USOO7671056 B2

(12) United States Patent (10) Patent No.: US 7,671,056 B2 Asselin et al. (45) Date of Patent: Mar. 2, 2010

(54) -PIPERIDINE ANTAGONISTS 6,995, 176 B2 2/2006 Bernotas et al. AND AGONISTS OF THE 5-HT, 7,041,695 B2 5, 2006 Cole 2003/0060513 A1 3/2003 Arneric et al. 2003, O220348 A1 11/2003 Xie et al. (75) Inventors: Magda Asselin, Mahwah, NJ (US); 2004, OO14972 A1 1/2004 Gottschlich et al. George Theodore Grosu, Pearl River, 2005/0032873 A1 2/2005 Hatzenbuhler et al. NY (US); Annmarie Louise Sabb, 2005, 0182049 A1 8, 2005 Howard Pennington, NJ (US); Wayne Everett 2005/O197356 A1 9, 2005 Graziani et al. Childers, New Hope, PA (US); Lisa 2005/O197379 A1 9, 2005 Summers et al. Marie Havran, Florence, NJ (US); 2005/0215561 A1 9, 2005 Ghosh et al. Zhongqi Shen, Plainsboro, NJ (US); 2005/0256103 A1 11/2005 Suzuki et al. James Jacob Bicksler, Titusville, NJ 2005/0282825 A1 12/2005 Malamas et al. (US); Dan Chaekoo Chong, Plainsboro, 2005/0282826 A1 12/2005 Malamas et al. 2006, O1828.05 A1 8, 2006 Pfeiffer et al. NJ (US) 2006/0287335 A1 12/2006 Sukoffet al. 2007/0027160 A1 2/2007 Asselin et al. (73) Assignee: LLC, Madison, NJ (US) 2007/O146072 A1 6/2007 Ohta et al. (*) Notice: Subject to any disclaimer, the term of this 2007,029.9083 A1 12/2007 Schmid et al. patent is extended or adjusted under 35 U.S.C. 154(b) by 280 days. (Continued) FOREIGN PATENT DOCUMENTS (21) Appl. No.: 11/450,942 EP 1203584 5, 2002 (22) Filed: Jun. 9, 2006 (Continued) (65) Prior Publication Data OTHER PUBLICATIONS US 2007/0027160 A1 Feb. 1, 2007 Araneda, et al., “5-Hydroxytryptamine and 5-Hydroxytryptamine Related U.S. Application Data Receptors Mediate Opposing Responses on Membrane Excitability in Rat Association Cortex'. Neuroscience, 40(2):399-412 (1991). (60) Provisional application No. 60/689,469, filed on Jun. 10, 2005. (Continued) Primary Examiner Emily Bernhardt (51) Int. Cl. (74) Attorney, Agent, or Firm Rebecca R. Barrett A6 IK 3/496 (2006.01) CO7D 40/4 (2006.01) (57) ABSTRACT CO7D 40.5/14 (2006.01) CO7D 409/14 (2006.01) The present invention relates to novel piperazine-piperidine CO7D 413/14 (2006.01) compounds. The compounds are useful as 5-HT1A binding (52) U.S. Cl...... 514/253.06; 514/253.07; agents, particularly as 5-HT1A receptor antagonists and ago 514/253.08: 514/253.09: 514/253.1: 514/253.11; nists. These compounds are useful in treating central nervous 544/363; 544/360; 544/364 system disorders, such as cognition disorders, anxiety disor (58) Field of Classification Search ...... None ders, depression and sexual dysfunction. The invention See application file for complete search history. relates to compounds and pharmaceutically acceptable salts (56) References Cited of formula (I): U.S. PATENT DOCUMENTS I 4,465,482 A 8, 1984 Tittel et al. 4,624,954. A 1 1/1986 Jirkovsky et al. 4,665,183 A 5/1987 Jirkovsky et al. 4,904,658 A 2/1990 Tsenget al. 5,219,857 A 6/1993 Tsenget al. R3 / \ N Ra R3 R14 5,260,331 A 11/1993 White et al. 5,288,748 A 2f1994 Wikstrom et al. 5,422,355 A 6, 1995 White et al. N N 5,538,956 A 7, 1996 Minchin et al. 6,084,130 A 7/2000 Romero et al. \ { pi 6,127,357 A 10, 2000 Cliffe et al. Rs R6 Rb Rs R16 R7 R8 6,465,482 B2 10/2002 Mewshaw et al. 6,469,007 B2 10/2002 Childers et al. wherein R.-R. R. R. and n are set forth in the specifica 6,586,436 B2 7/2003 Childers et al. tion. The invention also relates to pharmaceutical composi 6,620,808 B2 9, 2003 Van Der Klish et al. 6,635,270 B2 10/2003 Hong et al. tions comprising compounds and pharmaceutically accept 6,821,985 B2 11/2004 Chenard et al. able salts of formula (I'). 6.825,212 B2 11/2004 Bernotas et al. 6,878,742 B2 4/2005 Kreft et al. 67 Claims, No Drawings US 7,671,056 B2 Page 2

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Skraup, “Eine Syntheses Des Chinolins.”. Monatsh. 1, pp. 316-318 Pharmacology Biochemistry and Behavoior. Elsevier, US. vol. 60, (1880). No. 3, 1998, pp. 703-707. Thompson, et al., “7-Chloro-3methyl-3,4-dihydro-2H-1,2,4- benzothiadiazine S.S.-dioxide (IDRA21), a Congener of Aniracetam, Yamada, et al., “Benzothiadiazides Inhibit Rapid Glutamate Recep Potently Abates Pharmacologically Induced Cognitive Impairments tor Desensitization and Enhance Glutamatergic Synaptic Currents'. in Patas Monkeys”. Proc. Natl. Acad. Sci. USA. 92:7667-7671 J. Neurosc., 13:3904-3915 (1993). (1995). Zivkovic, et al., “7-Chloro-3-Methyl-3-4-Dihydro-2H-1.2.4 Trillant, Anne-Cecile et al. " Synergistic Neurochemical and Benzothiadiazine S.S.-Dioxide (IDRA21): A Benzothiadiazine Behavioural Effects of Fluoxetine and 5-HT1A Receptor Antago nists.” European Journal of Pharmacology, vol.357, No. 2-3, Sep. 18, Derivative that Enhances Cognition by Attenuating DL-O-Amino 1998, pp. 179-183. 2,3-Dihydro-5-Methyl-3-Oxo-4-Isoxazolepropanoic Acid (AMPA) Winter, J C et al. “The Discriminative Stimulus Effects of KA672, a Receptor Desensitization”. J. Pharmacol. Exp. Therap. 272:300-309 Putative Cognitive Enhancer: Evidence for a 5-htla Component.” (1995). US 7,671,056 B2 1. 2 PPERAZINE-PPERDINE ANTAGONSTS nyl, halogen, —CF. - NO. —CN, —ORs, —OSORs, AND AGONISTS OF THE 5-HT, RECEPTOR —SRs. —SORs. —SON(Rs), —N(Rs), C(O), —CORs, —CORs, —NRCORs, —NRCORs, Throughout this application, various publications are ref —NRCONCRs), or —CONCRs), erenced. The disclosures of these publications in their entire 5 R, and R, are each independently —H or —CH, and ties are hereby incorporated by reference into this application Rs is —H. linear or branched (C-C)-alkyl, (C-C)- in order to more fully describe the state of the art as known to haloalkyl, (C-C)-alkenyl, or (C-C)-alkynyl. those skilled therein as of the date of the invention described In another aspect, the invention provides compounds of the and claimed herein. Formula (I'): This patent disclosure contains material that is subject to 10 copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document I or the patent disclosure, as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise R R R12 R11 reserves any and all copyright rights whatsoever. 15 R3 / N Ra R13 R14 N \ R10 FIELD OF THE INVENTION The present invention relates to novel piperazine-piperi R4 N N N R9 dine compounds. The compounds are useful as 5-HT bind ing agents, particularly as 5-HT, receptor antagonists and \-( pi agonists. These compounds are useful in treating central ner Rs R6 Rb R15 R16 R Rs Vous system disorders, such as cognition disorders, anxiety disorders, and depression. 25 and pharmaceutically acceptable salts thereof, BACKGROUND OF THE INVENTION wherein R, R2, Rs. R4 Rs. Rs. R-7, Rs. Ro, Rio, R1, R12, R1s. Ra Rs, and Re, are each independently —H., (C-C)- Certain N-aryl-piperazine derivatives possess pharmaceu alkyl, (C-C)-haloalkyl, (C-C)-alkenyl, or (C-C)alky tical activity. In particular, certain N-aryl piperazine deriva nyl, halogen, —CF. - NO. —CN, —ORs, —OSORs, tives act on the central nervous system (CNS) by binding to 30 —SRs. —SORs. —SON(Rs), —N(Rs), C(O), 5-HT receptors. In pharmacological testing, it has been —CORs, —CORs, —NRCORs, —NRCORs, shown that the certain N-aryl-piperazine derivatives bind to —NRCON (Rs), or —CONCRs): receptors of the 5-HT, type. Many of the N-aryl piperazine R, and R, are each independently —H or —CH, and derivatives exhibit activity as 5-HT, antagonists. See, for Rs is —H. linear or branched (C-C)-alkyl, (C-C)- example, W. C. Childers, et al., J. Med. Chem., 48:3467-3470 35 haloalkyl, (C-C)-alkenyl, or (C-C)-alkynyl; and (2005), U.S. Pat. Nos. 6,465,482, 6,127,357, 6,469,007, and where n is an integer from 1 to 2. 6,586,436, and PCT Publication No. WO97/03982, the dis closures of which are incorporated herein by reference. In another aspect, the invention provides compounds of the Pharmaceutical compounds that interact with the 5-HT Formula (I"): receptor are useful to treat a wide variety of central nervous 40 system disorders, such as cognition disorders, anxiety disor I

ders, and depression. The present invention is directed to novel 5-HT, antagonists and agonists, which would be use R R ful for these and other uses. 45 R3 / \ Ra R13 SUMMARY OF THE INVENTION o In one aspect, the invention provides compounds of the R4 N N Formula (I): 50 \ { 5 Rb Rs (I) R2 R R12 R11 and pharmaceutically acceptable salts thereof, wherein R, R2, R. R. Rs. R. R-7, R-7, Rs. Ro, Rio, R. 55 R. R. R. Ris, and Rio, are each independently —H. R3 / \ Ra R13 R14 / \ R10 (C-C)-alkyl, (C-C)-haloalkyl, (C-C)-alkenyl, or (C- C)-alkynyl, halogen, —CF, —NO. —CN, —ORs, R4 N N N R9 —OSORs. —SRs. —SORs. —SON(Rs), —N(Rs), C(O), —CORs, —CORs. —NRCORs, \ { 60 —NRCORs, NRCONCRs), or —CONCRs), Rs R6 Rb R15 R16 R7 R8 R, and R, are each independently —H or —CH: Rs is —H; or linear or branched (C-C)-alkyl, (C-C)- and pharmaceutically acceptable salts thereof, haloalkyl, (C-C)-alkenyl, or (C-C)-alkynyl and wherein R, R2, R. R. Rs. R. R-7, Rs. Ro, Rio, R1, R12, 65 where the piperidine group can be attached to the nonhet R. R. Ris, and R are each independently —H., (C-C)- ero atom containing ring of the quinoline through positions alkyl, (C-C)-haloalkyl, (C-C)-alkenyl, or (C-C)-alky R7. R7, Rs. O Ro. US 7,671,056 B2 3 In another aspect, the invention provides compounds of the (III) Formula (I"a): R12 R11

Ra R13 R14 / \ R O (I"a) R2 R R12 Roo- R9 \ Na R3 / N Ra R3 R14 R. h R11 10 C-:Rb R15 R16 R7 Rs R4 N N N R10 and pharmaceutically acceptable salts thereof, ( R9 wherein Roo is selected from: Rs R6 Rb R15 R R8 15

(1 N O/ MO and pharmaceutically acceptable salts thereof, R20 R24 wherein R. R2, Rs. R4, Rs. R6. R7, Rs. R9. Rio R11, R12. R23 R. R. Ris, and Re, are each independently —H. R21 (C-C)-alkyl, (C-C)-haloalkyl, (C-C)-alkenyl, or R22 R26 R27 (C-C)-alkynyl, halogen, —CF —NO. —CN. N1S s/N —ORs. —OSORs, —SRs, —SORs, —SON 25 (R2s)2. —N(Rs), —C(O), —CORs. —CORs, —NRCORs, —NRCORs, —NRCONCRs), or —CONCRs), R28 R28 R, and R, are each independently —H or —CH, and Rs is —H; or linear or branched (C-C)-alkyl, (C-C)- 30 R29 R30 R29 R30 haloalkyl, (C-C)-alkenyl, or (C-C)-alkynyl. o1 NN In another aspect, the invention provides compounds of the Formula (II): 35 R28

R29 R30

(II) 40 and wherein R7, Rs. Ro. Rio. R11, R12, R13, R14, R1s. R16, R20. R2, R22. / \ / y R18 R2s, R24. R26, R27, R2s, R-29, and Rao are each independently N Ra N Q —H., (C-C)-alkyl, (C-C)-haloalkyl, (C-C)-alkenyl, or (C-C) alkynyl, halogen, —CF, —NO. —CN. —ORs, 45 R4 N N N A —OSORs. —SRs. —SORs. —SON(Rs), —N(Rs), C(O), —CORs, —CORs. —NRCORs, \ { SR \ 5* —NRCORs —NRCON (Rs), or—CONCRs): Rs Rb R15 R16 R, and R, are each independently —H or —CH: Rs is —H; or linear or branched (C-C)-alkyl, (C-C)- 50 haloalkyl, (C-C)-alkenyl, or (C-C)-alkynyl. In yet another aspect, the invention provides compounds of the Formula (IV): and pharmaceutically acceptable salts thereof, (IV) wherein R. Rs. Rs. R. R7, Rs and Ro are each inde 55 pendently —H., (C-C)-alkyl, (C-C)-haloalkyl, (C-C)- R32 R31 Ra R13 R14 alkenyl, or (C-C)-alkynyl, halogen, —CF. - NO. —CN. —ORs, —OSORs. —SRs. —SORs. —SON(Rs), A Y —N(Rs), C(O), —CORs, —CORs —NRCORs, R33 N N N —NRCORs, —NRCONCRs), or—CONCRs), 60 ( R39 R, and P are each independently —H or —CH: R34 R35 Rb Rs R16 R36 Rs is —H; or linear or branched (C-C)-alkyl, (C-C)- R38 haloalkyl, (C-C)-alkenyl, or (C-C)-alkynyl; and R37

R and Rs cannot both be hydrogen. 65 and pharmaceutically acceptable salts thereof, In a further aspect, the invention provides compounds of wherein X is CRs, N, O or S;Y is CRs NRs, O or S; with the Formula (III): the proviso that when X is CRs, Y is not N: US 7,671,056 B2 5 6 R13, R14, R1s. R16, R31, R32, R3s. R34, R3s. Rs6, R37, Ras includes administering to the patient an effective amount of a and Rare each independently —H., (C-C)-alkyl, (C-C)- compound or a pharmaceutically acceptable salt of a com haloalkyl, (C-C)-alkenyl, or (C-C)alkynyl, halogen, pound of Formula (I), Formula (I'). Formula (I"). Formula CF, —NO. —CN, —ORs, —OSORs, —SRs, (I"a), Formula (II), Formula (III), or Formula (IV). In one —SORs, —SON(Rs), —N(Rs), C(O), —CORs, embodiment, the method includes administering to the —CORs, —NRCORs, —NRCORs —NRCON patient a pharmaceutical composition comprising one or (Rs), or—CONCRs): R, and R, are each independently —H or —CH, and more of the compounds or pharmaceutically acceptable salts Rs is —H; or linear or branched (C-C)-alkyl, (C-C)- of compounds of Formulas (I), (I), (I"), (I"a), (II), (III), and haloalkyl, (C-C)-alkenyl, or (C-C)-alkynyl. 10 (IV) in an amount effective to treat Alzheimer's disease. In another aspect, the compounds and pharmaceutically In one aspect, the invention provides methods for treating acceptable salts of the compounds of Formulas (I), (I), (I"). mild cognitive impairment (MCI) to a patient in need thereof. (I"a), (II), (III), and (IV) are also useful when formulated as The method includes administering to the patient an effective pharmaceutical compositions. These pharmaceutical compo amount of a compound or a pharmaceutically acceptable salt sitions comprise compounds and pharmaceutically accept 15 able salts of the compounds of Formulas (I), (I), (I"), (II), of a compound of Formula (I), Formula (I'). Formula (I"), (III), or (IV) and a pharmaceutically acceptable carrier. Formula (I"a). Formula (II), Formula (III), or Formula (IV). In another aspect, the compounds and pharmaceutically In one embodiment, the method includes administering to the acceptable salts of the compounds of Formulas (I), (II), (I"). patient a pharmaceutical composition comprising one or (I"a), (II), (III), and (IV) are useful as 5-HT, receptor ago more of the compounds or pharmaceutically acceptable salts nists and antagonists. of compounds of Formulas (I), (I), (I"), (I"a), (II), (III), and In another aspect, the pharmaceutical compositions com (IV) in an amount effective to treat mild cognitive impair prising one or more compounds and pharmaceutically accept ment. able salts of the compounds of Formulas (I), (I), (I"), (I"a), In one aspect, the invention provides methods for treating (II), (III), or (IV) are useful as 5-HT, receptor agonists and 25 antagonists. depression to a patient in need thereof. The method includes In one aspect, the invention provides methods for treating administering to the patient an effective amount of a com a 5-HT-related disorder, comprising administering to a pound or a pharmaceutically acceptable salt of a compound of patient in need thereof one or more of the compounds or Formula (I), Formula (I'). Formula (I"). Formula (I"a), For pharmaceutically acceptable salts of compounds of Formulas 30 mula (II), Formula (III), or Formula (IV). In one embodiment, (I), (I), (I"). (I"a), (II), (III), and (IV) in a therapeutically the method includes administering to the patient a pharma effective amount to treat a 5-HT-related disorder. ceutical composition comprising one or more of the com In one aspect, the invention provides methods for treating pounds orpharmaceutically acceptable salts of compounds of a 5-HT-related disorder, comprising administering to a Formulas (I), (I), (I"). (I"a), (II), (III), and (IV) in an amount patient in need thereof a pharmaceutical formulation com 35 prising one or more of the compounds or pharmaceutically effective to treat depression. acceptable salts of compounds of Formulas (I), (I), (I"). (I"a), In one aspect, the treatment methods of the invention (II), (III), and (IV) in a therapeutically effective amount to include administering a second therapeutic agent. treat a 5-HT-related disorder. In one aspect, the invention provides methods for treating In one aspect, the invention provides methods for treating 40 sexual dysfunction associated with drug treatmentinapatient a cognition-related disorder, comprising administering to a patient in need thereof one or more of the compounds or in need thereof. The method includes administering to the pharmaceutically acceptable salts of compounds of Formulas patient an effective amount of a compound or a pharmaceu (I), (I), (I"). (I"a), (II), (III), and (IV) in a therapeutically tically acceptable salt of a compound of Formula (I). Formula effective amount to treat a cognition-related disorder. 45 (I'). Formula (I"). Formula (I"a). Formula (II), Formula (III), In one aspect, the invention provides methods for treating or Formula (IV). In one embodiment, the method includes a cognition-related disorder, comprising administering to a administering to the patient a pharmaceutical composition patient in need thereof a pharmaceutical formulation com comprising one or more of the compounds or pharmaceuti prising one or more of the compounds or pharmaceutically cally acceptable salts of compounds of Formulas (I), (I), (I"), acceptable salts of compounds of Formulas (I), (I), (I"). (I"a), 50 (I"a), (II), (III), and (IV) in an amount effective to treat sexual (II), (III), and (IV) in an amount effective to treat a cognition dysfunction. related disorder. In one aspect, the invention provides methods of improving In another aspect, the invention provides methods for treat sexual function in a patient in need thereof, the method com ing an anxiety-related disorder, comprising administering to a prising administering to the patient a pharmaceutically effec patient in need thereof one or more of the compounds or 55 tive amount of a compound or a pharmaceutically acceptable pharmaceutically acceptable salts of compound of Formulas salt of a compound of Formula (I), Formula (I'). Formula (I"), (I), (I), (I"). (I"a), (II), (III), and (IV) in an amount effective to Formula (I"a). Formula (II), Formula (III), or Formula (IV). treat an anxiety-related disorder. In one embodiment, the method includes administering to the In another aspect, the invention provides methods for treat patient a pharmaceutical composition comprising one or ing an anxiety-related disorder, comprising administering to a 60 patient in need thereof a pharmaceutical formulation com more of the compounds or pharmaceutically acceptable salts prising one or more of the compounds or pharmaceutically of compounds of Formulas (I), (I), (I"), (I"a), (II), (III), and acceptable salts of compound of Formulas (I), (I), (I"). (I"a), (IV) in an amount effective to improve sexual function. (II), (III), and (IV) in an amount effective to treat an anxiety In one aspect, the invention provides methods of synthe related disorder. 65 sizing the compounds and pharmaceutically acceptable salts In one aspect, the invention provides methods for treating of compounds of Formulas (I), (I), (I"), (I"a), (II), (III), and Alzheimer's disease to a patient in need thereof. The method (IV). US 7,671,056 B2 7 8 In another aspect, the invention provides compounds and The term “arylas used herein refers to an aromatic species pharmaceutically acceptable salts of compounds of Formulas containing 1 to 3 aromatic rings, either fused or linked. In one (I), (I), (I"). (I"a), (II), (III), and (IV) made by particular embodiment, the aryl group is optionally Substituted with one processes. or more of the following groups: - V-halogen, —V N. —V NO, V CN, V OR', V SR', DETAILED DESCRIPTION OF THE INVENTION - V SOR" - V SON(R) - V N(R') - V COR', - V COR', V NRCOR', V NR'COR', Definitions - V NR'CONR', or V CONCR), wherein each R is The term “(C-C)-alkyl” as used herein refers to a linear or independently hydrogen or unsubstituted (C-C)-alkyl; and branched, saturated hydrocarbon having from 1 to 6 carbon 10 wherein each V is independently a bond or (C-C)-alkyl. atoms. Representative (C-C)-alkyl groups include, but are The term “conditions effective to as used herein refers to not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec synthetic reaction conditions which will be apparent to those butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, iso skilled in the art of synthetic organic chemistry. hexyl, and neohexyl. In one embodiment, the (C-C)-alkyl The term “cyclic group’ as used herein includes a group is optionally substituted with one or more of the fol 15 cycloalkyl group and a heterocyclic group. Any suitable ring lowing groups: halogen, —N, NO. —CN. —OR', —SR', position of the cyclic group may be covalently linked to the —SOR', -SON(R') - N(R'), —COR', -COR', defined chemical structure. In one embodiment, the cyclic NRCOR', NR'COR', NR'CONR', or CONCR), group is optionally substituted with one or more of the fol wherein each R" is independently hydrogen or unsubstituted lowing groups: - V-halogen, —V N, -V NO, (C-C)-alkyl. V CN, V OR', V SR', V SOR', The term “(C-C)-alkenyl” as used herein refers to a linear - V SON(R'), - V N(R'), V COR', or branched hydrocarbon having from 2 to 6 carbon atoms - V COR', V NR'COR', V NR'COR', and having at least one carbon-carbon double bond. In one - V NR'CONR', or V CONCR), wherein each R' is embodiment, the (C-C)-alkenyl has one or two double independently hydrogen or unsubstituted (C-C)-alkyl; and bonds. The (C-C)-alkenyl moiety may exist in the E or Z 25 wherein each V is independently a bond or (C-C)-alkyl. conformation and the compounds of the present invention The term “cycloalkyl group’ as used herein refers to a include both conformations. In one embodiment, the (C-C)- three- to seven-membered Saturated or partially unsaturated alkenyl group is optionally Substituted with one or more of the carbon ring. Any suitable ring position of the cycloalkyl following groups: halogen, —N. —NO. —CN, —OR', group may be covalently linked to the defined chemical struc —SR', -SOR', -SON(R), N(R'), COR',-COR', 30 ture. Exemplary cycloalkyl groups include cyclopropyl. NRCOR', NR'COR', NR'CONR', or CONCR), cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In one wherein each R is independently hydrogen or unsubstituted embodiment, the cycloalkyl group is optionally substituted (C-C)-alkyl. with one or more of the following groups: —V-halogen, The term “(C-C)-alkynyl as used herein refers to a linear V. N. V NO, V CN, V OR', V SR', or branched hydrocarbon having from 2 to 6 carbon atoms 35 - V-SOR', V SON(R) - V. N.(R), V COR', and having at least one carbon-carbon triple bond. In one - V COR', V NR'COR', V NR'COR', embodiment, the (C-C)-alkenyl group is optionally Substi - V NR'CONR', or V CONCR), wherein each R is tuted with one or more of the following groups: halogen, independently hydrogen or unsubstituted (C-C)-alkyl; and N, NO, CN, OR', SR', SOR', -SON(R'), wherein each V is independently a bond or (C-C)-alkyl. N(R'), COR, COR, NRCOR, NRCOR', 40 The term “effective amount’ as used herein refers to an —NR'CONR', or -CON(R'), wherein each R" is indepen amount of a compound orpharmaceutically acceptable salt of dently hydrogen or unsubstituted (C-C)-alkyl. a compound that, when administered to an animal, is effective “(C-C)-haloalkyl refers to a C-C alkyl group, as to prevent, to at least partially ameliorate, or to cure, a con defined above, wherein one or more of the C-C alkyl dition from which the animal suffers or is suspected to suffer. group's hydrogen atoms has been replaced with —F. —Cl, 45 The term “halogen' as used herein refers to fluorine, chlo —Br or —I. Representative examples of an alkylhalo group rine, bromine, and iodine. include, but are not limited to. —CHF, —CC1, —CF, The term "heterocyclic group’ as used herein refers to a —CHCl, -CHCHBr, —CHCHI, —CHCHCHF, three- to seven-membered saturated, partially Saturated, or —CHCHCHCl, —CHCHCHCHBr, unsaturated cycloalkyl group in which one to four of the ring —CHCHCHCHI, - CHCHCHCHCHBr, 50 carbon atoms have been independently replaced with a N, O, —CHCHCHCHCHI, —CH-CH(Br)CH, -CHCH or Satom. Any Suitable ring position of the heterocyclic group (CI)CHCH, -CH(F)CHCH, C(CH)(CHCI), may be covalently linked to the defined chemical structure. —CHCHCHCHCHCHBr, and Exemplary heterocyclic groups include, but are not limited to, —CHCHCHCHCHCH.I. aZepanyl, azetidinyl, aziridinyl, furanyl, furazanyl, homopip The term “administer”, “administering, or “administra 55 erazinyl, imidazolidinyl, imidazolinyl, isothiazolyl, isox tion', as used herein refers to either directly administering a azolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, compound or pharmaceutically acceptable salt of the com oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, pound or a composition to an animal, or administering a piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolidinyl, prodrug derivative or analog of the compound or pharmaceu pyrazolinyl, pyrazolyl pyridaZinyl, pyridooxazolyl pyri tically acceptable salt of the compound or composition to the 60 doimidazolyl pyridothiazolyl, pyridinyl, pyrimidinyl, pyrro animal, which can form an equivalent amount of active com lidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, thiadi pound within the animal's body. azinyl, thiadiazolyl, thienyl, thienothiazolyl, thienooxazolyl, The term “animal' as used herein includes, without limi thienoimidazolyl, thiomorpholinyl, thiophenyl, triazinyl, and tation, a human, mouse, rat, guinea pig, dog, cat, horse, cow, triazolyl. In one embodiment, the heterocyclic group is pig, monkey, chimpanzee, baboon, or rhesus. In one embodi 65 optionally substituted with one or more of the following ment, the animal is a mammal. In another embodiment, the groups: —V-halogen, - V N - V—NO —V—CN. animal is a human. - V -OR', V SR', V SOR', V SON(R'), US 7,671,056 B2 9 10 - V N(R'), V COR', - V COR', The term “5-HT-related disorder” as used herein refers V NRCOR', V NRCOR', V NRCONR, or to a condition which is mediated through the 5-HT, receptor. —V CONCR'), wherein each R" is independently hydrogen In some embodiments, a 5-HT-related disorder is a condi or unsubstituted (C-C)-alkyl; and wherein each V is inde tion for which it would be beneficial to prevent activation of pendently a bond or (C-C)-alkyl. the 5-HT, receptor. In other embodiments, a 5-HT-related The term "isolated and purified as used herein refers to disorder is a condition for which it would be beneficial to separate from other components of a reaction mixture or a activate the 5-HT, receptor. In one embodiment, a 5-HT natural source. In certain embodiments, the isolate contains at related disorder affects the central nervous system (i.e., a least about 50%, at least about 55%, at least about 60%, at CNS-related disorder). Exemplary 5-HT-related disorders least about 65%, at least about 70%, at least about 75%, at 10 include, without limitation, depression, single episodic or least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98% of the compound or recurrent major depressive disorders, dysthymic disorders, pharmaceutically acceptable salt of the compound by weight depressive neurosis and neurotic depression, melancholic of the isolate. depression including anorexia, weight loss, insomnia, early The term “pharmaceutically acceptable salt”, as used 15 morning waking or psychomotor retardation; atypical depres herein, refers to salts derived from organic and inorganic sion (or reactive depression) including increased appetite, acids of a compound of the present invention. Exemplary salts hypersomnia, psychomotor agitation or irritability, seasonal include, but are not limited to, Sulfate, citrate, acetate, oxalate, affective disorder, pediatric depression, child abuse induced chloride, hydrochloride, bromide, hydrobromide, iodide, depression and postpartum depression; bipolar disorders or nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, manic depression, for example, bipolar I disorder, bipolar II lactate, salicylate, acid citrate, tartrate, oleate, tannate, pan disorder and cyclothymic disorder; conduct disorder, disrup tothenate, bitartrate, ascorbate. Succinate, maleate, gentisi tive behavior disorder; disorders of attention and learning nate, fumarate, gluconate, glucaronate, Saccharate, formate, such as attention deficit hyperactivity disorder (ADHD) and benzoate, glutamate, methanesulfonate, ethanesulfonate, dyslexia; behavioral disturbances associated with mental benzenesulfonate, p-toluenesulfonate, camphorsulfonate, 25 retardation, autistic disorder, pervasive development disorder napthalenesulfonate, propionate, Succinate, fumarate, male and conduct disorder; anxiety disorders such as panic disor ate, malonate, mandelate, malate, phthalate, and pamoate. der with or withoutagoraphobia, agoraphobia without history The term “pharmaceutically acceptable salt as used herein of panic disorder, specific phobias, for example, specific ani also refers to a salt of a compound of the present invention mal phobias, social anxiety, social phobia, obsessive-compul having an acidic functional group, Such as a carboxylic acid 30 sive disorder, stress disorders including post-traumatic stress functional group, and a base. Exemplary bases include, but disorder and acute stress disorder, and generalized anxiety are not limited to, hydroxide of alkali metals including disorders; borderline personality disorder; schizophrenia and Sodium, potassium, and lithium; hydroxides of alkaline earth other psychotic disorders, for example, Schizophreniform metals such as calcium and magnesium; hydroxides of other disorders, schizoaffective disorders, delusional disorders, metals, such as aluminum and Zinc, ammonia, organic amines 35 brief psychotic disorders, shared psychotic disorders, psy Such as unsubstituted or hydroxyl-substituted mono-, di-, or chotic disorders with delusions or hallucinations, psychotic tri-alkylamines, dicyclohexylamine; tributylamine; pyridine; episodes of anxiety, anxiety associated with psychosis, psy N-methyl, N-ethylamine; diethylamine; triethylamine; chotic mood disorders such as severe major depressive disor mono-, bis-, or tris-(2-OH-(C-C)-alkylamine). Such as der; mood disorders associated with psychotic disorders such N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxy 40 as acute mania and depression associated with bipolar disor ethyl)amine; N-methyl-D-glucamine; morpholine; thiomor der; mood disorders associated with Schizophrenia, Sub pholine; piperidine; pyrrolidine; and amino acids such as stance-induced psychotic disorder, shared psychotic disorder, arginine, , and the like. The term “pharmaceutically and psychotic disorder due to a general medical condition; acceptable salt” also includes hydrates of a compound of the delirium, , and amnestic and other cognitive or neu present invention. 45 rodegenerative disorders, such as Parkinson's disease (PD), The term “phenyl as used herein refers to a substituted or Huntington's disease (HD), Alzheimer's disease, senile unsubstituted phenyl group. In one embodiment, the phenyl dementia, dementia of the Alzheimer's type, mild cognitive group is optionally substituted with one or more of the fol impairment (MCI), memory disorders, loss of executive func lowing groups: —V-halogen, —V—N, -V NO. tion, vascular dementia, and other , for example, V CN, V OR', V SR', V SOR', 50 due to HIV disease, head trauma, Parkinson's disease, Hun - V SON(R'), - V N(R'), V COR', tington's disease, Pick's disease, Creutzfeldt-Jakob disease, - V COR', V NR'COR', V NR'COR', or due to multiple etiologies; cognitive deficits associated - V NR'CONR', or V CONCR), wherein each R is with neurological conditions including, for example, Parkin independently hydrogen or unsubstituted (C-C)-alkyl; and son's disease (PD), Huntington's disease (HD), Alzheimer's wherein each V is independently a bond or (C-C)-alkyl. 55 disease; movement disorders such as akinesias, dyskinesias, The term “substantially free of its corresponding opposite including familial paroxysmal dyskinesias, spasticities, enantiomer as used herein means that the compound con Tourette's syndrome, Scott syndrome, PALSYS and akinetic tains no more than about 10% by weight of its corresponding rigid syndrome; extra-pyramidal movement disorders such as opposite enantiomer. In other embodiments, the compound medication-induced movement disorders, for example, neu that is Substantially free of its corresponding opposite enan 60 roleptic-induced Parkinsonism, neuroleptic malignant syn tiomer contains no more than about 5%, no more than about drome, neuroleptic-induced acute dystonia, neuroleptic-in 1%, no more than about 0.5%, or no more than about 0.1% by duced acute akathisia, neuroleptic-induced tardive weight of its corresponding opposite enantiomer. An enanti dyskinesia and medication-induced postural tremor, chemi omer that is substantially free of its corresponding opposite cal dependencies and addictions (e.g., dependencies on, or enantiomer includes a compound that has been isolated and 65 addictions to, , heroin, cocaine, benzodiazepines, purified or has been prepared substantially free of its corre nicotine, or phenobarbitol); behavioral addictions such as an sponding opposite enantiomer. addiction to gambling; and ocular disorders such as glaucoma US 7,671,056 B2 11 12 and ischemic retinopathy; sexual dysfunction associated with nyl, halogen, —CF. - NO. —CN, —ORs, —OSORs, drug treatment (e.g., sexual dysfunction associated with —SRs. —SORs. —SON(Rs), —N(Rs), —C(O), SSRIs). —CORs, —CORs, —NRCORs, —NRCORs, One nonlimiting example of a 5-HT-related disorder is a —NRCONCRs), or —CONCRs), cognition-related disorder (e.g., cognitive dysfunction). R, and R, are each independently —H or —CH, and Exemplary cognition-related disorders include, without limi Rs is —H; or linear or branched (C-C)-alkyl, (C-C)- tation, mild cognitive impairment (MCI), dementia, delirium, haloalkyl, (C-C)-alkenyl, or (C-C)-alkynyl. amnestic disorder, Alzheimer's disease, Parkinson's disease, In one embodiment, R is —H., (C-C)-alkyl, —ORs, Huntington's disease, memory disorders including memory halogen, or —CF. In another embodiment, R is —H., (C- deficits associated with depression, senile dementia, demen 10 C)-alkyl, —ORs, halogen, or —CF and one of R. R. tia of Alzheimer's disease, cognitive deficits or cognitive Rs, and Reis —H., (C-C)-alkyl, —ORs, or halogen. In a dysfunction associated with neurological conditions includ further embodiment, R is —H., (C-C)-alkyl, —ORs, halo ing, for example, Parkinson's disease (PD), Huntington's gen, or—CF, one of R. R. Ris, and R is -H, (C-C)- disease (HD), Alzheimer's disease, depression and Schizo alkyl, -ORs, or halogen, and R-7, Rs. Ro Ro, R., and R2 phrenia (and other psychotic disorders such as paranoia and 15 are each hydrogen. In yet another embodiment, R is —H. mano-depressive illness); cognitive dysfunction in Schizo (C-C)-alkyl, —ORs, halogen, or —CF, one of R. R. phrenia, disorders of attention and learning Such as attention Rs, and Reis —H., (C-C)-alkyl, -ORs, or halogen, and deficit disorders (e.g., attention deficit hyperactivity disorder R2, R. R. Rs. R. R-7, Rs. Ro, Rio, R1, and R2 are each (ADHD)) and dyslexia, cognitive dysfunction associated hydrogen. In one embodiment, R is —H. (C-C)-alkyl, with developmental disorders such as Down's syndrome and —OR2s, halogen or—CF and R2, R. R. Rs. R. R-7, Rs. Ro, Fragile X syndrome, loss of executive function, loss of Rio R, R2, R1s. R14, Ris, and Rio are each hydrogen. learned information, vascular dementia, Schizophrenia, cog In one embodiment, R is —H., (C-C)-alkyl, —ORs, nitive decline, neurodegenerative disorder, and other demen halogen, or —CF. In another embodiment, R is —H., (C- tias, for example, due to HIV disease, head trauma, Parkin C)-alkyl, —ORs, halogen, or —CF and one of R. R. son's disease, Huntington's disease, Pick's disease, 25 Rs, and Reis —H., (C-C)-alkyl, —ORs, or halogen. In a Creutzfeldt-Jakob disease, or due to multiple etiologies. Cog further embodiment, R is —H., (C-C)-alkyl, —ORs, halo nition-related disorders also include, without limitation, cog gen, or—CF, one of R. R. Ris, and R is -H, (C-C)- nitive dysfunction associated with MCI and dementias such alkyl, -ORs, or halogen, and R-7, Rs. Ro Ro, R., and R2 as Lewy Body, vascular, and post stroke dementias. Cognitive are each hydrogen. In yet another embodiment, R is —H. dysfunction associated with Surgical procedures, traumatic 30 (C-C)-alkyl, —ORs, halogen, or —CF, one of R. R. brain injury or stroke may also be treated in accordance with Rs, and Reis —H., (C-C)-alkyl, -ORs, or halogen, and the present invention. R, R2, Rs. Rs. R. R-7, Rs. Ro, Rio, R1, and R2 are each Another nonlimiting example of a 5-HT-related disorder hydrogen. In one embodiment, R is —H., (C-C)-alkyl, is an anxiety-related disorder. Exemplary anxiety-related dis —ORs, halogen or—CF and R. R. R. Rs. R. R. Rs. Ro, orders include, without limitation, generalized anxiety disor 35 Rio R, R2, R1s. R14, Ris, and Rio are each hydrogen. der, attention deficit disorder, attention deficit hyperactivity In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, disorder, obsessive compulsive disorder, Substance addiction, halogen, or —CF. In another embodiment, Rs is —H., (C- withdrawal from drug, alcohol or nicotine addiction, panic C)-alkyl, —ORs, halogen, or —CF and one of R. R. disorder, panic attacks, post-traumatic stress disorder, pre Rs, and Reis —H., (C-C)-alkyl, —ORs, or halogen. In a menstrual dysphoric disorder, social anxiety disorder, eating 40 further embodiment, Rs is —H., (C-C)-alkyl, -ORs, halo disorders such as anorexia nervosa and bulimia nervosa, gen, or—CF, one of R. R. Ris, and R is -H, (C-C)- vasomotor flushing, and phobias, including Social phobia, alkyl, -ORs, or halogen, and R-7, Rs. Ro Ro, R., and R2 agoraphobia, and specific phobias. Substance addition are each hydrogen. In yet another embodiment, Rs is —H. includes, without limitation, drug, alcohol or nicotine addic (C-C)-alkyl, —ORs, halogen, or —CF, one of R. R. tion. 45 Rs, and Reis —H., (C-C)-alkyl, -ORs, or halogen; and R, R2, R. R. R. R-7, Rs. Ro, Rio, R1, and R2 are each Compounds of the Invention hydrogen. In one embodiment, Rs is —H., (C-C)-alkyl, In one embodiment, the present invention is directed to —ORs, halogen or—CF and R. R. R. R. R. R. Rs. Ro, compounds of the Formula (I): Rio, R. R. R. R. Ris, and R are each hydrogen. In a 50 further embodiment, one of R. R. Rs, and R is —H. (C-C)-alkyl, halogen, —CF, or —ORs; Rs is —H., (C- (I) C)-alkyl, —ORs, halogen, or—CF; and the remaining R R2 R R12 R11 groups are each hydrogen. In one embodiment, Rs is —H., (C-C)-alkyl, —ORs. 55 halogen, —CF. - NO or—CN. In another embodiment, Rs R3 / \ Ra R13 R14 / \ R10 is —H, (C-C)-alkyl, —ORs, halogen, —CF, —NO or —CN; one of R. R. R. R. Rs and Reis —H., (C-C)-alkyl, —ORs, halogen, or —CF, R., and R, are each indepen R4 N N N R9 dently —H or —CH; and each remaining R group is hydro 60 gen. In a further embodiment, Rs is —H., (C-C)-alkyl, Rs R6 \ {Rb R15 R16 R7 R8 —ORs, halogen, —CF, —NO or—CN; one of R. R. R. R. Rs and R is —H. (C-C)-alkyl, —ORs, halogen, or —CF, one of R. R. Rs, and R is —H., (C-C)-alkyl, and pharmaceutically acceptable salts thereof, —ORs, or halogen, and each remaining R group is hydro wherein R. R2, Rs. R4, Rs. R6. R7. Rs. R9. Rio R ls R12. 65 gen. In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, R. R. Ris, and R are each independently —H., (C-C)- halogen, —CF, —NO or—CN and one of R or Rs is —H. alkyl, (C-C)-haloalkyl, (C-C)-alkenyl, or (C-C)-alky (C-C)-alkyl, —ORs, halogen, or—CF, and each remain

