 Prepared from the product of Example 10 and 3-formylbenzoic acid. 5 (4-Bromo- phenvl)-(4-(1-ethyl-propyl)-piperazin-1- yl)-methanpne To a solution of 4-bromobenzoic acid (500 mg) and the product of Example 7 (710 mg) in DCM (20 mL) was added 1-{3-(dimethylamino} propyl}- 3-ethylcarbodiimide hydrochloride (713 mg), 1-hydroxybenzotrizole hydrate (570 mg), and N-methyl morphaline (1.54 mL). After 16 h the reaction mixture 10 was treated with 1 N NaOH (25 mL) acid extracted with DCM (3 x 75 mL) The organic layers were dried (Na2SO4), concentrated, and chnomatographed on silica gel (1-3% 2 M methanolic ammonla/DCM) to give the title compound as white-yellow solid (630 mg). {4-(Benzylamino-methyl)-phenyl}-{4-(1-ethyl-propyl)-piperezin-1-yl}- mathanone To a solution of the product of Example 12 (150 mg) and benzylamine 20 (0.062 mL) in DCM (5 mL) was added acetic acid (.03 mL) and sodium triacetoxyborohydride (165 mg). After 16 h the raction was treated with 1 N NaOH (20 mL) and extracted with DCM (3 x 20 mL). The organic layers were dried (Na2SO4), concentrated, and chromatographed (2-3% 2 M methanolic ammonia-DCM) to give the title compound as an oil (150 mg). 51 WO 2004/037801 PCT/US2003/033343 {4-(1-ethyl-propyl)-piperezin-1-yl}-{4-piperedin-1-ylmethyl-phenyl}- methanone Prepared from the product of Example 12 and piperidine. 1H NMR {400 MHz. CDCl3): 7.40-7.34 (m. 4H), 3.74 (brs, 2H), 3.53 (s, 5 2H), 3.39 (br s, 2H), 2.50-2.42 (m, 8H), 220-2.17 (m, 1H). 1.62-1,60 (m, 4H), 1,50-1.41 (m,4H), 1.43-1.27 (m, 2H), 0.92-0.88 (m, 6H). 10 (4-sec-Butyl-Piperazin-1-yl)-(4 -Piperidin-1 -ylmethyl-Phenyl)-methanone Prepared from the product of Example 11 and piperidine. 1H NMR (400 MHz, CDCl3); 7.36-7.30 (m, 4H), 3.75 (br s, 2H), 3.50- 3.32 (m, 4H), 2.55-2.24 (m, 9H), 1.60-1.48 (m, 5H), 1.46-1.36 (m, 2H), 1.34- 1.0 (m, 1 H) 0.95 (d, J = 6.6 Hz, 3H), 0.92-0.88 (m, 3H). 15 (4-sec-Butyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone Prepared from the product of Example 11 and aniline. 20 1H NMR (400 MHz, CDCl3): 7.43-7.32 (m, 4H), 7.15 (tt, J = 7.4, 5.4 Hz, 2H), 6.74-6.66 (m, 1H), 6.59 (dd, J=7.6, 1.0 Hz 2H), 4.33 (s, 2H), 4-2 (brs, 1H), 3.76 (brs, 2H), 3:41 (brs, 2H), 2.66-2.27 (m, 5H), 1.62-1.45 (m, 1H), 1.36-1.20 (m, 1H), 0.96 (d, J = 6.6 Hz, 3H), 0.90 (t,J = 7.4 Hz, 3H). 55 WO 2004/037801 PCT/US2003/033343 1H NMR (400 MHz, CDCl3): 7.40-7.34 (m, 8H), 7.23-7.26 (m, 1H), 3.85 (d, J = 9.1 Hz, 4H), 3.75 (br s, 2H), 3.40 (brs, 2H), 2.59-2.45 (m, 4H), 2.21- 2.18 (m, 1H), 1.67 (8, 1H), 1.50-1.43 (m, 2H). 1.35-1.28 (m, 2H). 0.92-0.39 (m. 6H). 5 The products of Example 21 through Example 42 were prepared in analogy with the procedure of Example 20 using the specified carbonyl compounds and amines. (4-Azeoan-1-ylmethyl-phenyl)-(1-ethyl-propyl)-piperazin-1-yl)- methanone Prepaned from the product of Example 12 and azepine. 15 1H NMR (400 MHz, CDCI3); 7.39-7.33 (m, 4H), 3.74 (br s, 2H), 3.65 (s, 2H), 3.40 (br s, 2H), 2.62-2.46 (m, 8H), 2.21-2.17 (m. 1H). 1.62 (br s, 8H), 1.50-1.43 (m, 2H), 1.34-1.27 (m, 2H), 0.92-0.89 (m, 6H). {4-(1-Ethyl-propyl)-pipergzin-1- yl}-{4-(decahydro-isoquinolin-2-ylmethyl- phenyl)-methanone 52 WO 2004/037801 PCT/US2003/033343 Prepared from the product of Example 12 acid decahydroisoquinoline- 1H NMR (400 MHz, CDCl3): 7.39-7.33 (m, 4H), 373 (br s, 2H), 3.52- 3.39 (m. 4H), 2.59-2.45 (m, 6H), 2.20-2.17 (m, 2H), 1.70-1.29 (m, 17H), 0.92- 0.83 (m, 6H). 5 (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl- picerazin-1-yl)-methanone Prepared from the product of Example 11 and azepine. 10 1H NMR (400 MHz, CDCI3): 7.35 (dd, J = 9.1, 8.1 Hz. 4H), 3.76 (br s, 2H), 3.63 (S, 2H), 3.42 (brs, 2H), 2.68-2.32 (m, 9H), 1,69-1.47 (m, 9H), 1.36- 1.20 (m. 1H), 0.96 (d. J = 6.6, 3H), 0.89 (t, J = 7.3, 3H). (4-sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl)-phenyl)-methanone Prepared from the product of Example 11 and dimethylamine hydrochloride. 1H NMR (400 MHz, CDCI3): 7.38-7.29 (m, 4H), 3.75 (br s, 2H), 3.42 (br 20 s, 4H), 2.66-2.30 (m, 5H), 2.22 (s, 6H), 1.58-1.46 (m, 1H), 1.34-1.20 (m, 1H). 0.95 (d, J = 6.57 Hz, 3H), 0.92-0.88 (m, 3H). 53 WO 2004/037801 PCT/US2003/033343 (4-sec-Butyl-piperazin-1- yl)-(4- pyrroIdin-1-ylmethy-phenyl)-methanone Prepared from the product of Example 11 and pyrrolidine. 5 1H NMR (400 MHz, CDCl3); 7.38-7.29 (m. 4H), 3.74 (br s, 2H). 3.60 (s. 2H), 3.40(br s, 2H), 2.64-2.34 (m, 9H), 1.81-1.70 (m, 4H), 1.59-1.45 (m, 1H), 1.33-1.19 (m. 1H), 0.94 (d, J= 5.57 Hz, 3H), 0.91-0.88 (m, 3H). {4-(1-Ethyl-propyl)-pipererazin-1-yl}-{4-pyrrolidin-1-ylmethyl-phenyl) methanone Prepared from the product of Example 12 and pyrrolidine. 1H NMR (400 MHz, CDCI3): 7.41-7.35 (m, 4H), 3.73-3.70 (m, 4H), 3.38 15 (br s, 2H), 2.59-2.45 (m, 8H), 2.20-2.17 (m, 1H), 1.83 (br s, 4H), 1.49-1.27 (m, 4H), 0.92-0.88 (m, 6H). 54 WO 2004/037801 PCT/US2003/033343 {4-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone Prepared from the product of Example 13 and dimethylamine 5 hydrochloride. 1H NMR (400 MHz, CDCl3): 7.41-7.31 (m, 4H), 3.79 (br s, 2H), 3.43 (s, 3H), 2.5 (br s, 2H), 2.37-2.34 (m, 3H), 2.24 (br s, 4H), 1.65 (br s, 4H), 1.52-1.40 (m, 2H), 1.39-1.26 (m. 2H) 0.91 (t, J = 7.3 Hz, 3H). (4-Butyl-piperazin-1-yl)-(4-{(4-trifluoromethyl-phenylamino)-methyl): phenyl)-methanone Prepared from the product of Example 13 and 4-trifluoromethyl- 15 phenytamine. 1H NMR (400 MHz, COCl3): 7.45-7.32 (m, 6H). 6.60 (d, J = 8.5 Hz, 2H), 4.59 (t, J = 5.6 Hz, 1H), 4.39 (d, J = 5.3 Hz, 2H), 3.79 (br s, 2H), 3,43 (br s, 2H), 2.60-2.30 (m, 6H), 1.55-1.43 (m, 2H), 1.40-1.25 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). 20 56 WO 2004/037801 PCT/US2003/033343 {4-(1-Mathyl-heptyI)-piperazin-1- yl)-(4-morpholin-4- ylmethyl- phenyl)- methanone 5 Prepared from the product of Example 14 and morpholine. 1H NMR (400 MHz, CDCla): 7.39-7.35 (m, 4H), 3.76 (br s, 2H), 3.68- 3.66 (m, 2H), 3.52 (s, 2H), 3.46 (br s, 2H), 2.64-2.45 (m, 10H), 1.51-1.47 (m, 1H), 1.30-1.26 (m, 10H), 1.02 (m, 3H), 0.90-0.87 (m, 3H). (4-(1 -Methyl-heptyl)-piperazin-1-yl)-(4-piperidin-1- ylmethyl- phenyl)- methanone Prepared from the product of Example 14 and piperidine. 15 1H NMR (400 MHz, CDCI3): 7.42-7.35 (m, 4H), 3.77 (br s, 2H). 3.58 (s. 2H), 3.42 (br s, 2H), 2.60-2.47 (m, 10H), 1.65 (br s, 4H), 1.50-1.46 (m, 1H), 1.33-1.28 (m, 10H), 0.97 (d, J = 8.5 Hz, 3H), 0.90-0.87 (m, 3H), 57 WO 2004/037801 3/033343 (4-isopropyl-piperazin-1-yI)-(4-[(4-trifluoromethyl-phenylamino)-methyl] phenyl}- methanone 5 Prepared from the product of Example 15 and 4-trifluoromethylanitine- 1H NMR (400 MHz, CDCl3): 7.41-7.36 (m, 6H), 6.62 (d, J = 8.5 Hz, 2H), 4.56-4.54 (m, 1H), 4.40 (d, J = 5.8 Hz, 2H), 3.83 (br s, 2H), 3.48 (br s, 2H), 2.80-2.77 (m, 1H), 2.63-2.50 (m, 4H), 1.08 (d, J = 6.6 Hz, 6H). (4-lsopropyl-piperazin-1-yl)-{4-(4-isopropyl-piperazin-1-ylmethyl)- phenyl}-methanons Prepared from the product of Example 15 and the product of Example 15 10 1H NMR (400 MHz, CDCl3): 7.37 (m, 4H), 3.78 (br s, 2H), 3.54 (s, 2H), 3.44 (br s, 2H), 2.76-2.46 (m, 14H), 1.11 (d, J = 6.6 Hzr 6H), 1.05 (d, J = 6.6 Hz. 6H). 58 WO 2004/037801 PCT/US2003/033343 (4-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piparidin-1- ylmethyl)- phenyl)-methanone 5 Prepared from the product of Example 13 and 3- trifluoromethyIpiperidine. 1H NMR (400 MHz, CDCl3): 7.74-7.47 (m, 4H), 4.96-4.74 (m, 5H), 4.46- 4.26 (m, 2H), 4.00-3.38 (m, 5H), 2.97-2.69 (m, 6H), 2.04-1.58 (m, 4H), 1.16-0.9 (m, 6H). 10 (4-Butyl-piperazin-1-yl)-(4-moroholin-4- yImethyl-phenyl)- methanone Prepared from the product of Example 13 and morpholine. 15 1H NMR (400 MHz, CDCI3): 7.35-7.31 (m, 4H), 3.79 (br s, 2H), 3.68 (t, J = 4.5 Hz, 4H), 3.48 (s, 2H) 3.41 (br s, 2H), 2.48 (br s, 2H), 2.44-2.40, (m, 4H), 2.33 (t, J = 7,6 Hz, 4H), 1.48-1.41 (m, 2H), 1.35-1.26 (m, 2H), 0.89 (t, J =7.3 Hz, 3H). 59 WO 2004/037801 PCT/US2003/033343 (4-Isopropyl-piperazin-1-yl)-(3-morpholin-4-yl methyl-phenyl)-methanone Prepared from the product of Example 18 and morpholine. 5 1H NMR (400 MKz, COCl3): 7.39-T.28 (m. 4H), 3.79 (br s, 2H), 3.71(t, J = 4.6 Hz, 4H), 3.52 (s, 2H), 3.42 (br s, 2H), 2.76-2.70 (m, 1H), 2.60 (br s, 2H), 2.46-2.44 (m, 6H), 1.05 (d. J = 6.5 Hz, 6H), (4-lsopropyl-piperazin-1-yl)-(3-piperidin-1-ylmethyl-phenyl)-methanone Prepared from the product of Example 16 and piperidine. 1H NMR (400 MHz COCI3): 7.37 (m, 3H), 7.28 (d, J = 1.7 Hz, 1H), 3.79 (br s, 2H), 3.48 (s, 2H), 3.42 (br s, 2H), 2.76-2.69 (m, 1H), 2.69 (br s, 2H), 2.45 15 (br s, 2H), 2.37 (br s, 2H), 1.59-1.54 (m, 4H), 1.44-1.42 (m, 2H), 1.05 (d, J = 6.5 HZ, 6H). 60 WO 2004/037801 PCT/US2003/033343 (4-Isopropyl-piserazin-1-yl)-(4-morpholin-4-ylmethyl-phenyI)-methanone Prepared from the product of Example 15 and morpholine. 5 1H NMR (400 MHz. CDCI3): 7.36 (s, 4H), 3.79 (br s. 2H), 3.71 (t, J = 4.7 Hz,4H), 3.51 (s, 2H), 3.44 (brs, 2H), 2.76-1.69 (m, 1H), 2.59 (br s, 2H), 2.44 (t, J = 4.4 Hz, 6H), 1.05 (d. J = 6.5 Hz, 6H). (4-lsopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone Pepered from the product of Example 15 and piperidine. 1H NMR (400 MHz, CDCl3): 7.35 (s, 4H), 3.79 (brs, 2H), 3.48 (br s, 2H), 3.45 (br s, 2H), 2.72 (m, 1H), 2.59 (br s, 2H), 2.45 (br s, 2H), 2.38 (br s, 4H), 15 1.60-1.55 (m, 4H), 1.48-1.40 (m, 2H), 1.06 (d, J = 6.3 Hz, 6H). 61 WO 2004/037801 PCT/US2003/033343 {3- (4-Benzyl-piperidin-1-ylmethyl)-phenyl}-(4- methyl-piperazin-1-yl- methanone Prepared from the product of Example 17 and 4-benzylpiperdine. 1H NMR (400 MHz, CDCl3); 7.37-7.10 (m, 9H), 3.80 (br s, 2H), 3.48 (s, 5 2H), 3.41 (br s, 2H), 2.87-2.79 (m, 2H), 2.53 (d, J = 7.0 Hz, 2H), 2.47 (br s, 2H), 2.33 (br s, 2H), 2.32 (s, 3H), 1.90 (ddd, J = 11.7, 11.7, 2.2 Hz, 2H), 1.63- 1.45 (m, 3H), 1.35-1.23 (m, 2H). (4-Methyl-piperazin-1-yl)-(4-morphoIin-4-ylmethyl-phenyl)- methanone dihydrochioride To a solution of the product of Example 16 (60 mg) and morpholine (0.025 mL) in DCM (5 mL) was added acetic acid (0.015 mL) and sodium 15 triacetoxyborohydride (83 mg). After 16 h the reaction was treated with 1 N NaOH (10mL) and extracted with DCM (3 x 20 mL). Organic layers were dried (Na2SO4), concentrated under reduced pressure, and chromatographed on silica gel (4% 2 M methanolic ammonia/DCM) to give the free base product. This material was converted into the dihydrochloride using methanol and 2 M 20 HCl in ether to form a white solid (35 mg). 1H NMR (400 MHz, CD3OD): 7.71 (d, J = 7.8 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 4.45 (s, 2H), 4.07-4.03 (m, 2H), 3.88-3.86 (m, 1H), 3.80 (t, J = 11.6 Hz, 2H), 3.62-3.39 (m, 6H), 3.27-3.17 (m, 5H), 2.96 (s, 3H). 25 The products of Example 44 through Example 62 were prepared in analogy to the procedure of Example 43 using the speeded carbonyl compounds and amines. 62 WO 2004/037801 PCT/US2003/033343 (4-Isopropyl-piperazin-1- yl)-{(4-trifluororoethyl-Pyridin-2-ylamino)- methyl)-phenyl}-methanone dihydrochloride 5 Prepared from the product of Example 15 and 4-trifluaromethyl-pyridin- 2-ylamine. 1H NMR (400 MHz, CO3OD): 8.08-8.06 (m, 1H), 7.58-7.45 (m, 4H), 7.39-7.35 (m, 1H), 7.14-7.10 (m, 1H), 4.76-4.70 (m, 2H), 3.58 (br s, 6H), 3.25- 3.23 (m, 2H), 1.41-1.30 (m, 7H). {4-(1-Ethyl-propyl)-pipgrazin-1-yl)-(4-phenylarninomethyl-phenyl)- methanone dihydrochloride 15 Prepared from the product of Example12 and ariline. 1H NMR (400 MHz CD3SOCD3); 7.76-7.63 (m, 4H), 7.53-7.41 (tt, J = 7.3, 6.6 Hz, 2H), 7.03 (t, J =7.2 Hz, 1H), 6.92 (dd, J = 7.6, 1.1 Hz, 2H), 5.60 (s. 1H), 4.68 (br s, 2H), 4.47 (br s, 1H), 4.05 (br s, 2H), 3.70 (br s, 2H), 2.90 (br s, 2H), 2.76 (br s, 2H), 1.84-1.70 (m, 2H)( 1.68-1.55 (m, 2H), 1.30-1.20 (m, 6H), 20 63 WO 2004/037801 PCT/US2003/033343 (4-Dimethylamlnomethyl-phenyl)-{4-(1-ethyl-anopyl)-piperazin-1-yl) methanone dihydrochloride 5 Prepared from the product of Example 12 and dimethylamine hydrochloride. 1H NMR (400 MHz, CD3OD); 7.76-7.44 (m, 4H), 4.52 (br s, 1H), 4.32- 4.25 (m, 2H), 3.83-3.56 (m, 2H), 3.23-2.33 (m, 4H), 2:76-2.55 (m, 6H), 2.54- 2.35 (m, 2H), 2.00-1.71 (m, 2H), 1.70-1.47 (m, 2H). 1.05-0.77 (m, 6H). 10 {4-(1-Ethyl-propyi)-piperazin-1- yl)-{(4-trifluoromethyl-phenylamino)- methyl}-phenyl}-methanone dihydrochloride 15 Prepared from the product of Example 12 and 4-trifluoromethylaniline. 1H NMR (400 MHz, CD3OD): 7.56-7.12 (m, 6H), 6.69-6.49 (m, 2H), 4.81 (s, 2H), 4.47-4.28 (n, 2H), 3.37-3.03 (m, 8H), 1.97-1.56 (m, 4H), 1.13-0.89 (m, 6H). 64 WO 2004/037801 PCT/US2003/033343 {4-(1 -Ethyl-propyl)-piperazin-1-yl)-(4-monpholin-4-ylmethyl- phenyl)- methaneno dihydrochloride 5 Prepared from the product of Example 12 and morpholine. 1H NMR (400 MHz, dmso-ds): 7.74 (d, J = 8.1 Hz, 2H), 7.55 (d, J = B.1 Hz, 2H), 4.36 (d, J = 4.8 Hz, 2H), 4.00-3.67 (m, 10H), 3.52-3.41 (m, 2H), 3.25- 3.13 (m, 2H), 3.11-2.99 (m, 3H), 1.97-1.80 (m, 2H), 1.69-1.52 (m, 2H), 0.96 (t, J = 7.58 Hz, 6H). 10 (4-(1-Ethyl-propyl)-piperazin-1-yl)-(4-(3-trifIuorometh yl-piperidin-1- ylmethyl)-Phenyl}-methanone dihydrochloride 15 Prepared from the product of Example 12 and 3- trifluonomethylpiperidine. 1H NMR (400 MHz, CD30D): 7.72 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 7.8, 2H), 4.87 (s, 2H), 4.50-4.40 (m, 2H), 3.75-3.41 (m, 8H), 3.20-2.84 (m, 4H), 2.09 (m, 2H), 2.00-1.50 (m, 6H), 1.12-1.02 (m, 6H)- 20 65 WO 2004/037801 PCT/US2003/033343 (4-sec-Buthyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)- phenyl)-methanone dihydrochloride 5 Prepared from the product of Example 11 and 3- trifluoromethyIpipendine. 1H NMR (400 MHz, CD3OD): 7.71 (d, J=8.3 Hz, 2H). 7.63 (d, J = 8.1 Hz, 2H), 4.86 (s, 2H), 4.52-4.40 (m, 2H), 3.75-3.45 (m, 8H), 3.23-2.96 (m, 5H), 2.17-2.00 (br m, 2H), 1.97-1.54 (m, 4H), 1.50-1.25 (m, 2H), 1.10-0.93 (m, 3H). 10 (4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-Phenyl)-methanone dihydrochloride 15 Prepared from the product of Example 11 and morpholine. 1H NMR (400 MHz, CD3OD): 7.71-7.62 (m, 4H), 4.43 (s, 2H), 4.14-3.59 (m, 7H), 3.52-3.11 (m,10H), 2.02-1.88 (m, 1H), 1.68-1.49 (m, 1H), 1.38 (d, J = 6.6 Hz, 3H), 1.04 (t, J = 7.3 Hz, 3H). 66 WO 2004/037801 PCT/US2003/033343 (4-Isopropyl-piperazin-1- yl)-{4-{(6-trifluoromethyl-pyrrdin-3-ylamino)- methylyphenyl)-methanon dihydrochIoride 5 Prepared from the product of Example 15 and 6-trifluoromethyl-pyridio 3-ylamine. 1H NMR (400 MHz, CD3OD): 6.16-8.11 (m, 1H), 7.61-7.74 (m, 1H), 7.53-7.46 (m, 5H), 4.92-4.09 (m, 2H), 4.56-4.51 (m, 2H), 3.56-3.52 (m, 4H), 3.28-3.21 (m, 2H), 1.40-1.46 (m, 7H)- 10 {4-{ (5-Chloro-pyridin-2-ylamino)-methyl}-phenyl)-(4-Isopropyl-piperazin- 1-yl)-methanone dihydrochloride 15 Prepared from the product of Example 15 and 5-chloro-pyridin-2- yiamine. 1H NMR (400 MHz, CD3OD): 8.04 (d, J = 2.5 Hz, 1H), 7.38-7.33 (m, 5H), 6.32 (d, J = 8.6 Hz, 1H), 5,05 (t, J = 5.6 Hz, 1H), 4.52 (d, J = 6.1 Hz, 2H), 3.78 (br s, 2H), 3.43 (br s, 2H), 2.72 (m, 1H), 2.58-2.44 (m, 4H), 1.04 (d, J = 20 6,6 Hz, 6H). 67 WO 2004/037801 PCT/US2003/033343 (4-Methyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone dihydrochioride 5 Prepared from the product of Example 16 and piperidine. 1H NMR (400 MHz, CD3OD) 7.68-7.60 (m, 4H), 4.36 (s, 2H), 3.73 (br s, 2H), 3.52-3.46 (m, 4H), 3.25 (br s, 4H), 3.00 (br s, 2H), 2.87 (s, 3H), 1.94-1.82 (m, 5H), 1.53 (br s, 1H). (4-lsopropyl-piperazin-1-yl)-(4-{(5-trifluoromethyl-pyridin-2- ylamino)- methyl)}-phenyl)-methanone dihydrochloride Prepared from the product of Example 15 and 5-trifluoromethyl-pyridin- 15 2-ylamine. 1H NMR (400 MHz, CD3OD): 8.31 (s, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.57 (s, 4h), 7.24 (d, J = 9.6 Hz, 1H), 4.75 (s, 2H), 3.60-3.46 (m, 6H), 3.24-3.21 (m, 2H), 1.41-1.40 (m, 7H). 68 WO 2004/037801 PCT/US2003/033343 (4-Isopropyl-piperazin-1-yl)-{4-(3-trifluoronoethyl-piperidin-1-ylmethyl)- phenyl-methanone dihydrochIoride 5 Prepared from the product of Example 15 and 3-trifluoromethyl- pipandine. 1H NMR (400 MHz, CD3OD); 7.74-7.64 (m,4H), 4.88 (s. 2H), 4.52-4.41 (m, 2H), 3.70-3.50 (m, 6H), 3.26-3.13 (m, 4H), 3.07-2.92 (m, 2H), 2.14-2.07 (m, 2H), 1.94-1.84 (m, 1H), 1.68-1.58 (m, 1H), 1.42-1.39 (m, 6H), 10 (4-Diethylaminomethyl-phenyI)-(4-isopropyI-piperazin-1- yl)-methanone dihydrochloride 15 Prepared from the product of Example 15 and diethylamine. 1H NMR (400 MHz, CD3OD): 7.70-7.64 (m, 4H), 4.42 (s, 2H), 3.61-3.57 (m, 6H), 3.25-3.22 (m, 6H), 1.42-1.30 (m, 13H), 69 WO 2004/037801 PCT/US2003/033343 {4-{Benzylamino-methyl)-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride 5 Prepared from the product of Example 15 and benzylamtne. 1H NMR (400 MHz, CD3OD): 7.67-7.43 (m, 9H), 4.33 (s, 2H) 4.29 {s, 2H), 3.61 -3.58 (m, 6H), 3.26-3.22 (m, 2H), 1.42-1.41 (d. J = 6.6 Hz, 7H). (4-Isopropyl-piperazin-1-yl)-(4-phenylaminomethyl-phonyl)-methanone dihydrochloride Prepared from the product of Example 15 and anlline. 1H NMR (400 MHz, CD3OD): 7.57-7.64 (m, 7H), 7.47-7.44 (m, 2H), 4.69 15 (s, 2H), 3.62-3.52 (m, 6H), 3.25-3.19 (m, 2H), 1.42-1.41 (d, J = 6.6 Hz, 7H). 70 WO 2004/037801 PCT/US2003/033343 (4-Azapan-1-ylmetnyl-pheny)-(4-isopropyI-piperazin-1- yl)-methanone dihydrochloride Prepared from the product of Example 15 and azepane. 1H NMR (400 MHz, CD3OD): 7.69 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.1 5 Hz, 2H), 4.43 (s, 2H), 3.60-3.43 (m, 8H), 3.23-3.20 (m, 4H), 1.97-1.90 (m, 4H). 1.79-1.73 (m, 4H), 1.42-1.46 (d, J = 6.6 Hz, 7H). 10 (4-Isopropyl-piperazin-1- yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone dihydrochloride Prepared from the product of Example 15 and pyrrolidine. 1H NMR (400 MBz, CD3OD): 7.69 (d, J = 8.3 Hz, 2H), 7.63 (d, J - 8.2 Hz, 2H), 4.46 (s. 2H), 3.61-3.51 (m, 8H), 3.26-3.20 (m, 4H), 2.22-2.18 (m, 2H), 15 2.06-2.03 (m, 2H), 1.42 (d, J = 6.6 Hz, 7H). (4-Dimethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone 20 dihydrochloride Prepared from the product of Example 15 and dimethylamine hydrochloride, 1H NMR (400 MHz, CD3OD)- 7.66 (br s, 4H), 4.40 (s, 2H), 3.65-3.54 (m, 4H), 3.26-3.20 (m, 4H), 2.89 (br s, 6H), 1.41 (d, J = 6.6 Hz, 7H), 71 WO 2004/037801 PCT/US2003/033343 (4-Isopropyl-piperazin-1-yl)-(4-[[(2-methoxy-ethyl)-propyl-aminol-methyl)- phenyl)-methanone 5 Prepared from the product of Example 15 and (2-methoxy-ethyl)-propyl- amine. 1H NMR (500 MHz, CDCl3): 7.41-7.34 (m, 4H), 3.79 (br s, 2H), 3.65 (s, 2H), 3.51-3.46 (m, 4H), 3.32 (s, 3H), 2.76-2.71 (m, 1H), 2.69-2.65 (m, 2H), 2.53 (br s, 2H), 2.46-2.43 (m, 4H), 1.67 (br s, 1H), 1.53-1.46 (m, 2H), 1.06 (d, J 10 = 6.5 Hz, 6H), 868 (t, J = 7.3 Hz, 3H). (4-{[Ethyl-(2-methoxy-ethyl)-amino]-methyl}-phenyl)-(4-isopropyl - 15 piperazin-1-yl)-methanone Prepared from the product of Example 15 and (2-methoxy-ethyl)-ethyl- amine. 1H NMR (400 MHz, CDCl3): 7.42-7.31 (m, 4H), 3.79 (br s, 2H), 3.70 (s, 2H)r 3.53-3.45 (m, 4H), 3.33 (s, 3H), 2.76-2,71 (m, 1H), 2.69-2-67 (m, 2H), 20 2.60-2.56 (m, 4H), 2.46 (s, 2H), 1.62 (br s, 1H), 1.11-1.01 (m, 8H). 74 WO 2004/037801 PCT/US2003/033343 4-Cyclohexyl-piperazine-1-carboxylic acid tert-butyl ester 5 Prepared in analogy to Example 1 from piperazine-1-carboxylic acid tert- butyl ester and cyclonexanone. 10 1-Cyclohexyl-piperazine dihydrochloride Prapaned in analogy to Example 6 from the product of Example 63, 15 4-(4-Cyclohgxyl-piperazine-1-carbonyl)-benzaldehyde Prepared in analogy ta Example 11 from the product of Example 64- The products of Example 66 through Example 72 were prepared in analogy to the procedure of Example 20 from the specified carbonyl 20 compounde and amines. 72 WO 2004/037801 PCT/US2003/033343 (4-Cyclohexyl-piperazine-1-yl)-(4-piperidin-1 -ylmethyl-phenyl)-methanone Prepared from the product of Example 65 and piperidine. 5 1H NMR (400 MHz, CDCI3): 7.35 (s, 4H), 3.78 (br s, 2H), 3.48 (s, 2H), 3,44 (br s, 2H), 2.64-2.51 (m, 4H), 2.37 (br s, 2H), 2.30-2.29 (m, 2H), 1.86-1.80 (m, 4H), 1.65-1.55 (m, 7H), 1.45-1.44 (m,2H), 1.24-1.19 (m, 4H), (4-Isopropyl-piperzin-1-yl)-(4-thiomorpholin-4-ylmethyl-phenyl)- methanone Prepared from the product of Example 15 and thromorpholine. 1H NMR (400 MHz, CDCI3): 7.40-7.30 (m, 4H), 3.90-3.63 (br m, 2H), 15 3.53 (s, 2H), 3.49-3.37 (br m, 2H), 2.81-2.63 (m, 9H), 2.63-2.52 (br m, 2H), 2.51-2.35 (br m, 2H), 1.05 (d, J = 6.5 Hz, 6H). 73 WO 2004/037801 PCT/US2003/033343 (4-Isopropyl-piperagin-1-yI)-(4-[(2-methoxy-ethyIamino)-methyl)-phenyl} methanone 5 Prepared from toe product of Example 15 and (2-methoxy-ethyl)-amine. 1H NMR (400 MHz, CDCl3); 7.36 (m, 4H). 3,84 (s, 2H), 3.75 (br s. 2H), 3.53-3.51 (m, 2H), 3.42 (br s, 2H), 3.62 (s, 3H), 2.81-2.79 (m, 2H), 2.77-2.74 (m, 1H), 2.62 (br s, 2H), 2.42 (br s, 2H), 1.70 (br s, 1H), 1 .05 (d, J = 6.5 Hz, 6H). 10 (4-Isopropyl-piperazin-1-yl)-[4-(pyridin-2-ylaminomethyI)-phenyl]- methanone 15 Prepared from the product of Example of 15 and 2-ammopyridine, 1H NMR (400 MHz, CDCI3): 8.16-8.10 (m, 1H), 7.46-7.36 (m, 5H), 6.65- 6.59 (m, 1H), 6.42-6.36 (m, 1H), 5.04 (t, J = 6,1 Hz, 1H), 4.57 (d, J = 5.9 Hz, 2H), 3.91-3.68 (br m, 2H), 3.56-3.36 (br m, 2H), 2.80-2.67 (m, 1H), 2.59-2.54 (br m, 2H), 2.53-2.34 (br m, 2H), 1.07 (d, J = 6.6 Hz, 6H). 20 75 WO 2004/037801 PCT/US2003/033343 (4-lsopropyl-piperazin-1-yl)-(4-[(2-methoxy-1-methyl-ethylamino)- methyl-phenyl]-methanone 5 Prepared from the product of example 15 and 2-methoxy-1-methyl- erthylamine. 1H NMR (500 MHz, CDCl3): 7.35-7.38 (m, 4H), 3.89 (d, J= 13.3, 1H), 3.82-3.75 (m, 3H), 3.45 (brs, 2H), 3.43-3.32 (m, 4H), 3.28-3.25 (m, 1H), 2.96- 2.92 (m, 1H), 2.75-2.53 (m, 1H), 2.65-2.20 (m, 5H), 1.06-1.04 (m, 9H). 10 BIOLOGICAL METHODS In Vitro Transfection of cells with human histamins receptor 15 A 10 cm tissue culture dish with a confluent monolsyer of SK-N-MC cells was split two days prior to transfeclion. Using sterile technique the media was removed and the cells were detached from the dish by the addition of trypsin. One fifth of the cells were then placed onto a new 10 cm dish. Cells were grown in a 37 ºC incubator with 5% CO2 in Minimal Essential Media Eagle with 20 10% Fetal Boylne Serum,After two days celle were approximately 80% confluent. These were removed from the dish with trypsirt and pelleted in a clinical centriluge. The pellet was then re-suspended in ADD ml complete madia and transfferred to an etectroporation cuvetle with a 0.4 cm gap between the electrodes. One microgram of supercoilad H3 receptor cDNA was added to 25 the cells and mixed. The voltage for the electroporation was set at 0.25 kV, the capacitance was set at 960 mF. After electroporation the cells were diluted into 10 mL camp fete media and plated onto four 10 cm dishes. Because of the variability in the efficiency of electroporation, four different concentrations of cells were plated. The ratios used were: 1:20, 1:10, 1:5, with the remainder of 76 WO 2004/037801 PCT/US2003/033343 the cells being added to the fourth dish. The cells were allowed to recover for 24 h before adding the selection media complete media with 600 mg/mL G418). After 10 days dishes were analyzed for surviving colonies of cells. Dishes with well-isolated colonies were used. Cells from individual colonies 5 were isolated and tested, SK-N-MC cells were used because they give efficient coupling for inhibition of adenylate cyclase. The clones that gave the most robust inhibition of adenylato cyclase in response to histamine were used for further study. 10 {3H}-N-methythistamine binding Cell pellets from histemtne H3 receptor-expressing SK-N-MC celts were homogenized in 20 mM TrisHCl/0.5 mM EDTA. Supernatsnts from an 600 g spin were collected, recentrifuged at 30,000 g for 30 min. Pellets were re- homogenized in 50 mM Tris/5 mM EDTA (pH 7.4). Membranes were 15 incubated with 0.8 nU {3H}-N-methythistamine plus/minus test compounds for 45 min at 25 ºC and harvested by rapid filtration over GR/C glass fiber filters (pretreated with 0.3 % polyethytenimine) followed by four washes with ice-cold buffer. Fillers were dried, added to 4 mL scinfillation cocktail and then counted on a liquid scintillation counter. Non-specific binding was defined with 10 mM 20 histamine. The pK1 values were calculated based on a Ka of 800 pM and a Iigand concentration ({L}) of 800 pM acoording to the formula: K1=(LC50)/(1+({L}/(Kd)) K1 values for exemplary compounds of the invention are listed in the table below. 77 WO 2004/037801 PCT/US2003/033343 78 WO 2004/037801 PCT/US2003/033343 F. Other Embodiments The features and advantages of the invention will be apparent to one of ordinary skill in view of the discussion, examples, embodiments, and claims relating to the invention. The invention also contemplates variations and 5 adaptations, based on the disclosure herein concerning the key features and advantages of the invention, and within the abilities of one of ordinary skill. 