USOO741998OB2

(12) United States Patent (10) Patent No.: US 7419,980 B2 Trybulski et al. (45) Date of Patent: Sep. 2, 2008

(54) FUSED-ARYLAND HETEROARYL 5,502,047 A 3/1996 Kavey ...... 514, 183 DERVATIVES AND METHODS OF THEIR 6,703,389 B2 3/2004 Wong et al...... 514,239.2 USE 2002/0107249 A1 8/2002 Wong et al...... 514,238.5 2004/00 19101 A1 1/2004 Karlstadt et al...... 514,464 (75) Inventors: Eugene John Trybulski, Huntingdon 2004.0143008 A1 7/2004 Deecher et al...... 514,521 Valley, PA (US); Paige Erin Mahaney, 2004/0152710 A1 8/2004 Deecher et al...... 514/255.04 Pottstown, PA (US); Lori Krim Gavrin, 2004/0180879 A1 9, 2004 Deecher et al...... 514,225.8 Philadelphia, PA (US); Joseph Peter Sabatucci, Collegeville, PA (US); Gary Paul Stack, Ambler, PA (US) FOREIGN PATENT DOCUMENTS (73) Assignee: Wyeth, Madison, NJ (US) DE 2556474 C2 8, 2004 (*) Notice: Subject to any disclaimer, the term of this EP O 310 268 A2 4, 1956 patent is extended or adjusted under 35 EP OO65 757 B1 1, 1985 U.S.C. 154(b) by 636 days. EP O 208 235 B1 1/1990 EP O3O3961 B1 4f1994 (21) Appl. No.: 10/963,064 EP 1266 659 A1 12/2002 GB 1243955 * 8/1971 (22) Filed: Oct. 12, 2004 JP 10218866 A2 8, 1998 O O WO WO 91.18602 A1 12, 1991 (65) Prior Publication Data WO 92/06082 A1 4, 1992 US 2005/O192283 A1 Sep. 1, 2005 WO 94.21610 A1 9, 1994 WO WO97/35586 A1 10, 1997 Related U.S. Application Data WO 97,44329 A1 11, 1997 (60) Provisional application No. 60/570,056, filed on May WO WO99/446O1 A1 9, 1999 11, 2004, provisional application No. 60/561,447. WO WOOO,59851 A1 10, 2000 filed on Apr. 12, 2004, provisional application No. WO WOO1 O1973 A2 1/2001 60/510,811, filed on Oct. 14, 2003. WO WO 02/064543 A2 8, 2002 WO WO 02/064543 A3 8, 2002 (51) Int. Cl. WO WO O2/O78691 A1 10, 2002 A 6LX 3L/2197 (2006.01) A6 IK 3/4965 (2006.01) CO7D 40/00 (2006.01) CO7D 403/00 (2006.01) (Continued) CO7D 405/00 (2006.01) OTHER PUBLICATIONS CO7D 409/00 (2006.01) CO7D 4II/00 (2006.01) Gray, et al., Do O2-Adrenoceptors Play an Integral Role in the CO7D 413/00 (2006.01) Antinociceptive Mechanism of Action of Antidepressant Com CO7D 417/00 (2006.01) pounds, Euro. J. of Pharm. 378, 161-168 (1999).* CO7D 49/00 (2006.01) CO7D 24I/04 (2006.01) (Continued) C07D 295/00 (2006.01) Primary Examiner James O. Wilson (52) U.S. Cl...... 514/252.13: 514/252.14; Assistant Examiner Erich A Leeser 514/253.01: 514/253.09: 514/253.1: 514/253.11; (74) Attorney, Agent, or Firm Thomas C. McKenzie 514/254.01: 514/254.05; 514/254.1: 514/255.05; 544/360; 544/373; 544/374; 544/379; 544/391; (57) ABSTRACT 544/397: 544/403:544/405 (58) Field544/373, of Classification 374,379,391,397, Search 403, ...... 405; 514/252.13, 544/360, A. present invention is directed- 0 to fit and Era. 514/252.14, 253.01, 253.09, 253.1, 253.11, erivatives, compositions containing these derivatives, an 5147254.01254.05 254.1255.05 methods of their use for the prevention and treatment of See application file for completes searchs history.s conditions ameliorated by monoamine reuptake including, interalia, vasomotor symptoms (VMS), sexual dysfunction, (56) References Cited gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromylagia syndrome, nervous system disor U.S. PATENT DOCUMENTS ders, and combinations thereof, particularly those conditions 3.454,554. A 7/1969 Biel et al...... 260/239 selected from the group consisting of major depressive dis 4,221,919 A 9, 1980 Grimova et al...... 562/.465 order, vasomotor symptoms, stress and urge urinary inconti 4,229,449 A 10/1980 Melloni et al...... 514,239.2 nence, fibromyalgia, pain, diabetic neuropathy, and combi 4,310,524. A 1/1982 Wiech et al...... 514,217 nations thereof. 4,535,186 A 8, 1985 Husbands et al...... 564,336 4,826,844 A 5/1989 Husbands et al...... 514,252 13 Claims, 2 Drawing Sheets US 7419,980 B2 Page 2

FOREIGN PATENT DOCUMENTS Kronenberg, F. et al., “Thermoregulatory Physiology of Menopausal Hot Flashes: A Review.” Can. J. Physiol. Pharmacol., 1987, 65:1312 WO WOO3,O37334 A1 5, 2003 1324. WO WOO3,053426 A1 T 2003 Loprinzi, C.L. et al., “Venlafaxine in management of hot flashes in WO WOO3,O77897 A1 9, 2003 Survivors of breast cancer: a randomized controlled trial. Lancet, WO WO 2004/O16272 A1 2, 2004 Dec. 16, 2000, 356(9247): 2059-2063. Loprinizi, C. L. etal. "Pilot Evaluation of Venlafaxine Hydrochloride OTHER PUBLICATIONS for the Therapy of Hot Flashes in Cancer Survivors,” Journal of U.S. Appl. No. 60/557.651, filed Mar. 30, 2004, Kim et al. Clinical Oncology, Jul. 1998, 16(7): 2377-2381. U.S. Appl. No. 60/557,831, filed Mar. 30, 2004, Kim et al. Mackinnon et al., “O-Adrenoceptors: more Subtypes but fewer func U.S. Appl. No. 60/569,863, filed May 11, 2004, Kim et al. tional differences. TIPS, 1994, 15: 119-123. U.S. Appl. No. 60/569,861, filed May 11, 2004, Vu. Merchenthaler et al., “The effect of estrogens and antiestrogens in a U.S. Appl. No. 10/963,458, filed Oct. 12, 2004, Mahaney et al. rat model for hot flush.” Maturitas, 1998, 30(3): 307-316. U.S. Appl. No. 10/962,881, filed Oct. 12, 2004, Mahaney. Morin, S. M., “Atomoxetine Selectively Induces Fos Expression in U.S. Appl. No. 10/962,897, filed Oct. 12, 2004, Deecher et al. the Rat Prefrontal Cortex.” Presented at Society for Neuroscience U.S. Appl. No. 10/963,111, filed Oct. 12, 2004, Trybulski et al. Annual Meeting (SFN); Nov. 2-7, 2002, Orlando, FL. U.S. Appl. No. 10/962,880, filed Oct. 12, 2004, Trybulski et al. Pacholczyk, T. et al., “Expression cloning of a cocaine-and antide U.S. Appl. No. 10/962.971, filed Oct. 12, 2004, Mahaney et al. pressant-sensitive human noradrenaline transporter,” Nature, 1991, U.S. Appl. No. 10/962,899, filed Oct. 12, 2004, Mahaney et al. 350(6316): 350-4. Clinical Trial: “Phase III Randomized Study of Panek, D.U. et al., “Effect of continuous intraventricular estrogen or Medroxyprogesterone Versus Venlafaxine in Women With catechol estrogen treatment on catecholamine turnover in various Symptomic Hot Flashes', www.clinicaltrials.gov sponsored by the brain regions.” J. Pharmacol. Exp. Ther:, 1986, 236(3), 646-652. National Institutes of Health, Study ID Nos. CDRO000069217; NCCTG-N99C7: NCI-PO2-0204, 2003, 6 pages. Prasad, P.D., et al., “Functional expression of the plasma membrane Acs, N. et al., “Estrogen improves impaired musculocutaneous vas serotonin transporter but not the vesicular monoamine transporter in cular adrenergic reactivity in pharmacologically ovariectomized rats: human placental trophoblasts and choriocarcinoma cells. Placenta, a potential peripheral mechanism for hot flashes?”. Endocrinology, 1996, 17(4): 201-7. 2001 15: 68-73. Quella, S. K. et al., “Pilot evaluation of Venlafaxine for the treatment Barlow, D. H., “Venlafaxine for hot flushes.' Lancet, Dec. 16, 2000, of hot flashes in men undergoing androgen ablation therapy for 356(9247): 2025-2026. prostate cancer.” The Journal of Urology, Jul. 1999, 162: 98-102. Barton, D. et al., “Hot Flashes—Aetiology and Management.” Drugs Reneric, J-Ph. et al., “Idazoxan and 8-OH-DPAT modify the behav and Aging, 2001, 18(8): 597-606. ioral effects induced by either NA, or 5-HT, or dual NA/5-HT Berendsen, H. H. G., “Hot Flushes and serotonin.” Journal of the reuptake inhibition in the rat forced Swimming test.” British Menopause Society, Mar. 2002, 8(1): 30-34. Nueropsychopharmacology, Apr. 2001, 24(4): 379-390. Berendsen, H. H. G., “Effect of tibolone and raloxifene on the tail Rosenberg, J. et al., “Hypothesis: pathogenesis of postmenopausal temperature of oestrogen-deficient rats.” European Journal of Phar hot flush.” Medical Hypotheses, 1991, 35: 349-350. macology, 2001, 419(1): 47-54. Shaw, C. R. “The perimenopausal hot flash: epidemiology, physiol Berendsen, H. H. G., “The role of serotonin in hot flushes.” ogy, and treatment.” Nurse Practitioner, Mar. 1997. 22:55-56,61-66. Maturitas, 2000, 36(3): 155-164. Stearns, V. et al., “Hot flushes.” Lancet, Dec. 7, 2002, 360(9348): Bundgaard, H., “Means to enhance penetration; Prodrugs as a means 1851-1861. to improve the delivery of peptide drugs.” Advanced Drug Deliver Stearns.V. et al., “Paroxetine controlled release in the treatment of Reviews, 1992, 8, 1-38. menopausal hot flashes,” JAMA, 2003, 289:2827-2834. Bundgaard, H. et al., “Glycolamide Esters as Biolabile Prodrugs of Stearns, V. et al., “A pilot trial assessing the efficacy of paroxetine Carboxylic Acid Agents: Synthesis, Stability, Bioconversion, and hydrochloride (Paxil) in controlling hot flashes in breast cancer Sur Physicochemical Properties,” J. of Pharmaceutical Sciences, Apr. vivors. Ann Oncol., 2000, 11:17-22. 1988, 77(4):285-298. Waldinger et al., “Treatment of hot flushes with mirtazapine: four Casper, R. F. et al., “Neuroendocrinology of menopausal flushes: an case reports.” Maturitas, 2000, 36(3): 165-168. hypothesis of flush mechanism.” Clinical Endocrinology, 1985, 22: Wilen, S.H. Tables of Resolving Agents and Optical Resolutions, pp. 293-312. 268-298, E.L. Eliel, Ed., University of Notre Dame Press, Notre Fink, G. et al., “Oestrogen and mental state.” Nature, 1996, Dame, IN 1972. 383(6598): 306. Wilen, S.H., et al., “Strategies in optical resolutions.” Tetrahedron, Freedman, R. R. et al., "Clonidine raises the Sweating threshold in 33:2725-2736, 1977. symptomatic but not asymptomatic postmenopausal women.” Fertil Zhang, W. et al., “Synergistic Effects of Olanzapine and Other ity & Sterility, 2000, 74(1): 20-3. Antipsychotic Agents in Combination with Fluoxetine on Freedman, R. R., “Physiology of hot flashes.” American Journal of Norepinephrine and Dopamine Release in Rat Prefrontal Cortex.” Human Biology, 2001, 13:453-464. Neuropsychopharmacology, 2000, 23(3): 250-262. French, N., "O-Adrenoceptors and I sites in the mammalian central nervous system.” Pharmacol. Ther. 1995, 68(2): 175-208. Bundgaard (ed.), Design of Prodrugs, Elsevier (1985), Ch. 1 (pp. Janowsky, D. S. et al., “Desipramine: an overview.” Journal of Clini 1-92), Ch. 4 (pp. 157-176), Ch. 5 (pp. 177-198), and Ch. 6 (pp. cal Psychiatry, 1984, 45(10 Pt 2): 3-9. 199-241). Katovich, M. J. et al., “Mechanisms Mediating the Thermal Widder, et al. (ed.), Methods in Enzymology, vol. 112, Academic Response to Morphine Withdrawal in Rats.” Proceedings of the Soci Press (1985), pp. 309-396. ety for Experimental Biology & Medicine, 1990, 193(2): 129-35. Higuchi and Stella (eds.), Prodrugs as Novel Drug Delivery Systems, Katovich, M. J. et al., “Alpha-adrenergic mediation of the tail skin American Chemical Society (1975), pp. 1-115 and 196-223. temperature response to naloxone in morphine-dependent rats.” Freedman, R. R. et al., “O2-Adrenergic mechanism in menopausal Brain Research, 1987, 426: 55-61. hot flushes.” Obstet Gynecol, 1990, 76:573-578. Krämer et al., In: Murphy et al., 3" Int'l Symposium on Recent Brick, K. et al., "Adaptive changes in thermoregulation and their Advances in Urological Cancer Diagnosis and Treatment-Proceed neuropharmacological basis' In: Schönbaum E. et al. (eds.). ings, Paris, France: SCI: 3-7 1992. Thermoregulation. Physiology and Biochemistry, New York. Krogsgaard-Larsen, et al., (ed). Design and Application of Prodrugs, Pergamon Press, (1991) pp. 255-307. Textbook of Drug Design and Development, Chapter 5, 113-191, Ahmar, M. et al., “Enzymatic resolution of methyl 2-alkyl-2- 1991. arylacetates’ Tetrahedron Lett., 1989, 30(50): 7053-7056. US 7419,980 B2 Page 3

Campaigne, E. et al., “Benzobthiophene Derivatives. XXVII. Monguzzi, R. et al., “Synthesis of new O-hydrazinoarylacetic acids 5-Methoxy-6-halo-3-b-acetamidoethylbenzobthiophenes, and derivatives.” Farmaco, Edizione Scientifica, 1976, 31(8), 549 Blocked Analogs of Melatonin.” J. Heterocyclic Chem. 1983, 20, 60. 1697-1703. Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Harrison, I. et al., “Nonsteroidal antiinflammatory agents. I. 6-Sub Gennaro, Mack Publishing Company, Easton, PA, 1985. stituted 2-naphthylacetic acids.” J. Med Chem. 1970, 13(2), 203-5. Eliel, E.L. Stereochemistry of Carbon Compounds, McGraw-Hill, Moon, S. et al., “An Efficient Conversion of Chiral O-Amino Acids to Enantiomerically Pure 3-Amino Cyclic Amines.” Synth. Commun. NY, 1962. 1998, 28(21), 3919-3926. Jacques, et al., Enantiomers, Racemates and Resolutions, Wiley Baker, Wet al., “Nonpeptide renin inhibitors employing a novel Interscience, New York, 1981. 3-aza(or Oxa)-2,4-dialkylglutaric acid moiety as a P2/P3 amide bond Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Syn replacement.” J. Med. Chem. 1992, 35 (10), 1722-1734. thesis 2d. Ed., Wiley & Sons, 1991. Ley, S.V. et al., “Use of polymer Supported reagents for clean multi Chemical Abstracts Service, Namiki, T. et al., step organic synthesis: preparation of amines and amine derivatives “Diphenyl(alkyl)piperazines and dopamine reuptake inhibitors con from alcohols for use in compound library generation.” J. Chem. Soc. taining them.” retrieved from STN. Accession No. 1998:535773 Perkin Trans. I; 15; 1998; 2239-2242. compounds within rn: 212828-72-3P, 212828-73-4p, 212828-74-5p, Manov et al., “Solid-Phase Synthesis of Polyamine Spider Toxins 212828-77-8p, 212828-72-3 (abstract) and JP 10218866 A2. and Correlation with the Natural Products by HPLC-MS/MS.” Helvetica Chimica Acta, 2002, 85(9):2827-2846. * cited by examiner U.S. Patent Sep. 2, 2008 Sheet 1 of 2 US 7419,980 B2

FIGURE 1

5HT

Thermoregulatory/ center Hypothalamus

Brainstem Spinal cord

Adrenals

Epinephrine

Normal skin temperature Or Hot flush (vasodilation and sweating) U.S. Patent US 7419,980 B2