US 7,671,056 B2 21 22 In one embodiment, R. R. R. R. R. Rs. Ro, Rio, and R. In one embodiment, R is —Hor—CH. R. Rs, and Rare are each hydrogen. each—Hor F: R is —H. F.—OCH, or—CF; R is —H, F, In one embodiment, R. R. R. R. R. R.s, and Rare each —OCHs; and Rs. Rs. R-7, Rio, R1, R12, R1s. R14, R1s. R16, R, hydrogen. and R, are each hydrogen. In one embodiment, R. R. R. R. R. R. R. and Rare In one embodiment, R is —H. —CF or (C-C)-alkyl, R. each hydrogen. and Rs are each —H, halogen, —ORs, or—CF, R7, Rs. Ro, In one embodiment, R. R. R. R. Rs. R. R-7, Rs. R3, and R. R. and R are each —H, halogen, -alkyl, —ORs. R2 are each hydrogen. —CF, or—NO, Reis —H or —CH In another embodiment, R. R. Rs, and R are each In one embodiment, Rasis (C-C)-haloalkyl. hydrogen. 10 In another embodiment, Rs is (C-C)-fluoroalkyl. In one embodiment, R. R. R-7, Rs. Ro, R2, R. R. Rs. In one embodiment, Rs is (C-C)-alkyl. In one embodi and R are each hydrogen. ment, R2s is —CH. In one embodiment, R, R2, R. R. R. R-7, Rs. Ro, R. R. In one embodiment, the compounds of Formula (I) are R. Ris, and R are each hydrogen. antagonists of the 5-HT, receptor. In another embodiment, In one embodiment, R. R. R. R. R. R-7, Rs. Ro Ro, 15 the compounds of Formula (I) are agonists of the 5-HT R. R. R. R. Ris, and R are each hydrogen. receptor. In one embodiment, R, R2, Rs. R. R. R-7, Rs. Rio, R. In another aspect, the invention provides compounds of the R. R. R. Ris, and R are each hydrogen. Formula (I"): In one embodiment, any one of R. R. R. R. Rs, and R. is —H., (C-C)-alkyl, —ORs, halogen or —CF; and any one of R7, Rs. Ro, Rio, R., and R is —H., (C-C)-alkyl, I —ORs, halogen, or —CF, —NO, or —CN. R2 R In one embodiment, any one of R. R. R. R. Rs, and R. is —H, (C-C)-alkyl, —ORs, halogen, —CF. - NO, or 25 R3 / \ Ra R13

—CN; and any two of R. R. R. R. R. and R are each o independently —H., (C-C)-alkyl, —ORs, halogen, —CF. In one embodiment, any one of R. R. R. R. Rs, and R. R4 N N is —H., (C-C)-alkyl, -ORs, halogen, —CF. - NO, or —CN; and any three of R7, Rs. R. R. R. and R2 are each \ { independently —H., (C-C)-alkyl, —ORs, halogen, —CF. 30 Rs R6 Rb R15 In one embodiment, any one of R. R. R. R. Rs, and R. is —H, (C-C)-alkyl, —ORs, halogen or —CF; and any and pharmaceutically acceptable salts thereof, one of R. R. Rs, and Reis —H, (C-C)-alkyl, —ORs, wherein R. R. R. R. Rs. R. R-7, R-7, Rs. R. Rio R, halogen or —CF. 35 R. R. R. Ris, and Rio, are each independently —H. In one embodiment, any one of R. R. R. R. R. and (C-C)-alkyl, (C-C)-haloalkyl, (C-C)-alkenyl, or (C- R is —H., (C-C)-alkyl, -ORs, halogen, —CF, —NO, C)-alkynyl, halogen, —CF, NO. —CN. —ORs. or —CN; and any one of R. R. Ris, and R is —H. —OSORs, —SRs - SORs, —SON(Rs), —N(Rs), (C-C)-alkyl, —ORs, halogen, —CF. —C(O), —CORs, —CORs, NRCORs. In one embodiment, R is —H., (C-C)-alkyl, —ORs, 40 —NRCORs, —NRCONCRs), or—CONCRs) except halogen, or -CF and any one of R. R. Ris, and R is for the R groups through which the piperidine is connected; —H., (C-C)-alkyl, —ORs, halogen or—CF; and any one R, and R, are each independently —H or —CH, and of R. R. R. R. R. and R is —H., (C-C)-alkyl, Rs is —H; or linear or branched (C-C)-alkyl, (C-C)- —ORs, halogen, or —CF, —NO, or —CN haloalkyl, (C-C)-alkenyl, or (C-C)-alkynyl; and In one embodiment, R is —H., (C-C)-alkyl, —ORs, 45 where the piperidine group can be attached to the non halogen, or -CF and any one of R. R. Ris, and R is hetero atom containing ring of the quinoline through posi —H., (C-C)-alkyl, -ORs, halogen or—CF; and any two tions R-7, R-7, Rs, or Ro. of R. R. R. R. R. and R are each independently —H. In one embodiment, R is —H., (C-C)-alkyl, —ORs, (C-C)-alkyl, —ORs, halogen, or—CF —NO, or—CN: halogen, or —CF. In another embodiment, R is —H., (C- wherein the any two of R7, Rs. R. R. R. and R2 can be 50 C)-alkyl, —ORs, halogen, or —CF and one of R. R. either on the same ring of the quinoline or on different rings. Rs, and Reis —H., (C-C)-alkyl, —ORs, or halogen. In a In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, further embodiment, R is —H., (C-C)-alkyl, —ORs, halo halogen, or -CF and any one of R. R. Ris, and R is gen, or—CF, one of R. R. Ris, and R is -H, (C-C)- —H., (C-C)-alkyl, —ORs, halogen or—CF; and any one alkyl, —ORs, or halogen or —CF; the piperidine is con of R7, Rs. R. Rio, R, and R2 is —H., (C-C)-alkyl, 55 nected through one of R7, R-7, Rs, or Ro, and the remainder of —ORs, halogen, or —CF, —NO, or —CN the R groups of the quinoline attached to the piperidine are In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, each hydrogen. In yet another embodiment, R is —H., (C- halogen, or -CF and any one of R. R. Ris, and R is C)-alkyl, —ORs, halogen, or—CF, one of R. R. Rs. —H., (C-C)-alkyl, -ORs, halogen or—CF; and any two and R is —H., (C-C)-alkyl, —ORs, or halogen; the pip of R7, Rs. R. Rio, R., and R2 are each independently —H. 60 eridine is connected through R7; and each remaining R group (C-C)-alkyl, —ORs, halogen, or—CF —NO, or—CN: is hydrogen. In yet another embodiment, R is —H., (C-C)- wherein the any two of R7, Rs. R. R. R. and R2 can be alkyl, —ORs, halogen, or —CF, one of R. R. Ris, and either on the same ring of the quinoline or on different rings. Reis —H., (C-C)-alkyl. —ORs, or halogen; the piperidine In one embodiment, R is —H or (C-C)-alkyl; R. Rs is connected through R7; and each remaining R group is and Ro are each—Horhalogen; R is —H, halogen, —ORs, 65 hydrogen. In yet another embodiment, R is —H, (C-C)- or—CF, Rs is —H, halogen, or—ORs, and R. R. R. R. alkyl, —ORs, halogen, or —CF, one of R. R. Ris, and R. R. Ris, R. R., and R, are each hydrogen. Reis —H, (C-C)-alkyl, —ORs, or halogen; the piperidine US 7,671,056 B2 23 24 is connected through Rs, and each remaining R group is Ro is —H., (C-C)-alkyl, —ORs, halogen, —CF, —NO or hydrogen. In yet another embodiment, R is —H., (C-C)- —CN; and each remaining R group is hydrogen except for the alkyl, —ORs, halogen, or —CF, one of R. R. Ris, and R group through which the piperidine is connected. In some Reis —H, (C-C)-alkyl, —ORs, or halogen; the piperidine embodiments, Rs is —H., (C-C)-alkyl, —ORs, halogen, or is connected through Ro; and each remaining R group is —CF, Ro is —H or halogen and each remaining R group is hydrogen. In one embodiment, R is —H. (C-C)-alkyl, —H or hydrogen except for the R group through which the —ORs, halogen or —CF, the piperidine is connected piperidine is connected. through R-7, and each remaining R group is hydrogen. In one In a further embodiment, Rs is —H., (C-C)-alkyl, embodiment, R is —H., (C-C)-alkyl, —ORs, halogen or —ORs, halogen, or—CF, one of R7, R-7, Rs. Ro Ro, R: —CF, the piperidine is connected through R7, and each 10 R is —H., (C-C)-alkyl, -ORs, halogen, —CF. - NO remaining R group is hydrogen. In one embodiment, R is or —CN except for the R group through which the piperidine —H., (C-C)-alkyl, —ORs, halogen or —CF, the piperi is connected; one of R. R. Rs, and R is —H., (C-C)- dine is connected through Rs, and each remaining R group is alkyl, —ORs, or halogen, and each remaining R group is hydrogen. In one embodiment, R is —H., (C-C)-alkyl, hydrogen except for the R group through which the piperidine —ORs, halogen or —CF, the piperidine is connected 15 is connected. through R. and each remaining R group is hydrogen. In a further embodiment, Rs is —H., (C-C)-alkyl, In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, —ORs, halogen, or —CF; and R, is —H., (C-C)-alkyl, halogen, or —CF. In another embodiment, Rs is —H., (C- —ORs, halogen, —CF —NO or—CN, and each remain C)-alkyl, —ORs, halogen, or —CF and one of R. R. ing R group is hydrogen except for the R group through which Rs, and Reis —H., (C-C)-alkyl, —ORs, or halogen. In a the piperidine is connected. In one embodiment, the piperi further embodiment, Rs is —H., (C-C)-alkyl, -ORs, halo dine is connected through R7; Rs is —H., (C-C)-alkyl, gen, or—CF, one of Rs. R. Ris, and R is -H, (C-C)- —ORs, halogen, or —CF; and R, is —H., (C-C)-alkyl, alkyl, —ORs, or halogen; the piperidine is connected —ORs, halogen, —CF, —NO or —CN. In one embodi through one of R7, R-7, Rs, or Ro, and the remainder of the R ment, the piperidine is connected through R7; Rs is —H or groups of the quinoline attached to the piperidine are each 25 —ORs, and R, is —H or halogen. hydrogen. In yet another embodiment, Rs is —H, (C-C)- In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, alkyl, —ORs, halogen, or —CF, one of R. R. Ris, and halogen, or —CF; two of R. R. R. R. R. R. R. are Reis —H., (C-C)-alkyl. —ORs, orhalogen; the piperidine each independently —H., (C-C)-alkyl, -ORs, halogen, is connected through R7; and each remaining R group is —CF, NO or CN except for the R group through which hydrogen. In yet another embodiment, Rs is —H., (C-C)- 30 alkyl, —ORs, halogen, or —CF, one of R. R. Ris, and the piperidine is connected; and each remaining R group is Reis —H. (C-C)-alkyl. —ORs, or halogen; the piperidine hydrogen except for the R group through which the piperidine is connected through R7; and each remaining R group is is connected. hydrogen. In yet another embodiment, Rs is —H, (C-C)- In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, alkyl, -ORs, halogen, or —CF, one of R. R. Rs, and 35 halogen, or —CF; two of R7, R-7, Rs. Ro Ro, R.; R2 are Reis —H, (C-C)-alkyl, —ORs, or halogen; the piperidine each independently —H., (C-C)-alkyl, —ORs, halogen, is connected through Rs, and each remaining R group is —CF, NO or CN except for the R group through which hydrogen. In yet another embodiment, Rs is —H, (C-C)- the piperidine is connected; one of R. R. Rs, and R is alkyl, —ORs, halogen, or —CF, one of R. R. Ris, and —H., (C-C)-alkyl, —ORs, or halogen, and each remaining Reis —H., (C-C)-alkyl. —ORs, orhalogen; the piperidine 40 Rgroup is hydrogen except for the R group through which the is connected through Ro; and each remaining R group is piperidine is connected. hydrogen. In one embodiment, Rs is —H., (C-C)-alkyl, In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, —ORs, halogen or —CF, the piperidine is connected halogen, or —CF; three of R7, R-7, Rs. Ro, Rio R, R2 are through R-7, and each remaining R group is hydrogen. In one each independently —H., (C-C)-alkyl, —ORs, halogen, embodiment, Rs is —H., (C-C)-alkyl, -ORs, halogen or 45 —CF, NO or CN except for the R group through which —CF, the piperidine is connected through R7, and each the piperidine is connected; one of R. R. Rs, and R is remaining R group is hydrogen. In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, or halogen, and each remaining —H., (C-C)-alkyl, —ORs, halogen or —CF, the piperi Rgroup is hydrogen except for the R group through which the dine is connected through Rs, and each remaining R group is piperidine is connected. hydrogen. In one embodiment, Rs is —H. (C-C)-alkyl, 50 In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, —ORs, halogen or —CF, the piperidine is connected halogen, or —CF, Ro is —H., (C-C)-alkyl, —ORs, halo through Ro, and each remaining R group is hydrogen. In a gen, —CF, —NO or—CN; and two of Rio R, and R2 are further embodiment, one of R. R. Rs, and R is —H. each independently —H., (C-C)-alkyl, -ORs, halogen, (C-C)-alkyl, halogen, —CF, or —ORs. Rs is —H., (C- —CF, NO, or —CN. In another embodiment, R is —H. C)-alkyl, —ORs, halogen, or—CF; and each remaining R 55 (C-C)-alkyl, -ORs, halogen, or —CF, Ro is —H., (C- group is hydrogen. C)-alkyl, —ORs, halogen, —CF, —NO or —CN; two of In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, Rio R, R2 are each independently —H. (C-C)-alkyl, halogen, or —CF and one of R7, R-7, Rs. R. Rio R, and —ORs, halogen, —CF —NO or—CN; and each remain R is —H. (C-C)-alkyl, —ORs, halogen, —CF, —NO ing R group is hydrogen except for the R group through which or —CN except for the R group through which the piperidine 60 the piperidine is connected. In some embodiments, Rs is —H is connected. In another embodiment, Rs is —H., (C-C)- or —ORs; R is —H or halogen; two of Ro, R. R. are alkyl, —ORs, halogen, or—CF and one of R7, R-7, Rs. Ro, each independently —H., (C-C)-alkyl, -ORs, halogen, R. R. or R is —H., (C-C)-alkyl, —ORs, halogen, —CF, —NO or —CN; and each remaining R group is —CF, NO or CN except for the R group through which hydrogen except for the R group through which the piperidine the piperidine is connected; and each remaining R group is 65 is connected. In some embodiments, Rs is —H or —OCH: hydrogen except for the R group through which the piperidine Ro is —H or halogen; two of Rio R, R2 are each indepen is connected. In some embodiments, Rs is —Hor—ORs and dently —H., (C-C)-alkyl, —ORs, halogen, —CF —NO US 7,671,056 B2 25 26 or—CN; and each remaining R group is hydrogen except for In one embodiment, Ro is —H., (C-C)-alkyl, —ORs, the R group through which the piperidine is connected. halogen, —CF, —NO or—CN. In another embodiment, R. In some embodiments. Rs is —H. —(C-C)-alkyl, is —H., (C-C)-alkyl, —ORs, halogen, —CF, —NO or —ORs, halogen, or —CF, Ro is —H., (C-C)-alkyl, —CN; one of R. R. R. R. Rs and R is —H., (C-C)- —ORs, halogen, —CF, —NO or —CN; R-7, Ro and R2 alkyl, —ORs, halogen, or —CF, R., and R, are each inde are each independently —H., (C-C)-alkyl, —ORs, halo pendently —H or —CH, and each remaining R group is gen, —CF, —NO or —CN; and each remaining R group is hydrogen except for the R group through which the piperidine hydrogen except for the R group through which the piperidine is connected. In a further embodiment, Ro is —H, (C-C)- is connected. In some embodiments, Rs is —H. —(C-C)- alkyl, -ORs, halogen, —CF —NO or —CN; one of R, alkyl, —ORs, halogen, or—CF, Ro is —H, (C-C)-alkyl, 10 R. R. R. Rs and R is —H., (C-C)-alkyl, —ORs, halo —ORs, halogen, —CF. - NO or —CN; Ro and R are gen, or—CF, one of R. R. Ris, and R is -H, (C-C)- each independently —H., (C-C)-alkyl, -ORs, halogen, alkyl, —ORs, or halogen; R and R, are each independently —CF, —NO or —CN; and each remaining R group is —H or —CH, and each remaining R group is hydrogen hydrogen except for the R group through which the piperidine except for the R group through which the piperidine is con is connected. In some embodiments. In some embodiments, 15 nected. In one embodiment, Ro is —H, (C-C)-alkyl, Rs is —H. —(C-C)-alkyl, -ORs, halogen, or—CF, Rois —ORs, halogen, —CF.—NO or—CN and one of R or Rs —H., (C-C)-alkyl, —ORs, halogen, —CF —NO or is —H., (C-C)-alkyl, —ORs, halogen, or —CF. In one —CN; R, and R are each independently —H., (C-C)- embodiment R is —H., (C-C)-alkyl, —ORs, halogen, alkyl, —ORs, halogen, —CF —NO or —CN; and each —CF, NO or —CN; and all other R groups are each remaining R group is hydrogen except for the R group hydrogen except for the R group through which the piperidine through which the piperidine is connected. is connected. In one embodiment, R is —H., (C-C)-alkyl, —ORs, halogen, —CF, —NO or —CN; one of R. R. In one embodiment, R is —H., (C-C)-alkyl, —ORs, Rs, and R is —H., (C-C)-alkyl, -ORs, or halogen, and halogen, or—CF and one of R-7, R-7, R. R. Rio R, and R each remaining R group is hydrogen except for the R group is —H., (C-C)-alkyl, —ORs, halogen, —CF, —NO or 25 through which the piperidine is connected. —CN. In another embodiment, R is —H., (C-C)-alkyl, In one embodiment, R, is —H., (C-C)-alkyl, —ORs, —ORs, halogen, or —CF, one of R7, R. R. R. Rio, R. halogen, —CF, —NO or —CN. In one embodiment, R, is and R is —H., (C-C)-alkyl, —ORs, halogen, —CF, —H., (C-C)-alkyl or halogen. In one embodiment, R, is —NO or —CN; and each remaining R group is hydrogen —H., (C-C)-alkyl, —ORs, halogen, —CF —NO or except for the R group through which the piperidine is con 30 —CN; one of R. R. R. R. Rs and Reis —H., (C-C)-alkyl, nected. In a further embodiment, R is —H., (C-C)-alkyl, —ORs, halogen, or—CF; and R, and R, are each indepen —OR2s, halogen, or -CF, one of R-7, R-7, RoRo Ro, R. dently —H or —CH; and each remaining R group is hydro R is —H. (C-C)-alkyl, —ORs, halogen, —CF, —NO gen, except for the R group through which the piperidine is or—CN; one of R. R. Ris, and Reis —H., (C-C)-alkyl, —ORs, or halogen, and each remaining R group is hydrogen connected. In one embodiment, R, is —H. (C-C)-alkyl, 35 —ORs, halogen, —CF, —NO or —N; one of R. R. R. except for the R group through which the piperidine is con R. Rs and R is —H. (C-C)-alkyl, —ORs, halogen, or nected. —CF; and each remaining R group is hydrogen, except for In one embodiment, one of R. R. Ris, and R is —H. the R group through which the piperidine is connected. (C-C)-alkyl, halogen, —CF, or —ORs. In one embodiment, Ro is —H., (C-C)-alkyl, —ORs, In one embodiment, Rs is —H., (C-C)-alkyl, —ORs. 40 halogen, —CF, —NO or -CN. In one embodiment, Ro is halogen, —CF, NO or—CN. In another embodiment, Rs —H., (C-C)-alkyl, —ORs, halogen, or —CF. In one is —H, (C-C)-alkyl, —ORs, halogen, —CF. - NO or embodiment, Ro is —H, CH, -OCH, —For —CF. In —CN; one of R. R. R. R. and R is —H., (C-C)-alkyl, one embodiment, Ro is —H., (C-C)-alkyl, —ORs, halo —ORs, halogen, or —CF, R., and R, are each indepen gen, —CF, —NO or—CN; one of R,R,R,R,Rs and R. dently —H or —CH; and each remaining R group is hydro 45 is —H., (C-C)-alkyl, —ORs, halogen, or —CF; and R. gen except for the R group through which the piperidine is and R, are each independently —H or —CH, and each connected. In a further embodiment, Rs is —H, (C-C)- remaining R group is hydrogen, except for the R group alkyl, —ORs, halogen, —CF, —NO or —CN; one of R, through which the piperidine is connected. In one embodi R. R. R. Rs, and R is —H, (C-C)-alkyl, —ORs, halo ment, Ro is —H, (C-C)-alkyl, —ORs, halogen, —CF, gen, or—CF, one of Rs. R. Ris, and R is -H, (C-C)- 50 —NO or —CN; one of R. R. R. R. Rs and R is —H. alkyl, —ORs, or halogen, R., and R, are each independently (C-C)-alkyl, —ORs, halogen, or—CF; and each remain —H or —CH, and each remaining R group is hydrogen ing R group is hydrogen, except for the R group through except for the R group through which the piperidine is con which the piperidine is connected. nected. In one embodiment, Rs is —H, (C-C)-alkyl, In one embodiment, R is —H., (C-C)-alkyl, —ORs. —ORs, halogen, —CF —NO or—CN and one of R or Rs 55 halogen, —CF, —NO or—CN. In one embodiment, R is is —H., (C-C)-alkyl, —ORs, halogen, or—CF and each —H., (C-C)-alkyl, halogen, or —CF. In one embodiment, remaining R group is hydrogen except for the R group R is —H, —CH-For-CF. In one embodiment, R is through which the piperidine is connected. In one embodi —H., (C-C)-alkyl, —ORs, halogen, —CF —NO or ment Rs is —H., (C-C)-alkyl, -ORs, halogen, —CF, —CN; one of R. R. R. R. Rs and Reis —H., (C-C)-alkyl, —NO or —CN; and all other R groups are each hydrogen 60 —ORs, halogen, or—CF; and R, and R, are each indepen except for the R group through which the piperidine is con dently —H or —CH; and each remaining R group is hydro nected. In one embodiment, Rs is —H, (C-C)-alkyl, gen, except for the R group through which the piperidine is —ORs, halogen, —CF —NO or —CN; one of R. R. connected. In one embodiment, R is —H., (C-C)-alkyl, Rs, and R is —H., (C-C)-alkyl, —ORs, or halogen, R, —ORs, halogen, —CF, —NO or —N; one of R. R. R. and R, are each independently —H or —CH, and each 65 R. Rs and R is —H. (C-C)-alkyl, —ORs, halogen, or remaining R group is hydrogen except for the R group —CF; and each remaining R group is hydrogen, except for through which the piperidine is connected. the R group through which the piperidine is connected. US 7,671,056 B2 27 28 In one embodiment, R is —H. (C-C)-alkyl, —ORs, In one embodiment, R is —H or (C-C)-alkyl; R. Rs halogen, —CF, —NO or -CN. In one embodiment, R is and Rs are each—Horhalogen; R is —H, halogen, —ORs. —H., (C-C)-alkyl, halogen, or —CF. In one embodiment, or—CF, Rs is —H, halogen, or—ORs, and R. R. R7, R-7, R is —H, —CH-For-CF. In one embodiment, R is Rs. Ro, R2, R. R. Ris, and R are each hydrogen except —H., (C-C)-alkyl, —ORs, halogen, —CF —NO or for the R group through which the piperidine is connected. In —CN; one of R. R. R. R. Rs and Reis —H., (C-C)-alkyl, one embodiment, R is —H or (C-C)-alkyl, R. Rs, and Ro —ORs, halogen, or—CF; and RandR, are each indepen are each —H or F: R is H. F. —ORs, or—CF; Rs is —H. dently —H or —CH; and each remaining R group is hydro F, or—OR2s, and Rs. R. R-7, R-7, Rs. Ro, R2, R. R. Rs. gen, except for the R group through which the piperidine is and R are each hydrogen except for the R group through connected. In one embodiment, R2 is —H. (C-C)-alkyl, 10 which the piperidine is connected. —ORs, halogen, —CF. - NO or—CN; one of R. R. R. In one embodiment, any one of R. R. R. R. Rs, and R. R. Rs and R is —H. (C-C)-alkyl, —ORs, halogen, or is —H., (C-C)-alkyl, —ORs, halogen; and any one of R7. —CF; and each remaining R group is hydrogen, except for R7, Rs. R. Rio, R., and R2 is —H, (C-C)-alkyl, —ORs, the R group through which the piperidine is connected. halogen, or —CF, —NO, or —CN except for the R group In one embodiment, R, R2, R. R. R-7, R-7, Ro, Rio, R. 15 through which the piperidine is connected. and R2, are each hydrogen except for the R group through In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, which the piperidine is connected. halogen or -CF; and any one of R-7, R-7, Rs. Ro, Rio, R. In one embodiment, R, R2, R. R. R-7, R-7, Rs. Rio, R. and R is —H., (C-C)-alkyl, —ORs, halogen, or —CF, and R are each hydrogen except for the R group through —NO, or —CN, except for the R group through which the which the piperidine is connected. piperidine is connected. In one embodiment, R. R. R. R. R. R. Rs. R. R. and In one embodiment, Rs is —H., (C-C)-alkyl, —ORs. R2 are each hydrogen except for the R group through which halogen or —CF; and any two of R7, R-7, Rs. Ro Ro, R. the piperidine is connected. and Rare each independently —H., (C-C)-alkyl, —ORs. In one embodiment, R. R. R. R. R-7, R-7, Rs. Ro Ro, halogen, or —CF —NO, or —CN, except for the R group and R, are each hydrogen except for the R group through 25 which the piperidine is connected. through which the piperidine is connected. In one embodiment, R. R. R. R. R. R-7, Rs, and R, are In one embodiment, Rs is —H., (C-C)-alkyl, —ORs. each hydrogen except for the R group through which the halogen or —CF; and any three of R7, R-7, Rs. Ro Ro, R. piperidine is connected. and R2 are each independently —H., (C-C)-alkyl, —ORs, In one embodiment, R. R. R. R. R-7, R-7, Rs. Ro, and 30 halogen, or —CF —NO, or —CN, except for the R group R, are each hydrogen except for the R group through which through which the piperidine is connected. the piperidine is connected. In one embodiment, any one of R. R. R. R. Rs, and R. In one embodiment, R, R2, R. R. R-7, R-7, Rs. Ro Ro, is —H., (C-C)-alkyl, —ORs, halogen; and any one of Rs. R, and R2, are each hydrogen except for the R group Ra Rs, and Reis —H., (C-C)-alkyl, —ORs, or halogen. through which the piperidine is connected. 35 In one embodiment, any one of R7, R-7, Rs. Ro Ro, R. In one embodiment, R, R2, R. R. R-7, R-7, Rs. Ro Ro, and R is —H., (C-C)-alkyl, —ORs, halogen, or —CF, R. R. R. R. Ris, and Rare each hydrogen except for —NO, or —CN except for the R group through which the the R group through which the piperidine is connected. piperidine is connected; and any one of R. R. Ris, and R. In one embodiment, R. R. R. R. R-7, R-7, Rs. Ro Ro, is —H., (C-C)-alkyl, —ORs, halogen or —CF. R, and R2 are each hydrogen except for the R group 40 In one embodiment, R is —H., (C-C)-alkyl, —ORs, through which the piperidine is connected. halogen, or -CF and any one of R. R. Ris, and R is In one embodiment, R, R2, R. R. Rs. R. R-7, R-7, Rio, —H., (C-C)-alkyl, —ORs, or halogen; and any one of R7, R. R. R. R. Ris, and Rare each hydrogen except for R7, Rs. R. Rio, R., and R2 is —H, (C-C)-alkyl, —ORs, the R group through which the piperidine is connected. halogen, or —CF, —NO, or —CN except for the R group In one embodiment, R. R. R. R. R. R. R. , R7, Ro, 45 through which the piperidine is connected. R1, and R2 are each hydrogen. In one embodiment, R is —H., (C-C)-alkyl, —ORs, In another embodiment, R. R. Rs, and R are each halogen, or -CF and any one of R. R. Ris, and R is hydrogen. —H., (C-C)-alkyl, —ORs, or halogen; and any two of R7, In one embodiment, R. R. R-7, R-7, Rio, R. R. R. R. R. R. R. R. and R are each independently —H. Ra Rs, and R are each hydrogen except for the R group 50 (C-C)-alkyl, —ORs, halogen, or—CF, —NO, or—CN through which the piperidine is connected. except for the R group through which the piperidine is con In one embodiment, R. R. R. R. R. R-7, Rs. Rio, R. nected; wherein the any two of R7, R-7, Rs. Ro, Rio R, and R2, R. R. Ris, and R1s are each hydrogen except for the R can be either on the same ring of the quinoline or on R group through which the piperidine is connected. 55 different rings. In one embodiment, R, R2, R. R. R. R-7, Rs. Ro, Rio, In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, R. R. R. R. Ris, and Rare each hydrogen except for halogen, or -CF3 and any one of R. R. Ris, and R is the R group through which the piperidine is connected. —H., (C-C)-alkyl, -ORs, or halogen; and any one of R7. In one embodiment, R is —H or (C-C)-alkyl; R and Rs R7, Rs. R. Rio, R., and R2 is —H, (C-C)-alkyl, —ORs, are each independently —H, halogen, —ORs, or—CF, R7. 60 halogen, or —CF. —NO, or—CN except for the R group R7, Rs. R. Rio R, and R2 are each independently —H. through which the piperidine is connected halogen, (C-C)-alkyl, —ORs, —CF, NO or CN except In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, for the R group through which the piperidine is connected. halogen, or -CF and any one of R. R. Ris, and R is In one embodiment, Rs is —H, halogen, or —ORs, and —H., (C-C)-alkyl, —ORs, or halogen; and any two of R7, Rs. Rs. R-7, R-7, Rs. Ro, R12, R13, R14, Ris, and R16 are each 65 R7, Rs. Ro Ro, R., and R2 are each independently —H. hydrogen except for the R group through which the piperidine (C-C)-alkyl, —ORs, halogen, or—CF, —NO, or—CN is connected. except for the R group through which the piperidine is con US 7,671,056 B2 29 30 nected; wherein the any two of R7, R-7, Rs. Ro, Rio R, and C)-alkyl, —ORs, halogen, or —CF and one of R. R. R can be either on the same ring of the quinoline or on Rs, and R is —H., (C-C)-alkyl, —ORs, or halogen. In a different rings. further embodiment, Rs is —H., (C-C)-alkyl, —ORs, halo In one embodiment, the piperidine N is connected through gen, or—CF, one of R. R. Ris, and R is -H, (C-C)- the R7 of the quinoline. In another embodiment, the piperi alkyl, -OR2s, or halogen, and R-7, Rs. Ro, Rio, R1, and R2 dine N is connected through the R-7, of the quinoline. In yet are each hydrogen. In yet another embodiment, Rs is —H. another embodiment, the piperidine N is connected through (C-C)-alkyl, —ORs, halogen, or —CF, one of R. R. the Rs of the quinoline. In still another embodiment, the Rs, and Reis —H., (C-C)-alkyl, -ORs, or halogen; and piperidine N is connected through the R of the quinoline. R. R. R. R. R. R-7, Rs. R. Rio R, and R2 are each In one embodiment, R2s is (C-C)-haloalkyl. 10 hydrogen. In one embodiment, Rs is —H. (C-C)-alkyl, In another embodiment, Rs is (C-C)-fluoroalkyl. —ORs, halogen or—CF and R,R,R,R,R, R-7, Rs. Ro, In one embodiment, Rs is (C-C)-alkyl. In one embodi Rio R, R2, R. R. Ris, and R are each hydrogen. In a ment, R2s is —CH. further embodiment, one of R. R. Rs, and R is —H. In one embodiment, the compounds of Formula (I") are (C-C)-alkyl, halogen, —CF, or —ORs. Rs is —H., (C- antagonists of the 5-HT, receptor. In another embodiment, 15 C)-alkyl, —ORs, halogen, or—CF; and each remaining R the compounds of Formula (I") are agonists of the 5-HT group is hydrogen. receptor. In one embodiment, R, is —H., (C-C)-alkyl, —ORs, In another embodiment, the compounds of Formula (I") halogen, —CF, —NO or —CN. In one embodiment, R, is have the Formula (I"a): —H., (C-C)-alkyl, —ORs, halogen, —CF —NO or —CN; one of R. R. R. R. Rs and Reis —H., (C-C)-alkyl, —ORs, halogen, or—CF; and RandR, are each indepen dently —H or —CH; and each remaining R group is hydro gen. In one embodiment, R, is —H., (C-C)-alkyl, —ORs. R2 R R12 halogen, —CF, —NO or —CN; one of R. R. R. R. Rs 25 and R is —H., (C-C)-alkyl, —ORs, halogen, or —CF; R3 / \ N Ra Rs 14 R. Na h R11 and each remaining R group is hydrogen. In one embodiment, R, is —H., (C-C)-alkyl, —ORs, halogen, —CF, —NO or —CN; and each remaining R group is hydrogen. R4 N N N R10 In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, R9 30 halogen, —CF, —NO or—CN. In another embodiment, Rs Rs R6 Rb R15 R Rs is —H., (C-C)-alkyl, —ORs, halogen, —CF, —NO or —CN; one of R,R,R,R,Rs and R is —H, (C-C)-alkyl, —ORs, halogen, or —CF, R, and R, are each indepen and pharmaceutically acceptable salts thereof, dently —H or —CH; and each remaining R group is hydro wherein R. R. R, R2, R. R. Rs. R. R-7, Rs. Ro Ro, 35 gen. In a further embodiment, Rs is —H., (C-C)-alkyl, R. R. R. R. Ris, Rio, and R2s are defined as above for —ORs, halogen, —CF. - NO or—CN; one of R. R. R. Formula (I") R. Rs and R is —H. (C-C)-alkyl, —ORs, halogen, or In one embodiment, R is —H., (C-C)-alkyl, —ORs, —CF, one of R. R. Ris, and R is —H, (C-C)-alkyl, halogen, or —CF. In another embodiment, R is —H., (C- —ORs, orhalogen, RandR, are eachindependently —Hor C)-alkyl, —ORs, halogen, or —CF and one of R. R. 40 —CH, and each remaining R group is hydrogen. In one Rs, and Reis —H., (C-C)-alkyl, —ORs, or halogen. In a embodiment, Rs is —H., (C-C)-alkyl, -ORs, halogen, further embodiment, R is —H., (C-C)-alkyl, —ORs, halo —CF, —NO or —CN; one of R or Rs is —H., (C-C)- gen, or—CF, one of Rs. R. Ris, and R is -H, (C-C)- alkyl, —ORs, halogen, or —CF, R., and R, are each inde alkyl, -ORs, or halogen, and R-7, Rs. R. Rio R, and R. pendently —H or —CH, and each remaining R group is are each hydrogen. In yet another embodiment, R is —H. 45 hydrogen. In one embodiment Rs is —H., (C-C)-alkyl, (C-C)-alkyl, —ORs, halogen, or —CF, one of R. R. —ORs, halogen, —CF —NO or —CN; and all other R Rs, and Reis —H., (C-C)-alkyl, —ORs, or halogen, and groups are each hydrogen. In one embodiment, Rs is —H. R2, R. R. Rs. R. R-7, Rs. Ro, Rio, R1, and R2 are each (C-C)-alkyl, —ORs, halogen, —CF —NO or —CN: hydrogen. In one embodiment, R is —H. (C-C)-alkyl, one of R. R. Rs, and R is —H, (C-C)-alkyl, —ORs. —OR2s, halogen or—CF and R2, R. R. Rs. R. R-7, Rs. Ro, 50 or halogen, R., and R, are each independently —H or —CH, Rio R, R2, R1s. R14, Ris, and Rio are each hydrogen. and each remaining R group is hydrogen. In one embodiment, R is —H., (C-C)-alkyl, —ORs, In one embodiment, Ro is —H., (C-C)-alkyl, —ORs, halogen, or —CF. In another embodiment, R is —H., (C- halogen, —CF. - NO or—CN. In another embodiment, Ro C)-alkyl, —ORs, halogen, or —CF and one of R. R. is —H, (C-C)-alkyl, —ORs, halogen, —CF, —NO or Rs, and Reis —H., (C-C)-alkyl, —ORs, or halogen. In a 55 —CN; one of R. R. R. R. Rs and Reis —H., (C-C)-alkyl, further embodiment, R is —H., (C-C)-alkyl, -ORs, halo —ORs, halogen, or —CF, R, and R, are each indepen gen, or—CF, one of Rs. R. Ris, and R is -H, (C-C)- dently —H or —CH; and each remaining R group is hydro alkyl, -ORs, or halogen, and R-7, Rs. R. Rio R, and R. gen. In a further embodiment, Ro is —H., (C-C)-alkyl, are each hydrogen. In yet another embodiment, R is —H. —ORs, halogen, —CF. - NO or—CN; one of R. R. R. (C-C)-alkyl, —ORs, halogen, or —CF, one of R. R. 60 R. Rs and R, is —H. (C-C)-alkyl, —ORs, halogen, or Rs, and Reis —H., (C-C)-alkyl, —ORs, or halogen, and —CF, one of R. R. Rs, and R is —H., (C-C)-alkyl, R, R2, Rs. Rs. R. R-7, Rs. Ro. Rio R, and R2 are each —ORs, or halogen, and each remaining R group is hydro hydrogen. In one embodiment, R is —H., (C-C)-alkyl, gen. In one embodiment, R is —H., (C-C)-alkyl, —ORs. —ORs, halogen or—CF and R. R. R. R. R. R7, Rs. Ro, halogen, —CF, —NO or —CN; one of R or Rs is —H. Rio R, R2, R1s. R14, Ris, and Rio are each hydrogen. 65 (C-C)-alkyl, —ORs, halogen, or—CF, and each remain In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, ing R group is hydrogen. In one embodiment Ro is —H. halogen, or —CF. In another embodiment, Rs is —H., (C- (C-C)-alkyl, —ORs, halogen, —CF —NO or —CN:

US 7,671,056 B2 33 34 In one embodiment, R, R2, R. R. R-7, Rs. Ro, Rio, and —CF, R7, Rs. R. Rio, R., and R2 are each independently Rare each hydrogen. —H, halogen, (C-C)-alkyl, -ORs, —CF, or—NO, R. In one embodiment, R, R2, R. R. R-7, Rs. Ro, Rio, and is —H or —CH. R, are each hydrogen. In one embodiment, R2s is (C-C)-haloalkyl. In one embodiment, R. R. R. R. R. R. and R are In another embodiment, Rs is (C-C)-fluoroalkyl. each hydrogen. In one embodiment, Rs is (C-C)-alkyl. In one embodi In one embodiment, R. R. R. R. R-7, RoRo and Rare ment, R2s is —CH. each hydrogen. In another aspect, the invention provides compounds of the In one embodiment, R, R2, R. R. Rs. R. R-7, Rs. Ro, and Formula (II): R2 are each hydrogen. 10 In another embodiment, R. R. Rs, and R are each hydrogen. (II) In one embodiment, R. R. R-7 , Ro Ro, R2, R1, R1a, Rs, and R are each hydrogen. 15 / \ A y Ris In one embodiment, R, R2, Rs. R. R. Rs. Ro, Rio, R. N Ra N Q R2, R. R. Ris, and R are each hydrogen. In one embodiment, R. R. R. R. R. R. Rio, R. R. R4 N N N A R. R. Ris, and Rio are each hydrogen. In one embodiment, any one of R7, Rs. Ro, Rio, R., and \ { SR \ Ž. R is —H., (C-C)-alkyl, -ORs, halogen, —CF, —NO, Rs Rb R15 R16 or —CN; and any one of R. R. Ris, and R is —H. (C-C)-alkyl, —ORs, halogen, —CF. and pharmaceutically acceptable salts thereof, In one embodiment, any one of R. R. R. R. Rs, and R. is —H, (C-C)-alkyl, —ORs, halogen or —CF; and any 25 wherein R. R. R. Rs. Rs. R. and R2s are defined as one of R7, Rs. Ro, Rio R, and R is —H., (C-C)-alkyl, above for Formula (I); —ORs, halogen, or —CF, —NO, or —CN. R7, Rio, and R are each independently —H., (C-C)- In one embodiment, any one of R. R. R. R. Rs, and R. alkyl, (C-C)-haloalkyl, (C-C)-alkenyl, or (C-C)-alky is —H, (C-C)-alkyl, —ORs, halogen or —CF; and any nyl, halogen, —CF —NO. —CN. —ORs, —OSORs. one of R. R. Rs, and Reis —H, (C-C)-alkyl, —ORs, 30 —SRs, —SORs, —SON(Rs), —N(Rs), —C(O), halogen or—CF. —CORs, —CORs, —NRCORs, —NRCORs, In one embodiment, R is —H., (C-C)-alkyl, —ORs. —NRCON (Rs), or —CONCRs), and halogen, or -CF3 and any one of R. R. Ris, and R is Ra and Rs cannot both be hydrogen. —H., (C-C)-alkyl, —ORs, halogen or—CF; and any one In one embodiment, R and Rs are each independently of R7, Rs. Ro, Rio, R., and R2 is —H., (C-C)-alkyl, 35 —H. —ORs, halogen, or (C-C)-alkyl; Rs and R are —ORs, halogen, or—CF —NO, or—CN. each independently —Hor—CH; and R7, Ris, and Ro are In one embodiment, R is —H., (C-C)-alkyl, —ORs, each independently —H. —ORs, halogen, (C-C)-alkyl, halogen, or -CF3 and any one of R. R. Ris, and R is —CF. - NO. —CN. In one embodiment, R and Rs are —H., (C-C)-alkyl, -ORs, halogen or—CF; and any two each independently —H. —OCH, F, or—CH; Rs and R. of R7, Rs. Ro, Rio R, and R2 are each independently —H. 40 are each independently —Hor—CH; and R7, Ris, and Rio (C-C)-alkyl, —ORs, halogen, or—CF, NO, or—CN: are each independently —H. —OCH, —F. —CH —CF, wherein the any two of R7, Rs. R. Rio, R., and R2 can be - NO. —CN, or —Br. either on the same ring of the quinoline or on different rings. In one embodiment, R and Rs are each independently In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, —H, or—ORs. Rs and R are each independently —H or halogen, or -CF3 and any one of R. R. Ris, and R is 45 —CH; and R, Rs, and R are each independently —H. —H., (C-C)-alkyl, -ORs, halogen or—CF; and any one —ORs, halogen, (C-C)-alkyl, or —CF. In one embodi of R7, Rs. Ro, Rio, R., and R2 is —H., (C-C)-alkyl, ment, Ra and Rs are each independently —H, or—ORs, R. —ORs, halogen, or—CF —NO, or—CN. R. R1s and R1s are hydrogen; and R17, Ris, and Rio are each In one embodiment, Rs is —H., (C-C)-alkyl, —ORs. independently —H. —ORs, halogen, (C-C)-alkyl, or halogen, or -CF3 and any one of R. R. Ris, and R is 50 —CF. —H., (C-C)-alkyl, —ORs, halogen or—CF; and any two In another embodiment, Ro is in the para position relative of R7, Rs. Ro, Rio R, and R2 are each independently —H. to the nitrogen of the piperidine. (C-C)-alkyl, —ORs, halogen, or—CF —NO, or—CN: In one embodiment, R, and Rs are located at positions 2 wherein the any two of R7, Rs. R. Rio, R., and R2 can be and 4 of the quinoline ring (i.e., at the ortho and parapositions either on the same ring of the quinoline or on different rings. 55 relative to the nitrogen of the quinoline ring). In one embodiment, R is —H or (C-C)-alkyl; R. Rs In one embodiment, Rs is —H., (C-C)-alkyl, —ORs. and Ro are each independently —H or halogen; R is —H. halogen, or —CF. halogen, —ORs, or —CF, Rs is —H, halogen, or—ORs: In another embodiment, Rs is —H. (C-C)-alkyl, —ORs, and R. R. R-7, R. R. R. R. R. R. and R, are each halogen, or —CF and one of Rs and R is —H., (C-C)- hydrogen. 60 alkyl, —ORs, or halogen. In one embodiment, R is —Hor—CH; R. Rs, and Rare In yet another embodiment, Rs is —H. (C-C)-alkyl, each independently —H or F: R is H. F. —OCH or —ORs, halogen, or —CF, R1s is —H., (C-C)-alkyl, —CF, Rs is —H. F. —OCH; and R. R. R-7, Rio, R. R. —ORs, or halogen, and R and R are each hydrogen. R. R. R. R. R. and R, are each hydrogen. 65 In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, In one embodiment, R is —H. —CF or (C-C)-alkyl, R. halogen, or —CF, R is —H., (C-C)-alkyl, —ORs, or and Rs are each independently —H, halogen, —ORs, or halogen, and R and Rs are each hydrogen. US 7,671,056 B2 35 36 In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, —H., (C-C)-alkyl, —ORs, halogen, or —CF; and one of halogen or—CF and R. R. R. R7, Rs and Ro are each Rs, and R is —H., (C-C)-alkyl, —ORs, halogen, or hydrogen. —CF. In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, In one embodiment, R is —H., (C-C)-alkyl, —ORs, halogen, or —CF and one of R7, Rs and R is —H., (C- halogen, or —CF and one of R7, Rs and Rio is —H., (C- C)-alkyl, —ORs, halogen, or —CF. In another embodi C)-alkyl, —ORs, halogen, or —CF. ment, Rs is —H, (C-C)-alkyl, —ORs, halogen, or—CF; In another embodiment, R is —H., (C-C)-alkyl, —ORs. one of R7, Rs and Rio is —H., (C-C)-alkyl, —ORs, halo halogen, or —CF and one of R7, Rs and Rio is —H., (C- gen, or—CF; and each remaining R group is hydrogen. C)-alkyl, —ORs, halogen, or—CF; and each remaining R In one embodiment, Rs. R7, Rs, and Rio are each inde 10 group is hydrogen. pendently —H., (C-C)-alkyl, —ORs, halogen or —CF In a further embodiment, R is —H., (C-C)-alkyl, and R. Rs, and R are each hydrogen. In one embodiment, —ORs, halogen, or —CF, one of R7, Rs and R is —H. Rs is —H. —ORs or halogen; R, and Rs are each indepen (C-C)-alkyl, —ORs, halogen, or —CF, one of Rs and dently —H., (C-C)-alkyl, —ORs, halogen or—CF. R is R is —H., (C-C)-alkyl, -ORs, or halogen; and each —Horhalogen; and R. R. R. Rs, and R are each hydro 15 remaining R group is hydrogen. gen. In a further embodiment, R is —H., (C-C)-alkyl, In one embodiment, R is —H., (C-C)-alkyl, —ORs. —ORs, halogen, or—CF; and any two of R7, Rs and Rio halogen, or —CF. are each independently —H., (C-C)-alkyl, —ORs, halo In another embodiment, R is —H., (C-C)-alkyl. —ORs. gen, or —CF. In one embodiment, R. R. Rs and Rio are halogen, or —CF and one of Rs, and R is —H., (C-C)- each independently —H., (C-C)-alkyl, —ORs, halogen, or alkyl, —ORs, or halogen. —CF and each remaining R group is hydrogen. In a further embodiment, R is —H, (C-C)-alkyl, In one embodiment, one of Rs and R is —H., (C-C)- —ORs, halogen, or —CF, one of Rs and R is —H. alkyl, halogen, —CF, or —ORs. In a further embodiment, (C-C)-alkyl, —ORs, or halogen; and R. R. and R are one of Rs and Reis —H. (C-C)-alkyl, halogen, —CF, or each hydrogen. 25 —ORs. Rs is —H., (C-C)-alkyl, —ORs, halogen, or In yet another embodiment, R is —H. (C-C)-alkyl, —CF; and each remaining R group is hydrogen. —ORs, halogen, or —CF, R1s is —H., (C-C)-alkyl, In a further embodiment, one of Rs and R is —H., (C- —ORs, or halogen, and Rs and R are each hydrogen. C)-alkyl, halogen, —CF, or —ORs; R is —H., (C-C)- In one embodiment, R is —H., (C-C)-alkyl, —ORs. alkyl, —ORs, halogen, or —CF; and each remaining R halogen, or —CF, R is —H., (C-C)-alkyl, —ORs, or 30 group is hydrogen. halogen, and Rs and Rs are each hydrogen. In one embodiment, R. Rs. R. R7, R1s and Rio are each In one embodiment, R is —H., (C-C)-alkyl, —ORs. hydrogen. halogen or—CF and Rs. Rs. R. R.17, R1s and Rio are each In one embodiment, R. R. R. R. 7, and Rs are each hydrogen. hydrogen. In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, 35 In one embodiment, R. Rs, and R are each hydrogen. halogen, or —CF and one of R7, Rs and Rio is —H., (C- In one embodiment, Rs. Rs. R. R7, R1s and Rio are each C)-alkyl, -ORs, halogen, or—CF. hydrogen. In one embodiment, Rs. Rs. R. R. 7, and R1s are each In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, hydrogen. halogen, or —CF and two of R7, Rs and R are each 40 In one embodiment, R. R. R. and R are each hydro independently —H., (C-C)-alkyl, —ORs, halogen, or gen. —CF. In one embodiment, Rs. Rs, and R are each hydrogen. In one embodiment, Rs. R. R. and R are each inde In one embodiment, Rs is —H. —ORs or halogen; Ra, pendently —H., (C-C)-alkyl, —ORs, halogen, or—CF. Rs. R. R. 7, and R1s are each hydrogen; and Rio is —H or In another embodiment, Rs is —H., (C-C)-alkyl. —ORs. 45 halogen. halogen, or —CF and one of R7, Rs and Rio is —H., (C- In one embodiment, Rs is —H. —OCH or F. R. R. R. C)-alkyl, —ORs, halogen, or—CF; and each remaining R R7, and Rs are each hydrogen; and R is —H or F. group is hydrogen. In one embodiment, Rs is —H. —OCH or F. R. Rs, and In another embodiment, Rs is —H., (C-C)-alkyl, —ORs, Rare each hydrogen; and one of Rs or R is —H or F. In halogen, or —CF and two of R7, Rs and R are each 50 one embodiment, Rs is —H. —OCH or F. R. Rs. Re and independently —H., (C-C)-alkyl, —ORs, halogen, or R7 are each hydrogen; and Rs and Rio are each indepen —CF; and each remaining R group is hydrogen. dently —H, —CH or halogen. In one embodiment, Rs. R. R. and R are each inde In one embodiment, R is hydrogen, Rs is —H. —ORs: pendently —H., (C-C)-alkyl, —ORs, halogen, or —CF and R7, Rs, and R are each independently —H. —ORs. and each remaining R group is hydrogen. 55 halogen, (C-C)-alkyl, or—CF. In one embodiment, R is In a further embodiment, Rs is —H., (C-C)-alkyl, hydrogen, Rs is —OR, R2, and Rs are each independently —ORs, halogen, or —CF, one of R7, Rs and R is —H. —H. —ORs, halogen, (C-C)-alkyl, or —CF; and Rio is (C-C)-alkyl, —ORs, halogen, or —CF; one of Rs and —H or halogen. R is —H., (C-C)-alkyl, —ORs, or halogen; and each In one embodiment, Rs is —H. —ORs orhalogen; R7 and remaining R group is hydrogen. 60 Rs are each independently —H., (C-C)-alkyl, —ORs, In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, halogen or —CF; R is Horhalogen; and R. R. R. Rs. halogen, or—CF; and any two of R7, Rs and Ro are each and R are each hydrogen. independently —H., (C-C)-alkyl, —ORs, halogen, or In one embodiment, R is —H. —OCH or F: R is —H, —CF; and one of Rs, and R is —H., (C-C)-alkyl, —OCH; Rs is —H. —CF, Ro is —H. F.; and R. R. R. —ORs, halogen, or—CF. 65 Rs, and R are each hydrogen. In one embodiment, Rs is —H., (C-C)-alkyl, —ORs, In one embodiment, R is —H. —ORs or halogen; Rs. halogen, or —CF, R17, Rs and Ro are each independently Rs. R. R., and Rs are each hydrogen; and Rio is —H or

US 7,671,056 B2 41 42 In one embodiment, Roo is the benzofuran above, R7, Rs. In one embodiment, Roo is the benzofuran above; one of Ro. Rio R, R2, R2, R2, R22 and R2s are each indepen Ro, R. R. and R2 is -H, (C-C)-alkyl, halogen, —CF, dently —H., (C-C)-alkyl, halogen, —CF, —ORs, —NO —ORs, —NO or —CN; and each remaining R group is H. or CN. In one embodiment, Roo is the benzofuran above; one of In one embodiment, R is the benzofuran above; R. Rs R7, Rs. R. Rio R, and R is -H, (C-C)-alkyl, halogen, Ro, Rio R, and R2, are each independently —H., (C-C)- —CF, —ORs, —NO or —CN; one of R. R. Ris, and alkyl, halogen, —CF —ORs, —NO or —CN; and R. R is —H., (C-C)-alkyl, halogen, —CF, —ORs, —NO R. Ris, and R1s are each hydrogen. or —CN; and each remaining R group is H. In one embodiment, Roo is the benzofuran above; Rs is In one embodiment, Roo is the benzofuran above; one of —H., (C-C)-alkyl, halogen, —CF —ORs, —NO or 10 R7, Rs. Ro, Ro R and R2 is -H, (C-C)-alkyl, halogen, —CN; and R7, Ro Ro, R., and R2 are each independently —CF, —ORs, —NO or —CN; and one of Ro, R. R. —H., (C-C)-alkyl, halogen, —CF, or —OCH. and R is —H., (C-C)-alkyl, halogen, —CF —ORs, In one embodiment, Roo is the benzofuran above; Rs is - NO, or CN. —H., (C-C)-alkyl, halogen, —CF —ORs —NO or In one embodiment, Roo is the benzofuran above; one of —CN; Rs and R are each independently —H., (C-C)- 15 R-7, Rs. Ro, Rio R and R2 is -H, (C-C)-alkyl, halogen, alkyl, halogen, —CF, or—OR2s, and R-7, Ro, Rio R, R2, —CF, —ORs, —NO or —CN; one of Ro, R. R. and R and Ra are each hydrogen. R is —H. (C-C)-alkyl, halogen, —CF —ORs, —NO In one embodiment, R is the benzofuran above; Rs is or —CN; and the remaining R groups are hydrogen. —H., (C-C)-alkyl, halogen, —CF —ORs —NO or In one embodiment, R is the benzofuran above; two of —CN; and R-7, Ro Ro, R. R. R. R. Rs, and Rare R7, Rs. Ro Ro, R., and R2 are each independently —H. each hydrogen. (C-C)-alkyl, halogen, —CF, —ORs, —NO or —CN: In one embodiment, Roo is the benzofuran above; Rs is and each remaining R group is hydrogen. —H., (C-C)-alkyl, halogen, —CF —ORs, —NO or In one embodiment, R is the benzofuran above; two of —CN; and R-7, Ro, Rio R, R2, R2, R2, R22 and R2 are 25 R. R. R. R. R. and R are each independently —H. each hydrogen. (C-C)-alkyl, halogen, —CF, —ORs, —NO or —CN: In one embodiment, R is the benzofuran above; Rsis —H one of Ro, R. R. and R2 is -H, (C-C)-alkyl, halogen, orhalogen and R-7, RoRo R11, R12, R20. R2, R22 and R2s are —CF, —ORs, —NO or —CN; and each remaining R each hydrogen. In one embodiment, R is the benzofuran group is hydrogen. above; Rs is —H or halogen and R-7, Ro, Rio, R, R2, R1s. 30 In one embodiment, R is the benzofuran above; two of R14, R1s. R16, R20 R2, R22 and R2s are each hydrogen. R7, Rs. Ro Ro, R., and R2 are each independently —H. In one embodiment, R is the benzofuran above; and Rs. (C-C)-alkyl, halogen, —CF, —ORs, —NO or —CN: and R2 are each —H or halogen. In one embodiment, Roo is one of Rao, R2, R22, and R2 is -H, (C-C)-alkyl, halogen, the benzofuran above; Rs and R are each —H or halogen; —CF, —ORs, —NO or —CN; one of R. R. Ris, and and each remaining R group is hydrogen. 35 R is —H., (C-C)-alkyl, halogen, —CF, —ORs, —NO In one embodiment, Roo is the benzofuran above; and Rs or —CN; and each remaining R group is hydrogen. and R are each independently —H. —Cl or —F. In one embodiment, Roo is the benzofuran above; Ro and In one embodiment, R is the benzofuran above; Rs and R are each independently —H., (C-C)-alkyl, halogen, R2 are each independently —H. —Cl or —F; and R-7, Ro, —CF, —ORs, —NO or —CN; and each remaining R Rio R, R2, R20. R21, and R2s are each hydrogen. 40 group is hydrogen. In one embodiment, R is the benzofuran In one embodiment, R is the benzofuran above; Rs and above; R and R2 are each independently —H or halogen; R2 are each independently —H. —Cl or —F; and R-7, Ro, and each remaining R group is hydrogen. Rio R, R2, R1s. R4: Ris. R16, R20 R21, and R2s are each In another embodiment, R is hydrogen. In one embodiment, Roo is the benzofuran above; R is 45 —H., (C-C)-alkyl, halogen, —CF —ORs, —NO or —CN; R7, Rs. Rio, and R2 are each independently —H. (C-C)-alkyl, halogen, —CF, or —OCH; and R. R. Rs, and R are each hydrogen. In one embodiment, Roo is the benzofuran above; R is 50 —H., (C-C)-alkyl, halogen, —CF —ORs, —NO or —CN; Rs and R are each independently —H., (C-C)- alkyl, halogen, —CF, or—OR2s, and R-7, Rs. Rio R, R2, R1a and Ra are each hydrogen. 55 In one embodiment, Roo is the benzofuran above; R is and R, R2, and R2, are each independently, —H, (C- —H., (C-C)-alkyl, halogen, —CF —ORs —NO or C)-alkyl, halogen, —CF —ORs —NO or —CN. In one —CN; and R-7, Rs. Rio R, R2, R. R. Ris, and R1s are embodiment, Roo is the benzo 1.4 dioxane above and R4, each hydrogen. R26, and R27 are each hydrogen. In one embodiment, R is the benzofuran above; R is 60 In one embodiment, R is the benzo 1.4 dioxane above —H., (C-C)-alkyl, halogen, —CF —ORs —NO or and R7, Rs. Ro, Rio, R1, R12, R1s. R14, Ris, and R1s are each —CN; and R-7, Rs. Rio R, R2, R2, R2, R22 and R2 are independently —H., (C-C)-alkyl, halogen, —CF, —ORs, each hydrogen. - NO, or CN. In one embodiment, Roo is the benzofuran above; one of In one embodiment, Roo is the benzo 1.4 dioxane above; R-7, Rs. Ro, Rio, R1, and R2 is -H, (C-C)-alkyl, halogen, 65 R7, Rs. Ro Ro, R., and R2 are each independently —H. —CF, —ORs, —NO or —CN; and each remaining R (C-C)-alkyl, halogen, —CF, —ORs, —NO or —CN: group is H. and R. R. Ris, and R1s are each hydrogen. US 7,671,056 B2 43 44 In one embodiment, Roo is the benzo 1.4 dioxane above and R7, Rs. Ro Rio R, R2, R1s. R4: Ris. R16, R24. R26. and R2, are each hydrogen. In one embodiment, Roo is the benzol,4 dioxane above and R-7, Rs. Ro, Rio R, R2, R1s. R4 Ris, R16, R2, R2, R27, R, and R, are each hydrogen. In one embodiment, R is the benzo 1.4 dioxane above and R is —H., (C-C)-alkyl, halogen, —CF —ORs, - NO, or CN. R29 R30 In one embodiment, Roo is the benzo 1.4 dioxane above; 10 R is —H., (C-C)-alkyl, halogen, —CF, —ORs —NO or —CN; Rs and R are each independently —H., (C-C)- and Rs. Ro and Rao are each independently —H., (C-C)- alkyl, halogen, —CF —ORs, —NO or —CN; and R7, Rs. alkyl, halogen, —CF, —ORs, —NO or —CN. Rio R, and R2 are each hydrogen. In one embodiment, Roo is the indole above and Rs. Ro, 15 and Ro are each hydrogen. In one embodiment, R is the benzo 1.4 dioxane above; In one embodiment, Roo is the indole above and R-7, Rs. Ro, Ro is —H., (C-C)-alkyl, halogen, —CF, —ORs, —NO or Rio R, R2, R. R. Ris, and R are each independently —CN; and R-7, Rs. Rio R, R2, R. R. Ris, and R1s are —H., (C-C)-alkyl, halogen, —CF —ORs, —NO or each hydrogen. CN. In one embodiment, Roo is the benzo 1.4 dioxane above; In one embodiment, R is the indole above; R. R. R. Rs is —H., (C-C)-alkyl, halogen, —CF, —ORs, —NO or Rio R, and R2 are each independently —H., (C-C)-alkyl, CN. halogen, —CF —ORs —NO or—CN; and R. R. Rs. In one embodiment, R is the benzo 1.4 dioxane above; and R are each hydrogen. Rs is —H., (C-C)-alkyl, halogen, —CF, —ORs, —NO or In one embodiment, Roo is the indole above; Rs is —H. —CN; Rs and R are each independently —H., (C-C)- 25 (C-C)-alkyl, halogen, —CF —ORs, —NO or —CN. alkyl, halogen, —CF —ORs, —NO or —CN; and R. R. In one embodiment, Roo is the indole above; Rs is —H. Rio R, and R2 are each hydrogen. (C-C)-alkyl, halogen, —CF, —ORs, —NO or —CN: and R-7, Rs. Rio R, R2, R2s, Rao, and Rao are each hydro In one embodiment, Roo is the benzo 1.4 dioxane above; gen. In one embodiment, Roo is the indole above; Rs is —Hor Rs is —H., (C-C)-alkyl, halogen, —CF, —ORs, —NO or 30 halogen and R7, Ro, Rio, R1, R12, R2s, R29, and Rso are each —CN; and R-7, Ro Ro, R. R. R. R. Rs, and Rare hydrogen. In one embodiment, Roo is the indole above; Rs is each hydrogen. —Horhalogen and R-7, Ro Ro, R. R. R. R. Ris, R. In one embodiment, Roo is the benzo 1.4 dioxane above; R2s, Rao, and Rao are each hydrogen. In one embodiment, Roo one of R. R. R. R. R. and R is —H., (C-C)-alkyl, is the indole above; Rs is —Horhalogen and R. R. R. R. halogen, —CF —ORs, —NO or—CN; and each remain 35 R12, R13, R14, R1s. R16, R2s, R29, Rao, R., and R, are each ing R group is hydrogen. hydrogen. In one embodiment, Roo is the benzo 1.4 dioxane above; In one embodiment, R is the indole above; Rs is —H. one of R7, Rs. Ro, Rio, R., and R is —H., (C-C)-alkyl, (C-C)-alkyl, halogen, —CF, —ORs, —NO or —CN: halogen, —CF, —ORs, —NO or —CN; one of R. R. and R7, Ro Rio, R1, R12, R1s. R4 Ris, and Rio are each and R, is —H., (C-C)-alkyl, halogen, —CF, —ORs. 40 hydrogen. —NO or —CN; and each remaining R group is hydrogen. In one embodiment, R is the indole above; Rs is —H. In one embodiment, Roo is the benzo 1.4 dioxane above; (C-C)-alkyl, halogen, —CF, —ORs, —NO or —CN: one of R. R. R. R. R., and R is —H., (C-C)-alkyl, Rs and R are each —H., (C-C)-alkyl, halogen, —CF, halogen, —CF, —ORs, —NO or —CN; one of R. R. —ORs —NO or —CN; and R. R. R. R. and Rare and R, is —H., (C-C)-alkyl, halogen, —CF, —ORs. 45 each hydrogen. —NO or —CN; one of R. R. Ris, and R is —H., (C- In one embodiment, R is the indole above; R is —H. C)-alkyl, halogen, —CF, -ORs, —NO or —CN; and (C-C)-alkyl, halogen, —CF, —ORs, —NO or —CN. each remaining R group is hydrogen. In one embodiment, Roo is the indole above; R is —H. (C-C)-alkyl, halogen, —CF, —ORs, —NO or —CN: In one embodiment, Roo is the benzo 1.4 dioxane above; 50 and R-7, Rs. R. R, R2, R2s, R-29, and Rao are each hydrogen. two of R7, Rs. Ro, Rio, R., and R2 are each independently In one embodiment, R is the indole above; R is —H. —H., (C-C)-alkyl, halogen, —CF —ORs —NO or (C-C)-alkyl, halogen, —CF, —ORs, —NO or —CN: —CN; and each remaining R group is hydrogen. and R7, Rs. Rio, R1, R12, R1s. R4 Ris, and Rio are each In one embodiment, Roo is the benzo 1.4 dioxane above; hydrogen. two of R. R. R. R. R. and R are each independently 55 In one embodiment, Roo is the indole above; R is —H. —H., (C-C)-alkyl, halogen, —CF —ORs —NO or (C-C)-alkyl, halogen, —CF, —ORs, —NO or —CN: —CN; one of R. R. and R, is —H, (C-C)-alkyl, halo Rs and R are each —H., (C-C)-alkyl, halogen, —CF, gen, —CF, —ORs, —NO or—CN; and each remaining R —ORs —NO or —CN; and R. R. R. R. and Rare group is hydrogen. each hydrogen. In one embodiment, R is the benzo 1.4 dioxane above; 60 In one embodiment, Roo is the indole above; one of R7, Rs. two of R7, Rs. Ro, Rio, R., and R2 are each independently R. R. R. and R is —H, (C-C)-alkyl, halogen, —CF, —H., (C-C)-alkyl, halogen, —CF —ORs —NO or —ORs, —NO or —CN; and each remaining R group is H. —CN; one of R. R. R-7 is —H. (C-C)-alkyl, halogen, In one embodiment, R is the indole above; one of R. R. R. —CF, —ORs, —NO or —CN; one of R. R. Ris, and Rio R, and R2 is —H or halogen and each remaining R R is —H., (C-C)-alkyl, halogen, —CF, —ORs, —NO 65 group is H. or —CN; and each remaining R group is hydrogen. In one embodiment, Roo is the indole above; one of R7, Rs. In a further embodiment, Roo is Ro, Rio R, and R is —H., (C-C)-alkyl, halogen, —CF,

US 7,671,056 B2 47 1-(1-benzobthiophen-3-yl-piperidin-4-yl)-4-(2-methoxy phenyl)-piperazine; or 3-4-4-(2-methoxyphenyl)-piperazin-1-yl)-1-piperidinyl Scheme 1 1,2-benzisoxazole; Ro R10 and pharmaceutically acceptable salts thereof. R8 R11 The compounds and pharmaceutically acceptable salts of N compounds of the present invention can contain an asymmet 2 ric carbon atom and some of the compounds or pharmaceu R N R12 tically acceptable salts of compounds of the invention can R99 --- contain one or more asymmetric centers, and can thus give R14 N R16 rise to optical isomers and diastereomers. While depicted N without respect to stereochemistry in the compounds and pharmaceutically acceptable salts of compounds of the is 1. D R13 R15 Rb N Ra present invention, the present invention includes such optical H O isomers and diastereomers, as well as racemic and resolved, (X) (XIV) enantiomerically pure R and S Stereoisomers, and also other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. Where a stereoisomer is preferred, it 20 can in some embodiments be provided substantially free of its Ra R13 R4 R7 Rs corresponding opposite enantiomer. In addition, the compounds and pharmaceutically accept able salts of compounds of the present invention can exist as polymorphs. Such polymorphs can be transient or isolatable 25 Roo- -: R9 as a stable product. Rb R15 R16 \ / R10 Prodrugs of the compounds or pharmaceutically accept able salts of compounds are also within the scope of the R12 R present invention. 30 (I), (II), (III) and (IV) Methods for Making the Compounds of the Invention

The compounds and pharmaceutically acceptable salts of 35 Scheme la illustrates the coupling of piperazine-piperidine compounds of the present invention can be prepared using a compounds of Formula (I), through reductive amination, variety of methods starting from commercially available wherein R. R. R-7, Rs. Ro, Rio, R1, R12, R1s. R14, Ris, R16, compounds, known compounds, or compounds prepared by and Roo areas defined above, and R can also be a substituted known methods. General synthetic routes to many of the or unsubstituted quinoline. A compound of Formula (X) is compounds of the invention are included in the following schemes. The methods for making some intermediates of the reacted with a compound of Formula (XIVb) under condi invention are described in WO2004/024731 and U.S. Pat. No. tions effective to bring about reductive amination at the pip 4,465,482, both of which are hereby incorporated by refer eridine carbonyl, such as those described in Scheme 1, ence. It is understood by those skilled in the art that protection as thereby providing the piperazine-piperidine compound of and deprotection steps not shown in the Schemes may be Formulas (I). required for these syntheses, and that the order of steps may be changed to accommodate functionality in the target mol ecule. Scheme 1 illustrates the coupling of piperazine-piperidine 50 Scheme la compounds of Formulas (I), (II), (III), and (IV) through R9 R10 reductive amination, wherein R. R. R. Rs. Ro, Rio, R. R. R. R. R. R. and Roo are as defined above, and Roo Rs N R11 can also be a Substituted or unsubstituted quinoline. A com pound of Formula (X) is reacted with a compound of Formula 55 2 (XIV) under conditions effective to bring about reductive R7 N R12 amination at the piperidine carbonyl, thereby providing the ()). piperazine-piperidine compound of Formulas (I), (II), (III), R14 N R16 and (IV). Reagents that can effect this coupling include, but N are not limited to, sodium cyanoborohydride and sodium triacetoxyborohydride. Suitable solvents for performing the reaction include, but are not limited to, dichloroethane and 1. D R13 R15 methanol and acids such as acetic acid and hydrochloride may R N Ra O optionally be added to the reaction. Reaction temperatures 65 (X) (XIVb) can vary, depend on the nature of the reactants, but usually span the range from 0°C. to the boiling point of the solvent. US 7,671,056 B2 49 50

-continued -continued Ra R13 R14 R7 R8 R2 R

5 Roo / \ pi R3 N R

Ri, R15 R16 \ / R10 10 R4 N -On -- R12 R11 Rs R6 R, (I) (XXXII) Ro R10 Scheme la' illustrates another method for making com 15 pounds of Formula (I), wherein R,R,R,R,R,R,R,R, Rs N R R7, Rs. Ro, Rio R, R2, R1s. R4 Ris, and Rio areas defined above, and Roo is an optionally substituted quinoline (n is also 2 He as defined above). A compound of Formula (Xa) is reacted R N R12 under conditions effective to provide the compound of For )n mula (XXXI). The compound of Formula (XXXI) is reacted W under conditions effective to provide the removal of the phe (XXXIII) nyl-methyl group, thereby providing the compound of For mula (XXXI). The compound of Formula (XXXII) is reacted R R Rs Ro with an alkyl-substituted quinoline of Formula (XXXII) hav 25 ing a good leaving group (W) under conditions effective to R3 / \ N R R7 produce a compound of Formula (I). Suitable leaving groups are known to those of skill in the art and include, without limitation, halogen, —OTs, —OMs or —OTr. 30 Rs R6 Rl Scheme 1a' (I) R4 R3 35 5 N 2 Scheme 1b illustrates the coupling of piperazine-piperi dine compounds of Formula (I"), through reductive amina 2 tion, wherein R. R. R7, R-7, Rs. Ro, Rio R, R2, R1s. R4, R6 N R Rs. R. Roo are as defined above except for the R group 40 through which the piperidine is connected; and n is as defined above; and Roo can also be a Substituted or unsubstituted 1. N D quinoline. A compound of Formula (X) is reacted with a R N Ra compound of Formula (XIVc) under conditions effective to bring about reductive amination at the piperidine carbonyl, (Xa) 45 such as those described in Scheme 1, thereby providing the piperazine-piperidine compound of Formula (I"). US 7,671,056 B2 51 52 substituted aniline compound of Formula (VII) is reacted -continued with an appropriate reagent under conditions effective to produce the quinoline compound of Formula (VIII). Numer ous reagents and conditions affect this transformation. Many of these can be found in a review by G. Jones (Synthesis of the Ra R13 R14 Quinoline Ring System, in Heterocyclic Compounds. Volume R 32 (Ouinolines), Interscience, New York, N.Y., 1977, pp. 93-318). One such reagent is glycerol, as originally described by Skraup (Monatsh. (1880), 1.316). R. R. R. R. R. and Roo- C-->R, 10 R of (VII) and (VIII) are as above for (I) and W is a good R, R-15 R16 leaving group, for example halogen, p-toluenesulfonyl (—OTs), methanesulfonyl (—OMs) or trifluoromethane sulfonyl (—OTr). The compound of Formula (VIII) is then reacted with a protected piperazine derivative under condi Scheme 2 illustrates the production of compounds of For 15 tions effective to provide a protected piperazino-quinoline of mula (I). As shown in Scheme 2, a compound of Formula (Xa) Formula (IX), where X is a protecting group. Protecting and a compound of Formula (XIV) can be reacted under groups are well known to those of skill in the art and include, conditions effective to produce the di-quinoline substituted without limitation, tert-butoxycarbonyl. Conditions that can piperazine-piperidine compound of Formula (I), such as effect this reaction include, but are not limited to, reacting the those described in Scheme 1. two components in the presence of a palladium complex Such as those described by Buchwald et al., J. Am. Chem. Soc. Scheme 2 118:7215 (1996) and Hartwig et al., J. Am. Chem. Soc. 118: R9 R10 7217 (1996). The protected piperazino-quinoline of Formula R (IX) is then reacted under conditions to promote the removal R4 3 Rs R11 of the protecting group (e.g., aqueous acid or mixtures of a Rs N R n 25 water miscible organic solvent and aqueous acid), providing 2 the Substituted piperazino-quinoline compound of Formula R 4. R R N R12 (Xb). Separately, compounds of Formula (XIV) are produced 6 -- R14 N R16 by beginning with an optionally Substituted aniline com N pound of Formula (XI) and reacting it as described above with 30 an appropriate reagent under conditions effective to produce the quinoline compound of Formula (XII). R. R. R. R. Rb 1. N l Ra R13 R15 R, and R of (XI) and (XII) areas above for Formula (I) and H O Wis a suitable leaving group Such as halogen, —OTs, —OMs (Xa) (XIV) or —OTr. The quinoline compound of Formula (XII) is then 35 reacted with a piperidin-4-one derivative under conditions Rs R6 Ra R 3 R14 R7 R8 effective to provide the compound of Formula (XIII) (e.g., a palladium-catalyzed coupling Such as that described above). The carbonyl group of the piperidin-4-one derivative is pro tected with a protecting group (X). Suitable protecting R4 N - R9 groups are well known to those of skill in the art and include, 40 without limitation, 1,3-dioxolane. The compound of Formula R3 \ / N Rb R 5 R 6 N \ / R O (XIII) is then reacted under conditions to promote the removal of the protecting group (e.g., aqueous acid or a mix R2 R R12 R11 ture of a water miscible organic solvent and aqueous acid), (I) providing the piperidin-4-one compound of Formula (XIVa). 45 The piperidin-4-one compound of Formula (XIVa) is then Scheme 3 illustrates the production of compounds of For reacted with the piperazino-quinoline compound of Formula mula (Xb) and Formula (XV) in which R. R. R. Rio, R. (Xb) as described above in Schemes 1 and 2 to produce the R2, R. R. Ris, and Rare each hydrogen and R. R. R. di-quinoline piperazine-piperidine compound of Formula Rs. R. R. Rs and Ro are as defined above. An optionally (XV).