79 WO 2004/037801 PCT/US2003/033343 22. A compound of claim 1, wherein H8 is C1-8 alkyl. 23. A compound of daim 1, wherein R9 is unsubstiluted or substituted phenyl. 5 24. A compound of claim 1, wherein R8 and R9 independently are C1-6 alkyl. 25. A compound of claim 1, wherein R8 and R9 are methyl. 10 26. A compound of claim 1, wherein R8 and R9 are ethyl 27. A compound of claim 21, wherein R9 is a elected from phenyl or 5-9 membered aromatic heterocyclyl, wherein said phenyl or aromatic heteracyclyl is optionally substituted with 1-3 substituents selected from 15 methoxy, hydroxy, halo, nitro, cyano, trifluoromethyl, and C1-8 alkyl. 28. A compound of claim 27, wherein R9 is selected from substituted or unsubstituted phenyl, pyridyl, pyrimidyl, furyl, thiofuryl, imdazolyl, (imidazolyl)C1-5 alkylene, oxazofyl, thiazolyl, 2,3-dihydro-indolyl, 20 benzimidazolyl, 2-oxobenzimidazolyl, (terrazolyl)C1-6 alkylene, tetrazolyl, (triazolyl)C1-6 alkylene, triazolyl, (pyrrolyl)C1-6 alkylene, pyrrolidinyl, and pyrrolyl. 29. A compound of claim 28, wherein R9 is phenyl. 25 30. A compound of claim 28, wherein R9 is substituted or unsubstituted pyridyl. 31. A compound of claim 1 wherein 30 R1 is C1-10 alkyl; X is O; R4 is G; L is -CH2-; and 84 WO 2004/037801 PCT/US2003/033343 Q is a saturated N-linked nitrogen-contain ing heterocyclyl 32. A compound of claim 31 wherein R1 is branched. 5 33. A compound of claim 31 wherein R1 is C3-5 alkyl. 34. A compound of claim 31, wherein wherein R1 is isopropyl. 35. A compound of claim 31, wherein Q is selected from substituted or 10 unsubstituted piperidinyl, diazepanyl, azepanyl, decahydroisoqulinolin-2- yl, pipenazinyl, pyrrolInyl, pymolidinyl, thlomorpholinyl, or morpholinyl. 36. A compound of claim 31, wherein Q is unsubstituted azepanyl, diazepanyl, morpfiolinyl, decahydroisoquinolin-2-yl, piperidlnyl, or 15 pyrrolidinyl. 37. A compound of claim 1 selected from the group consisting of: (4-{(Ethyl-(2-methoxy-ethyl)-amino]-methyl}-phenyl)-(4-isopropyl- piperazin-1-yl)-methanone; 20 (4-Azepan-1-yImethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-mathanone dihydrochloride; (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1 -yI)-methanone; (4-Azepan-1-ylmethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl)- methanone; 25 (4-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone; (4-Butyl-piperazin-1-yl)-(4-morpholin-4-yImethyl-phenyl)-methanone; (4-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)- phenyl}-methanone; (4-Buty l-pi pe razin-1 -y \ )-{4-{{4-tri flu o romethy !-p her>ytamino)-methy1}' 30 phenyl}-methanone; (4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl}-methanone; {4-Diethylaminomethyl-phenyl)-(4-Isopropyl-piperazin-1-yl)-methanone dihydrachloride; 85 WO 2004/037801 PCT/US2003/033343 (4-Dimethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride; (4-DimethylaminomethyI-phenyI)-{4-(1-ethyl-propyI)-piperazin-1-yl}- methanone dihydrochloride; 5 (4-Isopropyl-piperazin-1-yl)-(3-morpholin-4-ylmethyl-phenyl)-methanone; (4-lsopropyl-piperazin-1-yl)-(3-piperidin-1-ylmethyl-phenyl)-methanone; (4-Isopropyl-piperazin-1-yI)-(4-{[(2-methoxy-ethyI)-propyI-amino]-inethyI}- phenyl)-methanone; (4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone; 10 (4-Isopropyl-piperazin-1-yl)-(4-phenylaminomethylphenyl)-methanone dihydrochloride; (4-Isopropyl-pipenazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone; (4-Isopropyl-piperazin-1-yI)-{4-pyrrolidin-1-ylmethyl-phenyl)-methanone dihydrochloride; 15 (4-lsopropyl-piperazin-1-yl)-(4-thiomorpholin-4-ylmethyl-phenyl)- methanone; (4-Isopropyl-piperazin-1-yl)-{4-(3-influoromethyl-piperidin-1-ylmethyl) phenyl)-methanone dihydrochloride; (4-Isopopyl-piperazin-1-yl)-{4-(4-isopropyl-piperazin-1-ylmethyl)- 20 phenyl]-methanone; (4-Isopropyl-prperazin-1-yl)-{4-{(2-methoxy-ethylamino)-methyl)-pheny[}- methanone; (4-Isopropyl-piperazin-1-yI)- [4-(pyridin-2-ylaminomethyI)-phenyI]- methanone; 25 (4-lsopropyl-piperazin-1-yl)-[4-[(2-methoxy-1-methyl-ethylamino)- methyl]-phenyl]-methanone; (4 -Isopropyl -piperazin-1-yl)-{4-[{4-trifluoromethyl-phenylamino)-methyl}- phenyl}-methanone; (4-Isopropyl-piperazin-1-yl)-{4-{(4-trifluoromethyl-pyridin-2-ylamino)- 30 methyl)-phenyl}-methanone dihydrochloride; (4-Isopropyl-piperazin-1-yl)-{4-{(5-trifIuoromethyl-pyridin-2-ylamina)- methyl}-phenyl}-methanone dihydrochloride; 86 WO 2004/037801 PCT/US2003/033343 What is claimed is: 1. A composition comprising a compoand of formula (I): 5 wherein R1 is C1-10) alkyl, C3-8 alkenyl, C3-8 cycloalkyl, (C3-5 cycloalkyl)C1-5 alkyl, (C3-8 cycloalkyl)C3-8 alkenyl, or (C1-8 alkylcarbonyl)C1-8 alkyl; n is 1 or 2; 10 X is O or S; one of R2, R3 and R4 is G and the other two independency are hydrogen, fluoro, chlora, bromo, nitro, trifluoromethyl, methyl, or C1-3alkoxy; G is LQ; 15 L is unbranched -(CH2)m- wherein m is an integer from 1 to 7; Q is NR8R3 wherein R8 is independently selected from hydrogen, C1-5 alkyl, C3-8 alkenyl, 3-9 membered carbocyclyl, 3-12 membered heierocyclyl, phenyl, (6-9-membered heterocyclyl)C1-6 alkylene, and (phenyl)C1-5 alkylene; and R9 is independently selected from 20 Ct-s alkyl, C3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (6-9-membered heterocyclyl)C1-6 alkylens, and (phenyl)C1-6 alkytene, or Q is a saturated 3-12 membered N-linked hetorocydyl, wherein, in addition to the N-tinking nitrogen, the 3-12 membered 80 WO 2004/037801 PCT/US2003/033343 (4-Isopropyl-piperazin -1-yl)-{4-{(6-trifluoromethyl-pyridin-3-ylamino)- methyl}-phenyl}-methanona dihydrochloride; (4-Methyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)- methanone dihydrochlorid; 5 (4-Methyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl- phenyl)-methanone dihydrochloride; (4-sec-Butyl-piperazin-1-yl)-{4-dimethylaminomethyl-phenyl)- methanone; (4-sec-Buty-1-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone 10 dihydrochloride; (4-sec-Butyl-piperazin-1-yl)-(4-phertylaminomethyl-phenyl}-methanone; (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone; (4-sec-Butyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone; (4-sec-Butyl-piperazin-1-yl)-(4-(3-trifluoromethyl-piperidin-1-ylmethyl)- 15 phenyl)-methanone dihydrochloride; (3-(4-Benzyl-piperidin- 1-ylmethyl)-phenyl}-(4-methyl-piperazin-1-yl)- methanone; {4-(1-Ethyhpropyl)-piperazin-1-yl]-(4-morpholin-4-ylmethyl-phenyl)- methanone dihydrochloride; 20 {4-( 1 -Ethyl-propyl)-piperazin-1-yl}-{4-phenylaminomethyl-phenyl)- methanone dihydrochloride; {4-(1 -Ethyl-propyl)-piperazin-1-yl)-{4-piperidin-f-ylmethyl-phenyl)- methanone; {4-(1-Ethyl-prapyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)- 25 methanone; {4-(1-Ethyl-prapyl)-piperazin-1-yI)-(4-(3 -trifluoromethyl-piperidin-1- ylmethyl)-phenyl}-methanone dihydrochloride; {4-(1-Ethyl-pnopyl)-piperazin-1-yI)-(4-(decahydro-isoquinolin-2-ylmethyl)- phenyl)-methanone; 30 {4-(1 -Elhyl-propyl}-piperazin-1-yl}-{4-{(4-trifIuoromethyl-phenylamino)- methyl)-phenyl)-methanone dihydrochloride; {4-(1 -Mylethyl-heptyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)- methanone; 87 WO 2004/037801 PCT/US2003/033343 heterocyclyl may optionally contaln between 1 and 3 additional heteroatoms indeperidently selected from O, S, and NH; wherein Q is optionally substituted with 1-3 substituents independentiy selected from the group consisting of hydroxy, halo, 5 carboxamide, C1-5 alkyl, 5-9 membered or 6-9 membered heterocyclyl), -NH(5-9 membered or 6-9 membened heterocyclyl), -O(5-9 or 6-9 membered heterocyclyl), (5-9 membered or 6-9 membered heterocyclyl)C1-3 alkylene, C1-6 alkoxy, (C3-6 10 cycloalkyl)-O-, phenyl, (phenyl)C1-3 alkylena, and (phenyl)C1-3 alkylene-O-, where each of above heterocyclyl, phenyl, and alkyl groups may be options fly substituted with from 1 to 3 substituents independently selected from tifluoromethyl, methoxy, halo, nitro, cyano, hydroxy, and C1-3 alkyI; 15 provided however that when R1 is methyl, G is not piperidin-1-ylmethyl; and wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, cacbocyclyl, and aryl groups may each be independently and optionally substituted with between 1 and 3 20 substituents independently selected from trifluoromethyl, methoxy, halo, amino, nitro, hydroxy, and C1-3 alkyI; or a pharmaceutically acceptable salt, ester, tautomer, solvate or amide thereof. 25 2. A compound of claim 1, wherein R1 is C1-10 alkyl. 3. A compound of claim 1, wherein R1 is C3-5 alkyl. 4. A compound of claim 1, wherein wherein R1 is isopropyl. 30 5. A compound of claim 1 wherein n is 1. 6. A compound of claim 1, wherein wherein X is O. 81 WO 2004/037801 PCT/US2003/033343 7. A compound of claim 1, wherein one of R3 and R4 is G. 8. A compound of claim 1, wherein R4 is G, 5 9. A compound of claim 1, wherein L is unbranched -(CH2)m, wherein m is an integer from 1 to 4. 10. A compound of claim 1, wherein L is -CH2-. 10 11. A compound of claim 1, wherein L is -CH2CH2-. 12. A compound of claim 1 wharein Q is a saturated M-linked nitrogen- containing heterocyclyl. 15 13. A compound of claim 1, wherein Q is selected from substituted or unsubstituted piperidinyl, diazepanyl, azepanyl, decahydrolsoqulnolin-2- yl, piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpriolinyl, or morpholinyl. 20 14. A compound of claim 1, wherein O is unaubstituted piperndinyl, diazepanyl, azepanyl, decahydroisoquinolin-2-yl, piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, or morpholinyl. 15. A compound of claim 14, wherein Q is unsubstituted diazepanyl, 25 azspanyl, morpholinyl, decahydroisoquinolln-2-yl, piperidinyl, of pyrrolidinyl; 16. A compound of claim 1, wherein substituted Q are selected from N-(C1-6 alkyl)pipesrazinyl, N-phenyl-piperazinyl, 1,3,8-triaza-spiro{4.5}decyl, and 30 1,4-dioxa-8-aza-spiro{4.5}decyl, 17. A compound of claim 1, wherein Q is a monovalent radical of an amine selected from aziridine, 1,4,7-trioxa-10-aza-cyclododecane, thiazolidine, 82 WO 2004/037801 PCT/US2003/033343 1 -phenyI -1,3,8-friaza-spiro{4.5}decan-4-ono, piperidine-3-carboxylic acid diethylamde, 1,2,3,4,5,6-hexahydro-{2,3}hipyridinyl, 4-(3- trifluoromethyl-phenyl)-piperazine, 2-piperazin-1 -yl-pyrimidine, piperidine-4-carboxylic acid amide, methyl-(2-pyridin-2-yl-ethyl)-amine, 5 {2-(3,4-dimethoxy-phenyl)-ethyl}-methyl-amine, thromorphoIinyl, allyl- cyclopentyt-amine, [2-(1H-indol-3-yl-athyl)-methyl-amine, 1 -piperidin-4- yl-1,3-dihydro-benzoimidazol-2-one, 2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pynidin-2-yl-amine, phenylamine, pyridin-2-ylamine, 10 18. A compound of claim 1, wherein Q is selected from diazepanyl azepanyl, morpholinyl, piperidinyl, and pyrrolidinyl, optionally substituted with between 1 and 3 substituents selected from hydroxy, halo, cartioxamide, C1-6 alkyI, 5-9 membered or 6-9 membered heterocyclyl,- N(C1-6 alkyI)(5-9 membered or 6-9 membered heterocydyl), -NH(5-9 15 membered or 6-9 membered heterocyclyl),-O(5-9 or 6-9 membered heterocyclyl), (5-9 membered or 6-9 membered heterocyclyl)C1-3 alkylene, C1-5 alkoly, (C3-5 cyctoalkyl)-O-, phenyl, (phenyl)C1-3 alkylene, and (phenyl)G1-3 alkylene-O-, where each of above heteracyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 20 substituents independently selected from trifluoramethyl, methoxy, haIo, nitro, cyano, hydroxy, and C1-3 alkyL. 19. A compound of claim 12, wherein Q is substituted with a substituent comprising a 5-9 membered heterocyclyl group selected from pyridyl, 25 pyrimidyl, furyl, thiofuryl, Imidazolyi, (imidazolyl)C1-5 alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl, (tetrazolyl)C1-6 alkylene, tetrazolyl, (triazolyl)C1-5 alkylene, triazolyl, (pyrrolyl)C1-6 alkylens, pymolidinyl, and pyrrolyl, 30 20. A compound of claim 19, wherein Q is piperidinyl. 21. A compound of claim 1, wherein R8 is hydrogen. 83 WO 2004/037801 PCT/US2003/033343 {4-(1-Methyl-heptyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyhphenyl)- methanone; {4-(Benzylamino-metinyl)-phenyl}-(4-isopropyl)-piperazin-1-yl)-methanone dihydrochloride; 5 {4-(Benzylamino-methyl)-phenyl}-[4-{1-ethyl-propyl)-piperazin-1-yl}- methanone; and {4-{(5-Chloro-pyridin-2-ylamino)-methyl)-phenyl}-{4-Isopropyl-piperazin- 1-yl)-methanone dihydrochloride. 10 38. A compound of claim 1 selected from the group consisting of; (4-([Ethyl-(2-methoxy-ethyl)-amino]-methyl)-phenyl)-(4-isopropyl- piperazin-1-yl)-methanone; (4-Azepan-1-ylmethyl-Phenyl}-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride; 15 (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone; (4-Azepan-ylmethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl]- methanone; (4-B utyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl}-methanone; (4-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone; 20 (4-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)- phenyl]-methanone; (4 -Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methannone; (4-Diethylaminomethyl-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride; 25 (4-Dimethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride; (4-Dimethylaminomethyl-phenyl)-(4-{1-ethyl-propyl)-piperazin-1-yl}- methanone dihydrochloride; (4 - isopropyl-piperazin-1-yl)-(3-piperidin-1-ylmethyl-phenyl)-methanone, 30 (4-lsoprapyl-piperazin-1-yl)-(4-{[(2-methoxy-ethyl)-propyl-amino]-methyl]- phenyl)-methanone; (4-Isopropyl-piperazin-1-yI}-(4-morphoIin-4-ylmethyl-phenyl)-methanone; 88 WO 2004/037801 PCT/US2003/033343 (4-Isopropyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone dihydrochloride; (4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone; (4-lsopropyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyI)-methanone 5 dihydrochloride; (4-Isopropyl-piperazin-1-yl)-(4-thomorpholin-4-ylmethyl-phenyl)- methanone; (4-Isopropyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)- phenyl)-methanone dihydrochloride; 10 (4-lsopropyl-piperazin-1-yl)-{4-(4-isopropy-1-piperazin-1-ylmethyl)- phenyl)-methanone; (4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-ethylamino}-methyl]-phenyl}- methanone; (4-Isopropyl-piperzin-1-yl)-[4-{pyridin-2-ylaminomethyl)-phenyl]- 15 methanone; {4-lsopropy-piperazin-1-yl)-{4-[(2-methoxy-1-methyl-ethylamino)- methyl]-phenyl}-methanone; (4-Isopropyl-piperazin-1 -yl)-{4-{5-trifluoromethyl-pyridin-2-ylamino)- methyl-phenyl)-methanone dihydrochloride; 20 (4-lsoprapy-piperazin-1-yl)-((6-trifluoromethyl-pyridin-3-ylamino)- methyl-phenyl)-methanone dihydrochloride; (4-Methyl-piperazin-1-yl)-(4-morpholin-4-yImethyl-phenyl)-methanone dihydrachloride; (4-Methyl-piperazin-1-yl)-(4-piperdin-1-ylmethyl-phenyl-methanone 25 dihydrochloride; (4-sec-Butyl-piperazin-1-yI)-(4-dimethylaminomethyl-phenyl)- methanone; (4-sec-Butyl-piperazin-1-yl)-(4-morphalin-4-yImethyl-phenyl)-methanone dihydrochloride; 30 (4-sec-Butyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone; (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethy-phenyl)-methanone; (4-sec-Butyl-piperazin-1-yI)-(4-pyrrolidin -1 -ylmethyl-phenyl)-methanone; 89 WO 2004/037801 PCT/US2003/033343 {4-sec-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)- phenyl)-methanone dihydrochloride; (4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyI-phenyl)- mathanone dihydrochloride; 5 {4-(1-Ethyl-propyl)-piperazin-1-yl)-(4-piperidin-1 -ylmethyl-phenyl)- methanone; {4-(1-Ethyl-propyI)-pipenazin-1-yl)-(4-pyrrolidin-1-yImethyl-phenyl)- methanone; [4-{1-EthyI-propyl)-piperazin-1-yl}-{4-(3-trifluoramethyl-piperidin-1- 10 ylmethyl)-phenyl}-methanone dihydrochloride; {4- (1-EthyI-propyl)-piperazin-1-yl}-{4-(decahydro-isoquinolin-2-ylmethyI)- phenyl)-methanone; (4-(Benzylamino-methyl)-phenyl}-(4-Isopropyl-piperazin-1-yl)-methanone dihydrochloride; 15 {4-(Benzylamino-methyl)-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}- methanone; and {4-{(5-Chloro-pyridin-2-ylamino)-methyl)-phenyl}-(4-Isopropy\|-piperazin- 1-yl)-methanone dihydrochloride. 20 39. A compound of claim 1 selected from the group consisting of: (4-{[Ethyl-(2-methoxy-ethyl)-amino]-methyl}-phenyl)-{4-isopropyl- piperazin-1-yl)-methanone; (4-Azepan-1-ylmethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-metharnone dihydrochloride; 25 (4-Azepan-1-ylmethyl-phenyl)-(4-seo-butyI-piperazin-1-yl)-methanone; (4-Azepan-1 -ylmethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}- methanone; (4-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone; (4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone; 30 (4-Diethylaminomethyl-Phenyl)-(4-Isopropyl-piperazin-1-yl)-methanone dihydrochloride; (4-Dimethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride; 90 WO 2004/037801 PCT/US2003/033343 (4-Dimethylaminomethyl}-phenyl)-{4-{1-ethyl-propyl)-piperazin-1-yl}- methanenone dihydrochloride; (4-Isopropyl-piperazin-1-yl)-(4-[[(2-methoxy-ethyl)- propyl-amino]-methyl}- phenyl)-methanone; 5 (4-Isopropyl-piperazin-1-yl)-{4-morpholin-4-ylmethyl-phenyl)-methanone; {4-lsopropyl-piperazin-1-yl)-{4-piperidin-1-ylmethyl-phenyl}-methanone; (4-Isopropyl-piperazin-1-yl)-(4-pymolidin-1-ylmethyl-phenyl)-methanone dihydrochloride; {4-Isopropyl-piparazin-1-yl)-(4-thiornorpholin-4-ylmethyl-phenyl) 10 methanone; (4-lsopropyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)- phenyl}-methanone dihydrochloride; (4-Isopropyl-piperzin-1-yl)-(4-[(2-methoxy-ethylamino)-methyl]-phenyl)- methanone; 15 (4-lsopropy)-piperazin-1-yl}-[4-(pyridin-2-ylaminomethyl)-phenyl]- methanone; (4-lsopropyl-piperazin-1-yl)-(4-[(2-methoxy-1-methyl-ethylamino)- methyl]-phenyl}-methanone; (4-sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl}- 20 methanone; (4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone dihydrochloride; (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone; (4-sec-Butyl-piperazin-1-yl)-(4-pyrrolldin-1-ylmethyl-phenyl)-methanone; 25 {4-{1-Ethyl-propyl)-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)- methanone dihydnochlorids; {4-(1-Ethyl-propyl)-piperzin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)- methanone; {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)- 30 methanone; {4-(1-Ethyl-propyl)-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1- ylmethyl)-phenyl}-methanonedihydrochloride; 91 WO 2004/037801 PCT/US2003/033343 {4-{1-Ethyl-propyl)-piperazin-1-yl}-{4-(decahydro-isoquinolin-2-ylmethyl)- phenyl}-methanone; {4-(Benzylamino-methyl)-phenyl)-(4-isopropyl-piperazin-1-yl)-methanane dihydrochloride; and 5 {4-(Benzylamino-methyl)-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl)- methanone, 40. A compound of claim 1 selected from the group consisting of: (4-Azepan-1-ylmethyl-phenyl0-(4-isopropyl-piperazin-1-yl)-methanone 10 dihydrochloride; (4-Azepan -1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone; {4-Cyclahexyl-piperazin-1-yl)-(4 -piperidin-1-ylmethyl-phenyl)-methanone; (4-lsopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl}-methanone; (4-lsopropyl-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-rnethanone 15 dihydrochloride; (4-lsoprapyl-piperazin-1-yl)-[4-(3-trifluoromethyl-piperidin-1-ylmethyl)- phenyl)-methanone dihydrochloride; (4-sec-Butyl-piperazin-1-yl)-(4-aimethylaminomethyl-phenyl)- methanone: 20 (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone; (4-sec-Butyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone; {4- (1-Ethyl-propyl)-piperazin-1-yl)-(4-morphoIin-4-ylmethyl-phonyl)- methanone dihydrochloride; {4-(1-Ethyl-propyl)-piperazin -1-yl}-(4-piperidin-1-ylmethyl-phenyl)- 25 methanone; and {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)- methanone. 41. A compound of claim 1 selected from the group consisting of: 30 (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl}-methanone; (4-Isopropyl-piperazin-1-yI)-(4-piperidin-1-ylmethyl-phenyI)-methanone; (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl}-methanone; 92 WO 2004/037801 PCT/US2003/033343 {4-{1-Ethyl-propyl)-piperazin-1-yI)-(4-piperidin-1-ylmethyl-phenyl)- methanone; {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)- methanone; 5 (4- Isopropyl-piperazin-1-yl)-{4-morpholin-4-yImethyl-phenyl)-methanone; (4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-yImethyl-phenyl)-methanone dihydrochloride; and {4-(1-Ethyl-prapyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl}- methanone dihydrochloride. 10 42. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically-acceptable exciplent. 43. A compound of claim 1 isotopically-tabelled to be detectable by PET or 15 SPECT. 44. A method of Inhibiting histamine H3 receptor activity in a subject, comprising administering an effective amount of a compound of claim 1 to a subject in need of such inhibition of histamine H3 receptor activity. 20 45. A method of treating a subject having a disease or condition modulated by histamine H3 receptor activity, comprising administering to the subject a therapeuticslly effective amount of a compound of claim 1. 25 46. A method of claim 45, wherein said disease or condition is selected from the group consisting of sleep/wake disorders, arousa/vigilance disorders, migraine, asthma, dementia, cognitive dysfunction, neurogenic inflammation, mild cognitive impalrment (pre-dementia), Alzheimer's disease, epilepsy, narcolepsy, eating disorders, obesity, 30 motion sickness, vertigo, attention deficit hyperactiylly disorders, learning disondens, memory retention disorders, schizophrenia. substance abuse, bipolar disorders, manic disorders and depression, 93 WO 2004/037801 PCT/US2003/033343 nasal congestion, itch, allergic rhinitis, and upper airway aliergic response. 47. A method for treating a disease or condition modulated by at least ona 5 receptor selected from the histamine H1 receptor and the histamine H3 receptor, said method comprising (a) administering to a subject a jointly effective amount of a histamtae H1 receptor antagonist compound, and (b) administering to the subject a jointly effective amount of a compound of claim 1, said method providing a jointly tharapeutically effective 10 amount of said compounds. 48. The method of claim 47 wherein the histamine H1 receptor antagonist and the compound of claim 1 are present in the same dosage form. 15 49. A method for treating diseases or conditions modulated by at least one receptor selected from the histamine H2 receptor and the histamine H3 receptor in a subject, comprising (a) administering to the subjects jointly effective amount of a histamine H2 receptor antagonist compound, and (b) administering to the subject a jointly effective amount of a compound 20 of claim 1, said method proylding a jointly therapeutrcally effective amount of sard compounds. 50. The method of claim 39 wherein the histomine H2 receptor antagonist and the compound of claim 1 are present in the same dosage form, 25 51. A method for treating one or more disorders or conditions selected from he group consisting of sleep/wake disorders, narcolepsy, and ousal/vigilance disorders, comprising administering to a subject a erapeutically effective amount of a compound of claim 1, 30 52. A method for treating attention deficit hyperactivity disorders (ADHD), comprising administering to a subject a therapeutically effective amount of a campound of claim 1. 94 WO 2004/037801 PCT/US2003/033343 53. A method far treating one or more disorders or conditions selected from the group consisting of dementia. mild cognitive impalrment (pre- dementia), cognitive dysfunction, schizophrenia, depression, manic 5 disorders, bipolar disorders, and Iearning and memory disorders, comprising administering to a subject a therapeutically effective amount of a compound of claim 1. 54. A method for treating or preventing upper airway allergic response, itch, 10 nasal congestion, or allergic rhinitis, comprising administering to a subject a therapeutically effective amount of a compound of claim 1. 55. A method for studying disorders mediated by the histamine H3 receptor, comprising using an 18F-labeled or 11C-Isbelled compound of claim 1 as 15 a pasition emission tomography (PET) motecuter probe. 95 Substituted piperazinyl and diazapanyl benzamides and benzohipemides of fomula (I). compositions containing them, and methods or making and using them to treal histimine-mediated conditions.