US 7,419,980 B2 1. 2 FUSEDARYLAND HETEROARYL Men also experience hot flushes following steroid hor DERVATIVES AND METHODS OF THEIR mone (androgen) withdrawal. This is true in cases of age USE associated androgen decline (Katovich, et al., Proceedings of the Society for Experimental Biology & Medicine, 1990, 193 CROSS REFERENCE TO RELATED (2): 129-35) as well as in extreme cases of hormone depriva APPLICATIONS tion associated with treatments for prostate cancer (Ber endsen, et al., European Journal of Pharmacology, 2001, This application claims the benefit of U.S. Application 419(1): 47-54. As many as one-third of these patients will Nos. 60/510,811 filed Oct. 14, 2003, 60/561,447 filed Apr. 12, experience persistent and frequent symptoms severe enough 2004, and 60/570,056 filed May 11, 2004, the entire disclo 10 to cause significant discomfort and inconvenience. sures of which are herein incorporated by reference. The precise mechanism of these symptoms is unknown but generally is thought to represent disturbances to normal FIELD OF THE INVENTION homeostatic mechanisms controlling thermoregulation and vasomotor activity (Kronenberg et al., “Thermoregulatory The present invention relates to fused-aryland heteroaryl 15 Physiology of Menopausal Hot Flashes: A Review.” Can. J. derivatives, compositions containing these derivatives, and Physiol. Pharmacol., 1987, 65:1312-1324). methods of their use for the prevention and treatment of The fact that estrogen treatment (e.g. estrogen replacement conditions ameliorated by monoamine reuptake including, therapy) relieves the symptoms establishes the link between interalia, vasomotor symptoms (VMS), sexual dysfunction, these symptoms and an estrogen deficiency. For example, the gastrointestinal and genitourinary disorders, chronic fatigue menopausal stage of life is associated with a wide range of syndrome, fibromylagia syndrome, nervous system disor other acute symptoms as described above and these symp ders, and combinations thereof, particularly those conditions toms are generally estrogen responsive. selected from the group consisting of major depressive dis It has been Suggested that estrogens may stimulate the order, vasomotor symptoms, stress and urge urinary inconti activity of both the norepinephrine (NE) and/or serotonin 25 (5-HT) systems (J. Pharmacology & Experimental Thera nence, fibromyalgia, pain, diabetic neuropathy, and combi peutics, 1986, 236(3) 646-652). It is hypothesized that estro nations thereof. gens modulate NE and 5-HT levels providing homeostasis in the thermoregulatory center of the hypothalamus. The BACKGROUND OF THE INVENTION descending pathways from the hypothalamus via brainstem/ 30 spinal cord and the adrenals to the skin are involved in main Vasomotor symptoms (VMS), referred to as hot flushes and taining normal skin temperature. The action of NE and 5-HT night Sweats, are the most common symptoms associated reuptake inhibitors is known to impinge on both the CNS and with menopause, occurring in 60% to 80% of all women peripheral nervous system (PNS). The pathophysiology of following natural or Surgically-induced menopause. VMS are VMS is mediated by both central and peripheral mechanisms likely to be an adaptive response of the central nervous system 35 and, therefore, the interplay between the CNS and PNS may (CNS) to declining sex steroids. To date, the most effective account for the efficacy of dual acting SRI/NRIs in the treat therapies for VMS are hormone-based treatments, including ment of thermoregulatory dysfunction. In fact, the physi estrogens and/or some progestins. Hormonal treatments are ological aspects and the CNS/PNS involvement in VMS may very effective at alleviating VMS, but they are not appropriate account for the lower doses proposed to treat VMS (Loprinzi, for all women. It is well recognized that VMS are caused by 40 et al. Lancet, 2000, 356:2059-2063; Stearns et al., JAMA, fluctuations of sex steroid levels and can be disruptive and 2003, 289:2827-2834) compared to doses used to treat the disabling in both males and females. A hot flush can last up to behavioral aspects of depression. The interplay of the CNS/ thirty minutes and vary in their frequency from several times PNS in the pathophysiology of VMS and the presented data a week to multiple occurrences per day. The patient experi within this document were used to support the claims that the ences a hot flash as a Sudden feeling of heat that spreads 45 norepinephrine system could be targeted to treat VMS. quickly from the face to the chest and back and then over the Although VMS are most commonly treated by hormone rest of the body. It is usually accompanied by outbreaks of therapy (orally, transdermally, or via an implant), some profuse Sweating. It may sometimes occur several times an patients cannot tolerate estrogen treatment (Berendsen, hour, and it often occurs at night. Hot flushes and outbreaks of Maturitas, 2000, 36(3): 155-164, Fink et al., Nature, 1996, Sweats occurring during the night can cause sleep deprivation. 50 383 (6598): 306). In addition, hormone replacement therapy Psychological and emotional symptoms observed, such as is usually not recommended for women or men with or at risk nervousness, fatigue, irritability, insomnia, depression, for hormonally sensitive cancers (e.g. breast or prostate can memory loss, headache, anxiety, nervousness or inability to cer). Thus, non-hormonal therapies (e.g. fluoxetine, paroxet concentrate are considered to be caused by the sleep depriva ine SRIs and clonidine) are being evaluated clinically. tion following hot flush and night Sweats (Kramer et al., In: 55 WO9944601 discloses a method for decreasing hot flushes in Murphy et al., 3" Int'l Symposium on Recent Advances in a human female by administering fluoxetine. Other options Urological Cancer Diagnosis and Treatment-Proceedings, have been studied for the treatment of hot flashes, including Paris, France: SCI: 3-7 (1992)). steroids, alpha-adrenergic agonists, and beta-blockers, with Hot flushes may be even more severe in women treated for varying degree of success (Waldinger et al., Maturitas, 2000, breast cancer for several reasons: 1) many Survivors of breast 60 36(3): 165-168). cancer are given tamoxifen, the most prevalent side effect of It has been reported that Cadrenergic receptors play a role which is hot flush, 2) many women treated for breast cancer in thermoregulatory dysfunctions (Freedman et al., undergo premature menopause from chemotherapy, 3) Fertility & Sterility, 2000, 74(1): 20-3). These receptors are women with a history of breast cancer have generally been located both pre- and post-synaptically and mediate an inhibi denied estrogen therapy because of concerns about potential 65 tory role in the central and peripheral nervous system. There recurrence of breast cancer (Loprinzi, et al., Lancet, 2000, are four distinct Subtypes of the adrenergic receptors, i.e., 356(9247): 2059-2063). are C, C2, C2, and C2 (Mackinnon et al., TIPS, 1994, 15: 119; US 7,419,980 B2 3 4 French, Pharmacol. Ther., 1995, 68: 175). It has been tionally substituted with one or more R'), alkanoyl, reported that a non-select C.-adrenoceptor antagonist, alkoxycarbonyl, alkylaminocarbonyl, or amino; yohimbine, induces a flush and an O-adrenergic receptor R is H. (C-C)alkyl, or trifluoromethyl: agonist, clonidine, alleviates the yohimbine effect (Katovich, Rand Rare, independently, (C-C)alkyl or (C-C)cy et al., Proceedings of the Society for Experimental Biology & cloalkyl: Medicine, 1990, 193(2): 129-35, Freedman et al., Fertility & or R and R' can together form a ring of 4 to 8 carbon Sterility, 2000, 74(1): 20-3). Clonidine has been used to treat atoms; hot flush. However, using such treatment is associated with a where any carbonatom of said RandR may be optionally number of undesired side effects caused by high doses nec replaced with N. S. or O; essary to abate hot flash described herein and known in the 10 where RandR may be optionally substituted with Ror related arts. OH; or Given the complex multifaceted nature of thermoregula where R and R7 can form a ring with 4 to 8 carbons fused tion and the interplay between the CNS and PNS in maintain onto a cycloalkyl ring of 4 to 6 carbon atoms; ing thermoregulatory homeostasis, multiple therapies and R is H. (C-C)alkyl, benzyl (optionally substituted with approaches can be developed to target vasomotor symptoms. 15 benzyloxy or phenyloxy), naphthylmethyl (optionally The present invention focuses on novel compounds and com substituted with one or more R'), phenyl(C-C)alkyl positions containing these compounds directed to these and (optionally substituted with one or more R'), heteroaryl other important uses. methyl (optionally substituted with R"), cycloalkyl, cycloalkenyl, cycloalkylmethyl (where any carbonatom SUMMARY OF THE INVENTION can be optionally replaced with N. S. or O and where said cycloalkylmethyl can be optionally substituted with The present invention is Directed to fused-aryl and het OH, CF, halo, alkoxy, alkyl, benzyloxy, or alkanoy eroaryl derivatives, compositions containing these deriva loxy), cycloalkenylmethyl (where any carbon atom can tives, and methods of their use for the prevention and treat be optionally replaced with N. S. or O and where said ment of conditions ameliorated by monoamine reuptake 25 cycloalkylmethyl can be optionally substituted with OH, including, inter alia, vasomotor symptoms (VMS), sexual CF, halo, alkoxy, alkyl, benzyloxy, or alkanoyloxy); dysfunction, gastrointestinal and genitourinary disorders, or RandR, together with the nitrogenatom to which R chronic fatigue syndrome, fibromylagia syndrome, nervous is attached, form a ring optionally substituted with R: system disorders, and combinations thereof, particularly R is H. (C-C)alkyl, or (C-C)alkyl-C(=O); those conditions selected from the group consisting of major 30 t is 1, 2, or 3; and depressive disorder, vasomotor symptoms, stress and urge X is 0, 1, or 2. urinary incontinence, fibromyalgia, pain, diabetic neuropa In yet other embodiments, the present invention is directed thy, and combinations thereof. to compositions, comprising: In one embodiment, the present invention is directed to a. at least one compound of formula I; and compounds of formula I: 35 b. at least one pharmaceutically acceptable carrier. In another embodiment, the present invention is Directed to methods for treating or preventing a condition ameliorated by monoamine reuptake in a Subject in need thereof, comprising R8 R5 the step of: NN 14 40 administering to said Subject an effective amount of a com pound of formula I or pharmaceutically acceptable salt ); thereof. The conditions ameliorated by monoamine reuptake include 45 those selected from the group consisting of vasomotor Symp toms, sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromylagia syndrome, nervous system disorders, and combinations thereof, particu or a pharmaceutically acceptable salt thereof. larly those conditions selected from the group consisting of wherein: 50 major depressive disorder, vasomotor symptoms, stress and A is naphthyl, thiophenyl, pyridinyl, furanyl, benzofura urge urinary incontinence, fibromyalgia, pain, diabetic neur nyl, isobenzofuranyl. Xanthenyl, pyrrolyl, indolizinyl, opathy, and combinations thereof. isoindolyl, indolyl, benzothiophenyl, wherein any 1 to 3 In another embodiment, the present invention is directed to carbonatom(s) of said A can be optionally replaced with methods for treating or preventing vasomotor symptoms in a a nitrogen atom, and wherein said A is optionally Sub 55 Subject in need thereof, comprising the step of: stituted with one or more R'; administering to said subject an effective amount of at least W is H or OR; one compound of formula I or pharmaceutically accept R" is, independently, H, OH, alkyl, alkoxy, halo, trifluo able salt thereof. romethyl, alkanoyloxy, methylenedioxy, benzyloxy In yet another embodiment, the present invention is (optionally substituted with one or more R'), phenyloxy 60 directed to methods for treating or preventing a depression (optionally substituted with one or more R'), naphthy disorder in a Subject in need thereof, comprising the step of loxy (optionally substituted with one or more R'), nitro, administering to said subject an effective amount of at least trifluoromethoxy, nitrile, alkenyl, alkynyl, Sulfoxide, one compound of formula I or pharmaceutically accept Sulfonyl, Sulfonamido, phenyl (optionally substituted able salt thereof. with one or more R'), heteroaryl (optionally substituted 65 In yet other embodiments, the present invention is directed with one or more R'), heteroaryloxy (optionally substi to methods for treating or preventing sexual dysfunction in a tuted with one or more R'), heteroaryl methyloxy (op Subject in need thereof, comprising the step of: US 7,419,980 B2 5 6 administering to said Subject an effective amount of at least liter(s), “mL means milliliter(s), “mM” means millimolar, one compound of formula I or pharmaceutically accept “M” means molar, “immole” means millimole(s), “cm' means able salt thereof. centimeters, “SEM' means standard error of the mean and In further embodiments, the present invention is directed to “IU” means International Units. “A C” and A“EDs value” methods for treating or preventing pain in a subject in need means dose which results in 50% alleviation of the observed thereof, comprising the step of condition or effect (50% mean maximum endpoint). administering to said Subject an effective amount of at least “Norepinephrine transporter is abbreviated NET. one compound of formula I or pharmaceutically accept “Human norepinephrine transporter is abbreviated hNET. able salt thereof. “Serotonin transporter” is abbreviated SERT. In another embodiment, the present invention is directed to 10 “Human serotonin transporter is abbreviated hSERT. methods for treating or preventing gastrointestinal or geni “Norepinephrine reuptake inhibitor' is abbreviated NRI. tourinary disorder, particularly stress incontinence or urge “Selective norepinephrine reuptake inhibitor is abbrevi urinary incontinence, in a Subject in need thereof, comprising ated SNRI. the step of: “Serotonin reuptake inhibitor' is abbreviated SRI. administering to said subject an effective amount of a com 15 “Selective serotonin reuptake inhibitor is abbreviated pound of formula I or pharmaceutically acceptable salt SSRI. thereof. “Norepinephrine” is abbreviated NE. In another embodiment, the present invention is directed to “Serotonin is abbreviated 5-HT. methods for treating or preventing chronic fatigue syndrome “Subcutaneous” is abbreviated sc. in a Subject in need thereof, comprising the step of “Intraperitoneal' is abbreviated ip. administering to said subject an effective amount of a com “Oral” is abbreviated po. pound of formula I or pharmaceutically acceptable salt In the context of this disclosure, a number of terms shall be thereof. utilized. The term “treatment as used herein includes pre In another embodiment, the present invention is directed to Ventative (e.g., prophylactic), curative or palliative treatment methods for treating or preventing fibromylagia syndrome in 25 and “treating as used herein also includes preventative, cura a subject in need thereof, comprising the step of: tive and palliative treatment. administering to said subject an effective amount of a com The term “effective amount, as used herein, refers to an pound of formula I or pharmaceutically acceptable salt amount effective, at dosages, and for periods of time neces thereof. sary, to achieve the desired result with respect to prevention or 30 treatment of vasomotor symptoms, depression disorders, BRIEF DESCRIPTION OF THE DRAWINGS sexual dysfunction, or pain. In particular with respect to vaso motor symptoms, “effective amount” refers to the amount of The invention can be more fully understood from the fol compound or composition of compounds that would increase lowing detailed description and the accompanying drawings norepinephrine levels to compensate in part or total for the that form a part of this application. 35 lack of steroid availability in subjects subject afflicted with a FIG. 1 is an overview of estrogenaction on norepinephrine/ vasomotor symptom. Varying hormone levels will influence serotonin mediated thermoregulation. the amount of compound required in the present invention. FIG. 2 is a schematic representation of the interactions of For example, the pre-menopausal state may require a lower norepinephrine and serotonin and their respective receptors level of compound due to higher hormone levels than the (5-HT2, C. and C2-adrenergic). 40 peri-menopausal state. It will be appreciated that the effective amount of compo DETAILED DESCRIPTION OF THE INVENTION nents of the present invention will vary from patient to patient not only with the particular compound, component or com The present invention is Directed to fused-aryl and het position selected, the route of administration, and the ability eroaryl derivatives, compositions containing these deriva 45 of the components (alone or in combination with one or more tives, and methods of their use for the prevention and treat combination drugs) to elicit a desired response in the indi ment of conditions ameliorated by monoamine reuptake vidual, but also with factors such as the disease state or including, inter alia, vasomotor symptoms (VMS), sexual severity of the condition to be alleviated, hormone levels, age, dysfunction, gastrointestinal and genitourinary disorders, sex, weight of the individual, the state of being of the patient, chronic fatigue syndrome, fibromylagia syndrome, nervous 50 and the severity of the pathological condition being treated, system disorders, and combinations thereof, particularly concurrent medication or special diets then being followed by those conditions selected from the group consisting of major the particular patient, and other factors which those skilled in depressive disorder, vasomotor symptoms, stress and urge the art will recognize, with the appropriate dosage ultimately urinary incontinence, fibromyalgia, pain, diabetic neuropa being at the discretion of the attendant physician. Dosage thy, and combinations thereof. 55 regimens may be adjusted to provide the improved therapeu The following definitions are provided for the full under tic response. An effective amount is also one in which any standing of terms and abbreviations used in this specification. toxic or detrimental effects of the components are out As used herein and in the appended claims, the singular weighed by the therapeutically beneficial effects. forms “a,” “an and “the include the plural reference unless Preferably, the compounds of the present invention are the context clearly indicates otherwise. Thus, for example, a 60 administered at a dosage and for a time Such that the number reference to “an antagonist' includes a plurality of Such of hot flushes is reduced as compared to the number of hot antagonists, and a reference to “a compound is a reference to flushes prior to the start of treatment. Such treatment can also one or more compounds and equivalents thereof known to be beneficial to reduce the overall severity or intensity distri those skilled in the art, and so forth. bution of any hot flushes still experienced, as compared to the The abbreviations in the specification correspond to units 65 severity of hot flushes prior to the start of the treatment. With of measure, techniques, properties, or compounds as follows: respect to depression disorders, sexual dysfunction, and pain, “min' means minutes, “h” means hour(s), 'u' means micro the compounds of the present invention are administered at a US 7,419,980 B2 7 8 dosage and for a time such that there is the prevention, alle The term “subject' or “patient” refers to an animal includ viation, or elimination of the symptom or condition. ing the human species that is treatable with the compositions, For example, for an afflicted patient, compounds of for and/or methods of the present invention. The term “subject’ mula I may be administered, preferably, at a dosage of from or “subjects” is intended to refer to both the male and female about 0.1 mg/day to about 200 mg/day, more preferably from gender unless one gender is specifically indicated. Accord about 1 mg/day to about 100 mg/day and most preferably ingly, the term “patient comprises any mammal which may from about 1 mg/day to 50 mg/day for a time sufficient to benefit from treatment or prevention of vasomotor symptoms, reduce and/or substantially eliminate the number and/or depression disorders, sexual dysfunction, or pain, such as a severity of hot flushes or symptom or condition of the depres human, especially if the mammal is female, either in the sion disorder, sexual dysfunction, or pain. 10 pre-menopausal, peri-menopausal, or post-menopausal The terms “component.” “composition of compounds.” period. Furthermore, the term patient includes female ani “compound,” “drug. or “pharmacologically active agent” or mals including humans and, among humans, not only women “active agent” or “medicament” are used interchangeably of advanced age who have passed through menopause but herein to refer to a compound or compounds or composition also women who have undergone hysterectomy or for some of matter which, when administered to a Subject (human or 15 other reason have Suppressed estrogen production, such as animal) induces a desired pharmacological and/or physi those who have undergone long-term administration of cor ologic effect by local and/or systemic action. ticosteroids, suffer from Cushing's syndrome or have The terms “component”, “drug or “pharmacologically gonadal dysgenesis. However, the term “patient' is not active agent” or “active agent” or “medicament” are used intended to be limited to a woman. interchangeably herein to refer to a compound or compounds The terms “premature menopause' or “artificial meno or composition of matter which, when administered to an pause refer to ovarian failure of unknown cause that may organism (human or animal) induces a desired pharmaco occur before age 40. It may be associated with Smoking, logic and/or physiologic effect by local and/or systemic living at high altitude, or poor nutritional status. Artificial action. menopause may result from oophorectomy, chemotherapy, The term “modulation” refers to the capacity to either 25 radiation of the pelvis, or any process that impairs ovarian enhance or inhibit a functional property of a biological activ blood Supply. ity or process, for example, receptor binding or signaling The term “pre-menopausal” means before the menopause, activity. Such enhancement or inhibition may be contingent the term "peri-menopausal” means during the menopause and on the occurrence of a specific event, such as activation of a the term “post-menopausal” means after the menopause. signal transduction pathway and/or may be manifest only in 30 "Ovariectomy’ means removal of an ovary or ovaries and can particular cell types. The modulator is intended to comprise be effected according to Merchenthaler et al., Maturitas, any compound, e.g., antibody, Small molecule, peptide, oli 1998,30(3): 307-316. gopeptide, polypeptide, or protein, preferably small mol "Side effect” refers to a consequence other than the one(s) ecule, or peptide. for which an agent or measure is used, as the adverse effects As used herein, the term “inhibitor” refers to any agent that 35 produced by a drug, especially on a tissue or organ system inhibits, Suppresses, represses, or decreases a specific activ other then the one sought to be benefited by its administration. ity, such as serotonin reuptake activity or the norepinephrine In the case, for example, of high doses of NRIs or NRI/SRI reuptake activity. compounds alone, the term “side effect” may refer to such The term “inhibitor is intended to comprise any com conditions as, for example, vomiting, nausea, Sweating, and pound, e.g., antibody, Small molecule, peptide, oligopeptide, 40 flushes (Janowsky, et al., Journal of Clinical Psychiatry, polypeptide, or protein, preferably small molecule or peptide, 1984, 45(10 Pt 2): 3-9). that exhibits a partial, complete, competitive and/or inhibi Alkyl as used herein, refers to an aliphatic hydrocarbon tory effect on mammalian, preferably the human norepineph chain of 1 to about 20 carbonatoms, preferably 1 to 10 carbon rine reuptake or both serotonin reuptake and the norepineph atoms, more preferably, 1 to 6 carbon atoms, and even more rine reuptake, thus diminishing or blocking, preferably 45 preferably, 1 to 4 carbon atoms and includes straight and diminishing, Some or all of the biological effects of endog branched chains such as methyl, ethyl, n-propyl, isopropyl. enous norepinephrine reuptake or of both serotonin reuptake n-butyl, isobutyl, Sec-butyl, t-butyl, n-pentyl, isopentyl, neo and the norepinephrine reuptake. pentyl, n-hexyl, and isohexyl. Lower alkyl refers to alkyl Within the present invention, the compounds of formula I having 1 to 4 carbon atoms. may be prepared in the form of pharmaceutically acceptable 50 “Alkoxy.” as used herein, refers to the group R-O- salts. As used herein, the term "pharmaceutically acceptable where R is an alkyl group of 1 to 6 carbon atoms. salts' refers to salts prepared from pharmaceutically accept “Alkoxycarbonyl, as used herein, refers to the group able non-toxic acids, including inorganic salts, and organic R—O—C(=O)— where R is an alkyl group of 1 to 6 carbon salts. Suitable non-organic salts include inorganic and atOmS. organic acids such as acetic, benzenesulfonic, benzoic, cam 55 phorsulfonic, citric, ethenesulfonic, fumaric, gluconic, “Alkanoyl.” as used herein, refers to the group R C glutamic, hydrobromic, hydrochloric, isethionic, lactic, (=O)— where R is an alkyl group of 1 to 6 carbon atoms. malic, maleic, mandelic, methanesulfonic, mucic, nitric, “Alkanoyloxy, as used herein, refers to the group R C pamoic, pantothenic, phosphoric, Succinic, Sulfuric, tartaric (=O)—O— where Risan alkyl group of 1 to 6 carbonatoms. acid, p-toluenesulfonic and the like. Particularly preferred are 60 Alkylaminocarbonyl as used herein, refers to the group hydrochloric, hydrobromic, phosphoric, and Sulfuric acids, R NH CO =O)— where R is an alkyl group of 1 to 6 and most preferably is the hydrochloride salt. carbon atoms. Administering as used herein, means either directly Alkylcarbonylamino, as used herein, refers to the group administering a compound or composition of the present R—C(=O) NH where R is an alkyl group of 1 to 6 carbon invention, or administering a prodrug, derivative or analog 65 atOmS. which will forman equivalent amount of the active compound Alkenyl or “olefinic, as used herein, refers to an alkyl or substance within the body. group of at least two carbonatoms having one or more double US 7,419,980 B2 10 bonds, wherein alkyl is as defined herein. Alkenyl groups can nylpyrimidinyl, phenanthridinyl, phenanthrolinyl, be optionally substituted with one or more R', as defined phenoxazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, herein. phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridi Alkynyl as used herein, refers to an alkyl group of at least nyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl. two carbon atoms having one or more triple bonds, wherein pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl pyridazinyl, alkyl is as defined herein. Alkynyl groups can be optionally pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, substituted with one or more R', as defined herein. pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, Aryl as used herein, refers to an optionally substituted, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, qui mono-, di-, tri-, or other multicyclic aromatic ring system nuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroiso having from about 5 to about 50 carbon atoms (and all com 10 quinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1.2, binations and Subcombinations of ranges and specific num 3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- bers of carbon atoms therein), with from about 6 to about 10 thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, carbons being preferred. Non-limiting examples include, for thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1.2, example, phenyl, naphthyl, anthracenyl, and phenanthrenyl. 3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, Aryl groups can be optionally substituted with one or with 15 xanthenyl. Preferred heterocycles include, but are not limited one or more R', as defined herein. to, pyridinyl, furanyl, thienyl, pyrrolyl pyrazolyl, imidazolyl, “Heteroaryl, as used herein, refers to an optionally sub indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzo stituted, mono-, di-, tri-, or other multicyclic aromatic ring triazolyl, benzisoxazolyl, OXindolyl, benzoxazolinyl, orisati system that includes at least one, and preferably from 1 to noyl. Also included are fused ring and spiro compounds con about 4 Sulfur, oxygen, or nitrogen heteroatom ring members. taining, for example, the above heterocycles. Heteroaryl groups can have, for example, from about 3 to “Heteroarylmethyl as used herein, refers to the group about 50 carbon atoms (and all combinations and subcombi R—CH2— where R is a heteroaryl group, as defined herein. nations of ranges and specific numbers of carbon atoms “Heteroarylmethyloxy.” as used herein, refers to the group therein), with from about 4 to about 10 carbons being pre R—CH2—O— where R is a heteroaryl group, as defined ferred. Non-limiting examples of heteroaryl groups include, 25 for example, pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl pyrim herein. idyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl pyrazinyl, “Heteroaryloxy, as used herein, refers to the group pyrimidyl, quinolyl, isoquinolyl, thiophenyl, benzothienyl, R—O— where R is a heteroaryl group, as defined herein. isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benz “Heteroarylmethyloxy.” as used herein, refers to the group imidazolyl, and isoxazolyl. Heteroaryl groups can be option 30 R—CH2—O— where R is a heteroaryl group, as defined ally substituted with one or with one or more R', as defined herein. herein. “Cycloalkyl as used herein, refers to an optionally sub “Heterocyclic ring,” as used herein, refers to a stable 5- to stituted, alkyl group having one or more rings in their struc 7-membered monocyclic or bicyclic or 7- to 10-membered tures having from 3 to about 20 carbon atoms (and all com bicyclic heterocyclic ring that is saturated, partially unsatur 35 binations and Subcombinations of ranges and specific ated or unsaturated (aromatic), and which contains carbon numbers of carbon atoms therein), with from 3 to about 10 atoms and from 1 to 4 heteroatoms independently selected carbon atoms being preferred. Multi-ring structures may be from the group consisting of N, O and S and including any bridged or fused ring structures. Groups include, but are not bicyclic group in which any of the above defined heterocyclic limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, rings is fused to a benzene ring. The nitrogen and Sulfur 40 cyclooctyl, 2-4-isopropyl-1-methyl-7-Oxa-bicyclo[2.2.1 heteroatoms may optionally be oxidized. The heterocyclic heptanyl, 2-1.2.3,4-tetrahydro-naphthalenyl, and adaman ring may be attached to its pendant group at any heteroatom or tyl. carbonatom that results in a stable structure. The heterocyclic “Cycloalkylmethyl, as used herein, refers to the group rings described herein may be substituted on carbon or on a R—CH2— where R is a cycloalkyl group, as defined herein. nitrogen atom if the resulting compound is stable. If specifi 45 “Cycloalkenyl as used herein, refers to an optionally sub cally noted, a nitrogenatom in the heterocycle may optionally stituted, alkenegroup having one or more rings in their struc be quaternized. It is preferred that when the total number of S tures having from 3 to about 20 carbon atoms (and all com and O atoms in the heterocycle exceeds one, then these het binations and Subcombinations of ranges and specific eroatoms are not adjacent to one another. It is preferred that numbers of carbon atoms therein), with from 3 to about 10 the total number of S and O atoms in the heterocycle is not 50 carbon atoms being preferred. Multi-ring structures may be more than one. Examples of heterocycles include, but are not bridged or fused ring structures. Groups include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H, 6H-1.5.2-dithi limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, azinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carba cyclohexenyl, cyclooctenyl. Zole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, “Cycloalkenylmethyl, as used herein, refers to the group azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl. 55 R—CH2— where R is a cycloalkenyl group, as defined benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriaz herein. olyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benz imidazalonyl, carbazolyl, 4H-carbazolyl, Cl-, 3-, or Y-carboli "Sulfoxide,” as used herein, refers to a compound or moi nyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, ety containing the group —S(=O)—. 2H, 6H-1.5.2-dithiazinyl, dihydrofuro2,3-btetrahydrofu 60 "Sulfonamido.” as used herein, refers to a moiety contain ran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imida ing the group —S(O). NH-. Zolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, "Sulfonyl, as used herein, refers to a moiety containing the indolyl, isobenzofuranyl, isochromanyl, isolindazolyl, isoin group —S(O) -. dolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, "Halo’ or “halogen, as used herein, refers to chloro, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, Oxa 65 bromo, fluoro, and iodo. diazolyl, 1.2.3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadia In one embodiment, the present invention is directed to Zolyl, 1.3,4-oxadiazolyl, oxazolidinyl., oxazolyl, oxazolidi compounds of formula I: US 7,419,980 B2 11 12 carbonatom(s) of said A can be optionally replaced with a nitrogen atom, and wherein said A is optionally Sub I stituted with one or more R'; R8 R5 W is H or OR; R" is, independently, H, OH, alkyl, alkoxy, halo, trifluo NN ~, romethyl, alkanoyloxy, methylenedioxy, benzyloxy x( N (optionally substituted with one or more R'), phenyloxy ); (optionally substituted with one or more R'), naphthy W loxy (optionally substituted with one or more R'), nitro, A 10 trifluoromethoxy, nitrile, alkenyl, alkynyl, Sulfoxide, R6 Sulfonyl, Sulfonamido, phenyl (optionally substituted with one or more R'), heteroaryl (optionally substituted with one or more R'), heteroaryloxy (optionally substi or a pharmaceutically acceptable salt thereof. tuted with one or more R'), heteroaryl methyloxy (op wherein: 15 tionally substituted with one or more R'), alkanoyl, A is naphthyl, thiophenyl, pyridinyl, furanyl, benzofura alkoxycarbonyl, alkylaminocarbonyl, or amino; nyl, isobenzofuranyl. Xanthenyl, pyrrolyl, indolizinyl, R is H. (C-C)alkyl, or trifluoromethyl: isoindolyl, indolyl, benzothiophenyl, wherein any 1 to 3 RandR together form a ring of 4 to 8 carbon atoms; carbonatom(s) of said A can be optionally replaced with R is H. (C-C)alkyl, benzyl (optionally substituted with a nitrogen atom, and wherein said A is optionally Sub benzyloxy or phenyloxy), naphthylmethyl (optionally stituted with one or more R'; substituted with one or more R'), phenyl(C-C)alkyl W is H or OR; (optionally substituted with one or more R'), heteroaryl R" is, independently, H, OH, alkyl, alkoxy, halo, trifluo methyl (optionally substituted with R"), cycloalkyl, romethyl, alkanoyloxy, methylenedioxy, benzyloxy cycloalkenyl, cycloalkylmethyl (where any carbonatom (optionally substituted with one or more R'), phenyloxy 25 can be optionally replaced with N. S. or O and where (optionally substituted with one or more R'), naphthy said cycloalkylmethyl can be optionally substituted with loxy (optionally substituted with one or more R'), nitro, OH, CF, halo, alkoxy, alkyl, benzyloxy, or alkanoy trifluoromethoxy, nitrile, alkenyl, alkynyl, Sulfoxide, loxy), cycloalkenylmethyl (where any carbon atom can Sulfonyl, Sulfonamido, phenyl (optionally substituted be optionally replaced with N. S. or O and where said with one or more R'), heteroaryl (optionally substituted 30 cycloalkylmethyl can be optionally substituted with OH, with one or more R'), heteroaryloxy (optionally substi CF, halo, alkoxy, alkyl, benzyloxy, or alkanoyloxy); tuted with one or more R'), heteroaryl methyloxy (op or RandR, together with the nitrogenatom to which R tionally substituted with one or more R'), alkanoyl, is attached, form a ring optionally substituted with R: alkoxycarbonyl, alkylaminocarbonyl, or amino; R’ is H: R is H., (C-C)alkyl, or trifluoromethyl: 35 t is 1, or 2; and R and R7 are, independently, (C-C)alkyl or (C-C)cy X is 1, or 2. cloalkyl: In certain preferred embodiments, A is naphthyl, thiophe or R and R' can together form a ring of 4 to 8 carbon nyl, pyridinyl, furanyl, benzofuranyl, isobenzofuranyl, Xan atoms; thenyl, pyrrolyl, indolizinyl, isoindolyl, indolyl, ben where any carbonatom of said RandR may be optionally 40 Zothiophenyl. replaced with N. S. or O; In certain preferred embodiments, W is H. In certain other where R and R may be optionally substituted with Ror preferred embodiments, W is OR. OH; or In certain preferred embodiments, R' is, independently, H, where Rand R' can form a ring with 4 to 8 carbons fused OH, alkyl (especially methyl, ethyl, propyl, and butyl), onto a cycloalkyl ring of 4 to 6 carbon atoms; 45 alkoxy (especially methoxy and ethoxy), halo (especially R is H. (C-C)alkyl, benzyl (optionally substituted with chloro, fluoro, and bromo), trifluoromethyl, alkanoyloxy, benzyloxy or phenyloxy), naphthylmethyl (optionally methylenedioxy, benzyloxy, phenyloxy, naphthyloxy, nitro, substituted with one or more R'), phenyl (C-C)alkyl trifluoromethoxy, nitrile, alkenyl, alkynyl, sulfoxide, sulfo (optionally substituted with one or more R'), heteroaryl nyl, Sulfonamido, phenyl, heteroaryl, heteroaryloxy, het methyl (optionally substituted with R"), cycloalkyl, 50 eroaryl methyloxy, alkanoyl, alkoxycarbonyl, alkylami cycloalkenyl, cycloalkylmethyl (where any carbonatom nocarbonyl, or amino; can be optionally replaced with N. S. or O and where In certain preferred embodiments, R is Hor (C-C)alkyl said cycloalkylmethyl can be optionally substituted with (especially methyl, ethyl, propyl, and butyl. OH, CF, halo, alkoxy, alkyl, benzyloxy, or alkanoy In certain preferred embodiments, Rand Rare, indepen loxy), cycloalkenylmethyl (where any carbon atom can 55 dently, (C-C)alkyl (especially methyl, ethyl, propyl, and be optionally replaced with N. S. or O and where said butyl) or (C-C)cycloalkyl (especially cyclopropyl, cyclobu cycloalkylmethyl can be optionally substituted with OH, tyl, and cyclohexyl). CF, halo, alkoxy, alkyl, benzyloxy, or alkanoyloxy); In certain preferred embodiments, Rand R' can together or RandR, together with the nitrogenatom to which R form a ring of 4 to 8 carbon atoms. is attached, form a ring optionally substituted with R: 60 In certain preferred embodiments, R is H., (C-C)alkyl R is H., (C-C)alkyl, or (C-C)alkyl-C(=O); (especially methyl, ethyl, propyl, and butyl), benzyl, naphth t is 1, 2, or 3; and ylmethyl, phenyl(C-C)alkyl, heteroarylmethyl, or X is 0, 1, or 2. cycloalkyl (especially cyclopropyl, cyclobutyl, and cyclo In certain preferred embodiments, hexyl), cycloalkenyl, cycloalkylmethyl, cycloalkenylmethyl. A is naphthyl, thiophenyl, pyridinyl, furanyl, benzofura 65 In certain preferred embodiments, RandR, together with nyl, isobenzofuranyl. Xanthenyl, pyrrolyl, indolizinyl, the nitrogenatom to which R is attached, form a ring option isoindolyl, indolyl, benzothiophenyl, wherein any 1 to 3 ally substituted with R. US 7,419,980 B2 13 14 In certain preferred embodiments, R is Hor (C-C)alkyl 1-2-(4-aminopiperidin-1-yl)-1-(5-chlorothien-3-yl)ethyl (especially methyl or ethyl). cyclohexanol dihydrochloride: In certain preferred embodiments, t is 1. In certain other 1-1-(1-benzothien-3-yl)-2-piperazin-1-ylethylcyclohex preferred embodiments, t is 2. In yet certain other preferred anol dihydrochloride: embodiments, t is 3. 5 1-1-(1-methyl-1H-indol-3-yl)-2-piperazin-1-ylethylcyclo In certain preferred embodiments, x is 0. In certain other hexanol dihydrochloride; preferred embodiments, x is 1. In yet certain other preferred 1-1-(1H-indol-3-yl)-2-piperazin-1-ylethylcyclohexanol embodiments, X is 2. dihydrochloride; In certain preferred embodiments, A is naphthyl, ben 1-1-(2-chlorothien-3-yl)-2-piperazin-1-ylethylcyclohex Zothienyl, thienyl, quinolinyl or indolyl. 10 anol dihydrochloride: In certain preferred embodiments, R' is hydrogen, OH, 1-1-(5-chlorothien-3-yl)-2-(4-methylpiperazin-1-yl)ethyl halogen, C-Calkyl and C-Calkoxy. cyclohexanol dihydrochloride: In certain preferred embodiments, Rand R' for example (1R)-1-(5-chlorothien-3-yl)-2-(4-methylpiperazin-1-yl) may form a 4, 5, 6, 7 or 8 membered ring; e.g., a cyclohexyl ethylcyclohexanol dihydrochloride; ring, one carbon of which is optionally nitrogen. The ring 15 1-(1S)-1-(5-chlorothien-3-yl)-2-(4-methylpiperazin-1-yl) formed by Rand R7 may be for example substituted by Hor ethylcyclohexanol dihydrochloride; C-C alkyl. 1-1-(5-chloro-1-benzothien-3-yl)-2-piperazin-1-ylethylcy In certain preferred embodiments, when alkyl, R and R' clohexanol dihydrochloride; are, independently, methyl or ethyl. 1-1-(1-benzothien-2-yl)-2-piperazin-1-ylethylcyclohex In certain preferred embodiments, W is OH. anol dihydrochloride: In certain preferred embodiments, t is 1 or 2. 1-(2-piperazin-1-yl-1-quinolin-3-ylethyl)cyclohexanol dihy In certain preferred embodiments, x is 1. drochloride; In certain preferred embodiments, R is H. (C-C)alkyl 1-1-(1-naphthyl)-2-piperazin-1-ylethylcyclooctanol dihy (especially methyl, ethyl, propyl, and butyl), benzyl, naphth drochloride; ylmethyl, phenyl(C-C)alkyl, heteroarylmethyl, cycloalkyl 25 1-2-(4-methylpiperazin-1-yl)-1-(1-naphthyl)ethylcyclooc (especially cyclopropyl, cyclobutyl, and cyclohexyl), tanol dihydrochloride; cycloalkenyl, cycloalkylmethyl, or cycloalkenylmethyl. 1-1-(1-naphthyl)-2-piperazin-1-ylethylcycloheptanol dihy Preferred compounds of formula I include: drochloride; 1-1-(2-naphthyl)-2-piperazin-1-ylethylcyclobutanol dihy 1-2-(4-methylpiperazin-1-yl)-1-(1-naphthyl)ethylcyclo drochloride; 30 heptanol dihydrochloride; 1-1-(1-naphthyl)-2-piperazin-1-ylethylcyclohexanol dihy 1-1-(5-methoxy-1-benzothien-3-yl)-2-piperazin-1-ylethyl drochloride: cyclohexanol dihydrochloride: 1-1-(1-naphthyl)-2-piperazin-1-ylethylcyclopentanol dihy 1-1-(4-bromothien-2-yl)-2-piperazin-1-ylethylcyclohex drochloride; anol dihydrochloride: 3-ethyl-2-(1-naphthyl)-1-piperazin-1-ylpentan-3-ol dihy 35 4-ethyl-1-2-(4-methylpiperazin-1-yl)-1-(1-naphthyl)ethyl drochloride; cyclohexanol dihydrochloride: 1-2-(4-methylpiperazin-1-yl)-1-(1-naphthyl)ethylcyclo 4-methyl-1-2-(4-methylpiperazin-1-yl)-1-(1-naphthyl) pentanol dihydrochloride; ethylcyclohexanol dihydrochloride; 1-methyl-4-1-(2-naphthyl)-2-piperazin-1-ylethylpiperi 1-(2-piperazin-1-yl-1-pyridin-3-ylethyl)cyclohexanol trihy din-4-ol dihydrochloride; 40 drochloride; 1-1-(2-naphthyl)-2-piperazin-1-ylethylcyclohexanol dihy 1-(2-piperazin-1-yl-1-pyridin-3-ylethyl)cyclohexanol trihy drochloride; drochloride; 1-2-(4-methylpiperazin-1-yl)-1-(2-naphthyl)ethylcyclo 1-1-(6-methoxy-2-naphthyl)-2-piperazin-1-ylethylcyclo hexanol dihydrochloride; hexanol: 1-1-(1-naphthyl)-2-piperazin-1-ylethylcyclobutanol dihy 45 1-1-(6-methoxy-2-naphthyl)-2-(4-methylpiperazin-1-yl) drochloride; ethylcyclohexanol; and 1-2-(4-methylpiperazin-1-yl)-1-(1-naphthyl)ethylcyclobu pharmaceutically acceptable salts thereof. tanol dihydrochloride: Some of the compounds of the present invention may con 4-tert-butyl-1-1-(1-naphthyl)-2-piperazin-1-ylethylcyclo tain chiral centers and Such compounds may exist in the form 50 of Stereoisomers (i.e. enantiomers). The present invention hexanol dihydrochloride; includes all Such stereoisomers and any mixtures thereof 3-ethyl-1-(4-methylpiperazin-1-yl)-2-(1-naphthyl)pentan-3- including racemic mixtures. Racemic mixtures of the stere ol dihydrochloride; oisomers as well as the Substantially pure Stereoisomers are 4-ethyl-1-1-(1-naphthyl)-2-piperazin-1-ylethylcyclohex within the scope of the invention. The term “substantially anol dihydrochloride; 55 pure.” as used herein, refers to at least about 90 mole%, more 4-methyl-1-1-(1-naphthyl)-2-piperazin-1-ylethylcyclohex preferably at least about 95 mole %, and most preferably at anol dihydrochloride; least about 98 mole % of the desired stereoisomer is present 4-tert-butyl-1-2-(4-methylpiperazin-1-yl)-1-(1-naphthyl) relative to other possible stereoisomers. Preferred enanti ethylcyclohexanol dihydrochloride; omers may be isolated from racemic mixtures by any method 1-1-(2,5-dichlorothien-3-yl)-2-piperazine-1-ylethylcyclo 60 known to those skilled in the art, including high performance hexanol dihydrochloride; liquid chromatography (HPLC) and the formation and crys 1-1-(5-chlorothien-2-yl)-2-piperazin-1-ylethylcyclohex tallization of chiral salts or prepared by methods described anol dihydrochloride; herein. See, for example, Jacques, et al., Enantiomers, Race 1-1-(5-bromothien-2-yl)-2-piperazin-1-ylethylcyclohex mates and Resolutions (Wiley Interscience, New York, 1981); anol dihydrochloride; 65 Wilen, S. H., et al., Tetrahedron, 33:2725 (1977); Eliel, E. L. 1-1-(5-chlorothien-3-yl)-2-piperazin-1-ylethylcyclohex Stereochemistry of Carbon Compounds, (McGraw-Hill, NY. anol dihydrochloride; 1962); Wilen, S. H. Tables of Resolving Agents and Optical US 7,419,980 B2 15 16 Resolutions, p. 268 (E. L. Eliel, Ed., University of Notre c) converting a compound of formula I having a reactive Dame Press, Notre Dame, Ind. 1972). Substituent group to a compound of formula I having a The present invention includes prodrugs of the compounds different substituent group; or of formula I. “Prodrug. as used herein, means a compound d) converting a basic compound of formula I to a pharmaceu which is convertible in vivo by metabolic means (e.g. by 5 tically acceptable salt or vice versa. hydrolysis) to a compound of formula I. Various forms of For example, compounds of the present invention are Suit prodrugs are known in the art, for example, as discussed in ably prepared in accordance with the following general Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Wid description and specific examples. Variables used are as der, et al. (ed.), Methods in Enzymology, Vol. 4, Academic defined for formula I, unless otherwise noted. The reagents Press (1985); Krogsgaard-Larsen, et al., (ed). “Design and 10 used in the preparation of the compounds of this invention can Application of Prodrugs.” Textbook of Drug Design and be either commercially obtained or can be prepared by stan Development, Chapter 5, 113-191 (1991), Bundgaard, et al., dard procedures described in the literature. The reagents used Journal of Drug Deliver Reviews, 1992, 8:1-38, Bundgaard, in the preparation of the compounds of this invention can be J. of Pharmaceutical Sciences, 1988, 77:285 et seq.; and either commercially obtained or can be prepared by standard Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery 15 procedures described in the literature. In accordance with this Systems, American Chemical Society (1975). invention, compounds of formula I are produced by the fol Further, the compounds of formula I may exist in unsol lowing reaction schemes (Scheme 1-5). vated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the Solvated forms are considered equivalent to the Scheme 1 unsolvated forms for the purpose of the present invention. aldol reaction The compounds of the present invention may be prepared R OH Ketone in a number of ways well knownto those skilled in the art. The compounds can be synthesized, for example, by the methods R- 1. described below, or variations thereon as appreciated by the 25 O skilled artisan. All processes disclosed in association with the IV present invention are contemplated to be practiced on any R6 R7 Scale, including milligram, gram, multigram, kilogram, mul HO coupling reaction tikilogram or commercial industrial scale. Rl OH Amine As will be readily understood, functional groups present 30 may contain protecting groups during the course of synthesis. R-A Protecting groups are known per se as chemical functional O groups that can be selectively appended to and removed from V functionalities, such as hydroxyl groups and carboxyl groups. These groups are present in a chemical compound to render 35 R6 R7 Xn 1Y reduction Such functionality inert to chemical reaction conditions to HO r N reducing agent which the compound is exposed. Any of a variety of protect R N }x ing groups may be employed with the present invention. R-A Protecting groups that may be employed in accordance with O the present invention may be described in Greene, T. W. and 40 Wuts, P. G. M., Protective Groups in Organic Synthesis 2d. VI Ed., Wiley & Sons, 1991. Rs deprotection This invention also provides processes for preparing a R6 R7 Xn 1Y (if applicable) compound of formula I, which processes include one of the HO r N acid following: 45 R N )x a) reducing a compound of formula R VII Rs R6 R7 Y R8 R5 50 HO Xn 1 NN ~ Rl N )x x( N R )t- O I 55 W where A. Y-H, Rs, or P. R6 Pisanamine protecting group, preferably but not limited to R7 tert-butoxycarbonyl: 60 A is as previously defined and can be optionally Substituted wherein R. X., t, A and Ware as defined herein, to give a with one or more R, and compound of formula I; if necessary any reactive groups R, R2, R. R. Rs. R. R-7, Rs and X are as previously or sites being protected during the reaction by protecting defined. group(s) and removed thereafter; or Compounds of formula I can be prepared from compounds b)alkylating a compound of formula I wherein Rishydrogen 65 of formula VI via reduction followed by deprotection, where with an alkylating agent to give a compound of formula I Y=P; otherwise the deprotection step is omitted. Where wherein R is as defined herein excepting hydrogen; or P-tert-butoxycarbonyl, any conventional method for the US 7,419,980 B2 17 18 deprotection of a carbamate can be utilized for this conver sion. In accordance with the preferred embodiment of this invention, deprotection is carried out using a protic acid, i.e., Scheme 3 hydrochloric acid. Reduction is performed using any conven coupling reaction tional method of reducing an amide to an amine. In accor 5 Rs dance with the preferred embodiment of this invention, the HO r N Pd(0) or Pd(II)/RP compounds of formula VI are treated with a solution of borane in tetrahydrofuran and heated at 70-80° C. I or Br-AR Nu )x Compounds of formula VI can be prepared via the coupling 10 VII of compounds of formula V with an appropriately substituted R5 P deprotection secondary or primary amine. The reaction is carried out by R6 R XN N1 HO acid any conventional method for the activation of a carboxylic Her acid to form an amide. In the preferred embodiment of this NC-AR Nu )x invention, the carboxylic acid is treated with benzotriazol-1- 15 yloxytris(dimethylamino)phosphonium hexafluoro phos IX phate in the presence of an appropriately substituted second Rs R6 R Xn N1 H ary or primary amine and triethylamine. HO Compounds of formula V are prepared by reacting an R N )x appropriately Substituted ketone with an aryl or heteroary NC-A lacetic acid of formula IV via an aldol reaction. The aryl or heteroarylacetic acids of formula IV can be either commer cially obtained or are known compounds that can be prepared by standard procedures described in the literature. Com If it is desired to produce compounds of formula X where pounds of formula IV represent an organic acid having an 25 R'-nitrile, they can be formed from compounds of formula alpha carbon atom, so reaction with a ketone occurs at the IX, where P=an amine protecting group, preferably but not alpha carbon atom of this carboxylic acid. This reaction is limited to tert-butoxycarbonyl. In the case where P=tert-bu carried out by any conventional means of reacting the alpha toxycarbonyl, any conventional method for the deprotection carbon atom of a carboxylic acid with a ketone. Generally, in 30 of a carbamate can be utilized for this conversion. In accor these aldol reactions, a ketone is reacted with the dianion of dance with the preferred embodiment of this invention, the acetic acid. The anion can be generated with a strong deprotection is carried out using a protic acid, i.e., hydrochlo organic base Such as lithium diisopropylamide, as well as other organic lithium bases. This reaction is performed in low ric acid. boiling point solvents such as tetrahydrofuran at low tempera 35 Compounds of formula IX can beformed from compounds tures from -80° C. to about -50° C. being preferred. of formula VII where Riodine or bromine, and Y=P (See Scheme 1). Any conventional method for converting an aryl iodide oraryl bromide to an aryl nitrile can be utilized for this Scheme 2 conversion. According to the preferred embodiment of this Rs 40 invention, the aryl bromide of formula VII is treated with Zinc R6 R7 XN cyanide, 1,1'-bis(diphenylphosphino) ferrocine, Zinc dust, HO r NH alkylation and catalytic tris(dibenzylideneacetone)dipalladium. This reaction is performed in high boiling point solvents such as RR su )x N,N-dimethylformamide, under nitrogen, at elevated tem I 45 peratures from 100° C. to about 150° C. being preferred. 