Scheme 3 R4 R3 Rs s12 R4 R3 R R 5 N 2 2 R4 R4 R3 R6 N. R. R6 4n Rs Rs R N N N

He 2 ------

R6 NH2 R6 N. R. R. R. R 1. N D W W X l H Ra (VII) (VIII) US 7,671,056 B2

-continued R9 R10 Ro R10 Rs N R11 Rs s-RI

2 2 R9 R9 R10 R7 N R12 R N R12 Rs Rs N R11 N N HCI He- He- He 2 R NH2 R7 N R12 W W X O (XI) (XII) (XIII) (XIVa) R9 R10 R4 R3 Rs N R11 Rs n R Rs R6 Ra R Rs

2 R 7 4. R 2 A R6 N R -- He- R4 N N-O Ro N V ( N R3 N Rb N R10

Rb N Ra H O R R R12 R11 (Xb) (XIVa) (XV)

Alternative syntheses for the quinoline compounds of For is less than about 0.15 w 96 of the resulting salt form of the mulae (VIII) and (XII) are provided in Scheme 3a. The aniline 30 compound of Formula (I) or the compound of ormula (XV). compounds of Formulae (VII) and (XI) are reacted with an In further embodiments, the amount of each solvent is less appropriate reagent under conditions effective to product the than about 0.1 w "yo of the resulting salt form of the compound quinoline compounds of Formulae (XXXIV) and (XXXV) of Formula (I) or the compound of Formula (XV). In yet more where W is a leaving group. Reagents and conditions Suitable embodiments, the amount of each solvent is less than about for affecting this transformation are known to those of skill in 35 0.05 w % of the resulting salt form of the compound of the art and include, for example, methods described in G. Formula (1) or the compound of Formula (XV). In still more Jones, Supra. One exemplary reagent is glycerol, as described embodiments, the amount of each solvent is less than about above. The compounds of Formulae (XXXIV) and (XXXV) 0.025 w % of the resulting salt form of the compound of are then reacted with appropriate reagents to yield the desired 40 Formula (I) or the compound of Formula (XV). In additional intermediate compounds of Formulae (VIII) and (XI). embodiments, the amount of each solvent is less than about In Some embodiments, compounds of Formula (I) and For 0.02 w % of the resulting salt form of the compound of mula (XV) are further reacted to form a salt of the compounds Formula (I) or the compound of Formula (XV). In another of Formula (I) and Formula (XV) through an acid addition embodiment, the amount of each solvent is less than about process. In one nonlimiting example, one or more equivalents 45 0.01 w % of the resulting salt form of the compound of of an acid (e.g., hydrochloride, Succinic, or adipic acids) are Formula (I) or the compound of Formula (XV). In one reacted with the free base of a compound of Formula (I) and embodiment, the presence of chlorinated solvents is Formula (XV) to form an acid addition salt. Exemplary salts decreased significantly from the final isolated salt form of the include, without limitation, mono-, di-, tri- and tetra-acid compound of Formula (1) or the compound of Formula (XV). salts. 50 In one embodiment, there are no detectable chlorinated sol In Some embodiments, the acid addition step is modified to vents is the final isolated salt form of the compound of For allow for isolation of the salts of the compounds of Formula mula (I) or the compound of Formula (XV). In one embodi (I) and Formula (XV) without the use of potentially environ ment, the amount of chlorinated solvent present in the final mentally hazardous materials. In one embodiment, com isolated salt form of the compound of Formula (1) or the pounds of Formula (I) and Formula (XV) are reacted in the 55 compound of Formula (XV) is less than about 0.1%. In one presence of non-chlorinated solvents. In one embodiment, the embodiment, the amount of chlorinated solvent present in the non-chlorinated solvent is . final isolated salt form of the compound of Formula (I) and In some embodiments, the acid addition reaction is per the compound of Formula (XV) is less than about 0.05%. In formed under conditions that result in relatively low amounts one embodiment, the amount of chlorinated solvent present in of residual solvent found in the final product. In some 60 the final isolated salt form of the compound of Formula (I) embodiments, the amount of each individual residual solvent and the compound of Formula (XV) is less than about 0.01%. is present in an amount that is less than about 0.25 w 96 of the In one embodiment, the amount of chlorinated solvent resulting salt form of the compound of Formula (I) or For present in the final isolated salt form of the compound of mula (XV). In one embodiment, the amount of each residual Formula (1) and the compound of Formula (XV) is less than solvent is less than about 0.2 w"/6 of the resulting salt form of 65 about 0.001%. the compound of Formula (III) or the compound of Formula In some embodiments, the acid addition reaction occurs in (XV). In still other embodiments, the amount of each solvent the presence of organic solvents including, but not limited to, US 7,671,056 B2 55 56 tetrahydrofuran (THF), acetone, dichloromethane, and dichloroethane. In one embodiment, the organic solvents are -continued THF and acetone. In one embodiment, a compound of For mula (I) or a compound of Formula (XV) is mixed with a first Ro R10 organic solvent and then added to a solution that includes a second organic solvent and an acid. In one embodiment, the R8 N R11 first organic solvent is THF or acetone. In one embodiment, 2 the second organic solvent is THF or acetone. In one embodi R N R12 ment, the first organic solvent is THF and the second organic 10 Solvent is acetone. In one embodiment, a compound of For W mula (I) or a compound of Formula (XV) is mixed with THF (XII) prior to addition to a solution of acetone and an acid. In one embodiment, the acid is an organic acid. In one embodiment, the acid is a dicarboxylic acid. In one embodiment, the 15 organic acid is Succinic acid. Scheme 4 illustrates the production of a compound of Formula (In) in which Roo is an indole compound and R7, Rs. Ro. Rio R, R2, R2s, R29 and Rao are defined as above for Scheme 3a. Formula (III). A piperidin-4-one compound of Formula (XIVa) is produced as described above in Scheme 3. A dini R4 tro-toluene compound of Formula (XVI) is reacted with N.N- Rs dimethylformamide dimethyl acetal and pyrrolidine under conditions effective to bring about cyclization, thereby pro 25 viding an indol-4-ylamine compound of Formula (XVII). The R6 NH2 compound of Formula (XVII) is then reacted with a bis(2- W chloroethyl)-benzylamine under conditions effective to pro (VII) duce the compound of Formula (XVIII). The compound of Formula (XVIII) is then reacted under conditions effective to 30 remove the benzyl protecting group to produce a 4-piperazin R4 1-yl-indole of Formula (XIX). The piperazin-1-yl-indole R compound of Formula (XIX) is then reacted with the piperi din-4-one compound of Formula (XIVa) as described above 2 35 in Scheme 1 to produce the piperazine-piperidine compound R6 N of Formula (XX), which is a compound of Formula (III). W (XXXIV) Scheme 4 40 ON CH R4 R3 1. N,N-dimethylformamide R R 5 N 2 dimethyl acetal R28 NO -2. Pyrrollidine,- - DMF -> 3.120° C. 2 45 R6 N R R29 R30 W (XVI) (VIII) R9 50 N1S Rs bis(2-chloroethyl)- R NH benzylamine 28 2 He1000 c. heat, 1st, R NH2 55 W R29 R30 (XI) (XVII) Ro HN N Rs N 60 1.10% Pd/C, ammonium formate in EtOH He 2 2. Reflux, 2h R N

W 65 (XXXV) (XVIII) US 7,671,056 B2 57 58 Scheme 5a illustrates an alternative production of a benzo -continued 1,4-dioxane-piperazine compound having the Formula (XXIII) in which R. R. R. R. and R, are defined as R R8 above for Formula (III). A nitro-benzodioxane of Formula (XXI) is reacted under conditions effective to produce a com o-O R9 pound of Formula (XXII). The compound of Formula (XXII) is reacted with a bis(2-chloroethyl)amine under conditions N N R10 effective to produce a compound of Formula (XXIII). 10 R28 N NH R12 R11 \ / (XIVa) R29 R30 Scheme 5a (XIX) HN1S R Rs 15 O O - - N N Ro R24 -- NO -- R29 R30 N \ / R10 R26 R27 (XXI) R12 R11 (XX) 25 Scheme 5 illustrates the production of compounds of For O O mula (III) in which R is a benzo 1.4 dioxane compound and R. R. R7, Rs. Ro, Rio, R1, R12, R24. R26 and R27 are defined as above for Formula (III). A piperidin-4-one compound of 30 R24 - - NH2 1. bis(2-chloroethyle)amine Formula (XIVa) is produced as described above in Scheme 3. A benzo 1.4 dioxane-piperazine compound having the For R26 R27 mula (XXIII) is produced by reacting a piperidine with a (XXII) benzo 1.4 dioxane Substituted with a good leaving group, for example a halogen —OTs, —OMs or —OTr, under condi 35 tions effective to produce a compound of Formula (XXIII). The compound of Formula (XXIII) is reacted with the pip O O Ra eridin-4-one compound of Formula (XIVa) as described above in Scheme 1 to produce the benzo 1,4-dioxane pipera Zine-piperidine quinoline compound of Formula (XXIV). 40 -- N\ {NH R26 R27 Rb

45 (XXIII) O O Ra

-- NH Scheme 6 illustrates the production of a compound or R26 R27 Rb / \ R10 50 pharmaceutically acceptable salt of a compound of Formula (XXIII) (III) in which Roo is a benzofuran compound and R. R. R. Rs. Ro, Rio, R1, R12, R20. R2, R22 and R2s are defined as o-O-()-R, above for Formula (III). A piperidin-4-one compound of For R7 Rs mula (XIVa) is produced as described above in Scheme 3. The 55 (XIVa) benzofuranone of Formula (XXXI) is reacted with a pro R12 R11 tected piperazine under conditions effective to produce ben Zofuran-N-protected piperazine compound of Formula O/ \O Ra N / \ R10 (XXXII). Suitable protecting groups (X) are well known to those of skill in the art and include, without limitation, 60 ethoxycarbonyl. Deprotection of the N-protecting group (such as by hydrolysis) of the compound of Formula (XXXII) -- \- N-O R9 gives a compound of formula (V). The benzofuran-piperazine R26 R27 Rb R7 Rs of Formula (V) is then reacted with the piperidin-4-one com (XXIV) 65 pound of Formula (XIV) as described above in Scheme 1 to produce the piperazine-piperidine compound of Formula (XXV). US 7,671,056 B2

Scheme 6

R22 Ra R21 R23 /-( 1. TiCl4 in CH2Cl2 2. CHCl2 -- HN N-X 3. Heat R20 O ( O Rb (XXXI)

R22 R22 R21 R21 R R 23 Ra 1. NaOH 23 Ra 2. Heat R20 Her R20 7 Nv N-X b / N\ ( NH

Rb Rb (XXXII) (V)

R9 R10 Rs N R11

2 R N R12

N

O (XIVa) /6) R22 R21 R23 R14 R7 Rs b/ \ { N Rb Rs R16 \ / R10

R12 R

(XXV)

Scheme 7 illustrates the production of a compound or are well knownto those of skill in the art and include, without pharmaceutically acceptable salt of a compound of Formula limitation, tert-butoxycarbonyl. The compound of Formula (IV) in which R. R. R. R. Ris, Rio, Rs 1, R32, Ras, Ra, 60 (XXVII) is reacted under conditions effective to remove the Rs. R. R-7, Rs and Rao are defined as above for Formula protecting group, providing a phenyl-piperazine-piperidine (IV). As shown in Scheme 7, an optionally substituted phe compound of Formula (XXVIII). The phenyl-piperazine-pi nyl-piperazine compound of Formula (XXVI) is reacted with peridine compound of Formula (XXVII) is reacted with a an optionally substituted protected-piperazine under condi 65 bicyclic aryl compound of Formula (XXIX) possessing a tions effective to provide the compound of Formula (XXVII), suitable leaving group (W) under conditions effective to pro wherein X is a protecting group. Suitable protecting groups vide the compound of Formula (IV). US 7,671,056 B2

Scheme 7 R13 R14 R32 R31 Ra R32 R31 Ra R13 R14

A A HCI O N-X R3 N NH --- R33 N N N-X --

R15 R16 R34 R35 Rb R34 R35 Rb R15 R16 (XXVI) (XXVII) R32 R31 Ra R13 R14 R33 N - R34 R35 Rb Rs R16 (XXVIII)

R37 R36 R38 W R l 39 y-X (XXIX) R37 R36 Ra R13 R14 R31 R32 R38 ) ( l N N N R33 R39 y-X )-( Rb R15 R16 R35 R34 (XXX)