Full Text

More recently, several publications have described histamine H3 ligands
that do not contain an imidazole moiety, for example: Ganellin. C-R. et al.;
5 Walczynski, K. et al., Arch. Pharm. Pharm. Med. Chem. (Weinheim, Ger.)
1999, 332:389-398, Walczynski, K. et at., farmeco 1999, 54:584-694; Linney,
I.D. et al., J. Med Chem. 2000, 43:2362-2370; Tozer, M.J, and Kafindjian,
S.B., Exp, Opin. Ther. Pafents 2000, 10:1045-1055; U.S. Patent 5,352,707;
PCT Application WO 98/42458, Aug. 26, 1999; PCT Applfcatron WO
10 02/076925; and European Patent Application 0978512, Feb. 9, 2000.
The compounds of the present invention do not contain the imidazole
moiety, and its inherent liabilities, and yet maintain potency at the human H3
receptor as determined by receptor binding to the human histamine H3 receptor
(see Lovenberg, T.W. et al., Mol. Pharmacol 1999, 55:1101-1107). Screening
15 using the human receptor is particularly important for the identification of new
therapies for the treatment of human disease. Conventional binding assays
are determined using rat synaptosomas (Garbarg, M. et al., J. Pharmacol. Exp.
Ther. 1992, 263 (1):304-310), rat cortical membranes (West, R.E. et al., Mol.
Pharmacol. 1990, 33:610-613), and guinea pig brain (Korte, A. et al., Biochem.
20 Biophys, Res. Commun, 1990, I68(3):979-986). Only limited studies have
been performed previously using human tissue but these allude to significant
differences in the pharmacology of rodent and primate receptors (West, R.E. et
al., Eur. J. Pharmacol 1999,377:233-239).
We now descride a series of piperazinyl and diazepanyl benzamides and
25 benzthioamides with the ability to modulate the activity of the histamine
receptor, specifically the H3 receptor, without the inherent problems associated
with the presence of an imidazolyl moiety.
SUMMARY OF THE INVENTION
30 The present invention is directed to pharmaceutically active piperazinyl
and diazepanyl benzamides and benzthioamides, methods of making them,
and methods of using them. The invention features compounds of formula (I):
4

WO 2004/037801 PCT/US2003/033343

wherein
R1 is C1-10 alkyl, C3-8 atkenyl, C3-8 cycloalkyl, (C3-8 cycloaSkyl)C3-8 alkyl, (C3-8
5 cycloalkyl)C3-8 alkenyl, or (C1-8 afkylcarbonyl)C1-8 alkyl;
n is 1 or 2;
X is O or S;
one of R2, R3 and R4 is G and the other two independency are hydrogen,
fluoro, chloro, bromo, nitro, trifluoromethyl, methyl, or C1-3 alkoxy;
10 G is LQ;
L is unbranehed -(CH2)m- wherein in is an integer from 1 to 7 (preferably m is
1 to 4, more preferably m is 1);
Q is NR8R9 wherein R8 is Independently selected from hydrogen, C1-6 alkyl, C3-8
alkenyl, 3-9 membered carbocyclyl, 3-12 membered heterocyclyl
15 (preferably 5-9 or 5-8-membered heterocyctyl). phenyl, (6-9-mernbered
heterocyclyl)C1-5 alKylene, and (phenyl)C1-6 alkylene; and R9 is
Independently selected from C1-8 alkyl, C3-6 alkenyl, 6-9 membered
carbocyclyl, 3-12 membered heterocyclyl (preferably 5-9 or 5-8-
membered heterocyclyl), phenyl, (6-9-rnembered heterocyclyl)C1-5
20 alkylene, and (phenyl)C1-5 alkylene; or
Q is a saturated 3-12 rnembered N-linked heterocyclyl, wherein, in addition to
the N-Iinking nitrogen, the 3-12 membered heterocyclyl may optionally
contain between 1 and 3 additional hetenoafoms independently selected
from O, S.and NH;
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WO 2004/037801 PCT/US2003/033343
wherein Q is optionally substituted with 1-3 substituents independently selected
from the group consisting of hydroxy, halo, carboxamide, C1-6 alkyl, 5-9
membered or 6-9 membered heterocyclyl, -N(C1-6 alkyl)(5-9 membered
or 6-9 membered heteracyclyl), -NH(5-9 membered or 6-9 membered
5 heterocydyl), -O(5-9 or 6-9 membered heterocydyl), (5-9 membered or
6-9 membered heterocyclyl)C1-3 alkylene, C1-6 alkoxy. (C3-6 cycloalkyl)-
O-. phenyl, (phenyl)C1-3 alkylene, and (phenyl)C1-3 alkylene-O-, where
each of above heterocyclyl, phenyl, and alkyl groups rnay be optionally
substituted with fnom 1 to 3 substituents Independently selected from
10 trifluoromethyl, methoxy, halo, nitro, cyano, hydroxy, and C1-3 alkyI;
provided however that when R1 is methyl, G is not piperidin-1-ylmethyl; and
wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl,
carbocyclyl, and aryl groups may each be independently and optionally
substituted with between 1 and 3 substrtuents independently selected
15 from trifluonomethyl, methoxy, halo, amino, nitro, hydroxy, and C1-3 alkyl;
or a pharmaceutically acceptable salt, esterT tautomer, solvate or amide
thereof.
The invention also features a pharmaceutical composition comprising a
compound of the invention and a pharmaceutically acceptable carrier; and
20 methods of preparing or formulating such compositions. A composition of the
invention may further include more than one compound of the invention, or a
combination therapy (combination formulation or combination of differently
formulated active agents).
The invention also provides methods of treating certain conditions and
25 diseases, each of which methods includes administering a therapeutically
effective (or jointly effective) amount of a compound or composition of the
invention to a subject in need of such treatment. The disclosed compounds
are useful in methods for treating or preventing neurologic disorders including
sleep/wake and arousal/vigitance disorders (e.g. insomnia and jet lag),
30 attention deficit hyperactivity disorders (ADHD), learning and memory
disorders, cognitive dysfunction, migraine, neurogenic inflammation, dementia.
mild cognitive impairment (pro-dementia), Alzheimer's disease, epilepsy,
narcolepsy, eating disorders, obesity, motion sickness, vertigo, schizophrenia,
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WO 2004/037801 PCT/US2003/033343
substance abuse, bipolar disorders, manic disorders and depression, as well
as other histamine H3 receptor mediated disorders such as upper airway
allergic response, asthma, itch, nasal congestion and allergic chinitis in a
subject in need thereof. For example, the invention features methods for
5 preventing, inhibiting the progression of, or treating upper airway allergic
response, asthma, itch, nasal congestion and allergic rhinitis.
In yet another embodiment, the disclosed compounds may be used in a
combination therapy method including administering a Jointly effective dose of
an Ha antagonist and administering a Jointly effective dose of a histarnine H1
10 antagonist, such as loratidine (C LARI Tl N™), desloratidine (C LARINEXTM),
fexofenadine (ALLEGRA™) and cetirizine (ZYRTEC™), for the treatment of
allergic rhintis, nasal consestion, and altergie congestion.
In yet another embodiment, the disclosed compounds may be used in a
combination therapy method, including administering a jointly effective dose of
15 an H3 antagonist and administering a jointly effective dose of a
neurotransmitter re-uptake blocker, such as a selective serotonin re-uptake
inhibitor (SSRI) or a non-selective serotonin, dopamine or norepinephrine re-
uptake inhibitor, including fluoxetine (PROZAC™), sertraline (ZOLOFT™),
paroxeline (PAXIL™) and amitryptyline, for the treatment of depression, mood
20 disorders or schizophrenia.
Additional features and advantages of the invention will become
apparent from the detailed description and examples betow, and the appended
claims.
25 DETAILED DESCRIPTION OF THE INVENTION
The present invention provides phenylpiperidine compounds useful for the
treatment of disorders and conditions modulated by a histamine receptor,
A, Terms
30 Certain terms are defined below and by their usage throughout this
disclosure.
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examples include cydopropyl. cydobutyl, cyclopentyl, cyclohexyl, cyclohepfyl
and cyclooctyl.
As used herein, unless otherwise noted. "cycloalkenyl" shall denote a
three- to eight-membered, partially unsaturated, monocyclic, carbocyclic ring
5 structure, wherein the ring structure contains at least one double bond. Suitable
examples include cyclohexenyl, cyclopentenyl, cycloheptenyl, cydooctenyl,
cyclohex-1.3-dienyl and the like.
As used herein, unless otherwise noted, "aryl" shall refer to carbocyclic
aromatic groups such as phenyl, naphthyl, and the like. Divalent radicals include
10 phenylene (-C6H4-) which is preferably phen-1,4-dlyl, but may also be phen-1.3-
diyl.
As used herein, unless otherwise noted, "aralkyl" shall mean any alkyl
group substituted with an aryl group such as phenyl, naphthyl, and the like.
Examples of aralkyls include benzyl, phenethyl, and phenylprapyl
15 As used herein, unless otherwise noted, "carbocyclyl shall mean any
cyclic group consisting of 3-12 carbon atoms, and preferably 6-9 carbon atoms,
in the skeleton ring or rings, if the carbacycle is a fused or spiro bicyclic or
tricyclic group. A carbocycle may be saturated, unsaturated, partially
unsaturated, or aromatic. Examples include cycioalkyl, cycloalkenyl,
20 cycloalkynyl: specific examples include phenyl, benzyl. indanyl, and biphenyl. A
carbocycle may have substituents that are not carbon or hydrogen, such as
hydroxy, halo, halomethyl, and so on as provided elsewhere herein.
As used herein, unless otherwise noted, the terms 'heterecycle",
"heteracyclyl" and "heterocyclo" shall denote any three-, four-r five-, six-, seven-,
25 or eight-membered monocyclic, nine- or ten-membered bicyclic, or thirteen- or
fourteen-membered lricyclic ring structure containing at least one heteroatom
moiely selected from the group consisting of NH, O, SO, SO2, (C=O), and S, and
preferably NH, O, or S, optionally containing one to four additional heteroatoms
in each ring. In some embodiments, the heterocyclyl contains between 1 and 3
30 or between 1 and 2 additional heteroatoms. Unless otherwise specified, a
heteracyclyl may be saturated, partially unsaturated, aromatic or partially
aromatic. The heterocyclyl group may be attached at any hetenoatom or carbon
atom that results in the creation of a stable structure.
9

WO 2004/037803 PCT/US2003/033343
As used herein, "Ca-b," (where a and b are integers) refers to a radical
containing from a to 6 carbon atoms inclusive. For example, C1-3 denotes a
radical containing 1, 2 or 3 carbon atoms.
As used herein, "halo" or "halogen" shall mean monovalent radicals of
5 chlorine, bramine, fluorine and iodine.
As used herein, the term "alkyi", whether used alone or as part of a
substituent group, shall include straight and branched saturated carbon chains.
For example, alkyl radicate include methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, t-butyl, pentyl and the like. Unless otherwise noted, "lower"
10 when used with alkyl means a carbon chain composition of 1-4 carbon atoms.
"Alkylene" refers to a bivalent hydrocarbyl group, such as methylene (-CH2-),
elhylene (-CH3-CH2") or propylene (-CH2CH2CH2-), and so on.
As used herein, unless otherwise noted, "alkenyl" shall mean an
alkylene group with at least two hydrogen atoms replaced with a pi bond to
15 form a carbon-carbon double bond, such as properlyl, butenyl, pentenyl, and
so on. Where the alkenyl group is R8 or R9, the open radical (point of
attachment to the rest of the molecule) is on sp3 carbon, as illustrated by allyl,
and the double bond or bonds is therefore at feast alpha (if not befa, gamma,
etc) to the open radical.
20 As used herein, "alkylidene" refers to a saturated or unsaturated,
branched, straight-Chain or cyclic divalent hydrocarbon radical derived by
removal of two hydrogen atoms from the same carbon atom of a parent alkane,
alkene or alkyne. The divalent radical center forms a double bond with a single
atom on the rest of the motecule. Typical alkylidene radicals include, but are
25 not limited to, ethanylidene; propylidenes such as propan-1-ylidene, proparn-2-
ylidene, cyclopropan-1-yliden; butylidenes such as butan-1-ylidene, butan-2-
ylidene, 2-methyl-propan-1 -ylidene, cyclobutan-1-ylidene; and ths like.
As used herein, unless otherwise noted, "alkoxy" shall denote an oxygen
ether radical of the above-described straight or branched chain alkyl groups. For
30 example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the
like.
As used herein, unless otherwise noted, "cycloalkyl" shall denote a three-
to eight-membered, saturated monocyclic cartracyclic ring structure. Suitable
8

WO 2004/037801 PCT/US2003/03334
Exemplary monocyclic heterocyclic groups can Include pymolidlnyl,
pyrrolyl, indoiyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazoly!, Smidazolinyl
imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolmyl, isoxazolyl, thiazaolyl,
thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetraftydrofuryl,
5 thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopymotidinyl, 2-oxazepinyl, azepinyl, hexahydroazepinyl, 4-piperidinyl,
pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl,
tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl,
thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dixolane
10 and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl. thietanyl, thiiranyl.
triazinyl, triazolyl, tetrazolyl, azefidinyl and the like.
For example, where O is a saturated 3-12 membered N-linked
heterocyclyl, Q necessarily contains at least one nitrogen, and the carbon
atoms are sp3 hybridzed. Where Q is a fused bicyclic heterocyclyl, the carbon
15 atoms of the ring linked to U is sp3 hybridized, provided the adjacent ring (and
the common carbon atoms) may be sp2, such as an indanyl where one of the
carbon atoms has been replaced with nitrogen.
In general, exemplary bicyclic heterocyclyls include benzthiazolyl.
benzoxazolyl, benzaxazinyl, benzothienyl, quinuclidinyl, quinolinyl. quinolinyl-N-
20 oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzirmidazolyl, benzopyranyl,
indolizinyl, benzofuryl, chronnonyl, coumarinyl, cinnolinyl, quinoxalinyl,
indazolyl, pynrolopridyl, furopyridinyl (such as furo{2r3-c}pyridinyl, furo{3,1-
b}pyridinyl), or furo{2,3-b}pyridinyl}, dihydroisoindolyl, dihydroquinasolinyl (such
as 3.4-dihydro-4-oxo-quinszolinyl), tetrahydroquinolinyl (such as 1,2,3,4-
25 tetrahydroqurnolinyl), tetrahydroisoquinolinyl(such as 1,2,3,4-
tetrahydraisoquiunolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl,
benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl,
dihydrobenzofuryl,dihydrobenzothienyl,dihydrobenzothiopyranyl,
dihydrobenzothlopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isoindolyl,
30 tetrahydroincloazolyl (such as 4,5,6,7-tetrahydroindazolyl), isochromanyl,
isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl,
10

WO 2004/037801 PCT/US2003/033343
quinazotinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl.