5 Compounds of formula VII are prepared in Scheme 1. If it is XN-Rs desired to form compounds of formula VIII from compounds of formula X, the procedure outlined in Scheme 2 can be R Nu )x followed. R-S OC 50 VIII Scheme 4 coupling reaction If it is desired to produce compounds of formula VIII, they Rs can beformed from compounds of formula I, where Y-H, via 55 R6 R XN-P C-B(OH), an alkylation with an alkylhalide or via a reductive amination r N HePd(0) or Pd(II) with an aldehyde or ketone. Any conventional method of R N )x Na2CO3 O KPO alkylating a secondary amine with an alkyl halide can be Brro I-A utilized. In addition, any conventional method of performing VII a reductive amination can be utilized. In accordance with the 60 Rs deprotection preferred embodiment of this invention, when it is desired to R6 R7 Xn 1 P form compounds of formula VIII where Rs methyl, a mix HO r N acid ture of the amine and formaldehyde informic acid is heated at R N )x 60° C.-80°C. If is desired to form compounds of formula VIII A where Rs lower alkyl other than methyl, a mixture of the 65 amine and an appropriately substituted aldehyde or ketone in XI methylene chloride is treated with trisacetoxyborohydride. US 7,419,980 B2 19 20 embodiment of this invention, the aryl iodide or aryl bromide -continued of formula VII is treated with an appropriately substituted alkenyl or alkynyl Stannane and catalytic tetrakis(triph R6 R Rs H enylphosphine)palladium(0). This reaction is performed in HO 5 high boiling point solvents such as N,N-dimethylformamide C s or toluene, under nitrogen, at elevated temperatures from 90° ( ) R YA Nu )x C. to about 120° C. being preferred. Compounds of formula XIV are formed from compounds of formula XIV as XII described in Scheme 1. If it is desired to form compounds of 10 formula VIII from compounds of formula XIV, the procedure outlined in Scheme 2 can be followed. Compounds of formula VII, where R-bromine or iodine The compounds of formula I have an asymmetric carbon and where Y=P (see Scheme 1), can also be used to form atom. In accordance with this invention the preferred stereo compounds of formula XII, where C phenyl, substituted configuration is S. If it is desired to produce the R or the S phenyl, heteroaryl, or substituted heteroaryl, if it is desired. 15 isomer of the compounds of formula I, these compounds can Compounds of formula XII can be formed from compounds be isolated as the desired isomer by any conventional method. of formula VII where R-bromine or iodine via a cross Among the preferred means is to separate the isomers of coupling reaction with either an arylboronic acid or an aryl either the amide of formula VI or formula VII, where Y=P, or Stannane. Any conventional method for the cross coupling of the amine of formula I or formula VIII via either High Per an aryl iodide oraryl bromide with an arylboronic acidoraryl formance Liquid Chromatography (HPLC) or via Supercriti Stannane can be employed. In accordance with the preferred cal Fluid Chromatography. embodiment of this invention, the aryl iodide or aryl bromide The separation of Rand S isomers can also be achieved by of formula VII is treated with an appropriately substituted forming a lower alkyl ester of phenylacetic acids of formula arylboronic acid, a base, i.e. sodium carbonate or potassium V. Any conventional method for the formation of an ester phosphate, and catalytic tetrakis(triphenylphosphine)palla 25 from a carboxylic acid can be utilized. Separation is per dium(0) or 1,4-bis-(diphenylphosphine)butanepalladium formed using an enzymatic ester hydrolysis of any lower (II) dichloride. This reaction is performed in a high boiling alkyl esters corresponding to the compound of formula V point solvent such as N,N-dimethylformamide, 1,4-dioxane, (See, for example, Ahmar, M. Girard, C.; Bloch, R., Tetra or 1,2-dimethoxyethane in the presence of water, under nitro hedron Lett., 1989, 7053), which results in the formation of gen, at elevated temperatures from 70° C. to about 100° C. 30 corresponding chiral acid and chiral ester. The ester and the being preferred. If it is desired to form compounds of formula acid can be separated by any conventional method of sepa VIII from compounds of formula XII, the procedure outlined rating an acid from an ester. in Scheme 2 can be followed. In other embodiments, the invention is directed to pharma ceutical compositions, comprising: 35 a. at least compound of formula I orpharmaceutically accept Scheme 5 able salt thereof, and Rs coupling reaction b. at least one pharmaceutically acceptable carrier. R6 R XN- B-Sn(Bu), Generally, the compound of formula I or a pharmaceuti HO r Pd(0) cally acceptable salt thereof will be present at a level of from R N }x 40 about 0.1%, by weight, to about 90% by weight, based on the Brro I-A total weight of the pharmaceutical composition, based on the total weight of the pharmaceutical composition. Preferably, VII the compound of formula I or a pharmaceutically acceptable R6 R ra -P deprotection salt thereof will be present at a level of at least about 1%, by HO N acid 45 weight, based on the total weight of the pharmaceutical com position. More preferably, the compound of formula I or a B-AR Nu). pharmaceutically acceptable salt thereof will be present at a XIII level of at least about 5%, by weight, based on the total weight Rs of the pharmaceutical composition. Even more preferably, R6 R7 -Xn-H 50 the norepinephrine reuptake inhibitor or a pharmaceutically HO r N acceptable salt thereof will be present at a level of at least R N )x about 10%, by weight, based on the total weight of the phar B-A maceutical composition. Yet even more preferably, the com XIV pound of formula I or a pharmaceutically acceptable salt 55 thereof will be present at a level of at least about 25%, by weight, based on the total weight of the pharmaceutical com where Balkenyl or alkynyl. position. If it is desired to produce compounds of formula XIV. Such compositions are prepared in accordance with where B-alkynyl or alkenyl, they can be formed from com acceptable pharmaceutical procedures, such as described in pounds of formula VII, where R-bromine or iodine and 60 Remington's Pharmaceutical Sciences, 17th edition, ed. where Y=P (See Scheme 1). Compounds of formula XIII can Alfonoso R. Gennaro, Mack Publishing Company, Easton, be formed from compounds of formula VII where Pa. (1985). Pharmaceutically acceptable carriers are those R-bromine or iodine via a cross-coupling reaction with that are compatible with the other ingredients in the formu either an appropriately substituted alkenyl or alkynyl stan lation and biologically acceptable. nane. Any conventional method for the cross coupling of an 65 The compounds of this invention may be administered aryl iodide or aryl bromide with an alkenyl or alkynyl stan orally or parenterally, neat or in combination with conven nane can be employed. In accordance with the preferred tional pharmaceutical carriers. Applicable solid carriers can US 7,419,980 B2 21 22 include one or more Substances that may also act as flavoring disclosure, for example hot flush, Sweating, thermoregula agents, lubricants, solubilizers, Suspending agents, fillers, tory-related condition or disorder, or other. Such administra glidants, compression aids, binders or tablet-disintegrating tion includes use of each type of therapeutic agent in a con agents or an encapsulating material. In powders, the carrier is current manner. In either case, the treatment regimen will a finely divided solid that is in admixture with the finely provide beneficial effects of the drug combination in treating divided active ingredient. In tablets, the active ingredient is the conditions or disorders described herein. mixed with a carrier having the necessary compression prop The route of administration may be any route, which effec erties in Suitable proportions and compacted in the shape and tively transports the active compound of formula I to the size desired. The powders and tablets preferably contain up to appropriate or desired site of action, such as oral, nasal, 99% of the active ingredient. Suitable solid carriers include, 10 pulmonary, transdermal. Such as passive or iontophoretic for example, calcium phosphate, magnesium Stearate, talc, delivery, or parenteral, e.g. rectal, depot, Subcutaneous, intra Sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cel venous, intraurethral, intramuscular, intranasal, ophthalmic lulose, Sodium carboxymethyl cellulose, polyvinylpyrroli Solution or an ointment. Furthermore, the administration of dine, low melting waxes and ion exchange resins. compound of formula I with other active ingredients may be Liquid carriers may be used in preparing solutions, Suspen 15 concurrent or simultaneous. sions, emulsions, syrups, and elixirs. The active ingredient of It is believed that the present invention described presents this invention can be dissolved or Suspended in a pharmaceu a substantial breakthrough in the field of treatment, allevia tically acceptable liquid carrier Such as water, an organic tion, inhibition, and/or prevention of conditions ameliorated Solvent, a mixture of both orpharmaceutically acceptable oils by monoamine reuptake including, inter alia, vasomotor or fat. The liquid carrier can contain other Suitable pharma symptoms (VMS), sexual dysfunction, gastrointestinal and ceutical additives such as solubilizers, emulsifiers, buffers, genitourinary disorders, chronic fatigue syndrome, fibromy preservatives, Sweeteners, flavoring agents, Suspending lagia syndrome, nervous system disorders, and combinations agents, thickening agents, colors, Viscosity regulators, stabi thereof, particularly those conditions selected from the group lizers, or osmo-regulators. Suitable examples of liquid carri consisting of major depressive disorder, vasomotor Symp ers for oral and parenteral administration include water (par 25 toms, stress and urge urinary incontinence, fibromyalgia, ticularly containing additives as above, e.g. cellulose pain, diabetic neuropathy, and combinations thereof. derivatives, preferably sodium carboxymethyl cellulose solu Accordingly, in one embodiment, the present invention is tion), alcohols (including monohydric alcohols and polyhy directed to methods for treating or preventing a condition dric alcohols e.g. glycols) and their derivatives, and oils (e.g. ameliorated by monoamine reuptake in a subject in need fractionated coconut oil and arachis oil). For parenteral 30 thereof, comprising the step of administration the carrier can also be an oily ester Such as administering to said Subject an effective amount of a com ethyl oleate and isopropyl myristate. Sterile liquid carriers are pound of formula I or pharmaceutically acceptable salt used in sterile liquid form compositions for parenteral admin thereof. istration. Liquid pharmaceutical compositions, which are sterile 35 The conditions ameliorated by monoamine reuptake include Solutions or Suspensions, can be administered by, for those selected from the group consisting of vasomotor Symp example, intramuscular, intraperitoneal or Subcutaneous toms, sexual dysfunction, gastrointestinal and genitourinary injection. Sterile Solutions can also be administered intrave disorders, chronic fatigue syndrome, fibromylagia syndrome, nously. Oral administration may be either liquid or solid nervous system disorders, and combinations thereof, particu composition form. 40 larly those conditions selected from the group consisting of Preferably the pharmaceutical composition is in unit dos major depressive disorder, vasomotor symptoms, stress and age form, e.g. as tablets, capsules, powders, Solutions, Sus urge urinary incontinence, fibromyalgia, pain, diabetic neur pensions, emulsions, granules, or Suppositories. In Such form, opathy, and combinations thereof. the composition is sub-divided in unit dose containing appro “Vasomotor symptoms.” “vasomotor instability symp priate quantities of the active ingredient; the unit dosage 45 toms” and “vasomotor disturbances' include, but are not forms can be packaged compositions, for example packeted limited to, hot flushes (flashes), insomnia, sleep disturbances, powders, vials, ampoules, prefilled Syringes or Sachets con mood disorders, irritability, excessive perspiration, night taining liquids. The unit dosage form can be, for example, a Sweats, fatigue, and the like, caused by, inter alia, ther capsule or tablet itself, or it can be the appropriate number of moregulatory dysfunction. any such compositions in package form. 50 The term “hot flush” is an art-recognized term that refers to In another embodiment of the present invention, the com an episodic disturbance in body temperature typically con pounds useful in the present invention may be administered to sisting of a Sudden skin flushing, usually accompanied by a mammal with one or more other pharmaceutical active perspiration in a subject. agents such as those agents being used to treat any other The term “sexual dysfunction' includes, but is not limited medical condition present in the mammal. Examples of Such 55 to, condition relating to desire and/or arousal. pharmaceutical active agents include pain relieving agents, As used herein, gastrointestinal and genitourinary disor anti-angiogenic agents, anti-neoplastic agents, anti-diabetic ders' includes irritable bowel syndrome, symptomatic agents, anti-infective agents, or gastrointestinal agents, or GERD, hypersensitive esophagus, nonulcer dyspepsia, non combinations thereof. cardiac chest pain, biliary dyskinesia, Sphincter of Oddi dys The one or more other pharmaceutical active agents may be 60 function, incontinence (i.e., urge incontinence, stress incon administered in a therapeutically effective amount simulta tinence, genuine stress incontinence, and mixed neously (such as individually at the same time, or together in incontinence) (including the involuntary voiding of feces or a pharmaceutical composition), and/or successively with one urine, and dribbling or leakage or feces or urine which may be or more compounds of the present invention. due to one or more causes including but not limited to pathol The term “combination therapy” refers to the administra 65 ogy altering sphincter control, loss of cognitive function, tion of two or more therapeutic agents or compounds to treat overdistention of the bladder, hyperreflexia and/or involun a therapeutic condition or disorder described in the present tary urethral relaxation, weakness of the muscles associated US 7,419,980 B2 23 24 with the bladder or neurologic abnormalities), interstitial cys activate the descending autonomic pathways and result in titis (irritable bladder), and chronic pelvic pain (including, heat dissipation via vasodilation and Sweating (hot flush) but not limited to Vulvodynia, prostatodynia, and proctalgia). (FIG. 1). Accordingly, the estrogen deprivation may result in As used herein, "chronic fatigue syndrome' (CFS) is a altered norepinephrine activity. condition characterized by physiological symptoms selected Norepinephrine synthesized in perikarya of the brainstem from weakness, muscle aches and pains, excessive sleep, is released at the nerve terminals in the hypothalamus and malaise, fever, Sore throat, tender lymph nodes, impaired brainstem. In the hypothalamus, NE regulates the activity of memory and/or mental concentration, insomnia, disordered neurons residing in the thermoregulatory center. In the brain sleep, localized tenderness, diffuse pain and fatigue, and stem, NE innervates serotoninergic neurons (5HT), and act combinations thereof. 10 ing via adrenergic, and adrenergic postsynaptic receptors, As used herein, “fibromyalgia syndrome' (FMS) includes it stimulates the activity of the serotoninergic system. In FMS and other somatoform disorders, including FMS asso response, 5-HT neurons also modulate the activity the ther ciated with depression, Somatization disorder, conversion moregulatory center and feedback to NE neurons. Via this disorder, pain disorder, hypochondriasis, body dysmorphic feedback connection, 5-HT, acting via 5-HT, receptors, disorder, undifferentiated Somatoform disorder, and Somato 15 inhibit the activity of NE neurons. Norepinephrine in the form NOS. FMS and other somatoform disorders are accom synaptic cleft is also taken up by NE transporter (NET) panied by physiological symptoms selected from a general located in NE neurons. The transporter recycles NE and ized heightened perception of sensory stimuli, abnormalities makes it available for multiple neurotransmission (FIG. 2). in pain perception in the form of allodynia (pain with innocu The present invention provides a treatment for vasomotor ous stimulation), abnormalities in pain perception in the form symptoms by methods of recovering the reduced activity of of hyperalgesia (increased sensitivity to painful stimuli), and norepinephrine. Norepinephrine activity in the hypothalamus combinations thereof. or in the brainstem can be elevated by (i) blocking the activity As used herein, “nervous system disorders, includes of the NE transporter, (ii) blocking the activity of the presyn addictive disorders (including those due to alcohol, nicotine, aptic adrenergic receptor with an antagonist, or (iii) block and other psychoactive Substances) and withdrawal Syn 25 ing the activity of 5-HT on NE neurons with a 5-HT, antago drome, age-associated learning and mental disorders (includ nist. ing Alzheimer's disease), anorexia nervosa, bulimia nervosa, In another embodiment, the present invention is directed to attention-deficit disorder with or without hyperactivity disor methods for treating or preventing a depression disorder in a der bipolar disorder, pain (including chronic pain selected Subject in need thereof, comprising the step of: from the group consisting of lower back pain, atypical chest 30 administering to said subject an effective amount of at least pain, headache Such as cluster headache, migraine, herpes one compound of formula I or pharmaceutically accept neuralgia, phantom limb pain, pelvic pain, myofascial face able salt thereof. pain, abdominal pain, neck pain, central pain, dental pain, In yet other embodiments, the present invention is directed opioid resistant pain, visceral pain, Surgical pain, bone injury to methods for treating or preventing sexual dysfunction in a pain, pain during labor and delivery, pain resulting from 35 Subject in need thereof, comprising the step of: burns, post partum pain, angina pain, neuropathic pain Such administering to said subject an effective amount of at least as peripheral neuropathy and diabetic neuropathy, post-op one compound of formula I or pharmaceutically accept erative pain, and pain which is co-morbid with nervous sys able salt thereof. tem disorders described herein), cyclothymic disorder, In another embodiment, the present invention is directed to depression disorder (including major depressive disorder, 40 methods for treating or preventing gastrointestinal or geni refractory depression adolescent depression and minor tourinary disorder, particularly stress incontinence or urge depression), dysthymic disorder, generalized anxiety disor urinary incontinence, in a subject in need thereof, comprising der (GAD), obesity (i.e., reducing the weight of obese or the step of: overweight patients), obsessive compulsive disorders and administering to said Subject an effective amount of a com related spectrum disorders, oppositional defiant disorder, 45 pound of formula I or pharmaceutically acceptable salt panic disorder, post-traumatic stress disorder, premenstrual thereof. dysphoric disorder (i.e., premenstrual syndrome and late In another embodiment, the present invention is directed to luteal phase dysphoric disorder), psychotic disorders (includ methods for treating or preventing chronic fatigue syndrome ing Schizophrenia, Schizoaffective and Schizophreniform dis in a subject in need thereof, comprising the step of orders), seasonal affective disorder, sleep disorders (such as 50 administering to said Subject an effective amount of a com narcolepsy and enuresis), social phobia (including Social pound of formula I or pharmaceutically acceptable salt anxiety disorder), selective serotonin reuptake inhibition thereof. (SSRI)“poop out’ syndrome (i.e., wherein a patient who fails In another embodiment, the present invention is directed to to maintain a satisfactory response to SSRI therapy after an methods for treating or preventing fibromylagia syndrome in initial period of satisfactory response). 55 a Subject in need thereof, comprising the step of: In one embodiment, the present invention is directed to administering to said Subject an effective amount of a com methods for treating or preventing vasomotor symptoms in a pound of formula I or pharmaceutically acceptable salt Subject in need thereof, comprising the step of: thereof. administering to said Subject an effective amount of at least In further embodiments, the present invention is directed to one compound of formula I or pharmaceutically accept 60 methods for treating or preventing pain in a Subject in need able salt thereof. thereof, comprising the step of When estrogen levels are low or estrogen is absent, the administering to said subject an effective amount of at least normal levels between NE and 5-HT is altered and this altered one compound of formula I or pharmaceutically accept change in neurotransmitter levels may result in changes in the able salt thereof. sensitivity of the thermoregulatory center. The altered chemi 65 The pain may be, for example, acute pain (short duration) cal levels may be translated in the thermoregulatory center as or chronic pain (regularly reoccurring or persistent). The pain heat sensation and as a response, the hypothalamus may may also be centralized or peripheral. US 7,419,980 B2 25 26 Examples of pain that can be acute or chronic and that can The compounds useful in this invention may also be used to be treated in accordance with the methods of the present treat acute and/or chronic pains associated with female con invention include inflammatory pain, musculoskeletal pain, ditions, which may also be referred to as female-specific pain. bony pain, lumbosacral pain, neck or upper back pain, vis Such groups of pain include those that are encountered solely ceral pain, Somatic pain, neuropathic pain, cancer pain, pain or predominately by females, including pain associated with caused by injury or Surgery such as burn pain or dental pain, menstruation, ovulation, pregnancy or childbirth, miscar or headaches such as migraines or tension headaches, or riage, ectopic pregnancy, retrograde menstruation, rupture of combinations of these pains. One skilled in the art will rec a follicular or corpus luteum cyst, irritation of the pelvic ognize that these pains may overlap one another. For viscera, uterine fibroids, adenomyosis, endometriosis, infec example, a pain caused by inflammation may also be visceral 10 tion and inflammation, pelvic organ ischemia, obstruction, or musculoskeletal in nature. intra-abdominal adhesions, anatomic distortion of the pelvic In a preferred embodiment of the present invention the viscera, ovarian abscess, loss of pelvic Support, tumors, pel compounds useful in the present invention are administered vic congestion or referred pain from non-gynecological in mammals to treat chronic pain Such as neuropathic pain CalSCS. associated for example with damage to or pathological 15 changes in the peripheral or central nervous systems; cancer EXAMPLES pain; visceral pain associated with for example the abdomi nal, pelvic, and/or perineal regions or pancreatitis; muscu The present invention is further defined in the following loskeletal pain associated with for example the lower or upper Examples, in which all parts and percentages are by weight back, spine, fibromylagia, temporomandibular joint, or myo and degrees are Celsius, unless otherwise stated. It should be fascial pain syndrome; bony pain associated with for example understood that these examples, while indicating preferred bone or joint degenerating disorders such as osteoarthritis, embodiments of the invention, are given by way of illustration rheumatoid arthritis, or spinal Stenosis; headaches Such only. From the above discussion and these examples, one migraine or tension headaches; or pain associated with infec skilled in the art can ascertain the essential characteristics of tions such as HIV, sickle cell anemia, autoimmune disorders, 25 this invention, and without departing from the spirit and scope multiple Sclerosis, or inflammation Such as osteoarthritis or thereof, can make various changes and modifications of the rheumatoid arthritis. invention to adapt it to various usages and conditions. In a more preferred embodiment, the compounds useful in this invention are used to treat chronic pain that is neuropathic Reference Example 1-a pain, visceral pain, musculoskeletal pain, bony pain, cancer 30 pain or inflammatory pain or combinations thereof, in accor Aldol Reaction: Preparation of Acid Intermediates dance with the methods described herein. Inflammatory pain can be associated with a variety of medical conditions such as A solution of Diisopropylamine (7.87 mL, 56.2 mmol) in osteoarthritis, rheumatoid arthritis, Surgery, or injury. Neuro dry tetrahydrofuran (50 mL) under nitrogen was cooled to pathic pain may be associated with for example diabetic 35 -78° C. and treated dropwise with a solution of n-butyl neuropathy, peripheral neuropathy, post-herpetic neuralgia, lithium (2.5M in hexanes, 22 mL, 55.0 mmol). The resulting trigeminal neuralgia, lumbar or cervical radiculopathies, solution was warmed to 0° C. and stirred for 15 min. The fibromyalgia, glossopharyngeal neuralgia, reflex sympa solution was re-cooled to -78° C. and treated, via cannula, thetic dystrophy, casualgia, thalamic syndrome, nerve root with a solution of 3-chlorophenylacetic acid (4.0 g, 23.4 avulsion, or nerve damage cause by injury resulting in periph 40 mmol) in tetrahydrofuran (20 mL). The reaction was then eral and/or central sensitization Such as phantom limb pain, allowed to warm to 25°C. where it was stirred for 45 minutes reflex sympathetic dystrophy or postthoracotomy pain, can and was then re-cooled to -78°C. A solution of cyclohex cer, chemical injury, toxins, nutritional deficiencies, or viral anone (3.65 mL, 35.3 mL) in tetrahydrofuran (10 mL) was or bacterial infections such as shingles or HIV, or combina then added via cannula, and the resulting mixture was stirred tions thereof. The methods of use for compounds of this 45 at -78°C. for 1.5 h. The reaction was then quenched by the invention further include treatments in which the neuropathic addition of a saturated aqueous solution of ammonium chlo pain is a condition secondary to metastatic infiltration, adi ride, and the tetrahydrofuran was removed in vacuo. The posis dolorosa, burns, or central pain conditions related to resulting residue was dissolved in a 2N aqueous solution of thalamic conditions. sodium hydroxide (30 mL) and washed with ethyl acetate As mentioned previously, the methods of the present inven 50 (1x30 mL). The aqueous layer was then acidified to pH=1 tion may be used to treat pain that is somatic and/or visceral with the addition of a 2 Naqueous solution of hydrochloric in nature. For example, Somatic pain that can be treated in acid. The product was extracted with ethylacetate (3x30 mL), accordance with the methods of the present invention include and the combined organic extracts were dried over magne pains associated with structural or soft tissue injury experi sium sulfate and concentrated in vacuo to yield 6.05 g (96%) enced during Surgery, dental procedures, burns, or traumatic 55 of pure (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acidas body injuries. Examples of visceral pain that can be treated in a white solid. HRMS: calcd for CHCIO, 268.0866; accordance with the methods of the present invention include found (ESI FT), 291.0748. those types of pain associated with or resulting from maladies b) In an analogous manner, (3-bromophenyl)(1-hydroxycy of the internal organs such as ulcerative colitis, irritable bowel clohexyl)acetic acid was prepared from 3-bromopheny syndrome, irritable bladder, Crohn's disease, rheumatologic 60 lacetic acid and cyclohexanone. HRMS: calcd for (arthralgias), tumors, gastritis, pancreatitis, infections of the CHBrO, 312.0361; found (ESI FT), 350.99924. organs, or biliary tract disorders, or combinations thereof. c) In an analogous manner, (1-hydroxycyclobutyl)(2-naph One skilled in the art will also recognize that the pain treated thyl)acetic acid was prepared from 2-napthylacetic acid according to the methods of the present invention may also be and cyclobutanone. HRMS: calcd for CHO, related to conditions of hyperalgesia, allodynia, or both. 65 256.1099: found (ESI FT), 279.09927. Additionally, the chronic pain may be with or without periph d) In an analogous manner, 3,4-dichloro-alpha-(1-hydroxy eral or central sensitization. cyclohexyl)benzeneacetic acid was prepared from 3,4- US 7,419,980 B2 27 28 dichlorophenylacetic acid and cyclohexanone. MS (ESI) S) In an analogous manner, (1-hydroxycyclopentyl)(1-naph m/Z301/303/305 (IM-HI); Anal. Calcd for CHCIO: thyl)acetic acid was prepared from 1-napthylacetic acid C, 55.46; H, 5.32: N, 0.00. Found: C, 55.42; H, 5.30; N, and cyclopentanone. MS (ESI) m/z 269 (IM-HI); HRMS: O.O.O. calcd for C.H.O., 270.1256: found (ESI FT), e) In an analogous manner, (1-hydroxycyclohexyl)(1-naph 5 2931 1485. thyl)acetic acid was prepared from 1-napthylacetic acid t) In an analogous manner, 2-(3-bromophenyl)-3-ethyl-3-hy and cyclohexanone. MS (ESI) m/z 283 (IM-HI); HRMS: droxypentanoic acid was prepared from 3-bromopheny calcd for CHOs, 284.1412; found (ESI FT), lacetic acid and 3-pentanone. MS (ESI) m/z.299/301 (M- 3.07.13OO1. HI); HRMS: calcd for CHBrO, 300.0361; found f) In an analogous manner, (1-hydroxycyclohexyl)3-(trifluo 10 (ESI FT), 323.02505. romethoxy)phenyl)acetic acid was prepared from 3-trif u) In an analogous manner, 2-(3-chlorophenyl)-3-hydroxy-3- luoromethoxyphenylacetic acid and cyclohexanone. propylhexanoic acid was prepared from 3-bromopheny HRMS: calcd for CHF.O., 318.1079; found (ESI), lacetic acid and 4-heptanone. MS (ESI) m/z 283/285 (M+ 317.1013. HI"); HRMS: calcd for CHCIO, 284.1179; found g) In an analogous manner, (1-hydroxycyclohexyl)-4-(trif 15 (ESI FT), 307.1074. luoromethoxy)phenyl)acetic acid was prepared from 4-tri V) In an analogous manner, 2-(3-chlorophenyl)-3-ethyl-3- fluoromethoxyphenylacetic acid and cyclohexanone. MS hydroxypentanoic acid was prepared from 3-chloropheny (ESI) m/z. 317 (IM-HI). lacetic acid and 3-pentanone. MS (ESI) m/z 255/257 (M+ h) In an analogous manner, (4-bromophenyl)(1-hydroxycy HI"). clohexyl)acetic acid was prepared from 4-bromopheny w) In an analogous manner, 3-ethyl-3-hydroxy-2-(1-naph lacetic acid and cyclohexanone. MS (ESI) m/z. 313/315 thyl)pentanoic acid was prepared from 1-napthylacetic (IM+H"); Anal. Calcd for CHBrO: C, 53.69; H, 5.47: acid and 3-pentanone. MS (ESI) m/z 271 (M-H). N, 0.00. Found: C, 53.87; H, 5.42: N, 0.00. X) In an analogous manner, (4-hydroxy-1-methylpiperidin-4- i) In an analogous manner, (3,4-dichlorophenyl)(4-hydroxy yl)(2-naphthyl)acetic acid was prepared from 2-napthy 1-methylpiperidin-4-yl)acetic acid was prepared from 3,4- 25 lacetic acid and 1-methyl-4-piperidone. HRMS: calcd for dichlorophenylacetic acid and 1-methyl-4-piperidone. CH, NO. 299.1521: found (ESI FT), 300.15911. HRMS: calcd for CH-ClNO, HCl, 353.0352; found y) In an analogous manner, 2-(3-bromo-4-methoxyphenyl)- (ESI FT), 318.0653. 3-ethyl-3-hydroxypentanoic acid was prepared from j) In an analogous manner, (3-bromophenyl)(1-hydroxycy 3-bromo-4-methoxyphenylacetic acid and 3-pentanone. clobutyl)acetic acid was prepared from 3-bromopheny 30 MS (ESI) m/z 329/331 (IM+H"). lacetic acid and cyclobutanone. HRMS: calcd for Z) In an analogous manner, (4-benzyloxyphenyl)(1-hydroxy CHBrOs. 284.0048; found (ESI FT), 306.993.37. cyclobutyl)acetic acid was prepared from 4-benzylox k) In an analogous manner, (1-hydroxycyclobutyl)3-(trifluo yphenylacetic acid and cyclobutanone. romethoxy)phenyl)acetic acid was prepared from 3-trif aa) In an analogous manner, (3-chlorophenyl)(1-hydroxy luoromethoxyphenylacetic acid and cyclobutanone. 35 decahydronapthyl)acetic acid was prepared from 3-chlo HRMS: calcd for CHFO, 290.0766; found (ESI), rophenylacetic acid and decahydronapthlene-1-one. MS 289.0686. (ESI) m/z 321/323 (M-HI). 1) In an analogous manner, (3-bromo-4-methoxyphenyl)(1- bb) In an analogous manner, (3-bromo-4-methoxyphenyl)(4- hydroxycyclohexyl)acetic acid was prepared from tert-butyl-1-hydroxycyclohexyl)acetic acid was prepared 3-bromo-4-methoxyphenylacetic acid and cyclohexanone. 40 from 3-bromo-4-methoxyphenylacetic acid and 4-tert-bu MS (ESI) m/z 341/343 (M-HI); HRMS: calcd for tylcyclohexanone. MS (ESI) m/z 397/399 (M-HI): CHBrO4, 342.0467: found (ESI FT), 341.03897. HRMS: calcd for CHBrO 398.1093; found (ES m) In an analogous manner, (1-hydroxycyclohexyl)3-(trif I FT), 421.09875. luoromethylphenyl)acetic acid was prepared from 3-trif cc) In an analogous manner, (3-chlorophenyl)(2-hydroxy luoromethylphenylacetic acid and cyclohexanone. MS 45 decahydronapthyl)acetic acid was prepared from 3-chlo (ESI) m/z 301 (IM-HI); HRMS: calcd for CHFO, rophenylacetic acid and decahydronapthlene-2-one. MS 302.1130; found (ESI FT), 325.1024. (ESI) m/z 321/323 (M-HI). n) In an analogous manner, (4-benzyloxyphenyl)(1-hydroxy dd) In an analogous manner, (4-tert-butyl-1-hydroxycyclo cyclohexyl)acetic acid was prepared from 4-benzylox hexyl)(1-naphthyl)acetic acid was prepared from yphenylacetic acid and cyclohexanone. 50 1-napthylacetic acid and 4-tert-butylcyclohexanone. MS o). In an analogous manner, (1-hydroxycyclobutyl)(1-naph (ESI) m/z 339 (M-HI); HRMS: calcd for CHO, thyl)acetic acid was prepared from 1-napthylacetic acid 340.2038; found (ESI FT), 363.193.09. and cyclobutanone. ee) In an analogous manner, (3-chlorophenyl)(4-hydroxytet p) In an analogous manner, (3,4-dichlorophenyl)(1-hydroxy 55 rahydro-2H-pyran-4-yl)acetic acid was prepared from cyclobutyl)acetic acid was prepared from 3,4-dichlorophe 3-chlorophenylacetic acid and tetrahydro-2H-pyran-4- nylacetic acid and cyclobutanone. HRMS: calcd for one. MS (ESI) m/z. 269 (M-HI); HRMS: calcd for CHClO, 274.0163; found (ESI FT), 273.00881. CHCIO 270.0659; found (ESI FT), 293.05499. q) In an analogous manner, (1-hydroxycyclohexyl)(2-naph ff) In an analogous manner, (3-bromophenyl)(4-tert-butyl-1- thyl)acetic acid was prepared from 2-napthylacetic acid 60 hydroxycyclohexyl)acetic acid was prepared from 3-bro and cyclohexanone. HRMS: calcd for CHOs, mophenylacetic acid and 4-tert-butylcyclohexanone. MS 284.1412: found (ESI FT), 323.10414. (ESI) m/z. 367/369 (IM-HI); HRMS: calcd for r) In an analogous manner, (3-bromophenyl)(4-hydroxy-1- CHBrO,368.0987; found (ESI FT), 391.0878. methylpiperidin-4-yl)acetic acid was prepared from 3-bro gg) In an analogous manner, 2-(3-bromophenyl)-3-hydroxy mophenylacetic acid and 1-methyl-4-piperidone. HRMS: 65 3-propylhexanoic acid was prepared from 3-bromopheny calcd for CHBrNO.HCl, 363.0237; found (ESI FT), lacetic acid and 4-heptanone. MS (ESI) m/z, 327/329 (M+ 328.05356. HI). US 7,419,980 B2 29 30 hh) In an analogous manner, 2-(3-chlorophenyl)-3.3-dicyclo XX) In an analogous manner, (1-methyl-1H-indol-3-yl)(1-hy propyl-3-hydroxypropanoic acid was prepared from droxycyclohexyl)acetic acid was prepared from N-Me 3-chlorophenylacetic acid and dicyclopropyl ketone. MS thyl-3-indole acetic acid and cyclohexanone. (ESI) m/z 279.0801 (IM-HI); HRMS: calcd for yy) In an analogous manner, (1-(tert-butyl-dimethyl-silanyl)- CHCIO, 280.0866; found (ESI), 279.0801; Anal. 1H-indol-3-yl)(1-hydroxycyclohexyl)acetic acid was pre Calcd for CH-CIO: C, 64.17; H, 6.10: N, 0.00. Found: pared from 1-(tert-butyl-dimethyl-silanyl)-1H-indol-3- C, 64.05; H, 6.31; N, 0.00. yl)-acetic acid' and cyclohexanone. ii) In an analogous manner, (3-bromophenyl)(1-hydroxy-3.3, 'Solid-phase synthesis of polyamine spider toxins and correlation with the natural products by HPLC-MS/MS. Manov, Nikolay: Tzouros, Manuel; 5.5-tetramethylcyclohexyl)acetic acid was prepared from Chesnov, Sergiy; Bigler, Laurent; Bienz, Stefan. Institute of Organic Chem 3-bromophenylacetic acid and 3,3,5,5-tetramethylcyclo 10 istry, University of Zurich, Zurich, Switz. Helvetca Chimica Acta (2002), hexanone. MS (ESI) m/z. 367/369 (IM-HI). 85 (9), 2827-2846 ii) In an analogous manner, (4-ethyl-1-hydroxycyclohexyl)- ZZ) In an analogous manner, (1-hydroxycyclohexyl)(1,1'-bi (1-naphthyl)acetic acid was prepared from 1-napthylacetic phenyl-4-yl)acetic acid was prepared from 4-biphenylace acid and 4-ethylcyclohexanone. MS (ESI) m/z. 311 (M- tic acid and cyclohexanone. MS (ESI) m/z 309 (M-H-) HI). 15 aaa) In an analogous manner (1-hydroxycyclobutyl)4-trif kk) In an analogous manner, (3-chlorophenyl)(4-tert-butyl luoromethoxy)phenyl)acetic acid was prepared from 4-tri 1-hydroxycyclohexyl)acetic acid was prepared from fluoromethoxyphenyl acetic acid and cyclobutanone. MS 3-chlorophenylacetic acid and 4-tert-butylcyclohexanone. (ESI) m/z 289 (IM-HI). ll) In an analogous manner, (4-methyl-1-hydroxycyclo bbb) In an analogous manner (1-hydroxycyclohexyl)-4-phe hexyl)-(1-naphthyl)acetic acid was prepared from noxyphenyl)acetic acid was prepared from 4-phenoxyphe 1-napthylacetic acid and 4-methylcyclohexanone. MS nylacetic acid and cyclohexanone. MS (ESI) m/z 325 (M- (ESI) m/z 297 (IM-HI). HI). mm) In an analogous manner, (3-bromophenyl)(4-hydrox ccc) In an analogous manner (1-hydroxycyclohexyl)3-phe ytetrahydro-2H-pyran-4-yl)acetic acid was prepared from noxyphenyl)acetic acid was prepared from 3-phenoxyphe 3-bromophenylacetic acid and tetrahydro-2H-pyran-4- 25 nylacetic acid and cyclohexanone. MS (ESI) m/z 325 (M- one. MS (ESI) m/z. 313/315 (M+H"); HRMS: calcd for HI). Anal. Calcd for CHO, 0.1 HO: C, 73.19; H, 6.82. CHBrO 314.0154: found (ESI FT), 315.02244. Found: C, 73.04; H, 6.88. nn) In an analogous manner, (3-benzyloxyphenyl)(1-hy droxycyclohexyl)acetic acid was prepared from 3-benzy ddd) In an analogous manner, (1-naphthyl)(1-hydroxycy 30 clooctyl)acetic acid was prepared from 1-naphthyl acetic loxyphenylacetic acid and cyclohexanone. acid acid and cyclooctanone. oo) In an analogous manner, (3-bromophenyl)(2-hydroxy-2- eee) In an analogous manner, 4-(benzyloxy)-3-chlorophe adamantyl)acetic acid was prepared from 3-bromopheny nyl(1-hydroxycyclohexyl)acetic acid was prepared from lacetic acid and adamantanone. MS (ESI) m/z. 363/365 (M-HI). 4-(benzyloxy)-3-chlorophenyl)acetic acid (DE 2556474, pp.) In an analogous manner, (3-bromo-4-methoxyphenyl)(4- 35 1976, M. Kucher; B. Brunova: J. Grimova: N. Oldrich) and hydroxytetrahydro-2H-pyran-4-yl)acetic acid was pre cyclohexanone. MS (ESI) m/z. 373; pared from 3-bromo-4-methoxyphenylacetic acid and tet m) In an analogous manner, (1-naphthyl)(1-hydroxycyclo rahydro-2H-pyran-4-one. MS (ESI) m/z 343/345 (M- heptyl)acetic acid was prepared from 1-napthylacetic acid HI); HRMS: calcd for CHBrOs. 344.0259; found and cycloheptanone. (ESI FT), 367.01582. 40 ggg.) In an analogous manner, 2-(3-chlorophenyl)-3-hy qq) In an analogous manner, (3-benzyloxyphenyl)(1-hy droxy-3-methylbutanoic acid was prepared from 3-chlo droxycyclobutyl)acetic acid was prepared from 3-benzy rophenylacetic acid and acetone. MS (ES) m/z 226.9. loxyphenylacetic acid and cyclobutanone. hhh) In an analogous manner, (3-chlorophenyl)(1-hydroxy rr) In an analogous manner, (5-chlorothien-2-yl)(1-hydroxy 3.35.5-tetramethylcyclohexyl)acetic acid was prepared cyclohexyl)acetic acid was prepared from 5-chloro-2- 45 from 3-chlorophenylacetic acid and 3,3,5,5-tetramethylcy thiophene-3-acetic acid (Example 142) and cyclohex clohexanone. MS (ES) m/z 323.2. anone. MS (ESI) m/z 273/275 (IM-H-). iii) In an analogous manner, (1-hydroxy-cyclohexyl)-(5- SS) In an analogous manner, (5-bromothien-2-yl)(1-hydroxy methoxy-benzobthiophen-3-yl)-acetic acid was prepared cyclohexyl)acetic acid was prepared from 5-bromo-2- from 5-methoxy benzobthiophene acetic acid (Cam thiophene acetic acid (Example 143) and cyclohexanone. 50 paigne, E. Kim, C. S.; Pinza, M.; Pifferi, G.J. Heterocyclic MS (ESI) m/z 317/319 (M+H+) Chem. 1983, 20, 1697-1703) and cyclohexanone. HRMS: tt) In an analogous manner, 1-benzothien-3-yl(1-hydroxycy calcd for CHFO 318.1079; found (ESI), 317.1013. clohexyl)acetic acid was prepared from 1-benzothien-3-yl iii) In an analogous manner, (2-hydroxy decahydronapthyl) acetic acid and cyclohexanol. MS (ESI) m/z 289 (IM-H-) 55 (1-napthyl)acetic acid was prepared from 1-napthylacetic uu) In an analogous manner, (2-bromophenyl)(1-hydroxycy acid and decahydronapthlene-2-one. MS (ESI) m/z 337 clohexyl)acetic acid was prepared from 2-bromopheny (M-HI). lacetic acid and cyclohexanol. MS (ESI) m/z.311/313 (M- kkk) In an analogous manner, (3-chlorophenyl)(4-methyl-1- H-) hydroxycyclohexyl)acetic acid was prepared from 3-chlo VV) In an analogous manner, (4-bromophenyl)(1-hydroxycy 60 rophenylacetic acid and 4-methylcyclohexanone. MS clohexyl)acetic acid was prepared from 4-bromopheny (ESI) m/z 281/283 (M-HI). lacetic acid and cyclohexanone. MS (ESI) m/z. 313/315 Ill) Step 1: A mixture of 4-(chloromethyl)dibenzyl (0.92 g. 4 (IM+H"); Anal. Calcd for CHBrO: C, 53.69; H, 5.47: mmol) and potassium cyanide (0.039 g, 6 mmol) in N,N'- N, 0.00. Found: C, 53.87; H, 5.42: N, 0.00. dimethylformamide (20 mL) was heated at 80°C. for 16 ww.) In an analogous manner, (4-bromophenyl)(1-hydroxy 65 hours. At the end of this time the solution was poured into cyclobutyl)acetic acid was prepared from 4-bromopheny water and extracted 2 times with ethyl acetate. The extracts lacetic acid and cyclobutanone. were combined and filtered through a plug of silica gel. The US 7,419,980 B2 31 32 filtrate was concentrated to yield 4-(phenethylphenyl)ac prepared from (3-trifluoromethoxy-phenyl)-acetic acid etonitrile as an oil which was used in the next step without and 3(R)-methyl-cyclopentanone. further purification. rrr) In an analogous manner, (1-hydroxy-2,2-dimethyl-cyclo Step 2: 4-(Phenethylphenyl)acetonitrile from the above pentyl)-(3-trifluoromethoxy-phenyl)-acetic acid was pre reaction was treated with a 6 Naqueous solution of hydro pared from (3-trifluoromethoxy-phenyl)-acetic acid and chloric acid (10 mL) and heated at 95° C. for 4 h. The 2,2-dimethyl-cyclopentanone. reaction was cooled to 0°C. and solid potassium hydroxide SSS) In an analogous manner, (1-hydroxycyclohexyl)(6-meth was added until pH 14 was achieved. The solution was oxy-2-naphthyl)acetic acid was prepared from (6-meth washed twice with diethyl ether and the resulting aqueous oxy-2-naphthyl)acetic acid (Harrison, Ian Thomas; Lewis, layer was then acidified to pH1 with concentrated hydro 10 Brian; Nelson, Peter, Rooks, Wendell; Roszkowski, Ado chloric acid. The product was extracted with diethyl ether lph; Tomolonis, Albert; Fried, John H.J.Med. Chem. 1970, (2x50 mL) and the combined ethereal extracts were dried 13, 203-5) and cyclohexanone. MS (ES) m/z. 313.0; over magnesium Sulfate and concentrated. Trituration with HRMS: calcd for CHO+H+, 315.15909; found (ESI, hexane and fitration of the resulting solid afforded 0.64 g of M+H+), 315.159. 4-(2-phenylethyl)phenyl)acetic acid as an off white solid. 15 ttt) In an analogous manner, (3-chloro-4-methoxyphenyl)-1 MS (ESI) m/z 239. (1-hydroxycyclohexyl)acetic acid was prepared from Step 3: In an analogous manner (as Reference Example (3-chloro-4-methoxyphenyl)acetic acid and cyclohex I-a), (1-hydroxycyclohexyl)4-(2-phenylethyl)phenyl anone. MS(ESI) m/z 297 (IM-HI). acetic acid was prepared from 4-(2-phenylethyl)phenyl uuu) In an analogous manner, (1-hydroxycyclohexyl)-(4- acetic acid and cyclohexanone. MS (ESI) m/z 337. phenethyloxyphenyl)acetic acid was prepared from mmm) Step 1: 3-Fluoro-4-hydroxyphenylacetic acid (0.85g. (4-phenethyloxyphenyl)acetic acid and cyclohexanone. 3.62 mmol) and of benzyl bromide (1.30 g, 7.60 mmol) MS(ESI) m/z. 353 (M-H-). were added to a flask containing N,N'-dimethylformamide VVV) Step 1: In an analogous manner to Reference Example (20 mL). Potassium carbonate (1.25 g, 9.00 mmol) was I-mmm, step 1 4-2-(4-fluoro-phenyl)-ethoxy)-phenyl then added, and the solution was heated at 50° C. for 4 25 acetic acid was prepared from (4-hydroxyphenyl)acetic hours. A 2 Naqueous solution of sodium hydroxide (10 acid and 2-(4-fluorophenyl)ethyl bromide. MS(ESI) m/z. mL) was added and heating was maintained for an addi 273 (IM-HI). tional 16 hours. At the end of this time the solution was Step 2: In an analogous manner (as Reference Example poured into water and washed twice with diethyl ether. The I-a). {4-2-(4-fluoro-phenyl)-ethoxy)-phenyl-(1-hy ethereal extracts were discarded and the aqueous layer was 30 droxy-cyclohexyl)-acetic acid was prepared from {4-2- acidified with concentrated hydrochloric acid until pH 1 (4-fluoro-phenyl)-ethoxyl-phenyl)-acetic acid and cyclo was achieved. The product was then extracted with diethyl hexanone. MS(ESI) m/z. 371 (M-HI) ether (2x50 mL). The combined ethereal layers were dried www.) Step 1: In an analogous manner to Reference Example over magnesium sulfate and concentrated to afford 0.95g I-mmm, step 1 4-(2-naphthalen-1-yl-ethoxy)-phenyl of 4-benzyloxy-3-fluorophenylacetic acid which was used 35 acetic acid was prepared from (4-hydroxyphenyl)acetic as such in the next step. MS (ESI) m/z 325. acid and 1-(2-bromoethyl)napthalene. MS(ESI) m/z. 305 Step 2: In an analogous manner (as Reference Example (M-HI). I-a). 4-(benzyloxy)-3-fluorophenyl(1-hydroxycyclo Step 2: In an analogous manner (as Reference Example hexyl)acetic acid was prepared from 4-(benzyloxy)-3- I-a). (1-hydroxy-cyclohexyl)-4-(2-naphthalen-1-yl fluorophenyl)acetic acid and cyclohexanone. MS (ESI) 40 ethoxy)-phenyl-acetic acid was prepared from 4-(2- m/Z 357. naphthalen-1-yl-ethoxy)-phenyl-acetic acid and cyclo nnn) In an analogous manner, 4-(benzyloxy)-3-methox hexanone. MS(ESI) m/z 403 (IM-HI) yphenyl(1-hydroxycyclohexyl)acetic acid was prepared XXX) Step 1: In an analogous manner to Reference Example from 4-(benzyloxy)-3-methoxyphenyl)acetic acid and I-mmm, step 1 4-2-(4-methoxy-phenyl)-ethoxyl-phe cyclohexanone. MS (ES) m/z. 369.0. 45 nyl)-acetic acid was prepared from (4-hydroxyphenyl) ooo) Step 1: In an analogous manner to Reference Example acetic acid and 4-(2-chloroethyl)anisole. MS(ESI) m/z 273 I-mmm, step 1 {3-chloro-4-(3-methoxybenzyl)oxyl (M-HI). phenyl)acetic acid was prepared from 3-chloro-4-hy Step 2: In an analogous manner (as Reference Example droxy-phenyl)acetic acid and 3-methoxybenzyl chloride. I-a), (1-hydroxy-cyclohexyl)-4-2-(4-methoxy-phenyl)- 50 ethoxyl-phenyl)-acetic acid was prepared from {4-2-(4- Step 2: In an analogous manner (as Reference Example methoxy-phenyl)-ethoxyl-phenyl)-acetic acid and cyclo I-a), 3-chloro-4-(3-methoxy-benzyloxy)-phenyl(1-hy hexanone. MS(ESI) m/z 383 (IM-HI) droxy-cyclohexyl)acetic acid was from 3-chloro-4-(3- yyy) Step 1: In an analogous manner to Reference Example methoxybenzyl)oxyphenyl)acetic acid and cyclohex I-mmm, step 1 (4-cyclohexylmethoxy-phenyl)-acetic acid aOC. 55 was prepared from (4-hydroxyphenyl)acetic acid and ppp) Step 1: In an analogous manner to Reference Example cyclomethyl bromide. MS(ESI) m/z 247 (IM-HI). I-mmm, step 1 {3-chloro-4-(2-methoxybenzyl)oxyl Step 2: In an analogous manner (as Reference Example phenyl)acetic acid was prepared from 3-chloro-4-hy I-a), (4-cyclohexylmethoxy-phenyl)-(1-hydroxy-cyclo droxy-phenyl)acetic acid and 2-methoxybenzyl chloride. hexyl)-acetic acid was prepared from (4-cyclohexyl MS (ES) m/z 304.9. 60 methoxy-phenyl)-acetic acid and cyclohexanone. Step 2: In an analogous manner (as Reference Example MS(ESI) m/z 345 (IM-HI) I-a), 3-chloro-4-(2-methoxy-benzyloxy)-phenyl-(1-hy ZZZ) Step 1: To a stirred solution of (4-hydroxyphenyl)acetic droxy-cyclohexyl)-acetic acid was from 3-chloro-4-(2- acid methyl ester (0.33 g, 0.002 mole), S-(-)-sec-phen methoxybenzyl)oxyphenyl)acetic acid and cyclohex ethyl alcohol (0.24g, 0.002 mole) and triphenylphosphine aOC. 65 (0.52g, 0.002 mole) in anhydrous tetrahydrofuran (6 mL) qqq) In an analogous manner, (3R)-1-hydroxy-3-methylcy was added dropwise over 15 minutes diisopropylaZodicar clopentyl3-(trifluoromethoxy)phenyl)acetic acid was boxylate (0.40 g, 0.002 mole) in tetrahydrofuran (16 mL). US 7,419,980 B2 33 34 The reaction solution was stirred for 1 h at room tempera Step 2: A solution of 4-(3-chlorophenyl)(1-hydroxycyclo ture and was then evaporated to dryness in vacuo. To the hexyl)acetylpiperazine-1-carboxylate (200 mg, 0.46 mmol) residue was added methanol (12 mL) and sodium hydrox in dry tetrahydrofuran (3 mL) under nitrogen was treated ide (0.44 g., 0.011 mole), and the reaction solution was dropwise with a solution of borane (1.0M in tetrahydrofuran, stirred under reflux for 1 h. The methanol was then 1.60 mL, 1.60 mmol). The resulting solution was heated at removed in vacuo, and to the residue was added 12 mL of 70° C. for 2 h, after which time the reaction was cooled in an water. After stirring for 1 h, the precipitated triphenylphos ice bath and was treated dropwise with a 2Naqueous solution phine oxide was removed by Suction filtration. The aque of hydrochloric acid (1 mL). The reaction was again heated at ous filtrate was extracted with 25 mL of ethyl acetate. The 10 70° C. for 1 h, and was then cooled and treated with methanol ethyl acetate phase was discarded and the aqueous phase (1 mL). After the solvent was removed in vacuo, the resulting was acidified with concentrated hydrochloric acid giving residue was dissolved in water (5 mL) and was washed with the solid product 4-((1R)-1-phenylethoxyphenyl)acetic ethyl acetate (1x4 mL). The aqueous layer was basified with acid. MS(ESI) m/z 253 (M-HI). the addition of a 2 Naqueous solution of sodium hydroxide 15 until the pH=10. The product was extracted with ethyl acetate Step 2: In an analogous manner (as Reference Example (4x5 mL) and the combined organic extracts were dried over I-a), (1-hydroxycyclohexyl)-4-((1R)-1-phenylethoxyphe magnesium Sulfate and concentrated in vacuo to yield 146 mg nyl)acetic acid was prepared from 4-((1R)-1-phenylethoX (99%) 1-1-(3-chlorophenyl)-2-piperazin-1-ylethylcyclo yphenyl)acetic acid and cyclohexanone. MS(ESI) m/z. 353 hexanol as a colorless oil. HRMS: calcd for C.H.CINO, (M-HI) 322.1812; found (ESI FT), 323.18977. 1-1-(3-Chlorophe aaaa) Step 1: In an analogous manner to Reference Example nyl)-2-piperazin-1-ylethylcyclohexanol (146 mg) was dis I-ZZZ, Step 1 4-(1S)-1-phenylethoxyphenyl)acetic acid was solved in methanol (0.5 mL) and treated with a saturated prepared from (4-hydroxyphenyl)acetic acid and R-(+)- methanolic solution of hydrochloric acid (0.5 mL) followed by diethyl ether. After crystallizing in the refrigerator for 16h, sec-phenethyl alcohol. MS(ESI) m/z 253 (M-HI). 25 Step 2: In an analogous manner (as Reference Example the resulting solid was collected, washed with diethyl ether I-a), (1-hydroxycyclohexyl)-4-((1S)-1-phenylethoxyphe and dried in vacuo to yield 110 mg (60%) 1-1-(3-chlorophe nyl)acetic acid was prepared from 4-(1S)-1-phenylethoX nyl)-2-piperazin-1-ylethylcyclohexanol dihydrochloride as a white solid. MS (ESI) m/z 323/325 (M+H"); HRMS: yphenyl)acetic acid and cyclohexanone. MS(ESI) m/z. 353 calcd for C.H.CIN.O.2.00 HCl, 394.1345; found (ES (M-HI). 30 I FT), 323.18831. Example 1 Example 2