Schemes 1-7 illustrate the synthetic methodology used to 45 pounds of the invention, can be administered orally. The prepare particular compounds of the present invention. compound of the invention can also be administered by any One of skill in the art will recognize that Schemes 1-7 can other convenient route, for example, by infusion or bolus be adapted to produce the other compounds according to the injection, by absorption through epithelial or mucocutaneous present invention and that other methods may be used to linings (e.g., oral, rectal, Vaginal, and intestinal mucosa, etc.) produce the compounds of the present invention. 50 and can be administered together with another therapeutic Therapeutic Administration agent. Administration can be systemic or local. Various known delivery systems, including encapsulation in lipo When administered to an animal, the compounds or phar Somes, microparticles, microcapsules, and capsules, can be maceutically acceptable salts of the compounds can be 55 used. administered neat or as a component of a composition that Methods of administration include, but are not limited to, comprises a physiologically acceptable carrier or vehicle. A intradermal, intramuscular, intraperitoneal, intravenous, Sub pharmaceutical composition of the invention can be prepared cutaneous, intranasal, epidural, oral, Sublingual, intracere using a method comprising admixing the compound or a bral, intravaginal, transdermal, rectal, by inhalation, or topi pharmaceutically acceptable salt of the compound and a 60 physiologically acceptable carrier, excipient, or diluent. cal, particularly to the ears, nose, eyes, or skin. In some Admixing can be accomplished using methods well known instances, administration will result of release of the com for admixing a compound or a pharmaceutically acceptable pound or a pharmaceutically acceptable salt of the compound salt of the compoundanda physiologically acceptable carrier, into the bloodstream. The mode of administration is left to the excipient, or diluent. 65 discretion of the practitioner. The present pharmaceutical compositions, comprising In one embodiment, the compound of the invention is compounds or pharmaceutically acceptable salts of the com administered orally. US 7,671,056 B2 63 64 In another embodiment, the compound of the invention is can also be employed as liquid excipients, particularly for administered intravenously. injectable solutions. Suitable physiologically acceptable In another embodiment, it may be desirable to administer excipients also include starch, glucose, lactose, Sucrose, gela the compound of the invention locally. This can be achieved, tin, malt, rice, flour, chalk, silica gel, sodium Stearate, glyc for example, by local infusion during Surgery, topical appli erol monostearate, talc, sodium chloride, dried skim milk, cation, e.g., in conjunction with a wound dressing after Sur glycerol, propylene, glycol, water, ethanol and the like. The gery, by injection, by means of a catheter, by means of a present compositions, if desired, can also contain minor Suppository or edema, or by means of an implant, said implant amounts of wetting or emulsifying agents, or pH buffering being of a porous, non-porous, or gelatinous material, includ agents. ing membranes, such as Sialastic membranes, or fibers. 10 Liquid carriers may be used in preparing solutions, Suspen In certain embodiments, it can be desirable to introduce the sions, emulsions, syrups, and elixirs. The compound or phar compound of the invention into the central nervous system, maceutically acceptable salt of the compound of this inven circulatory system or gastrointestinal tract by any suitable tion can be dissolved or Suspended in a pharmaceutically route, including intraventricular, intrathecal injection, acceptable liquid carrier Such as water, an organic solvent, a paraspinal injection, epidural injection, enema, and by injec 15 mixture of both, or pharmaceutically acceptable oils or fat. tion adjacent to the peripheral nerve. Intraventricular injec The liquid carrier can contain other Suitable pharmaceutical tion can be facilitated by an intraventricular catheter, for additives including solubilizers, emulsifiers, buffers, preser example, attached to a reservoir, such as an Ommaya reser Vatives, Sweeteners, flavoring agents, Suspending agents, WO1. thickening agents, colors, viscosity regulators, stabilizers, or Pulmonary administration can also be employed, e.g., by osmo-regulators. Suitable examples of liquid carriers for oral use of an inhaler or nebulizer, and formulation with an aero and parenteral administration include water (particularly con Solizing agent, or via perfusion in a fluorocarbon or synthetic taining additives as above, e.g., cellulose derivatives, includ pulmonary Surfactant. In certain embodiments, the com ing sodium carboxymethyl cellulose solution), (in pound or a pharmaceutically acceptable salt of the compound cluding monohydric alcohols and polyhydric alcohols, e.g., can be formulated as a Suppository, with traditional binders 25 glycols) and their derivatives, and oils (e.g., fractionated and excipients such as triglycerides. coconut oil and arachis oil). For parenteral administration the In another embodiment, the compound of the invention can carrier can also be an oily ester Such as ethyl oleate and be delivered in a vesicle, in particular a liposome (see Langer, isopropyl myristate. Sterile liquid carriers are used in sterile Science 249:1527-1533 (1990) and Treat et al., Liposomes in liquid form compositions for parenteral administration. The the Therapy of Infectious Disease and Cancer 317-327 and 30 liquid carrier for pressurized compositions can be haloge 353-365 (1989)). nated hydrocarbon or other pharmaceutically acceptable pro In yet another embodiment, the compound of the invention pellant. can be delivered in a controlled-release system or Sustained The present compositions can take the form of Solutions, release system (see, e.g., Goodson, in Medical Applications Suspensions, emulsion, tablets, pills, pellets, capsules, cap of Controlled Release, vol. 2, pp. 115-138 (1984)). Other 35 controlled or Sustained-release systems discussed in the Sules containing liquids, powders, Sustained-release formu review by Langer, Science 249:1527-1533 (1990) can be lations, Suppositories, emulsions, aerosols, sprays, Suspen used. In one embodiment, a pump can be used (Langer, Sci sions, or any other form Suitable for use. In one embodiment, ence 249:1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. the composition is in the form of a capsule. Other examples of Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); 40 Suitable physiologically acceptable excipients are described and Saudek et al., N. Engl. J. Med. 321:574 (1989)). In in Remington's Pharmaceutical Sciences 1447-1676 (Al another embodiment, polymeric materials can be used (see fonso R. Gennaro, ed., 19th ed. 1995). Medical Applications of Controlled Release (Langer and In one embodiment, the compound or a pharmaceutically Wise eds., 1974); Controlled Drug Bioavailability, Drug acceptable salt of the compound is formulated in accordance Product Design and Performance (Smolen and Ball eds., 45 with routine procedures as a composition adapted for oral 1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. administration to humans. Compositions for oral delivery can Chem. 2:61 (1983); Levy et al., Science 228:190 (1935); be in the form of tablets, lozenges, buccal forms, troches, During et al., Ann. Neural. 25:351 (1989); and Howard et al., aqueous or oily Suspensions or solutions, granules, powders, J. Neurosurg, 71:105 (1989)). emulsions, capsules, syrups, or elixirs for example. Orally The present compositions can optionally comprise a Suit 50 administered compositions can contain one or more agents, able amount of a physiologically acceptable excipient. for example, Sweetening agents such as fructose, aspartame Such physiologically acceptable excipients can be liquids, or saccharin, flavoring agents such as peppermint, oil of win Such as water and oils, including those of petroleum, animal, tergreen, orcherry; coloring agents; and preserving agents, to Vegetable, or synthetic origin, such as peanut oil, soybean oil, provide a pharmaceutically palatable preparation. In pow mineral oil, Sesame oil and the like. The physiologically 55 ders, the carrier can be a finely divided solid, which is an acceptable excipients can be saline, gum acacia, gelatin, admixture with the finely divided compound or pharmaceu starch paste, talc, keratin, colloidal silica, urea and the like. In tically acceptable salt of the compound. In tablets, the com addition, auxiliary, stabilizing, thickening, lubricating, and pound orpharmaceutically acceptable salt of the compound is coloring agents can be used. In one embodiment the physi mixed with a carrier having the necessary compression prop ologically acceptable excipients are sterile when adminis 60 erties in Suitable proportions and compacted in the shape and tered to an animal. The physiologically acceptable excipient size desired. The powders and tablets can contain up to about should be stable under the conditions of manufacture and 99% of the compound or pharmaceutically acceptable salt of storage and should be preserved against the contaminating the compound. action of microorganisms. Water is a particularly useful Capsules may contain mixtures of the compounds or phar excipient when the compound or a pharmaceutically accept 65 maceutically acceptable salts of the compounds with inert able salt of the compound is administered intravenously. fillers and/or diluents such as pharmaceutically acceptable Saline solutions and aqueous dextrose and glycerol solutions starches (e.g., corn, potato, or tapioca starch), Sugars, artifi US 7,671,056 B2 65 66 cial Sweetening agents, powdered celluloses (such as crystal sages including epithelial and mucosal tissues. Such admin line and microcrystalline celluloses), flours, gelatins, gums, istrations can be carried out using the present compounds or etc. pharmaceutically acceptable salts of the compounds, in Tablet formulations can be made by conventional compres lotions, creams, foams, patches, Suspensions, solutions, and Sion, wet granulation, or dry granulation methods and utilize Suppositories (e.g., rectal or vaginal). pharmaceutically acceptable diluents, binding agents, lubri Transdermal administration can be accomplished through cants, disintegrants, Surface modifying agents (including Sur the use of a transdermal patch containing the compound or factants), Suspending or stabilizing agents (including, but not pharmaceutically acceptable salt of the compound and a car limited to, magnesium Stearate, Stearic acid, Sodium lauryl rier that is inert to the compound or pharmaceutically accept Sulfate, talc, Sugars, lactose, dextrin, starch, gelatin, cellulose, 10 able salt of the compound, is non-toxic to the skin, and allows methyl cellulose, microcrystalline cellulose, sodium car delivery of the agent for systemic absorption into the blood boxymethyl cellulose, carboxymethylcellulose calcium, stream via the skin. The carrier may take any number of forms polyvinylpyrrolidine, alginic acid, acacia gum, Xanthan gum, Such as creams or ointments, pastes, gels, or occlusive Sodium citrate, complex silicates, calcium carbonate, glycine, devices. The creams or ointments may be viscous liquid or Sucrose, Sorbitol, dicalcium phosphate, calcium sulfate, lac 15 semisolid emulsions of either the oil-in-water or water-in-oil tose, kaolin, mannitol, Sodium chloride, low melting waxes, type. Pastes comprised of absorptive powders dispersed in and ion exchange resins.) Surface modifying agents include petroleum or hydrophilic petroleum containing the active nonionic and anionic Surface modifying agents. Representa ingredient may also be suitable. A variety of occlusive devices tive examples of surface modifying agents include, but are not may be used to release the compound or pharmaceutically limited to, poloxamer 188, benzalkonium chloride, calcium acceptable salt of the compound into the blood stream, Such Stearate, cetostearl alcohol, cetomacrogol emulsifying wax, as a semi-permeable membrane covering a reservoir contain Sorbitan esters, colloidal silicon dioxide, phosphates, sodium ing the compound or pharmaceutically acceptable salt of the dodecylsulfate, magnesium aluminum silicate, and triethano compound with or without a carrier, or a matrix containing the lamine. active ingredient. Moreover, when in a tablet or pill form, the compositions 25 The compounds orpharmaceutically acceptable salts of the can be coated to delay disintegration and absorption in the compounds of the invention may be administered rectally or gastrointestinal tract, thereby providing a Sustained action vaginally in the form of a conventional Suppository. Supposi over an extended period of time. Selectively permeable mem tory formulations may be made from traditional materials, branes Surrounding an osmotically active driving compound including cocoa butter, with or without the addition of waxes or a pharmaceutically acceptable salt of the compound are 30 to alter the Suppository's melting point, and glycerin. Water also Suitable for orally administered compositions. In these soluble Suppository bases, such as polyethylene glycols of latter platforms, fluid from the environment surrounding the various molecular weights, may also be used. capsule can be imbibed by the driving compound, which The compound or a pharmaceutically acceptable salt of the Swells to displace the agent or agent composition through an compound can be administered by controlled-release or Sus aperture. These delivery platforms can provide an essentially 35 tained-release means or by delivery devices that are known to Zero order delivery profile as opposed to the spiked profiles of those of ordinary skill in the art. Such dosage forms can be immediate release formulations. A time-delay material Such used to provide controlled- or Sustained-release of one or as glycerol monostearate or glycerol Stearate can also be used. more active ingredients using, for example, hydropropylm Oral compositions can include standard excipients such as ethyl cellulose, other polymer matrices, gels, permeable mannitol, lactose, starch, magnesium Stearate, sodium sac 40 membranes, osmotic systems, multilayer coatings, micropar charin, cellulose, and magnesium carbonate. In one embodi ticles, liposomes, microspheres, or a combination thereof to ment, the excipients are of pharmaceutical grade. provide the desired release profile in varying proportions. In another embodiment, the compound or a pharmaceuti Suitable controlled- or sustained-release formulations known cally acceptable salt of the compound can be formulated for to those skilled in the art, including those described herein, intravenous administration. Typically, compositions for intra 45 can be readily selected for use with the active ingredients of venous administration comprise sterile isotonic aqueous the invention. The invention thus encompasses single unit buffer. Where necessary, the compositions can also include a dosage forms suitable for oral administration such as, but not solubilizing agent. Compositions for intravenous administra limited to, tablets, capsules, gelcaps, and caplets that are tion can optionally include a local anesthetic Such as adapted for controlled- or Sustained-release. lignocaine to lessen pain at the site of the injection. Generally, 50 In one embodiment a controlled- or Sustained-release com the ingredients are Supplied either separately or mixed position comprises a minimal amount of the compound or a together in unit dosage form, for example, as a dry lyophilized pharmaceutically acceptable salt of the compound to treat or powder or water-free concentrate in a hermetically sealed prevent a 5-HT-related disorder in a minimal amount of container Such as an ampule or Sachette indicating the quan time. Advantages of controlled- or Sustained-release compo tity of active agent. Where the compound or a pharmaceuti 55 sitions include extended activity of the drug, reduced dosage cally acceptable salt of the compound is to be administered by frequency, and increased compliance by the animal being infusion, it can be dispensed, for example, with an infusion treated. In addition, controlled- or Sustained-release compo bottle containing sterile pharmaceutical grade water or saline. sitions can favorably affect the time of onset of action or other Where the compound or a pharmaceutically acceptable salt of characteristics, such as blood levels of the compound or a the compound is administered by injection, an ampule of 60 pharmaceutically acceptable Salt of the compound, and can sterile water for injection or saline can be provided so that the thus reduce the occurrence of adverse side effects. ingredients can be mixed prior to administration. Controlled- or Sustained-release compositions can initially In another embodiment, the compound or pharmaceuti release an amount of the compound or a pharmaceutically cally acceptable salt of the compound can be administered acceptable salt of the compound that promptly produces the transdermally through the use of a transdermal patch. Trans 65 desired therapeutic or prophylactic effect, and gradually and dermal administrations include administrations across the continually release other amounts of the compound or a phar surface of the body and the inner linings of the bodily pas maceutically acceptable salt of the compound to maintain this US 7,671,056 B2 67 68 level of therapeutic or prophylactic effect over an extended In one embodiment, the pharmaceutical composition is in period of time. To maintain a constant level of the compound unit dosage form, e.g., as a tablet, capsule, powder, solution, or a pharmaceutically acceptable salt of the compound in the Suspension, emulsion, granule, or Suppository. In Such form, body, the compound or a pharmaceutically acceptable salt of the composition is sub-divided in unit dose containing appro the compound can be released from the dosage format a rate 5 priate quantities of the active ingredient; the unit dosage form that will replace the amount of the compound or a pharma can be packaged compositions, for example, packeted pow ceutically acceptable salt of the compound being metabolized ders, vials, ampoules, prefilled Syringes or Sachets containing and excreted from the body. Controlled- or sustained-release liquids. The unit dosage form can be, for example, a capsule of an active ingredient can be stimulated by various condi or tablet itself, or it can be the appropriate number of any such tions, including but not limited to, changes in pH, changes in 10 compositions in package form. Such unit dosage form may temperature, concentration or availability of enzymes, con contain from about 0.01 mg/kg to about 250 mg/kg, and may centration or availability of water, or other physiological con be given in a single dose or in two or more divided doses. ditions or compounds. Variations in the dosage will necessarily occur depending In certain embodiments, the present invention is directed to upon the species, weight and condition of the patient being prodrugs of the compounds or pharmaceutically acceptable 15 treated and the patients individual response to the medica salts of compounds of the present invention. Various forms of ment. prodrugs are known in the art, for example as discussed in In one embodiment, the unit dosage form is about 0.01 to Bundgaard (ed.), Design of Prodrugs, Elsevier (1985); Wid about 1000 mg. In another embodiment, the unit dosage form der et al. (ed.), Methods in Enzymology, Vol. 4, Academic is about 0.01 to about 500 mg; in another embodiment, the Press (1985); Kgrogsgaard-Larsen et al. (ed.); "Design and unit dosage form is about 0.01 to about 250 mg; in another Application of Prodrugs, Textbook of Drug Design and embodiment, the unit dosage form is about 0.01 to about 100 Development, Chapter 5, 113-191 (1991); Bundgaard et al., mg; in another embodiment, the unit dosage form is about Journal of Drug Delivery Reviews, 8:1-38 (1992); Bundgaard 0.01 to about 50 mg; in another embodiment, the unit dosage et al., J. Pharmaceutical Sciences, 77:285 et seq. (1988); and form is about 0.01 to about 25 mg; in another embodiment, Higuchi and Stella (eds.), Prodrugs as Novel Drug Delivery 25 the unit dosage form is about 0.01 to about 10 mg; in another Systems, American Chemical Society (1975). embodiment, the unit dosage form is about 0.01 to about 5 The amount of the compound or a pharmaceutically mg; and in another embodiment, the unit dosage form is about acceptable salt of the compound delivered is an amount that is 0.01 to about 10 mg: effective for treating or preventing a 5-HT-related disorder. The compound or a pharmaceutically acceptable salt of the In addition, in vitro or in vivo assays can optionally be 30 compound can be assayed in vitro or in vivo for the desired employed to help identify optimal dosage ranges. The precise therapeutic or prophylactic activity prior to use in humans. dose to be employed can also depend on the route of admin Animal model systems can be used to demonstrate safety and istration, the condition, the seriousness of the condition being efficacy. treated, as well as various physical factors related to the The present methods for treating or preventing a 5-HT individual being treated, and can be decided according to the 35 related disorder can further comprise administering another judgment of a health-care practitioner. Equivalent dosages therapeutic agent to the animal being administered the com may be administered over various time periods including, but pound or a pharmaceutically acceptable salt of the compound. not limited to, about every 2 hours, about every 6 hours, about In one embodiment the other therapeutic agent is adminis every 8 hours, about every 12 hours, about every 24 hours, tered in an effective amount. about every 36 hours, about every 48 hours, about every 72 40 Effective amounts of the other therapeutic agents are well hours, about every week, about every two weeks, about every knownto those skilled in theart. However, it is well within the three weeks, about every month, and about every two months. skilled artisan's purview to determine the other therapeutic The number and frequency of dosages corresponding to a agent's optimal effective amount range. The compound or a completed course of therapy will be determined according to pharmaceutically acceptable salt of the compound and the the judgment of a health-care practitioner. The effective dos 45 other therapeutic agent can act additively or, in one embodi age amounts described herein refer to total amounts admin ment, synergistically. In one embodiment of the invention, istered; that is, if more than one compound or a pharmaceu where another therapeutic agent is administered to an animal, tically acceptable salt of the compound is administered, the the effective amount of the compound or a pharmaceutically effective dosage amounts correspond to the total amount acceptable salt of the compound is less than its effective administered. 50 amount would be where the other therapeutic agent is not The amount of the compound or a pharmaceutically administered. In this case, without being bound by theory, it is acceptable salt of the compound that is effective for treating believed that the compound or a pharmaceutically acceptable or preventing a 5-HT-related disorder will typically range salt of the compound and the other therapeutic agent act from about 0.001 mg/kg to about 600 mg/kg of body weight synergistically. In some cases, the patientin need of treatment per day, in one embodiment, from about 1 mg/kg to about 600 55 is being treated with one or more other therapeutic agents. In mg/kg body weight per day, in another embodiment, from Some cases, the patient in need of treatment is being treated about 10 mg/kg to about 400 mg/kg body weight per day, in with at least two other therapeutic agents. another embodiment, from about 10 mg/kg to about 200 In one embodiment, the other therapeutic agent is selected mg/kg of body weight per day, in another embodiment, from from the group consisting of one or more anti-depressant about 10 mg/kg to about 100 mg/kg of body weight per day, 60 agents, anti-anxiety agents, anti-psychotic agents, or cogni in another embodiment, from about 1 mg/kg to about 10 tive enhancers. Examples of classes of that mg/kg body weight per day, in another embodiment, from can be used in combination with the active compounds of this about 0.001 mg/kg to about 100 mg/kg of body weight per invention include norepinephrine reuptake inhibitors, selec day, in another embodiment, from about 0.001 mg/kg to about tive serotonin reuptake inhibitors (SSRIs), NK-1 receptor 10 mg/kg of body weight per day, and in another embodiment, 65 antagonists, monoamine oxidase inhibitors (MAOS), revers from about 0.001 mg/kg to about 1 mg/kg of body weight per ible inhibitors of monoamine oxidase (RIMAS), serotonin day. and noradrenaline reuptake inhibitors (SNRIs), corticotropin US 7,671,056 B2 69 70 releasing factor (CRF) antagonists, C.-adrenoreceptorantago Exp. Therap., 272:300-309: Thompson et al., 1995, Proc. nists, and atypical antidepressants. Suitable norepinephrine Natl. Acad. Sci. USA, 92:7667-7671), 3-bicyclo[2.2.1]hept reuptake inhibitors include tertiary amine tricyclics and sec 5-en-2-yl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine ondary amine tricyclics. Suitable tertiary amine tricyclics and 7-sulfonamide-1,1-dioxide (Yamada, et al., 1993, J. Neurosc. secondary amine tricyclics include , clomi 13:3904-3915): 7-fluoro-3-methyl-5-ethyl-1,2,4-benzothia pramine, , imipramine, , dothiepin, diazine-SS-dioxide; and compounds described in U.S. Pat. , , , , protrip No. 6,620.808 and International Patent Application Nos. WO tyline, , and . Suitable 94/02475, WO 96/38414, WO 97/36907, WO 99/51240, and selective serotonin reuptake inhibitors include fluoxetine, cit WO 99/42456), benzodiazepine (BZD)/GABA receptor olopram, escitalopram, fluvoxamine, paroxetine and Sertra 10 complex modulators (e.g., progabide, gengabine, Zaleplon, line. Examples of monoamine oxidase inhibitors include iso carboxazid, phenelZine, and tranylcypromine. Suitable and compounds described in U.S. Pat. Nos. 5,538,956, 5,260, reversible inhibitors of monoamine oxidase include moclobe 331, and 5,422,355); serotonin antagonists (e.g., 5-HT recep mide. Suitable serotonin and noradrenaline reuptake inhibi tor modulators, including other 5-HT, antagonist com tors of use in the present invention include Venlafaxine, nefa 15 pounds and 5-HT antagonists (including without limitation Zodone, milnacipran, and dulloxetine. Suitable CRF compounds described in U.S. Pat. Nos. 6,727,236, 6,825,212, antagonists include those compounds described in Interna 6,995,176, and 7,041,695)); nicotinics (e.g., niacin); musca tional Patent Publication Nos. WO94/13643, WO 94/13644, rinics (e.g., xanomeline, CDD-01 02, cevimeline, talsaclid WO 94/13661, WO 94/13676 and WO 94/13677. Suitable ine, oxybutin, tolterodine, propiverine, tropsium chloride and atypical anti-depressants include , lithium, nefaz darifenacin); monoamine oxidase type B (MAOB) inhibitors odone, and . Suitable NK-1 receptor (e.g., rasagiline, selegiline, deprenyl, lazabemide, Safina antagonists include those referred to in International Patent mide, clorgyline, pargyline, N-(2-aminoethyl)-4-chloroben Publication WOO 1/77100. Zamide hydrochloride, and N-(2-aminoethyl)-5(3-fluorophe Anti-anxiety agents that can be used in combination with nyl)-4-thiazolecarboxamide hydrochloride); the active compounds of this invention include without limi 25 phosphodiesterase (PDE) inhibitors (e.g., PDE IV inhibitors, tation benzodiazepines and serotonin 1A (5-HT) agonists roflumilast, arofylline, cilomilast, rolipram, RO-20-1724, or antagonists, especially 5-HT, partial agonists, and corti theophylline, denbufylline, ARIFLO, CDP-840 (a tri-aryl cotropin releasing factor (CRF) antagonists. Exemplary Suit ethane) CP80633 (a pyrimidone), RP 73401 (Rhone-Poulenc able benzodiazepines include alprazolam, chlordiazepoxide, Rorer), denbufylline (SmithKline Beecham), arofylline clonazepam, chloraZepate, diazepam, halazepam, lorazepam, 30 (Almirall), CP-77,059 (Pfizer), pyrid2.3dpyridazin-5-ones oxazepam, and prazepam. Exemplary Suitable 5-HT, recep (Syntex), EP-685479 (Bayer), T440 (Tanabe Seiyaku), and tor agonists or antagonists include buspirone, flesinoxan, SDZ-ISQ-844 (Novartis)): G proteins; channel modulators: gepirone and . immunotherapeutics (e.g., compounds described in U.S. Anti-psychotic agents that are used in combination with Patent Application Publication No. US 2005/0197356 and the active compounds of this invention include without limi 35 US 2005/0197379); anti-amyloid or amyloid lowering agents tation aliphatic phethiazine, a piperazine , a (e.g., bapineuZumab and compounds described in U.S. Pat. butyrophenone, a Substituted benzantide, and a thioxanthine. No. 6,878,742 or U.S. Patent Application Publication Nos. Additional examples of such drugs include without limitation US 2005/0282825 or US 2005/0282826); statins and peroxi , , , , , some proliferators activated receptor (PPARS) modulators aripiprazol, and . In some cases, the drug is an 40 (e.g., gemfibrozil (LOPIDR), fenofibrate (TRICORR), anticonvulsant, e.g., phenobarbital, phenyloin, primidone, or rosiglitazone maleate (AVANDIAR), pioglitazone (Ac carbamazepine. tosTM), rosiglitazone (AvandiaTM), clofibrate and bezafi Cognitive enhancers that are co-administered with the brate); cysteinyl protease inhibitors; an inhibitor of receptor 5-HT, antagonist compounds of this invention include, for advanced glycation endproduct (RAGE) (e.g., ami without limitation, drugs that modulate neurotransmitter lev 45 noguanidine, pyridoxaminem carnosine, phenazinediamine, els (e.g., acetylcholinesterase or cholinesterase inhibitors, OPB-9195, and tenilsetam); direct or indirect neurotropic cholinergic receptor agonists or serotonin receptor antago agents (e.g., Cerebrolysin(R), piracetam, oxiracetam, AIT-082 nists), drugs that modulate the level of soluble AB, amyloid (Emilieu, 2000, Arch. Neurol. 57:454)); beta-secretase fibril formation, or amyloid plaque burden (e.g., Y-secretase (BACE) inhibitors, C-Secretase, immunophilins, caspase-3 inhibitors, B-secretase inhibitors, antibody therapies, and 50 inhibitors, Src kinase inhibitors, tissue plasminogen activator degradative enzymes), and drugs that protect neuronal integ (TPA) activators, AMPA (alpha-amino-3-hydroxy-5-methyl rity (e.g., antioxidants, kinase inhibitors, caspase inhibitors, 4-isoxazolepropionic acid) modulators, M4 agonists, JNK3 and hormones). Other representative candidate drugs that are inhibitors, LXRagonists, H3 antagonists, and angiotensin IV co-administered with the compounds of the invention include antagonists. Other cognition enhancers include, without limi cholinesterase inhibitors, (e.g., (COGNEX(R), done 55 tation, acetyl-1-carnitine, citicholine, huperzine, DMAE pezil (ARICEPTR), (EXELONR) (dimethylaminoethanol), Bacopa monneiri extract, Sage (REMINYL(R), metrifonate, physostigmine, and Huperzine extract, L-alpha glyceryl phosphoryl choline, Ginko biloba A), N-methyl-D-aspartate (NMDA) antagonists and agonists and Ginko biloba extract, Vinpocetine, DHA, nootropics (e.g., dextromethorphan, , dizocilpine maleate including Phenyltropin, Pikatropin (from Creative Com (MK-801), , remacemide, eliprodil, amantadine, D-cy 60 pounds, LLC, Scott City, Mo.), besipirdine, linopirdine, closerine, felbamate, ifenprodil, CP-101606 (Pfizer), Delu Sibopirdine, estrogen and estrogenic compounds, idebenone, cemine, and compounds described in U.S. Pat. Nos. 6,821, T-588 (Toyama Chemical, Japan), and FK960 (Fujisawa 985 and 6,635,270), ampakines (e.g., cyclothiazide, Pharmaceutical Co. Ltd.). Compounds described in U.S. Pat. aniracetam, CX-516 (Ampalex(R), CX-717, CX-516, Nos. 5,219,857, 4,904,658, 4,624,954 and 4,665,183 are also CX-614, and CX-691 (Cortex Pharmaceuticals, Inc. Irvine, 65 useful as cognitive enhancers as described herein. Cognitive Calif.), 7-chloro-3-methyl-3-4-dihydro-2H-1,2,4-benzothia enhancers that act through one or more of the above mecha diazine S.S.-dioxide (see Zivkovic et al., 1995, J. Pharmacol. nisms are also within the scope of this invention. US 7,671,056 B2 71 72 In one embodiment, the compound or a pharmaceutically In another embodiment, the pharmaceutically acceptable acceptable salt of the compound of the invention and cogni carrier is Suitable for oral administration and the composition tive enhancer act additively or, in one embodiment, Synergis comprises an oral dosage form. tically. In one embodiment, where a cognitive enhancer and a compound or a pharmaceutically acceptable salt of the com Therapeutic or Prophylactic Uses pound of the invention are co-administered to an animal, the effective amount of the compound or pharmaceutically In one embodiment, the compounds or pharmaceutically acceptable salt of the compound of the invention is less than acceptable salts of the compounds of the present invention are its effective amount would be where the cognitive enhancer useful as 5-HT, receptor antagonists. In another embodi agent is not administered. In one embodiment, where a cog 10 ment, the compounds or pharmaceutically acceptable salts of nitive enhancer and a compound or a pharmaceutically the compounds of the present invention are useful as 5-HT acceptable salt of the compound of the invention are co receptor agonists. Compounds that are 5-HT, antagonists administered to an animal, the effective amount of the cogni and/or agonists can readily be identified by those skilled in the tive enhancer is less than its effective amount would be where art using numerous art-recognized methods, including stan the compound or pharmaceutically acceptable salt of the 15 dard pharmacological test procedures such as those described invention is not administered. In one embodiment, a cognitive herein. Accordingly, the compounds and pharmaceutically enhancer and a compound or a pharmaceutically acceptable acceptable salts of the compounds of the present invention are salt of the compound of the invention are co-administered to useful for treating a mammal with a 5-HT-related disorder. an animal in doses that are less than their effective amounts One non-limiting example of a disorder that 5-HT, receptor would be where they were no co-administered. In these cases, antagonists are useful for treating is cognition-related disor without being bound by theory, it is believed that the com der, while a non-limiting example of a disorder that 5-HT pound or a pharmaceutically acceptable salt of the compound receptor agonists are useful for treating is anxiety-related and the cognitive enhancer act synergistically. disorder. In some embodiments, the compounds and pharma In one embodiment, the other therapeutic agent is an agent ceutical salts of the invention are useful for improving cog useful for treating Alzheimer's disease or conditions associ 25 nitive function or cognitive deficits. Examples of improve ate with Alzheimer's disease. Such as dementia. Exemplary ments in cognitive function include, without limitation, agents useful for treating Alzheimer's disease include, with memory improvement and retention of learned information. out limitation, donepezil, rivastigmine, galantamine, meman Accordingly, the compounds and pharmaceutical salts of the tine, and tacrine. invention are useful for slowing the loss of memory and In one embodiment, the compound or a pharmaceutically 30 cognition and for maintaining independent function for acceptable salt of the compound is administered concurrently patients afflicted with a cognition-related disorder. Thus, in with another therapeutic agent. one embodiment, the compounds and pharmaceutically In one embodiment, a composition comprising an effective acceptable salts of the compounds of the present invention amount of the compound or a pharmaceutically acceptable that act as 5-HT, receptor antagonists are useful for treating 35 a mammal with a cognition-related disorder. In one embodi salt of the compound and an effective amount of another ment, the compounds and pharmaceutically acceptable salts therapeutic agent within the same composition can be admin of the compounds of the present invention that act as 5-HT istered. receptor antagonists are useful for improving the cognitive In another embodiment, a composition comprising an function of a mammal. Similarly, in one embodiment, the effective amount of the compound or a pharmaceutically 40 compounds and pharmaceutically acceptable salts of the acceptable salt of the compound and a separate composition compounds of the present invention that act as 5-HT, recep comprising an effective amount of another therapeutic agent toragonists are useful for treating a mammal with an anxiety can be concurrently administered. In another embodiment, an related disorder. effective amount of the compound or a pharmaceutically In one embodiment, the invention provides a method for acceptable salt of the compound is administered prior to or 45 treating a 5-HT-related disorder, comprising administering Subsequent to administration of an effective amount of to a mammal in need thereof a compound or a pharmaceuti another therapeutic agent. In this embodiment, the compound cally acceptable salt of the compound of Formula (I), For or a pharmaceutically acceptable salt of the compound is mula (I'). Formula (I"), Formula (I"a). Formula (II), Formula administered while the other therapeutic agent exerts its (III) or Formula (IV) in an amount effective to treat a 5-HT therapeutic effect, or the other therapeutic agent is adminis 50 related disorder. In one embodiment, the invention provides a tered while the compound or a pharmaceutically acceptable method for treating a cognition-related disorder, comprising salt of the compound exerts its preventative or therapeutic administering to a mammal in need thereof a compound or a effect for treating or preventing a 5-HT-related disorder. pharmaceutically acceptable salt of the compound of For Thus, in one embodiment, the invention provides a com mula (I), Formula (I'). Formula (I"). Formula (I"a), Formula position comprising an effective amount of the compound or 55 (II), Formula (III) or Formula (IV) in an amount effective to a pharmaceutically acceptable salt of the compound of the treat a 5-HT-related disorder. In one embodiment, the present invention and a pharmaceutically acceptable carrier. invention provides a method for treating an anxiety-related In another embodiment, the composition further comprises a disorder, comprising administering to a mammal in need second therapeutic agent. thereof a compound or a pharmaceutically acceptable salt of In another embodiment, the composition further comprises 60 the compound of Formula (I), Formula (I'). Formula (I"), a therapeutic agent selected from the group consisting of one Formula (I"a), Formula (II), Formula (III) or Formula (IV) in or more other antidepressants, anti-anxiety agents, anti-psy an amount effective to treat a 5-HT-related disorder. chotic agents or cognitive enhancers. Antidepressants, anti In one embodiment, the invention provides a method for anxiety agents, anti-psychotic agents and cognitive enhancers treating Alzheimer's disease, comprising administering to a Suitable for use in the composition include the antidepres 65 mammal in need thereof a compound or a pharmaceutically sants, anti-anxiety agents, anti-psychotic agents and cogni acceptable salt of a compound of Formula (I), Formula (I), tive enhancers provided above. Formula (I"). Formula (Ia"), Formula (II), Formula (III), or US 7,671,056 B2 73 74 Formula (IV) in an amount effective to treat Alzheimer's treatment in a patient in need thereof. The method includes disease. In one embodiment, the method for treating Alzhe administering to the patient an effective amount of one or imer's disease includes administering a second therapeutic more of the compounds disclosed herein. In some embodi agent. In some embodiments, the second therapeutic agent is ments, the drug treatment is antidepressant drug treatment, an anti-depressant agent, an anti-anxiety agent, an anti-psy- 5 antipsychotic drug treatment, or anticonvulsant drug treat chotic agent, or a cognitive enhancer. ment. The compound can be a compound orpharmaceutically In one embodiment, the invention provides a method for acceptable salt of a compound of Formula (I), Formula (I), treating mild cognitive impairment (MCI), comprising Formula (I"). Formula (I"a), Formula (II), Formula (III), or administering to a mammal in need thereof a compound or a Formula (IV). pharmaceutically acceptable salt of a compound of Formula 10 In certain embodiments, the drug associated with sexual (I), Formula (I'). Formula (I"). Formula (Ia"), Formula (II), dysfunction is a selective serotonin reuptake inhibitor (SSRI) Formula (III), or Formula (IV) in an amount effective to treat (for example, fluoxetine, citalopram, escitalopram oxalate, mild cognitive impairment (MCI). In one embodiment, the fluvoxamine maleate, paroxetine, or Sertraline), a tricyclic method for treating MCI includes administering a second antidepressant (for example, desipramine, amitriptyline, therapeutic agent. In some embodiments, the second thera- 15 amoXipine, , doxepin, imipramine, nortrip peutic agent is an anti-depressant agent, an anti-anxiety tyline, , trimipramine, dothiepin, butriptyline, agent, an anti-psychotic agent, or a cognitive enhancer. iprindole, or lofepramine), an aminoketone class compound In one embodiment, the invention provides a method for (for example, bupropion). In some embodiments, the drug is treating depression, comprising administering to a mammal a monoamine oxidase inhibitor (MAOI) (for example, in need thereofa compound or a pharmaceutically acceptable 20 phenelZine, isocarboxazid, or tranylcypromine), a serotonin salt of a compound of Formula (I), Formula (I'). Formula (I"), and norepinepherine reuptake inhibitor (SNRI) (for example, Formula (Ia"). Formula (II), Formula (III), or Formula (IV) in Venlafaxine, , milnacipran, dulloxetine), a norepi an amount effective to treat depression. In one embodiment, nephrine reuptake inhibitor (NR) (for example, reboxetine), the method for treating depression includes administering a a partial 5-HT agonist (for example, buspirone), a 5-HT second therapeutic agent. In some embodiments, the second 25 receptor antagonist (for example, nefazodone), a typical therapeutic agent is an anti-depressant agent, an anti-anxiety antipsychotic drug, or an drug. agent, an anti-psychotic agent, or a cognitive enhancer. Examples of Such antipsychotic drugs include aliphatic phet In some embodiments, the invention provides a pharma hiazine, a piperazine phenothiazine, abutyrophenone, a Sub ceutical composition for treating a 5-HT-related disorder, stituted benzamide, and a thioxanthine. Additional examples the composition including a compound or pharmaceutically 30 of such drugs include haloperidol, olanzapine, clozapine, ris acceptable salt of a compound of Formula (I), Formula (I), peridone, pimozide, aripiprazol, and Ziprasidone. In some Formula (I"), Formula (I"a), Formula (II), Formula (III), or cases, the drug is an anticonvulsant, e.g., phenobarbital, phe Formula (IV). In some embodiments, the invention provides nyloin, primidone, or carbamazepine. In some cases, the a pharmaceutical composition for treating a cognition-related patient in need of treatment for sexual dysfunction is being disorder, the composition including a compound or pharma- 35 treated with at least two drugs that are antidepressant drugs, ceutically acceptable salt of a compound of Formula (I), antipsychotic drugs, anticonvulsant drugs, or a combination Formula (I'). Formula (I"). Formula (I"a), Formula (II), For thereof. mula (III), or Formula (IV). In some embodiments, the inven In some embodiments of the invention, the sexual dysfunc tion provides a pharmaceutical composition for treating an tion comprises a deficiency in penile erection. anxiety-related disorder, the composition including a com- 40 The invention also provides a method of improving sexual pound or pharmaceutically acceptable salt of a compound of function in a patient in need thereof. The method includes Formula (I), Formula (I'). Formula (I"). Formula (I"a), For administering to the patient a pharmaceutically effective mula (II), Formula (III), or Formula (IV). amount of one or more of the compounds disclosed herein. In one embodiment, the invention provides a pharmaceu The compound can be a compound or pharmaceutically tical composition for treating Alzheimer's disease, the com- 45 acceptable salt of a compound of Formula (I), Formula (I), position including a compound or a pharmaceutically accept Formula (I"). Formula (I"a), Formula (II), Formula (III), or able salt of a compound of Formula (I), Formula (I'). Formula Formula (IV). (I"), Formula (Ia"). Formula (II), Formula (III), or Formula In another embodiment, the invention provides a pharma (IV). ceutical composition for treating sexual dysfunction associ In one embodiment, the invention provides a pharmaceu- 50 ated with drug treatment, the composition including a com tical composition for treating mild cognitive impairment pound or pharmaceutically acceptable salt of a compound of (MCI), the composition including a compound or a pharma Formula (I), Formula (I'). Formula (I"). Formula (I"a), For ceutically acceptable salt of a compound of Formula (I), mula (II), Formula (III), or Formula (IV). In some embodi Formula (I'). Formula (I"). Formula (Ia"), Formula (II), For ments, the drug is an antidepressant, an antipsychotic, or an mula (III), or Formula (IV). 55 anticonvulsant. In other embodiments, the compound orphar In one embodiment, the invention provides a pharmaceu maceutically acceptable salt of the compound is effective for tical composition for treating depression, the composition ameliorating sexual dysfunction in an animal model of sexual including a compound or a pharmaceutically acceptable salt dysfunction associated with drug treatment, for example, in of a compound of Formula (I), Formula (I'). Formula (I"), an animal model of sexual dysfunction that is an antidepres Formula (Ia"). Formula (II), Formula (III), or Formula (IV). 60 sant drug-induced model of sexual dysfunction. In one embodiment, the compounds or pharmaceutically The compounds and pharmaceutically acceptable salts of acceptable salts of the compounds of the present invention are the compounds of Formula (I), Formula (I), Formula (I"), useful for treating sexual dysfunction, e.g., sexual dysfunc Formula (I"a). Formula (II), Formula (III) or Formula (IV) are tion associated with drug treatment such as drug treatment also useful in the manufacture of medicaments for treating a with an antidepressant, an antipsychotic, or an anticonvul- 65 5-HT-related disorder in a mammal. Similarly, the com sant. Accordingly, in one embodiment, the invention provides pounds and pharmaceutically acceptable salts of the com a method for treating sexual dysfunction associated with drug pounds of Formula (I), Formula (I'). Formula (I"). Formula US 7,671,056 B2 75 76 (I"a), Formula (II), Formula (III) or Formula (IV) are also -continued useful in the manufacture of medicaments for treating a cog nition-related disorder in a mammal. Also, the compounds -O N and pharmaceutically acceptable salts of the compounds of Formula (I), Formula (I'). Formula (I"). Formula (I"a), For 5 2 mula (II), Formula (III) or Formula (IV) are also useful in the manufacture of medicaments for treating an anxiety-related disorder in a mammal. To a solution of 3.3 g of 8-chloro-6-hydroxyquinoline 10 (Step 1, 3.3 g) in dimethylformamide was added KCO (3.8 EXAMPLES g), followed by iodomethane (5.2 g). The mixture was stirred at room temperature overnight. Water was then added and the Preparation of Piperazine-Piperidine Compounds aqueous mixture was extracted with CHC1. The combined organic layers were dried over anhydrous MgSO, filtered A) Preparation of 6-Methoxy-8-4-1-(8-quinolinyl)- and concentrated on a rotary evaporator. The crude product 4-piperidinyl)-1-piperazinylquinoline and Interme 15 was purified by flash chromatography on silica gel using diates 100% CHCl, to give 2.2 g of the desired product as a beige solid; MP=74-75° C.; MS (ES) m/z (relative intensity): 194 (M+H)" (100). 3) 6-Methoxy-8-1-(tert-butoxycarbonyl)-4-piper / \ M \ aZinoquinoline

O CYMAP 25 1. N Pd(dba), -- NaOt-Bu 2 N N HCO3 O C3 C loc O 30 1 N 1) 8-Chloro-6-hydroxyquinoline 2 N HO N 35 C 2 t-BOC 40 To a mixture of 8-chloro-6-methoxyquinoline (Step 2, 2.7 g) in anhydrous tetrahydrofuran, was added tris(dibenzylide In a 500 ml 3-necked flask equipped with a mechanical neacetone)dipalladium(0) (Pd(dba), 0.064 g), sodium tert stirrer, a reflux condenser, were added in order ferrous sulfate butoxide (1.9 g), 2-dicyclohexylphosphino-2'-(N,N-dim (2.0 g), 4-amino-3-chlorophenol hydrochloride (6.4g, com 45 ethylamino)biphenyl (CYMAP, 0.08 g) and tert mercially available), nitrobenzene (2.9 mL) and a solution of butoxycarbonylpiperazine (3.4 g). The mixture was refluxed boric acid (3.0 g) in glycerol (16 g). Then concentrated Sul for 5 hours under a nitrogen atmosphere. The reaction was furic acid (9 mL) was added drop by drop with cooling. The then cooled to room temperature, diluted with ether, filtered ice bath was removed and replaced by an oil bath and the through celite and concentrated on a rotary evaporator. The mixture was heated cautiously to 120° C. for 2 hours, then at 50 crude material was purified by flash chromatography using 150° C. and kept stirring under this temperature for 20 hours. 100% CHCl to give 4.0 g of the desired product as a beige After cooling, the reaction was poured on crushed ice and the solid; mp=92-93° C.; MS (ES) m/z (relative intensity): 344 resulting solution was neutralized with K2CO3. The product (M+H) (100). separated as a light brown solid that was filtered off, washed 4) 6-Methoxy-8-piperazinoquinoline with water and hexanes and dried in a vacuum oven (35°C.) 55 overnight giving 7 g (77%) of the desired product. MS (ES) m/z (relative intensity): 180 (M"+-H, 100). 1. O N 2 D HCI 2) 8-Chloro-6-methoxyquinoline N OX8le 60 Her HO N K2CO3 CHI 2 3 N C 65 C t-BOC US 7,671,056 B2 77 78 -continued 6) 1-quinolin-8-yl-piperidin-4-one

N 5 2 N BINAP, Pd(dba) -e- NaOt-Bu

10 O Br

15 To a solution of 6-methoxy-8-1-(tert-butoxycarbonyl)-4- piperazinoquinoline (Step 3, 4.0 g) in 20 mL of Dioxane was 2 2 added 10 mL of 4 NHCl/Dioxane. The mixture was stirred at N N room temperature overnight. The resulting precipitate was N aq. HCI N CO --- CO collected by vacuum filtration, dissolved in water, neutralized with aqueous Sodium hydroxide and extracted with CHCl2. The combined organic layers were dried over anhydrous NaSO, filtered and concentrated on a rotary evaporator to O O O give 2.8 g of the desired product as a beige solid; MP=105 25 107° C.; MS (ES) m/z (relative intensity): 244 (M+H)" (100).

5) 8-(1,4-Dioxa-8-azaspairo4.5 dec-8-yl)guinoline To a solution of (4.0 g) 8-(1,4-Dioxa-8-azaspairo4.5 dec 30 8-yl)guinoline (Step 4, 4.0 g) in 10 mL of tetrahydrofuran was added 10 mL of 2N HC1. The reaction was stirred at room temperature overnight. The mixture was then diluted with water, made basic with aqueous sodium hydroxide and N BINAP, Pd(dba) extracted with CHC1. The combined organic layers were -- He 35 NaOt-Bu dried over anhydrous and the product is extracted with 2 N CHCl, dried over NaSO filtered and concentrated on a B O O rotary evaporator and to give 3.2 g of the desired product as a r \ f sticky yellow oil; MS (ES) m/z (relative intensity): 227 N 40 (M+H)" (100).

2 7) 6-Methoxy-8-4-1-(8-quinolinyl)-4-piperidinyl N 1-piperazinylquinoline N 45

-O N O O 2 50 N --

To a solution of 8-bromoquinoline (commercially avail able, 4.0 g) in 20 mL of anhydrous tetrahydrofuran, was added tris(dibenzylideneacetone)dipalladium(0) (Pd(dba), 55 CN 0.2 g), Sodium tert-butoxide (2.6 g), 2,2'-bis(diphenylphos H phino)-1,1'-binapthyl (BINAP, 0.1 g), tetrakis-(triph N enylphosphine)palladium(0) (0.1 g) and 1,4-dioxo-8-aza spiro-4,5-decane (3.3 g). The mixture was refluxed for 3 4. 1) NaBHCN hours under a nitrogen atmosphere. The reaction mixture was 60 2) HC/EtO then cooled to room temperature, diluted with ether, filtered through celite and concentrated on a rotary evaporator. The crude material was then purified by flash chromatography on silica gel using hexane/ethyl acetate to give 3.0 g of the 65 desired product as a brown oil; MS (ES) m/z (relative inten CO sity): 271 (M+H)" (100). US 7,671,056 B2 79 80 2) 6-Fluoro-8-1-(tert-butoxycarbonyl)-4-piperazino -continued quinoline / \ M \

BINAP, Pd(dba) He NaOt-Bu HCO D 8-O-O-3 10 Br t-BOC To a solution of 0.247 g of 6-methoxy-8-piperazino-quino F line (Step 4) in 10 mL of dichloroethane, was added 0.226 g N of 1-quinolin-8-yl-piperidin-4-one (Step 6) followed by 15 2 0.274 g of sodium triacetoxyborohydride and 0.1 mL acetic N acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CHC1. The organic phase was washed with water and dried over magnesium Sulfate. The product crys C tallized and filtered to give 0.200 g of the desired product. Mp. 194-197° C.; MS (ES) m/z (relative intensity): 454 t-BOC (M+-H, 100).

B) Preparation of 6-fluoro-8-4-1-(8-quinolinyl)-4- 25 To a mixture of 6-fluoro-8-bromoquinoline (Step 1, 2.2 g) piperidinyl)-1-piperazinylquinoline and in anhydrous tetrahydrofuran, was added tris(dibenzylidene Intermediates acetone)dipalladium(0) (Pd(dba), 0.045 g) sodium tert-bu toxide (1.3 g), 2,2'-bis(diphenylphosphino)-1,1'-binapthyl (BINAP, 0.044g), 0.052 g tetrakis(triphenylphosphine)-pal 30 ladium (O) (0.052 g) and tert-butoxycarbonyl-piperazine (2.2 g). The mixture was refluxed for 3 hours under a nitrogen / \ / \ atmosphere. The reaction was then cooled to room tempera ture, diluted with ether, filtered through celite and concen trated on a rotary evaporator. The crude material was purified 35 by flash chromatography using 100% CHCl to give 3.0 g of the desired product as a brown oil; MS (ES) m/z (relative 3 O C3 intensity): 332 (M+H)" (100).

40 3) 6-fluoro-8-piperazinoquinoline 1) 6-Fluoro-8 bromoquinoline

F F 45 N N m-nitrobenzene Sulfonic acid 2 He N N HCI N Dioxane N Br 50 N N N H 2 N t-BOC 55 Br To a solution of 6-fluoro-8-1-(tert-butoxycarbonyl)-4- piperazinoquinoline (Step 2, 3.0 g) in 10 mL. Dioxane was To a mixture of 2-bromo-4-fluoroaniline (commercially added 10 mL of 4 NHCl/Dioxane. The mixture was stirred at available, 7.0 g), glycerol (7.0 g) and m-nitrobenzene Sulfonic room temperature overnight. The resulting precipitate was acid sodium salt (13.0 g) was added 20 ml of 70% sulfuric 60 acid dropwise. The reaction temperature was raised to 150° C. collected by vacuum filtration, dissolved in water, neutralized for 4 hr. The mixture then was cooled to room temperature, with aqueous sodium hydroxide and extracted with CHCl, poured on ice water and filtered through celite. The filtrate The combined organic layers were dried over anhydrous was neutralized with NaOH and the resulting precipitate was Na2SO, filtered and concentrated on a rotary evaporator to collected by vacuum filtration to yield 3.47 g of the title 65 give 1.9 g of the desired product as an off-white solid. Mp. compound as a light yellow solid; MP=75-78° C.; MS (ES) 101-103° C.; MS (ES) m/z (relative intensity): 233 (M+H)" m/z (relative intensity): 227 (M+H)" (100). (100). US 7,671,056 B2 81 82 4) 6-fluoro-8-4-1-(8-quinolinyl)-4-piperidinyl)-1- 1) 5-Fluoro-8 chloroquinoline piperazinylquinoline

N F N 2 2 10 N

N -- To a mixture of (5.0 g) 2-chloro-5-fluoroaniline (commer ON 15 cially available, 6.0 g), glycerol (6.0 g) and m-nitrobenzene H sulfonic acid sodium salt (11.0 g), was added 20 ml of 70% Sulfuric acid dropwise. The reaction temperature was raised N to 140°C. for 2 hr. The mixture was then cooled, poured on 2O ice water and filtered through celite. The filtrate was neutral 2 ized with NaOH and extracted with CHC1. The combined N organic layers were dried over anhydrous MgSO and con 1) NaBHCN centrated on a rotary evaporator. The crude product was puri N 2) HC/EtO fied by flash chromatography on silica gel using 100% 25 CHCl to give 3.7g of the desired product of a yellow solid; MP=74-76° C.; MS (ES) m/z (relative intensity): 182 (M+H)" (100). O 2) 8-(1,4-Dioxa-8-azaspiro4.5 dec-5-yl)-5-fluoro / \\, // \ 30 quinoline

N N N F V M 35

F N CYMAP, 2 -- Po?dba2(dba)3 N NaOt-Bu To a solution of 0.247 g of 6-fluoro-8-piperazino-quinoline 40 C O O (Step 3) in 10 mL of dichloroethane, was added 0.226 g of 1-quinolin-8-yl-piperidin-4-one (Example A, Step 6, above) F followed by 0.274 g of sodium triacetoxyborohydride and 0.1 mL acetic acid. The reaction was stirred at room temperature N overnight. It was quenched with 1N NaOH, and the product 45 2 was extracted with CHC1. The organic phase was washed N with water and dried over magnesium sulfate. The product crystallized and filtered to give 0.200 g of the desired product. N Mp: 211° C.; MS (ES) m/z (relative intensity): 442 (M"+-H, 50 100). O O C) Preparation of 5-fluoro-8-4-4-(8-quinolinyl)-1- piperazinyl)-1-piperidinyl-quinoline and Intermedi 55 ates To a solution of 5-fluoro-8-chloroquinoline (Step 1, 1.12 g) in 20 mL of anhydrous tetrahydrofuran, was added 0.085 g of tris(dibenzylideneacetone)dipalladium(0) (Pd(dba), 0.085 g). Sodium tert-butoxide (0.83 g), 2-dicyclohexylphosphino 60 2'-(N,N-dimethylamino)-biphenyl (CYMAP, 0.036 g), and / \, \ \ 1,4-dioxo-8-azaspiro-4,5-decane (1.05 g). The mixture was refluxed for 6 hours under a nitrogen atmosphere. The reac tion mixture was then cooled to room temperature, diluted 65 with ether, filtered through celite and concentrated on a rotary 8. CCC evaporator. The crude material was then purified by flash chromatography on silica gel using hexane/ethyl acetate to US 7,671,056 B2 83 84 give 0.700 g of the desired product as a brown oil; MS (ES) D) Preparation of 8-4-4-(1H-indole-4-yl)-1-piper m/z (relative intensity): 289 (M+H)" (100). azinyl)-1-piperidinylquinoline 3) 1-(5-Fluoroquinolin-8-yl)piperidin-4-one M \

F F

N N 10 HNN a 2 2 N N 9 OCC N aq. HCI N To a solution of 0.270g of 1-quinolin-8-yl-piperidin-4-one 15 (Example A, Step 6, above) and 0.240 g of 4-piperazino indole (commercially available) in 15 mL CHC1 was added 0.327 g of sodium triacetoxyborohydride and 0.2 mL acetic C\ / CO acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CHC1. The organic phase was washed with A solution of 8-(1,4-dioxa-8-azaspiro4.5 dec-5-yl)-5- water, dried over magnesium sulfate and evaporated. The fluoroquinoline (Step 2, 2.1 g)) in 10 mL of 1:1 tetrahydro product crystallized to give 0.200 g of the desired product. furan/2Naqueous HCl was stirred at room temperature over Mp: 256°C.; MS (ES) m/z (relative intensity): 412 (M"+-H, night. The reaction mixture was diluted with water, made 25 100). basic with 1N aqueous NaOH and extracted with CHC1. The combined organic layers were dried over anhydrous E) Preparation of 8-4-4-(2,3-dihydro-1,4-benzo1, MgSO4, filtered and concentrated on a rotary evaporator to 4 dioxane-5-yl)-1-piperazinyl)-1- give 1.68g of the desired product as a yellow solid, which was piperidinylquinoline pure enough to use in Subsequent reactions; MS m/Z 245 30 M+H". 4) 5-fluoro-8-4-4-(8-quinolinyl)-1-piperazinyl)-1- / \, / \ piperidinyl-quinoline 35