Exemplary tricyclic heterocylclic groups include acridinyl, phenaxazinyl,
phenazinyl, phenothiazinyl, carbozolyl, perminidinyl, phenanthrolinyl, carbolinyl,
5 naphthothlenyI, thianthrenyl, and the like.
Preferred heterocyclyl groups Include morpholinyl, thlomorpholinyl.
piperidinyl, piperazinyl, pyrrolidinyl, pyrimidinyl, pyridyl, pyrrolyl, imidazolyl,
oxazolyl, isoxazolyl, acridinyl, azepinyl, hexahydroazepinyl, azatidinyl, indolyl,
isoindolyl, thiazolyl, thiadiazolyl, quinollnyl, isoquinolinyl, 1,2,3,4-
10 tetrahydroquinolinyl, 1,3,4-trihydrolsoquinoIinyl, 4,5,6,7-tetrahydroindadolyl,
benzoxazinyl, benzoaxzolyl, benzthiazolyl, benzimidazoly], tetrazolyl, oxadiazolyl,

As used herein, unless otherwise noted, the term "heterocyclyl-alkyl" or
"heterocyclyl-alkylene" shall denote any alkyl group substituted with a
15 heterocyclyl group, wherein the heterocycyl-alkyl group is bound through the
alkyI portion to the central part of the motecule. Suitable examples of
heterocyclyl-alkyl groups include, but are not limited to piperidinyl methyl,
pyrrolidinylmelhyl, piperidinylethyl, piperazinylmethyl, pyrrolyibutyl,
piperidinylisobutyl pyridylmethyl, pyrimidylethyl, and the like.
20 When a particular group is "substituted" (e.g., aIkyl. alkylene, cycloaIkyl.
aryi, heterocyclyl, heteroaryl), that group may have one or more substituents,
preferably from one to five substituents, more preferably from one to three
substituents, most preferably from one to two substituents, independently
selected from the list of substituents.
25 It is intended that the definition of any substituent or variable at a
particular location in a molecule be independent of its definitions elsewhere in
that molecule. It is understood that substituents and substitution patterns on
the compounds of this invention can be selected by one of ordinary skill in the
11

WO 2004/037801 PCT/US2003/03343
art to provide compounds that are chemically stable and that can be readily
synthesized by techniques known in the art as well as those methods set forth
herein.
Under standard nomenclature used throughout this disclosure, the
5 terminaI portion of the designated side chain is described first, followed by the
adjacant functionality toward the point of attachment. Thus, for example, a
"phenyl(alkyl)amido(alkyl)" substituent refers to a group of the formula

10 The term 'sufcsject" as used herein, refers to an animal, preferably a
mammal, most preferably a human, who has been the object of treatment
observation or experiment.
The term "therapeutically effective amount" as used herein, means that
amount of active compound or pharmaceutical agent that elicits the biological or
15 medicinal response in a tissue system, animal or human that is being sought by
a researcher, voterinarian, medical doctor or other clinician, which includes
prevention, inhibition of onset, or alteviation of the symptoms of the disease or
disorder being treated.
As used herein, the term "composilion" is intended to encompass a
20 product comprising the specified ingredients in the specified amounts, as well
as any product which results, directly or indirectly, from combinations of the
specified Ingredients in the specified amounts.
Abbreviations used in the specification, particularly in the Schemes and
Examples, are as follows:
25

12

WO 2004/037801 PCT/US2003/033343

B. Compounds
Ths invention features compounds of formula (1):

5
wherein
R1 is C1-10 alkyl, C3-8 alkenyl, C3-8 cydoalkyl, (C3-8 cycloalkyl)C1-6 alkyl, (C3-8
cycloalkyl)C3-8 alkenyl, or (C1-8 alkytcarbonyl)C1-8 alkyl,
n is 1 or 2;
10 X is O or S;
one of R2, R3 and R4 is G and the other two independently are hydrogen,
fluoro, chioro, bromo, nitro, trifluoromethyl, methyl, or C1-3 alkoxy;
G is LQ;
13

WO 2004/037801 PCT/US2003/033343
L is unbranched -(CH2)m- wherein m is an integer from 1 to 7;
Q is NR8R9 wherein R6 is independently selected from hydrogen, C1-5 alkyI, C3-6
alkenyl, 3-9 membered carbocyclyl, 3-12 membered heterocyclyl
(preferably 5-9 or 5-3-membered heterocyelyl), phenyl, (B-9-membered
5 heteracyclyl)C1-8 alkylene, and (phenyl )C1-6 alkylene; and R9 is
independently selected from C1-5 alkyI, C3-8 alkenyl, 6-9 membered
carbocyclyl, 3-12 membered heterocyclyl (preferably 5-9 or 5-8-
membered heterocyclyl), phenyl, (6 9-membered heterocyclyl)C1-6
alkylene, and (phenyl)C1-5 alkylene; or
10 Q is a saturated 3-12 membered N-linked hetenocyclyl, wherein, in addition to
the N-linking nitrogen, the 3-12 membered heterocyclyl may optionally
contain between 1 and 3 additional heteroatoms independently selected
from O,S, and NH;
wherein Q is optionally substituted with 1-3 substituents independently selected
15 from the group consisting of hydroxy, halo, carboxamide, C1-6 alkyl, 5-9
membered or 6-9 membered heterocyclyl, -N(C1-6alkyl)(5-9 membered
or 6-9 membered heterocyclyl), -NH(5-9 membered or 6-9 membered
heterocyclyl), -O(5-9 or 6-9 membered heterocyclyl), (5-9 membered or
6-9 membered heterocyclyt)C1-3 alkylene, C1-6 alkoxy, (C3-6cycloalkyl)-
20 O-, phenyl, (phenyl)C1-3 alkylene, and (phenyl)C1-3 alkylene-O-, where
each of above heteracyclyl, phenyl, and alkyl groups may be optionally
substituted with from 1 to 3 substituents independently selected from
trifluoromethyl, methoxy, halo, nitro, cyano, hydroxy, and C1-3 alkyl;
provided however that when R1 is methyl, G is not piperidin-1-ylmethyl; and
25 wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl,
carbocyclyl, and aryl groups may each be independently and optionally
substituted with between 1 and 3 substituents independently selected
from trifluoromethyl, methoxy, halo, amino, nitro, hydroxyl, and C1-3
alkyl;
30 or a pharmaceutically acceptable salt, ester, tautomer, solvate or amide
thereof.
Preferred compounds of formula (1) include those wherein;
14

WO 2004/037801 PCT/US2003/033343
(a)n is 1:
(b) R1 is C1-10 alkyl (preferably branched);
(c) R1 is branched C3-5 alkyl;
(d) one of R2, R3 and R4 is G; (preferably one of R3 and R4 is G)
5 (e) R4 is G;
(f) L is unbranched -(CH2)m-, wherein m is an integer from 1 to 4;
g) is -CH2-;
h) Q is a saturated N-linked nitrogen-containing heterocyclyl;
(i) Q is substituted or unsubstituted piperidinyl, diazepanyl, azepanyl,
10 decahydroisoquinolin-2-yl, piperazinyl, pyrrolinyl, pymolidinyl, thiomorpholinyl,
or morpholirtyl;
(j) Q is unsubstituted diazepanyl, azepanyl, morpholinyl,
decahydroisoquinolin 2-yl, piperldinyl, or pyrrolidinayl;
(k) substituted Q are selected from N-(C1-6 alkyl)piperazinyl, N-phenyl-
15 piperazinyl, 1,3,8-triaza-spiro{4.5}decyl, and 1,4-dioxa-B-aza-spiro{4.5}decyl;
(I) Q is a monovalent radical of an amine selected from aziridine, 1,4,7-
trioxa-10-aza-cyclododecane, thiazolidine, 1-phenyl-1,3,8-triaza-
spiro{4.5}decan-4-one, piperidins-3-carboxylic acid diethylarnide, 1,2,3,4,5,6-
hexahydro-{2.3}bipyridinyl, 4-(3 -trifluoromelhyl-phenyl)-piperazine, 2-piperazin-
20 1-yl-pyrimidine, piperidine-4-carboxylic acid amide, methyl-(2-pyridin-2-yl-
ethyl )-amine. {2-(3.4-dimethoxy-phenyl)-ethyl methyl-amine. thiomorpholinyl,
allyl-cydopenlyl-amine, {2(1 H-indol-3-yl)-ethyl}-methyl-amine, 1-piperidin-4-yl-
1,3-dihydro-benzoimidazol-2-one, 2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-
yl-pyridin-2-yl-amine, phenylamine, and pyridin-2-ylamine;
25 (m) Q is selected from diazepanyl, azepanyl, morpholinyl, piperidinyl,
and pymolidinyl, optionally substituted with between 1 and 3 substituente
independently selected from hydroxy, halo, carboxamide, C1-6 alkyl, 5-9
membered or 6-9 membered heterocyclyl, -N(C1-6 aIkyl) (5-9 membered or 6-9
membered heterocyclyl), -NH(5-9 membered or 6-9 membered heterocyclyl),
30 -O(5-9 or 6-9 membered heterocyclyl), (5-9 membered or 6-9 membered
heterocyclyl)C1-3 alkylene, C1-6 alkoxy, (C3-6 cycloalkyl)-O-, phenyl. (phenyl)C1-3
alkylene, and (phenyl)C1-3 alkylene-O-, where each of above heterocyclyl,
phenyl, and alkyl groups may be optionally substituted with from 1 to 3
15

WO 2004/03780l PCT/US2003/033343
substituents independently selected from trifluoromethyl, methoxy, halo, nitro,
cyano, hydroxy, and C1-3 alkyl;
(n) Q is substituted with a substituent comprising a 5-9 membered or 6-9
membered heterocyclyl group selected from: pyridyl, pyrimldyl, furyl, thiofuryl,
5 imidazolyl, (imkiazolyl)C1-6 alkylene, oxazolyl, thiazolyl, 2.3 dihydro indolyl,
benzimidazolyl, 2-oxobenzimidazalyl, (ietrazolyI)C1-6 alkylene, tetrazolyl,
(triazolyl)C1-6 alkylene, triazolyl, (pyrrolyl)C1-6 alkylene, pyrrolidinyl, and pyrrolyl;
(o) Q is piperidinyl;
(p) R8 is hydrogen;
10 (q)R9 is C1-6 alkyl;
(r) R9 is unsubstituted or substituted phenyl;
(s) R6 and R9 independently are C1-8 alkyl;
(t) R8 and R9 are methyl;
(u) R8 and R9 are ethyl;
15 (v) R9 is selected from phenyl or 5-8 membered aromatic heterocyclyl,
wherein said phenyl or aromatic hetenocyclyl is optionally substituted with 1-3.
substituents selected from methoxy, hydroxy, halo, nitro, cyano, trifluoromethyl,
and C1-8 alkyI;
(w) R9 is selected from substituted or unsubstituted phenyl, pyridyl,
20 pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C1-6 alkylene, oxazolyl.
thlazolyl, 2,3-dihydro-indolyl, benzimidazlyl, 2-oxobenzimidazolyl,
(tetrazolyl)C1-6 alkylene, tetrazolyl, (triazolyl)C1-6 alkylene,1 triazolyl, (pymolyl)C1-6
alkylene, pyrrolidinyl, and pyrrolyl;
(x) R9 is substituted or unsubstituted pyridyl;
25 (y) X is O; and
(z) combinations of (a)} through (z) above.
Examples of compounds of the invention include:
(4-{( Ethyl-(2-methoxy-ethyl)-amino]-methyl}-phenyl)-(4-isopropyl-piperazin-1-
30 yl)-methanone;
(4-Azepan-1 -ylmethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone
dihydrochlonde:
{4-Azepan-1-yImethyl-pheny)-(4-see-butyl-piperazin-1 -yl)-methanone;
16

WO 2004/03780l PCT/US2003/033343
(4-Azepan-1 -ylmethyI-phenyl)-{4-(1-ethyl- p ropyI)-piperszin-1-yl}-methanone;
(4-Butyl-piperazin-1-yl)- {4-dimethylaminomethyl)-phernyl-methanone;
(4 -Butyl)-piperazin-1 -yl )-(4-morpholin-4-ylmethyl -phenyl)-methanone;
(4-Butyl-piperazin-1 -yl) {4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-
5 methanone;
(4-Butyl-piperazin-1-yl)-{4-{(4-trifluonamethyl-phenylamlno)-methyl}-phenyI) -
methanone;
(4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-yImethyl-phenyl)-methanone:
(4-Diethylamimethyl-phenyl)-(4-isopropyl-piparazin-1-yl)-methanone
10 dihydrachloride;
(4 -Dimethylaminomethyl-phenyl)-(4-isopropy)-piperazi n-1-yl)- methanone
dihydrochforide;
(4-Dimethylaminomethyl -phenyl)-{4-{1-ethyl-propyl )-piperazin-1-yl}-methanone
dinydrocinloride;
15 (4-Isoprapyl-piperazin-1-yl)-(3-morpholin-4-yI methyl-phenyl)-methanone;
(4-IsopropyI-piperazin-1-yl-(3-Piperidin-1-ylmethyl-phenyl-methanone;
(4-isopropyl-piperazin-1 -yl)-(4-{[{2-methoxy-ethyI)-propy-amino)-methyl}-
phenyl)-methgnone;
{4-Isopropyl-pi0perazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;
20 (4-isopropyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone
dihydrochforide;
(4 - Isopropyl-piparazin-1-yl)-(4-piperidin-1-yl methyl- phenyl)-methanone;
(4-Isopropyl-piperazin-1-yl}-(4-pyrralidin-1-ylmethyl-phenyI)- methanone
dihydrochforide;
25 (4-Isopropyl-piperazin-1-yl)- (4-thiomorpholin -4-ylmethyI-phenyl)-methanone;
(4- Isopropyl-piperazin-1-yl )-{4-(3-trifluoromethyl-piperidin-1-yl) methyI)- phenyl}-
methanone dihydrochforide;
(4- Isapcopyl-piperazin-1-yl)-(4-(4-isoprapyl-piperzin-1-ylmethyl phenyl)-
methanone;
30 (4-Isopropyl-piperazin-1-yl)-(4-[(2-methoxy-ethylamino)-methyl]-phenyl)-
methanone;
(4- Isopropyl- piperazin-1 -yl )-[4-( pyridin-2-ylamirometh yl)-phenyl] -methanone;
17

WO 2004/037801 PCT/US2003/0333801
(4-lsopropyl -piperazin-1 -yl)-(4-(2 -methoxy- 1 -methyl-ethylamino)-methyl)-
phenyl}-methanone;
(4-lsopropyl -piperazin-1 -yl)-{4-{(4-trifluoromethyl-phenylamlno)-methyl}-
phenyl}-methanone;
5 (4-lsopropyl -piperazin-1 -yl)-(4-{(4-trifluoromithyl-pyridin-2-ylamino)-methyI}-
phenyl}-methanone dihydrochloride;
(4-lsopropyl -piperazin-1 -yl)-{4-{(5-trifluoromethyl-pyridin-2-ylamino)-methyl}-
phenyl)-methanone dihydroohioride;
(4-lsopropyl -piperazin-1 -yl)-{4-{(6-trifIuoromethyl-pyridin-3-ylsmino)-methyl)-
10 phenyl}-methanone dihydrochlorids;
(4-lsopropyl -piperazin-1 -yl)-(4-morphoiln-4-ylmethyl-phenyl)-methanone
dihydrochloride;
(4-lsopropyl -piperazin-1 -yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone
dihydrochloride;
15 (4-lsopropyl -piperazin-1 -yl)-{4 -dimethylaminomethyl-phenyl)-methanone;
(4-sec-Butyl-piperazin-1-yl)-{4-morpholln-4-ylmethyl-phenyl)-methanone
dihydrochloride;
(4-lsopropyl -piperazin-1 -yl)-(4-phenylaminomethyl-phenyl)-methanone:
(4-lsopropyl -piperazin-1 -yl)-(4-pipendin-1 -ylmethyl-phenyl )-methanone;
20 (4-lsopropyl -piperazin-1 -yl)-(4-pyrrolidin-1 -ylmethyl-pheriyl)-methanone;
(4-lsopropyl -piperazin-1 -yl)-[4-(3-trifluoromethyl-piperidin-1-ylmethyl )-phenyl}-
methanone dihydrocfiloride;
{3-(4-Benzyl-pipendin-1 -yImethyl)-phenyl)-(4-methyl-piperazin-1-yl)- methanone;
(4-(1 -Ethyl-propyl)-piperazin-1 -yl)-(4-morpholin-ylmethyl-phenyl)-methanone
25 dihydnochloride;
(4-lsopropyl -piperazin-1 -yl)-{4-phenylaminamethyl-phenyl)- methanone
dihydrochlonde;
(4-lsopropyl -piperazin-1 -yl)-(4-piperidin-1-ylmethyl-phenyl)- methanone;
(4-lsopropyl -piperazin-1 -yl)-(4-pyrrolidin-1 -ylmethyl-phenyl)-methanone;
30 (4-lsopropyl -piperazin-1 -yl)-(4-(3-trifluoromethyl-piperrodin-1-ylmethyl)-
phenyl}-methanone dihydrochloride;
(4-lsopropyl -piperazin-1 -yl)-{4-(decahydro-isoquInolin-2-ylmethyl)-
phenyl)-methanone;
18

WO 2004/037801 PCT/US2003/0333801
(4-(1-Ethyl-propyl)-piperazin)-{4-{[4-trifluoromethyJ-phenylamino)-methyl}
phenyl}-methanone dihydrochloride;
{4-{1 -Methyl-heptyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-
methanone:
5 (4-(1-Methyl-heptyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone;
(4 -(Benzylamino-methyl)-phenyl}-{4-isopropyl-piperazin-1-yl)- methanone
dihydrochloride;
{4-(Benzylamino-methyl)phenyl}-{4-{1 -ethyl-propyl)-piperazin-1-yl}- methanone;
and
10 {4-{(5-Chloro-pyridin-2-ylamino)-methyl}-phenyl}- (4-isopropyl -piperazin-1 -yl)-
methanone dihydrochloride.
Preferred example compounds include:
(4-{[EthyI-(2-methoxy-ethyl)-annino]-methyl}-p henyl)-(4-isopropyl-piperazin-1-
15 yl)-methanone;
{4-Azepan-1 -ylmethyl-phenyl)-(4-isopropyl-piperazin-1 -yl)-methanone
dihydrochloride:
(4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1 -yl)-methanone;
(4-Azepan -1 -yimethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl} methanone;
20 (4-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;
(4-Butyl-piperazin-1-yl}-(4-morphollin-4-ylmethyl-phenyl)-methanone;
(4-Butyl-piperazin-1-yl)-(4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl)-
methanone;
(4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;
25 (4-Diethylaminomethyl-phenyl)-(4-Isopropyl-piperazin-1-yl)-Methanone
dihydrocholoride;
(4-Dimethyl aminamethyl-phenyl)-(4-isopropyhpiperazin-1-yl)-methanone
dihydrochloride;
(4-Dimethyiaminomethyl-phenyl)-{4-(1-ethyl-propyl)-prperazin-1-yl}-methanone
30 dihydrochloride;
(4-Isopropyl-pipenazin-1-yl)-(3-piperidin-1 -ylmethyl- phenyl)-methanone;
(4-lsopropy-1-piperazin-1-yl)-(4-{[(2-methoxy-ethyl)-propyl-aminol-methyl}-
phenyl)-methanone;
19

WO 2004/037801 PCT/US2003/033343
{4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-yI methyl-phenyl)-methanone;
(4-Isopropyl-pipenazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone
dihydnochloride;
(4-lsopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phanyl)-methanone;
5 (4-lsopnapyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone
dihydrochloride;
(4-Isopropyl-piperazin-1-yl)-(4-thiomorphoIin-4 -ylmethyl-phenyl)-methanone;
(4-Isopnopyl-piperazin-1-yl)-{4-(3-trifluoroinethyl-piperidin-1-ylmethyl}-phenyl}-
methanone dihydrochioride;
10 {4-Isopropyl-piperazin-1-yl)-{4-(4-isopropyl-piperazin-1-ylmethyl)-phenyl}-
methanone;
(4 -Isopropyl-piperazin-1-yl)-(4-[(2-methoxy-ethylamino)-methl]-phenyl}-
methsnone;
(4-Isopropyl-piperazin-1-yl)-(4-(pyridin-2-ylaminomethyI)-phenyl)-methanone;
15 (4-Isopropyl-pipenazin-1-yl)-{4-[(2-metho5xy-1-methyl-ethylamino)-methyl]-
phenyl)-methanone;
(4-lsopropyl-piperazin-1-yI)-{4-{(5-trifIuoromethyl-pyildin-2-ylamino)-methyl}-
phenyl)-methanone dihydrochloride;
(4-Isopropyl-piperazin-1-yl)-{4-{(6-trifluoromethyl-pyridin-3-ylamino)-methyl}-
20 phenyl}-methanone dihydrochloride;
(4-Methyl-piperazin-1-yl)- (4-morpholin-4-ylmethyl- phenyl)-methanone
dihydrochloride;
(4-Methyl-piperazin-1-yl)-(4 -piperidin-1-yImethyl-phenyI}-methanone
dihydrochloride;
25 (4 -sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone-
(4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
dihydrochloride;
(4-sec-Butyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone:
(4-sec-Butyl-piperazin-1-yl)-{4-piperidin-1-ylmethyl-phenyl)-methanone;
30 (4-sec-Butyl-piperazin-1-yl)-(4-pyrrolid in-1-ylmethyl-phennyl)-methanone;
(4-sec-Butyl-piperazin-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-
methanone dihydnochloricle;
20

WO 2004/037801 PCT/US2003/033343
{4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone
dihydrochloride,
{4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-piperidin--ylmethyl- phenyI)-methanone;
{4-(1-ElhyI-propyl)-piperazin-1yl}-(4-pynrolidin-1-ylmethyl-phenyl)-methanone;
5 {4-(1-Ethyl-propyl)-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)
phenyl)-methanoae dihydrachloride;
{4-(1-Ethyl-propyl)-piperazin-1-yl)-(4-{decahydro-Isoquinolin-2-ylmethyl)-
phenyl}-methanone;
{4-(Benzylanrtino-methyl)-phenyl}-(4-isopropyl-piperazin-1-yl)- methanone
10 dihydrachloride;
{4-(Benzytanino-methyl)-phsnyl}-(4-(1-ethyl-propyl)-piperzin-1-yl}-methanone;
and
{4-{(5-Chloro-pyridin-2-ylamino)-methyl}-phenyl}-(4-isopropyl-piperazin-1-yl)-
methanone dihydoachloride.
15
More preferred example compounds include:
(4-{[Ethyl-(2-methoxy-ethyI)-amino]-methyl}-phenyl)-(4-isopropyl-piperazin-1-
yl)-methanone.
(4-Azepan-1-ylmethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone
20 dihydrochloride;
(4-Azepan-1 -ylmethyl-phenyl)-(4-sec-butyl-piperazin-1 -yl)-methanone;
(4- Azepan-1 -ylmethyl-phenyl)-(4-(1-ethyl-propyl)-piperzin-1-yl}- methanone;
(4-Butyl -piperazin-1-yl)-(4-inorpholin-4 -yImethyl-phenyl}-methanone;
(4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;
25 (4- Diethylaminomethyl-phenyl)-(44-isopropyl-piperazin-1-yl)-methanone
dihydrochloride;
(4-Dimethylaminanrtethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone
dihydrochloride;
(4- Dirmethylaminomethyl-phenyl)-{4 -(1 -ethyl-prapyl)-piperazin-1-yl}-methanone
30 dihydrochloride,
(4-Isopropyl-piperazin-1-yl)-(4-{[{2-methoxy-ethyI)-propyl-amino)-methyl}-
phenyl)-methanone;
(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl- phenyl)-methanone;
21

WO 2004/037801 PCT/US2003/033343
{4-Isoprapyl-pipenazin-1-yl)-(4-piperdin-1-ylmethyl-phenyl)- methanone;
(4-lsopropylpiperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone
dihydrochloride;
{4-lsoppyl-piperazin-1-yl)-(4-thiomorpholin-4-ylmethal-phenyl)-methanone
5 (4-Isopropyl-piperazin-1-yl)-(4-(3-trifluoromethyl-piperidin-1-ylmethyl}-phenyl}-
methanone dihydrochloride;
(4-Isopropyl-piperazin-1-yl }-{4-[(2-methoxy-ethylamino)-methyl]-phenyl}-
methanons;
(4-Isopropyl-piperazin-1-yl)-[4-(pyridin-2-ylaminometnyl)-phenyl}-methanonne
10 (4-Isopropyl-piperazin-1-yl)-(4-[(2-methoxy-1-methyl-ethylamino)-methyl]-
phenyl]-metrianone;
(4 -sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;
(4-sec- Butyl-piperazin-1-yI)- (4-morpholin-4-ylmethyl- phenyl)-methanone
dihydrochloride;
15 (4-sec-Butyl-plperazin-1-yl)-{4-piperidin-1-ylmethyl-phenyl)-methanone;
(4-sec-Butyl-piperazin-1-yl }-{4-pymolidin-1-ylmethyl-phenyl)-methanone;
{4- (1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)- methanone
dihydrachloride;
{4-(1-Ethyl-propyl)-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;
20 {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;
{4-(1-Ethyl-propyl)- piperazin-1-yl]-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-
phenyl}-methanone dihydrochloride;
{4-{1- Ethyl-propyl)- piperazin-1-yl}-{4(decahydro-isoquinolin-Z-ylmethyl)-
phenyl)-methanone;
25 {4-{Bentzylamino-methyl)-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone
dihydrochloride: and
{4-(Benzylamino-methyl)-phenyl}-{4-(1-ethyl-propyl)-piperazin-1-yl} methanone.
Even more preferred example compounds include:
30 (4-Azepan-1-ylmethyl-phenyl)-(4-Isopropyl-piperazin-1-yl)-methanone
dihydrochloride;
(4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone;
(4-Cyclohexyl-piperazin-1-yl)-(4-pipendin-1-ylmethyl-phenyl)-methanone:
22

WO 2004/037801 PCT/US2003/033343
(4-lsopropyl-piperrazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;
{4-lsopropyl-piperazin-1-yl)-(4-pyrrolidin-1-yImethyl-phenyl)-methanone
dihydrochloride;
(4-Isopropyl-piperazin-1-yl)-{4-(3-trifluoromethyl -piperidin-1-ylmethyl)-phenyl}-
5 methanonedihydrpchloride;
(4-sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl)-phenyl)-methanone;
(4-seo-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl}-methanone;
(4-sec-ButyIpiperazin-1-yl)-(4-pyttolidin-1-ylmethyl-phenyl)-methanone;
(4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-pheayl)-methanone
10 dihydrochloride;
{4-(1-Etnyl-propyl)-piperazin-yl)-{4-piperidin-1-ylmthyl-phenyl)-methanone;
and
{4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone,
15 Yet even more preferred example compounds include:
(4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone;
(4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;
(4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;
{4«(1-Ethyl-propyl)-piperazin-1-yl}-(4-piperdin-1-ylmethyl-phenyl)-methahone;
20 {4-(1-Elhyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;
(4-lsopropyl-piperazin-1-yl)-{4-morpholin-4-ylmethyl-phenyl)-methanone;
(4-sec-Butyl-piperazin-1-yl)-[4-morpholin-4-ylmethyl-phenyl)-methanone
dihydrochoride; and
{4-(1- Ethyl-propyI)-piperazin-1-yl)-(4-morpholin-4-yImethyl-phenyI)- methanone
25 dihydrochoride;
The invention also provides compounds that are useful as synthetic
intermediates of the compounds of the invention. Such compounds, which
themselves may or may not have pharmaceutical activity, include those
30 provided in the schemes and synthetic examples.
The invention also conternplates compounds isotopically-labelled to be
detectable by positron emission tomography (PET) or single-photon emission
computed tomography (SPECT) useful for studying H3-mediated disorders.
23

WO 2004/037801 PCT/US2003/033343
During any of the processes for preparation of the compounds of the
present invention, it may be necessary and/or desirable to protect sensitive or
reactive groups on any of the molecules concerned. In addition, compounds of
the invention may be modified by using protecting groups; such compounds,
5 precursors, of prodrugs are also within the scope of the invention. This may be
achieved by means of conventional protecting groups, such as those described
in "Protective Groups, in Organic Chemistry", ed, J.F.W. McOmie, Plenum
Press, 1973: and T.W. Greene & P.G.M. Wuts, "Protective Groups in Organic
Synthesis". 3rd ed., John Wlley & Sons, 1999. The protecting groups may be
10 removed at a convenrient subsequent stage using methods known from the art,
HYDROXYL PROTECTING GROUPS
Protection for the hydroxyl group includes methyl ethers, substituted
15 methyl ethersr substituted ethyl ethers, substitute benzyl ethers, and silyi
ethers,
Substituted Methyl Ethers
Examples of substituted methyl ethers include methyoxymethyl,
20 methylthiomethyl, t-butylthlomethyl, (phenyldimethylsilyl)methoxymethyl,
benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl,
guaiacolmethyl, f-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-
methoxyethoxymethyl, 2,2,2-trichloroethoxymethyt, bis(2-chloroethoxy)methyl,
2-(trimethylsily)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl,
25 tetrahydrothiopyranyl,1-methoxycyclohexyl,4-methoxytetrahydropyranyl, 4-
methaxytetrahydrothiopyronyl, 4-methoxytetrahydrothiopyranyl S.S-dioxioide, 1-
{(2-chloro-4 - methyl)phenyl}-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl,
tetrahydrofuranyl, tetrahydrothiofuranyl and 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-
trimethyl-4.7-methanobenzofuran-2-yI.
30
Substituted Ethyl Ethers
Examples of substituted ethyl ethers include 1-ethoxyethyl, 1-(2-
chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1- benzyloxyethyl, 1-
24