1-1-(3-chlorophenyl)-2-piperazin-1-ylethylcyclo 35 1-2-(1,4'-bipiperidin-1-yl)-1-(3-chlorophenyl)ethyl hexanol Dihydrochloride cyclohexanol Dihydrochloride O 40 OH

45 OH

C 50 C Step 1: A solution of (3-chlorophenyl)(1-hydroxycyclo hexyl)acetic acid (Reference Example 1-a) (5.4 g. 20.1 In an analogous manner to Example 1, step 1 1-2-(1,4'- mmol), benzotriazol-1-yloxytris(dimethylamino)phospho 55 bipiperidin-1-yl)-1-(3-chlorophenyl)-2-oxoethylcyclohex nium hexafluorophosphate (14.22 g, 32.15 mmol), and tert anol was prepared from (3-chlorophenyl)(1-hydroxycyclo butyl 1-piperazinecarboxylate (5.99 g, 32.15 mmol) in meth hexyl)acetic acid (Reference Example 1-a) and N-(4- ylene chloride (20 mL) was treated with triethylamine (8.4 piperidine)piperidine. MS (ESI) m/z. 419/421 (M+H"): mL, 60.3 mmol). The reaction was stirred at 25°C. for 16 h, HRMS: calcd for CHCINO, 418.2387: found (ESI), after which time the solvent was removed in vacuo and the 60 419.2451. product was purified via Biotage Horizon (FLASH 40 M, In an analogous manner to Example 1, step 2 1-2-(1,4'- silica, gradient from 0% EtOAc/hexane to 30% EtOAc/hex bipiperidin-1-yl)-1-(3-chlorophenyl)ethylcyclohexanol ane) to yield 7.10 g (81%) tert-butyl 4-(3-chlorophenyl)(1- dihydrochloride was prepared from 1-2-(1,4'-bipiperidin-1'- hydroxycyclohexyl)acetylpiperazine-1-carboxylate as a 65 yl)-1-(3-chlorophenyl)-2-oxoethylcyclohexanol. MS (ESI) white foam. HRMS: calcd for CHCINO. 436.2129: m/z 405/.407 (M+H"); HRMS: calcd for C.H.CINO.2.00 found (ESI FT), 437.21996. HC1,476.2128; found (ESI), 405.2664. US 7,419,980 B2 35 36 Example 3 Example 5 1-1-(3-chlorophenyl)-2-(4-pyrrolidin-1-ylpiperidin 1-1-(2-naphthyl)-2-piperazin-1-ylethylcyclobutanol 1-yl)ethylcyclohexanol Dihydrochloride Dihydrochloride

KO 10 ON

OH 15 CO-5 In an analogous manner to Example 1, Step 1 tert-butyl C 4-(1-hydroxycyclobutyl)(2-naphthyl)acetylpiperazine-1- carboxylate was prepared from (1-hydroxycyclobutyl)(2- In an analogous manner to Example 1, step 1 1-1-(3- chlorophenyl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)-2-oxoet naphthyl)acetic acid (Reference Example 1-c) and tert-butyl hylcyclohexanol was prepared from (3-chlorophenyl)(1-hy 1-piperazinecarboxylate. HRMS: calcd for CHNO, droxycyclohexyl)acetic acid (Reference Example 1-a) and 424.2362; found (ESI FT), 425.24337. 4-(1-pyrrolidinyl)piperidine. 25 In an analogous manner to Example 1, step 2 1-1-(2- In an analogous manner to Example 1, step 2 1-1-(3- naphthyl)-2-piperazin-1-ylethylcyclobutanol dihyrochlo chlorophenyl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)ethylcy ride was prepared from tert-butyl 4-(1-hydroxycyclobutyl) clohexanoldihydrochloride was prepared from 1-1-(3-chlo (2-naphthyl)acetylpiperazine-1-carboxylate. HRMS: calcd rophenyl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)-2-oxoethyl 30 for CHNO.2.00 HCl, 382.1579: found (ESI FT), cyclohexanol. MS (ESI) m/z 391/393 (IM+H"); HRMS: 3.11.21184. calcd for CHCINO.2.00 HCl, 462.1971; found (ESI), 391.2497. Example 6 Example 4 35 1-2-(1,4'-bipiperidin-1-yl)-1-(3,4-dichlorophenyl) 1-2-(1,4'-bipiperidin-1-yl)-1-(3-bromophenyl)ethyl ethylcyclohexanol Dihydrochloride cyclohexanol Dihydrochloride

40

45

OH OH

50 C

C Br

In an analogous manner to Example 1, step 1 1-2-(1,4'- 55 In an analogous manner to Example 1, step 1 1-2-(1,4'- bipiperidin-1-yl)-1-(3-bromophenyl)-2-oxoethylcyclohex bipiperidin-1-yl)-1-(3,4-dichlorophenyl)-2-oxoethylcyclo anol was prepared from (3-bromophenyl)(1-hydroxycyclo hexanol was prepared from 3,4-dichloro-alpha-(1-hydroxy hexyl)acetic acid (Reference Example 1-b) and N-(4- cyclohexyl)benzeneacetic acid (Reference Example 1-d) and piperidine)piperidine. MS (ESI) m/z 463 (M+H"); HRMS: N-(4-piperidine)piperidine. calcd for CHBrNO. 462.1882; found (ESI), 463. 1975. 60 In an analogous manner to Example 1, step 2 1-2-(1,4'- In an analogous manner to Example 1, step 2 1-2-(1-(4'- bipiperidin-1-yl)-1-(3-bromophenyl)ethylcyclohexanol bipiperidin-1-yl)-1-(3,4-dichlorophenyl)ethylcyclohexanol dihydrochloride was prepared from 1-2-(1,4'-bipiperidin-1'- dihydrochloride was prepared from 1-2-(1,4'-bipiperidin-1'- yl)-1-(3-bromophenyl)-2-oxoethylcyclohexanol. MS m/z. yl)-1-(3,4-dichlorophenyl)-2-oxoethylcyclohexanol. MS 449/451 (M+H"); HRMS: calcd for CHBrNO.2.00 65 m/Z 439/441/443 (M+H"); HRMS: calcd for HC1, 520.1623: found (ESI), 449.2149. CHC1.N.O.2.00 HCl, 510, 1738; found (ESI), 439.2267. US 7,419,980 B2 37 38 Example 7 Example 9 1-1-(3-bromophenyl)-2-(4-pyrrolidin-1-ylpiperidin 1-1-(3-bromo-4-methoxyphenyl)-2-(4-pyrrolidin-1- 1-yl)ethylcyclohexanol Dihydrochloride ylpiperidin-1-yl)ethylcyclohexanol Dihydrochloride

