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Wo 2007/016496 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 8 February 2007 (08.02.2007) PCT WO 2007/016496 A2 (51) International Patent Classification: (74) Agents: KADLECEK, Ann et al.; Neurogen Corporation, A61K 31/551 (2006.01) A61K 31/4545 (2006.01) 35 Northeast Industrial Road, Branford, Connecticut 06405 A61K 31/55 (2006.01) A61K 31/454 (2006.01) (US). A61K 31/497 (2006.01) C07D 403/02 (2006.01) A61K 31/496 (2006.01) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (21) International Application Number: AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, PCT/US2006/029761 CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HN, HR, HU, ID, IL, IN, IS, JP, (22) International Filing Date: 28 July 2006 (28.07.2006) KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, (25) Filing Language: English LU, LV,LY,MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (30) Priority Data: 60/704,722 2 August 2005 (02.08.2005) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): NEURO- GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, GEN CORPORATION [US/US]; Patent Department, 35 ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), Northeast Industrial Road, Branford, Connecticut 06405 European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (US). FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT, (72) Inventors; and RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, (75) Inventors/Applicants (for US only): XIE, Linghong GN, GQ, GW, ML, MR, NE, SN, TD, TG). [US/US]; 136 Renee's Way, Guilford, Connecticut 06437 (US). OCHTERSKI, Joseph W. [US/US]; 14 Edgewood Declarations under Rule 4.17: Court, Middlefield, Connecticut 06455 (US). GAO, Yang — as to applicant's entitlement to apply for and be granted a [CN/US]; 524 Opening Hill Road, Madison, Connecticut patent (Rule 4.17(U)) 06443 (US). HAN, Bingsong [CN/US]; 55 North Avenue, — as to the applicant's entitlement to claim the priority of the North Haven, Connecticut 06473 (US). CALDWELL, earlier application (Rule 4.17(Hi)) Timothy M. [US/US]; 244 South Union Street, Guilford, Connecticut 06437 (US). XU, Yuelian [CN/US]; 48 Published: Highland Avenue, East Haven, Connecticut 06513 (US). — without international search report and to be republished PETERSON, John M. [US/US]; 119 Maple Avenue, upon receipt of that report Durham, Connecticut 06422 (US). GE, Ping [US/US]; 718R Higganum Road, Durham, Connecticut 06422 (US). For two-letter codes and other abbreviations, refer to the "G uid OHLIGER, Robert [US/US]; 20 Glen Grove Road Ext., ance Notes on Codes and Abbreviations" appearing at the beg in Deep River, Connecticut 06417 (US). ning of each regular issue of the PCT Gazette. (54) Title: DIPIPERAZINYL KETONES AND RELATED ANALOGUES (57) Abstract: Dipiperazinyl ketones and related analogues are provided, as are methods for their preparation and use. Such com pounds may generally be used to modulate ligand binding to histamine H3 receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of disorders in humans, domesticated companion animals and livestock animals. Pharmaceutical com positions and therapeutic methods are provided, as are methods for using such ligands for detecting histamine H3 receptors {e.g., receptor localization studies). DIPIPERAZINYL KETONES AND RELATED ANALOGUES FIELD OF THE INVENTION This invention relates generally to dipiperazinyl ketones and related analogues, and to the use of such compounds for treating conditions responsive to histamine H3 receptor modulation. The invention further relates to the use of such compounds as probes for the detection and localization of histamine H3 receptors. DESCRIPTION O F THE SEQUENCE LISTING SEQ ID NO: 1 human H3 receptor 5' fragment forward primer SEQ ID NO:2 human H3 receptor 5' fragment reverse primer SEQ ID NO: 3 human H 3 receptor 3' fragment forward primer SEQ ID NO:4 human H3receptor 3' fragment reverse primer SEQ ID NO: 5 rat Ga 1 forward primer α SEQ ID NO: 6 rat G ,j2 reverse primer SEQ ID NO: 7 chimeric human H3 receptor - rat GcCj cDNA sequence SEQ ID NO: 8 chimeric human H3 receptor rat Go polypeptide sequence BACKGROUND O F THE INVENTION Hormones and neurotransmitters regulate a wide variety of biological functions, often via specific receptor proteins located on the surface of living cells. Many of these receptors carry out intracellular signaling via the activation of coupled guanosine triphosphate-binding proteins (G proteins); such receptors are collectively called G protein-coupled receptors or