WO 2004/037801 PCT/US2003/033343
methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsitylethyl, 2-
(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-
dinitropbenyl and benzyl
5 Substituted Benzyl Ethers
Examples of substituted benzyl ethers include p-methoxybenzyl, 3,4-
dimethoxy benzyl, o-ritrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl,
p-cyanobenzyl, p-phenyl benzyl, 3- and 4-picolyl, 3-methyl-2-picolyl N-oxido,
diphenylmethyl, p, p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenyImethyl, a
10 naphthyldiphenylmethyl, p-methoxyphenyldiphen ylmethyl,di(p-
methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4-
bromophenacyloxy)phenyldiphenylmethyl,4,4',4",-tris(4,5-
dichlorophthallmidophenyl)methyl,4,4',4"-tris(fevulinoyloxyphenyl)methyl,
4,4',4"-tris(benzoyl oxyphenyI)methyl, 3- (imidazol-1-ylmethyl)bis(4',4"-
15 dimethoxyphesnyl)methyl,1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl,9-anthryl,
9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithioIan 2-yl, and
benzisothiazolyl S,S-dioxido.
Silyl Ethers
20 Examples of sityl ethers include trimethylsityl, triethyIsilyl, triisopropyIsilyI.
dimethylisopropylsilyl, diethylisopropytsilyl, dimethyithexylsilyl, t-
butyldimethylsilyl, t-butydiphenylsilyl, tribenzylsily tri-p-xylysilyl, triphenylsilyl,
diphenylmethylsilyl, and t-butylmethoxyphenyleylsilyl.
25 Esters
In addition to ethers a hydroxyl group may be protected as an ester.
Examples of esters include formate, benzoylformate, acetate, chloroacetate,
dichloroacetate, trichloroacetate, triflueroacetate, methoxyacetate,
triphenylmethoxyacetate, phertoxyacetate, p-chiorophenoxyacetate, p-P-
30 phenylacetate, 3-phenylpropionate, 4-oxopertanoate(levulinate),4,4-
(ethylenedithia)penfanoate, pivatoate, adamantoate, crotonate, 4-
methaxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-
trimethylbenzolte(mesitoate)
25

WO 2004/037801 PCT/US2003/033343
Carbonates
Examples of carbonates include methyl, 9-fluorenytmethyl, ethyl, 2,2,2-
trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulforiyl)ethyl, 2-
5 (triphenylphosphonlo)ethyl, Esobutyl, vinyl. anyl, r-nitrophenyl, benzyl, -
methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, r-nitrobenzyl, S-benzyl
thiocarbonate, 4-ethoxy-1-naphthyl, and methyl dithiocarbonate.
Assisted Cleavage
10 Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate;
4-nitro-4-methylpentanoate, o-tribromomethyl)benzoate, 2-
formylbenzenesuffonate, 2-(methylthiomethoxy)ethyl carbonate, 4-
(methythromethoxy)butyrate, and 2-(methythiomethylxymethyl)benzoate.
15 Miscellaneous Esters
Examples of misoellaneous eaters Include 2,6-dichloro-4-
methylphenoxyacetate, 2,6-dichlono-4-(1,1,3,3-
tetra methylbutyl)phenoxyacetate, 2,4-bis (1,1-dimethylpropyl)phenoxyacetate,
chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-
20 butenoate{figloate), o-(methoxycarbonyl)benzoate, r-P-benzoate, a-
naphthoate, nitrate, alkyl N,N,N,N -tetramethylphospborodiamidste, N-
phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4-
dinitrophenylsulfenate
25 Sulfonates
Examples of sulfonates include sulfate, methanesulfonate(mesylate),
benzylsulfonate, and tosylate.
PROTECTION FOR 1,2- AND 1,3 DIOLS
30
Cyclic Acetels and Ketals
Examples of cyclic acetals and ketals include methylene, ethylidene, 1-t-
butylethylidene, 1-phenylethylidene, (4-methoxyphenyl)ethylidene, 2,2,2-
26

WO 2004/037801 PCT/US2003/033343
trichloroethylidene, acetonide (isopropylidene), cyclopentylidene,
cyclohesxylidene. cycloheptylidene, benzylidene, r-methoxybenzylidene. 2,4-
dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and 2-nitrobenzylidene.
5 Cyclic Ortho Esters
Examples of cyclic ortho esters include methoKymethylene,
ethoxymethvlene, dimsthoxymethylene, 1-methoxyethylidene, 1-
ethoxyethylidfne, 1,2-dimethoxyethylidene, a-methoxybenzylidene, 1-(N,N-
dimethylamino)ethylidene derivative, a-(N,N-dimethylamino)benzyiIdene
10 derivative, and 2-oxacyclopeatylideae,
Silyl Derivatives
Examples of silyl derivatives include di- f-butylsilylene group, and 1,3-
(1,1,3,3-fetraisopropyldisiloxanylidene)derivative.
15
AMINO PROTECTING GROUPS
Protection for the amino group includes carbamatesr amides, and
special -NH protective groups.
20
Examples of carbannates include methyl and ethyl carbamates,
substituted ethyl carbanates, assisted cleavage carbamates, photolytic
cleavage carbarnates, urea-type derivatives, and miscellaneous carbamates.
25 Carbamates
Examples of methyl and ethyl carbanates include methyl and ethyl, 9-
fluorenylmethyl, 9-(2-sulfo)fluoreriylimethyl, 9-(2,7-dioromo)fluarenylrnethyl, 2,7-
methoxyphenacyl.
30
Substituted Ethyl
Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl, 2-
trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methyl ethyl. 1.1-dimethyl-2-
27

WO 2004/037801 PCT/US2003/033343
haloethyI, 1,1 -dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichforoethyl,1-
methyl-1-(4-biphenylyl)ethyl, 1-(3.5-di-butylphertyl)-1-methylethyl, 2-(2'- and
4' -pyridyl)ethyI, 2-{N, N-dicydohexyIcarboxamido)ethyl, f-butyl, 1 -adamantyI.
vinyl allyl. 1-Isopropyl allyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N-
5 hydroxypiperidinyl alkyldithio, berreyl, r-methoxybenzyl, r-nitrobsnzyl, r-
bromobenzyl, r-chtorobenzyl, 2,4-dichlorobenzyl, 4-meylsorlfonylnylbenzyl, 9-
anthrylmethyl and diphenylmethyl.
Assisted Cleavage
10 Exampies of asststed cleavage include 2-methylthioethyl, 2-
methylsulfonyfelhyl, 2-(r-toluenesulfonyl)ethyl, {2-(1.3-dithianyl)}methyl, 4-
methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl, 2-
triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl. m-chloro-r-
acyloxybenzyl, r-(dihydnaxyboryl)benzyl, 5-benzisoxazolylmethyl, and 2-
15 (trifluotromettyl)-6-chromonyl methyl.
Phototytic Cleavage
Examples of photolytic cleavage include m-nitrophenyl, 3,5-
dimethoxybenzyl, o-nitrobenzyl. 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o-
20 nitrophenyl)methyl,
Urea-Type Derivatives
Examples of urea-type derivatives include phenothiazinyl-(10)-cartionyl
derivative, N'-r-toluenesulfonylaminocanbonyl, and N'-
25 phenylaminothiocarbonyl.
Miscellaneous Carbamates
Examples of miscellaneous carbamates include f-amyl. S-benzyl
thiocarbamate. p-cyanobenzyl. cyclobutyl, cyciohexyl, cyclopentyl,
30 cyclopropytmethyI, p-decyloxybenzyl ,dilsqpropylmethyl 2,2-
dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl 1,1-dimethyl-3-
(N,N-dimeihylcarboxamido)propyl,1,1-dimethylpropynyl, di{2-pyrldyI)methyl, 2-
furanylmethyl, 2-iodoethyl, Isobomyl isobulyl, isonicolinyl, r-{p'-
28

WO 2004/037801 PCT/US2003/033343
methoxyphenyIazo)benzyl, 1-methylcyclobutyI, 1-methyl cyclohexyl, 1-methyl-1-
cycloprapylmethyl. 1-methyl-(3,5-dimethoxyphenyl)ethyl, 1-methyl-1-{p-
phienylazaphenyl)ethyl, 1-methyl-1-phenytethyl, 1 -methyl- 1-(4-pyridyI) ethyl.
phenyl, p-(phenylazo)benzyl, 2,4,6-tri-1-butylphenyl, 4-
5 (trimethytammonim)benzyl, and 2,4,6-trimethylbeneyl-
Examples of amides include:
Amides
10 N-formy), W-acetyl. M-choroacetyl, N-trichioroacetyl, N-trifluoroacetyl N-
phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-pyrldylcarboxamlde, N-
benzoylphenylalanyl derivative, N-benzoyl, N-p-phenylbenzoyl.
Assisted Cleavage
15 N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl, (N'-
dithiobenzyloxycarbonylamino)acetyl, N-3-(r-hydroxyphenyl)propionyI, N-3-(o-
nitrophenyl)propionyl, N-2-methyl-2-{o-nitrophenoxy)propionyl,N-2-methyl-2-(o-
phenytazophenoxy)propeonyl, N-4-chlorabutyryl, N-3-methyl-a-nitrabutylyl, N-o-
nitrocinnamoyl, N-acetylmethionine derivative, N-o-nitrobeneoyl, N-o-
20 (benzoyloxymethyl)benzoyl, and 4,5-diphenyl-3-oxazolin-2-one.
Cyclic Imide Derivatives
N-phthalimide, N-dithiasuccinoyl. N-2.3-diphenylmaleoyl, N-2,5-
dimethyipyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-
25 subtituted 1,3-dimethyl-1,3,5-triazacyclohrexan-2-one, 5-substituted 1,3-
dibenzyl-1,3,5-triazacyclohexan-2-one, and 1-substituted 3,5-dinitro-4-
pyridonyl.
SPECIAL - NH PROTECTIVE GROUPS
30
Exarnples of special NH protective groups include:
N-AlkyI and N-Aryl Amines
29

WO 2004/037801 PCT/US2003/033343
N-methyl, H-allyl, N-(2-{trimethylsllyl)ethoxy)methyl, N-3-acetoxyplopyl,
N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N-
benzyl N-4-methoxybenzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl,
N-triphenylmethyl, N-(4-methoxyphenyl)dipheny,methyl, N-9-phenylfluoreny, N-
5 2,7-dichloro-9-fluorenyimethylene, N-ferrocenylmethyl, and N-2-picolylamine
N'-oxide.
Imine Derivatives
N-1.1-dimethythiomethylerie, N-benzylidene, N-p-methoxybenzylidene.
10 N-diphenyltnethylene, N-[(2-pyridyl)mesityl}methylene, and N-{N' ,N'-
dimethylammornethylene).
PROTECTION FOR THE CARBONYL GROUP
15 Acyclic Acetals and Ketals
Examples of acyclic acetals and ketals include dimethyl, bis(2,2,2
trichloroethyl). dibenzyl, bis{2-nitnobenzyl) and diacetyl
Cyclic Acetals and Ketals
20 Examples of cyclic acetals and ketals include1,3-dioxanes,5-
inethylene-1,3-dioxane, 5,6-dibromo-1,3-dioxane, 5-{2-pyridyl}-1,3-dioxane,
1,3 dioxolanes, 4-bromomethyl 1, 3-dioxolane, 4-(3-butenyl)-1,3-dioxolane, 4-
phenyl-1,3-dioxolane, 4-(2-nitrophenyl)-1,3-dioxolane, 4,5-dimethoxymethyl
1,3-dioxolane; O,O'-phenylenadioxy and 1,5-dihydro-3H-2,4-benzodioxepin.
25
Acyclic Dithio Acetals and Ketals
Examples of acycilc dithio acetals and ketals include S,S'-dimethyl.
S,S'-diethyl, S,S'-dipropyl, S,S'-dibutyl, S,S'-dipentyl, S.S'-diphenyl, S,S'-
dibenzyl and S,S'-diacetyl.
30
Cyclic Dithio Acetals and Ketals
Examples of cyclic dithio acetals and ketals include 1,3-dithiane. 1,3-
dithiolane and 1,5-dihydro-3H-2,4-benzodithiepin.
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WO 2004/037801 PCT/US2003/033343
Acyclic Monothio Acetals and Ketals
Examples of acyclic monothio acetals and ketals include O-trimethylsilyI-
S-alkyl. O-methyl-S-alkyl or -S-phenyl and G-methyl-S-2 (methylthio)ethyl
5
Cyclic Monothio Acetals and Ketals
Examples of cyclic monothio acetals and ketals include 1,3-
oxathiolanes.
MISCELLANEOUS DERIVATIVES
10
O-Substituted Cyanohydrins
Examples of O-substituted cyanohydnins include O-acetyl, O-
trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.
15 Substituted Hydrazanes
Examples of substituted hydra zones indude N,N-dimethyl and 2,4-
dinitrophenyl.
Oxime Derivatives
20 Examples of oxime derivatives include O-methyl. O-benzyl and O-
phenylthiomethyl.
Imines
Substituted Methylene Derivatives, Cyclic Derivatives
25 Examples of substituted methylene and cyclic derivatives include
oxazolidines, 1-methyl-2(1-hydroxyalkyl)imidazoles. N,N'-
and methyIaluminum bis{2,6-di-t-butyl-4-methytphenoxide)(MAD)complex.
30 MONOPROTECTION OF DlCARBOMYL COMPOUMDS
Setective Protection Of a-and b-Diketones
31

WO 2004/037801 PCT/US2003/03343
Examples of selective prortection of a-and b-diketones include
enarmines, enol acetates, enol ethers, methyl, ethyl, i-butyl, piperidinyl,
morpholinyl. 4-methyl-1,3-dioxolanyl, pyrrolidiny), benzyl, S-butyl, and
trimethylsilyl.
5
Cyclic Ketals, Monothio and Dithio Ketals
Examples of cyclic ketals, monothio and dithio Ketals include
bismethylenedioxy derivatives and teframethylbismethylenedioxy derivatives-
10 PROTECTION FOR THE CARBOXYL GROUP
Esters
Substituted Methyl Esters
Examples of substituted methyl esters include 9-fluorenylmethyl,
15 methoxymethyl, methylthiamethyl, tetrahydropyranyl. tetrahydrofuranyl,
methoxyethoxymethyl, 2-(trimethylsily)ethoxymethyl, benzyloxymethyl,
phenacyl, r-bromophenacyl, a-methylphenacyl, r-methoxyphenacyl,
carboxamidomethyl, and N-phthalimidomethyl.
20 2-Substituted Ethyl Esters
Examples of 2-substituted ethyl esters include 2,2,2-trichloraethyl,
2-haloethyl, wchloroalkyl., 2-(trimethylsilyl)ethyl, 2-methylthioethyl, 1,3-
dithianyl-2-methyl, 2-(r-nitrophenylsulfenyl)ethyl, 2-(r-toluenesutfonyl)ethyl.
2-(2'-pyridyl)ethyl, 2-(diphenylphosphno)ethhyl, 1-methyl-1-phenylethyl, t-
25 butyl, cyclopenrtyl, cyclohexyl. allyl, 3-buten-1-yl, A-(trimethylsityl)-2-buten-1-yl
cinnamyl, a-methylcinnamyl, phemyl,r-(methylmercapto)phenyl and benzyl.
Substituted Berzyl Esters
Examples of substituted benzyl esters in dude triphenyl methyl,
30 diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2(9,10-
dioxo)anthrymethyl, 5-dibenzosuberyl, 1-pyrenyImethyl, 2-(trifluoromethyl)-6-
chromylmethyl, 2,4,6-trimethylbenzyl, r-bromobenzyl. o-nitrobenzyl, r-
32

WO 2004/037801 PCT/US2003/033343
nitrobenzyl, r-methaxybenzyl, 2,6-dimethaxybenzyl, 4-(methylsulfuytryl)beozyl, 4-
sulfobenzyl, plperonyl, 4-picoyl and p-P-benzyl.
Silyl Esters
5 Examples of silyl esters include trimethylsilyl, triethylsilyl. t-
butyldimethylsilyl, i-propyldimethylsilyl, phertyldimethylsrlyl and di-t-
butylmethylsilyi.
Activated Esters
10 Examples of activated esters include thiols.
Miscellaneous Derivatives
Examples of miscellaneous derivatives include oxazoles, 2-alkyl-1,3-
oxazolines, 4-alky-5-oxo-1,3-oxazolidines. 5-alkyl-4-oxo-1,3-dioxolanes, ortho
esters, phenyl group and pentaaminooobatt(Ill) complex.
15
Stannyl Estesrs
Examples of stannyl esters include triethylstannyl and tri-n-butylstannyl.
AMIDES AND HYDRA21DE5
20
Amides
Examples of amides include N,N-dimethyl. pyrrolidinyl, piperidmyl, 5,6-
dihydrophenanthridinyl, o-nitroanllides, N-7-nitroindolyl, N-8-Nitro-1,2,3,4-
tetrahydroquinolyl, and r-P-benzenesulfonamides.
25
Hydrazides
Examples of hydrozides Include N-phenyl and N,N'-disopropyl-
The compounds of the invention can be prepared according to the
30 methods described in the next section.
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WO 2004/037801 PCT/US2003/03343
C. Synthesis
The compounds of the invention can be prepared according to
traditional synthetic organic methods and matrix or combinatorial chemistry
methods, as shown in Scheme 1 below and in Examples 1-72. A person of
5 ordinary skill will be aware of variations and adaptations of the schemes and
examples provided to achieve the compounds of the invention.
One skilled in the art will recognize that synthesis of the compounds of
the present invention may be effected by purchasing intermediate or protected
intermediate compounds described in any of the Schemes disclosed herein.
10 Throughout the schemes when the reacting functionality is located at R4, one
skilled to the art will recognize that the choice of R4 is illustrative only and that
the reacting functionality could also be located at.R3 or R2 also.
One skilled in the art will further recognize that during any of the
processes for preparation of the compounds of the present invention, it may be
15 necessary and/or desirabIe to protect sensitive or reactive groups on any of the
molecules concerned. This may be achieved by means of conventional
protecting groups, such as those described in "Protective Groups in Organic
Chemistry", ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene &
P.G.M. Wute, "Protective Groups in Organic Synthesis". John Wiley & Sons,
20 1991. The protecting groups may be removed at a convenient subsequent
stage using methods known from the art.
Compounds of formula (XIII) may be prepared according to the
processes outlined in Scheme 1. One skilled in the art will recognize that the
location of formyl functionality at R4 is for illustrative purposes only and that the
25 formyl group may also be located at R2 or R3.
34

WO 2004/037801 PCT/US2003/033343

A compound of formula (Xlll) is prepared as outlined in Scheme 1 from a
15 compound of formula (V), in which the group M2 represents a nitrogen-
protecting group. One skilled in the art will be capable of selecting a protecting
group that is compatible with the transformations in Scheme 1. In a particularly
35

WO 2004/037801 PCT/US2003/033343
preferred embodiment, the group M1 is tert-butyl-cartiamoyl. A compound of
formula (VI) is obtained from a compound of formula (V) by reacting a
compound of formula (V) with an aldehyde or ketone under reductive amination
conditions in the presence of a reductant such as sodium
5 triacetoxyboro hydride, sodium cyanoborohydride, or phenylsilane in a solvent
such as THF, DCE, DCM, methanol, ethanol, or ether at a temperature
between 0 and 30 °C, One skilled in the art will recognize that the use of a
promoter or catalyst with acidic character such as organometallie complexes or
carboxylic acids may increase the rate of the reaction and/or reduce the
10 formation of by-products, in a particularly preferred embodiment, a compound
of formula (V) is reacted with an aldehyde or ketone, acetic acid, and sodium
trracetoxyhorohyrdide in DCE at room temperature. A compound of formula
(VII) is obtained from a compound of formula (VI) by reacting a compound of
formula (VI) with a reagent capable of removing the protecting group M1 under
15 nitrogen-deprotection conditions. In a preferred embodiment a compound of
formula (VI), in which the protecting group M1 is tert-butyl carbamoyl, is reacted
with an acid such as anhydrous hydrogen chloride in a solvent such as dioxane
or etherat room temparature. A compound of fovmula (IX) is obtained by
reacting a compound of formula (VlI) with a compound of formula (VIll) under
20 amide-formation conditions. In a preferred embodiment, a compound of
formula (VIII), either as a free base or as s mineral acid salt, is reacted with a
compound of formula (VIII) in the presence of a dehydrating agent and a base
in a solvent at a temperature between 0 °C and 60 °C. In a particularly
preferred embodiment, a compound of formula (VII) as a hydrochloride salt is
25 used, the dehydrating agent is 143-(dimethylamino)propyl]-3-ethylcarbodlimide
hydrochloride and 1-hydroxybenzotriazole hydrate, and the base is N-
methylmarpholine. A compound of formula (XIII) is obtained by reacting a
compound of formula (IX) with a compound of formula (XI) in the presence of a
reducing agent under reductive amination conditions, as outfined in step A. A
30 compound of formula (X) is obtained by reacting a compound of formula (V)
with a compound of formula (Vlll) under amide formation conditions as outlined
in step C. A compound of formula (XII) is obtained by reacting a campound of
formula (X) with a compound of formula (XI) under reductive amination
36

WO 2004/037801 PCT/US2003/033343
conditions, as described in step A. A compound of formula (XIV) is obtained
by reacting a compound at formula (XII) with a reagent capable of removing
the protecting group M1 under nitrogen-depiotection conditions, as oullined in
step B. A compound of formula (XIII) is obtained by reacting a compound of
5 formula (XIV) with an aldehyde or ketone under reductive amination conditions
as outlined in step A. Compounds of the present invention may also be
conveniently prepared using various other chemical intermediates. For
example, variants of aldehyde (VIII) or amide (IX) could be accessed from a
corresponding alyl halide, such as an aryl bromide, via a palladium mediated
10 coupling With a tormyl, carbonyl, or nitrile equivalent.
D. Formulation. Administration, and Therapy
The disclosed compounds, alone or in combination (with, for example, a
histamine H1, receptor antagonist), are useful for treating of preventing
15 naurologic disorders induding sleeplwake and arousallviglliance disorders {e.g.
insomnia and jet lag), attention deficit hyperactivity disorders (ADHD), teaming
and memory disorders, cognitive dysfunction, migraine, neurogenic
inflammation, dementia, and cognitive impaiment (pre-dementia), Alzheimer's
disease, epilepsy, narcolepsy, eating disorders, obesity, motion sickness,
20 vertigo, schizophrenic sabstance abuse, bipolar disorders, manic disorders
and depression, as well as other histamine H3 receptor mediated disorders
such as upper airway allergic response, asthma, itch, nasal congestion and
allergic rhinitis in a subject in need thereof.
25 1. Formulation and Administration
The compounds or compositions of the invention may be formulated and
administered to a subject by any conventional route of administration.
including, but not imited to, intravenous, oral, subcutaneous, intrarnuscular,
intradermal and parenteral admsnistration. The quantity of the compound
30 which is effective for treating each condition may vary, and can be determined
by one of ordinary skil0l in the art.
For use in medicine, the salts of the compounds of this invention refer to
non-toxic "pharmaceutically aocepteble salts". Other salts may, however, be
37

WO 2004/037801 PCT/US2003/033343
useful in the preparation of compounds according to this, invention or of their
pharmaceuticaIIy acceptable salts. Suitable pharmaceutically acceptable salts
of the compounds include add addition salts that may, for example, be formed
by mixing a solution of the compound with a -solution of a pharmaceutically
5 acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic
acid, succinic acid, acetic add, benzoic acid, citric acid, tartaric acid, carbonic
acid or phosphorio acid. Furthermore, where the compounds of the invention
carry an acidic molety. suitable pharmaceuticlly acceptable salts thereof may
include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal
10 salts, e.g., calcium or magnesium salts; and salts formed with suitable organic
figands, e.g., quaternary ammonium salts.
Thus representative pharmaceutically acceptable salts include the
following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,
bitartrate, borate, bromide, calcium edetate, camsylate. carbonate, chloride,
15 clavulanate. citrate. ditiydrochioride, edstate, editsylate, estolate, esytete,
fumerate, gluceplate, gluconate, glutamate, glycollylarsanilate,
hexylresorcinate. hydrabamine, hydrobromide, hydrochloride,
hydroxynapthoate, iodide, isothionate, lactate, lactabionate, laurate, malate,
maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,
20 mucate. napsylate, nitrate, N-methylglucamine ammonium salt oleate,
pamoate (embonate), palmitate, panfothanate, phosphate/diphosphate,
polygalacturonate, salivate, stearate, sulfate, subaostate, sucinate, tannats,
tartrate, teoclate, tosylate, triethiodide and valerate.
Tne present invention includes within its scope, prodrugs of the
25 compounds of this invention, in general, such prodrugs will be functional
derivatives of the compounds that are readily convertible in vivo into the
required compound. Thus, in the methods of treatment of the present
invention, the term "administering" shall encompass the treatment of the
various disorders described with the compound specifically disclosed or with a
30 compound that may not be specifically disclosed, but which converts to the
specified compound in vivo after administration to the patient. Conventional
procedures for the selection and preparation of suitable prodrug derivatives are
described, for example, in "Design of Prodrugs", ed. H. Bundgaard. Elsevier,
38

W0 2004/037801 PCT/US2003/033343
1985. In addition to salts, the invention provides the esters, amides, and other
protected or derivatived forms of the described compounds.
Where the compounds according to this invention have at least one
chiral center, they may accordingly exist as enantiomers. Where the
5 compounds possess two or more chiral centers, they may additionally exist as
diastereomers. It is to be understood that all such isomers and mixtures
thereof are encompassed within the scope of the present invention.
Furthermore, some of the crystalline forms for the compounds may exist as
potymorphs and as such are intended-to be included in the present invention,
10 In addition, some of the compounds may form solvates with water (i.e.,
hydrates) or common organic; solvents, and such solvatee are also intended to
be encompassed within the scope of this invention.
The present invention also provides pharmaceutical compositions
comprising one or more compounds of this invention in association with a
15 phannaceutically acceptable carrier and optionally additional phamaceutical
agents such as H1 antagonists or SSRls. Preferably these compositions are in
unit dosage forms such as pills, tablets, caplets, capsules (each including
immediate release, timed release and sustained release formulations),
powders, granules, sterile parenteral solutions or suspensions (including
20 syrups and emulsions), metered aerosol or liquid sprays, drops, ampoules,
autoinjector devices or suppositories; for oral, parenteral, intranasal, sublingual
or rectal administration, or for administration by inhalation or insufflation.
Alternativesy, the composition may be presented in a form suitable for once-
weekly or once-monthly administration; for example, an insoluble salt of the
25 active compound, such as the decanoats salt, may be adapted to provide a
depot pysparaticin for intramuscular injection. For preparing solid compositions
such as tablets, the principal active ingredient is mixed with a pharmaceutical
carrier, e.g, conventional tableting ingredients such as com starch, lactose,
sucrose, sorbitol, talc, steatic acid, magnesium, stearate, dicalcium phosphate
30 or gums, and other pharmaceutical diluents, e,g, water, to form a solid pre-
formulation composition containing a homogeneous mixture of a compound of
the present invention, or a pharmaceutically acceptable salt thereof. When
referring to these pre-formulation compositions as homogeneous, it is meant
39