KO 10 KO

OH OH 15

Br Br In an analogous manner to Example 1, step 1 1-1-(3- bromophenyl)-2-oxo-2-(4-pyrrolidin-1-ylpiperidin-1-yl) In an analogous manner to Example 1, step 1 1-1-(3- ethylcyclohexanol was prepared from (3-bromophenyl)(1- bromo-4-methoxyphenyl)-2-(4-pyrrolidin-1-ylpiperidin-1- hydroxycyclohexyl)acetic acid (Reference Example 1-b) and 25 yl)-2-oxoethylcyclohexanol was prepared from (3-bromo-4- 4-(1-pyrrolidinyl)piperidine. MS (ESI) m/z 449 (M+H"); methoxyphenyl)(1-hydroxycyclohexyl)acetic acid HRMS: calcd for CHBrNO, 448.1725; found (ESI), (Reference Example 1-1) and 4-(1-pyrrolidinyl)piperidine. 449.1789. In an analogous manner to Example 1, step 2 1-1-(3- In an analogous manner to Example 1, step 2 1-1-(3- bromo-4-methoxyphenyl)-2-(4-pyrrolidin-1-ylpiperidin-1- bromophenyl)-2-(4-Pyrrolidin-1-ylpiperidin-1-yl)ethylcy 30 clohexanol dihydrochloride was prepared from 1-1-(3-bro yl)ethylcyclohexanol dihydrochloride was prepared from mophenyl)-2-oxo-2-(4-pyrrolidin-1-ylpiperidin-1-yl)ethyl 1-1-(3-bromo-4-methoxyphenyl)-2-(4-pyrrolidin-1-ylpip cyclohexanol. MS m/z 435/437 (IM+H"); HRMS: calcd for eridin-1-yl)-2-oxoethylcyclohexanol. MS m/z. 465/467 CHBrNO.2.00 HCl, 506.1466: found (ESI), 435.2021. (IM+H"); HRMS: calcd for CHBrNO.2.00 HCl, 35 536.1572: found (ESI), 465.2096. Example 8 Example 10 1-2-(1,4'-bipiperidin-1-yl)-1-(3-bromo-4-methox yphenyl)ethylcyclohexanol Dihydrochloride 1-2-(benzylamino)-1-(3,4-dichlorophenyl)ethyl 40 cyclobutanol Hydrochloride

45

OH OH 50

C

C Br 55 In an analogous manner to Example 1, step 1 N-benzyl-2- In an analogous manner to Example 1, step 1 1-2-(1,4'- (3,4-dichlorophenyl)-2-(1-hydroxycyclobutyl)acetamide bipiperidin-1-yl)-1-(3-bromo-4-methoxyphenyl)-2-oxoet was prepared from (3,4-dichlorophenyl)(1-hydroxycyclobu hylcyclohexanol was prepared from (3-bromo-4-methox tyl)acetic acid (Reference Example 1-p) and benzylamine. yphenyl)(1-hydroxycyclohexyl)acetic acid (Reference 60 Example 1-1) and N-(4-piperidine)piperidine. HRMS: calcd for CHC1NO, 363.0793; found (ES In an analogous manner to Example 1, step 2 1-2-(1,4'- I FT), 364,08658. bipiperidin-1-yl)-1-(3-bromo-4-methoxyphenyl)ethylcy In an analogous manner to Example 1, step 21-2-(benzy clohexanol dihydrochloride was prepared from 1-2-(1,4'- lamino)-1-(3,4-dichlorophenyl)ethylcyclobutanol hydro bipiperidin-1-yl)-1-(3,4-dichlorophenyl)-2-oxoethyl 65 chloride was prepared from N-benzyl-2-(3,4-dichlorophe cyclohexanol. MS m/z. 479/481 (IM+H"); HRMS: calcd for nyl)-2-(1-hydroxycyclobutyl)acetamide. HRMS: calcd for CHBrNO.2.00 HC1,550.1728; found (ESI), 479.2269. CHC1NO.HC1,385.0767; found (ESI FT), 350. 10832. US 7,419,980 B2 39 40 Example 11 1-1 -(3,4-dichloropheryExample S5 13 (methylamino)pip 1-1-(3,4-dichlorophenyl)-2-(4-pyrrolidin-1-ylpiperi eridin-1-yl)ethylcyclohexanol Dihydrochloride din-1-yl)ethylcyclohexanol Dihydrochloride CH3 HN

KO 10 OH

C OH 15 C

Step 1: In an analogous manner to Example 1, step 1 C tert-butyl (1-(3,4-dichlorophenyl)(1-hydroxycyclohexyl) C acetylpiperidin-4-yl)carbamate was prepared from 3.4- dichloro-alpha-(1-hydroxycyclohexyl)benzeneacetic acid (Reference Example 1-d) and 4-N-boc-aminopiperidine. MS In an analogous manner to Example 1, step 1 1-1-(3,4- (ES) m/z 485.2 (M+H"); HRMS: calcd for CHC1.N.O. dichlorophenyl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)-2-oxo 484.1896; found (ESI), 485.1987. ethylcyclohexanol was prepared from 3,4-dichloro-alpha 25 Step 2: A solution of tert-butyl {1-(3,4-dichlorophenyl) (1-hydroxycyclohexyl)benzeneacetic acid (Reference (1-hydroxycyclohexyl)acetylpiperidin-4-yl)carbamate Example 1-d) and 4-(1-pyrrolidinyl)piperidine. (364 mg. 0.75 mmol) in dry tetrahydrofuran (1 mL), under In an analogous manner to Example 1, step 2 1-1-(3,4- nitrogen, was treated with a solution of borane (1.0 M in dichlorophenyl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)ethyl tetrahydrofuran, 2.62 mL, 2.62 mmol). The reaction was 30 heated at 74° C. for 2 h, after which time the reaction was cyclohexanol dihydrochloride was prepared from 1-1-(3,4- cooled and quenched by the addition of methanol (4 mL). The dichlorophenyl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)-2- solvents were removed in vacuo, and the products were puri oxoethylcyclohexanol. MS m/Z 425/427/429 (M+H"): fied via Biotage Horizon (FLASH 25 M, silica, gradient from HRMS: calcd for CHC1.N.O.2.00 HCl, 496.1582: found 10% EtOAc/hexane to 90% EtOAc/hexane) to yield 187 mg (ESI), 425.2129. 35 (53%) tert-butyl {1-2-(3,4-dichlorophenyl)-2-(1-hydroxy cyclohexyl)ethylpiperidin-4-yl)carbamate as a white foam which eluted first and 88 mg (31%) 1-1-(3,4-dichlorophe Example 12 nyl)-2-[4-(methylamino)piperidin-1-yl)ethylcyclohexanol 1-2-(benzylamino)-1-(2-naphthyl)ethylcyclobu as a colorless oil which eluted second. tert-butyl {1-2-(3,4- 40 dichlorophenyl)-2-(1-hydroxycyclohexyl)ethylpiperidin-4- tanol Hydrochloride y1}carbamate: MS (ES) m/z 471.3 (IM+H"); HRMS: calcd for CHC1.N.O., 470.2103; found (ESI), 471.2165. 1-1- (3,4-dichlorophenyl)-2-4-(methylamino)piperidin-1-yl ethylcyclohexanol: MS m/z 385/387/389 (IM+H"). 1-1- 45 (3,4-dichlorophenyl)-2-4-(methylamino)piperidin-1-yl H ethylcyclohexanol was converted to the dihydrochloride salt N with a methanolic solution of hydrochloric acid and diethyl ether to yield 45 mg (41%) 1-1-(3,4-dichlorophenyl)-2-4- (methylamino)piperidin-1-yl)ethylcyclohexanol dihydro 50 chloride as a white solid. HRMS: calcd for CHC1.N.O.2.00 HCl, 456.1269; found (ESI),385.183. COrl Example 14 1-2-(4-aminopiperidin-1-yl)-1-(3,4-dichlorophenyl) ethylcyclohexanol Dihydrochloride 55

In an analogous manner to Example 1, step 1 N-benzyl-2- HN (1-hydroxycyclobutyl)-2-(2-naphthyl)acetamide was pre pared from (1-hydroxycyclobutyl)(2-naphthyl)acetic acid (Reference Example 1-c) and benzylamine. HRMS: calcd for 60 CHNO. 345.1729; found (ESI FT), 346.17885. OH In an analogous manner to Example 1, Step 21-2-(benzy lamino)-1-(2-naphthyl)ethylcyclobutanol hydrochloride was prepared from N-benzyl-2-(1-hydroxycyclobutyl)-2-(2- 65 C naphthyl)acetamide. HRMS: calcd for CHNO.HCl, 367. 1703; found (ESI FT), 332.20146. C US 7,419,980 B2 41 42 A solution of tert-butyl {1-2-(3,4-dichlorophenyl)-2-(1- din-3-yl)-carbamic acid tert-butyl ester was prepared from hydroxycyclohexyl)ethylpiperidin-4-yl)carbamate (130 (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acid (Refer mg, 0.28 mmol) (Example 13), in diethyl ether (2 mL) was ence Example 1-a) and (3S)-(-)-3-(tert-butoxycarbony treated with a 4N solution of hydrogen chloride in dioxane (1 lamino)pyrrolodine. mL). The resulting solution was stored at 25° C. for 16 h, In an analogous manner to Example 1, step 2 1-2-(3S)- during which time crystals began to form. The mixture was 3-aminopyrrolidin-1-yl)-1-(3-chlorophenyl)ethylcyclohex transferred to the refrigerator where it was stored for an anol dihydrochloride was prepared from {(S)-1-(2-(3- additional 16 h. The resulting crystals were collected, washed Chloro-phenyl)-2-(1-hydroxy-cyclohexyl)-acetyl with diethyl ether, and dried in vacuo to yield 101 mg (82%) pyrrolidin-3-yl)-carbamic acid tert-butyl ester. HRMS: calcd 1-2-(4-aminopiperidin-1-yl)-1-(3,4-dichlorophenyl)ethyl 10 for C.H.CINO.2.00 HCl, 394.1345; found (ESI), cyclohexanol dihydrochloride as a white solid. MS m/z. 371/ 323.1884. 373/375 (IM+H"); HRMS: calcd for CHC1.N.O.2.00 HCl, 442.11.12; found (ESI), 371.1642. Example 17

Example 15 15 1-1-(3-chlorophenyl)-2-[4-(methylamino)piperidin 4-2-(benzylamino)-1-(3,4-dichlorophenyl)ethyl-1- 1-yl)ethylcyclohexanol Dihydrochloride methylpiperidin-4-ol Dihydrochloride

CH

25 OH OH

C CH 30 C C

In an analogous manner to Example 1, step 1 N-benzyl-2- In an analogous manner to Example 1, Step 1 tert-butyl (3,4-dichlorophenyl)-2-(4-hydroxy-1-methylpiperidin-4-yl) {1-(3-chlorophenyl)(1-hydroxycyclohexyl)acetylpiperi acetamide was prepared from (3,4-dichlorophenyl)(4-hy 35 din-4-yl)carbamate was prepared from (3-chlorophenyl)(1- droxy-1-methylpiperidin-4-yl)acetic acid (Reference hydroxycyclohexyl)acetic acid (Reference Example 1-a) and Example 1-i) and benzylamine. HRMS: calcd for 4-N-boc-aminopiperidine. MS m/z 451/453 (M--HI); CHCINO, 406. 1215; found (ESI FT), 407.12885. HRMS: calcd for CHCINO. 450.2285; found (ESI), In an analogous manner to Example 1, Step 2 4-2-(benzy 451.2353. lamino)-1-(3,4-dichlorophenyl)ethyl-1-methylpiperidin-4- 40 In an analogous manner to Example 13, step 2 1-1-(3- ol dihydrochloride was prepared from N-benzyl-2-(3,4- chlorophenyl)-2-4-(methylamino)piperidin-1-yl dichlorophenyl)-2-(4-hydroxy-1-methylpiperidin-4-yl) ethylcyclohexanol dihydrochloride was prepared from tert acetamide. HRMS: calcd for CHCl, N.O.2.00 HCl, butyl {1-(3-chlorophenyl)(1-hydroxycyclohexyl)acetyl 464.0956; found (ESI FT), 393.14924. 45 piperidin-4-yl)carbamate. MS m/z 351/353 (M+H"); Example 16 HRMS: calcd for CHCINO.2.00 HCl, 422.1658; found (ESI), 351.2208. 1-2-((3S)-3-aminopyrrolidin-1-yl)-1-(3-chlorophe nyl)ethylcyclohexanol Dihydrochloride Example 18 50 1-2-(4-aminopiperidin-1-yl)-1-(3-bromophenyl) ethylcyclohexanol Dihydrochloride HN

55 KO HN OH

OH 60

C

65 Br In an analogous manner to Example 1, step 1 (S)-1-(2-(3- Chloro-phenyl)-2-(1-hydroxy-cyclohexyl)-acetyl-pyrroli US 7,419,980 B2 43 44 In an analogous manner to Example 1, Step 1 tert-butyl In an analogous manner to Example 1, step 1 1-2-(1,4'- {1-(3-bromophenyl)(1-hydroxycyclohexyl)acetylpiperi bipiperidin-1-yl)-1-3-(trifluoromethyl)phenyl)-2-oxoethyl din-4-yl)carbamate was prepared from (3-bromophenyl)(1- cyclohexanol was prepared from (1-hydroxycyclohexyl)3- hydroxycyclohexyl)acetic acid (Reference Example 1-b) and (trifluoromethoxy)phenyl)acetic acid (Reference Example 4-N-boc-aminopiperidine. MS (ES) m/z. 495.2 (M--HI); 5 1-f) and N-(4-piperidine)piperidine. HRMS: calcd for CHBrNO. 494.1780; found (ESI), In an analogous manner to Example 1, step 2 1-2-(1,4'- 495.1864. bipiperidin-1-yl)-1-3-(trifluoromethyl)phenyl In an analogous manner to Example 13, step 2 tert-butyl ethylcyclohexanol dihydrochloride was prepared from {1-2-(3-bromophenyl)-2-(1-hydroxycyclohexyl)ethylpip (1-hydroxycyclohexyl)-3-(trifluoromethoxy)phenyl)acetic eridin-4-yl)carbamate was prepared from tert-butyl {1-(3- 10 bromophenylphenyl)(1-hydroxycyclohexyl)acetylpiperi acid, m/z. 439 (M+H"); HRMS: calcd for din-4-yl)carbamate. MS (ES) m/z 481.3 (IM+H"); HRMS: C.H.F.N.O.2.00 HCl, 510.2392; found (ESI), 439.2928. calcd for CHBrNO. 480.1988; found (ESI), 481.2081. In an analogous manner to Example 14, 1-2-(4-aminopi Example 21 peridin-1-yl)-1-(3-bromophenyl)ethylcyclohexanol dihy 15 drochloride was prepared from tert-butyl {1-2-(3-bro 1-1-(1-naphthyl)-2-piperazin-1-ylethylcyclohex mophenyl)-2-(1-hydroxycyclohexyl)ethylpiperidin-4- anol Dihydrochloride y1}carbamate. HRMS: calcd for CHBrNO.2.00 HCl, 452.0997; found (ESI), 381.1525. Example 19 1-1-(3-bromophenyl)-2-[4-(methylamino)piperidin 1-yl)ethylcyclohexanol Dihydrochloride CH3 25 HN

OH

In an analogous manner to Example 1, Step 1 tert-butyl Br 35 4-(1-hydroxycyclohexyl)(1-naphthyl)acetylpiperazine-1- In an analogous manner to Example 1, Step 1 tert-butyl carboxylate was prepared from (1-hydroxycyclohexyl)(1- {1-(3-bromophenyl)(1-hydroxycyclohexyl)acetylpiperi naphthyl)acetic acid (Reference Example 1.-e) and tert-butyl din-4-yl)carbamate was prepared from (3-bromophenyl)(1- 1-piperazinecarboxylate. MS (ESI) m/z 453 (M--HI); hydroxycyclohexyl)acetic acid (Reference Example 1-b) and 40 HRMS: calcd for CHNO. 452.2675; found (ESI FT), 4-N-boc-aminopiperidine. MS (ES) m/z. 495.2 (M--HI); 453.27518. HRMS: calcd for CHBrNO. 494.1780; found (ESI), 495.1864. In an analogous manner to Example 1, step 2 1-1-(1- In an analogous manner to Example 13, step 2 1-1-(3- naphthyl)-2-piperazin-1-ylethylcyclohexanol dihydrochlo bromophenyl)-2-4-(methylamino)piperidin-1-yl) ride was prepared from tert-butyl 4-(1-hydroxycyclohexyl) ethylcyclohexanol dihydrochloride was prepared from tert 45 (1-naphthyl)acetylpiperazine-1-carboxylate. MS (ESI) m/z. butyl {1-(3-bromophenylphenyl)(1-hydroxycyclohexyl) 339 (IM+H"); HRMS: calcd for CHNO.HC1,374.2125; acetylpiperidin-4-yl)carbamate. MS (ESI) m/z 395 (IM+ found (ESI FT), 339.24268. HI); HRMS: calcd for CH, BrNO.2.00 HC1, 466.1153; found (ESI), 395.1708. Example 22 50 Example 20 1-2-(1,4'-bipiperidin-1'-yl)-1-3-(trifluoromethyl) 1-2-(1,4'-bipiperidin-1-yl)-1-(2-naphthyl)ethyl phenylethylcyclohexanol Dihydrochloride cyclohexanol Dihydrochloride

55

60 OH

65 CF US 7,419,980 B2 45 46 In an analogous manner to Example 1, step 1 1-2-(1,4'- A solution of 1-(2-piperazin-1-yl-1-3-(trifluoromethoxy) bipiperidin-1-yl)-1-(2-naphthyl)-2-oxoethylcyclohexanol phenylethylcyclohexanol (590 mg, 1.59 mmol) (see was prepared from (1-hydroxycyclohexyl)(2-naphthyl)acetic Example 23), in formic acid (3.1 mL) at 50° C., was treated acid (Reference Example 1-q) and N-(4-piperidine)piperi with an aqueous solution of formaldehyde (37% in water, 1.3 dine. In an analogous manner to Example 1, step 2 1-2-(1,4'- mL, 1.94 mmol). The reaction was heated at 70° C. for 1.5 h. bipiperidin-1-yl)-1-(2-naphthyl)ethylcyclohexanol dihy after which time the reaction was poured into water (50 mL) drochloride was prepared from 1-2-(1,4'-bipiperidin-1-yl)- and basified to pH=10 with the addition of a 2 Naqueous 1-(2-naphthyl)-2-oxoethylcyclohexanol. MS m/z. 421 (IM+ solution of sodium hydroxide. The product was then HI"); HRMS: calcd for CHNO.2.00 HCl, 492.2674; 10 extracted with ethyl acetate (3x20 mL), and the combined found (ESI), 421.3224. organic extracts were dried over magnesium sulfate and con centrated to yield 442 mg (72%) 1-2-(4-methylpiperazin-1- Example 23 yl)-1-3-(trifluoromethoxy)phenylethylcyclohexanol as a colorless oil. The product was dissolved in methanol (0.5 mL) 1-2-piperazin-1-yl-1-3-(trifluoromethoxy)phenyl and the resulting solution was treated with a saturated metha ethylcyclohexanol Dihydrochloride nolic solution of hydrochloric acid (0.5 mL) followed by diethyl ether (2 mL). The solution was stored in the refrigera tor for 16 h. The resulting precipitate was filtered and washed with diethyl ether to yield 299 mg (57%) 1-2-(4-methylpip erazin-1-yl)-1-3-(trifluoromethoxy)phenyl ethylcyclohexanol dihydrochloride as a white solid. HRMS: O calcd for CHF.N.O.2.00 HCl, 458.1715; found (ESI), OH 387.2263. 25 Example 25 1-2-(4-aminopiperidin-1-yl)-1-(3-bromo-4-methox OCF 30 yphenyl)ethylcyclohexanol Dihydrochloride

In an analogous manner to Example 1, Step 1 tert-butyl HN 4-(1-hydroxycyclohexyl)-3-(trifluoromethoxy)phenyl acetylpiperazine-1-carboxylate was prepared from (1-hy 35 droxycyclohexyl)3-(trifluoromethoxy)phenyl)acetic acid (Reference Example 1-f) and tert-butyl 1-piperazinecarboxy OH late. HRMS: calcd for CHFNOs, 486.2342; found (ESI), 487.2398. In an analogous manner to Example 1, step 2 1-2-piper 40 azin-1-yl-1-3-(trifluoromethoxy)phenyl ethylcyclohexanol dihydrochloride was prepared from tert butyl 4-(1-hydroxycyclohexyl)-3-(trifluoromethoxy) Br phenyl)acetylpiperazine-1-carboxylate. HRMS: calcd for 45 CHF.N.O.2.00 HCl, 444.1558; found (ESI), 373.2095. In an analogous manner to Example 1, Step 1 tert-butyl {1-(3-bromo-4-methoxyphenyl)(1-hydroxycyclohexyl) Example 24 acetylpiperidin-4-yl)carbamate was prepared from 1-2-(4-methylpiperazin-1-yl)-1-3-(trifluo (3-bromo-4-methoxyphenyl)(1-hydroxycyclohexyl)acetic romethoxy)phenylethylcyclohexanol Dihydrochlo 50 acid (Reference Example 1-1) and 4-N-boc-aminopiperidine. ride MS (ES) m/z 525.2 (IM+H"); HRMS: calcd for CHBrNOs 524.1886; found (ESI), 525.1971. In an analogous manner to Example 13, step 2 tert-butyl 55 {1-2-(3-bromo-4-methoxyphenyl)-2-(1-hydroxycyclo hexyl)ethylpiperidin-4-yl)carbamate was prepared from tert-butyl {1-(3-bromo-4-methoxyphenyl)(1-hydroxycyclo hexyl)acetylpiperidin-4-yl)carbamate. MS (ES) m/z 511.4 OH (IM+H"); HRMS: calcd for CHBrNO, 510.2093: 60 found (ESI), 511.2147. In an analogous manner to Example 14, 1-2-(4-aminopi peridin-1-yl)-1-(3-bromo-4-methoxyphenyl)ethylcyclohex anol dihydrochloride was prepared from tert-butyl {1-2-(3- OCF 65 bromophenyl)-2-(1-hydroxycyclohexyl)ethylpiperidin-4- y1}carbamate. MS m/z 411/413 (IM+H"); HRMS: calcd for C.H. BrNO2.00 HCl, 482.1102: found (ESI), 411.1656. US 7,419,980 B2 47 48 Example 26 Example 28 1-2-(4-pyrrolidin-1-ylpiperidin-1-yl)-1-3-(trifluo 1-2-piperazin-1-yl-1-4-(trifluoromethoxy)phenyl romethyl)phenylethylcyclohexanol Dihydrochlo ethylcyclohexanol Dihydrochloride ride

KO 10 Cls.

OH 15 FC

In an analogous manner to Example 1, Step 1 tert-butyl 4-(1-hydroxycyclohexyl)4-(trifluoromethoxy)phenyl OCF acetylpiperazine-1-carboxylate was prepared from (1-hy droxycyclohexyl)-4-(trifluoromethoxy)phenyl)acetic acid (Reference Example 1-g) and tert-butyl 1-piperazinecar In an analogous manner to Example 1, step 1 1-2-(4- boxylate. MS (ESI) m/z 487 (M+H"). pyrrolidin-1-ylpiperidin-1-yl)-1-3-(trifluoromethyl)phe In an analogous manner to Example 1, step 21-2-piper nyl-2-oxoethylcyclohexanol was prepared from (1-hy 25 azin-1-yl-1-4-(trifluoromethoxy)phenyl droxycyclohexyl)3-(trifluoromethyl)phenyl)acetic acid ethylcyclohexanol dihydrochloride was prepared from tert (Reference Example 1-m) and 4-(1-pyrrolidinyl)piperidine. butyl 4-(1-hydroxycyclohexyl)4-(trifluoromethoxy) In an analogous manner to Example 1, step 2 1-2-(4- phenyl)acetylpiperazine-1-carboxylate. MS m/z. 373 (M+ pyrrolidin-1-ylpiperidin-1-yl)-1-3-(trifluoromethyl)phenyl H'); Anal. Calcd for CHF.N.O.2.00 HC1 2.10 H.O: C, ethylcyclohexanol dihydrochloride was prepared from 30 1-2-(4-pyrrolidin-1-ylpiperidin-1-yl)-1-3-(trifluorom 47.23; H, 6.93: N, 5.80. Found: C, 46.93; H, 6.80. ethyl)phenyl)-2-oxoethylcyclohexanol. MS m/Z 425 (M+ Example 29 HI"); HRMS: calcd for CHFN.2.00 HCl, 496.2235: found (ESI), 425.2789. 1-1-(3-bromo-4-methoxyphenyl)-2-[4-(methy 35 Example 27 lamino)piperidin-1-yl)ethylcyclohexanol Dihydro chloride 1-1-4-(benzyloxy)phenyl)-2-piperazin-1- ylethylcyclohexanol Dihydrochloride 40 CH M HN

N 45 O OH OH

H3C 50 No Br

In an analogous manner to Example 1, Step 1 tert-butyl In an analogous manner to Example 1, Step 1 tert-butyl 55 {1-(3-bromo-4-methoxyphenyl)(1-hydroxycyclohexyl) 4-4-(benzyloxy)phenyl(1-hydroxycyclohexyl)acetylpip acetylpiperidin-4-yl)carbamate was prepared from erazine-1-carboxylate was prepared from (4-benzyloxyphe (3-bromo-4-methoxyphenyl)(1-hydroxycyclohexyl)acetic nyl)(1-hydroxycyclohexyl)acetic acid (Reference Example acid (Reference Example 1-1) and 4-N-boc-aminopiperidine. 1-n) and tert-butyl 1-piperazinecarboxylate. MS (ESI) m/z. MS (ES) m/z 525.2 (IM+H"); HRMS: calcd for 509 (M+H"); HRMS: calcd for CHNOs, 508.2937: 60 CHBrNO. 524.1886; found (ESI), 525.1971. found (ESI), 509.3027. In an analogous manner to Example 13, step 2 1-1-(3- In an analogous manner to Example 1, step 1-1-4-(ben bromo-4-methoxyphenyl)-2-4-(methylamino)piperidin-1- Zyloxy)phenyl)-2-piperazin-1-ylethylcyclohexanol dihy yl)ethylcyclohexanol dihydrochloride was prepared from drochloride was prepared from tert-butyl 4-4-(benzyloxy) tert-butyl {1-(3-bromo-4-methoxyphenyl)(1-hydroxycyclo phenyl(1-hydroxycyclohexyl)acetylpiperazine-1- 65 hexyl)acetylpiperidin-4-yl)carbamate. MS (ESI) m/z 425 carboxylate. HRMS: calcd for CHNO.2.00 HCl, (IM+H"); HRMS: calcd for CHBrNO.2.00 HCl, 466.2154; found (ESI), 395.2683. 496.1259; found (ESI), 425.1793.

US 7,419,980 B2 51 52 Example 34 Example 36 1-1-(3-chlorophenyl)-2-pyrrolidin-1-ylethylcyclo 1-1-(3-chlorophenyl)-2-[4-(dimethylamino)piperi hexanol Hydrochloride din-1-yl)ethylcyclohexanol Dihydrochloride

CH3 KO 10 OH OH 15

C C In an analogous manner to Example 1, step 1 1-1-(3- chlorophenyl)-2-oxo-2-pyrrolidin-1-ylethylcyclohexanol A solution of 1-2-(4-aminopiperidin-1-yl)-1-(3-chlo was prepared from (3-chlorophenyl)(1-hydroxycyclohexyl) rophenyl)ethylcyclohexanol (50 mg, 0.15 mmol) (see acetic acid (Reference Example 1-a) and pyrrolidine. MS Example 35), in formic acid (0.28 mL) was treated with an (ESI) m/z 322/324 (M+H"); HRMS: calcd for 25 aqueous solution of formaldehyde (37% in water, 0.12 mL). CHCINO, 321.1496; found (ESI FT), 322.15603. The reaction was heated at 70° C. for 1 h, after which time the In an analogous manner to Example 1, step 2 1-1-(3- reaction was diluted with water (3 mL) and basified to pH=10 chlorophenyl)-2-pyrrolidin-1-ylethylcyclohexanol hydro with a 2 Naqueous solution of sodium hydroxide. The prod chloride was prepared from 1-1-(3-chlorophenyl)-2-oxo-2- uct was extracted with ethyl acetate (4x5 mL), and the com 30 bined organic extracts were dried over magnesium Sulfate and pyrrolidin-1-ylethylcyclohexanol. HRMS: calcd for concentrated in vacuo. The resulting colorless oil was treated CHCINO.HC1, 343.1470; found (ESI FT), 308.17736. with methanolic hydrochloric acid and diethyl ether to yield 32 mg (53%) 1-1-(3-chlorophenyl)-2-[4-(dimethylamino) Example 35 piperidin-1-yl)ethylcyclohexanol dihydrochloride as a 35 white solid. HRMS: calcd for CHCINO.HCl, 400.2048; 1-2-(4-aminopiperidin-1-yl)-1-(3-chlorophenyl) found (ESI), 365.2349. ethylcyclohexanol Dihydrochloride Example 37

40 4-1-(3,4-dichlorophenyl)-2-piperazin-1-ylethyl-1- HN methylpiperidin-4-ol Trihydrochloride OH 45 O OH 50 C

C CH3 In an analogous manner to Example 1, Step 1 tert-butyl {1-(3-chlorophenyl)(1-hydroxycyclohexyl)acetylpiperi C din-4-yl)carbamate was prepared from (3-chlorophenyl)(1- 55 hydroxycyclohexyl)acetic acid (Reference Example 1-a) and In an analogous manner to Example 1, Step 1 tert-butyl 4-N-boc-aminopiperidine. MS m/z 451/453 (M--HI); 4-(3,4-dichlorophenyl)(4-hydroxy-1-methylpiperidin-4-yl) HRMS: calcd for CHCINO 450.2285; found (ESI), acetylpiperazine-1-carboxylate was prepared from (3,4- 60 dichlorophenyl)(4-hydroxy-1-methylpiperidin-4-yl)acetic 451.2353. acid (Reference Example 1-i) and tert-butyl 1-piperazinecar In an analogous manner to Example 13, step 2 1-2-(4- boxylate. HRMS: calcd for CHC1NO. 485.1848; aminopiperidin-1-yl)-1-(3-chlorophenyl)ethylcyclohexanol found (ESI FT), 486. 19305. dihydrochloride was prepared from tert-butyl {1-(3-chlo In an analogous manner to Example 1, step 2 4-1-(3,4- rophenyl)(1-hydroxycyclohexyl)acetylpiperidin-4- 65 dichlorophenyl)-2-piperazin-1-ylethyl-1-methylpiperidin y1}carbamate. MS m/z 337/339 (IM+H"); HRMS: calcd for 4-ol trihydrochloride was prepared from tert-butyl 4-(3,4- CHCIN.O.2.00 HC1,408.1502; found (ESI), 337.2022. dichlorophenyl)(4-hydroxy-1-methylpiperidin-4-yl)acetyl US 7,419,980 B2 53 54 piperazine-1-carboxylate. HRMS: calcd for acetylpiperidin-4-yl)carbamate. MS (ES) m/z 471.4 (IM+ CH.ClN.O.3.00 HCl, 479.0831; found (ESI FT), HI"); HRMS: calcd for CHFNO, 470.2756; found 372.16065. (ESI), 471.2852. In an analogous manner to Example 14, 1-2-(4-aminopi Example 38 peridin-1-yl)-1-3-(trifluoromethyl)phenyl ethylcyclohexanol dihydrochloride was prepared from tert 1-2-(benzylamino)-1-(3,4-dichlorophenyl)ethyl butyl (1-2-(1-hydroxycyclohexyl)-2-3-(trifluoromethyl) cyclohexanol Hydrochloride phenylethylpiperidin-4-yl)carbamate. MS m/z. 371 (M+ HI"); HRMS: calcd for CHF.N.O.2.00 HCl, 442.1766: 10 found (ESI), 371.2309. Example 40 1-2-(benzylamino)-1-(3-bromophenyl)ethylcy 15 clobutanol Hydrochloride OH