F 3 O C3 To a solution of 1-quinolin-8-yl-piperidin-4-one (Example N N 40 A, Step 6, above, 0.220 g) in 10 mL of dichloroethane, was 2 2 added 0.226 g of 8-piperazino-1,3-benzdioxane (Childers et N N al., J. Med. Chem, 48:3467 (2005), 0.226 g) followed by 1) NaBH(OAc)3 0.274 g of sodium triacetoxyborohydride and 0.1 mL acetic acid. The reaction was stirred at room temperature overnight. 45 It was quenched with 1N NaOH, and the product was C -- N extracted with CHC1. The organic phase was washed with N H water, dried over magnesium sulfate and evaporated. The O product crystallized to give 0.140 g of the desired product. 50 Mp: 226°C.; MS (ES) m/z (relative intensity): 431 (M"+-H, 100). F) Preparation of 5-fluoro-8-4-4-(5-fluoro-1-ben Zofuran-3-yl)-1-piperazinyl)-1-piperidinylquinoline 55 To a solution of 0.120 g of 1-(5-fluoro-quinolin-8-yl)-pip eridin-4-one (Step 3, 0.22 g) and 8-piperazin-1-ylquinoline (Oruz, et al., J. Med. Chem. 45:4128 (2002), 0.19 g) was added of 0.19 g sodium triacetoxyborohydride and 0.1 mL 60 acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CHC1. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 75 ml of silica gel using 100% Ethyl 65 acetate, to give 0.30g of the desired product. Mp: 224°C.; MS (ES) m/z (relative intensity): 442 (M+-H, 100). US 7,671,056 B2 85 86 1) 4-(5-fluorobenzofuran-3-yl)-piperazine-1-car a brown oil and was used without further purification; MS boxylic acid ethyl ester (ES) m/z (relative intensity): 221 (M+H)" (100). 3) 5-fluoro-8-4-4-(5-fluoro-1-benzofuran-3-yl)-1- piperazinyl)-1-piperidinylquinoline - / / \ TiCL4 He 10 is - CHCl2

15 2 N M / NH -- - /

N 1) NaBHCN O / N )- He 2 2) CHCL N To a stirred solution of TiCl, (1M solution in CHC1.7ml) and 5-fluoro-benzofuran -3-one (Cagniant, et al., Comptus Rendus des Seances Acad. de Sci., Ser: C, 282:993 (1976), 3.0 25 g) (3.0 g, 19.7 mmol) in methylene chloride (200 ml) at -10° C., ethyl-1-piperizine carboxylate (commercially available) (3.9 g, 35 mmol) was slowly added. After the addition, the reaction mixture was warmed to room temperature and slowly refluxed for 24 hours. After cooling to room tempera 30 ture, the reaction was quenched with 2 Naqueous HC1. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layers were washed well with water and dried over anhydrous MgSO, then filtered and concentrated resulting in a brown 35 oil. Yield: 3.5g, (60%); MS (ESI) m/z 293 M+-H". \ / 2) 4-(5-fluorobenzofuran-3-yl)-piperazine CO 40 To a solution of 0.200 g of 1-(5-fluoro-quinolin-8-yl)-pip eridin-4-one (Example C, Step 3, 0.20 g) and 5-fluoro-3- piperazino benzofuran (Step 2, 0.20 g) in CHCl (10 mL) was added sodium triacetoxyborohydride (0.224 g) and 0.02 mL acetic acid. The reaction was stirred at room temperature 45 overnight. It was quenched with 1N NaOH, and the product / V O NaOH was extracted with CH2Cl2. The organic phase was washed O / N fN { HerCHCl2 with water and dried over magnesium sulfate. The product was filtered through 100 ML of silica gel using 50% Ethyl F 50 acetate/Hexanes then 100% Ethyl acetate to give 0.100 g of the desired product. Mp: 187-189°C.; MS (ES) m/z (relative intensity): 449 (M"+-H, 100). G) Preparation of 1-1-(1-benzothien-3-yl)-4-pip N NH 55 V / eridinyl-4-(2-methoxyphenyl)piperazine Table 1, #18 4-(5-fluorobenzofuran-3-yl)-piperazine-1-carboxylic acid ethyl ester (Step 1.3 g) was dissolved in 95% ethanol and 3N 60 aqueous Sodium hydroxide (25 mL) was added. The reaction mixture was stirred at reflux for 24 hours. The mixture was then cooled to room temperature, concentrated on a rotary evaporator to remove the ethanol and extracted with chloro form. The combined organic layers were washed with brine, 65 -O-O-S) dried over anhydrous MgSO filtered and concentrated on a rotary evaporator. The desired product (0.8 g) was obtained as US 7,671,056 B2 87 88 1) 4-(1-Benzylpiperidin-4-yl)-1-(2-methoxyphenyl) (14.4 g) as a yellow oil which was used without further piperazine purification. The compound was characterized as the dihy drochloride salt, which was formed by dissolving the oil in ethanol and treating it with an excess of 1 NHCl/EtO to give an off-white precipitate, which was collected by vacuum fil tration, washed with Et2O and dried in vacuo; MP. 274-288° O)- O C.; MS (ES) m/z (relative intensity): 276 (M+H)" (100). -- 3) 1-1-(1-benzothien-3-yl)-4-piperidinyl)-4-(2- 10 methoxyphenyl)piperazine

HN Y NaBH(OAc)3 \ / 15 HCO | --

HCO IO-O-()\ / --

Sodium triacetoxyborohydride (21.2 g) was added portion wise to a stirred solution of 1-(2-methoxyphenyl)piperazine 25 (commercially available, 19.23 g) and 1-benzyl-4-piperidone (commercially available, 18.93 g) in CHCl (300 mL) at S | O)-O\ / room temperature, followed by glacial acetic acid (6 mL). The resulting mixture was stirred at room temperature for 24 hours. The reaction was made basic by careful addition of 30 saturated aqueous NaHCO. The organic layer was separated, A solution of 3-bromo-benzothiophene (commercially washed with brine, dried over anhydrous MgSO, filtered and available, 0.232 g) and 4-(4-(2-methoxyphenyl)piperazin-1- concentrated on a rotary evaporator to give the desired prod yl)piperidine (Step 2, 0.30 g) in tetrahydrofuran was added uct (20.65 g) as an off-white solid which was used without sodium tert-butoxide (0.15g), tris-(dibenzylideneacetone)di further purification. The compound was characterized as the 35 palladium(0) (Pd(dba), 0.10 g) and 2-dicyclohexylphos dihydrochloride salt, which was formed by dissolving the free phino-2'-(N,N-dimethylamino)-biphenyl (CYMAP, 0.01 g). base in ethanol and treating it with an excess of 1 NHC1/EtO The reaction was heated at reflux for 24 hours. It was then to give a white solid, which was collected by vacuum filtra cooled and filtered through celite. The filtrate was evaporated tion, washed with EtO and dried in vacuo; MP. 238-242°C.; and purified by flash chromatography on silica gel using ethyl MS (ES) m/z (relative intensity) 366 (M+H)" (100). 40 acetate/hexanes to give 0.10 g of the desired product. MP: 156-158°C.; MS (ES) m/z (relative intensity): 408 (M+H)" 2) 4-(4-(2-Methoxyphenyl)piperazin-1-yl)piperidine (100). H) Preparation of 3-4-4-(2-methoxyphenyl)-1- 45 piperazinyl)-1-piperidinyl-1,2-benzisoxazole A V H2, Pd/C N N N Her V v 50 psig 1) 1,2-benzoxazole-3-trifluoromethylsulfonate

HCO 50 OH OSOCF N (CFSO2)2O N IO)-O S ) N He- N 55 M M H3CO O O

A solution of 4-(1-benzylpiperidine-4-yl)-1-(2-methox To a cold solution (-15°C.) of benzo-D-isoxazole-3-ol yphenyl)piperazine (Step 1, 20.0 g) in ethanol (120 mL) (2.0 g) in CHCl (20 mL) and triethylamine (4.5 g), was containing acetic acid (12 mL) was hydrogenated over 10% 60 added a solution of trifluoromethanesulfonic anhydride (5.0 palladium on carbon (1 g) at 50 psig on a Parr apparatus for 12 g) in CHCl (10 mL) dropwise with. The reaction was stirred hours. The catalyst was removed by filtration through Celite at 0°C. for one hour and then poured into ice water. The and the mixture was concentrated to dryness on a rotary mixture was extracted with CHCl2. The organic phase was evaporator. The residue was partitioned between chloroform dried over anhydrous MgSO, filtered and concentrated on a and Saturated aqueous NaHCO. The combined organic lay 65 rotary evaporator to give 3.0 g of the desired product as a ers were dried over anhydrous MgSO, filtered and concen brown oil, which was used immediately without character trated on a rotary evaporator to provide the desired product ization or further purification. US 7,671,056 B2 89 90 2) 3-4-4-(2-methoxyphenyl)-1-piperazinyl)-1-pip 2) 6-Chloro-8-4-4-(1H-indole-4-yl)-1-piperazinyl eridinyl-1,2-benzisoxazole 1-piperidinylquinoline

OCH 5 C N -

N II N N M O 10 I C N H

15 O / \ b- O)-O\ / HCO O-O.\ / 1,2-benz-isoxazole-3-trifluoromethyl sulfonate I (Step 1, 0.50 g) and 4-(4-(2-methoxyphenyl)piperazin-1-yl)piperi HN 2 C dine (Example G, Step 2, above, 0.514 g) were added to a cold suspension of CsCO, (0.92 g) in acetonitrile (6 mL) under vigorous stirring. The reaction mixture was stirred at room To a solution of 1-(6-chloro-quinolin-8-yl)-piperidin-4- temperature for 48 hours. The mixture was then filtered and 25 one (Step 1, 0.13 g) and of 4-piperazino-indole (commer concentrated on a rotary evaporator. The residue was dis cially available, 0.100 g) in 15 mL CHCl in 10 mL of solved in water extracted with CHCl, dried over anhydrous dichloroethane, was added 0.137 g of sodium triacetoxyboro MgSO4, filtered and concentrated on a rotary evaporator. The desired product was purified by flash chromatography on hydride and 0.1 mL acetic acid. The reaction was stirred at 30 room temperature overnight. It was quenched with 1N NaOH, silica gel using ethyl acetate/hexane to give 0.34 g as an and the product was extracted with CHCl2. The organic off-white solid; MP 71-73° C.; MS (ES) m/z (relative inten phase was washed with water and dried over magnesium sity): 393 (M+H)" (100). sulfate. The product was filtered through 100 ml of silica gel I) Preparation of 6-Chloro-8-4-4-(1H-indole-4-yl)- using 100% Ethyl acetate, to give 0.070 g of the desired 1-piperazinyl)-1-piperidinylquinoline 35 product. Mp: 224° C.; MS (ES) m/z (relative intensity): 447 (M"+-H, 100). J) Preparation of 8-4-1-(7-Fluoroquinolin-8-yl) / \ piperidin-4-yl)piperazin-1-yl-6-methoxyquinoline 40 (Table 1, #24) / \ / \ 9 OCC 45 1) 1-(6-Chloro-8-quinolinyl)-4-piperidinone 3 O C3 C 50

1) 7,8-Difluroquinoline (intermediate)

55 N

2 F N

O 60 This compound was prepared from the known 8-bromo-6- chloroquinoline (Lachowicz et al., Rocz. Chem., 40:1848 To a mixture of 2,3-difluoroaniline (commercially avail (1966)) using a synthetic sequence and reagents identical to able, 3.57 g), glycerol (5.55 g) and m-nitrobenzene sulfonic those described for the synthesis of 1-quinolin-8-yl-piperi acid sodium salt (10.12 g) was added dropwise 70% HSO din-4-one (Step 5. Example A, above). The compound was 65 (20 mL). The reaction was heated at 135°C. for 3.5 hours and obtained as an off-white solid; MP: 223-225° C.; MS (ES) then cooled to room temperature. It was poured over ice, m/z (relative intensity): 261 (M+H)" (100). made basic with 50% aqueous NaOH and extracted with US 7,671,056 B2 91 92 EtO. The combined organic layers were washed with brine, tered and concentrated on a rotary evaporator. The crude dried over anhydrous MgSO and concentrated on a rotary product was purified by flash chromatography on silica gel evaporator to give 4.13 g of the desired product as a light using hexane/ethyl acetate to give 1.17 g of the desired prod brown solid; MS (ES) m/z (relative intensity): 166 (M+H)" uct as a yellow oil; MS (ES) m/z (relative intensity): 245 (100). (M+H)" (100). 2) 8-(1,4-Dioxa-8-azaspiro 4.5 dec-8-yl)-7-fluoro 4) 8-4-1-(7-Fluoroquinolin-8-yl)piperidin-4-yl) quinoline and 7-(1,4-Dioxa-8-azaspiro4.5 dec-8-yl)- piperazin-1-yl-6-methoxyquinoline (Final product) 8-fluoroquinoline (Intermediates) 10 / \ / \

2 F N and 10) 15 O-O.\ / V F

OC O To a solution of 1-(7-fluoroquinolin-8-yl)piperidin-4-one \ / (Step 3, 0.26 g) and 6-methyoxy-8-(1-piperazinyl)cquinoline N (Example A, Step 4: 0.26 g) in anhydrous methanol (10 mL) was added sodium cyanoborohydride (0.11 g). The resulting 2 mixture was stirred at room temperature under nitrogen for 18 N N 25 hours. An additional aliquot of sodium cyanoborohydride F (0.11 g) was added and stirring at room temperature was continued for another 24 hours. The resulting reaction mix Cl ture was poured into brine and extracted with ethyl acetate. The combined organic layers were dried over anhydrous 30 NaSO filtered and concentrated on a rotary evaporator. The A mixture of 7,8-difluoroquinoline (Step 1, 0.50 g) and crude product was purified by flash chromatography on silica dioxa-8-azaspiro-4.5-decane (5 mL) was heated at 120° C. gel using hexanefacetone to give the desired product, which for 48 hours. The reaction was cooled to room temperature, was converted to its trihydrochloride salt in CHCl using 1M poured into water and extracted with EtO. The combined HC1/EtO to provide 0.12 g of a yellow solid; MS (ES) m/z organic layers were dried over anhydrous NaSO, filtered 35 and concentrated on a rotary evaporator. The crude residue (relative intensity): 472 (M+H)" (100). was purified by flash chromatography on silica gel. Eluting with 30% ethyl acetate in hexane provided 0.39 g of 8-(1.4- K) 6-Fluoro-8-4-T-(8-fluoroquinolin-7-yl)piperi dioxa-8-azaspiro4.5 dec-8-yl)-7-fluoroquinoline as yellow din-4-yl)piperazin-1-ylquinoline (Table 1, #25) oil; MS (ES) m/z (relative intensity): 289 (M+H)" (100). 40 The eluent was then switched to 50% ethyl acetate in hexane, which provided 0.23 g of the regioisomeric 7-(1.4- dioxa-8-azaspirola.5dec-8-yl)-8-fluoroquinoline as a white solid; MS (ES) m/z (relative intensity): 289 (M+H)" (100). 45 \ / 3) 1-(7-Fluoroquinolin-8-yl)piperidin-4-one (Inter O-O. mediate) N 50 1) 1-(8-Fluoroquinolin-7-yl)piperidin-4-one (Inter 2 mediate) F N

N 55

2 O N N

60 C To a solution of 8-(1.4-dioxa-8-azaspiro4.5 dec-8-yl)-7- O1C F fluoroquinoline (Step 2, 1.73 g) in tetrahydrofuran (50 mL) was added aq. 2N aqueous HCl (10 mL). The resulting mix To a solution of 7-(1.4-dioxa-8-azaspiro4.5 dec-8-yl)-8- ture was stirred at 50° C. for 3 hours. The reaction mixture fluoroquinoline (Example J, Step 2: 1.30 g) in tetrahydrofu was then cooled to room temperature, poured into 2.5 N 65 ran (60 mL) was added aq. 2N aqueous HCl (10 mL). The aqueous NaOH and extracted with ethyl acetate. The com resulting mixture was stirred at room temperature for 18 bined organic layers were dried over anhydrous MgSO, fil hours and then heated at 60° C. for 5 hours. The reaction US 7,671,056 B2 93 94 mixture was cooled to room temperature, poured into 1N tography on silica using hexane/ethyl acetate to give 0.74 g of aqueous NaOH and extracted with ethyl acetate. The com the desired product as a white solid; MS (ES) m/z (relative bined organic layers were dried over anhydrous MgSO, fil intensity): 334 (M+H)" (100). tered and concentrated on a rotary evaporator. The crude product was purified by flash chromatography using hexane/ 2) 8-Bromo-3-(trifluoromethyl)guinoline acetone to give 0.89 g of the desired product as a yellow solid; MS (ES) m/z (relative intensity): 245 (M+H)" (100). (intermediate) 2) 6-Fluoro-8-4-1-(8-fluoroquinolin-7-yl)piperi din-4-yl)piperazin-1-ylquinoline (Final product) 10 N CF To a solution of 1-(8-fluoroquinolin-7-yl)piperidin-4-one (Step 1, 0.25 g) and 6-fluoro-8-(1-piperazinyl)cquinoline (Ex 2 ample B, Step 3: 0.25 g) in anhydrous methanol (10 mL) was N added sodium cyanoborohydride (0.11 g). The resulting mix 15 Br ture was stirred at room temperature for 18 hours. An addi tional aliquot of sodium cyanoborohydride (0.10 g) was added and stirring at room temperature was continued for A mixture of cuprous iodide (0.25 g) and potassium fluo another 24 hours. The reaction mixture was poured into brine ride (0.077 g) was placed under a high vacuum and heated and extracted with ethyl acetate. The combined organic layers until the solid assumed a sight green color. The cooled solid were dried over anhydrous NaSO, filtered and concentrated mass was suspended in anhydrous N-methylpyrrolidinone (5 on a rotary evaporator. The crude product was isolated by mL) and then treated with 8-bromo-3-iodoquinoline (Step 1. flash chromatography on silica gel using hexanefacetone to 0.40g), followed by trifluoromethyl-trimethylsilane (0.17g). give the desired product as a off-white solid, which was The resulting mixture was stirred at 50° C. for 18 hours. The converted to its trihydrochloride salt in CHCl2/EtO diethyl 25 ether using 1M HCl/EtO to provide 0.11g as a yellow solid; mixture was then cooled to room temperature and poured into MS (ES) m/z (relative intensity): 460 (M+H)" (100). 15% aqueous NH-OH and then extracted with EtO. The organic layer was washed with water and brine, dried over L) 8-4-4-(6-Methoxyquinolin-8-yl)piperazin-1-yl) anhydrous NaSO4, filtered and concentrated on a rotary piperidin-1-yl)-3-(trifluoromethyl)guinoline 30 evaporator. The crude product was purified by flash chroma (Table 1, #22) tography on silica gel using hexane/ethyl acetate to give 0.24 g of the desired product as a brown oil; MS (ES) m/z (relative intensity); 277 (M+H)" (100). 35 3) 8-(1,4-Dioxa-8-azaspiro4.5 dec-8-yl)-3-(trifluo romethyl)cquinoline (intermediate)

40 N CF

2 SCO N V 45

1) 8-Bromo-3-iodoquinoline (intermediate) O O 50

N To a solution of mixture 8-bromo-3-(trifluoromethyl) 2 quinoline (Step 2, 0.22 g) in anhydrous tetrahydrofuran was added tris(dibenzylideneacetone)dipalladium(0) (Pd(dba), Br 0.03 g), sodium tert-butoxide (0.085 g), 2,2'-bis(diphe nylphosphino)-1,1'-binapthyl (BINAP, 0.02 g), tetrakis To a solution of 8-bromoquinoline (commercially avail (triphenylphosphine)palladium(0) (0.037) g) and 1.4-dioxo able, 1.0 g) in glacial acetic acid (6 mL) was added portion 60 8-azaspiro-4.5-decane (0.14 g). The resulting mixture was wise, N-iodosuccinimide (1.08 g). The resulting mixture was stirred at 70° C. for 18 hours under a nitrogen atmosphere. stirred at 70° C. for 18 hours. The reaction was cooled to room The reaction was then cooled to room temperature, diluted temperature and concentrated on a rotary evaporator. The with CHCl, filtered through celite and concentrated on a residue was taken up in CH2Cl and washed with Saturated rotary evaporator. The crude product was purified by flash aqueous NaHCO and brine. The organic layer was dried over 65 chromatography on silica gel using hexane/ethyl acetate to anhydrous NaSO4, filtered and concentrated on a rotary give 0.21 g of the desired product as a beige solid; MS (ES) evaporator. The crude product was purified by flash chroma m/z (relative intensity); 399 (M+H)" (100). US 7,671,056 B2 95 96 4) 1-3-(Trifluoromethyl)cquinolin-8-yl)piperidin-4- 1) 8-4-(1-Benzylpiperidin-4-yl)piperazin-1-yl)-6- one (intermediate) methoxyquinoline (intermediate) / \ ) N CF 2 10 SCO V To a stirred mixture of 6-methoxy-8-piperazinoquinoline 15 (Example A, Step 4, 0.24 g) and 4-benzyl-1-piperidinone (0.20 mL) in methanol (12 mL) was added glacial acetic acid (0.06 g), followed by sodium cyanoborohydride (0.123 g). The resulting mixture was stirred at room temperature for 18 hours. The reaction was then concentrated on a rotary evapo A solution of 8-(1.4-dioxa-8-azaspiro4.5 dec-8-yl)-3-(tri rator and re-dissolved in CHC1. The solution was washed fluoromethyl)cquinoline (Step 3, 0.19 g) in tetrahydrofuran (3 with water and brine and then dried over anhydrous NaSO, mL) was treated with 2Naqueous HCl (1 mL) and then stirred filtered and concentrated on a rotary evaporator. The crude at 40° C. for 18 hours. The mixture was cooled to room product was purified by flash chromatography on silica gel using hexane/ethyl acetate to give 0.23g of the desired prod temperature and concentrated on a rotary evaporator. The 25 residue was taken up in CHCl, washed with water and brine, uct as an off-white solid; MS (ES) m/z (relative intensity); dried over anhydrous NaSO, filtered and concentrated on a 417 (M+H)" (100). rotary evaporator to give 0.11 g of the desired product as a 2) 6-Methoxy-8-(4-piperidin-4-ylpiperazin-1-yl) yellow oil; MS (ES) m/z (relative intensity); 295 (M+H)" quinoline (intermediate) (100). 30

5) 8-4-4-(6-Methoxyquinolin-8-yl)piperazin-1-yl) piperidin-1-yl)-3-(trifluoromethyl)guinoline 35 N\ / -On A mixture of 6-methoxy-8-piperazinoquinoline (Example A, Step 4: 0.0825g) and 1-3-(trifluoromethyl)cquinolin-8-yl) O piperidin-4-one (0.1 g) in methanol (5 mL) was treated with 40 sodium cyanoborohydride (Step 4, 0.032 g). The resulting mixture was stirred at room temperature for 18 hours and then A solution of 8-4-(1-benzylpiperidin-4-yl)piperazin-1- concentrated on a rotary evaporator. The residue was taken up yl-6-methoxyquinoline (Step 1, 0.22 g) and vinylchlorofor in CHC, washed with water and brine, dried over anhydrous mate (0.067 mL) in anhydrous CHCl (5 mL) was stirred at NaSO, filtered and concentrated on a rotary evaporator. The 45 reflux for 1 hour. The reaction was cooled to room tempera crude product was purified by flash chromatography on silica ture and then concentrated on a rotary evaporator. The residue gel using hexane/ethyl acetate to give the desired product, was taken up in dioxane (5 mL), treated with concentrated which was converted to its dihydrochloride salt in using 1N HCl (0.35 mL) and stirred at room temperature for 1 hour. The HC1/EtO to yield 0.035 g as a yellow solid; MS (ES) m/z resulting reaction was concentrated on a rotary evaporator, 50 taken up in ethanol (1 mL) and stirred at 50° C. for 30 minutes. (relative intensity): 522 (M+H)" (100). The reaction was again concentrated on a rotary evaporator and partitioned between CHCl and 1 Naqueous NaOH. The M) 6-Methoxy-8-4-1-(quinolin-8-ylmethyl)piperi organic layer was washed with water and then brine and was din-4-yl)piperazin-1-ylquinoline (Table 1, #23) then dried over anhydrous NaSO filtered and concentrated 55 on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using ethyl acetate/metha nol/conc, NHOH to give 0.14 g of the desired product as a yellow oil; MS (ES) m/z (relative intensity); 326 (M+H)" (100). 60 3) 6-Methoxy-8-4-1-(cquinolin-8-ylmethyl)piperi din-4-yl)piperazin-1-ylquinoline (final product) SCO NF To a mixture of 6-methoxy-8-(4-piperidin-4-ylpiperazin 65 1-yl)cquinoline (Step 2, 0.06 g) and 8-(bromo)methylduino V line (commercially available, 0.055 g) in anhydrous dimeth ylsulfoxide (5 mL) was added anhydrous KCO (0.051 g). US 7,671,056 B2 97 98 The resulting mixture was stirred at 70° C. for 18 hours. The anhydrous MgSO4, filtered and concentrated on a rotary reaction mixture was cooled to room temperature and parti evaporator to give the desired product (0.5 g) as a yellow tioned between ethyl acetate and water. The organic layer was solid; MP. 70-73° C.; MS (ES) m/z (relative intensity) 179 washed with water and brine and was then dried over anhy (M+H)" (100). drous Na2SO4, filtered and concentrated on a rotary evapora tor to give the desired product, which was converted to its dihydrochloride salt in CHCl using 1N HC1/EtO to give 2) 6-Chloro-8-piperazin-1-yl-quinoline 0.31 g of a light yellow solid; MS (ES) m/z (relative inten sity); 468 (M+H)" (100). 10 N) Preparation of 8-4-1-(8-quinolinyl)-4-piperidi nyl-1-piperazinylquinoline (Table 1, #3) / \ N

(CICH2CH2)2N HCI 15 NH2 --- / \ / \ C / \ 8 CO 8 N Using the synthetic methods described in previous N NH examples, 8-(piperazin-1-yl)guinoline (Oruz et al., J. Med. \ / 25 Chem. 45:4128 (2002)) and 1-quinolin-8-yl-piperidin-4-one C (Example A, Step 5, above) were reacted with sodium triac etoxyborohydride to give the desired product as a light yellow solid; MP 194-196° C.; MS (ES) m/z (relative intensity) 424 8-amino-6-chloroquinoline (Step 1, 0.49 g) and bis(chlo (M+H)" (100). roethyl)amine hydrochloride (0.49 g) were dissolved in chlo 30 O) Preparation of 6-chloro-8-4-4-(6-chloro-8- robenzene (13 mL) and heated with vigorous stirring at 135° quinolinyl)-1-piperazinyl)-1-piperidinylquinoline C. for 5 days. The reaction was cooled to room temperature, diluted with water and extracted with EtO. The aqueous (Table 1, #4) phase was made basic by addition of solid NaCO3 and then 35 extracted with EtO. The combined organic layers were dried over anhydrous Na2SO, filtered and concentrated on a rotary evaporator to give the desired compound (0.20 g) as a yellow / \, \ \ semi-solid; MS (ES) m/z (relative intensity) 248 (M--H)" (100). 40 3) Preparation of 6-chloro-8-4-4-(6-chloro-8- C CO 8 quinolinyl)-1-piperazinyl)-1-piperidinylquinoline 45

1) 6-Chloro-8-aminoquinoline C N

2 -- 50 N / \ / \, Fe -- NO AcOH NH2 CN 55 H 21 C C C NaBH(OAc)3 N N To a hot suspension of 6-chloro-8-nitroquinoline (Mosher, 60 et al., Org. Syn. 27:48 (1947), 0.8 g) in a mixture of ethanol/ glacial acetic acid/water (2:2:1, 25 mL) was added iron pow der (0.5 g) portionwise. The resulting mixture was stirred at reflux for 1.5 hours. The reaction was the cooled to room temperature, filtered through celite and made basic by addi 65 tion of Solid Na2CO. The aqueous mixture was extracted CO with EtO. The combined organic layers were dried over US 7,671,056 B2 99 100 R) Preparation of 5-chloro-8-4-1-(8-quinolinyl)-4- -continued piperidinyl-1-piperazinylquinoline (Table 1, #8) / \ / \ Co-C8 3/ \ O C3/ \ Using the synthetic methods described in previous 1) 5-Chloro-8-(trifluoromethylsulfonyloxy)guinoline examples, 6-chloro-8-(piperazin-1-yl)guinoline (Step 2) and 15 1-quinolin-8-yl-piperidin-4-one (Example 1, Step 1, above) were reacted with sodium triacetoxyborohydride to give the desired product as an off-white solid; MP 269-271° C.; MS C (ES) m/z (relative intensity) 493 (M+H)" (100). P) Preparation of 8-4-1-(6-chloro-8-quinolinyl)-4- N piperidinyl-1-piperazinyl-6-fluoroquinoline 2 (Table 1, #5) N 25 OSOCF

To a Suspension of 5-chloro, 8-hydroxy-quinoline (com mercially available, 8.95 g) in 100 ml CHCl, TEA is added 30 (20 ml). The mixture becomes homogeneous and is then cooled to -15°C. The suspension dissolved, then cooled to -15°C. A solution of 21.1 g of triflic anhydride in 50 ml of CHCl is added drop by drop with cooling. After complete addition, the reaction was stirred at -15° C. for hour. The 35 reaction was diluted with CHC1 washed with a solution of NaHCO, then with water dried and the solvent was removed to give 15.0 g of product. MP: 80-83° C. MS (ES) m/z (rela tive intensity): 312 (M+-H, 100 C 21 40 2) 5-Chloro-8-(4-tert-butoxycarbonyl)-piperazin-1- NaBH(OAc)3 ylquinoline N N

45 C

N CO 2 50 N / \ / \

55 3 O C3 OBOC To a mixture of 5-chloro-8-(trifluoromethylsulfonyloxy) Using the synthetic methods described in previous 60 quinoline (Step 1, 4.0 g) in tetrahydrofuran (30 mL), was added 5.9 g of cesium carbonate (5.9 g), 2,2'-bis(diphe examples, 6-fluoro-8-(piperazin-1-yl)guinoline (Example B. nylphosphino)-1,1'-binapthyl (BINAP, 0.36 g), palladium Step 3, above) and 1-quinolin-8-yl-piperidin-4-one (Example acetate (0.12 g) and tert-butoxycarbonylpiperazine (2.8 g). I, Step 1, above) were reacted with sodium triacetoxyboro The mixture was refluxed for 5 hours. The reaction mixture hydride to give the desired product as a white solid; MP. 65 was then cooled to room temperature, diluted with EtO. 256-258° C.; MS (ES) m/z (relative intensity) 477 (M+H)" filtered through celite and concentrated on a rotary evapora (100). tor. The crude material was purified by flash chromatography US 7,671,056 B2 101 102 on silica gel using CH2Cl to give 2.4 g of the desired product as an off-white solid; MP. 127° C. MS (ES) m/z (relative -continued intensity): 348 (M+H)" (100). NaBH(OAc)3 3) 5-Chloro-8-piperazinoquinoline --

C 10 N

2 O 15 8ccC-C 83 To a solution of 5-chloro-8-(4-tert-butoxycarbonyl)-pip Using the synthetic methods described in previous erazin-1-ylquinoline (Step 2, 2.2g) in dioxane (10 mL), was examples, 2-methyl-8-(piperazin-1-yl)guinoline (Oruz, et added 4 NHCl/dioxane (5 mL). The mixture was stirred at al., J. Med. Chem. 45:4128 (2002)) and 1-quinolin-8-yl-pip room temperature overnight. The formed precipitate was col 25 eridin-4-one (Example A, Step 5, above) were reacted with lected by vacuum filtration, dissolved in water, made basic sodium triacetoxyborohydride to give the desired product as with solid NaHCO and extracted with CHC1. The com a light brown semi-solid; MS (ES) m/z (relative intensity) 438 bined organic layers were dried over anhydrous Na2SO4. (M+H)" (100). filtered and concentrated on a rotary evaporator to give 1.0 g of the desired product as a brown semi-solid; MS (ES) m/z. 30 T) Preparation of 6-chloro-8-4-1-(8-quinolinyl)-4- (relative intensity): 248 (M+H)" (100). piperidinyl-1-piperazinylquinoline (Table 1, #11) 4)5-Chloro-8-4-1-(8-quinolinyl)-4-piperidinyl)-1- piperazinylquinoline 35

/ \ / \ C CO 8 40 O 45 Using the synthetic methods described in previous NaBH(OAc)3 examples, 5-chloro-8-(piperazin-1-yl)guinoline (Step 3) and He 1-quinolin-8-yl-piperidin-4-one (Example A, Step 5, above) were reacted with sodium triacetoxyborohydride to give the CC desired product as a beige solid; MP. 201-203° C.; MS (ES) 50 m/z (relative intensity) 459 (M+H)" (100). S) Preparation of 2-methyl-8-4-1-(8-quinolinyl)-4- piperidinyl-1-piperazinylquinoline (Table 1, #10) 55 / \ / \ N

60 C 3 O C3 Using the synthetic methods described in previous 65 examples, 6-chloro-8-(piperazin-1-yl)guinoline (Example O. O step 2, above) and 1-quinolin-8-yl-piperidin-4-one (Example A, Step 5, above) were reacted with sodium triacetoxyboro US 7,671,056 B2 103 104 hydride to give the desired product as a white solid; MP. (triphenylphosphine)-palladium (O) (0.04 g) and tert-butoxy 209-211° C.; MS (ES) m/z (relative intensity) 459 (M+H)" carbonyl-piperazine (2.33 g). The mixture was refluxed for 3 (100). hours under a nitrogen atmosphere. The reaction was then cooled to room temperature, diluted with ether, filtered U) Preparation of 8-4-1-(8-quinolinyl)-4-piperidi through celite and concentrated on a rotary evaporator. The nyl-1-piperazinyl-5-(trifluoromethyl)guinoline crude material was purified by flash chromatography on slilca (Table 1, #12) gel using 100% CHCl to give 0.85g of the desired product as an off-white solid; MP 105-107°C.; MS (ES) m/z (relative intensity): 332 (M+H)" (100). 10 / \ / \ 3) 8-(1-piperazinyl)-5-(trifluoromethyl)cquinoline

15 3 O C3 CF3 N

1) 8-Bromo-5-(trifluorommethyl)guinoline 2

CF CF

25 glycerol N -e- O 2 NH2 N To a solution of tert-butyl 4-5-(trifluoromethyl)-8-quino Br Br linyl-1-piperazine-carboxylate (Step 2, 0.85g) in 5 mL diox 30 ane was added 5 mL of 4 NHCl/dioxane. The mixture was To a mixture of 2-bromo-4-(trifluoromethyl)aniline (com stirred at room temperature overnight. The reaction was con mercially available, 5.0 g), glycerol (3.8 g) and m-nitroben centrated on a rotary evaporator, dissolved in water, neutral Zene sulfonic acid sodium salt 7.0 g) was added 18 ml of 70% ized with aqueous sodium hydroxide and extracted with Sulfuric acid dropwise. The reaction temperature was raised 35 CHC1. The combined organic layers were dried over anhy to 150° C. for 4 hours. The mixture then was cooled to room drous NaSO filtered and concentrated on a rotary evapora temperature, poured on ice water and filtered through celite. tor to give 0.65 g of the desired product as an off-white solid; The filtrate was neutralized with NaOH and the resulting MP. 155-157° C.; MS (ES) m/z (relative intensity): 282 precipitate was collected by vacuum filtration to yield 3.00 g (M+H)" (100). of the title compound as a brown solid that was used without 40 further purification; MS (ES) m/z (relative intensity): 277 4) 8-4-1-(8-quinolinyl)-4-piperidinyl)-1-piperazi (M+H)" (100). nyl-5-(trifluoromethyl)-quinoline 2) Tert-butyl 4-5-(trifluoromethyl)-8-quinolinyl)-1- piperazinecarboxylate 45 CF N CF3 50 N N 2 N

55 ON O H --k 60 To a mixture of 5-bromo-8-trifluoromethylsulfonyloxy) quinoline (Step 1, 2.83 g) in anhydrous tetrahydrofuran (38 mL), was added tris(dibenzylideneacetone)dipalladium(0) 65 (Pd(dba), 0.04 g) sodium tert-butoxide (5.1 g), 2,2'-bis C (diphenylphosphino)-1,1'-binapthyl (BINAP, 0.04g), tetrakis US 7,671,056 B2 105 106

-continued -continued - Co-C3/ \ 8 8/ \ cc \ 3\ Using the synthetic methods described in previous 10 examples, 5-(trifluoromethyl)-8-(piperazin-1-yl)guinoline Using the synthetic methods described in previous (Step 3) and 1-quinolin-8-yl-piperidin-4-one (Example A, examples, 5-fluoro 8-(piperazin-1-yl)guinoline (Prepared Step 5, above) were reacted with sodium triacetoxyborohy from commercially available 5-fluoro-8-hydroxyquinoline dride to give the desired product as a white solid; MP. 202 using the methodology described for Example R, step 3. 204°C.; MS (ES) m/z (relative intensity) 492 (M+H)" (100). 15 above) and 1-quinolin-8-yl-piperidin-4-one (Example A, Step 5, above) were reacted with sodium triacetoxyborohy V) 5-Methoxy-8-4-1-(8-quinolinyl)-4-piperidinyl dride to give the desired product as a yellow solid; MP 222 1-piperazinyl-quinoline (Table 1, #14) 224°C.; MS (ES) m/z (relative intensity) 442 (M+H)" (100). No Y) 8-4-4-(1-Benzofuran-3-yl)-1-piperazinyl)-1- piperidinyl-6-chloroquinoline (Table 1, #16) N N

2 2 NaBH(OAc)3 25

N

30 C -- CO NaBH(OAc)3 / \ / \ 35 N H /O N\ / -O / \ Using the synthetic methods described in previous 40 examples, 5-methoxy-8-(piperazin-1-yl)guinoline (prepared from 2-chloro-5-methoxyaniline using the methodology Cb/ CO described for the preparation of Example N. Step 3, above) and 1-quinolin-8-yl-piperidin-4-one (Example A, Step 5. 45 above) were reacted with sodium triacetoxyborohydride to Using the synthetic methods described in previous give the desired product as a beige solid; MP. 218-220° C.; examples, 1-(1-benzofuran-3-yl)piperazine (Prepared from MS (ES) m/z (relative intensity) 454 (M+H)" (100). commercially available benzofuran-3-one using the method ology described for Example F. Step 2, above) and 1-quinolin X) Preparation of 5-fluoro-8-4-4-(8-quinolinyl)-1- 50 8-yl-piperidin-4-one (Example A, Step 5, above) were piperazinyl-1-piperidinylquinoline (Table 1, #15) reacted with sodium triacetoxyborohydride to give the desired product as a yellow solid; MP. 86-88° C.; MS (ES) m/z (relative intensity) 447 (M+H)" (100).