W0 2004/037801 PCT/US2003/033343
that the active ingredient is dispersed evenly throughout the composition so
that the composition may be readily subdivided into equally effective dosage
forms such as Eablets, pilis and capsules. This solid pre-formulation
composition is then subdivided into unit dosage forme of the type described
5 above containing from 5 to about 1000 mg of the active ingredient of the
present invention. Examples include 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, 35
mg, 50 mg, 76 mg, 100 mg, 120 mg, 160 mg, and so on. The tablets or pills of
the disclosed compositions can be coated or otherwise compounded to provide
a dosage form affording the advantage of prolonged action. For example, the
10 tablet or pill can comprise an inner dosage and an outer dosage component,
the latter being in the form of an envelope over the former. The two
components can be separated by an enteric layer, which serves to resist
disintegration in the stomach and permits the inner component to pass intact
into the duodenum or to be delayed in release. A variety of material can be
15 used for such enteric layers or coatings, such materials including a number of
polymeric acids with such materials as shellac, cetyl alcohol and cellulose
acetate.
The liquid forms in which the compounds and compositions of the
present invention may be incorporated for administration orally or by injection
20 include, aqueous solutions, suitably flavored syrups, aqueous or oil
suspensions, and flavored emulsions with edible oils such as cottonseed oil,
sesame oil, cocanut oil or peanut oil, as well as elixirs and similar
pharmaceutical vehlcles. Suitable dispersing or suspending agents for
aqueous suspensions, include synthetic and natural gums such as tragacanth,
25 acacia, alginate, dextran, sodium carboxymetriylceliulose, methylcellulose,
polyvinyl-pymolidone or getelim.
Where the processes for the preparetion of the compounds according to
the invention give rise to mixture of slereoisomers, these isomers may be
separated by conventional techniques such as preparative chromatography.
30 The compounds may be prepared in racemic form, or individual enantiomers
may be prepared either by enantiospecific synthesis or by resolution. The
compounds may, for example, be resolved into their component enantiomers
by standard techniques., such as the fomation of diaestereomeric pairs by salt
40

WO2004/037801 PCT/US2003/033343
formation With an optically active acid, such as (-)-di-p-tolucyl-d-tartaric acid
and/Or (+)-di-p-toluayl-1-tartaric acid followed by fractional crystallization and
regeneration of the free base. The compounds may also be resolved by
formation of diastereomeric esters or amides, followed by chromatographic
5 separation and removal of the chiral auxiliary. Alternatively, the compounds
may be resoled using a chiral HPLC column.
Advantageously, compounds of the present invention may be
administered in a single daily dose, of the total daily dosage may be
administered in divided doses of two, three or four times daily. Furthermore,
10 compounds for the presant invention can be administered in infransal form via
topical use of suitable intranasal vehicles, or via trsnsdermal skin patches well
known to those of ordinary skill in that art. To be adminstered in the form of a
transdermal delivery system, the dosage administration will, of course, be
continuous rather than intermittent throughout the dosage regimen.
15 For instance, for oral adminstration to the fom of a tablet or capsule, the
active drug component can be combined with an oral, non-toxic pharmaceutically
acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover,
when desired or necessary, suitable binders, lubricants, disintegrating agents
and coloring agents can also be incorporated into the mixture. Suitable binders
20 include, without limitation, starch, gelatin, natural sugars such as glucose or
beta-actnse, com sweetsners, natural and synthetic gums such as scads,
tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium
benzoate, sodium acetate, sodium chloride and the like. Disintegrators include,
without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the
25 like.
The compound of the present invention can also be administered in the
form of liposome delivery systems, such as small unilamellar vesicles, large
unilannellar vesicles, and multilamellar vesicles. Liposomea can be foimecf from
a variety of phospholipids, such as cholesterol, stearylamine or
30 phophatidylcholines.
Compounds of the present invention may also be delivered by the use of
monoclonal antibodies as Individual carriers to which the compound molecules
are coupled. The compounds of the present invention may also be coupled with
41

W0 2004/037801 PCT/US2003/033343
soluble polymers as targetable drug carriers. Such polymers can include
polyvinylpytrolidone, pyran copotymer, polyhydroxypropylmethacryamidephenot,
polyhydroxyethylaspartanmidephenol, or polyethyleneoxidepolylysine substituted
with palmitoyl residue. Furthermore, the compounds of the present invention
5 may be coupled to a class of biodegradable polymers useful in achieving
controlled release of a drug, for example, polylactic acid, polyepsilon
caprolactone, polyhydroxy butyric acid, polyoesters, polyacetals,
polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block
copolymers of hydrogels.
10 Compounds of this invention may be administered in any of the foregoing
compositions and according to dosage regimens established in the art whenever
treatment is required.
The daily dosage of the products may be varied over a wide range from 1
to 1,000 mg per adult human per day. For oral administration, the compositions
15 are preferably provided in the form of tablets containing 1.0, 5.0,10.0,15.0, 25.0,
50.0,100, 250 and 500 milligrams of the active ingredient for the symptomatic
adjustment of the dosage to the subject to be treated. An effective amount of
the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to
about 20 mg/kg of body weight per day. Preferably, the range is from about 0.02
20 mg/kg to about 10 mg/kg of body weight per day, and especially from about 0.05
mg/kg to about 10 mg/kg of body weight per day. The compounds may be
administered an a regjmen of 1 to 4 times per day.
Optimal dosages to be administered may be readily determined by those
skilled in the art, and will vary with the particular compound used, the mode of
25 administraton, the strength of the preparatron, the mode of administratran, and
the advancement of the disease condition. In addition, factors associated with
the particular patient being treated, inducting patient age, weight, diet and time of
administration, with result in the need to adjust dosages,
30 2. Combination Therapy
The disclosed compounds are useful in combinallon with other
therapeutic agents, Including H1 receptor antagonists. H2 receptor antagonists,
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WO 2004/037801 PCT/US2003/033343
and neuretransmitter modulators such as SSRIs and non-selective serotonin
re-uptake inhibitors (NSSRIs).
Methods are known in the art for determining effective doses for
therapeutic and prophylactic purposes for the disclosed pharmaceutical
5 compositions or the disclosed, drug cambinations, whether or not formulated in
the same composition. For therapeutic purposes, the term "jointly effective
amount" as used herein, means that amount of each active compound or
pharmaceutical agent, alone or in combination, that elicits the biological or
medicinal response in a tissue system, animal or human that is being sought
10 by a nesearcher, veterinarian, medical doctor or other clinicianm, which includes
alleviation of the symptoms of the disease or disorder being treated. For
prophylactic purposes (i.e., inhibiting the onset or progression of a disorder),
the term "jointiy effective amount" refers to that amount of each active
compound or pharmaceutical agent, alone or in combination, that inhibits in a
15 subject the onset or progression of a disorder as being sought by a researcher,
veterinarian, medical doctor or other clinician, the delaying of which disorder is
mediated, at least in part, by the modulation of one or more histamine
receptors. Thus, the present invention provides combinations of two or more
drugs wherein, for example, (a) each drug is administered in an independently
20 therapeutically or prophylactically effective amount; (b) at least one drug in the
combination is administered in an amount that is sub-therapeutic or sub-
prophylactic if administered alone, but is therapeutic or prophylactic when
administered in combination with the second or additional drugs according to
the invention; or (c) both drugs are administered in an amount that is sub-
25 therapeutic or sub-prophylactic if administered alone, but are therapeutic or
prophylactic when administered together. Combinations of three or more drugs
are analogously possible. Methods of combination therapy include co-
administration of a single formulation containing all active agentsl essentially
contemporaneous administration of more than one formulation; and
30 administration of two or more active agents separately formulated,
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WO 2004/037801 PCT/US2003/033343
E. Examples
In order to illustrate the invention, the following examples are Included.
These examples do not limit the invention. They are only meant to suggest a
method of practicing the invention. Those skilled in the art may find other
5 methods of practicing the invention, which are obvious to them. However,
those methods are deemed to be within the scope of this invention.
Protocol for Preparative Raversed-Phass HPLC
Gilson®
10 Column: YMC-Pack ODS-A, 5 mm, 75x30 mm
Flow rate: 25 mL/min
Detection: l = 220 & 254 nm
Gradient (acetonitrile/water, 0.05% trifluaraacetic acid)
1) 0.0 min 15% acetonitrile/85% water
15 2) 20.0 min 99% acelonitrile/1% water
Protocol for HPLC (Reversed-Phase)
Hewlett Packard Series 1100
Column; Agilent ZORBAX® Bonus RP, 5 mm, 4.6x250 mm
Flow rate: 1 mL/min
20 Detection: l = 220 & 254 nm
Gradient (acetonitrile/water, 0.05% trifluoroacetic acid)
1) 0.0 min 1% acetonitrile /39% water
2) 20.0 min 99% acetonitrile/1% water
25 Mass spectra were obtained on an Agilent series 1100 MSD using
electrospray ionization (ESI) in either positive or negative modes as indicated.
Thin-layer chromatography was perfomred using Merck silica gel 60 F254
2.5 cm x 7.5 cm 250 mm or 5.0 cm x 10.0 cm 250 mm pre-coated silica gel
plates. Preparative thin-layer chromatography was performed using EM
30 Science silica gel 60 F254 20 cm x 20 cm 0.5 mm pre-coated plates with a 20
cm x 4 cm concentrating zone.
NMR spectra were obtained on either a Bruker model DPX400 (400
MHz) or DPX500 (500 MHz) spectra meter. The format of the 1H NMR data
44

WO 2004/07801 PCT/US/2003/03343
below is: chemical shift in ppm down field of the letra methylsilane reference
(multiplicity, coupling constant J in Hz, integration).
Example 1

4-sec-Butyl-pjperazine-1-carboxylic_acid tert-butyl ester
A mixture of piperazine-l-carboxylic acid tert-butyl ester (7.00 g), 3-pentanone
(3,89 g), glacial acetic acid (2.22 mL) and sodium triacetoxyborohydride (11.95
i) in dichloromethane (DCM, 200 mL) was stirred for 18 n at room temparature.
10 The reaction mixture was quenched with 1 N aqueous NaOH (80 mL) and stimed
for 2,5 h at room temperature. Additional water (10D mL) was added, and the
resulting mixture was extracted with DCM (3 x 100 mL). Extracts were combined
and washed with water (2 x 100 mL), dried (Na2SO4), and concentrated under
reduced pressure, yielding the title compound (6.28 g).
15
The products of Example 2 through Example 5 were prepared in
analogy with the procedure of Example 1 using the specified carbonyl
compound and amine.

4-(1-Ethyl-propyl)-piperazine-1-carbogxylic acid tert-butyl ester
prepared, from 3-pertanone and piperazine-1 -carboxylic acid tert-butyl
ester
45

WO 2004/037801 PCT/US2003/033343

4-_Butyl-piperganezin-1-carboxylic acid tert-butyl ester
5 Prepared from butanal and piperazine-1-carboxylic acid fert-butyl ester.

4-(1-Methyl-heptyl)-piperazine-1-carboxylic acid tert-butyl ester
10 Prepared from 2-oclanone and piperaztne-i-carboxylic acid tert-butyl
ester.

15 4-Isopropyl-piperazine-1-carboxylic acid tert-butyl ester
Prepared from acetone and piperazine-1-carboxylic acid tert-butyl ester.
46

WO 2004/037801 PCT/US2003/033343

1-sec-Butyl-piperzin dihydrocholoride
To a solution of the product of Example 1 (6.28 g) in methanol (120 mL)
5 at 5 °C was added 4 M HCl in dioxane (100 mL). The reaction mixture was
stirred at room temperature. After 24 h, the solvent was evaporated under
vacuum. Ethyl ether was added and evaporated to dryness under vacuum (2 x
100 mL). The resulting white solid was dried under vacuum for 24 h yielding
the title compound as its dihydrochloride salt (4.93 g) as a white solid.
10
The products of Example 7 through Example 10 were prepared in
analogy to the procedure of Example 6 from the specified tert-butylcarbamate.

15
1 -(1 -Ethyl-propyl)-piperazine dihyrirochloride
Prepared from the product of Example 2.

20
1 -Butyl-piperazine dihyldrochlorids
Prepared from the product of Example 3.
47

WO 2004/037801 PCT/US2003/033343

1-(1-Methyl-neotyl)-piperazine dihvdrochloride
Prepared from the product of Example 4.
5

1-Isoprgpyl- piperazine dihydrochloride
Prepared from the product of Example 5.
10

4-(4-sec-Butyl-piperazine-1-carbonyl)-benzaldehyde
The product of Example 6 (3.2 g) and 4-formylbenzoic acid (2.102 g)
15 were suspended in DCM (130 mL) under nitrogen. 1-{3-
(Dimethylamino)priopyl-3-ethylcacbodilmide hydrochloride (3.96 g), 1-
hydroxybenzotriazole hydrate (3.06 g) and N-methylrpoipholine (9,432 g) were
added in sequence to the above suspension. The reaction mixture was stirred
under nitrogen for 24 h. DCM (100 mL) was added, the resulting mixture was
20 washed with 10 % aqueous NaOH solution (2 x 50 mL) and water (2 x 100
mL), and the separated organic phase was dried over anhydrous MgSO4, and
concentrated under reduced pressure to yield the crude product (3.75 g).
Chromatography of the residue on silica gel (2-5% 2 M methanolic
ammonia/DCM) yieled the title compound (2.75 g).
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WO 2004/037801 PCT/US2003/033343
The products of Example 12 through Example 18 were prepared in
analogy to the procedure of Example 11 using the specified prperazine
derivatives and carboxylic acids.
5

4-{4-(1-Ethyl-propyl)-pipgrazine-1-cabopnyl-benzaldehyde
Prepared from the product of Example 7 and 4-formylbenzoic acid.
10

4-(4-Butyl-piperazine-1 -tarbonyl)-benzaldenyde
Prepared from the product of Example 8 and 4-formybenzoic acid.
15

4-{4-(1-Methtyl-hepyl)-piperzine-1-carbonyl)-benzaldehyde
Prepared from the product of Example 9 and 4-formylbenzoic acid.
20
49

WO 2004/037801 PCT/US2003/033343

4-(4-lsopropyl-piperazine-1-carbonyl-1-benzaIdehyde
Prepared from the product of Example 10 and 4-formylbenzolic acid.
5

4-(4-Methyl-piperazine-1-carbonyl)-benaldehyde
Prepared from N-methylpiperazine and 4-formylbenzole acid.
10

3-(4-Methy-piperazine-1-carbony)-benzaidehyde
Prepared from N-methylpiperazine and 4-formylbenzoic acid.
15

3-(4-lsosropyl-piperazine-1-carbonyl)-benzaldehyde
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WO 2004/037801 PCT/US2003/033343
Prepared from the product of Example 10 and 3-formylbenzoic acid.

5 (4-Bromo- phenvl)-(4-(1-ethyl-propyl)-piperazin-1- yl)-methanpne
To a solution of 4-bromobenzoic acid (500 mg) and the product of
Example 7 (710 mg) in DCM (20 mL) was added 1-{3-(dimethylamino} propyl}-
3-ethylcarbodiimide hydrochloride (713 mg), 1-hydroxybenzotrizole hydrate
(570 mg), and N-methyl morphaline (1.54 mL). After 16 h the reaction mixture
10 was treated with 1 N NaOH (25 mL) acid extracted with DCM (3 x 75 mL) The
organic layers were dried (Na2SO4), concentrated, and chnomatographed on
silica gel (1-3% 2 M methanolic ammonla/DCM) to give the title compound as
white-yellow solid (630 mg).

{4-(Benzylamino-methyl)-phenyl}-{4-(1-ethyl-propyl)-piperezin-1-yl}-
mathanone
To a solution of the product of Example 12 (150 mg) and benzylamine
20 (0.062 mL) in DCM (5 mL) was added acetic acid (.03 mL) and sodium
triacetoxyborohydride (165 mg). After 16 h the raction was treated with 1 N
NaOH (20 mL) and extracted with DCM (3 x 20 mL). The organic layers were
dried (Na2SO4), concentrated, and chromatographed (2-3% 2 M methanolic
ammonia-DCM) to give the title compound as an oil (150 mg).
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WO 2004/037801 PCT/US2003/033343
{4-(1-ethyl-propyl)-piperezin-1-yl}-{4-piperedin-1-ylmethyl-phenyl}-
methanone
Prepared from the product of Example 12 and piperidine.
1H NMR {400 MHz. CDCl3): 7.40-7.34 (m. 4H), 3.74 (brs, 2H), 3.53 (s,
5 2H), 3.39 (br s, 2H), 2.50-2.42 (m, 8H), 220-2.17 (m, 1H). 1.62-1,60 (m, 4H),
1,50-1.41 (m,4H), 1.43-1.27 (m, 2H), 0.92-0.88 (m, 6H).

10 (4-sec-Butyl-Piperazin-1-yl)-(4 -Piperidin-1 -ylmethyl-Phenyl)-methanone
Prepared from the product of Example 11 and piperidine.
1H NMR (400 MHz, CDCl3); 7.36-7.30 (m, 4H), 3.75 (br s, 2H), 3.50-
3.32 (m, 4H), 2.55-2.24 (m, 9H), 1.60-1.48 (m, 5H), 1.46-1.36 (m, 2H), 1.34-
1.0 (m, 1 H) 0.95 (d, J = 6.6 Hz, 3H), 0.92-0.88 (m, 3H).
15

(4-sec-Butyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone
Prepared from the product of Example 11 and aniline.
20 1H NMR (400 MHz, CDCl3): 7.43-7.32 (m, 4H), 7.15 (tt, J = 7.4, 5.4 Hz,
2H), 6.74-6.66 (m, 1H), 6.59 (dd, J=7.6, 1.0 Hz 2H), 4.33 (s, 2H), 4-2 (brs,
1H), 3.76 (brs, 2H), 3:41 (brs, 2H), 2.66-2.27 (m, 5H), 1.62-1.45 (m, 1H),
1.36-1.20 (m, 1H), 0.96 (d, J = 6.6 Hz, 3H), 0.90 (t,J = 7.4 Hz, 3H).
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WO 2004/037801 PCT/US2003/033343
1H NMR (400 MHz, CDCl3): 7.40-7.34 (m, 8H), 7.23-7.26 (m, 1H), 3.85
(d, J = 9.1 Hz, 4H), 3.75 (br s, 2H), 3.40 (brs, 2H), 2.59-2.45 (m, 4H), 2.21-
2.18 (m, 1H), 1.67 (8, 1H), 1.50-1.43 (m, 2H). 1.35-1.28 (m, 2H). 0.92-0.39 (m.
6H).
5
The products of Example 21 through Example 42 were prepared in
analogy with the procedure of Example 20 using the specified carbonyl
compounds and amines.

(4-Azeoan-1-ylmethyl-phenyl)-(1-ethyl-propyl)-piperazin-1-yl)-
methanone
Prepaned from the product of Example 12 and azepine.
15 1H NMR (400 MHz, CDCI3); 7.39-7.33 (m, 4H), 3.74 (br s, 2H), 3.65 (s,
2H), 3.40 (br s, 2H), 2.62-2.46 (m, 8H), 2.21-2.17 (m. 1H). 1.62 (br s, 8H),
1.50-1.43 (m, 2H), 1.34-1.27 (m, 2H), 0.92-0.89 (m, 6H).

{4-(1-Ethyl-propyl)-pipergzin-1- yl}-{4-(decahydro-isoquinolin-2-ylmethyl-
phenyl)-methanone
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WO 2004/037801 PCT/US2003/033343
Prepared from the product of Example 12 acid decahydroisoquinoline-
1H NMR (400 MHz, CDCl3): 7.39-7.33 (m, 4H), 373 (br s, 2H), 3.52-
3.39 (m. 4H), 2.59-2.45 (m, 6H), 2.20-2.17 (m, 2H), 1.70-1.29 (m, 17H), 0.92-
0.83 (m, 6H).
5

(4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl- picerazin-1-yl)-methanone
Prepared from the product of Example 11 and azepine.
10 1H NMR (400 MHz, CDCI3): 7.35 (dd, J = 9.1, 8.1 Hz. 4H), 3.76 (br s,
2H), 3.63 (S, 2H), 3.42 (brs, 2H), 2.68-2.32 (m, 9H), 1,69-1.47 (m, 9H), 1.36-
1.20 (m. 1H), 0.96 (d. J = 6.6, 3H), 0.89 (t, J = 7.3, 3H).

(4-sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl)-phenyl)-methanone
Prepared from the product of Example 11 and dimethylamine
hydrochloride.
1H NMR (400 MHz, CDCI3): 7.38-7.29 (m, 4H), 3.75 (br s, 2H), 3.42 (br
20 s, 4H), 2.66-2.30 (m, 5H), 2.22 (s, 6H), 1.58-1.46 (m, 1H), 1.34-1.20 (m, 1H).
0.95 (d, J = 6.57 Hz, 3H), 0.92-0.88 (m, 3H).
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WO 2004/037801 PCT/US2003/033343

(4-sec-Butyl-piperazin-1- yl)-(4- pyrroIdin-1-ylmethy-phenyl)-methanone
Prepared from the product of Example 11 and pyrrolidine.
5 1H NMR (400 MHz, CDCl3); 7.38-7.29 (m. 4H), 3.74 (br s, 2H). 3.60 (s.
2H), 3.40(br s, 2H), 2.64-2.34 (m, 9H), 1.81-1.70 (m, 4H), 1.59-1.45 (m, 1H),
1.33-1.19 (m. 1H), 0.94 (d, J= 5.57 Hz, 3H), 0.91-0.88 (m, 3H).

{4-(1-Ethyl-propyl)-pipererazin-1-yl}-{4-pyrrolidin-1-ylmethyl-phenyl)
methanone
Prepared from the product of Example 12 and pyrrolidine.
1H NMR (400 MHz, CDCI3): 7.41-7.35 (m, 4H), 3.73-3.70 (m, 4H), 3.38
15 (br s, 2H), 2.59-2.45 (m, 8H), 2.20-2.17 (m, 1H), 1.83 (br s, 4H), 1.49-1.27 (m,
4H), 0.92-0.88 (m, 6H).

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WO 2004/037801 PCT/US2003/033343

{4-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone
Prepared from the product of Example 13 and dimethylamine
5 hydrochloride.
1H NMR (400 MHz, CDCl3): 7.41-7.31 (m, 4H), 3.79 (br s, 2H), 3.43 (s,
3H), 2.5 (br s, 2H), 2.37-2.34 (m, 3H), 2.24 (br s, 4H), 1.65 (br s, 4H), 1.52-1.40
(m, 2H), 1.39-1.26 (m. 2H) 0.91 (t, J = 7.3 Hz, 3H).

(4-Butyl-piperazin-1-yl)-(4-{(4-trifluoromethyl-phenylamino)-methyl):
phenyl)-methanone
Prepared from the product of Example 13 and 4-trifluoromethyl-
15 phenytamine.
1H NMR (400 MHz, COCl3): 7.45-7.32 (m, 6H). 6.60 (d, J = 8.5 Hz, 2H),
4.59 (t, J = 5.6 Hz, 1H), 4.39 (d, J = 5.3 Hz, 2H), 3.79 (br s, 2H), 3,43 (br s,
2H), 2.60-2.30 (m, 6H), 1.55-1.43 (m, 2H), 1.40-1.25 (m, 2H), 0.92 (t, J = 7.3
Hz, 3H).
20
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{4-(1-Mathyl-heptyI)-piperazin-1- yl)-(4-morpholin-4- ylmethyl- phenyl)-
methanone
5 Prepared from the product of Example 14 and morpholine.
1H NMR (400 MHz, CDCla): 7.39-7.35 (m, 4H), 3.76 (br s, 2H), 3.68-
3.66 (m, 2H), 3.52 (s, 2H), 3.46 (br s, 2H), 2.64-2.45 (m, 10H), 1.51-1.47 (m,
1H), 1.30-1.26 (m, 10H), 1.02 (m, 3H), 0.90-0.87 (m, 3H).

(4-(1 -Methyl-heptyl)-piperazin-1-yl)-(4-piperidin-1- ylmethyl- phenyl)-
methanone
Prepared from the product of Example 14 and piperidine.
15 1H NMR (400 MHz, CDCI3): 7.42-7.35 (m, 4H), 3.77 (br s, 2H). 3.58 (s.
2H), 3.42 (br s, 2H), 2.60-2.47 (m, 10H), 1.65 (br s, 4H), 1.50-1.46 (m, 1H),
1.33-1.28 (m, 10H), 0.97 (d, J = 8.5 Hz, 3H), 0.90-0.87 (m, 3H),
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(4-isopropyl-piperazin-1-yI)-(4-[(4-trifluoromethyl-phenylamino)-methyl]
phenyl}- methanone
5 Prepared from the product of Example 15 and 4-trifluoromethylanitine-
1H NMR (400 MHz, CDCl3): 7.41-7.36 (m, 6H), 6.62 (d, J = 8.5 Hz, 2H),
4.56-4.54 (m, 1H), 4.40 (d, J = 5.8 Hz, 2H), 3.83 (br s, 2H), 3.48 (br s, 2H),
2.80-2.77 (m, 1H), 2.63-2.50 (m, 4H), 1.08 (d, J = 6.6 Hz, 6H).