C

C OH In an analogous manner to Example 1, step 1 N-benzyl-2- (3,4-dichlorophenyl)-2-(1-hydroxycyclohexyl)acetamide 25 was prepared from 3,4-dichloro-alpha-(1-hydroxycyclo hexyl)benzeneacetic acid (Reference Example 1-d) and ben Zylamine. HRMS: calcd for CHC1NO391. 1106; found Br (ESI FT), 392.11598. 30 In an analogous manner to Example 1, step 2 4-1-(3,4- In an analogous manner to Example 1, step 1 N-benzyl-2- dichlorophenyl)-2-piperazin-1-ylethyl-1-methylpiperidin (3-bromophenyl)-2-(1-hydroxycyclobutyl)acetamide was 4-ol hydrochloride was prepared from N-benzyl-2-(3,4- prepared from (3-bromophenyl)(1-hydroxycyclobutyl)acetic dichlorophenyl)-2-(1-hydroxycyclohexyl)acetamide. acid (Reference Example 1-) and benzylamine. HRMS: HRMS: calcd for CHC1-NO HCl, 413.1080; found (ES 35 calcd for CHBrNO, 373.0677; found (ESI FT), I FT), 378.13864. 374O7415. In an analogous manner to Example 1, step 21-2-(benzy Example 39 lamino)-1-(3-bromophenyl)ethylcyclobutanol hydrochlo 1-2-(4-aminopiperidin-1-yl)-1-3-(trifluoromethyl) ride was prepared from N-benzyl-2-(3-bromophenyl)-2-(1- phenylethylcyclohexanol Dihydrochloride 40 hydroxycyclobutyl)acetamide. HRMS: calcd for CHBrNO.HC1, 395.0652; found (ESI FT), 360.09546. Example 41 HN 45 1-2-(benzylamino)-1-(3-chlorophenyl)ethylcyclo hexanol Hydrochloride

OH

50

CF OH 55 In an analogous manner to Example 1, Step 1 tert-butyl (1-(1-hydroxycyclohexyl)-3-(trifluoromethylphenyl acetylpiperidin-4-yl)carbamate was prepared from (1-hy C droxycyclohexyl)3-(trifluoromethyl)phenyl)acetic acid 60 (Reference Example 1-m) and 4-N-boc-aminopiperidine. MS (ES) m/z. 485.3 (IM+H"); HRMS: calcd for CHF.N.O. In an analogous manner to Example 1, step 1 N-benzyl-2- 484.2549; found (ESI), 485.2612. (3-chlorophenyl)-2-(1-hydroxycyclohexyl)acetamide was In an analogous manner to Example 13, step 2 tert-butyl prepared from (3-chlorophenyl)(1-hydroxycyclohexyl)ace (1-2-(1-hydroxycyclohexyl)-2-3-(trifluoromethylphenyl 65 tic acid (Reference Example 1-a) and benzylamine. HRMS: ethylpiperidin-4-yl)carbamate was prepared from tert-butyl calcd for CHCINO, 357.1496; found (ESI FT), (1-(1-hydroxycyclohexyl)-3-(trifluoromethyl)phenyl 358.156O7. US 7,419,980 B2 55 56 In an analogous manner to Example 1, Step 21-2-(benzy ate. MS (ES) m/z 325.3 (M+H"); HRMS: calcd for lamino)-1-(3-chlorophenyl)ethylcyclohexanol hydrochlo C, H.N.O.2.00 HC1, 396.1735; found (ESI),325.2272. ride was prepared from N-benzyl-2-(3-chlorophenyl)-2-(1- hydroxycyclohexyl)acetamide. HRMS: calcd for Example 44 CHCINO.HC1,379.1470; found (ESI FT), 344.17761. 5 4-2-(benzylamino)-1-(3-bromophenyl)ethyl-1-me Example 42 thylpiperidin-4-ol Dihydrochloride 1-2-(cyclohexylamino)-1-(3,4-dichlorophenyl)ethyl cyclohexanol Hydrochloride 10

OH 15

OH CH Br C In an analogous manner to Example 1, step 1 N-benzyl-2- C (3-bromophenyl)-2-(4-hydroxy-1-methylpiperidin-4-yl)ac etamide was prepared from (3-bromophenyl)(4-hydroxy-1- In an analogous manner to Example 1, step 1 N-cyclo 25 methylpiperidin-4-yl)acetic acid (Reference Example 1-r) hexyl-2-(3,4-dichlorophenyl)-2-(1-hydroxycyclohexyl)ac and benzylamine. HRMS: calcd for CHBrNO, etamide was prepared from 3,4-dichloro-alpha-(1-hydroxy 416.1099: found (ESI FT), 417.11652. cyclohexyl)benzeneacetic acid (Reference Example 1-d) and In an analogous manner to Example 1, step 2 4-2-(benzy cyclohexylamine. MS (ESI) m/z. 384/386/388 (M+H"). lamino)-1-(3-bromophenyl)ethyl-1-methylpiperidin-4-ol In an analogous manner to Example 1, step 2 1-2-(cyclo 30 dihydrochloride was prepared from N-benzyl-2-(3-bro hexylamino)-1-(3,4-dichlorophenyl)ethylcyclohexanol mophenyl)-2-(4-hydroxy-1-methylpiperidin-4-yl)aceta hydrochloride was prepared from N-cyclohexyl-2-(3,4- mide. HRMS: calcd for CHBrNO.2.00 HCl, 474,0840: dichlorophenyl)-2-(1-hydroxycyclohexyl)acetamide. MS found (ESI FT), 403.13802. (ESI) m/z. M+H+ (370/372/374); HRMS: calcd for CHC1-NO.HCl, 405. 1393; found (ESI), 370.1687; Anal. 35 Example 45 Calcd for CHC1NO.HCl: C, 59.05; H, 7.43; N, 3.44. Found: C, 59.00; H, 7.49; N, 3.37. 1-1-(1-naphthyl)-2-piperazin-1-ylethylcyclopen tanol Dihydrochloride Example 43 40 1-2-(4-aminopiperidin-1-yl)-1-(1-naphthyl)ethyl cyclobutanol Dihydrochloride

45 HN

50

55 In an analogous manner to Example 1, Step 1 tert-butyl 4-(1-hydroxycyclopentyl)(1-naphthyl)acetylpiperazine-1- carboxylate was prepared from (1-hydroxycyclopentyl)(1- naphthyl)acetic acid (Reference Example 1-s) and tert-butyl In an analogous manner to Example 1, Step 1 tert-butyl 1-piperazinecarboxylate. MS (ESI) m/z. 439 (M+H"); {1-(1-hydroxycyclobutyl)(1-naphthyl)acetylpiperidin-4- 60 HRMS: calcd for CHNO. 438.2519; found (ESI), y1}carbamate was prepared from (1-hydroxycyclobutyl)(1- 439.2563. naphthyl)acetic acid (Reference Example 1-o) and 4-N-boc In an analogous manner to Example 1, step 2 1-1-(1- aminopiperidine. MS (ES) m/z. 439.3 (M+H"). naphthyl)-2-piperazin-1-ylethylcyclopentanol dihydrochlo In an analogous manner to Example 1, step 2 1-2-(4- ride was prepared from tert-butyl 4-(1-hydroxycyclopentyl) aminopiperidin-1-yl)-1-(1-naphthyl)ethylcyclobutanol 65 (1-naphthyl)acetylpiperazine-1-carboxylate. MS (ESI) m/z. dihydrochloride was prepared from tert-butyl {1-(1-hy 325 (M+H"); HRMS: calcd for CHNO.2.00 HCl, droxycyclobutyl)(1-naphthyl)acetylpiperidin-4-yl)carbam 396.1735; found (ESI), 325.2267. US 7,419,980 B2 57 58 Example 46 Example 48 1-2-piperazin-1-yl-1-3-(trifluoromethoxy)phenyl 1-1-(3-bromophenyl)-2-(cyclohexylamino)ethyl ethylcyclobutanol Dihydrochloride cyclohexanol Hydrochloride

O 10 OH

OH 15

OCF

In an analogous manner to Example 1, Step 1 tert-butyl Br 4-(1-hydroxycyclobutyl)-3-(trifluoromethoxy)phenyl acetylpiperazine-1-carboxylate was prepared from (1-hy In an analogous manner to Example 1, Step 1 2-(3-bro droxycyclobutyl)-3-(trifluoromethoxy)phenyl)acetic acid mophenyl)-N-cyclohexyl-2-(1-hydroxycyclohexyl)aceta (Reference Example 1-k) and tert-butyl 1-piperazinecar 25 mide was prepared from (3-bromophenyl)(1-hydroxycyclo boxylate. HRMS: calcd for CHFNOs, 458.2029; found hexyl)acetic acid (Reference Example 1-b) and (ESI), 459.2118. cyclohexylamine. MS (ESI) m/z 394/396 (M+H"). In an analogous manner to Example 1, step 21-2-piper In an analogous manner to Example 1, step 2 1-1-(3- azin-1-yl-1-(3-(trifluoromethoxy)phenyl bromophenyl)-2-(cyclohexylamino)ethylcyclohexanol ethylcyclobutanol dihydrochloride was prepared from tert 30 hydrochloride was prepared from 2-(3-bromophenyl)-N-cy butyl 4-(1-hydroxycyclobutyl)3-(trifluoromethoxy) clohexyl-2-(1-hydroxycyclohexyl)acetamide. MS (ESI) m/z. phenyl)acetylpiperazine-1-carboxylate. HRMS: calcd for 380/382 (IM+H"); HRMS: calcd for CHBrNO.HCl, CHF.N.O.2.00 HCl, 416.1245; found (ESI), 345. 1801. 415.1278; found (ESI), 380.1574. 35 Example 47 Example 49 1-2-(4-fluorobenzyl)amino-1-3-(trifluoromethyl) 1-2-4-(methylamino)piperidin-1-yl)-1-(2-naphthyl) phenylethylcyclohexanol Hydrochloride ethylcyclohexanol Dihydrochloride 40

CH

45

OH

50

CF

In an analogous manner to Example 1, step 1 N-(4-fluo 55 In an analogous manner to Example 1, Step 1 tert-butyl robenzyl)-2-(1-hydroxycyclohexyl)-2-3-(trifluoromethyl) {1-(1-hydroxycyclohexyl)(2-naphthyl)acetylpiperidin-4- phenyl)acetamide was prepared from (1-hydroxycyclohexyl) y1}carbamate was prepared from (1-hydroxycyclohexyl)(2- 3-(trifluoromethyl)phenyl)acetic acid (Reference Example naphthyl)acetic acid (Reference Example 1-c) and 4-N-boc 1-m) and 4-fluorobenzylamine. MS (ESI) m/z. 410 (M--H"). aminopiperidine. MS (ES) m/z 467.3 (IM+H"); HRMS: In an analogous manner to Example 1, step 2 1-2-(4- 60 calcd for CHNO. 466.2832; found (ESI), 467.2902. fluorobenzyl)amino-1-3-(trifluoromethyl)phenyl In an analogous manner to Example 13, Step 2 1-2-4- ethylcyclohexanol hydrochloride was prepared from N-(4- (methylamino)piperidin-1-yl)-1-(2-naphthyl)ethylcyclo fluorobenzyl)-2-(1-hydroxycyclohexyl)-2-3- hexanol dihydrochloride was prepared from tert-butyl-1-(1- (trifluoromethyl)phenyl)acetamide. MS (ESI) m/z 396 (IM+ 65 hydroxycyclohexyl)(2-naphthyl)acetylpiperidin-4- HI"); HRMS: calcd for CHFNO.HCl, 431.1639; found y1}carbamate. MS m/z. 367 (M+H"); HRMS: calcd for (ESI), 396.1931. CHNO.2.00 HCl, 438.2205; found (ESI), 367.2763. US 7,419,980 B2 59 60 Example 50 Example 52 2-(3-bromophenyl)-3-ethyl-1-piperazin-1-ylpentan 2-(3-chlorophenyl)-3-ethyl-1-piperazin-1-ylpentan 3-ol Dihydrochloride 3-ol Dihydrochloride

O 10 OH O OH

15

Br C In an analogous manner to Example 1, Step 1 tert-butyl 4-2-(3-bromophenyl)-3-ethyl-3-hydroxypentanoylpipera In an analogous manner to Example 1, Step 1 tert-butyl Zine-1-carboxylate was prepared from 2-(3-bromophenyl)-3- 4-2-(3-chlorophenyl)-3-ethyl-3-hydroxypentanoylpipera ethyl-3-hydroxypentanoic acid (Reference Example 1-t) and Zine-1-carboxylate was prepared from 2-(3-chlorophenyl)-3- tert-butyl 1-piperazinecarboxylate. MS (ESI) m/z 469/471 ethyl-3-hydroxypentanoic acid (Reference Example 1-v) and (M+H"); HRMS: calcd for CHBrNO. 468.1624; 25 tert-butyl 1-piperazinecarboxylate. MS (ESI) m/Z 425/427 found (ESI FT), 469.17071. (IM+H"). In an analogous manner to Example 1, step 2 2-(3-bro In an analogous manner to Example 1, step 2 2-(3-chlo mophenyl)-3-ethyl-1-piperazin-1-ylpentan-3-ol dihydro rophenyl)-3-ethyl-1-piperazin-1-ylpentan-3-ol dihydrochlo chloride was prepared from tert-butyl 4-2-(3-bromophenyl)- ride was prepared from tert-butyl 4-2-(3-chlorophenyl)-3- 3-ethyl-3-hydroxypentanoylpiperazine-1-carboxylate. MS 30 ethyl-3-hydroxypentanoylpiperazine-1-carboxylate. MS (ESI) m/z. 355/357 (M+H"); HRMS: calcd for CHBrNO.2.00 HCl, 426,0840; found (ESI FT), (ESI) m/z. 311/313 (LM+H"); HRMS: calcd for 355.13878. CHCIN.O.HC1,346.1579; found (ESI FT), 311.18803.

Example 51 35 Example 53 4-1-(3-chlorophenyl)-2-piperazin-1-ylethylheptan 3-ethyl-2-(1-naphthyl)-1-piperazin-1-ylpentan-3-ol 4-ol Dihydrochloride Dihydrochloride

40

O 45 OH OH

50 C

In an analogous manner to Example 1, Step 1 tert-butyl In an analogous manner to Example 1, Step 1 tert-butyl 4-2-(3-chlorophenyl)-3-hydroxy-3-propylhexanoylpipera 55 Zine-1-carboxylate was prepared from 2-(3-chlorophenyl)-3- 4-2-(3-chlorophenyl)-3-ethyl-3-hydroxypentanoylpipera hydroxy-3-propylhexanoic acid (Reference Example 1-u) Zine-1-carboxylate was prepared from 3-ethyl-3-hydroxy-2- and tert-butyl 1-piperazinecarboxylate. MS (ESI) m/z 453/ (1-naphthyl)pentanoic acid (Reference Example 1-w) and 455 (IM+H"); HRMS: calcd for CHCINO, 452.2442: tert-butyl 1-piperazinecarboxylate. MS (ESI) m/z. 441.2766 found (ESI FT), 453.25255. 60 (IM+H"); HRMS: calcd for CHNO. 440.2675; found In an analogous manner to Example 1, step 2 4-1-(3- (ESI), 441.2766. chlorophenyl)-2-piperazin-1-ylethylheptan-4-ol dihydro In an analogous manner to Example 1, Step 23-ethyl-2-(1- chloride was prepared from tert-butyl 4-2-(3-chlorophenyl)- naphthyl)-1-piperazin-1-ylpentan-3-ol dihydrochloride was 3-hydroxy-3-propylhexanoylpiperazine-1-carboxylate. MS prepared from tert-butyl 4-2-(3-chlorophenyl)-3-ethyl-3- (ESI) m/z 339/341 (IM+H"); HRMS: calcd for 65 hydroxypentanoylpiperazine-1-carboxylate. MS (ESI) m/z. CHCINO.2.00 HCl, 410.1658; found (ESI FT), 327 (M+H"); HRMS: calcd for CHNO.2.00 HCl, 339.21916. 398.1892; found (ESI), 327.2426. US 7,419,980 B2 61 62 Example 54 Example 56 1-2-(4-aminopiperidin-1-yl)-1-(1-naphthyl)ethyl 1-2-(4-methylpiperazin-1-yl)-1-(1-naphthyl)ethyl cyclohexanol Dihydrochloride cyclopentanol Dihydrochloride

HN

10

15

In an analogous manner to Example 1, Step 1 tert-butyl {1-(1-hydroxycyclohexyl)(1-naphthyl)acetylpiperidin-4- In an analogous manner to Example 1, step 1 1-2-(4- y1}carbamate was prepared from (1-hydroxycyclohexyl)(1- methylpiperazin-1-yl)-1-(1-naphthyl)-2-oxoethylcyclopen naphthyl)acetic acid (Reference Example 1-e) and 4-N-boc tanol was prepared from (1-hydroxycyclopentyl)(1-naph aminopiperidine. MS (ESI) m/z 467 (M+H"). 25 thyl)acetic acid (Reference Example 1-s) and In an analogous manner to Example 1, step 2 1-2-(4- N-methylpiperazine. MS (ESI) m/z. 353 (M+H"). aminopiperidin-1-yl)-1-(1-naphthyl)ethylcyclohexanol dihydrochloride was prepared from tert-butyl {1-(1-hy In an analogous manner to Example 1, step 2 1-2-(4- droxycyclohexyl)(1-naphthyl)acetylpiperidin-4- methylpiperazin-1-yl)-1-(1-naphthyl)ethylcyclopentanol dihydrochloride was prepared from 1-2-(4-methylpiperazin y1}carbamate. MS (ESI) m/z. 353 (M+H"); HRMS: calcd 30 for CHNO.2.00 HCl, 424.2048; found (ESI), 353.2583. 1-yl)-1-(1-naphthyl)-2-oxoethylcyclopentanol. MS m/z339 (IM+H"); HRMS: calcd for CHNO.2.00 HCl, Example 55 410.1892; found (ESI), 339.2419.

1-1-(3-bromophenyl)-2-(1,2,3,4-tetrahydronaphtha 35 len-1-ylamino)ethylcyclohexanol Hydrochloride Example 57 1-1-(3-chlorophenyl)-2-morpholin-4-ylethylcyclo hexanol Hydrochloride 40

45 OH O OH

50

C

In an analogous manner to Example 1, step 1 2-(3-bro 55 mophenyl)-2-(1-hydroxycyclohexyl)-N-1,2,3,4-tetrahy In an analogous manner to Example 1, step 1 1-1-(3- dronaphthalen-1-ylacetamide was prepared from (3-bro chlorophenyl)-2-morpholin-4-yl-2-oxoethylcyclohexanol mophenyl)(1-hydroxycyclohexyl)acetic acid (Reference was prepared from (3-bromophenyl)(1-hydroxycyclohexyl) Example 1-b) and 1,2,3,4-tetrahydro-1-napthylamine. MS acetic acid (Reference Example 1-b) and morpholine. (ESI) m/z 442/444 (M+H"). 60 HRMS: calcd for C.H.CINO,337.1445; found (ESI FT), In an analogous manner to Example 1, step 2 1-1-(3- bromophenyl)-2-(1,2,3,4-tetrahydronaphthalen-1-ylamino) 338.1521. ethylcyclohexanol hydrochloride was prepared from 2-(3- In an analogous manner to Example 1, step 2 1-1-(3- bromophenyl)-2-(1-hydroxycyclohexyl)-N-1,2,3,4- chlorophenyl)-2-morpholin-4-ylethylcyclohexanol hydro tetrahydronaphthalen-1-ylacetamide. MS (ESI) m/z. 428/430 65 chloride was prepared from 1-1-(3-chlorophenyl)-2-mor (M+H"); HRMS: calcd for CHBrNO.HCl, 463.1278: pholin-4-yl-2-oxoethylcyclohexanol. HRMS: calcd for found (ESI), 428.1593. CHCINOHC1, 359.1419; found (ESI FT), 324. 17137. US 7,419,980 B2 63 64 Example 58 Example 60 4-1-(3-bromophenyl)-2-piperazin-1-ylethyl-1-me 1-1-(3-bromophenyl)-2-(3-chlorobenzyl)amino thylpiperidin-4-ol Dihydrochloride ethylcyclohexanol Hydrochloride

"O 10 C OH OH

15 CH3 Br Br

In an analogous manner to Example 1, Step 1 tert-butyl In an analogous manner to Example 1, Step 1 2-(3-bro 4-(3-bromophenyl)(4-hydroxy-1-methylpiperidin-4-yl) mophenyl)-N-(3-chlorobenzyl)-2-(1-hydroxycyclohexyl)ac acetylpiperazine-1-carboxylate was prepared from (3-bro etamide was prepared from (3-bromophenyl)(1-hydroxycy mophenyl)(4-hydroxy-1-methylpiperidin-4-yl)acetic acid clohexyl)acetic acid (Reference Example 1-b) and (Reference Example 1-r) and tert-butyl 1-piperazinecarboxy 25 3-chlorobenzylamine. MS (ESI) m/z 436/438/440 (M+H"). late. HRMS: calcd for CHBrNO. 495.1733; found (ES In an analogous manner to Example 1, step 2 1-1-(3- I FT), 496.18082. bromophenyl)-2-(3-chlorobenzyl)amino In an analogous manner to Example 1, step 2 4-1-(3- ethylcyclohexanol hydrochloride was prepared from 2-(3- bromophenyl)-2-piperazin-1-ylethyl-1-methylpiperidin-4- bromophenyl)-N-(3-chlorobenzyl)-2-(1- ol dihydrochloride was prepared from tert-butyl 4-(3-bro 30 mophenyl)(4-hydroxy-1-methylpiperidin-4-yl)acetyl hydroxycyclohexyl)acetamide. MS (ESI) m/z. 422/424/426 piperazine-1-carboxylate. HRMS: calcd for (IM+H"); HRMS: calcd for C. H. BrCINO.HCl, 457.0575: CHBrNO.3.00 HCl, 489,0716; found (ESI FT), found (ESI), 422,0873. 382.14952. 35 Example 61 Example 59 1-2-(benzylamino)-1-(3-bromophenyl)ethylcyclo 1-methyl-4-1-(2-naphthyl)-2-piperazin-1-ylethyl hexanol Hydrochloride piperidin-4-ol Dihydrochloride 40

45

OH OH

50 CO Na CH3 Br In an analogous manner to Example 1, Step 1 tert-butyl 4-(4-hydroxy-1-methylpiperidin-4-yl)(2-naphthyl)acetyl 55 piperazine-1-carboxylate was prepared from (4-hydroxy-1- In an analogous manner to Example 1, step 1 N-benzyl-2- methylpiperidin-4-yl)(2-naphthyl)acetic acid (Reference (3-bromophenyl)-2-(1-hydroxycyclohexyl)acetamide was Example 1-X) and tert-butyl 1-piperazinecarboxylate. prepared from (3-bromophenyl)(1-hydroxycyclohexyl)ace HRMS: calcd for CHNO. 467.2784; found (ESI FT), tic acid (Reference Example 1-b) and benzylamine. HRMS: 468.28561. 60 calcd for CHBrNO. 401.0990; found (ESI FT), In an analogous manner to Example 1, step 21-methyl-4- 402.10557. 1-(2-naphthyl)-2-piperazin-1-ylethylpiperidin-4-ol dihy In an analogous manner to Example 1, step 21-2-(benzy drochloride was prepared from tert-butyl 4-(4-hydroxy-1- lamino)-1-(3-bromophenyl)ethylcyclohexanol hydrochlo methylpiperidin-4-yl)(2-naphthyl)acetylpiperazine-1- 65 ride was prepared from N-benzyl-2-(3-bromophenyl)-2-(1- carboxylate. HRMS: calcd for CHNO.3.00 HCl, hydroxycyclohexyl)acetamide. HRMS: calcd for 461. 1767; found (ESI FT), 354.25401. CHBrNO.HCl, 423.0965; found (ESI FT), 388.12785. US 7,419,980 B2 65 66 Example 62 In an analogous manner to Example 24, 1-2-(4-meth ylpiperazin-1-yl)-1-(2-naphthyl)ethylcyclohexanol dihy 1-2-(benzylamino)-1-(2-naphthyl)ethylcyclohex drochloride was prepared from 1-1-(2-naphthyl)-2-piper anol Hydrochloride azin-1-ylethylcyclohexanol (see Example 63). MS (ESI) m/z. 353 (M+H"); HRMS: calcd for CHNO.2.00 HCl, 424.2048; found (ESI FT), 353.25994. Example 65 10 OH 2-(3-bromo-4-methoxyphenyl)-3-ethyl-1-piperazin 1-ylpentan-3-ol Dihydrochloride

15 In an analogous manner to Example 1, step 1 N-benzyl-2- (1-hydroxycyclohexyl)-2-(2-naphthyl)acetamide was pre pared from (1-hydroxycyclohexyl)(2-naphthyl)acetic acid Cls. (Reference Example 1-q) and benzylamine. HRMS: calcd for CHNO, 373.2042; found (ESI FT), 374.21082. In an analogous manner to Example 1, Step 21-2-(benzy lamino)1-(2-naphthyl)ethylcyclohexanol hydrochloride HC was prepared from N-benzyl-2-(1-hydroxycyclohexyl)-2-(2- Br naphthyl)acetamide. HRMS: calcd for CHNO.HCl, 25 In an analogous manner to Example 1, Step 1 tert-butyl 395.2016; found (ESI FT), 360.23164. 4-2-(3-bromo-4-methoxyphenyl)-3-ethyl-3-hydroxypen Example 63 tanoylpiperazine-1-carboxylate was prepared from 2-(3- 1-1-(2-naphthyl)-2-piperazin-1-ylethylcyclohex bromo-4-methoxyphenyl)-3-ethyl-3-hydroxypentanoic acid anol Dihydrochloride 30 (Reference Example 1-y) and tert-butyl 1-piperazinecar boxylate. MS (ESI) m/z,499/501 (M+H"); HRMS: calcd for CHBrNO. 498.1729; found (ESI), 499.1793. In an analogous manner to Example 1, step 2 2-(3-bromo 4-methoxyphenyl)-3-ethyl-1-(4-methylpiperazin-1-yl)pen 35 tan-3-ol dihydrochloride was prepared from tert-butyl 4-2- (3-bromo-4-methoxyphenyl)-3-ethyl-3-hydroxypentanoyl piperazine-1-carboxylate. MS m/z 385/387 (M+H"): HRMS: calcd for CHBrNO.2.00 HCl, 456.0946; found 40 (ESI), 385.1494. In an analogous manner to Example 1, Step 1 tert-butyl Example 66 4(1-hydroxycyclohexyl)(2-naphthyl)acetylpiperazine-1- carboxylate was prepared from (1-hydroxycyclohexyl)(2- 2-(3-bromo-4-methoxyphenyl)-3-ethyl-1-(4-meth naphthyl)acetic acid (Reference Example 1-c) and tert-butyl 45 ylpiperazin-1-yl)pentan-3-ol Dihydrochloride 1-piperazinecarboxylate. MS (ESI) m/z. 453 (M+H"). In an analogous manner to Example 1, step 2 1-1-(2- naphthyl)-2-piperazin-1-ylethylcyclohexanol dihydrochlo ride was prepared from tert-butyl 4(1-hydroxycyclohexyl)(2- naphthyl)acetylpiperazine-1-carboxylate. MS (ESI) m/Z339 50 (M+H"); HRMS: calcd for CHNO.2.00 HCl, 410, 1892; found (ESI FT), 339.2426. Example 64 OH 1-2-(4-methylpiperazin-1-yl)-1-(2-naphthyl)ethyl 55 cyclohexanol Dihydrochloride HC

Br 60 In an analogous manner to Example 24, 2-(3-bromo-4- methoxyphenyl)-3-ethyl-1-(4-methylpiperazin-1-yl)pentan 3-ol dihydrochloride was prepared from 2-(3-bromo-4-meth oxyphenyl)-3-ethyl-1-(4-methylpiperazin-1-yl)pentan-3-ol 65 (see Example 65). MS (ESI) m/z 399/401 (M+H"); HRMS: calcd for CH BrNO.2.00 HCl, 470.1102: found (ESI), 399.1632. US 7,419,980 B2 67 68 Example 67 311 (M+H"); HRMS: calcd for C.H.N.O.2.00 HCl, 382.1579; found (ESI), 3112127. 1-1-(3-chlorophenyl)-2-(cyclohexylamino)ethyl cyclohexanol Hydrochloride Example 69 1-2-(4-methylpiperazin-1-yl)-1-(1-naphthyl)ethyl cyclobutanol Dihydrochloride

10

N OH 15 OH O) C

In an analogous manner to Example 1, step 1 2-(3-chlo rophenyl)-N-cyclohexyl-2-(1-hydroxycyclohexyl)aceta 25 In an analogous manner to Example 24, 1-2-(4-meth mide was prepared from (3-chlorophenyl)(1-hydroxycyclo ylpiperazin-1-yl)-1-(1-naphthyl)ethylcyclobutanol dihydro hexyl)acetic acid (Reference Example 1-a) and chloride was prepared from 1-1-(1-naphthyl)-2-piperazin-1- cyclohexylamine. MS (ESI) m/z. 350/352 (M+H"). ylethylcyclobutanol (see Example 68). MS (ES) m/z 325.3 In an analogous manner to Example 1, step 2 1-1-(3- (IM+H"); HRMS: calcd for C, H.N.O.2.00 HCl, chlorophenyl)-2-(cyclohexylamino)ethylcyclohexanol 30 hydrochloride was prepared from 2-(3-chlorophenyl)-N-cy 396.1735; found (ESI), 325.2278. clohexyl-2-(1-hydroxycyclohexyl)acetamide. MS (ESI) m/z. Example 70 336/338 (M+H"); HRMS: calcd for CHCINO.HCl, 371.1783; found (ESI), 336.206. 1-1-4-(benzyloxy)phenyl)-2-piperazin-1- 35 ylethylcyclobutanol Dihydrochloride Example 68 1-1-(1-naphthyl)-2-piperazin-1-ylethylcyclobutanol Dihydrochloride 40 "O OH 45

50

In an analogous manner to Example 1, Step 1 tert-butyl 4-4-(benzyloxy)phenyl(1-hydroxycyclobutyl)acetylpip 55 erazine-1-carboxylate was prepared from (4-benzyloxyphe nyl)(1-hydroxycyclobutyl)acetic acid (Reference Example In an analogous manner to Example 1, Step 1 tert-butyl 1-z) and tert-butyl 1-piperazinecarboxylate. MS (ESI) m/z. 4-(1-hydroxycyclobutyl)(1-naphthyl)acetylpiperazine-1- 481 (M+H"); HRMS: calcd for CHNOs, 480.2624; carboxylate was prepared from (1-hydroxycyclobutyl)(1- 60 found (ESI), 481.2716. naphthyl)acetic acid (Reference Example 1-o) and tert-butyl In an analogous manner to Example 1, step 2 1-1-4- 1-piperazinecarboxylate. MS (ESI) m/Z 425 (M+H"). (benzyloxy)phenyl)-2-piperazin-1-ylethylcyclobutanol In an analogous manner to Example 1, step 2 1-1-(1- dihydrochloride was prepared from tert-butyl 4-4-(benzy naphthyl)-2-piperazin-1-ylethylcyclobutanol dihydrochlo 65 loxy)phenyl(1-hydroxycyclobutyl)acetylpiperazine-1-car ride was prepared from tert-butyl 4-(1-hydroxycyclobutyl) boxylate. HRMS: calcd for CHNO2.00 HCl, (1-naphthyl)acetylpiperazine-1-carboxylate. MS (ESI) m/z. 438.1841; found (ESI), 367.2389. US 7,419,980 B2 69 70 Example 71 Example 73 1-1-4-(benzyloxy)phenyl-2-(4-methylpiperazin-1- 1-1-(3-bromo-4-methoxyphenyl)-2-(4-methylpiper yl)ethylcyclobutanol Dihydrochloride azin-1-yl)ethyl-4-tert-butylcyclohexanol Dihydro chloride