F 55 Z) Preparation of 5-fluoro-4-methoxy-8-(4-(4-(6- methoxyquinolin-8-yl)piperazin-1-yl)piperidin-1-yl)- 2-(trifluoromethyl)cquinoline and Intermediates 2 | 2 NaBH(OAc)3 N N 60 N CO CO O O HN

C.N C. -----, C F H 65 PPA O US 7,671,056 B2 107 108 2) 8-Chloro-5-fluoro-4-methoxy-2-(trifluoromethyl) -continued quinoline FC FC / \ OH / \ OCH 5 -- CHI C F C F N 10 5196 100% 2 O CYMAP, Pd(dba)3 -- OX)O NaOt-Bu 15 To a solution of 8-Chloro-5-fluoro-2-(trifluoromethyl) FC quinolin-4-ol (Step 1.3.54g, 13.3 mmol. 1 eq.) in acetone (75 mL) was added anhydrous KCO (3.88 g, 28.0 mmol. 2.1 / \ OCH eq.), followed by iodomethane (1.8 mL, 28.9 mmol. 2.17 eq.). The resulting mixture was stirred at reflux for 1.5 hours. An 2O additional aliquot of iodomethane (1.8 mL, 28.9 mmol. 2.17 eq.) was added and reflux was continued for an additional 1 hour. The reaction was cooled to room temperature, poured CXC-O-4% onto ice and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO, filtered 25 and concentrated on a rotary evaporator to give 3.72 g (100% yield) of the desired productasayellow solid, which was used / \ OCH in Subsequent reactions without further purification. An ana N lytical sample was prepared by recrystallization from hexane/ ethyl acetate; MP=198-200° C.; MS (ES) m/z (relative inten o-O F 30 sity): 280 (M+H)" (100). 3) 8-(1,4-Dioxa-8-azaspiro4.5 dec-8-yl)-5-fluoro-4- 770, methoxy-2-(trifluoromethyl)-quinoline

35 F 1 1) 8-Chloro-5-fluoro-2-(trifluoromethyl)cquinolin-4-ol N

40 2 N CF F OH N N 45 2 N CF O O C

50 A solution of ethyl 4.4.4-trifluoroacetoacetate (commer To a solution of 8-chloro-5-fluoro-4-methoxy-2-(trifluo cially available, 4 mL. 27.3 mmol. 1.05 eq.) in polyphospho romethyl)cquinoline (Step 2, 1.24 g, 4.45 mmol. 1 eq.) in ric acid (22 mL) was heated to 100° C. 2-chloro-5-fluoroa anhydrous tetrahydrofuran (44 mL) was added tris(diben niline (3.78 g. 26.0 mmol. 1 eq.) was added slowly to the Zylideneacetone)-dipalladium(0) (Pd(dba), 0.125 g, 0.14 stirred hot solution. The resulting reaction mixture was fur 55 mmol, 0.03 eq.), sodium tert-butoxide (0.69 g, 7.18 mmol. ther heated to 150° C. and then stirred at that temperature 1.61 eq.), 2-dicyclohexyl-phosphino-2'-(N,N-dimethy overnight (approximately 18 hours). The reaction was cooled lamino)biphenyl (CYMAP, 0.054 g., 0.14 mmol, 0.03 eq.), to room temperature and water was added carefully. The and 1,4-dioxo-8-azaspiro-4,5-decane (0.8 mL, 6.24 mmol. resulting light brown precipitate was collected by vacuum 1.4 eq.). The resulting mixture was stirred at 70° C. overnight 60 (approximately 18 hours) under a nitrogen atmosphere. The filtration, washed with water and dissolved in ethyl acetate. reaction was then cooled to room temperature, diluted with The ethyl acetate solution was washed with brine, dried over ether, filtered through a plug of silica gel and concentrated on anhydrous MgSO and concentrated on a rotary evaporator. a rotary evaporator. The crude product was purified by flash The crude product was purified by flash chromatography on chromatography on silica gel using hexane/ethyl acetate to silica gel using hexane/ethyl acetate to give 3.54 g (51% 65 give 1.09 g (64% yield) of the desired product as a beige solid; yield) of the desired product as an off-white solid; MP=141 MP=101-103° C.; MS (ES) m/z (relative intensity): 387 142; MS (ES) m/z (relative intensity): 266 (M+H)" (100). (M+H)" (100). US 7,671,056 B2 109 110 4) 1-(5-Fluoro-4-methoxy-2-(trifluoromethyl)cquino mmol. 1 eq.) and 6-methoxy-8-(1-piperazinyl)cquinoline (EX lin-8-yl)piperidin-4-one ample A, Step 4, 0.30 g, 1.23 mmol. 1.37 eq.) in anhydrous methanol (20 mL) was added sodium cyanoborohydride (0.103 g, 1.64 mmol. 1.82 eq.). The resulting mixture was stirred overnight at room temperature under nitrogen (app. 18 F 1 hr). An additional aliquot of sodium cyanoborohydride (0.10 g, 1.59 mmol. 1.76 eq.) was added and stirring at room tem perature was continued overnight. The resulting reaction N mixture was poured into brine and extracted with ethyl 10 2 acetate. The organic layer was dried over anhydrous Sodium N CF Sulfate and concentrated on a rotary evaporator to a yellow oil. The desired product was isolated by chromatography on a 40 N g silica column (1000 mL 20% acetone in hexane followed by 500 mL 30% acetone in hexane) as a yellow solid (0.113 g, 15 22% yield). The free base was converted to its trihydrochlo ride sesquihydrate salt by dissolving it in dichloromethane (3 mL), adding diethyl ether (9 mL), cooling in an ice bath and O adding 1M HCl/Et2O (1 mL). The resulting yellow solid was collected by vacuum filtration, washed with ether and dried in To a solution of 8-(1,4-dioxa-8-azaspiro4.5 dec-8-yl)-5- vacuo to give 0.152 g. MS (ES) m/z (relative intensity): 570 fluoro-4-methoxy-2-(trifluoro-methyl)cquinoline (Step 3, 0.6 (M+H)" (100). g, 1.56 mmol. 1 eq.) in tetrahydrofuran (20 mL) was added 2N aqueous HCl (6 mL). The resulting mixture was stirred at 70° AA) Preparation of 5-fluoro-8-(4-(4-(6-methox C. for 5 hours. The reaction was cooled to room temperature, yduinolin-8-yl)piperazin-1-yl)piperidin-1-yl)guino poured into 1 Naqueous sodium hydroxide and extracted with 25 line trihydrochloride dihydrate ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate to give 0.41 g of the desired product as a light yellow solid; MP=171-173 C; MS 30 N (ES) m/z (relative intensity): 343 (M+H)" (100). \ /

5) 5-fluoro-4-methoxy-8-(4-(4-(6-methoxyquinolin N NH + 8-yl)piperazin-1-yl)piperidin-1-yl)-2-(trifluorom \ / ethyl)cquinoline trihydrochloride 35 H3CO \ \ 1) NaBHCN 40 o-O F 2) HC/EtO N M \ 45 \ / N N N F \ / -O OCH H3CO 50 1) NaBHCN --- 2) HC/EtO o-O F 0.25 g (0.001 mol) of 1-(5-fluoro-quinolin-8-yl)-piperidin 4-one (Example C, Step 3) and 0.25 g (0.001 mol) of 6-meth oxy-8-piperazin-1-yl-quinoline (Example A, Step 4) were stirred in 20 mL of anhydrous methanol. 1.1 eq, (0.07 gm) of N / \ OCH Sodium cyanoborohydride was added and the reaction was stirred at room temperature for eighteen hours. The reaction \ / } 3 mixture was concentrated on a rotary evaporator and the 60 residue was taken up in ethyl acetate and washed with water. N\ / -O F The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator. The desired product was obtained by flash chromatography on silica gel column using ethyl acetate and converted to the trihydrochlo 65 ride salt using methanolic HCl to yield 0.15gm (24%) of the To a solution of 1-5-fluoro-4-methoxy-2-(trifluorom title compound as a yellow solid. Mp: 200-202°C.; MS (ES) ethyl)cquinolin-8-ylpiperidin-4-one (Step 4, 0.31 g, 0.9 m/Z (relative intensity): 472 (M--H)+ (100). US 7,671,056 B2 111 112 BB) Preparation of 5-Fluoro-8-(4-(4-(6-methox yduinolin-8-yl)piperazin-1-yl)piperidin-1-yl)-quino -continued line and Intermediates F t-BuONa, Pd(dba)3, N ---BINAP Toluene -- 2 O N NH Br O 10 750 C. 15 F

N 15 2 N HCI 2 Her N NaON He CON IPAC C D 2HC OC O N H 25 F

N

2 Adipic 30 N Acid

ON 35 H CO O N COOH NaOH He 40 2 CHCl2 N EtOAc Toluene

-O 45 COOH CN H / \ / \ O N 50 3 to Yo O-O. F 2 -O N

55 1) 6-methoxy-8-(1-piperazinyl)cquinoline CN H A mixture of 8-amino-6-methoxyquinoline (150.0g, 0.862 Br mol) and bis(2-chloroethyl)amine (219 g, 1.23 mol) in 6 60 parts (volume of hexanol vs weight of 8-amino-6-methox NH2 ycuinoline) of 1-hexanol (900 mL) was heated to 145° C. and Glycerol He stirred for 21 hours. Upon completion, the reaction mixture is H2SO4 4-nitrophenol cooled 50-60° C., and 507 g of aqueous NaOH solution was 135-145° C. added slowly. The reaction mixture was cooled to 25-30°C. 2h 65 and isopropyl acetate (750 mL) was added. The mixture was clarified through a celite pad. The aqueous phase was then split off. The organic solution was treated with a slurry of US 7,671,056 B2 113 114 adipic acid (126g, 0.862 mol) in isopropyl acetate (250 ml). Alternatively, 8-bromo-5-fluoroquinoline was prepared by The resulting mixture was stirred for 16 hours to form adding a warm mixture containing 2-bromo-5-fluoroaniline 6-methoxy-8-(1-piperazinyl)cquinoline adipate salt. The adi (100 g, 1.0 eq), 4-nitrophenol (40 g, 0.54 eq), and glycerol (97 pate salt was filtered and washed with isopropyl acetate g, 2.0 eq) over 1.5 hours to sulfuric acid (267ml) and water (2x150 ml) and dried by nitrogen flow to give adipate of 5 (114 mL) at 140-150° C. The initial mixture showed 37.8% 6-Methoxy-8-piperazin-1-yl-quinoline (186 g, 55% yield) 4-nitrophenol by relative HPLC area %. Samples showed with -97% HPLC area, 88% strength purity in 51% yield. 4.7% 4-nitrophenol immediately after adding 50% of mixed The salt can be recrystallized from a mixture of methanol starting materials and 5.0% immediately after adding all of and isopropyl acetate if further purification is required. To the materials. The yield upon workup was 87.5%, with total 10 impurities 0.29%. Addition of less (0.46 eq, 34 g) 4-nitrophe purify the adipate salt, 580 g of the crude adipate salt and 2.8 nol also successfully produced the intermediate of interest at liter of methanol were mixed and heated to 65° C. and a dark acceptable yield. Solution was obtained. To this solution was charged slowly 1.1 liter of isopropyl acetate over 40 min at about 63°C. The 3) 1-(5-fluoroquinolin-8-yl)piperidin-4-one mixture was stirred at about 63°C. for about 1 hand cooled to 15 0-5°C. After stirring at 0-5°C. for 2 hours, the mixture was To a 5-L jacketed cylindrical reactor equipped with an filtered and washed with 300 ml ofisopropyl acetate and dried impeller-style agitator, condenser, thermocouple, and with airflow. Yield, 395 g, 68.1% recovery yield. vacuum/nitrogen inlet was charged 2-L. 15% toluene Solution To liberate 6-methoxy-8-(1-piperazinyl)cquinoline from its of8-bromo-5-fluoroquinoline, 209 g of 1,4-Dioxa-8-azaspiro adipate salt, 100 g (0.257 mol) of the adipate salt was added 4.5 decane. Meanwhile in a 500-mL Erlenmeyer flask, a into a 2-L reactor followed by the addition of 500 ml of suspension of 16.5 g (26.5 mmol)+-1,1'-binaphthalene-2,2'- dichloromethane. To this mixture was added 100 g of water diylbis diphenyl-Phosphine, and 6.08 g (6.64 mmol) trisul followed by the slow (in about 15 min) addition of 41 g of (1.2-m:4.5-m)-(1E.4E)-1,5-diphenyl-1,4-pentadien-3-one 50% sodium hydroxide solution to maintain the pH in the dipalladium in 260 g of toluene was prepared. This freshly 13-14 range, adding sodium hydroxide Solution as necessary 25 made Suspension was charged into the 5-L reactor followed if the pH is below 10. The organic bottom layer was separated by a rinse of 170g of toluene. 166 g sodium tert-butoxide was and filtered through a pad of activated basic aluminum oxide then charged into the reactor followed by a rinse with 430g of (100 g. 6.5 cm diameterx3 cm depth). The pad was washed toluene. The reactor was degassed by vacuum to less than 125 with 100 ml ofisopropyl acetate twice. The dichloromethane mmHg and then filled with nitrogen to atmosphere three was replaced by toluene by distillation under vacuum (450 to 30 times. The mixture was then heated to 50-60° C. and stirred 500 mm Hg) while 3x150 ml of toluene was added into the for 1 h and then heat to 65-75° and stirred at this temperature reactor until the final Volume was about 135 ml. Some white for about 10 hours. The mixture was cooled to 40-50° C. and solid precipitated after distillation, the solid was removed by then quenched with 800g of water. The lower aqueous layer filtration, the filter cake was washed with 50 ml of toluene. was split off and the volume of the organic layer was reduced Final volume, 185 ml, purity 97.56%, solution strength 35 to about 1.5 L by vacuum distillation. To this residual was 27.4%) charged 2.28 kg of 20% sulfuric acid at 25-30°C. The mixture was stirred for an hour and was clarified by filtration and a 2) 8-bromo-5-fluoroquinoline bi-phase filtrate was obtained. The aqueous phase was split and retained. Toluene 870 g was added to the aqueous solu To a 2-L reactor equipped with a mechanic agitator, a 40 tion and the mixture was neutralized by slowly adding 770 g condenser, a thermocouple, a baffle, and nitrogen inlet were 50% sodium hydroxide solution. The lower aqueous layer charged 228g of water, 200 g of 2-bromo-5-fluoroaniline and was split off and extracted with 600 g of toluene. The organic 80 g of 4-nitrophenol. To this mixture was charged 96% layers were combined and the volume of the reaction was sulfuric acid in 10-30 min at 20-120° C. The mixture was reduced to about 1 L by vacuum distillation. The residue was heated to 135-140°C. and 194g of glycerol was charged into 45 cooled to room temperature and 480 g of toluene was charged. the reactor over two hours at 135-145° C. The mixture was The mixture was heated to 45-55° C. to form a clear solution, held at 135-145° C. for 1 hour after the addition. The reaction which was filtered through a celite/charcoal pad to remove mixture was cooled to below 20-50° C. and slowly transferred palladium. The filtrate was concentrated by vacuum distilla to a 5-L reactor containing 1100 g of water and 1210 g of tion to about 0.7 L and diluted with 620 g heptane, cooled to toluene. The 2-L reactor was washed with 300 g of water and 50 -15 to -5°C. to form a slurry. The solid was collected by the wash was combined into the 5-L reactor. The pH of the filtration. The product was dried by airflow at room tempera contents in the 5-L reactor was adjusted to pH 8-10 by adding ture. Typical yield is about 70%. approximately 1233 g (1370 mL) ammonium hydroxide (28 30% NH) at 20-40° C. The mixture was stirred at room 4) 5-fluoro-8-4-4-(6-methoxyquinolin-8-yl)piper temperature for 15 min and the solid by-product was filtered 55 azin-1-yl)piperidin-1-ylquinoline off while the filtrate was retained. The filter cake was washed with 400 ml of toluene and the all the filtrate was combined Toluene (118 g), sodium triacetoxyborohydride (44.5 g) and charged a 3-L reactor. About 500 ml of 8.5% KOH solu were mixed at 0°C. to room temperature. To this mixture was tion was charged into the 3-L reactor and stirred for 10 min charged a premixed toluene Solution of 6-methoxy-8-(1-pip and bottom aqueous layer was spit off. A second portion of 60 erazinyl)cquinoline (Step 1, 160g, 27.4 wt % in toluene) and 500 ml of 8.5% KOH solution was added and the mixture was 1-(5-fluoroquinolin-8-yl)piperidin-4-one (Step 3, 41 g). The stirred for 15 min and the bottom aqueous layer was split off. resulting mixture was stirred for 2 to 3 hours at about 30° C. Water 500 ml was added and Stirred for 15 min before the KOH solution (443 g 9% in water) was charged to quench the bottom aqueous layer was split off. The organic layer was residual sodium triacetoxyborohydride. Heptane (118 g) was heated to distill off about 100-200 ml of toluene to azeotro 65 added to further precipitate the product. The product was then pically remove water. A clear solution will be obtained. Typi filtered and washed with ethanol (2x100 ml). Yield 68g, 86%. cal yield 178 g real 8-bromo-5-fluoroquinoline, ~75%. This crude product (67 g) was dissolved in 586 g dichlo US 7,671,056 B2 115 116 romethane and passed through a charcoal/celite pad to To a 1-L reactor a mechanic stirrer, a thermocouple, and remove palladium. The dichloromethane was distilled off nitrogen inlet was charged with 380 g of butanol, 42 g of while 400g of ethanol was slowly added at the same time. The 8-amino-6-methyoxyquinoline, and 97 g of compound B resulting slurry was filtered and washed with ethanol twice (nor-mustard free amine). The mixture was heated to 100° C. (65 g+100 g). The product was dried in oven at 55° C. over for 18 hours before cooled to 0-5°C. The Solid was formed night. Purification recovery yield 59.9 g, 89.4%. upon cooling and was filled with nitrogen protection (Solid is hygroscopic). The filter cake was washed with 100 g cold CC) 6-methoxy-8-(1-piperazinyl)cquinoline butanol and 2x200 g of MTBE. The solid was dissolved in 160 g of water to obtain an orange solution. This orange Solution was slowly charged into a 2-L reactor containing a 10 potassium hydroxide solution prepared with 537g water and 60 g 45% KOH. The product was precipitated upon addition into the base. The slurry was stirred for 1 h and then filtered. NBn HCI MTBE NBI -- The filter cake was washed with 100 g water, 100 g MeOH and 100 g methyl tert-butyl ether. The product was dried 15 C C under vacuum at 50° C. Weight=48.2g, 60% To a 100 ml flask equipped with a stirrer, a thermocouple, A B a condenser and nitrogen inlet was charged ethanol (2B) 27 g. 1. O N compound C (2 g), methylcyclohexene (10g) and 0.6 g of dry BOH 10% palladium on carbon. The mixture was heated to reflux He for 30 hand cooled to ambient temperature. The palladium on N 100° C. carbon was filtered off, the solvent was removed by rotavap, and the resulting compound isolated (weight 1.7 g (>100%, the product contained Small amount of solvent)).

25 DD) 1-(5-fluoroquinolin-8-yl)piperidin-4-one 2 N ON coHC 30 H2SO4 CN Bn Br s so C NH2 O 35 Na" 859% OH 2 N He F roo 40 OH OH C F Pd/C, 10% dry Pd(dba)3, NaOt-Bu, Bn N Pd(PPh3)4, CYMAP 45 2 -O N N

2 Br N F F 50 N N

2 2 O N N 55 6-methoxy-8-(1-piperazinyl)cquinoline (Example P. Step 1) is also prepared as shown in the reaction scheme above. To a 2 L reactor equipped with a mechanic stirrer, an addition C N funnel, athermocouple, nitrogeninlet and a bottom outlet was O O added 442 g of water, 134.5 g (0.5 mol) compound A and 177 60 \ / O g methyl tert-butyl ether. To this mixture was slowly added 125 ml 5 N sodium hydroxide in 20 min. The mixture was stirred for 10 min and the aqueous layer was split off. The organic layer was washed with 20% aq. Sodium chloride solu 1-(5-fluoroquinolin-8-yl)piperidin-4-one (Example P. tion twice (2x200 g). The methyl tert-butyl ether was distilled 65 Step 3) is also prepared as shown in the reaction scheme off and the product was obtained as an oil, crude yield: 117 above. To a 500 ml flask equipped with a stirrer, a thermo g-100% yield (still containing trace amount solvent). couple, a condenser and nitrogen inlet were charged 50 g US 7,671,056 B2 117 2-bromo-5-fluoroaniline and 60 g glycerol. The mixture was heated to 60° C. and 55 g nitrobenzene sulfonic acid was -continued charged in portion. The mixture was then heated to 100-110 HOOC COOH C., started charge 200 ml 70% sulfuric acid. After sulfuric FC acid addition, the mixture was heat to 130° C. and stirred for 5 3 hours before cooled to room temperature. Water (300g) was HOOC COOH added and a grayish by product was filtered off. The filtrate was slowly added into a 2-L reactor containing a mix of 420 g 50% NaOH, 420 g of water, 352 g methyl tert-butyl ether. 10 After filtering off Small amount Solid, the aqueous layer was split off and the organic layer was washed with 10% NaOH -O (2x100 ml), 20% NaCl (2x200ml), the solvent was removed, weight 56 g., 89.8%. 15 The free base of 5-fluoro-4-methoxy-8-(4-(4-(6-methoxy To a 2-L reactor with a stirrer, athermocouple, a condenser quinolin-8-yl)-piperazin 1-yl)-piperidin-1-yl)-2-trifluorom and nitrogen inlet were charged 8-bromo-5fluoroquinoline ethyl-quinoline was prepared as described in Example Z. This (50 g), tetrahydrofuran (795 g), Pd2(dba) (3.78 g), Cymap compound was further isolated by conversion to a disuccinic (1.6 g), and 1,4-Dioxa-8-azaspiro4.5 decane (47.3 g). the acid. To a 12-L reactor equipped with heating mantle, ther mixture was heated to reflux (66° C.) and the reaction was mocouple and nitrogen inlet were charged 124 g of Succinic complete. The reaction mixture was quenched into a 5 L acid and 2470 g of acetone. The mixture was heated to 50° C. reactor containing 1000 g of water and 640 g of MTBE. The and a colorless solution was formed. Meanwhile, in a 3-L bottom aqueous layer was split off and the organic layer was flask were charged 240 g of 5-fluoro-4-methoxy-8-(4-(4-(6- washed with 5% NaOH (1120 g) and 20% NaCl (2x100 g). methoxy-quinolin -8-yl)-piperazin-1-yl)-piperidin-1-yl)-2- 25 trifluoromethyl-quinoline and 2250 g of tetrahydrofuran The solvent was evaporated, weight 87 g vs 79.4 g by theory. (THF). 5-Fluoro-4-methoxy-8-(4-(4-(6-methoxy-quinolin The remaining steps are as described above in Example P. 8-yl)-piperazin-1-yl)-piperidin-1-yl)-2-trifluoromethyl Step 3. quinoline in THF mixture was heated to 50° C. and a yellow solution was achieved. This yellow solution was slowly (over 30 the course of about 3 hours) charged into the 12-L reactor DD) Preparation of 6-methoxy-8-4-(1-(5-fluoro)- while maintaining both solutions at a temperature of about quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl)-quino 50° C. The resulting slurry was stirred over night at room temperature, and then cooled to 5-10° C. After stirring at line trisuccinate salt (Polymorph Form A) 5-10°C. for 2 hours, the slurry was filtered and the product 35 was washed with acetone 3x600 ml. The product was dried 6-Methoxy-8-4-(1-(5-fluoro)-quinolin-8-yl-piperidin-4- with airflow at room temperature for 3 hours. yl)-piperazin-1-yl)-quinoline (1.5089 g) was slurried in 100 The weight of the resulting product was 311 g, or about mL of dichloromethane (99.8% HPLC) to obtain a clear light 91.6% yield. NMR analysis indicated that the compound was yellow solution of free base. Succinic acid (99%; 258.6 mg) the disuccinate salt form of 5-fluoro-4-methoxy-8-(4-(4-(6- was dissolved in 17 mLofacetone (99%HPLC). Then 15.275 40 methoxy-quinolin-8-yl)-piperazin-1-yl)-piperidin-1-yl)-2- mL of the succinic acid solution was added to 20 mL of the trifluoromethyl-quinoline. In addition, residual solvents were free base solution slowly. No immediate precipitation was found at concentrations of 0.047% for acetone, 0.027% for observed. The resulting solution was allowed to evaporate to THF, and 0.14% for water. dryness at room temperature. The Solid was analyzed by BIOLOGICAL ASSAYS AND PROCEDURES powder X-ray diffraction and found to be crystalline having 45 Form A. Novel Object Recognition Model EE) Preparation of 5-Fluoro-4-methoxy-8-(4-(4-(6- Male Long-Evans hooded rats (~200 g at the time of test methoxy-quinolin-8-yl)-piperazin-1-yl)-piperidin-1- 50 ing) were individually housed with ad libitum access to food yl)-2-trifluoromethyl-quinoline disuccinate salt and water. Novel object recognition (NOR) training and test ing was performed in a circular field (diameter-70 cm, 30 cm high) constructed out of plastic and containing soiled bedding (without feces). The field was surrounded by black curtains to 55 mask extra-field cues and was located in a dimly lit room (~10 lux at the level of the area) in the presence of white noise (-65 dB). Animal performance was tracked by video and moni tored by an experimenter located outside of the testing room. Objects, constructed with Duplo(R) (Lego), could be affixed to 60 the floor in one of four locations spaced evenly around the field approximately 10 cm from the field's edge. To avoid possible olfactory cues, multiple copies of the objects were used throughout the study and were cleaned with a 30% ethanol solution between animals. He 65 The visual recognition task was divided into 3 sessions— 2 HOOC COOH habituation, a sample trial and a choice trial. During habitu ation the animals were placed into the field containing 2 US 7,671,056 B2 119 120 identical yellow cubes (~10 cmx10 cmx10 cm) and were Novel Object Recognition Model: The Novel Object Rec allowed to explore the field for ten minutes. Following habitu ognition Model was employed as described above. Sub ation, rats were returned to their home cage. One day after threshold doses (doses that did not provide a positive effect on habituation, animals were dosed with a test compound and recognition memory) of Aricept(R) and representative com following the pretreatment interval the sample trial was ini pounds of this invention were administered to test animals tiated. During the sample trial, rats were allowed to explore and their effects on recognition memory were recorded as the field, now containing two identical stimuli (complex, described above. multicolored, Duplo objects; ~10 cmx10 cmx10 cm) located Treatments: Animals were treated with a compound of the at opposing compass points, for 5 minutes. The amount of invention 60 minutes prior to the sample trials. Each candi time investigating the objects was recorded for the entire trial. 10 date compound was dissolved in an appropriate vehicle and Investigation was defined as orientation toward the object administered orally. The same animals were then treated with with the nose of the rat within <2 cm of the object. Following Aricept(R) 30 minutes prior to the sample trials. Aricept(R) was the sample trial rats were returned to their home cages for the dissolved in an appropriate vehicle and administered intrap 48 hour inter-trial interval and then tested in the choice trial eritoneally. for recognition memory. The choice trial consisted of a 5 15 Animals were separately administered sub-threshold doses minute exploration of the field containing both a familiar, of Aricept(R) (0.5 mg/kg i.p.) or a representative compound of previously explored, object and a novel object with an inves the invention (0.1 mg/kg p.o.). When administered separately, tigator again recording contact time. The location of the the contact times for the animals in the familiar and novel objects, counterbalanced across treatment groups, remained environments were not statistically different (P<0.05). Co constant for each animal during the habituation, sample and administration of Aricept(R) and the each of candidate com choice trials. pounds at the same doses used in the separate administration The effect of treatment on object exploration during trial test for each agent resulted in a statistically significant one was examined using a one-way ANOVA on total contact decrease in the contact time for the familiar environment time followed by Fisher's LSD group mean pair-wise com compared to the novel environment (P<0.05). The decrease in parisons. The amount of time exploring the novel and familiar 25 contact time averaged more than 10 seconds. These data objects across treatment groups was analyzed using a Suggest co-administration of a representative compound of repeated measures ANOVA followed by Fisher's LSD post the invention and a cognitive enhancer resulted in a positive hoc comparisons. Significantly more time spent exploring the effect of recognition memory, as demonstrated by the animals novel object than the familiar one represents intact recogni spending significantly more time exploring the novel object tion memory for that treatment group. Control and untreated 30 than the familiar one. These data demonstrate that this test is animals show no significant differences between familiar and effective in identifying a synergistic effect between represen novel object exploration following the 48 hour delay indicat tative compounds and cognitive enhancers to enhance cogni ing no memory for the sample trial (significant differences are tion. evident with shorter delays). 35 Treatment of Sexual Dysfunction Treatments: Animals were treated with a compound of the An animal model was used to demonstrate the utility of invention 60 minutes prior to the sample trials. Each candi treating or preventing sexual dysfunction, e.g., sexual dys date compound was dissolved in the appropriate vehicle and function associated with SSRI treatment, with compounds of administered orally at 1 ml/kg. this invention. The animal model is based on the finding that Representative compounds of the invention were tested 40 sexually experienced rats that are administered an SSRI, a according to the protocol described. In these experiments, a drug used to treat certain conditions such as depression, dis positive effect of a compound on recognition memory is play a reduction in the number of non-contact penile erec demonstrated by animals spending significantly more time tions. SSRI treatment is associated with sexual dysfunction in exploring the novel object than the familiar one. It was found human Subjects. In general, the animal model exposes sexu that the tested compounds had a positive effect on recognition 45 ally experienced male rats (Sprague-Dawley rats) to female memory. Doses of the representative compounds of the inven rats in estrous in a novel testing arena that is not the regular tion that were identified as having a positive effect in this housing environment. The number of non-contact penile assay were dosed at 0.3-10 mg/kg p.o., with 10 mg/kg p.o. erections is assayed over a specified test period, e.g., 30 being the highest dose tested. These data demonstrate that minutes (Sukoff, Rizzo, et al., 2006, Society for Neurosci. selected compounds of the invention are useful for improving 50 Abstr. 559.4: U.S. Application Ser. No. 60/682.3379, filed recognition memory, and that the protocol is suitable for May 19, 2005). In the experiments described herein, animals identifying compounds that have a positive effect on recog were generally treated either with 0.9% saline (vehicle) or a nition memory. drug (i.e., a compound of the invention) in the vehicle. The ability of fluoxetine, an SSRI associated with sexual Synergy of Test Compounds with 55 dysfunction in humans, to cause sexual dysfunction in the Acetylcholinesterase Inhibitors animal model was tested by examining a 10 mg/kg dose of fluoxetine or vehicle alone (0.9% saline), each administered Acetylcholinesterase inhibitors are currently used to treat intraperitoneally, once daily for 14 days, on the number of mild cognitive deficits resulting from Alzheimer's disease. non-contact penile erections over a 30 minute trial period. However, the use of acetylcholinesterase inhibitors is hin 60 Fluoxetine produced a decrease in sexual function under dered by the side effects often seen with this class of thera these experimental conditions compared to treatment with peutic agent, and have limited efficacy. Representative com vehicle alone. These data demonstrate that sexual dysfunc pounds of the invention were shown to have a synergistic tion is induced in the animal model using SSRIs, thereby effect on the cognitive enhancing properties of a representa providing Support for the validity of using the animal model. tive acetylcholinesterase inhibitor, Aricept(R), lowering the 65 To examine the time course of the effects of a drug that dose of both agents required to obtain efficacy in the Novel causes sexual dysfunction, rats that were handled and tested Object Recognition Model. as described above were treated acutely: rats were treated US 7,671,056 B2 121 122 with vehicle for 6 days, and on the test day (day 7) instead of for controlling serotonin release, responding to elevated sero vehicle, the animals received a single dose of fluoxetine in tonin levels by inhibiting neurotransmitter release. The 2-4 vehicle (i.p.). For a subchronic (7 day) study, fluoxetine was week delay is thought to be the time required for these autore administered each day for 7 days and the animals were evalu ceptors to become desensitized. A 5-HT, antagonist that acts ated ontest day 7. For the chronic 14 day study, fluoxetine was to block the pre-synaptic autoreceptor would be expected to administered each day for 14 days and the animals were tested inhibit the contribution of these autoreceptors to acute sero on day 14. Each fluoxetine dose was 10 mg/kg in vehicle and tonin levels. The result should be an acute, Sustained increase was delivered i.p. on each of the test days as described above. in serotonin levels and a reduction in the onset of SSRI drug The testing session for each section of the study was begun action. immediately following compound administration and the 10 behavior observed for 30 minutes immediately following the The ability of the compounds of this invention to reduce drug administration. time for onset of action of the representative SSRI fluoxetine It was found that both a sub-chronic and chronic adminis was assessed using in vivo microdialysis. Using 2-3% hal tration of fluoxetine were associated with a significant othane anesthesia (Fluothane; Zeneca, Cheshire, UK), male increase in sexual dysfunction, further demonstrating the util 15 Sprague-Dawley rats (280-350 g; Charles River, Wilmington, ity of the animal model for sexual dysfunction testing. Mass.) were secured in a stereotaxic frame with ear and To test the ability of the compounds of this invention to incisor bars (David Kopf, Tujunga, Calif.) while a microdi ameliorate the effects of sexual dysfunction, sexually expe alysis guide cannula (CMA/12, CMA Microdialysis, Swe rienced rats were administered fluoxetine using a subchronic den) was directed above the dorsal lateral frontal cortex (A/P+ (7 day) or chronic (14 day) schedule and then tested for sexual 3.2 mm, M/L-3.5 mm, D/L-1.3 mm). Coordinates were function as described above. A single acute dose of a test taken with a flat skull using the rat brain atlas of Paxinos and compound given intraperitoneally after 7 or 14 days of flu Watson (1986). The guide cannula was secured to the skull with two stainless-steel screws (Small Parts, Roanoke, Va.) oxetine ameliorated sexual dysfunction as demonstrated by and dental acrylic (Plastics One, Roanoke, Va.). Following a the compounds ability to significantly reverse the fluoxetine 24 h post-operative recovery, animals were individually induced decrease in non-contact penile erections. Doses of 25 selected test compounds of the invention that were effective housed in Plexiglas cages (45 cm) where they had free access in this model were 0.1-1 mg/kg i.p., with 1 mg/kg i.p. being to water and standard rat chow. the highest dose tested. For in vivo neurochemical experiments, a microdialysis To further test the ability of compounds described hereinto probe (CMA/12; active membrane length 2 mm; OD 0.5 mm; ameliorate the effects of sexual dysfunction, sexually expe 30 20kD cut-off) was pre-washed with artificial CSF (aCSF; 125 rienced rats were co-administered fluoxetine (10 mg/kg i.p.) mMNaCl, 3 mM KC1, 0.75 mM MgSO and 1.2 mM CaCl, and selected compounds of the invention once daily for 14 pH 7.4) according to the manufacturers specifications. On the days and then tested for sexual function as described above. morning of the study, probes were inserted, via the guide Chronic dosing of the selected compounds of this invention cannula, into the frontal cortex and perfused with aOSF at 1 ameliorated the sexual dysfunction induced by chronic dos 35 ul/min. Following a 3 hour stabilization period, three control ing of fluoxetine, as demonstrated by the compounds ability samples (20 ul) were collected to establish a steady baseline. to significantly reverse the fluoxetine-induced decrease in Immediately following the last baseline sample, animals were non-contact penile erections. Doses of the selected test com treated with the compound of the invention (10 mg/kg p.o. in pounds that were effective in this model were 0.3-1 mg/kg 2% TweenTM, 0.5% methyl cellulose, using a dose volume of i.p., with 1 mg/kg i.p. being the highest dose tested. 40 1 ml/kg). Thirty minutes later rats were dosed with vehicle or These data demonstrate this test is successful in identifying fluoxetine (30 mg/kg. s.c.). Subsequent microdialysis samples compounds that can be used to treat sexual dysfunction asso were collected for 3 h post-injection and analyzed for 5-HT ciated with treatment with antidepressants (e.g., SSRIs). content by high performance liquid chromatography Moreover, these data demonstrate the test is useful for iden (HPLC). The HPLC conditions have been described previ tifying compounds that are efficacious for treating sexual 45 ously (Beyer et al., J Psychopharmacol. 16(4): 297-304 dysfunction, e.g., that is associated with antidepressant treat (2002)). All neurochemical data were acquired using the ment, whether the treatment with the test compound is initi Atlas Software package (Thermo Labsystems, Beverly, ated at the same time as antidepressant treatment (e.g., SSRI Mass.) and compared to an external standard curve. The fimol treatment) or when the treatment with the test compound is concentrations of all neurotransmitters during the baseline provided after initiation of treatment with the antidepressant. 50 samples were averaged and this value denoted as 100%. Sub Further, these data demonstrate that the candidate compounds sequent sample values were expressed as a percent change tested ameliorated sexual dysfunction associated with treat from this preinjection baseline value (or 96 change from base ment with antidepressants (e.g., SSRIS) and Suggest the line). Neurochemical data, excluding preinjection values, candidate compounds are efficacious for treating sexual dys were analyzed by a two-way analysis of variance (ANOVA) function. 55 with repeated measures (time). Post-hoc analyses were made using the Bonferroni/Dunns adjustment for multiple com Enhancement of SSRI Activity parisons. Acute treatment with fluoxetine did not increase serotonin SSRIs are currently used to treat depression in humans. levels in the frontal cortex of text animals. However, co They are thought to exert their antidepressant effect by 60 administration of representative compounds of the invention increasing serotonin levels in the brain. One liability of SSRIs caused a significant increase in fronatal cortex serotonin lev is a delay between initiation of drug treatment and onset of els. Representative compounds of this invention had no effect antidepressant action, which can be 2-4 weeks. This delay in on frontal cortex serotonin levels when administered. Doses onset of action is thought to be associated with an acute of representative compounds of this invention that were effec stimulation of pre-synaptic 5-HT, autoreceptors induced by 65 tive in enhancing the effect of acute fluoxetine treatment were the elevated levels in serotonin (which result from inhibition 3-10 mg/kg p.o., with 10 mg/kg p.o. being the highest dose of serotonin re-uptake). These autoreceptors are responsible tested. These data demonstrate this test is effective in identi US 7,671,056 B2 123 124 fying compounds of the invention that are able to shorten the perature, the reaction was terminated by the addition of ice time to onset of action for SSRIs. cold buffer and rapid filtration using a M-96 Brandel Cell Harvester (Gaithersburg, Md.) through a GF/B filter pre Cell line soaked for 30 minutes in 0.5% polyethyleneimine. Table 1 provides Ki values for the tested compounds. The PCR cloning of the human 5-HT, receptor subtype from a human genomic library has been described previously cAMP Measurements (Chanda et al., Mol. Pharmacol., 43:516 (1993)). A stable Chinese hamsterovary cell line expressing the human 5-HT receptor subtype (5-HTCHO cells) was employed 10 Measurements were performed as described in Dunlop, J. throughout this study. Cells were maintained in DMEM et al., Supra. Assays were performed by incubating the cells supplemented with 10% fetal calfserum, non-essential amino with DMEM containing 25 mM HEPES, 5 mM theophylline acids and penicillin/streptomycin. and 10 uM pargyline for a period of 20 minutes at 37° C. Functional activity was assessed by treating the cells with Radioligand Binding forskolin (1 uM final concentration) followed immediately by 15 test compound (6 different concentrations) for an additional Radioligand binding assays were performed as described 10 minutes at 37°C. In separate experiments, 6 concentra in Dunlop, J. et al., J. Pharmacol. and Toxicol. Methods 40: tions of antagonist were preincubated for 20 min prior to the 47-55 (1998), which is incorporated by reference. Cells were addition of 10 nM 8-OH-DPAT and forskolin. The reaction grown to 95-100% confluency as a monolayer before mem was terminated by removal of the media and addition of 0.5 branes were harvested for binding studies. Cells were gently ml ice cold assay buffer. Plates were stored at -20°C. prior to scraped from the culture plates, transferred to centrifuge assessment of cAMP formation by a cAMP SPA assay (Am tubes, and washed twice by centrifugation (2000 rpm for 10 ersham). min., 4° C.) in buffer (50 mM Tris; pH 7.5). The resulting Compounds of the invention were tested according to the pellets were aliquoted and placed at -80° C. On the day of 25 protocol described. The data demonstrate the protocol is assay, the cells were thawed on ice, and resuspended in buffer. effective for identifying compounds that have 5-HT agonist Studies were conducted using HI8-OH-DPAT as the radio activity and 5-HT, antagonist activity. 5-HT agonist activ ligand. The binding assay was performed in 96 well microti ity is demonstrated by inhibiting the forskolin-induced ter plates in a final total volume of 250 uL of buffer. Compe increase in cAMP levels and the results reported as ECso tition experiments were performed by using seven different 30 values (Table 1, Agonist Activity EC50). Compounds hav concentrations of unlabelled drug and a final ligand concen ing 5-HT, antagonist activity show no effect on forskolin tration of 1.5 nM. Non-specific binding was determined in the induced increases in cAMP levels on their own, but block the presence of 10 uM 5HT. Saturation analysis was conducted 8-OH-DPAT-induced inhibition of forskolin-stimulated by using HI8-OH-DPAT at concentrations ranging from increases in cAMP levels. Results are required as ICs values 0.3-30 nM. Following a 30 minute incubation at room tem (Table 1, “Antagonist Activity IC50)

TABLE 1.