(4-lsopropyl-piperazin-1-yl)-{4-(4-isopropyl-piperazin-1-ylmethyl)-
phenyl}-methanons
Prepared from the product of Example 15 and the product of Example
15 10
1H NMR (400 MHz, CDCl3): 7.37 (m, 4H), 3.78 (br s, 2H), 3.54 (s, 2H),
3.44 (br s, 2H), 2.76-2.46 (m, 14H), 1.11 (d, J = 6.6 Hzr 6H), 1.05 (d, J = 6.6
Hz. 6H).
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(4-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piparidin-1- ylmethyl)-
phenyl)-methanone
5 Prepared from the product of Example 13 and 3-
trifluoromethyIpiperidine.
1H NMR (400 MHz, CDCl3): 7.74-7.47 (m, 4H), 4.96-4.74 (m, 5H), 4.46-
4.26 (m, 2H), 4.00-3.38 (m, 5H), 2.97-2.69 (m, 6H), 2.04-1.58 (m, 4H), 1.16-0.9
(m, 6H).
10

(4-Butyl-piperazin-1-yl)-(4-moroholin-4- yImethyl-phenyl)- methanone
Prepared from the product of Example 13 and morpholine.
15 1H NMR (400 MHz, CDCI3): 7.35-7.31 (m, 4H), 3.79 (br s, 2H), 3.68 (t, J
= 4.5 Hz, 4H), 3.48 (s, 2H) 3.41 (br s, 2H), 2.48 (br s, 2H), 2.44-2.40, (m, 4H),
2.33 (t, J = 7,6 Hz, 4H), 1.48-1.41 (m, 2H), 1.35-1.26 (m, 2H), 0.89 (t, J =7.3
Hz, 3H).
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(4-Isopropyl-piperazin-1-yl)-(3-morpholin-4-yl methyl-phenyl)-methanone
Prepared from the product of Example 18 and morpholine.
5 1H NMR (400 MKz, COCl3): 7.39-T.28 (m. 4H), 3.79 (br s, 2H), 3.71(t, J
= 4.6 Hz, 4H), 3.52 (s, 2H), 3.42 (br s, 2H), 2.76-2.70 (m, 1H), 2.60 (br s, 2H),
2.46-2.44 (m, 6H), 1.05 (d. J = 6.5 Hz, 6H),

(4-lsopropyl-piperazin-1-yl)-(3-piperidin-1-ylmethyl-phenyl)-methanone
Prepared from the product of Example 16 and piperidine.
1H NMR (400 MHz COCI3): 7.37 (m, 3H), 7.28 (d, J = 1.7 Hz, 1H), 3.79
(br s, 2H), 3.48 (s, 2H), 3.42 (br s, 2H), 2.76-2.69 (m, 1H), 2.69 (br s, 2H), 2.45
15 (br s, 2H), 2.37 (br s, 2H), 1.59-1.54 (m, 4H), 1.44-1.42 (m, 2H), 1.05 (d, J =
6.5 HZ, 6H).
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(4-Isopropyl-piserazin-1-yl)-(4-morpholin-4-ylmethyl-phenyI)-methanone
Prepared from the product of Example 15 and morpholine.
5 1H NMR (400 MHz. CDCI3): 7.36 (s, 4H), 3.79 (br s. 2H), 3.71 (t, J = 4.7
Hz,4H), 3.51 (s, 2H), 3.44 (brs, 2H), 2.76-1.69 (m, 1H), 2.59 (br s, 2H), 2.44
(t, J = 4.4 Hz, 6H), 1.05 (d. J = 6.5 Hz, 6H).

(4-lsopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone
Pepered from the product of Example 15 and piperidine.
1H NMR (400 MHz, CDCl3): 7.35 (s, 4H), 3.79 (brs, 2H), 3.48 (br s, 2H),
3.45 (br s, 2H), 2.72 (m, 1H), 2.59 (br s, 2H), 2.45 (br s, 2H), 2.38 (br s, 4H),
15 1.60-1.55 (m, 4H), 1.48-1.40 (m, 2H), 1.06 (d, J = 6.3 Hz, 6H).

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{3- (4-Benzyl-piperidin-1-ylmethyl)-phenyl}-(4- methyl-piperazin-1-yl-
methanone
Prepared from the product of Example 17 and 4-benzylpiperdine.
1H NMR (400 MHz, CDCl3); 7.37-7.10 (m, 9H), 3.80 (br s, 2H), 3.48 (s,
5 2H), 3.41 (br s, 2H), 2.87-2.79 (m, 2H), 2.53 (d, J = 7.0 Hz, 2H), 2.47 (br s,
2H), 2.33 (br s, 2H), 2.32 (s, 3H), 1.90 (ddd, J = 11.7, 11.7, 2.2 Hz, 2H), 1.63-
1.45 (m, 3H), 1.35-1.23 (m, 2H).

(4-Methyl-piperazin-1-yl)-(4-morphoIin-4-ylmethyl-phenyl)- methanone
dihydrochioride
To a solution of the product of Example 16 (60 mg) and morpholine
(0.025 mL) in DCM (5 mL) was added acetic acid (0.015 mL) and sodium
15 triacetoxyborohydride (83 mg). After 16 h the reaction was treated with 1 N
NaOH (10mL) and extracted with DCM (3 x 20 mL). Organic layers were dried
(Na2SO4), concentrated under reduced pressure, and chromatographed on
silica gel (4% 2 M methanolic ammonia/DCM) to give the free base product.
This material was converted into the dihydrochloride using methanol and 2 M
20 HCl in ether to form a white solid (35 mg).
1H NMR (400 MHz, CD3OD): 7.71 (d, J = 7.8 Hz, 2H), 7.62 (d, J = 8.1
Hz, 2H), 4.45 (s, 2H), 4.07-4.03 (m, 2H), 3.88-3.86 (m, 1H), 3.80 (t, J = 11.6
Hz, 2H), 3.62-3.39 (m, 6H), 3.27-3.17 (m, 5H), 2.96 (s, 3H).
25 The products of Example 44 through Example 62 were prepared in
analogy to the procedure of Example 43 using the speeded carbonyl
compounds and amines.
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(4-Isopropyl-piperazin-1- yl)-{(4-trifluororoethyl-Pyridin-2-ylamino)-
methyl)-phenyl}-methanone dihydrochloride
5 Prepared from the product of Example 15 and 4-trifluaromethyl-pyridin-
2-ylamine.
1H NMR (400 MHz, CO3OD): 8.08-8.06 (m, 1H), 7.58-7.45 (m, 4H),
7.39-7.35 (m, 1H), 7.14-7.10 (m, 1H), 4.76-4.70 (m, 2H), 3.58 (br s, 6H), 3.25-
3.23 (m, 2H), 1.41-1.30 (m, 7H).

{4-(1-Ethyl-propyl)-pipgrazin-1-yl)-(4-phenylarninomethyl-phenyl)-
methanone dihydrochloride
15 Prepared from the product of Example12 and ariline.
1H NMR (400 MHz CD3SOCD3); 7.76-7.63 (m, 4H), 7.53-7.41 (tt, J =
7.3, 6.6 Hz, 2H), 7.03 (t, J =7.2 Hz, 1H), 6.92 (dd, J = 7.6, 1.1 Hz, 2H), 5.60 (s.
1H), 4.68 (br s, 2H), 4.47 (br s, 1H), 4.05 (br s, 2H), 3.70 (br s, 2H), 2.90 (br s,
2H), 2.76 (br s, 2H), 1.84-1.70 (m, 2H)( 1.68-1.55 (m, 2H), 1.30-1.20 (m, 6H),
20
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(4-Dimethylamlnomethyl-phenyl)-{4-(1-ethyl-anopyl)-piperazin-1-yl)
methanone dihydrochloride
5 Prepared from the product of Example 12 and dimethylamine
hydrochloride.
1H NMR (400 MHz, CD3OD); 7.76-7.44 (m, 4H), 4.52 (br s, 1H), 4.32-
4.25 (m, 2H), 3.83-3.56 (m, 2H), 3.23-2.33 (m, 4H), 2:76-2.55 (m, 6H), 2.54-
2.35 (m, 2H), 2.00-1.71 (m, 2H), 1.70-1.47 (m, 2H). 1.05-0.77 (m, 6H).
10

{4-(1-Ethyl-propyi)-piperazin-1- yl)-{(4-trifluoromethyl-phenylamino)-
methyl}-phenyl}-methanone dihydrochloride
15 Prepared from the product of Example 12 and 4-trifluoromethylaniline.
1H NMR (400 MHz, CD3OD): 7.56-7.12 (m, 6H), 6.69-6.49 (m, 2H), 4.81
(s, 2H), 4.47-4.28 (n, 2H), 3.37-3.03 (m, 8H), 1.97-1.56 (m, 4H), 1.13-0.89 (m,
6H).
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{4-(1 -Ethyl-propyl)-piperazin-1-yl)-(4-monpholin-4-ylmethyl- phenyl)-
methaneno dihydrochloride
5 Prepared from the product of Example 12 and morpholine.
1H NMR (400 MHz, dmso-ds): 7.74 (d, J = 8.1 Hz, 2H), 7.55 (d, J = B.1
Hz, 2H), 4.36 (d, J = 4.8 Hz, 2H), 4.00-3.67 (m, 10H), 3.52-3.41 (m, 2H), 3.25-
3.13 (m, 2H), 3.11-2.99 (m, 3H), 1.97-1.80 (m, 2H), 1.69-1.52 (m, 2H), 0.96 (t,
J = 7.58 Hz, 6H).
10

(4-(1-Ethyl-propyl)-piperazin-1-yl)-(4-(3-trifIuorometh yl-piperidin-1-
ylmethyl)-Phenyl}-methanone dihydrochloride
15 Prepared from the product of Example 12 and 3-
trifluonomethylpiperidine.
1H NMR (400 MHz, CD30D): 7.72 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 7.8,
2H), 4.87 (s, 2H), 4.50-4.40 (m, 2H), 3.75-3.41 (m, 8H), 3.20-2.84 (m, 4H),
2.09 (m, 2H), 2.00-1.50 (m, 6H), 1.12-1.02 (m, 6H)-
20
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(4-sec-Buthyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-
phenyl)-methanone dihydrochloride
5 Prepared from the product of Example 11 and 3-
trifluoromethyIpipendine.
1H NMR (400 MHz, CD3OD): 7.71 (d, J=8.3 Hz, 2H). 7.63 (d, J = 8.1
Hz, 2H), 4.86 (s, 2H), 4.52-4.40 (m, 2H), 3.75-3.45 (m, 8H), 3.23-2.96 (m, 5H),
2.17-2.00 (br m, 2H), 1.97-1.54 (m, 4H), 1.50-1.25 (m, 2H), 1.10-0.93 (m, 3H).
10

(4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-Phenyl)-methanone
dihydrochloride
15 Prepared from the product of Example 11 and morpholine.
1H NMR (400 MHz, CD3OD): 7.71-7.62 (m, 4H), 4.43 (s, 2H), 4.14-3.59
(m, 7H), 3.52-3.11 (m,10H), 2.02-1.88 (m, 1H), 1.68-1.49 (m, 1H), 1.38 (d, J =
6.6 Hz, 3H), 1.04 (t, J = 7.3 Hz, 3H).
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(4-Isopropyl-piperazin-1- yl)-{4-{(6-trifluoromethyl-pyrrdin-3-ylamino)-
methylyphenyl)-methanon dihydrochIoride
5 Prepared from the product of Example 15 and 6-trifluoromethyl-pyridio
3-ylamine.
1H NMR (400 MHz, CD3OD): 6.16-8.11 (m, 1H), 7.61-7.74 (m, 1H),
7.53-7.46 (m, 5H), 4.92-4.09 (m, 2H), 4.56-4.51 (m, 2H), 3.56-3.52 (m, 4H),
3.28-3.21 (m, 2H), 1.40-1.46 (m, 7H)-
10

{4-{ (5-Chloro-pyridin-2-ylamino)-methyl}-phenyl)-(4-Isopropyl-piperazin-
1-yl)-methanone dihydrochloride
15 Prepared from the product of Example 15 and 5-chloro-pyridin-2-
yiamine.
1H NMR (400 MHz, CD3OD): 8.04 (d, J = 2.5 Hz, 1H), 7.38-7.33 (m,
5H), 6.32 (d, J = 8.6 Hz, 1H), 5,05 (t, J = 5.6 Hz, 1H), 4.52 (d, J = 6.1 Hz, 2H),
3.78 (br s, 2H), 3.43 (br s, 2H), 2.72 (m, 1H), 2.58-2.44 (m, 4H), 1.04 (d, J =
20 6,6 Hz, 6H).
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(4-Methyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone
dihydrochioride
5 Prepared from the product of Example 16 and piperidine.
1H NMR (400 MHz, CD3OD) 7.68-7.60 (m, 4H), 4.36 (s, 2H), 3.73 (br s,
2H), 3.52-3.46 (m, 4H), 3.25 (br s, 4H), 3.00 (br s, 2H), 2.87 (s, 3H), 1.94-1.82
(m, 5H), 1.53 (br s, 1H).

(4-lsopropyl-piperazin-1-yl)-(4-{(5-trifluoromethyl-pyridin-2- ylamino)-
methyl)}-phenyl)-methanone dihydrochloride
Prepared from the product of Example 15 and 5-trifluoromethyl-pyridin-
15 2-ylamine.
1H NMR (400 MHz, CD3OD): 8.31 (s, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.57
(s, 4h), 7.24 (d, J = 9.6 Hz, 1H), 4.75 (s, 2H), 3.60-3.46 (m, 6H), 3.24-3.21 (m,
2H), 1.41-1.40 (m, 7H).
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(4-Isopropyl-piperazin-1-yl)-{4-(3-trifluoronoethyl-piperidin-1-ylmethyl)-
phenyl-methanone dihydrochIoride
5 Prepared from the product of Example 15 and 3-trifluoromethyl-
pipandine.
1H NMR (400 MHz, CD3OD); 7.74-7.64 (m,4H), 4.88 (s. 2H), 4.52-4.41
(m, 2H), 3.70-3.50 (m, 6H), 3.26-3.13 (m, 4H), 3.07-2.92 (m, 2H), 2.14-2.07 (m,
2H), 1.94-1.84 (m, 1H), 1.68-1.58 (m, 1H), 1.42-1.39 (m, 6H),
10

(4-Diethylaminomethyl-phenyI)-(4-isopropyI-piperazin-1- yl)-methanone
dihydrochloride
15 Prepared from the product of Example 15 and diethylamine.
1H NMR (400 MHz, CD3OD): 7.70-7.64 (m, 4H), 4.42 (s, 2H), 3.61-3.57
(m, 6H), 3.25-3.22 (m, 6H), 1.42-1.30 (m, 13H),
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{4-{Benzylamino-methyl)-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone
dihydrochloride
5 Prepared from the product of Example 15 and benzylamtne.
1H NMR (400 MHz, CD3OD): 7.67-7.43 (m, 9H), 4.33 (s, 2H) 4.29 {s,
2H), 3.61 -3.58 (m, 6H), 3.26-3.22 (m, 2H), 1.42-1.41 (d. J = 6.6 Hz, 7H).

(4-Isopropyl-piperazin-1-yl)-(4-phenylaminomethyl-phonyl)-methanone
dihydrochloride
Prepared from the product of Example 15 and anlline.
1H NMR (400 MHz, CD3OD): 7.57-7.64 (m, 7H), 7.47-7.44 (m, 2H), 4.69
15 (s, 2H), 3.62-3.52 (m, 6H), 3.25-3.19 (m, 2H), 1.42-1.41 (d, J = 6.6 Hz, 7H).

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(4-Azapan-1-ylmetnyl-pheny)-(4-isopropyI-piperazin-1- yl)-methanone
dihydrochloride
Prepared from the product of Example 15 and azepane.
1H NMR (400 MHz, CD3OD): 7.69 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.1
5 Hz, 2H), 4.43 (s, 2H), 3.60-3.43 (m, 8H), 3.23-3.20 (m, 4H), 1.97-1.90 (m, 4H).
1.79-1.73 (m, 4H), 1.42-1.46 (d, J = 6.6 Hz, 7H).

10 (4-Isopropyl-piperazin-1- yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone
dihydrochloride
Prepared from the product of Example 15 and pyrrolidine.
1H NMR (400 MBz, CD3OD): 7.69 (d, J = 8.3 Hz, 2H), 7.63 (d, J - 8.2
Hz, 2H), 4.46 (s. 2H), 3.61-3.51 (m, 8H), 3.26-3.20 (m, 4H), 2.22-2.18 (m, 2H),
15 2.06-2.03 (m, 2H), 1.42 (d, J = 6.6 Hz, 7H).

(4-Dimethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone
20 dihydrochloride
Prepared from the product of Example 15 and dimethylamine
hydrochloride,
1H NMR (400 MHz, CD3OD)- 7.66 (br s, 4H), 4.40 (s, 2H), 3.65-3.54 (m,
4H), 3.26-3.20 (m, 4H), 2.89 (br s, 6H), 1.41 (d, J = 6.6 Hz, 7H),
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(4-Isopropyl-piperazin-1-yl)-(4-[[(2-methoxy-ethyl)-propyl-aminol-methyl)-
phenyl)-methanone
5 Prepared from the product of Example 15 and (2-methoxy-ethyl)-propyl-
amine.
1H NMR (500 MHz, CDCl3): 7.41-7.34 (m, 4H), 3.79 (br s, 2H), 3.65 (s,
2H), 3.51-3.46 (m, 4H), 3.32 (s, 3H), 2.76-2.71 (m, 1H), 2.69-2.65 (m, 2H),
2.53 (br s, 2H), 2.46-2.43 (m, 4H), 1.67 (br s, 1H), 1.53-1.46 (m, 2H), 1.06 (d, J
10 = 6.5 Hz, 6H), 868 (t, J = 7.3 Hz, 3H).

(4-{[Ethyl-(2-methoxy-ethyl)-amino]-methyl}-phenyl)-(4-isopropyl -
15 piperazin-1-yl)-methanone
Prepared from the product of Example 15 and (2-methoxy-ethyl)-ethyl-
amine.
1H NMR (400 MHz, CDCl3): 7.42-7.31 (m, 4H), 3.79 (br s, 2H), 3.70 (s,
2H)r 3.53-3.45 (m, 4H), 3.33 (s, 3H), 2.76-2,71 (m, 1H), 2.69-2-67 (m, 2H),
20 2.60-2.56 (m, 4H), 2.46 (s, 2H), 1.62 (br s, 1H), 1.11-1.01 (m, 8H).
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4-Cyclohexyl-piperazine-1-carboxylic acid tert-butyl ester
5 Prepared in analogy to Example 1 from piperazine-1-carboxylic acid tert-
butyl ester and cyclonexanone.

10 1-Cyclohexyl-piperazine dihydrochloride
Prapaned in analogy to Example 6 from the product of Example 63,

15 4-(4-Cyclohgxyl-piperazine-1-carbonyl)-benzaldehyde
Prepared in analogy ta Example 11 from the product of Example 64-
The products of Example 66 through Example 72 were prepared in
analogy to the procedure of Example 20 from the specified carbonyl
20 compounde and amines.
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(4-Cyclohexyl-piperazine-1-yl)-(4-piperidin-1 -ylmethyl-phenyl)-methanone
Prepared from the product of Example 65 and piperidine.
5 1H NMR (400 MHz, CDCI3): 7.35 (s, 4H), 3.78 (br s, 2H), 3.48 (s, 2H),
3,44 (br s, 2H), 2.64-2.51 (m, 4H), 2.37 (br s, 2H), 2.30-2.29 (m, 2H), 1.86-1.80
(m, 4H), 1.65-1.55 (m, 7H), 1.45-1.44 (m,2H), 1.24-1.19 (m, 4H),

(4-Isopropyl-piperzin-1-yl)-(4-thiomorpholin-4-ylmethyl-phenyl)-
methanone
Prepared from the product of Example 15 and thromorpholine.
1H NMR (400 MHz, CDCI3): 7.40-7.30 (m, 4H), 3.90-3.63 (br m, 2H),
15 3.53 (s, 2H), 3.49-3.37 (br m, 2H), 2.81-2.63 (m, 9H), 2.63-2.52 (br m, 2H),
2.51-2.35 (br m, 2H), 1.05 (d, J = 6.5 Hz, 6H).
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(4-Isopropyl-piperagin-1-yI)-(4-[(2-methoxy-ethyIamino)-methyl)-phenyl}
methanone
5 Prepared from toe product of Example 15 and (2-methoxy-ethyl)-amine.
1H NMR (400 MHz, CDCl3); 7.36 (m, 4H). 3,84 (s, 2H), 3.75 (br s. 2H),
3.53-3.51 (m, 2H), 3.42 (br s, 2H), 3.62 (s, 3H), 2.81-2.79 (m, 2H), 2.77-2.74
(m, 1H), 2.62 (br s, 2H), 2.42 (br s, 2H), 1.70 (br s, 1H), 1 .05 (d, J = 6.5 Hz,
6H).
10

(4-Isopropyl-piperazin-1-yl)-[4-(pyridin-2-ylaminomethyI)-phenyl]-
methanone
15 Prepared from the product of Example of 15 and 2-ammopyridine,
1H NMR (400 MHz, CDCI3): 8.16-8.10 (m, 1H), 7.46-7.36 (m, 5H), 6.65-
6.59 (m, 1H), 6.42-6.36 (m, 1H), 5.04 (t, J = 6,1 Hz, 1H), 4.57 (d, J = 5.9 Hz,
2H), 3.91-3.68 (br m, 2H), 3.56-3.36 (br m, 2H), 2.80-2.67 (m, 1H), 2.59-2.54
(br m, 2H), 2.53-2.34 (br m, 2H), 1.07 (d, J = 6.6 Hz, 6H).
20
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(4-lsopropyl-piperazin-1-yl)-(4-[(2-methoxy-1-methyl-ethylamino)-
methyl-phenyl]-methanone
5 Prepared from the product of example 15 and 2-methoxy-1-methyl-
erthylamine.
1H NMR (500 MHz, CDCl3): 7.35-7.38 (m, 4H), 3.89 (d, J= 13.3, 1H),
3.82-3.75 (m, 3H), 3.45 (brs, 2H), 3.43-3.32 (m, 4H), 3.28-3.25 (m, 1H), 2.96-
2.92 (m, 1H), 2.75-2.53 (m, 1H), 2.65-2.20 (m, 5H), 1.06-1.04 (m, 9H).
10
BIOLOGICAL METHODS
In Vitro
Transfection of cells with human histamins receptor
15 A 10 cm tissue culture dish with a confluent monolsyer of SK-N-MC cells
was split two days prior to transfeclion. Using sterile technique the media was
removed and the cells were detached from the dish by the addition of trypsin.
One fifth of the cells were then placed onto a new 10 cm dish. Cells were
grown in a 37 ºC incubator with 5% CO2 in Minimal Essential Media Eagle with
20 10% Fetal Boylne Serum,After two days celle were approximately 80%
confluent. These were removed from the dish with trypsirt and pelleted in a
clinical centriluge. The pellet was then re-suspended in ADD ml complete
madia and transfferred to an etectroporation cuvetle with a 0.4 cm gap between
the electrodes. One microgram of supercoilad H3 receptor cDNA was added to
25 the cells and mixed. The voltage for the electroporation was set at 0.25 kV, the
capacitance was set at 960 mF. After electroporation the cells were diluted into
10 mL camp fete media and plated onto four 10 cm dishes. Because of the
variability in the efficiency of electroporation, four different concentrations of
cells were plated. The ratios used were: 1:20, 1:10, 1:5, with the remainder of
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WO 2004/037801 PCT/US2003/033343
the cells being added to the fourth dish. The cells were allowed to recover for
24 h before adding the selection media complete media with 600 mg/mL
G418). After 10 days dishes were analyzed for surviving colonies of cells.
Dishes with well-isolated colonies were used. Cells from individual colonies
5 were isolated and tested, SK-N-MC cells were used because they give
efficient coupling for inhibition of adenylate cyclase. The clones that gave the
most robust inhibition of adenylato cyclase in response to histamine were used
for further study.
10 {3H}-N-methythistamine binding
Cell pellets from histemtne H3 receptor-expressing SK-N-MC celts were
homogenized in 20 mM TrisHCl/0.5 mM EDTA. Supernatsnts from an 600 g
spin were collected, recentrifuged at 30,000 g for 30 min. Pellets were re-
homogenized in 50 mM Tris/5 mM EDTA (pH 7.4). Membranes were
15 incubated with 0.8 nU {3H}-N-methythistamine plus/minus test compounds for
45 min at 25 ºC and harvested by rapid filtration over GR/C glass fiber filters
(pretreated with 0.3 % polyethytenimine) followed by four washes with ice-cold
buffer. Fillers were dried, added to 4 mL scinfillation cocktail and then counted
on a liquid scintillation counter. Non-specific binding was defined with 10 mM
20 histamine. The pK1 values were calculated based on a Ka of 800 pM and a
Iigand concentration ({L}) of 800 pM acoording to the formula:
K1=(LC50)/(1+({L}/(Kd))
K1 values for exemplary compounds of the invention are listed in the
table below.