10

OH OH 15

HC CH CH3 Br CH In an analogous manner to Example 24, 1-1-4-(benzy loxy)phenyl-2-(4-methylpiperazin-1-yl)ethylcyclobutanol In an analogous manner to Example 1, step 1 1-1-(3- dihydrochloride was prepared from 1-1-4-(benzyloxy)phe bromo-4-methoxyphenyl)-2-(4-methylpiperazin-1-yl)-2- nyl)-2-piperazin-1-ylethylcyclobutanol (see Example 70). oxoethyl-4-tert-butylcyclohexanol was prepared from HRMS: calcd for CHNO2.00 HCl, 452.1997: found 25 (3-bromo-4-methoxyphenyl)(4-tert-butyl-1-hydroxycyclo (ESI), 381.2526. hexyl)acetic acid (Reference Example 1-bb) and N-meth ylpiperazine. MS (ESI) m/z, 481/483 (IM+H"). Example 72 In an analogous manner to Example 1, step 2 1-1-(3- 30 bromo-4-methoxyphenyl)-2-(4-methylpiperazin-1-yl) 1-1-(3-chlorophenyl)-2-piperazin-1-ylethyldecahy ethyl-4-tert-butylcyclohexanol dihydrochloride was pre dronaphthalen-1-ol Dihydrochloride pared from tert-butyl 1-1-(3-bromo-4-methoxyphenyl)-2- (4-methylpiperazin-1-yl)-2-oxoethyl-4-tert butylcyclohexanol. MS (ESI) m/z 467/469 (M+H"): 35 HRMS: calcd for CHBrNO.2.00 HCl, 538.1728; found (ESI), 467.2258. "O Example 74 OH 40 2-1-(3-chlorophenyl)-2-piperazin-1-ylethyldecahy dronaphthalen-2-ol Dihydrochloride

45 C O In an analogous manner to Example 1, Step 1 tert-butyl 50 OH 4-1-(3-chlorophenylphenyl)(1-hydroxydecahydronapthyl) acetylpiperazine-1-carboxylate was prepared from (3-chlo rophenyl)(1-hydroxydecahydronapthyl)acetic acid (Refer 55 ence Example 1-aa) and tert-butyl 1-piperazinecarboxylate. C MS (ESI) m/z 491/493 (M+H"). In an analogous manner to Example 1, Step 1 tert-butyl In an analogous manner to Example 1, step 2 1-1-(3- 60 4-1-(3-chlorophenylphenyl)(2-hydroxydecahydronapthyl) chlorophenyl)-2-piperazin-1-ylethyldecahydronaphthalen acetylpiperazine-1-carboxylate was prepared from (3-chlo 1-ol dihydrochloride was prepared from tert-butyl 4-1-(3- rophenyl)(2-hydroxydecahydronapthyl)acetic acid (Refer chlorophenylphenyl)(1-hydroxy decahydronapthyl)acetyl ence Example 1-cc) and tert-butyl 1-piperazinecarboxylate. piperazine-1-carboxylate. MS (ES) m/z. 377.3 (M+H"); 65 MS (ESI) m/z 491/493 (M+H"). HRMS: calcd for CHCINO.2.00 HCl, 448.1815; found In an analogous manner to Example 1, step 2 2-1-(3- (ESI), 377,2351. chlorophenyl)-2-piperazin-1-ylethyldecahydronaphthalen

US 7,419,980 B2 73 74 Example 79 Example 81 1-1-(3-bromophenyl)-2-(4-methylpiperazin-1-yl) 4-1-(3-bromophenyl)-2-piperazin-1-ylethylheptan ethyl-4-tert-butylcyclohexanol Dihydrochloride 4-ol Dihydrochloride O OH 10

OH

CH3 15 Br In an analogous manner to Example 1, Step 1 tert-butyl CH 4-2-(3-bromophenyl)-3-hydroxy-3-propylhexanoylpipera Br CH3 Zine-1-carboxylate was prepared from 2-(3-bromophenyl)-3- hydroxy-3-propylhexanoic acid (Reference Example 1-gg) In an analogous manner to Example 1, step 1 1-1-(3- and tert-butyl 1-piperazinecarboxylate. MS (ES) m/z. 497.2 (IM+H"). bromophenyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl-4- In an analogous manner to Example 1, step 2 4-1-(3- tert-butylcyclohexanol was prepared from (3-bromophenyl) bromophenyl)-2-piperazin-1-ylethylheptan-4-ol dihydro (4-tert-butyl-1-hydroxycyclohexyl)acetic acid (Reference chloride was prepared from tert-butyl 4-2-(3-bromophenyl)- Example 1-ff) and N-methylpiperazine. MS (ESI) m/z 451/ 25 3-hydroxy-3-propylhexanoylpiperazine-1-carboxylate. MS 453 (M+H"). (ES) m/z 383.2 (M+H"); HRMS: calcd for In an analogous manner to Example 1, step 2 1-1-(3- CH, BrNO.2.00 HC1,454.1153; found (ESI), 383.1705. bromophenyl)-2-(4-methylpiperazin-1-yl)ethyl-4-tert-bu Example 82 tylcyclohexanol dihydrochloride was prepared from 1-1-(3- 30 bromophenyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl-4- 4-1-(3-bromophenyl)-2-(4-methylpiperazin-1-yl) tert-butylcyclohexanol. MS (ESI) m/z. 437/439 (M+H"); ethylheptan-4-ol Dihydrochloride HRMS: calcd for CHBrNO.2.00 HCl, 508.1623: found (ESI), 437.2154. 35 Example 80 N OH 1-1-(3,4-dichlorophenyl)-2-(4-fluorobenzyl) aminoethylcyclohexanol Hydrochloride 40

Br

45 In an analogous manner to Example 24, 4-1-(3-bro OH mophenyl)-2-(4-methylpiperazin-1-yl)ethylheptan-4-ol dihydrochloride was prepared from 4-1-(3-bromophenyl)-2- piperazin-1-ylethylheptan-4-ol (see Example 81). MS (ES) 50 m/z 397.2 (M+H"); C HRMS: calcd for CHBrNO.2.00 HCl, 468.1310; found (ESI), 397.1865. C Example 83

In an analogous manner to Example 1, Step 1 2-(3,4-dichlo 55 1-1-(3,4-dichlorophenyl)-2-morpholin-4-ylethyl rophenyl)-N-(4-fluorobenzyl)-2-(1-hydroxycyclohexyl)ac cyclobutanol Hydrochloride etamide was prepared from 3,4-dichloro-alpha-(1-hydroxy cyclohexyl)benzeneacetic acid (Reference Example 1-d) and 4-fluorobenzylamine. MS (ESI) m/z 410/412/414 (M+H"). In an analogous manner to Example 1, step 2 1-1-(3.4- 60 O dichlorophenyl)-2-(4-fluorobenzyl)amino OH ethylcyclohexanol hydrochloride was prepared from 2-(3,4- dichlorophenyl)-N-(4-fluorobenzyl)-2-(1- hydroxycyclohexyl)acetamide. MS (ESI) m/z 396/398/400 65 (M+H"); HRMS: calcd for CHCIFNO.HCl, 431.0986: C found (ESI), 396.1277. C US 7,419,980 B2 75 76 In an analogous manner to Example 1, step 1 1-1-(3,4- was prepared from (3-chlorophenyl)(1-hydroxycyclohexyl) dichlorophenyl)-2-morpholin-4-yl-2-oxoethylcyclobutanol acetic acid (Reference Example 1-a) and piperidine. HRMS: was prepared from (3,4-dichlorophenyl)(1-hydroxycyclobu calcd for CHCINO, 335.1652: found (ESI FT), tyl)acetic acid (Reference Example 1-p) and morpholine. 336.17194. HRMS: calcd for CHCINO. 343.0742; found (ES In an analogous manner to Example 1, step 2 1-1-(3- I FT), 344,08102. chlorophenyl)-2-piperidin-1-ylethylcyclohexanol hydro In an analogous manner to Example 1, step 2 1-1-(3,4- chloride was prepared from 1-1-(3-chlorophenyl)-2-oxo-2- dichlorophenyl)-2-morpholin-4-ylethylcyclobutanol hydro piperidin-1-ylethylcyclohexanol. HRMS: calcd for chloride was prepared from 1-1-(3,4-dichlorophenyl)-2- CHCINO.HC1, 357.1626; found (ESI FT), 322.19304. morpholin-4-yl-2-oxoethylcyclobutanol. HRMS: calcd for 10 C.H. C.NO, HC1,365,0716; found (ESI_FT), 330.10064. Example 86 Example 84 2-(3-chlorophenyl)-1,1-dicyclopropyl-3-(4-meth ylpiperazin-1-yl)propan-1-ol Dihydrochloride 1-1-(3-bromo-4-methoxyphenyl)-2-piperazin-1- ylethyl-4-tert-butylcyclohexanol Dihydrochloride 15

OH

OH

25 CH C CH3 Br CH In an analogous manner to Example 1, Step 1 tert-butyl 30 4-2-(3-chlorophenyl)(3.3-dicyclopropyl-3-hydroxypropyl) In an analogous manner to Example 1, step 1 tert-butyl acetylpiperazine-1-carboxylate was prepared from 2-(3- 4-(3-bromo-4-methoxyphenyl)(4-tert-butyl-1-hydroxycy chlorophenyl)-3,3-dicyclopropyl-3-hydroxypropanoic acid clohexyl)acetylpiperazine-1-carboxylate was prepared from (Reference Example 1-hh) and N-methylpiperazine. MS (3-bromo-4-methoxyphenyl)(4-tert-butyl-1-hydroxycyclo (ESI) m/z. 363 (M+H"). hexyl)acetic acid (Reference Example 1-bb) and tert-butyl 35 In an analogous manner to Example 1, step 2 2-(3-chlo 1-piperazinecarboxylate. MS (ESI) m/z 567/569 (M+H"); rophenyl)-1,1-dicyclopropyl-3-(4-methylpiperazin-1-yl) HRMS: calcd for CHBrNO. 566.2355; found (ESI), propan-1-ol dihydrochloride was prepared from tert-butyl 567.2435. 4-2-(3-chlorophenyl)(3.3-dicyclopropyl-3-hydroxypropyl) In an analogous manner to Example 1, step 2 1-1-(3- 40 acetylpiperazine-1-carboxylate. MS (ESI) m/z 349.2037 bromo-4-methoxyphenyl)-2-piperazin-1-ylethyl-4-tert-bu (IM+H"); HRMS: calcd for CHCINO.2.00 HCl, tylcyclohexanol dihydrochloride was prepared from tert-bu 420.1502; found (ESI), 349.2037. tyl 4-(3-bromo-4-methoxyphenyl)(4-tert-butyl-1- hydroxycyclohexyl)acetylpiperazine-1-carboxylate. MS Example 87 (ESI) m/z 453/455 (IM+H"); HRMS: calcd for 45 1-1-(3-bromophenyl)-2-piperazin-1-ylethyl-3,3,5, CHBrNO2.00 HC1,524.1572: found (ESI), 453.2119. 5-tetramethylcyclohexanol Dihydrochloride Example 85 1-1-(3-chlorophenyl)-2-piperidin-1-ylethylcyclo hexanol Hydrochloride 50 O OH CH 55 CH3 N

OH Br HC CH 60 In an analogous manner to Example 1, Step 1 tert-butyl 4-(3-bromophenyl)(1-hydroxy-3,3,5,5-tetramethylcyclo C hexyl)acetylpiperazine-1-carboxylate was prepared from 65 (3-bromophenyl)(1-hydroxy-3,3,5,5-tetramethylcyclohexyl) In an analogous manner to Example 1, step 1 1-1-(3- acetic acid (Reference Example 1-ii) and tert-butyl 1-pipera chlorophenyl)-2-oxo-2-piperidin-1-ylethylcyclohexanol Zinecarboxylate. US 7,419,980 B2 77 78 In an analogous manner to Example 1, step 2 1-1-(3- Example 90 bromophenyl)-2-piperazin-1-ylethyl-3,3,5,5-tetramethyl cyclohexanol dihydrochloride was prepared from tert-butyl 1-(1-(3-bromophenyl)-2-[4-(trifluoromethyl)ben 4-(3-bromophenyl)(1-hydroxy-3,3,5,5-tetramethylcyclo Zylaminoethyl)cyclohexanol Hydrochloride hexyl)acetylpiperazine-1-carboxylate. MS (ES) m/z 423.2 5 (M+H"); HRMS: calcd for CHBrNO,422.1933; found (ESI), 423.2015. FC

Example 88 10

1-1-(3-bromophenyl)-2-(4-methylpiperazin-1-yl) OH ethyl-3,3,5,5-tetramethylcyclohexanol Dihydrochlo ride 15

Br H3C n ^ In an analogous manner to Example 1, Step 1 2-(3-bro N mophenyl)-2-(1-hydroxycyclohexyl)-N-4-(trifluoromethyl) OH CH3 benzyl)acetamide was prepared from (3-bromophenyl)(1-hy CH droxycyclohexyl)acetic acid (Reference Example 1-b) and 25 4-trifluoromethylbenzylamine. MS (ESI) m/z 470/472 (M+ HI). In an analogous manner to Example 1, step 2 1-(1-(3- Br H3C CH3 bromophenyl)-2-[4-(trifluoromethyl)benzyl)aminoethyl) cyclohexanol hydrochloride was prepared from 2-(3-bro 30 mophenyl)-2-(1-hydroxycyclohexyl)-N-4-(trifluoromethyl) In an analogous manner to Example 24, 1-1-(3-bro benzyl)acetamide. MS (ESI) m/z 456/458 (M+H"); HRMS: mophenyl)-2-(4-methylpiperazin-1-yl)ethyl-3,3,5,5-tet calcd for CHBrFNO.HCl, 491.0838; found (ESI), ramethylcyclohexanol dihydrochloride was prepared from 456.1147. 1-1-(3-bromophenyl)-2-piperazin-1-ylethyl-3,3,5,5-tet 35 ramethylcyclohexanol (see Example 87). MS (ES) m/z. 437.3 Example 91 (M+H"); HRMS: calcd for CHBrNO.2.00 HCl, 4-ethyl-1-1-(1-naphthyl)-2-piperazin-1-ylethylcy 508.1623: found (ESI), 437.2162. clohexanol Dihydrochloride Example 89 40 3-ethyl-1-(4-methylpiperazin-1-yl)-2-(1-naphthyl) pentan-3-ol Dihydrochloride 45

OH

55 In an analogous manner to Example 1, Step 1 tert-butyl 4-1-(1-naphthyl)-(4-ethyl-1-hydroxycyclohexyl)acetylpip erazine-1-carboxylate was prepared from (4-ethyl-1-hy droxycyclohexyl)-(1-naphthyl)acetic acid (Reference Example 1-) and tert-butyl 1-piperazinecarboxylate. MS 60 (ESI) m/z, 481 (M+H"): In an analogous manner to Example 24, 3-ethyl-1-(4-me In an analogous manner to Example 1, Step 24-ethyl-1-1- thylpiperazin-1-yl)-2-(1-naphthyl)pentan-3-ol dihydrochlo (1-naphthyl)-2-piperazin-1-ylethylcyclohexanol dihydro ride was prepared from 3-ethyl-2-(1-naphthyl)-1-piperazin chloride was prepared from tert-butyl 4-1-(1-naphthyl)-(4- 1-ylpentan-3-ol (see Example 53). MS (ESI) m/z 341 (M+ 65 ethyl-1-hydroxycyclohexyl)acetylpiperazine-1- HI"); HRMS: calcd for CHNO.2.00 HCl, 412.2048; carboxylate. MS (ESI) m/z. 367 (M+H"); HRMS: calcd for found (ESI), 341.2583. CHNO.2.00 HCl, 438.2205; found (ESI), 367.2749. US 7,419,980 B2 79 80 Example 92 In an analogous manner to Example 24, 2-(3-chlorophe nyl)-3-ethyl-1-(4-methylpiperazin-1-yl)pentan-3-ol dihy 1-2-(4-methylpiperazin-1-yl)-1-3-(trifluo drochloride was prepared from 2-(3-chlorophenyl)-3-ethyl romethoxy)phenylethylcyclobutanol Dihydrochlo 1-piperazin-1-ylpentan-3-ol (see Example 52). (ESI) m/z. ride 325/327 (M+H"); HRMS: calcd for CHCIN.O.2.00 HC1, 396.1502; found (ESI), 325.2032.

N 10 OH Example 95 1-1-(3-bromophenyl)-2-morpholin-4-ylethylcy clobutanol Hydrochloride 15 OCF In an analogous manner to Example 24, 1-2-(4-meth ylpiperazin-1-yl)-1-3-(trifluoromethoxy)phenyl ethylcyclobutanol dihydrochloride was prepared from 1-2- piperazin-1-yl-1-3-(trifluoromethoxy)phenyl ethylcyclobutanol (see Example 46). HRMS: calcd for O CHF.N.O.2.00 HCl, 430.1402: found (ESI), 359.1965. OH Example 93 25 4-tert-butyl-1-1-(3-chlorophenyl)-2-piperazin-1- ylethylcyclohexanol Dihydrochloride Br Nu1. 30 OH In an analogous manner to Example 1, step 1 1-1-(3- bromophenyl)-2-morpholin-4-yl-2-oxoethylcyclobutanol 35 was prepared from (3-bromophenyl)(1-hydroxycyclobutyl) CH acetic acid (Reference Example 1-j) and morpholine. HRMS: calcd for CHBrNO, 353.0627; found (ESI FT), CH3 C CH 354.06919. In an analogous manner to Example 1, Step 1 tert-butyl 4-(4-tert-butyl-1-hydroxycyclohexyl)(3-chlorophenyl) 40 acetylpiperazine-1-carboxylate was prepared from (3-chlo In an analogous manner to Example 1, step 2 1-1-(3- rophenyl)(4-tert-butyl-1-hydroxycyclohexyl)acetic acid bromophenyl)-2-morpholin-4-ylethylcyclobutanol hydro (Reference Example 1-kk) and tert-butyl 1-piperazinecar chloride was prepared from tert-butyl 4-(4-tert-butyl-1-hy boxylate. MS (ES) m/z 493.4 (IM+H"). 45 droxycyclohexyl)(3-chlorophenyl)acetylpiperazine-1- In an analogous manner to Example 1, step 24-tert-butyl carboxylate. HRMS: calcd for CHBrNO, HC1,375.0601; 1-1-(3-chlorophenyl)-2-piperazin-1-ylethylcyclohexanol found (ESI FT), 340.08898. dihydrochloride was prepared from tert-butyl 4-(4-tert-bu tyl-1-hydroxycyclohexyl)(3-chlorophenyl)acetylpipera Example 96 zine-1-carboxylate. MS (ESI) m/z. 379 (M+H"); HRMS: 50 calcd for CHCINO, 378.2438: found (ESI), 379.2513. 1-1-(3-bromophenyl)-2-piperazin-1-ylethyl-4-tert Example 94 butylcyclohexanol Dihydrochloride 2-(3-chlorophenyl)-3-ethyl-1-(4-methylpiperazin-1- yl)pentan-3-ol Dihydrochloride 55

HC 3 r N 60 OH Cls.

CH 65 CH3 Br CH US 7,419,980 B2 81 82 In an analogous manner to Example 1, Step 1 tert-butyl In an analogous manner to Example 1, Step 1 2-(3-bro 4-(3-bromophenyl)(4-tert-butyl-1-hydroxycyclohexyl) mophenyl)-N-(4-fluorobenzyl)-2-(1-hydroxycyclohexyl)ac acetylpiperazine-1-carboxylate was prepared from (3-bro etamide was prepared from (3-bromophenyl)(1-hydroxycy mophenyl)(4-tert-butyl-1-hydroxycyclohexyl)acetic acid clohexyl)acetic acid (Reference Example 1-b) and (Reference Example 1-ff) and tert-butyl 1-piperazinecar 4-fluorobenzylamine. MS (ESI) m/z 420/422 (M+H"). boxylate. MS (ESI) m/z 537/539 (M+H"); In an analogous manner to Example 1, step 2 1-1-(3- HRMS: calcd for C.H. BrNO, 536.2250; found (ESI), bromophenyl)-2-(4-fluorobenzyl)amino 537.2324. ethylcyclohexanol hydrochloride was prepared from 2-(3- In an analogous manner to Example 1, step 2 1-1-(3- bromophenyl)-N-(4-fluorobenzyl)-2-(1-hydroxycyclohexyl) bromophenyl)-2-piperazin-1-ylethyl-4-tert-butylcyclohex 10 anol dihydrochloride was prepared from tert-butyl 4-(3-bro acetamide. MS (ESI) m/z 406 (IM+H"); MS (ESI) m/z 408 mophenyl)(4-tert-butyl-1-hydroxycyclohexyl)acetyl (IM-HI); HRMS: calcd for C, H, BrFNO.HCl, 441.0870; piperazine-1-carboxylate. MS (ESI) m/z 423/425 (M+H"); found (ESI), 406. 1173. HRMS: calcd for CHBrNO.2.00 HCl, 494.1466: found (ESI), 423.1994. 15 Example 99 Example 97 1-1-(3-bromophenyl)-2-morpholin-4-ylethylcyclo hexanol Hydrochloride 4-methyl-1-1-(1-naphthyl)-2-piperazin-1-ylethyl cyclohexanol Dihydrochloride Nr 25 O OH

Br

35 In an analogous manner to Example 1, step 1 1-1-(3- In an analogous manner to Example 1, step 1 tert-butyl bromophenyl)-2-morpholin-4-yl-2-oxoethylcyclohexanol 4-1-(1-naphthyl)-(4-methyl-1-hydroxycyclohexyl)acetyl was prepared from (3-bromophenyl)(1-hydroxycyclohexyl) piperazine-1-carboxylate was prepared from (4-methyl-1- acetic acid (Reference Example 1-b) and morpholine. hydroxycyclohexyl)-(1-naphthyl)acetic acid (Reference HRMS: calcd for C.H. BrNO,381,0940; found (ESI FT), Example 1-ll) and tert-butyl 1-piperazinecarboxylate. MS 40 382.10O32. (ESI) m/z 467 (M+H"). In an analogous manner to Example 1, step 2 1-1-(3- In an analogous manner to Example 1, step 2 4-methyl-1- bromophenyl)-2-morpholin-4-ylethylcyclohexanol hydro 1-(1-naphthyl)-2-piperazin-1-ylethylcyclohexanol dihy chloride was prepared from 1-1-(3-bromophenyl)-2-mor drochloride was prepared from tert-butyl 4-1-(1-naphthyl)- pholin-4-yl-2-oxoethylcyclohexanol. HRMS: calcd for (4-methyl-1-hydroxycyclohexyl)acetylpiperazine-1- 45 C.HBrNO.HCl, 403.0914; found (ESI FT), 368. 12137. carboxylate. MS (ESI) m/z. 353 (M+H"); HRMS: calcd for CHNO.2.00 HCl, 424.2048; found (ESI), 353.2599. Example 100 Example 98 4-tert-butyl-1-2-(4-methylpiperazin-1-yl)-1-(1- 50 1-1-(3-bromophenyl)-2-(4-fluorobenzyl)amino naphthyl)ethylcyclohexanol Dihydrochloride ethylcyclohexanol Hydrochloride

55

OH 60

Br 65 US 7,419,980 B2 83 84 In an analogous manner to Example 24, 4-tert-butyl-1-2- Example 103 (4-methylpiperazin-1-yl)-1-(1-naphthyl)ethylcyclohexanol dihydrochloride was prepared from 4-tert-butyl-1-1-(1- 4-1-(3-bromophenyl)-2-piperazin-1-ylethyltetrahy naphthyl)-2-piperazin-1-ylethylcyclohexanol (see Example dro-2H-pyran-4-ol Dihydrochloride 76). MS (ESI) m/z 409 (IM+H"); HRMS: calcd for CHNO.2.00 HCl, 480.2674; found (ESI), 409.3207. Example 101 10 4-tert-butyl-1-1-(3-chlorophenyl)-2-(4-methylpiper O azin-1-yl)ethylcyclohexanol Dihydrochloride OH

15

Br

OH In an analogous manner to Example 1, Step 1 tert-butyl 4-(3-bromophenyl)(4-hydroxytetrahydro-2H-pyran-4-yl) acetylpiperazine-1-carboxylate was prepared from (3-bro mophenyl)(4-hydroxytetrahydro-2H-pyran-4-yl)acetic acid CH (Reference Example 1-mm) and tert-butyl 1-piperazinecar CH3 25 boxylate. MS (ESI) m/z,483/485 (M+H"); HRMS: calcd for C CH C.H. BrNOs, 482.1416: found (ESI), 483.1508. In an analogous manner to Example 1, step 2 4-1-(3- bromophenyl)-2-piperazin-1-ylethyltetrahydro-2H-pyran In an analogous manner to Example 24, 4-tert-butyl-1-1- 4-ol dihydrochloride was prepared from tert-butyl 4-(3-bro (3-chlorophenyl)-2-(4-methylpiperazin-1-yl)ethylcyclo mophenyl)(4-hydroxytetrahydro-2H-pyran-4-yl)acetyl hexanol dihydrochloride was prepared from 4-tert-butyl-1- piperazine-1-carboxylate. MS (ESI) m/z. 369/371 (M+H"): 1-(3-chlorophenyl)-2-piperazin-1-ylethylcyclohexanol HRMS: calcd for C.H. BrNO2.00 HC1,440.0633; found (see Example 93). MS (ESI) m/z 393 (M+H"); HRMS: (ESI), 369.1166. calcd for CHCINO.2.00 HCl, 464.2128; found (ESI), 393.2673. 35 Example 104 1-1-3-(benzyloxy)phenyl)-2-piperazin-1- Example 102 ylethylcyclohexanol Dihydrochloride 1-methyl-4-2-morpholin-4-yl-1-(2-naphthyl)ethyl piperidin-4-ol Hydrochloride 40 O 45 OH

OH

50

c c Nn CH

In an analogous manner to Example 1, step 1 1-methyl-4- 55 2-morpholin-4-yl-1-(2-naphthyl)-2-oxoethylpiperidin-4-ol was prepared from (4-hydroxy-1-methylpiperidin-4-yl)(2- naphthyl)acetic acid (Reference Example 1-X) and morpho In an analogous manner to Example 1, Step 1 tert-butyl line HRMS: calcd for CHNO. 368.2100; found (ES 60 4-3-(benzyloxy)phenyl(1-hydroxycyclohexyl)acetylpip I FT), 369.21652. erazine-1-carboxylate was prepared from (3-benzyloxyphe In an analogous manner to Example 1, step 21-methyl-4- nyl)(4-hydroxycyclohexyl)acetic acid (Reference Example 2-morpholin-4-yl-1-(2-naphthyl)ethylpiperidin-4-ol 1-nn) and tert-butyl 1-piperazinecarboxylate. MS (ESI) m/z. hydrochloride was prepared from 1-methyl-4-2-morpholin 509 (M+H"); HRMS: calcd for CHNOs, 508.2937: 4-yl-1-(2-naphthyl)-2-oxoethylpiperidin-4-ol. HRMS: 65 found (ESI), 509.2997. calcd for CHNO2.00 HCl, 426.1841; found (ESI FT), In an analogous manner to Example 1, step 2 1-1-3- 355.23761. (benzyloxy)phenyl)-2-piperazin-1-ylethylcyclohexanol US 7,419,980 B2 85 86 dihydrochloride was prepared from tert-butyl 4-3-(benzy Example 107 loxy)phenyl(1-hydroxycyclohexyl)acetylpiperazine-1-car boxylate. HRMS: calcd for CHNO2.00 HCl, 2-1-(3-bromophenyl)-2-piperazin-1-ylethylada 466.2154; found (ESI), 395.2676. mantan-2-ol Dihydrochloride Example 105 1-(1-(3-chlorophenyl)-2-[4-(trifluoromethyl)ben Zylaminoethyl)cyclohexanol Hydrochloride 10 C OH FC 15

OH Br

In an analogous manner to Example 1, Step 1 tert-butyl 4-(3-bromophenyl)(2-hydroxy-2-adamantyl)acetylpipera C Zine-1-carboxylate was prepared from (3-bromophenyl)(2- hydroxy-2-adamantyl)acetic acid (Reference Example 1-oo) 25 and tert-butyl 1-piperazinecarboxylate. MS (ESI) m/z 533/ In an analogous manner to Example 1, step 1 2-(3-chlo 535 (IM+H"). rophenyl-2-(1-hydroxycyclohexyl)-N-4-(trifluoromethyl) In an analogous manner to Example 1, step 2 2-1-(3- benzyl)acetamide was prepared from (3-chlorophenyl)(1-hy bromophenyl)-2-piperazin-1-ylethyladamantan-2-ol dihy droxycyclohexyl)acetic acid (Reference Example 1-a) and 30 drochloride was prepared from tert-butyl 4-(3-bromophe 4-trifluoromethylbenzylamine. MS (ESI) m/z. 426/428 (M- nyl)(2-hydroxy-2-adamantyl)acetylpiperazine-1- HI). carboxylate. MS (ESI) m/z. 419,421 (M+H"); HRMS: calcd In an analogous manner to Example 1, step 2 1-(1-(3- for C.H. BrNO.2.00 HCl, 490.1153; found (ESI), chlorophenyl)-2-[4-(trifluoromethyl)benzyl)aminoethyl) 419.1682. cyclohexanol hydrochloride was prepared from 2-(3-chlo 35 rophenyl)-2-(1-hydroxycyclohexyl)-N-4-(trifluoromethyl) Example 108 benzyl)acetamide. MS (ESI) m/z. M+H+ (412/414). 1-1-3-(benzyloxy)phenyl-2-(4-methylpiperazin-1- Example 106 40 yl)ethylcyclohexanol Dihydrochloride 1-2-morpholin-4-yl-1-(2-naphthyl)ethylcyclohex anol Hydrochloride

45 N rN OH 50 OH

55 In an analogous manner to Example 1, step 1 1-2-morpho lin-4-yl-1-(2-naphthyl)-2-oxoethylcyclohexanol was pre pared from (1-hydroxycyclohexyl)(2-naphthyl)acetic acid (Reference Example 1-q) and morpholine. HRMS: calcd for 60 CHNO, 353.1991; found (ESI FT), 354.20523. In an analogous manner to Example 24, 1-1-3-(benzy In an analogous manner to Example 1, step 21-2-morpho loxy)phenyl-2-(4-methylpiperazin-1-yl)ethylcyclohexanol lin-4-yl-1-(2-naphthyl)ethylcyclohexanol hydrochloride dihydrochloride was prepared from 1-1-3-(benzyloxy)phe was prepared from 1-2-morpholin-4-yl-1-(2-naphthyl)-2- 65 nyl)-2-piperazin-1-ylethylcyclohexanol (see Example 104). oxoethylcyclohexanol. HRMS: calcd for CHNO, HCl, HRMS: calcd for CHNO2.00 HCl, 480.2310; found 375. 1965; found (ESI FT), 340.2256. (ESI), 409.2838. US 7,419,980 B2 87 88 Example 109 Example 111 1-2-morpholin-4-yl-1-(2-naphthyl)ethylcyclobu 1-1-3-(benzyloxy)phenyl)-2-piperazin-1- tanol Hydrochloride ylethylcyclobutanol Dihydrochloride

HN 10 r N O OH COrl 15 In an analogous manner to Example 1, step 1 1-2-morpho lin-4-yl-1-(2-naphthyl)-2-oxoethylcyclobutanol was pre pared from (1-hydroxycyclobutyl)(2-naphthyl)acetic acid (Reference Example 1-c) and morpholine. HRMS: calcd for CHNO. 325.1678; found (ESI FT), 326.17435. c In an analogous manner to Example 1, step 21-2-morpho 25 In an analogous manner to Example 1, Step 1 tert-butyl lin-4-yl-1-(2-naphthyl)ethylcyclobutanol hydrochloride 4-3-(benzyloxy)phenyl(1-hydroxycyclobutyl)acetylpip was prepared from 1-2-morpholin-4-yl-1-(2-naphthyl)-2- erazine-1-carboxylate was prepared from (3-benzyloxyphe oxoethylcyclobutanol. HRMS: calcd for CHNO, HCl, nyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 347.1652; found (ESI FT), 312.19602. 1-qq) and tert-butyl 1-piperazinecarboxylate. MS (ESI) m/z. 30 481 (M+H"); HRMS: calcd for CHNOs, 480.2624; Example 110 found (ESI), 481.272. In an analogous manner to Example 1, step 2 1-1-3- 4-1-(3-bromo-4-methoxyphenyl)-2-piperazin-1- (benzyloxy)phenyl)-2-piperazin-1-ylethylcyclobutanol ylethyltetrahydro-2H-pyran-4-ol Dihydrochloride dihydrochloride was prepared from tert-butyl 4-3-(benzy 35 loxy)phenyl(1-hydroxycyclobutyl)acetylpiperazine-1-car boxylate. HRMS: calcd for CHNO2.00 HCl, 438.1841; found (ESI), 367.2357. Example 112 40 1-1-(3,4-dichlorophenyl)-2-morpholin-4-ylethyl OH cyclohexanol Hydrochloride