5HT. Affinity G- \-/ S-O-

5-HT1A Antagonist Agonist Affinity Activity Activity G G Ki IC50 EC50

A. -O 21 O.40 nM 3.86 nM s N 2

B F N N O.46 nM 250 nM 4. % US 7,671,056 B2 125 126

TABLE 1-continued

5HT. Affinity

G- S-O- 2

5-HT1A Antagonist Agonist Affinity Activity Activity Ki IC50 EC50

6.85 nM

N

2

N 24.0 nM

2

2.40 nM

1.69 nM 10.8 nM

26.67 nM 22.03 nM

145 nM 2.53 M

US 7,671,056 B2 129 130

TABLE 1-continued

5HT. Affinity

O-O-\ / 2

5-HT1A Antagonist Agonist Affinity Activity Activity Ki IC50 EC50

O40 mM N

2

N O40 nM 10.0 nM

2

21 SOOM NA

N n 2

C 21 106 nM NA

N

C

N

2

10 N 3.28 nM

2

US 7,671,056 B2 133 134 Rs is —H; or linear or branched (C-C)-alkyl, (C- 15. A compound of Formula (I"): C)-haloalkyl, (C-C)-alkenyl, or (C-C)-alkynyl: and I n is 0, 1 or 2. R2 R 2. The compound or pharmaceutically acceptable salt of the compound of claim 1, wherein Rs is —H, (C-C)-alkyl, R3 / \ N Ra R3 —ORs, halogen, or —CF. 3. The compound or pharmaceutically acceptable salt of R4 N N the compound of claim 1, wherein Ro is —H, (C-C)-alkyl, —ORs, halogen, —CF. - NO, or —CN. Rs R6 Rb R15 4. The compound or pharmaceutically acceptable salt of the compound of claim 1, wherein Rio is —H., (C-C)-alkyl, and pharmaceutically acceptable salts thereof, —ORs, halogen, —CF, —NO, or —CN. 15 wherein 5. The compound or pharmaceutically acceptable salt of R. R2, Rs. R4, Rs. R6. R7. R7, Rs. R9. Rio. R11, R12. R1s. Ra Rs, and Re, are each independently —H., (C- the compound of claim 1, wherein R is —H., (C-C)-alkyl, C)-alkyl, (C-C)-haloalkyl, (C-C)-alkenyl, (C- —ORs, halogen, —CF. - NO, or —CN. C)-alkynyl, halogen, —CF, —NO. —CN. 6. The compound or pharmaceutically acceptable Salt of —ORs, —OSORs, —SRs, —SORs, —SON the compound of claim 1, wherein Rs is —H, (C-C)-alkyl, (R2s)2. —N(Rs), —CORs. —CORs. —ORs, halogen, or —CF; and Ro is —H., (C-C)-alkyl, —NRCORs, NRCORs —NRCON —ORs, halogen, —CF, —NO, or —CN. (Rs), or —CONCRs) except for the R group 7. The compound or pharmaceutically acceptable salt of through which the piperidine is connected; the compound of claim 1, wherein R is —H., (C-C)-alkyl, 25 R, and R, are each independently —H or —CH: Rs is —H; or linear or branched (C-C)-alkyl, (C- —ORs, halogen, —CF —NO, or—CN; one of R. R. R. C)-haloalkyl, (C-C)-alkenyl, or (C-C)-alkynyl: R. Rs, and R is —H., (C-C)-alkyl, —ORs, halogen, or and —CF, RandR, are each independently —Hor—CH; and where the piperidine group can be attached to the non R7, Rs. Ro, Rio, R1, R12, R1s. Rat Rs. R16, and the five 30 hetero atom containing ring of the quinoline through remaining Substituents of R. R. R. R. Rs, and Rare each positions R, R-7, Rs, or R. hydrogen. 16. The compound or pharmaceutically acceptable salt of 8. The compound or pharmaceutically acceptable salt of the compound of claim 15, wherein any one of R. R. R. R. the compound of claim 1, wherein Rs is —H., (C-C)-alkyl, Rs, and Reis —H., (C-C)-alkyl, —ORs, halogen, or—CF; —ORs, halogen, or —CF and one of R7, Rs. R. Rio, R. 35 and any one of R-7, R-7, Rs. Ro, Rio, R1, and R2 is —H. and R is —H., (C-C)-alkyl, —ORs, halogen, —CF, (C-C)-alkyl, —ORs, halogen, —CF, —NO, or —CN. —NO, or —CN. except for the R group through which the piperidine is con 9. The compound or pharmaceutically acceptable salt of nected. the compound of claim 1, wherein R is —H. —CF (C-C)- 40 17. The compound or pharmaceutically acceptable salt of alkyl; R and Rs are each independently —H, halogen, the compound of claim 15, wherein Rs is —H, (C-C)-alkyl, —OR2s, or -CF, R7, Rs. Ro, Rio, R1, and R2 are each —ORs, halogen, or —CF; and any one of R7, R-7, Rs. Ro, independently —H, halogen, -alkyl, —ORs, —CF, or R. R. and R is —H., (C-C)-alkyl, -ORs, halogen, —CF, NO, or —CN, except for the R group through —NO; R is —H or —CH. which the piperidine is connected. 10. The compound or pharmaceutically acceptable salt of 45 18. The compound or pharmaceutically acceptable salt of the compound of claim 1, wherein any one of R. R. R. R. the compound of claim 15, wherein Rs is —H, (C-C)-alkyl, Rs, and Reis —H., (C-C)-alkyl, —ORs, halogen, or—CF; —ORs, halogen, or —CF; and any two of R. R. R. R. and any one of R. R. R. R. R. and R is —H, (C-C)- Rio R, and R2 are each independently —H., (C-C)-alkyl, alkyl, —ORs, halogen, —CF. - NO, or—CN. —ORs, halogen, —CF, —NO, or—CN, except for the R 11. The compound or pharmaceutically acceptable salt of 50 group through which the piperidine is connected. the compound of claim 1, wherein any one of R. R. R. R. 19. The compound or pharmaceutically acceptable salt of Rs, and Reis —H., (C-C)-alkyl. —ORs, halogen, or—CF: the compound of claim 15, wherein Rs is —H, (C-C)-alkyl, and any two of R7, Rs. Ro Ro, R., and R2 are each inde —ORs, halogen, or —CF; and any three of R7, R-7, Rs. Ro, pendently —H., (C-C)-alkyl, —ORs, halogen, —CF, 55 Rio R, and R2 are each independently —H., (C-C)-alkyl, —NO, or —CN. —ORs, halogen, —CF, —NO, or—CN, except for the R 12. The compound or pharmaceutically acceptable salt of group through which the piperidine is connected. the compound of claim 1, wherein any one of R. R. R. R. 20. The compound or pharmaceutically acceptable salt of Rs, and Reis —H., (C-C)-alkyl, —ORs, halogen, or—CF; the compound of claim 15, wherein Rs is —H, (C-C)-alkyl, and any three of R-7, Rs. R. Rio R, and R2 are each 60 —ORs, halogen, or —CF; and R-7 is —H., (C-C) -alkyl, independently is —H., (C-C)-alkyl, —ORs, halogen, —ORs, halogen, —CF. —NO or—CN, and R. R. R.R. Rs. Rs. R-7, Rs. Ro, Rio, R1, R12, R13, R14, Ris, R16, R. and —CF, NO, or—CN. R, are each hydrogen except for the R group through which 13. The compound or pharmaceutically acceptable salt of the piperidine is connected. the compound of claim 1, wherein Rs is (C-C)-alkyl. 65 21. The compound or pharmaceutically acceptable salt of 14. The compound or pharmaceutically acceptable salt of the compound of claim 20, wherein the piperidine is con the compound of claim 1, wherein n is 1. nected through R7. US 7,671,056 B2 135 136 22. The compound or pharmaceutically acceptable salt of —ORs, halogen, or —CF and R-7 is —H., (C-C) -alkyl, the compound of claim 15, wherein Rs (C-C)-alkyl. —ORs, halogen, —CF —NO, or—CN; and R. R. R. 23. The compound or pharmaceutically acceptable salt of R4 Rs. Rs. Rs. Ro, Rio, R1, R12, R13, R14, Ris, R16, R. and the compound of claim 15, wherein the piperidine is con R, are each hydrogen. nected through R7. 33. The compound or pharmaceutically acceptable salt of 24. The compound or pharmaceutically acceptable salt of the compound of claim 29, wherein Rs is (C-C)-alkyl. the compound of claim 15, wherein the piperidine is con 34. A compound of Formula (II): nected through R7. 25. The compound or pharmaceutically acceptable salt of the compound of claim 15, wherein the piperidine is con 10 (II) nected through Rs. 26. The compound or pharmaceutically acceptable salt of / \ W y Ris the compound of claim 15, wherein the piperidine is con N Ra N SY nected through R. 27. A compound of Formula (I"a): 15 /-( - )-(Rr

(I"a) Rs R6 Rb R15 R16 R R R12 or a pharmaceutically acceptable salt thereof, wherein R3 ( ) 7- R13 R14 R.' Ne h R11 Ra Rs. Rs. R. R. 7, R1s and Rio are each indepen dently —H., (C-C)-alkyl, (C-C)-haloalkyl, (C- R4 N N N N R10 25 C)-alkenyl, (C-C)-alkynyl, halogen, —CF, \ { —NO. —CN, —ORs, —OSORs, —SRs, Rs R6 Rb K. R. , —SORs, —SON(Rs), —N(Rs), —CORs, —CORs, —NRCORs, —NRCORs, —NRCONCRs), or—CONCRs), and pharmaceutically acceptable salts thereof, 30 R, and R, are each independently —H or —CH: wherein R, R2, R. R. Rs. R. R-7, Rs. Ro, Rio R, R2, Rs is —H; or linear or branched (C-C)-alkyl, (C- R13, R14, Ris, and R16, are each independently —H, C)-haloalkyl, (C-C)-alkenyl, or (C-C-alkynyl); (C-C)-alkyl, (C-C)-haloalkyl, (C-C)-alkenyl, (C- and C)-alkynyl, halogen, —CF. - NO. —CN. —ORs. Ra and Rs cannot both be hydrogen. —OSORs, —SRs, - SORs, —SON(Rs), 35 35. The compound or pharmaceutically acceptable salt of —N(Rs), —CORs, —CORs. —NRCORs. the compound of claim 34, wherein R and Rs are each inde —NRCORs, —NRCONCRs), or—CONCRs), pendently —H. —ORs, halogen, or (C-C)-alkyl; Rs and R, and R, are each independently —H or —CH, and Re are each independently —Hor—CH, and R7, Ris, and Rs is —H; or linear or branched (C-C)-alkyl, (C-C)- Ro are each independently —H. —ORs, halogen, (C-C)- haloalkyl, (C-C)-alkenyl, or (C-C)-alkynyl. 40 alkyl, -CF, NO, or—CN. 28. The compound or pharmaceutically acceptable salt of 36. The compound or pharmaceutically acceptable salt of the compound of claim 27, wherein Rs is —H., (C-C)-alkyl, the compound of claim 34, wherein R and Rs are each inde —ORs, halogen, or —CF. pendently —H. —OCH, F, or —CH: Rs and R are each 29. The compound or pharmaceutically acceptable salt of independently —Hor—CH, and R7, Ris, and Ro are each the compound of claim 27, wherein any one R. R. R. R. 45 independently —H. F. —CH, —CF, NO. —CN or Br. Rs, and Reis —H., (C-C)-alkyl. —ORs, halogen, or—CF: 37. The compound or pharmaceutically acceptable salt of and any one of R-7, Rs. Ro, Rio, R1, and R2 is -H, (C-C)- the compound of claim 34, wherein R and Rs are each inde alkyl, —ORs, halogen, —CF. - NO, or—CN. pendently —H, or —ORs, and R7, Rs, and R are each 30. The compound or pharmaceutically acceptable salt of independently —H. —ORs, halogen, (C-C)-alkyl, or the compound of claim 27, wherein Rais—H., (C-C)-alkyl, 50 —CF. —ORs, halogen, or—CF and any one of R. R. Rs, and 38. The compound or pharmaceutically acceptable salt of Reis —H. (C-C)-alkyl, —ORs, or halogen; and any two the compound of claim 34, wherein R and Rs are each inde of R7, Rs. Ro, Rio, R., and R2 is —H., (C-C)-alkyl, pendently —H. —ORs, R. Rs, and R are each indepen —ORs, halogen, —CF, —NO, or—CN; and wherein the dently —H. —ORs, halogen, (C-C)-alkyl, or —CF; and any two R7, Rs. Ro, Rio, R., and R2 can be either on the 55 the remaining R groups are hydrogen. same ring of the quinoline or on different rings. 39. The compound or pharmaceutically acceptable salt of 31. The compound or pharmaceutically acceptable salt of the compound of claim 34, wherein Rio is in the para position the compound of claim 27, wherein Rs is —H., (C-C)-alkyl, relative to the nitrogen of the piperidine. —ORs, halogen, or—CF and any one of R. R. Ris, and 40. The compound or pharmaceutically acceptable salt of Reis —H. (C-C)-alkyl, —ORs, halogen; and any two of 60 the compound of claim34, wherein R, and Rs are located at R. R. R. R. R. and R are each independently —H. positions 2 and 4 of the quinoline ring. (C-C)-alkyl, —ORs, halogen, —CF, —NO, or —CN: 41. The compound or pharmaceutically acceptable salt of and wherein the any two of R. R. R. R. R. and R can the compound of claim 34, wherein Rs is (C-C)-alkyl, be either on the same ring of the quinoline or on different —ORs, halogen, or —CF and one of R7, Ris, and Rio is rings. 65 (C-C)-alkyl, —ORs, halogen, or—CF. 32. The compound or pharmaceutically acceptable salt of 42. The compound or pharmaceutically acceptable salt of the compound of claim 29, wherein Rs is —H, (C-C)-alkyl, the compound of claim 34, wherein Rs is —H., (C-C)-alkyl, US 7,671,056 B2 137 138 —ORs, halogen, or —CF and two of R7, Ris, and Ro are 6-fluoro-8-(4-(1-(5-fluoroquinolin-8-yl)piperidin-4-yl) each independently —H., (C-C)-alkyl, -ORs, halogen, or piperazin-1-yl)guinoline; —CF. 6-methoxy-8-(4-(1-(6-bromoquinolin-8-yl)piperidin-4- 43. The compound or pharmaceutically acceptable salt of yl)piperazin-1-yl)guinoline; the compound of claim 34, wherein Rs is —H., (C-C)-alkyl, 5 6-methoxy-8-(4-(1-(6-fluoroquinolin-8-yl)piperidin-4-yl) —ORs, halogen, or —CF and R7, Ris, and Rio are each piperazin-1-yl)guinoline; independently —H., (C-C)-alkyl, —ORs, halogen, or 6-fluoro-8-(4-(1-(7-fluoroquinolin-8-yl)piperidin-4-yl) —CF. piperazin-1-yl)guinoline; 44. The compound or pharmaceutically acceptable salt of 6-methoxy-8-4-1-(8-fluoroquinolin-7-yl)piperidin-4- the compound of claim 34, wherein Rs is —H., (C-C)-alkyl, 10 yl)piperazin-1-ylquinoline; —ORs, halogen, or —CF and one of R7, Ris, and Rio is 6-methoxy-8-4-1-(2-trifluoromethyl-4-methoxyquino —H., (C-C)-alkyl, —ORs, halogen, or—CF; and R. Rs. lin-7-yl)piperidin-4-yl)piperazin-1-ylquinoline; R. R. R., and the two remaining Substituents from R7, Rs. 6-methoxy-8-(4-(1-(2-trifluoromethyl-4-methoxyquino and R are each hydrogen. lin-8-yl)piperidin-4-yl)piperazin-1-yl)guinoline; 45. The compound or pharmaceutically acceptable salt of 15 5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1- the compound of claim 1 wherein the compound is yl)piperidin-1-yl)-2-trifluoromethylduinoline; 6-methoxy-8-4-(1-quinolin-8-yl-piperidin-4-yl)-piper 5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1- azin-1-yl)-quinoline; yl)piperidin-1-yl)-3-trifluoromethylduinoline; 6-fluoro-8-4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin 5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1- 1-yl)-quinoline; yl)piperidin-1-yl)-4-trifluoromethylduinoline; 5-fluoro-8-4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin 2,5-difluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin 1-yl)-quinoline; 1-yl)piperidin-1-yl)guinoline; 7-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1- 3,5-difluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin yl)piperidin-1-yl)guinoline; 1-yl)piperidin-1-yl)guinoline; or 6-fluoro-8-4-1-(8-fluoroquinolin-7-yl)piperidin-4-yl) 25 piperazin-1-ylquinoline; 4,5-difluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin 3-trifluoromethyl-8-(4-(4-(6-methoxyquinolin-8-yl)pip 1-yl)piperidin-1-yl)guinoline. erazin-1-yl)piperidin-1-yl)guinoline; 46. A pharmaceutical formulation comprising an effective 6-methoxy-8-(4-(1-(cquinolin-8-ylmethyl)piperidin-4-yl) amount of the compound or a pharmaceutically acceptable piperazin-1-yl)guinoline; 30 salt of the compound of claim 1 and a pharmaceutically 5-fluoro-4-methoxy-8-(4-(4-(6-methoxyquinolin-8-yl) acceptable carrier. piperazin-1-yl)piperidin-1-yl)-2-(trifluoromethyl) 47. The pharmaceutical formulation of claim 46, further quinoline; comprising a second therapeutic agent. 5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1- 48. The pharmaceutical formulation of claim 47, wherein yl)piperidin-1-yl)guinoline; 35 the second therapeutic agent is a selective serotonin reuptake 8-4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl inhibitor or a cholinesterase inhibitor. quinoline; 49. A pharmaceutical formulation comprising an effective 6-chloro-8-4-(4-(6-chloro)-quinolin-8-yl-piperidin-1- amount of the compound or a pharmaceutically acceptable yl)-piperazin-1-yl)-quinoline; salt of the compound of claim 15 and a pharmaceutically 6-fluoro-8-4-(4-(6-chloro)-quinolin-8-yl-piperidin-1-yl)- 40 acceptable carrier. piperazin-1-yl)-quinoline; 50. The pharmaceutical formulation of claim 49, further 5-chloro-8-4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin comprising a second therapeutic agent. 1-yl)-quinoline; 51. The pharmaceutical formulation of claim 50, wherein 2-methyl-8-4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin the second therapeutic agent is a selective serotonin reuptake 1-yl)-quinoline; 45 inhibitor or a cholinesterase inhibitor. 6-chloro-8-4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin 52. A pharmaceutical formulation comprising an effective 1-yl)-quinoline; amount of the compound or a pharmaceutically acceptable 8-4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl-5- salt of the compound of claim 27 and a pharmaceutically trifluoromethyl-quinoline; acceptable carrier. 5-methoxy-8-4-(1-quinolin-8-yl-piperidin-4-yl)-piper 50 azin-1-yl)-quinoline; 53. The pharmaceutical formulation of claim 52, further 5-fluoro-8-4-(4-quinolin-8-yl-piperazin-1-yl)-piperidin comprising a second Therapeutic agent. 54. The pharmaceutical formulation of claim 53, wherein 1-yl)-quinoline; the second therapeutic agent is a selective serotonin reuptake 6-methoxy-8-4-(2-methylduinolin-8-yl-piperidin-4-yl)- inhibitor or a cholinesterase inhibitor. piperazin-1-yl)-quinoline; 55 6-fluoro-8-(4-(1-(2-methylduinolin-8-yl)piperidin-4-yl) 55. A pharmaceutical formulation comprising an effective piperazin-1-yl)guinoline; amount of the compound or a pharmaceutically acceptable 6-methoxy-8-4-(3-methylduinolin-8-yl-piperidin-4-yl)- salt of the compound of claim 34 and a pharmaceutically piperazin-1-yl)-quinoline; acceptable carrier. 6-methoxy-8-(4-(1-(4-methylduinolin-8-yl)piperidin-4- 60 56. The pharmaceutical formulation of claim 55, further yl)piperazin-1-yl)guinoline; comprising a second therapeutic agent. 6-methoxy-8-(4-(1-(2,4-dimethylduinolin-8-yl)piperidin 57. The pharmaceutical formulation of claim 56, wherein 4-yl)piperazin-1-yl)guinoline; the second therapeutic agent is a selective serotonin reuptake 6-methoxy-8-(4-(1-(2,4-dimethyl-5-fluoroquinolin-8-yl) inhibitor or a cholinesterase inhibitor. piperidin-4-yl)piperazin-1-yl)cquinoline; 65 58. A method of synthesizing a compound comprising: 6-methoxy-8-(4-(1-(2-(trifluoromethyl)cquinolin-8-yl)pip a) reacting an optionally Substituted aniline compound of eridin-4-yl)piperazin-1-yl)guinoline; Formula (VII): US 7,671,056 B2 139 140 c) reacting the protected piperazino-quinoline of Formula (IX) under conditions effective to provide a substituted (VII) piperazino-quinoline compound of Formula (Xb): NH2

(Xb) R4 W R R

Rs R6 R3 / \ Ra 10 wherein: R4 / K. W is a leaving group; R. Rs, and R are each independently —H., (C-C)- \ { alkyl, (C-C)-haloalkyl, (C-C) -alkenyl, (C-C)- Rs R6 Rb alkynyl, halogen, —CF, —NO. —CN, —ORs, —SRs, —SORs, -SON(Rs), —N(Rs), d) reacting a second optionally Substituted aniline com —CORs, —CORs. —NRCORs. pound of Formula (XI): —NRCORs, NRCON (Rs), or —CON (R2s)2: Rs is —H; or linear or branched (C-C)-alkyl, (C- (XI) C)-haloalkyl, (C-C)-alkenyl, or (C-C)-alkynyl, under conditions effective to produce an optionally Substi tuted quinoline of Formula (VIII): 25

(VIII) HN

30 wherein R7, Rs, and R. are each independently —H., (C-C)- alkyl, (C-C)-haloalkyl, (C-C)-alkenyl, (C-C)- alkynyl, halogen, —CF —NO. —CN. —ORs. —SRs —SORs —SON(Rs), —N(Rs), 35 —CORs, —CORs, —NRCORs, —NRCORs, NRCON (Rs), or —CON (R2s)2: Rs is —H; or linear or branched (C-C)-alkyl, (C- C)-haloalkyl, (C-C)-alkenyl, or (C-C-alkynyl: wherein: 40 R. R. and R are each independently —H, (C-C)- and alkyl, (C-C)-haloalkyl, (C-C) -alkenyl, (C-C)- W is a leaving group alkynyl, halogen, —CF, —NO. —CN, —ORs, under conditions effective to produce a second option —SRs, -SORs, -SON(Rs), —N(Rs), ally substituted quinoline of Formula (XII): —CORs, —CORs, —NRCORs, 45 —NRCORs, NRCON(Rs), or – CON (R2s)2: (XII) b) reacting the quinoline of Formula (VIII) with a protected piperazine derivative under conditions effective to pro vide a protected piperazino-quinoline of Formula (IX): 50

(IX) \ / R10

55 R2 R11

wherein R. R. and R. are each independently —H. R4 N N-X (C-C)-alkyl, (C-C)-haloalkyl, (C-C)-alkenyl, 60 (C-C)alkynyl, halogen, —CF. - NO. —CN, —ORs, —SRs, —SORs, —SON(Rs), Rs R6 Rb —N(Rs), —CORs, —CORs, —NRCORs, —NRCORs, NRCON(Rs), or – CON wherein: (R2s)2: 65 Rs is —H; or linear or branched (C-C)-alkyl, (C- R, and R, are each independently —H or —CH and C)-haloalkyl, (C-C)-alkenyl, or (C-C)-alkynyl: X is a protecting group and US 7,671,056 B2 141 142 W is a leaving group CF, NO, CN, OR2s. OSORs, e) reacting the quinoline of Formula (XII) with a protected —SRs —SORs —SON(Rs), —N(Rs), piperidin-4-one derivative, under conditions effective to —CORs, —CORs. —NRCORs. provide a compound of Formula (XIII): —NRCORs, NRCON (Rs), or —CON (R2s)2: (XIII) R Rs R, and R, are each independently —H or —CH, and Rs is —H; or linear or branched (C-C)-alkyl, (C- X N R C)-haloalkyl, (C-C)-alkenyl, or (C-C)-alkynyl: prepared by the method comprising: a) reacting an optionally Substituted aniline compound of N / K. Formula (VII): R2 R11 15

wherein X is a protecting group; (VII) f) reacting the compound of Formula (XIII) under condi NH2 tions effective to provide a piperidin-4-one compound of (XIVa): 2O

(XIVa) R

wherein W is a leaving group; under conditions effective to produce an optionally Substi N / K. tuted quinoline of Formula (VIII): 30 R12 R11 g) reacting the compound of For (VIII) mula (Xb) with the substituted piperidin-4-one com poundprovide of a Formulapiperazine-piperidine (XIVa) under conditionscompound effectivehaving the to is Formula (XV): (XV) R2 R R R11 40 Rs R6 R3 / \ Ra / \ R10. b) reacting the leaving group of the quinoline of Formula (VIII) with a protected piperazine derivative under con R4 N \- -O Ro 45 ditions effective to provide a protected piperazino Rs R6 Rb R Rs quinoline of Formula (XI): 59. A compound of Formula (XV): 50

(XV) (IX) R R R12 R11 R3 / \ Ra / \ R10 55

R4 N\ { -O Ro 60 Rs R6 Rb R Rs

wherein wherein X is a protecting group. R. R2, Rs. R4, Rs. R6. R7. Rs. R9. Rio R and R12 are 65 c) reacting the protected piperazino-quinoline of Formula each independently —H. (C-C)-alkyl, (C-C)-ha (IX) under conditions effective to provide a substituted loalkyl, (C-C)-alkenyl, or (C-C)alkynyl, halogen, piperazine compound of Formula (Xb): US 7,671,056 B2 143

(Xb) (XIVa) R2 R R3 / \ Ra

10

Rs R6 Rb

15 g) reacting the Substituted piperazine compound of For d) reacting a second optionally Substituted aniline com mula (X) with the substituted piperidin-4-one com pound of Formula (XI): pound of Formula (XIV) under conditions effective to provide a piperazine-piperidine compound having the Formula (XV): (XI) (XV) R2 R R12 R11

25 R3 / \ R 8. 10. HN R4 o N/-( N -ON wherein W is a leaving group; 30 under conditions effective to produce a second optionally Rs R6 \- b R7 Substituted quinoline of Formula (XII): 60. A compound of Formula (I): (XII) 35

(I) R12 R11 40 N / R. Ra R13 O R2 R11 Roo /-( )-( 45 e) reacting the leaving group of the second quinoline of Formula (XII) with a protected piperidin-4-one deriva Rb R15 R16 Rs tive under conditions effective to provide the compound (XIII): 50 or a pharmaceutically acceptable salt thereof, wherein (XIII) R7 Roo is x-O-( )- 55 N R10 \ / 60 R2 R11

wherein X is a protecting group. 65 f) reacting the compound of Formula (XIII) under condi tions effective to provide the compound of (XIVa): US 7,671,056 B2 145 146 R. R2, Rs. R4, Rs. R6. R7. Rs. R9. Rio. R11. R12. Ris. wherein Ra Rs, and Re, are each independently —H., (C- Roo is C)-alkyl, (C-C)-haloalkyl, (C-C)-alkenyl, (C- C)-alkynyl, halogen, —CF —NO. —CN. —ORs, —OSORs, —SRs, —SORs, —SON (R2s)2. —N(Rs), —CORs. —CORs. —NRCORs, NRCORs, NRCON (Rs), or —CON(Rs); R, and R, are each independently —H or —CH, and 10 Rs is —H; or linear or branched (C-C)-alkyl, (C- C)-haloalkyl, (C-C)-alkenyl, or (C-C)-alkynyl, prepared by the method comprising: reacting a Substituted piperazine compound of Formula (X): 15 Rs R6 (X) Ra R1, R2, Rs. R4 Rs. Rs. R-7, Rs. Ro, R1, R1, R12, R1, R14, Rs, and Re, are each independently —H. (C-C)- ) alkyl, (C-C)-haloalkyl, (C-C)-alkenyl, (C-C)- HN N-Roo alkynyl, halogen, —CF, —NO. —CN, —ORs, —OSORs, —SRs, —SORs, —SON(Rs), R ) / —N(Rs), —CORs, —CORs. —NRCORs. —NRCONCRs), or—CONCRs), with a substituted piperidin-4-one compound of Formula 25 (XIV): R, and R, are each independently —H or —CH: Rs is —H; or linear or branched (C-C)-alkyl, (C- (XIV) C)-haloalkyl, (C-C)-alkenyl, or (C-C)-alkynyl: R12 R11 and 30 n is 1 or 2: R13 R14 N \ R10 prepared by the method comprising: reacting a Substituted piperazine compound of Formula O N Ro (X): 35

R15 R16 R7 R8 under conditions effective to bring about reductive amina (X) tion at the piperidine carbonyl, thereby providing an piperazine-piperidine compound having the Formula 40 (I): (I) R12 R11 45 Ra R13 R14 N \ R10 with a substituted piperidin-4-one compound of For mula (XIVb): Roo-N - R9 50 (XIVb) R13 R14 R7 R8 61. A compound of Formula (I): 55 O N Ro (I) pi R. R.13 R14 R Rs R15 R16

Roo- N N R9 60 \ { pi R. Rs R16 N / K. under conditions effective to bring about reductive ami 65 nation at the piperidine carbonyl, thereby providing a R12 R11 piperazine-piperidine compound having the or a pharmaceutically acceptable salt thereof, Formula (I): US 7,671,056 B2 147 148

(I) (X) R. R.13 R14 R R8

Roo- N N R9 \ { pi R -ON Ra R. Rs R16 \ / R10. 10 with a compound of formula (XIVc): R12 R11

(XIVc)

62. A compound of Formula (I"): 15

(I") R12 N21 R Ra R13 R14 R.' A N R10 Roo- N N 25 ( R 2 R9 Ri, R15 R16 Rs under conditions effective to bring about reductive ami nation at the piperidine carbonyl, thereby providing a or a pharmaceutically acceptable salt thereof, 30 piperazine-piperidine compound having the Formula wherein (I"): Roo is (I") 35 R12 N21 R11 Ra R13 R14 40 / ( R.' 1N R10. Roo- N N ( R 2 R9 Rs R6 Ri, R15 R 45 R. R2. Rs. R4, Rs. R. R7. R7, Rs. Ro. Rio R ls R12, Rs. 63. The pharmaceutical composition of claim 55, wherein Ra Rs, and Rare each independently —H., (C- Ra and Rs are each independently —H. —OCH, F, or C)-alkyl, (C-C)-haloalkyl, (C-C)-alkenyl, (C- —CH; Rs and R are each independently —H or —CH: C)-alkynyl, halogen, —CF, —NO. —CN. 50 and R7, Ris, and Ro are each independently —H. F. —CH, —ORs, —OSORs, —SRs, —SORs, —SON - CF, NO, CN or Br. (R2s)2. —N(Rs), —CORs. —CORs, 64. The pharmaceutical composition of claim 55, wherein —NRCORs, NRCORs, NRCON Ra and Rs are each independently —H or —ORs, R7, Rs. (Rs), or —CONCRs) except for the R group and R are each independently —H. —ORs, halogen, (C- 55 C)-alkyl, or—CF; and Rs. R. R. and R, are hydrogen. through which the piperidine is connected; 65. The compound or pharmaceutically acceptable salt of R, and R, are each independently —H or —CH: the compound of claim 1, wherein n is 0. Rs is —H; or linear or branched (C-C)-alkyl, (C- 66. The compound or pharmaceutically acceptable salt of C)-haloalkyl, (C-C)-alkenyl, or (C-C)-alkynyl: the compound of claim 1 wherein the compound is 5-fluoro and 60 8-(4-(4-(6-methoxyquinolin-8-yl) piperazin-1-yl)piperidin where the piperidine group can be attached to the non 1-yl)guinoline. hetero atom containing ring of the piperidine through 67. A pharmaceutical composition comprising a com pound or a pharmaceutically acceptable salt of a compound positions R, R-7, Rs, or Ro: wherein the compound is 5-fluoro-8-(4-(4-(6-methoxyquino prepared by the method comprising: 65 lin-8-yl)piperazin-1-yl)piperidin-1-yl)guinoline. reacting a Substituted piperazine compound of Formula (X): k k k k k