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WO 2004/037801 PCT/US2003/033343

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WO 2004/037801 PCT/US2003/033343
F. Other Embodiments
The features and advantages of the invention will be apparent to one of
ordinary skill in view of the discussion, examples, embodiments, and claims
relating to the invention. The invention also contemplates variations and
5 adaptations, based on the disclosure herein concerning the key features and
advantages of the invention, and within the abilities of one of ordinary skill.
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WO 2004/037801 PCT/US2003/033343
22. A compound of claim 1, wherein H8 is C1-8 alkyl.
23. A compound of daim 1, wherein R9 is unsubstiluted or substituted
phenyl.
5
24. A compound of claim 1, wherein R8 and R9 independently are C1-6 alkyl.
25. A compound of claim 1, wherein R8 and R9 are methyl.
10 26. A compound of claim 1, wherein R8 and R9 are ethyl
27. A compound of claim 21, wherein R9 is a elected from phenyl or 5-9
membered aromatic heterocyclyl, wherein said phenyl or aromatic
heteracyclyl is optionally substituted with 1-3 substituents selected from
15 methoxy, hydroxy, halo, nitro, cyano, trifluoromethyl, and C1-8 alkyl.
28. A compound of claim 27, wherein R9 is selected from substituted or
unsubstituted phenyl, pyridyl, pyrimidyl, furyl, thiofuryl, imdazolyl,
(imidazolyl)C1-5 alkylene, oxazofyl, thiazolyl, 2,3-dihydro-indolyl,
20 benzimidazolyl, 2-oxobenzimidazolyl, (terrazolyl)C1-6 alkylene, tetrazolyl,
(triazolyl)C1-6 alkylene, triazolyl, (pyrrolyl)C1-6 alkylene, pyrrolidinyl, and
pyrrolyl.
29. A compound of claim 28, wherein R9 is phenyl.
25
30. A compound of claim 28, wherein R9 is substituted or unsubstituted
pyridyl.
31. A compound of claim 1 wherein
30 R1 is C1-10 alkyl;
X is O;
R4 is G;
L is -CH2-; and
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WO 2004/037801 PCT/US2003/033343
Q is a saturated N-linked nitrogen-contain ing heterocyclyl
32. A compound of claim 31 wherein R1 is branched.
5 33. A compound of claim 31 wherein R1 is C3-5 alkyl.
34. A compound of claim 31, wherein wherein R1 is isopropyl.
35. A compound of claim 31, wherein Q is selected from substituted or
10 unsubstituted piperidinyl, diazepanyl, azepanyl, decahydroisoqulinolin-2-
yl, pipenazinyl, pyrrolInyl, pymolidinyl, thlomorpholinyl, or morpholinyl.
36. A compound of claim 31, wherein Q is unsubstituted azepanyl,
diazepanyl, morpfiolinyl, decahydroisoquinolin-2-yl, piperidlnyl, or
15 pyrrolidinyl.
37. A compound of claim 1 selected from the group consisting of:
(4-{(Ethyl-(2-methoxy-ethyl)-amino]-methyl}-phenyl)-(4-isopropyl-
piperazin-1-yl)-methanone;
20 (4-Azepan-1-yImethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-mathanone
dihydrochloride;
(4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1 -yI)-methanone;
(4-Azepan-1-ylmethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl)-
methanone;
25 (4-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;
(4-Butyl-piperazin-1-yl)-(4-morpholin-4-yImethyl-phenyl)-methanone;
(4-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-
phenyl}-methanone;
(4-Buty l-pi pe razin-1 -y \ )-{4-{{4-tri flu o romethy !-p her>ytamino)-methy1}'
30 phenyl}-methanone;
(4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl}-methanone;
{4-Diethylaminomethyl-phenyl)-(4-Isopropyl-piperazin-1-yl)-methanone
dihydrachloride;
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WO 2004/037801 PCT/US2003/033343
(4-Dimethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone
dihydrochloride;
(4-DimethylaminomethyI-phenyI)-{4-(1-ethyl-propyI)-piperazin-1-yl}-
methanone dihydrochloride;
5 (4-Isopropyl-piperazin-1-yl)-(3-morpholin-4-ylmethyl-phenyl)-methanone;
(4-lsopropyl-piperazin-1-yl)-(3-piperidin-1-ylmethyl-phenyl)-methanone;
(4-Isopropyl-piperazin-1-yI)-(4-{[(2-methoxy-ethyI)-propyI-amino]-inethyI}-
phenyl)-methanone;
(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;
10 (4-Isopropyl-piperazin-1-yl)-(4-phenylaminomethylphenyl)-methanone
dihydrochloride;
(4-Isopropyl-pipenazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;
(4-Isopropyl-piperazin-1-yI)-{4-pyrrolidin-1-ylmethyl-phenyl)-methanone
dihydrochloride;
15 (4-lsopropyl-piperazin-1-yl)-(4-thiomorpholin-4-ylmethyl-phenyl)-
methanone;
(4-Isopropyl-piperazin-1-yl)-{4-(3-influoromethyl-piperidin-1-ylmethyl)
phenyl)-methanone dihydrochloride;
(4-Isopopyl-piperazin-1-yl)-{4-(4-isopropyl-piperazin-1-ylmethyl)-
20 phenyl]-methanone;
(4-Isopropyl-prperazin-1-yl)-{4-{(2-methoxy-ethylamino)-methyl)-pheny[}-
methanone;
(4-Isopropyl-piperazin-1-yI)- [4-(pyridin-2-ylaminomethyI)-phenyI]-
methanone;
25 (4-lsopropyl-piperazin-1-yl)-[4-[(2-methoxy-1-methyl-ethylamino)-
methyl]-phenyl]-methanone;
(4 -Isopropyl -piperazin-1-yl)-{4-[{4-trifluoromethyl-phenylamino)-methyl}-
phenyl}-methanone;
(4-Isopropyl-piperazin-1-yl)-{4-{(4-trifluoromethyl-pyridin-2-ylamino)-
30 methyl)-phenyl}-methanone dihydrochloride;
(4-Isopropyl-piperazin-1-yl)-{4-{(5-trifIuoromethyl-pyridin-2-ylamina)-
methyl}-phenyl}-methanone dihydrochloride;
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WO 2004/037801 PCT/US2003/033343
What is claimed is:
1. A composition comprising a compoand of formula (I):

5
wherein
R1 is C1-10) alkyl, C3-8 alkenyl, C3-8 cycloalkyl, (C3-5 cycloalkyl)C1-5 alkyl,
(C3-8 cycloalkyl)C3-8 alkenyl, or (C1-8 alkylcarbonyl)C1-8 alkyl;
n is 1 or 2;
10 X is O or S;
one of R2, R3 and R4 is G and the other two independency are
hydrogen, fluoro, chlora, bromo, nitro, trifluoromethyl, methyl, or
C1-3alkoxy;
G is LQ;
15 L is unbranched -(CH2)m- wherein m is an integer from 1 to 7;
Q is NR8R3 wherein R8 is independently selected from hydrogen, C1-5
alkyl, C3-8 alkenyl, 3-9 membered carbocyclyl, 3-12 membered
heierocyclyl, phenyl, (6-9-membered heterocyclyl)C1-6 alkylene,
and (phenyl)C1-5 alkylene; and R9 is independently selected from
20 Ct-s alkyl, C3-6 alkenyl, 6-9 membered carbocyclyl, 3-12
membered heterocyclyl, phenyl, (6-9-membered heterocyclyl)C1-6
alkylens, and (phenyl)C1-6 alkytene, or
Q is a saturated 3-12 membered N-linked hetorocydyl, wherein, in
addition to the N-tinking nitrogen, the 3-12 membered
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WO 2004/037801 PCT/US2003/033343
(4-Isopropyl-piperazin -1-yl)-{4-{(6-trifluoromethyl-pyridin-3-ylamino)-
methyl}-phenyl}-methanona dihydrochloride;
(4-Methyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)- methanone
dihydrochlorid;
5 (4-Methyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl- phenyl)-methanone
dihydrochloride;
(4-sec-Butyl-piperazin-1-yl)-{4-dimethylaminomethyl-phenyl)-
methanone;
(4-sec-Buty-1-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
10 dihydrochloride;
(4-sec-Butyl-piperazin-1-yl)-(4-phertylaminomethyl-phenyl}-methanone;
(4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;
(4-sec-Butyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;
(4-sec-Butyl-piperazin-1-yl)-(4-(3-trifluoromethyl-piperidin-1-ylmethyl)-
15 phenyl)-methanone dihydrochloride;
(3-(4-Benzyl-piperidin- 1-ylmethyl)-phenyl}-(4-methyl-piperazin-1-yl)-
methanone;
{4-(1-Ethyhpropyl)-piperazin-1-yl]-(4-morpholin-4-ylmethyl-phenyl)-
methanone dihydrochloride;
20 {4-( 1 -Ethyl-propyl)-piperazin-1-yl}-{4-phenylaminomethyl-phenyl)-
methanone dihydrochloride;
{4-(1 -Ethyl-propyl)-piperazin-1-yl)-{4-piperidin-f-ylmethyl-phenyl)-
methanone;
{4-(1-Ethyl-prapyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-
25 methanone;
{4-(1-Ethyl-prapyl)-piperazin-1-yI)-(4-(3 -trifluoromethyl-piperidin-1-
ylmethyl)-phenyl}-methanone dihydrochloride;
{4-(1-Ethyl-pnopyl)-piperazin-1-yI)-(4-(decahydro-isoquinolin-2-ylmethyl)-
phenyl)-methanone;
30 {4-(1 -Elhyl-propyl}-piperazin-1-yl}-{4-{(4-trifIuoromethyl-phenylamino)-
methyl)-phenyl)-methanone dihydrochloride;
{4-(1 -Mylethyl-heptyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-
methanone;
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WO 2004/037801 PCT/US2003/033343
heterocyclyl may optionally contaln between 1 and 3 additional
heteroatoms indeperidently selected from O, S, and NH;
wherein Q is optionally substituted with 1-3 substituents independentiy
selected from the group consisting of hydroxy, halo,
5 carboxamide, C1-5 alkyl, 5-9 membered or 6-9 membered
heterocyclyl), -NH(5-9 membered or 6-9 membened heterocyclyl),
-O(5-9 or 6-9 membered heterocyclyl), (5-9 membered or 6-9
membered heterocyclyl)C1-3 alkylene, C1-6 alkoxy, (C3-6
10 cycloalkyl)-O-, phenyl, (phenyl)C1-3 alkylena, and (phenyl)C1-3
alkylene-O-, where each of above heterocyclyl, phenyl, and alkyl
groups may be options fly substituted with from 1 to 3 substituents
independently selected from tifluoromethyl, methoxy, halo, nitro,
cyano, hydroxy, and C1-3 alkyI;
15 provided however that when R1 is methyl, G is not piperidin-1-ylmethyl;
and
wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl,
cycloalkyl, cacbocyclyl, and aryl groups may each be
independently and optionally substituted with between 1 and 3
20 substituents independently selected from trifluoromethyl,
methoxy, halo, amino, nitro, hydroxy, and C1-3 alkyI;
or a pharmaceutically acceptable salt, ester, tautomer, solvate or amide
thereof.
25 2. A compound of claim 1, wherein R1 is C1-10 alkyl.
3. A compound of claim 1, wherein R1 is C3-5 alkyl.
4. A compound of claim 1, wherein wherein R1 is isopropyl.
30
5. A compound of claim 1 wherein n is 1.
6. A compound of claim 1, wherein wherein X is O.
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WO 2004/037801 PCT/US2003/033343
7. A compound of claim 1, wherein one of R3 and R4 is G.
8. A compound of claim 1, wherein R4 is G,
5
9. A compound of claim 1, wherein L is unbranched -(CH2)m, wherein m is
an integer from 1 to 4.
10. A compound of claim 1, wherein L is -CH2-.
10
11. A compound of claim 1, wherein L is -CH2CH2-.
12. A compound of claim 1 wharein Q is a saturated M-linked nitrogen-
containing heterocyclyl.
15
13. A compound of claim 1, wherein Q is selected from substituted or
unsubstituted piperidinyl, diazepanyl, azepanyl, decahydrolsoqulnolin-2-
yl, piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpriolinyl, or morpholinyl.
20 14. A compound of claim 1, wherein O is unaubstituted piperndinyl,
diazepanyl, azepanyl, decahydroisoquinolin-2-yl, piperazinyl, pyrrolinyl,
pyrrolidinyl, thiomorpholinyl, or morpholinyl.
15. A compound of claim 14, wherein Q is unsubstituted diazepanyl,
25 azspanyl, morpholinyl, decahydroisoquinolln-2-yl, piperidinyl, of
pyrrolidinyl;
16. A compound of claim 1, wherein substituted Q are selected from N-(C1-6
alkyl)pipesrazinyl, N-phenyl-piperazinyl, 1,3,8-triaza-spiro{4.5}decyl, and
30 1,4-dioxa-8-aza-spiro{4.5}decyl,
17. A compound of claim 1, wherein Q is a monovalent radical of an amine
selected from aziridine, 1,4,7-trioxa-10-aza-cyclododecane, thiazolidine,
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WO 2004/037801 PCT/US2003/033343
1 -phenyI -1,3,8-friaza-spiro{4.5}decan-4-ono, piperidine-3-carboxylic acid
diethylamde, 1,2,3,4,5,6-hexahydro-{2,3}hipyridinyl, 4-(3-
trifluoromethyl-phenyl)-piperazine, 2-piperazin-1 -yl-pyrimidine,
piperidine-4-carboxylic acid amide, methyl-(2-pyridin-2-yl-ethyl)-amine,
5 {2-(3,4-dimethoxy-phenyl)-ethyl}-methyl-amine, thromorphoIinyl, allyl-
cyclopentyt-amine, [2-(1H-indol-3-yl-athyl)-methyl-amine, 1 -piperidin-4-
yl-1,3-dihydro-benzoimidazol-2-one, 2-(piperidin-4-yloxy)-pyrimidine,
piperidin-4-yl-pynidin-2-yl-amine, phenylamine, pyridin-2-ylamine,
10 18. A compound of claim 1, wherein Q is selected from diazepanyl
azepanyl, morpholinyl, piperidinyl, and pyrrolidinyl, optionally substituted
with between 1 and 3 substituents selected from hydroxy, halo,
cartioxamide, C1-6 alkyI, 5-9 membered or 6-9 membered heterocyclyl,-
N(C1-6 alkyI)(5-9 membered or 6-9 membered heterocydyl), -NH(5-9
15 membered or 6-9 membered heterocyclyl),-O(5-9 or 6-9 membered
heterocyclyl), (5-9 membered or 6-9 membered heterocyclyl)C1-3
alkylene, C1-5 alkoly, (C3-5 cyctoalkyl)-O-, phenyl, (phenyl)C1-3 alkylene,
and (phenyl)G1-3 alkylene-O-, where each of above heteracyclyl, phenyl,
and alkyl groups may be optionally substituted with from 1 to 3
20 substituents independently selected from trifluoramethyl, methoxy, haIo,
nitro, cyano, hydroxy, and C1-3 alkyL.
19. A compound of claim 12, wherein Q is substituted with a substituent
comprising a 5-9 membered heterocyclyl group selected from pyridyl,
25 pyrimidyl, furyl, thiofuryl, Imidazolyi, (imidazolyl)C1-5 alkylene, oxazolyl,
thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl,
(tetrazolyl)C1-6 alkylene, tetrazolyl, (triazolyl)C1-5 alkylene, triazolyl,
(pyrrolyl)C1-6 alkylens, pymolidinyl, and pyrrolyl,
30 20. A compound of claim 19, wherein Q is piperidinyl.
21. A compound of claim 1, wherein R8 is hydrogen.
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WO 2004/037801 PCT/US2003/033343
{4-(1-Methyl-heptyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyhphenyl)-
methanone;
{4-(Benzylamino-metinyl)-phenyl}-(4-isopropyl)-piperazin-1-yl)-methanone
dihydrochloride;
5 {4-(Benzylamino-methyl)-phenyl}-[4-{1-ethyl-propyl)-piperazin-1-yl}-
methanone; and
{4-{(5-Chloro-pyridin-2-ylamino)-methyl)-phenyl}-{4-Isopropyl-piperazin-
1-yl)-methanone dihydrochloride.
10 38. A compound of claim 1 selected from the group consisting of;
(4-([Ethyl-(2-methoxy-ethyl)-amino]-methyl)-phenyl)-(4-isopropyl-
piperazin-1-yl)-methanone;
(4-Azepan-1-ylmethyl-Phenyl}-(4-isopropyl-piperazin-1-yl)-methanone
dihydrochloride;
15 (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone;
(4-Azepan-ylmethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl]-
methanone;
(4-B utyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl}-methanone;
(4-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;
20 (4-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-
phenyl]-methanone;
(4 -Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methannone;
(4-Diethylaminomethyl-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone
dihydrochloride;
25 (4-Dimethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone
dihydrochloride;
(4-Dimethylaminomethyl-phenyl)-(4-{1-ethyl-propyl)-piperazin-1-yl}-
methanone dihydrochloride;
(4 - isopropyl-piperazin-1-yl)-(3-piperidin-1-ylmethyl-phenyl)-methanone,
30 (4-lsoprapyl-piperazin-1-yl)-(4-{[(2-methoxy-ethyl)-propyl-amino]-methyl]-
phenyl)-methanone;
(4-Isopropyl-piperazin-1-yI}-(4-morphoIin-4-ylmethyl-phenyl)-methanone;
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WO 2004/037801 PCT/US2003/033343
(4-Isopropyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone
dihydrochloride;
(4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;
(4-lsopropyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyI)-methanone
5 dihydrochloride;
(4-Isopropyl-piperazin-1-yl)-(4-thomorpholin-4-ylmethyl-phenyl)-
methanone;
(4-Isopropyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-
phenyl)-methanone dihydrochloride;
10 (4-lsopropyl-piperazin-1-yl)-{4-(4-isopropy-1-piperazin-1-ylmethyl)-
phenyl)-methanone;
(4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-ethylamino}-methyl]-phenyl}-
methanone;
(4-Isopropyl-piperzin-1-yl)-[4-{pyridin-2-ylaminomethyl)-phenyl]-
15 methanone;
{4-lsopropy-piperazin-1-yl)-{4-[(2-methoxy-1-methyl-ethylamino)-
methyl]-phenyl}-methanone;
(4-Isopropyl-piperazin-1 -yl)-{4-{5-trifluoromethyl-pyridin-2-ylamino)-
methyl-phenyl)-methanone dihydrochloride;
20 (4-lsoprapy-piperazin-1-yl)-((6-trifluoromethyl-pyridin-3-ylamino)-
methyl-phenyl)-methanone dihydrochloride;
(4-Methyl-piperazin-1-yl)-(4-morpholin-4-yImethyl-phenyl)-methanone
dihydrachloride;
(4-Methyl-piperazin-1-yl)-(4-piperdin-1-ylmethyl-phenyl-methanone
25 dihydrochloride;
(4-sec-Butyl-piperazin-1-yI)-(4-dimethylaminomethyl-phenyl)-
methanone;
(4-sec-Butyl-piperazin-1-yl)-(4-morphalin-4-yImethyl-phenyl)-methanone
dihydrochloride;
30 (4-sec-Butyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone;
(4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethy-phenyl)-methanone;
(4-sec-Butyl-piperazin-1-yI)-(4-pyrrolidin -1 -ylmethyl-phenyl)-methanone;
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WO 2004/037801 PCT/US2003/033343
{4-sec-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-
phenyl)-methanone dihydrochloride;
(4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyI-phenyl)-
mathanone dihydrochloride;
5 {4-(1-Ethyl-propyl)-piperazin-1-yl)-(4-piperidin-1 -ylmethyl-phenyl)-
methanone;
{4-(1-Ethyl-propyI)-pipenazin-1-yl)-(4-pyrrolidin-1-yImethyl-phenyl)-
methanone;
[4-{1-EthyI-propyl)-piperazin-1-yl}-{4-(3-trifluoramethyl-piperidin-1-
10 ylmethyl)-phenyl}-methanone dihydrochloride;
{4- (1-EthyI-propyl)-piperazin-1-yl}-{4-(decahydro-isoquinolin-2-ylmethyI)-
phenyl)-methanone;
(4-(Benzylamino-methyl)-phenyl}-(4-Isopropyl-piperazin-1-yl)-methanone
dihydrochloride;
15 {4-(Benzylamino-methyl)-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-
methanone; and
{4-{(5-Chloro-pyridin-2-ylamino)-methyl)-phenyl}-(4-Isopropy|-piperazin-
1-yl)-methanone dihydrochloride.
20 39. A compound of claim 1 selected from the group consisting of:
(4-{[Ethyl-(2-methoxy-ethyl)-amino]-methyl}-phenyl)-{4-isopropyl-
piperazin-1-yl)-methanone;
(4-Azepan-1-ylmethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-metharnone
dihydrochloride;
25 (4-Azepan-1-ylmethyl-phenyl)-(4-seo-butyI-piperazin-1-yl)-methanone;
(4-Azepan-1 -ylmethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-
methanone;
(4-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;
(4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;
30 (4-Diethylaminomethyl-Phenyl)-(4-Isopropyl-piperazin-1-yl)-methanone
dihydrochloride;
(4-Dimethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone
dihydrochloride;
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WO 2004/037801 PCT/US2003/033343
(4-Dimethylaminomethyl}-phenyl)-{4-{1-ethyl-propyl)-piperazin-1-yl}-
methanenone dihydrochloride;
(4-Isopropyl-piperazin-1-yl)-(4-[[(2-methoxy-ethyl)- propyl-amino]-methyl}-
phenyl)-methanone;
5 (4-Isopropyl-piperazin-1-yl)-{4-morpholin-4-ylmethyl-phenyl)-methanone;
{4-lsopropyl-piperazin-1-yl)-{4-piperidin-1-ylmethyl-phenyl}-methanone;
(4-Isopropyl-piperazin-1-yl)-(4-pymolidin-1-ylmethyl-phenyl)-methanone
dihydrochloride;
{4-Isopropyl-piparazin-1-yl)-(4-thiornorpholin-4-ylmethyl-phenyl)
10 methanone;
(4-lsopropyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-
phenyl}-methanone dihydrochloride;
(4-Isopropyl-piperzin-1-yl)-(4-[(2-methoxy-ethylamino)-methyl]-phenyl)-
methanone;
15 (4-lsopropy)-piperazin-1-yl}-[4-(pyridin-2-ylaminomethyl)-phenyl]-
methanone;
(4-lsopropyl-piperazin-1-yl)-(4-[(2-methoxy-1-methyl-ethylamino)-
methyl]-phenyl}-methanone;
(4-sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl}-
20 methanone;
(4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
dihydrochloride;
(4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;
(4-sec-Butyl-piperazin-1-yl)-(4-pyrrolldin-1-ylmethyl-phenyl)-methanone;
25 {4-{1-Ethyl-propyl)-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-
methanone dihydnochlorids;
{4-(1-Ethyl-propyl)-piperzin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-
methanone;
{4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-
30 methanone;
{4-(1-Ethyl-propyl)-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-
ylmethyl)-phenyl}-methanonedihydrochloride;
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WO 2004/037801 PCT/US2003/033343
{4-{1-Ethyl-propyl)-piperazin-1-yl}-{4-(decahydro-isoquinolin-2-ylmethyl)-
phenyl}-methanone;
{4-(Benzylamino-methyl)-phenyl)-(4-isopropyl-piperazin-1-yl)-methanane
dihydrochloride; and
5 {4-(Benzylamino-methyl)-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl)-
methanone,
40. A compound of claim 1 selected from the group consisting of:
(4-Azepan-1-ylmethyl-phenyl0-(4-isopropyl-piperazin-1-yl)-methanone
10 dihydrochloride;
(4-Azepan -1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone;
{4-Cyclahexyl-piperazin-1-yl)-(4 -piperidin-1-ylmethyl-phenyl)-methanone;
(4-lsopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl}-methanone;
(4-lsopropyl-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-rnethanone
15 dihydrochloride;
(4-lsoprapyl-piperazin-1-yl)-[4-(3-trifluoromethyl-piperidin-1-ylmethyl)-
phenyl)-methanone dihydrochloride;
(4-sec-Butyl-piperazin-1-yl)-(4-aimethylaminomethyl-phenyl)-
methanone:
20 (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;
(4-sec-Butyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;
{4- (1-Ethyl-propyl)-piperazin-1-yl)-(4-morphoIin-4-ylmethyl-phonyl)-
methanone dihydrochloride;
{4-(1-Ethyl-propyl)-piperazin -1-yl}-(4-piperidin-1-ylmethyl-phenyl)-
25 methanone; and
{4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-
methanone.
41. A compound of claim 1 selected from the group consisting of:
30 (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl}-methanone;
(4-Isopropyl-piperazin-1-yI)-(4-piperidin-1-ylmethyl-phenyI)-methanone;
(4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl}-methanone;
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WO 2004/037801 PCT/US2003/033343
{4-{1-Ethyl-propyl)-piperazin-1-yI)-(4-piperidin-1-ylmethyl-phenyl)-
methanone;
{4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-
methanone;
5 (4- Isopropyl-piperazin-1-yl)-{4-morpholin-4-yImethyl-phenyl)-methanone;
(4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-yImethyl-phenyl)-methanone
dihydrochloride; and
{4-(1-Ethyl-prapyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl}-
methanone dihydrochloride.
10
42. A pharmaceutical composition, comprising a compound of claim 1 and a
pharmaceutically-acceptable exciplent.
43. A compound of claim 1 isotopically-tabelled to be detectable by PET or
15 SPECT.
44. A method of Inhibiting histamine H3 receptor activity in a subject,
comprising administering an effective amount of a compound of claim 1
to a subject in need of such inhibition of histamine H3 receptor activity.
20
45. A method of treating a subject having a disease or condition modulated
by histamine H3 receptor activity, comprising administering to the subject
a therapeuticslly effective amount of a compound of claim 1.
25 46. A method of claim 45, wherein said disease or condition is selected from
the group consisting of sleep/wake disorders, arousa/vigilance
disorders, migraine, asthma, dementia, cognitive dysfunction,
neurogenic inflammation, mild cognitive impalrment (pre-dementia),
Alzheimer's disease, epilepsy, narcolepsy, eating disorders, obesity,
30 motion sickness, vertigo, attention deficit hyperactiylly disorders,
learning disondens, memory retention disorders, schizophrenia.
substance abuse, bipolar disorders, manic disorders and depression,
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WO 2004/037801 PCT/US2003/033343
nasal congestion, itch, allergic rhinitis, and upper airway aliergic
response.
47. A method for treating a disease or condition modulated by at least ona
5 receptor selected from the histamine H1 receptor and the histamine H3
receptor, said method comprising (a) administering to a subject a jointly
effective amount of a histamtae H1 receptor antagonist compound, and
(b) administering to the subject a jointly effective amount of a compound
of claim 1, said method providing a jointly tharapeutically effective
10 amount of said compounds.
48. The method of claim 47 wherein the histamine H1 receptor antagonist
and the compound of claim 1 are present in the same dosage form.
15 49. A method for treating diseases or conditions modulated by at least one
receptor selected from the histamine H2 receptor and the histamine H3
receptor in a subject, comprising (a) administering to the subjects jointly
effective amount of a histamine H2 receptor antagonist compound, and
(b) administering to the subject a jointly effective amount of a compound
20 of claim 1, said method proylding a jointly therapeutrcally effective
amount of sard compounds.
50. The method of claim 39 wherein the histomine H2 receptor antagonist
and the compound of claim 1 are present in the same dosage form,
25
51. A method for treating one or more disorders or conditions selected from
he group consisting of sleep/wake disorders, narcolepsy, and
ousal/vigilance disorders, comprising administering to a subject a
erapeutically effective amount of a compound of claim 1,
30
52. A method for treating attention deficit hyperactivity disorders (ADHD),
comprising administering to a subject a therapeutically effective amount
of a campound of claim 1.
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WO 2004/037801 PCT/US2003/033343
53. A method far treating one or more disorders or conditions selected from
the group consisting of dementia. mild cognitive impalrment (pre-
dementia), cognitive dysfunction, schizophrenia, depression, manic
5 disorders, bipolar disorders, and Iearning and memory disorders,
comprising administering to a subject a therapeutically effective amount
of a compound of claim 1.
54. A method for treating or preventing upper airway allergic response, itch,
10 nasal congestion, or allergic rhinitis, comprising administering to a
subject a therapeutically effective amount of a compound of claim 1.
55. A method for studying disorders mediated by the histamine H3 receptor,
comprising using an 18F-labeled or 11C-Isbelled compound of claim 1 as
15 a pasition emission tomography (PET) motecuter probe.

95

Substituted piperazinyl and diazapanyl benzamides and benzohipemides of fomula (I). compositions containing
them, and methods or making and using them to treal histimine-mediated conditions.

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Patent Number

218978

Indian Patent Application Number

00952/KOLNP/2005

PG Journal Number

16/2008

Publication Date

18-Apr-2008

Grant Date

16-Apr-2008

Date of Filing

24-May-2005

Name of Patentee

JANSSEN PHARMACEUTICA N.V.

Applicant Address

TURNHOUTSEWEG 30, B-2340 BEERSE, BELGIUM

Inventors:

#	Inventor's Name	Inventor's Address
1	RICHARD L. APODACA	8448 VIA SONOMA, #98, LA JOLLA, CA 92037
2	JILLA A. JABLONOWSKI	13651 FREEPORT ROAD, SAN DIEGO, CA 92129
3	KIEV S. LY	10620 DABNEY DRIVE, #172, SAN DIEGO, CA 92126
4	CHANDRAVADAN R. SHAH	14213 DALHOUSIE ROAD, SAN DIEGO, CA 92129
5	DEVIN M. SWANSON	3121 MORNING WAY, LA JOLLA, CA 92037
6	WEI XIAO	4043 CARMEL SPRINGS WAY, SAN DIEGO, CA 92130

PCT International Classification Number

C07D 295/18

PCT International Application Number

PCT/US2003/033343

PCT International Filing date

2003-10-21

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/420,495	2002-10-23	U.S.A.