GPCRs. The important role of GPCRs in the regulation of cell and organ function has attracted attention to these receptors as targets for new pharmaceutical agents. Histamine is a multifunctional chemical transmitter that signals through specific cell surface GPCRs. To date, four histamine receptor subtypes have been identified: Hl, H2, H3 and H4. Histamine H3 receptor is a presynaptic GPCR that is found primarily in the central nervous system, although lower levels are also found in the peripheral nervous system. Genes encoding the H3 receptor have been reported in various organisms, including humans (see Lovenberg et al. (1999) Molecular Pharmacology 55:1101-07), and alternative splicing of this gene appears to result in multiple isoforms. The histamine H3 receptor is an auto- and hetero-receptor whose activation leads to''a (including histamine, acetylcholine, norepinephrine and glutamate) from neurons in the brain, and is involved in the regulation of processes such as sleep and wakefulness, feeding and memory. In certain systems, the histamine H3 receptor may be constitutively active. Antagonists of histamine H3 receptor increase synthesis and release of cerebral histamine and other neurotransmitters, inducing an extended wakefulness, an improvement in cognitive processes, a reduction in food intake and a normalization of vestibular reflexes. Such antagonists may find use as therapeutics for central nervous system disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia, mood and attention alterations including attention deficit hyperactivity disorder and attention deficit disorder, memory and learning disorders, cognitive disorders (such as mild cognitive impairment and cognitive deficits in psychiatric pathologies), epilepsy, migraine, and disorders associated with the regulation of sleep and wakefulness, as well as in the treatment and prevention of conditions such as obesity, eating disorders, diabetes, vertigo, motion sickness and allergic rhinitis. Accordingly, the histamine H3 receptor is an important target for new therapeutics for conditions responsive to H3 receptor modulation. The present invention fulfills this need, and provides further related advantages. SUMMARY OF THE INVENTION The present invention provides dipiperazinyl ketones and related analogues of Formula I: R6 -A- Q-B -Ri Formula I and pharmaceutically acceptable salts, solvates (e.g., hydrates) and esters of such compounds. Within Formula I: Q is C(=O), C(-OH), N(R 5)CC=O), N(R 5)C(R3)(R4)C(=O), C(R3)(R4)CC=O), C(R3XR4)CHC-OH), CC=O)OC(R3)CR4)CC=O) or C(=O)OC(R 3)(R4)C(-OH) wherein: R3 and R are independently chosen from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkyl ether and (C3-C6cycloalkyl)Co-C2alkyl, or R3 and R4 are taken together to form an optionally substituted 4- to 6-membered cycloalkyl or heterocycloalkyl ring; and R5 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkyl ether or (C3-C6cycloalkyl)Co-C2alkyl; A is a 4- to 8-membered cycloalkyl or heterocycloalkyl group, each of which is optionally substituted, and each of which is preferably substituted with from 0 to 4 substituents independently chosen from (i) hydroxy, halogen, oxo, C1-Qalkyl, CpQalkoxy and C1-C4alkanoyl; (ii) groups that are taken together with a substituent of R to from a spiro ring that is optionally substituted and is preferably substituted with from 0 to 4 substituents independently chosen from halogen, cyano, hydroxy, amino, oxo, C1-Qalkyl, (C3-C8cycloalkyl)C 0-C2alkyl, C1-C4haloalkyl, C1-C4alkoxy and substituents that are taken together to form a fused 5- to 7-membered ring; and (iii) and groups that are taken together to form a Cr C3alkylene bridge; (a) a 5- to 7-membered heterocycloalkyl group that comprises at least one nitrogen atom and is optionally substituted, each of which heterocycloalkyl is preferably substituted with from 0 to 4 substituents independently chosen from C1-C4alkyl, C1-C4alkoxy, hydroxy, cyano, and groups that are taken together to form a C1-C3alkylene bridge; or (b) mono- or di-(C1-C6alkyl)aminoC0-C6alkyl; Ri is C1-C6alkyl, C2-C6alkenyl, C2-C alkynyl, mono- or di-(C1-C6alkyl)amino, (C3-C8cycloalkyl)C0- C4alkyl, (3- to 8-membered heterocycloalkyl)Co-C4alkyl, (6- to 10-membered aryl)C0-C4alkyl or (5- to 10-membered heteroaryl)Co-C4alkyl, each of which is optionally substituted, and each of which is preferably substituted with from 0 to 4 substituents independently chosen from oxo, halogen, cyano, hydroxy, amino, nitro, aminocarbonyl, C1-C6alkyl, C1-C8alkenyl,
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