45

Br O 50 OH In an analogous manner to Example 1, Step 1 tert-butyl 4-(3-bromo-4-methoxyphenyl)(4-hydroxytetrahydro-2H pyran-4-yl)acetylpiperazine-1-carboxylate was prepared from (3-bromo-4-methoxyphenyl)(4-hydroxytetrahydro C 2H-pyran-4-yl)acetic acid (Reference Example 1-pp) and 55 tert-butyl 1-piperazinecarboxylate. MS (ESI) m/z 513/515 C (M+H"); HRMS: calcd for CHBrNO, 512.1522; In an analogous manner to Example 1, step 1 1-1-(3,4- found (ESI), 513.16. dichlorophenyl)-2-morpholin-4-yl-2-oxoethylcyclohexanol In an analogous manner to Example 1, step 2 4-1-(3- 60 was prepared from 3,4-dichloro-alpha-(1-hydroxycyclo bromo-4-methoxyphenyl)-2-piperazin-1-ylethyltetrahydro hexyl)benzeneacetic acid (Reference Example 1-d) and mor 2H-pyran-4-ol dihydrochloride was prepared from tert-butyl pholine. HRMS: calcd for CHCINO, 371.1055; found 4-(3-bromo-4-methoxyphenyl)(4-hydroxytetrahydro-2H (ESI FT), 372.11122. pyran-4-yl)acetylpiperazine-1-carboxylate. MS (ESI) m/z. In an analogous manner to Example 1, step 2 1-1-(3,4- 399/401 (IM+H"); HRMS: calcd for CHBrNO, 2.00 65 dichlorophenyl)-2-morpholin-4-ylethylcyclohexanol HC1,470.0739; found (ESI), 399.1266. hydrochloride was prepared from 1-1-(3,4-dichlorophenyl)- US 7,419,980 B2 89 90 2-morpholin-4-yl-2-oxoethylcyclohexanol. HRMS: calcd Example 115 for CHCINO, HCl, 393. 1029; found (ESI FT), 358.13358. 1-1-3-(benzyloxy)phenyl-2-(4-methylpiperazin-1- yl)ethylcyclobutanol Dihydrochloride Example 113 1-2-(4-fluorobenzyl)amino-1-(2-naphthyl)ethyl cyclohexanol Hydrochloride HC NN 10 Nr OH

15 OH

In an analogous manner to Example 1, step 1 N-(4-fluo robenzyl)-2-(1-hydroxycyclohexyl)-2-(2-naphthyl)aceta c mide was prepared from (1-hydroxycyclobutyl)(2-naphthyl) 25 acetic acid (Reference Example 1-c) and In an analogous manner to Example 24, 1-1-3-(benzy 4-fluorolbenzylamine. MS (ESI) m/z. 372 (IM+H H2O). loxy)phenyl-2-(4-methylpiperazin-1-yl)ethylcyclobutanol In an analogous manner to Example 1, step 2 1-2-(4- dihydrochloride was prepared from 1-1-3-(benzyloxy)phe fluorobenzyl)amino-1-(2-naphthyl)ethylcyclohexanol nyl)-2-piperazin-1-ylethylcyclobutanol (see Example 111). hydrochloride was prepared from N-(4-fluorobenzyl)-2-(1- 30 hydroxycyclohexyl)-2-(2-naphthyl)acetamide. MS m/z. 378 HRMS: calcd for CHNO2.00 HCl, 452.1997: found (M+H"); HRMS: calcd for CHFNO.HCl, 413.1922: (ESI),381.2524. found (ESI), 378.2234. Example 116 35 Example 114 4-1-(3-bromophenyl)-2-morpholin-4-ylethyl)-1- 4-1-(3,4-dichlorophenyl)-2-morpholin-4-ylethyl)-1- methylpiperidin-4-ol Dihydrochloride methylpiperidin-4-ol Dihydrochloride 40 O O 45 OH OH

CH 50 C CH3 Br C

In an analogous manner to Example 1, step 1 4-1-(3,4- In an analogous manner to Example 1, step 1 4-1-(3- dichlorophenyl)-2-morpholin-4-yl-2-oxoethyl-1-methylpi 55 bromophenyl)-2-morpholin-4-yl-2-oxoethyl-1-methylpip peridin-4-ol was prepared from (3,4-dichlorophenyl)(4-hy eridin-4-ol was prepared from (3-bromophenyl)(4-hydroxy droxy-1-methylpiperidin-4-yl)acetic acid (Reference 1-methylpiperidin-4-yl)acetic acid (Reference Example 1-r) Example 1-i) and morpholine. HRMS: calcd for and morpholine. HRMS: calcd for CHBrNO. CHCINO, 386.1164; found (ESI FT), 387.12304. 60 396.1049; found (ESI FT), 397.11148. In an analogous manner to Example 1, step 2 4-1-(3,4- In an analogous manner to Example 1, step 2 4-1-(3- dichlorophenyl)-2-morpholin-4-ylethyl-1-methylpiperidin bromophenyl)-2-morpholin-4-ylethyl-1-methylpiperidin-4- 4-ol dihydrochloride was prepared from 4-1-(3,4-dichlo rophenyl)-2-morpholin-4-yl-2-oxoethyl-1- ol dihydrochloride was prepared from 4-1-(3-bromophe methylpiperidin-4-ol. HRMS: calcd for 65 nyl)-2-morpholin-4-yl-2-oxoethyl-1-methylpiperidin-4-ol. CHC1NO2.00 HCl, 444.0905; found (ESI FT), HRMS: calcd for C.H. BrNO, HCl, 418.1023; found (ES 373.14421. I FT), 383.13261. US 7,419,980 B2 91 92 Example 117 Example 119 1-(1-(3-chlorophenyl)-2-4-(6-methoxy-2-naphthyl) 1-1-(3-chlorophenyl)-2-[4-(cyclohex-3-en-1-ylm methylpiperazin-1-yl)ethyl)cyclohexanol Dihydro ethyl)piperazin-1-yl)ethylcyclohexanol Dihydro chloride chloride

10 ON OH HC No N OH

15

C In an analogous manner to Example 117, 1-1-(3-chlo C rophenyl)-2-[4-(cyclohex-3-en-1-ylmethyl)piperazin-1-yl ethylcyclohexanol dihydrochloride was prepared from 1-1- (3-chlorophenyl)-2-piperazin-1-ylethylcyclohexanol (see Example 1) and 3-cyclohexene-1-carboxaldehyde. MS (ESI) A solution of 1-1-(3-chlorophenyl)-2-piperazin-1-yl m/z. M+H+ (417/419); HRMS: calcd for ethylcyclohexanol (see Example 1) (200 mg. 0.62 mmol) 25 C.H.CINO.2.00 HCl, 488.2128; found (ESI), 417.2655. and 6-methoxy-2-napthaldehyde (173 mg 0.93 mmol) in Example 120 dichloroethane (4 mL) was treated with sodium trisacetoxy borohydride (195 mg, 0.92 mmol). The reaction was placed 6-(4-2-(3-chlorophenyl)-2-(1-hydroxycyclohexyl) on a shaker and where it was stirred for 16h. The reaction was ethylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2- then washed with a 2 Naqueous solution of hydrochloric acid 30 ol Dihydrochloride (2x2 mL), and the organic layer was stored at 25°C. for 16 h. The resulting precipitate was collected, washed with diethyl ether and dried in vacuo to yield 194 mg (64%) 1-(1-(3- chlorophenyl)-2-4-(6-methoxy-2-naphthyl)methylpiper r azin-1-yl)ethyl)cyclohexanol dihydrochloride as a white 35 O Nu solid. MS (ESI) m/z 493/.495 (IM+H"); HRMS: calcd for OH C.H.CINO.2.00 HCl, 564.2077; found (ESI FT), OH 493.2632. 40 Example 118 C 1-1-(3-chlorophenyl)-2-[4-(cyclopropylmethyl) In an analogous manner to Example 117, 6-(4-2-(3-chlo piperazin-1-yl)ethylcyclohexanol Dihydrochloride rophenyl)-2-(1-hydroxycyclohexyl)ethylpiperazin-1- 45 yl)methyl)tetrahydro-2H-pyran-2-ol dihydrochloride was prepared from 1-1-(3-chlorophenyl)-2-piperazin-1-ylethyl cyclohexanol (see Example 1) and 3,4-dihydro-2H-pyran-2- carboxaldehyde. HRMS: calcd for C.H.CINO.2.00 HCl, 50 508.2026; found (ESI), 419.2455. vro Example 121 OH 1-1-(3-chlorophenyl)-2-[4-(3-phenylbutyl)piper azin-1-yl)ethylcyclohexanol Dihydrochloride 55

C

In an analogous manner to Example 117, 1-1-(3-chlo 60 O rophenyl)-2-[4-(cyclopropylmethyl)piperazin-1-yl OH ethylcyclohexanol dihydrochloride was prepared from 1-1- (3-chlorophenyl)-2-piperazin-1-ylethylcyclohexanol (see Example 1) and cyclopropanecarboxaldehyde. MS (ESI) m/z. 65 M+H+ (377/379); HRMS: calcd for CHCINO.2.00 HCl, 448.1815; found (ESI), 377,2347. C

US 7,419,980 B2 97 98 In an analogous manner to Example 117, 1-2-4-4-(ben Example 134 Zyloxy)benzylpiperazin-1-yl)-1-(3-chlorophenyl)ethylcy clohexanol dihydrochloride was prepared from 1-1-(3-chlo 1-1-(3-chlorophenyl)-2-[4-(pyridin-3-ylmethyl) rophenyl)-2-piperazin-1-ylethylcyclohexanol (see Example piperazin-1-yl)ethylcyclohexanol Dihydrochloride 1) and 4-benzyloxybenzaldehyde. MS (ESI) m/z 519/521 (M+H"); HRMS calcd for CHCINO.2.00 HCl, 590.2234; found (ESI FT), 519.27544.

Example 132 10

1-1-(3-chlorophenyl)-2-[4-(4-phenoxybenzyl)piper OH azin-1-yl)ethylcyclohexanol Dihydrochloride

15

C O In an analogous manner to Example 117, 1-1-(3-chlo OH rophenyl)-2-[4-(pyridin-3-ylmethyl)piperazin-1-yl ethylcyclohexanol dihydrochloride was prepared from 1-1- (3-chlorophenyl)-2-piperazin-1-ylethylcyclohexanol (see Example 1) and 3-pyridinecarboxaldehyde. MS (ESI) m/z. 25 M+H+ (414/416); HRMS: calcd for CHCINO.2.00 C HC1,485.1767; found (ESI), 414.2301. Example 135 30 In an analogous manner to Example 117, 1-1-(3-chlo 1-1-(3',4'-dichloro-1,1'-biphenyl-3-yl)-2-piperazin rophenyl)-2-[4-(4-phenoxybenzyl)piperazin-1-yl) 1-ylethylcyclohexanol Dihydrochloride ethylcyclohexanol dihydrochloride was prepared from 1-1- (3-chlorophenyl)-2-piperazin-1-ylethylcyclohexanol (see Example 1) and 4-phenoxybenzaldehyde. MS (ESI) m/z. 505/ 35 507 (IM+H"); HRMS: calcd for CHCINO.2.00 HCl, 576.2077; found (ESI FT), 505.26224.

Example 133 40 1-1-(3-chlorophenyl)-2-[4-(pyridin-4-ylmethyl) piperazin-1-yl)ethylcyclohexanol Dihydrochloride

45 Step 1: In an analogous manner to Example 1, step 1 tert-butyl 4-(3-bromophenyl)(1-hydroxycyclohexyl)acetyl piperazine-1-carboxylate was prepared from (3-bromophe nyl)(1-hydroxycyclohexyl)acetic acid (Reference Example N 50 1-b) and tert-butyl 1-piperazinecarboxylate. HRMS: calcd OH for CHBrNO. 480.1624; found (ESI FT), 481.16857. Step 2: A solution of tert-butyl 4-(3-bromophenyl)(1-hy droxycyclohexyl)acetylpiperazine-1-carboxylate (2.12 g, 4.40 mmol) in dry tetrahydrofuran (10 mL) under nitrogen 55 was treated dropwise with a solution of borane (1.0 M in C tetrahydrofuran, 13.2 mL, 13.2 mmol). The resulting solution was heated at 70° C. for 2 h, after which time the reaction was cooled in an ice bath, treated dropwise with methanol (15 mL) 60 and concentrated. The resulting viscous, colorless oil was In an analogous manner to Example 117, 1-1-(3-chlo re-dissolved in ethyl acetate (25 mL), washed with a saturated rophenyl)-2-[4-(pyridin-4-ylmethyl)piperazin-1-yl aqueous solution of Sodium bicarbonate, water, brine, dried ethylcyclohexanol dihydrochloride was prepared from 1-1- over sodium sulfate, filtered, and concentrated to give a white (3-chlorophenyl)-2-piperazin-1-ylethylcyclohexanol (see Solid, which was purified via flash column chromatography Example 1) and 4-pyridinecarboxaldehyde. MS (ESI) m/z. 65 (silica, gradient from 10% ethyl acetate/hexane to 20% ethyl M+H+ (414/416); HRMS: calcd for CHCINO.2.00 acetate/hexane) to yield 2.02 g (98%) tert-butyl 4-2-(3-bro HC1,485.1767; found (ESI), 414.23.07. mophenyl)-2-(1-hydroxycyclohexyl)ethylpiperazine-1-car US 7,419,980 B2 99 100 boxylate as a white powder. MS (ESI) m/z 467/469 (IM+ Example 137 HI"); HRMS: calcd for CHBrNO, 466. 1831; found (ESI), 467.1899; Anal. Calcd for CHBrNO: C, 59.10; 1-1-(4-chloro-1,1'-biphenyl-3-yl)-2-piperazin-1- H, 7.55; N, 5.99. Found: C, 59.14; H, 7.72: N, 5.77. ylethylcyclohexanol Dihydrochloride Step 3: A mixture of tert-butyl 4-2-(3-bromophenyl)-2-(1- hydroxycyclohexyl)ethylpiperazine-1-carboxylate (0.72 g, 1.55 mmol) and tetrakis(triphenylphosphine)palladium (37 mg, 0.032 mmol. 10 mol%) in 1,2-dimethoxyethane (30 mL) was stirred for 10 min at room temperature. To this mixture was added sequentially 3,4-dichlorophenyl boronic acid 10 (0.44 g, 2.32 mmol) and a 2M aqueous solution of sodium carbonate (0.8 mL, 1.6 mmol. 5 equivalent), and the mixture was heated at reflux until all starting material was consumed and precipitation of black palladium occurred (3 h). After cooling, water was added and the reaction mixture was 15 extracted with ethyl acetate (30 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude Solid, which was purified via In an analogous manner to Example 135, step 3 tert-butyl flash column chromatography (silica, gradient from 0% ethyl 4-2-(4-chloro-biphenyl-3-yl)-2-(1-hydroxycyclohexyl) acetate/hexane to 30% ethyl acetate/hexane) to yield 0.55g ethylpiperazine-1-carboxylate was prepared from tert-butyl (67%) of tert-butyl 4-2-(3',4'-dichloro-biphenyl-3-yl)-2-(1- 4-2-(3-bromophenyl)-2-(1-hydroxycyclohexyl)ethylpip hydroxycyclohexyl)ethylpiperazine-1-carboxylate as a erazine-1-carboxylate (see Example 135, step 2) and 4-chlo foam, which was used as such in the next step. rophenylboronic acid. Step 4: tert-butyl 4-2-(3',4'-dichloro-biphenyl-3-yl)-2-(1- 25 hydroxycyclohexyl)ethylpiperazine-1-carboxylate (0.39 g In an analogous manner to Example 135, step 4 1-1-(4'- 0.73 mmol) was dissolved in diethyl ether (15 mL) then a 2N chloro-1,1'-biphenyl-3-yl)-2-piperazin-1-ylethylcyclohex ethereal solution of hydrochloric acid (10 mL) was added. anol dihydrochloride was prepared from tert-butyl 4-2-(4'- Methanol (approximately 1 mL) was then added until the chloro-biphenyl-3-yl)-2-(1-hydroxycyclohexyl)ethyl resulting precipitate dissolved, and the homogeneous solu 30 piperazine-1-carboxylate. MS (ESI) m/z 399/401 (M+H"): tion was stirred for 18 h. The precipitated product was col HRMS: calcd for CHCINO.2.00 HCl, 470.1658; found lected by filtration, washed with diethyl ether and dried in a (ESI),399.2203. vacuum oven at 50° C. to yield 0.28 g (81%) of 1-1-(3',4'- dichloro-1,1'-biphenyl-3-yl)-2-piperazin-1-ylethylcyclo Example 138 hexanol dihydrochloride as a white solid. MS (ESI) m/z. 433/ 35 435/437 (M+H"); HRMS: calcd for CHNOC1.2.00 1-1-(3'-methoxy-11'-biphenyl-3-yl)-2-piperazin-1- HC1,433.1813; found (ESI), 433.1813. ylethylcyclohexanol Dihydrochloride Example 136 40 1-1-(1,1'-biphenyl-3-yl)-2-piperazin-1-ylethylcy clohexanol Dihydrochloride

45

50

In an analogous manner to Example 135, step 3 tert-butyl 4-2-(3'-methoxy-biphenyl-3-yl)-2-(1-hydroxycyclohexyl) 55 ethylpiperazine-1-carboxylate was prepared from tert-butyl In an analogous manner to Example 135, step 3 tert-butyl 4-2-(3-bromophenyl)-2-(1-hydroxycyclohexyl)ethylpip 4-2-(1,1'-biphenyl-3-yl)-2-(1-hydroxycyclohexyl)ethyl erazine-1-carboxylate (see Example 135, step 2) and 3-meth piperazine-1-carboxylate was prepared from tert-butyl 4-2- oxyphenylboronic acid. (3-bromophenyl)-2-(1-hydroxycyclohexyl)ethylpiperazine 1-carboxylate (see Example 135, step 2) and phenylboronic 60 acid. In an analogous manner to Example 135, step 4 1-1-(3'- In an analogous manner to Example 135, step 4 1-1-(1,1'- methoxy-11'-biphenyl-3-yl)-2-piperazin-1-ylethylcyclo biphenyl-3-yl)-2-piperazin-1-ylethylcyclohexanol dihydro hexanol dihydrochloride was prepared from tert-butyl 4-2- chloride was prepared from tert-butyl 4-2-(1,1'-biphenyl-3- (3'-methoxy-biphenyl-3-yl)-2-(1-hydroxycyclohexyl)ethyl yl)-2-(1-hydroxycyclohexyl)ethylpiperazine-1- 65 piperazine-1-carboxylate. MS (ESI) m/z 395 (IM+H"): carboxylate. MS (ESI) m/z. M+H+ (365); HRMS: calcd for HRMS: calcd for C.H.N.O.2.00 HCl, 466.2154: found CHNO.2.00 HCl, 436.2048; found (ESI), 365.2575. (ESI), 395.269. US 7,419,980 B2 101 102 Example 139 Example 141 1-1-(3'-chloro-1,1'-biphenyl-3-yl)-2-piperazin-1- 1-1-(2,5-dichlorothien-3-yl)-2-piperazine-1-ylethyl ylethylcyclohexanol Dihydrochloride cyclohexanol Dihydrochloride

10

OH

15 C In an analogous manner to Example 135, step 3 tert-butyl 4-2-(3'-chloro-biphenyl-3-yl)-2-(1-hydroxycyclohexyl) Step 1: A solution of 3-thiophene acetic acid (1.42 g, 10.0 mmol) in acetic acid (10 mL) was treated with N-chlorosuc ethylpiperazine-1-carboxylate was prepared from tert-butyl cinimide (3.1 g, 23 mmol. 2.3 equivalents), and the Solution 4-2-(3-bromophenyl)-2-(1-hydroxycyclohexyl)ethylpip was stirred for 12 hat room temperature then concentrated in erazine-1-carboxylate (see Example 135, step 2) and 3-chlo vacuo. The residue was diluted with water and stirred for 1 h rophenylboronic acid. whereupon the resulting solid was collected by filtration. The In an analogous manner to Example 135, step 4 1-1-(3'- solid was dried in a vacuum oven at room temperature for 10 chloro-1,1'-biphenyl-3-yl)-2-piperazin-1-ylethylcyclohex 25 hours providing 1.51 g (72%) of (2,5-dichlorothien-3-yl)ace anol dihydrochloride was prepared from tert-butyl 4-2-(3'- tic acid as a brown solid, which was used as Such in the next chloro-biphenyl-3-yl)-2-(1-hydroxycyclohexyl)ethyl step. MS (ESI) m/z. 209/21 1/213 (LM-H-). piperazine-1-carboxylate. MS (ESI) m/z 399/401 (M+H"); Step 2: In an analogous manner to Example 1, step 1 HRMS: calcd for CHCINO.2.00 HCl, 470.1658; found tert-butyl 4-(2,5-dichlorothien-3-yl)acetylpiperazine-1- (ESI),399.2183. 30 carboxylate was prepared from 2,5-dichlorothiophene-3-ace tic acid and tert-butyl 1-piperazinecarboxylate. The product Example 140 was crystallized from ethyl acetate:hexane to yield a colorless 1-1-(2'-fluoro-1,1'-biphenyl-3-yl)-2-piperazin-1- solid. ylethylcyclohexanol maleate 35 Step 3: A solution of diisopropyl amine (0.80 mL, 5.6 mmol) in dry tetrahydrofuran (10 mL) under nitrogen was cooled to -78° C. and treated dropwise with a solution of n-butyllithium (1.6M in hexanes, 3.5 mL, 5.6 mmol). To this reaction was added dropwise a solution of tert-butyl 4-(2,5- dichlorothien-3-yl)acetylpiperazine-1-carboxylate (1.7 g. 40 4.5 mmol) in tetrahydrofuran (10 mL). After the addition was complete, the solution was stirred for 0.5 hrat -78°C. where upon cyclohexanone (0.57 mL, 5.6 mmol) was added via syringe. The solution was stirred for an additional 0.5h. The reaction was quenched with a saturated aqueous solution of 45 ammonium chloride and then warmed to room temperature. The solution was diluted with ethyl acetate; the organic phase was separated, and was washed with a 2Naqueous solution of In an analogous manner to Example 135, step 3 tert-butyl hydrochloric acid (1x10 mL). The organic extract was dried 4-2-(2'-fluoro-biphenyl-3-yl)-2-(1-hydroxycyclohexyl) 50 over magnesium sulfate and concentrated. Chromatography ethylpiperazine-1-carboxylate was prepared from tert-butyl of the residue via Biotage (FLASH 40 M, silica, 30% ethyl 4-2-(3-bromophenyl)-2-(1-hydroxycyclohexyl)ethylpip acetate/hexane) provided 1.2 g (58%) of 4-(2,5-dichlo erazine-1-carboxylate (see Example 135, step 2) and 2-flo rothien-3-yl)(1-hydroxycyclohexyl)acetylpiperazine-1-car rophenylboronic acid. boxylate as a white foam. MS (ESI) m/z 477/479/481 (M+ In an analogous manner to Example 135, step 4 1-1-(2- 55 HI), HRMS: calcd for CHC1NOS, 476.1303; found fluoro-1,1'-biphenyl-3-yl)-2-piperazin-1-ylethylcyclohex (ESI), 477.1362. anol dihydrochloride was prepared from tert-butyl 4-2-(2- Step 4: In an analogous manner to Example 135, Step 2 fluoro-biphenyl-3-yl)-2-(1-hydroxycyclohexyl)ethyl tert-butyl 4-2-(2,5-dichlorothien-3-yl)-2-(1-hydroxycyclo piperazine-1-carboxylate. The compound was neutralized hexyl)ethylpiperazine-1-carboxylate was prepared from with 10% aqueous potassium carbonate, and the residue dis 60 tert-butyl 4-(2,5-dichlorothien-3-yl)(1-hydroxycyclohexyl) Solved in methanol. One equivalent of maleic acid was then acetylpiperazine-1-carboxylate. MS (ESI) m/z. 463/465/467 added and the Solution was concentrated. The product was (IM+H"), HRMS: calcd for CHC1-NOS, 462.1511: triturated with diethyl ether to yield 1-1-(2'-fluoro-1,1'-bi found (ESI), 463. 1594. phenyl-3-yl)-2-piperazin-1-ylethylcyclohexanol maleate as Step5: In an analogous manner to Example 135, step 4 a colorless solid. MS (ESI) m/z 383 (IM+H"); Anal. Calcd 65 1-1-(2,5-dichlorothien-3-yl)-2-piperazine-1-ylethylcyclo for CHFN.O. C.H.O. 0.50HO: C, 66.25; H, 7.15; N, hexanol dihydrochloride was prepared from tert-butyl 4-2- 5.52. Found: C, 66.03; H, 7.38; N, 5.31. (2,5-dichlorothien-3-yl)-2-(1-hydroxycyclohexyl)ethylpip US 7,419,980 B2 103 104 erazine-1-carboxylate and isolated as a colorless powder. MS (1-hydroxycyclohexyl)acetic acid (Reference Example 1-ss) (ESI) m/z. M+H+ (363/365/367); HRMS: calcd for and tert-butyl 1-piperazinecarboxylate. MS (ESI) m/z. 487/ CHCINOS.2.00 HCl, 434.0520; found (ESI), 489 (M+H+. 363.1035. In an analogous manner to Example 1, step 2, 1-1-(5- bromothien-2-yl)-2-piperazin-1-ylethylcyclohexanol dihy Example 142 drochloride was prepared from tert-butyl 4-(5-bromothien 2-yl)(1-hydroxycyclohexyl)acetylpiperazine-1- 1-1-(5-chlorothien-2-yl)-2-piperazin-1-ylethylcy carboxylate. MS (ESI) m/z. 373/375 (IM+H"). Anal. Calcd clohexanol Dihydrochloride for CHBrNOS.2.00 HCl: C, 43.06; H, 6.10: N, 6.28. 10 Found: C, 43.76; H, 6.12: N, 5.60. Example 144 1-1-(5-chlorothien-3-yl)-2-piperazin-1-ylethylcy clohexanol Dihydrochloride 15

OH

N - OH C

In an analogous manner to Example 141, step 1 (5-chlo rothien-3-yl)acetic acid was prepared from 2-thiophene ace 25 S tic acid and N-chlorosuccinimide. (This acid was used in Reference Example 1-rr) MS (ES) m/z 175.0 (IM-H-). In an analogous manner to Example 1, Step 1 tert-butyl In an analogous manner to Example 1, Step 1 tert-butyl 4-(5-chlorothien-3-yl)acetylpiperazine-1-carboxylate was 4-(5-chlorothien-2-yl)(1-hydroxycyclohexyl)acetylpipera prepared from 5-chlorothiophene-3-acetic acid and tert-bu Zine-1-carboxylate was prepared from (5-chlorothien-2-yl) 30 tyl 1-piperazinecarboxylate. MS (ES) m/z 289.0 (IM+H (1-hydroxycyclohexyl)acetic acid (Reference Example 1-rr) C4H8+); HRMS: calcd for C15H21CIN2O3S, 344,0961: and tert-butyl 1-piperazinecarboxylate. MS (ESI) m/z. 443/ found (ESI), 345. 1018 ° Monguzzi, R.: Libassi, G.; Pinza, M.; Pifferi, G. Synthesis of new a-hydrazi 445 (M+H+). noarylacetic acids and derivatives. Farnaco, Edizione Scientifica (1976), 31 (8), In an analoguous manner to Example 1, step 2 1-1-(5- 549-60. chlorothien-2-yl)-2-piperazin-1-ylethylcyclohexanol dihy 35 In an analogous manner to Example 141, step 3. tert-butyl drochloride product was prepared from tert-butyl 4-(5-chlo 4-2-(5-chlorothien-3-yl)-2-(1-hydroxycyclohexyl)ethyl rothien-2-yl)(1-hydroxycyclohexyl)acetylpiperazine-1- piperazine-1-carboxylate was prepared from tert-butyl 4-(5- carboxylate. MS (ESI) m/z 329/331 (M+H"); Anal. Calcd chlorothien-3-yl)acetylpiperazine-1-carboxylate and cyclo for CHCINOS 2.00 HCl: C, 47.83; H, 6.77: N, 6.97. 40 hexanone. MS (ESI) m/z 429 (IM+H"); HRMS: calcd for Found: C, 48.31; H, 7.40; N, 6.21. CHCINOS, 428. 1900; found (ESI), 429.1973. In an analogous manner to Example 135, step 2, tert-butyl Example 143 4-2-(5-chlorothien-3-yl)-2-(1-hydroxycyclohexyl)ethyl piperazine-1-carboxylate was prepared from tert-butyl 4-2- 1-1-(5-bromothien-2-yl)-2-piperazin-1-ylethylcy (5-chlorothien-3-yl)-2-(1-hydroxycyclohexyl)ethylpipera clohexanol Dihydrochloride 45 Zine-1-carboxylate. In an analogous manner to Example 135, step 4 1-1-(5- chlorothien-3-yl)-2-piperazin-1-ylethylcyclohexanol dihy drochloride was prepared from tert-butyl 4-2-(5-chlo rothien-3-yl)-2-(1-hydroxycyclohexyl)ethylpiperazine-1- carboxylate. MS (ES) m/z 329/331 (M+H"); HRMS: calcd for CHCINOS.2.00 HCl, 400.0910; found (ESI), OH 3.29.1444. Example 145 55 1-2-(4-aminopiperidin-1-yl)-1-(5-chlorothien-3-yl) ethylcyclohexanol Dihydrochloride B

60 In an analogous manner to Example 141, step 1 (5-bro mothien-3-yl)acetic acid was prepared from 2-thiophene ace tic acid and N-bromosuccinimide. (This product was used in OH Reference Example 1-ss). In an analogous manner to Example 1, step 1, tert-butyl 65 4-(5-bromothien-2-yl)(1-hydroxycyclohexyl)acetylpipera Zine-1-carboxylate was prepared from (5-bromothien-2-yl)

US 7,419,980 B2 111 112 In an analogous manner to Example 1, Step 1 tert-butyl Example 158 4-(2-chlorothien-3-yl)acetylpiperazine-1-carboxylate was prepared from (2-chlorothien-3-yl)acetic acid and tert-butyl 1-1-(1,1'-biphenyl-4-yl)-2-(4-methylpiperazin-1- 1-piperazinecarboxylate. MS (ES) m/z 289.0 (M+H ylethylcyclohexanol Dihydrochloride C4H8+); HRMS: calcd for CHCINOS, 344,0961: 5 found (ESI), 345. 1057. In an analogous manner to Example 141, step 3 tert-butyl 4-(2-chlorothien-3-yl)(1-hydroxycyclohexyl)acetylpipera Zine-1-carboxylate was prepared from tert-butyl 4-(2-chlo 10 rothien-3-yl)acetylpiperazine-1-carboxylate and cyclohex aOC. In an anlogous manner to Example 135, step 2 tert-butyl 4-2-(2-chlorothien-3-yl)-2-(1-hydroxycyclohexyl)ethyl piperazine-1-carboxylate was prepared from tert-butyl 4-(2- chlorothien-3-yl)(1-hydroxycyclohexyl)acetylpiperazine 1-carboxylate. MS (ESI) m/z 429/431 (M+H+); HRMS: calcd for CHCINOS, 428.1900; found (ESI), 429.1967. In an analogous manner to Example 135, step 4 1-1-(2- In an analogous manner to Example 24, 1-1-(1,1'-biphe chlorothien-3-yl)-2-piperazine-1-ylethylcyclohexanol dihy nyl-4-yl)-2-(4-methylpiperazin-1-ylethylcyclohexanol drochloride was prepared from tert-butyl 4-2-(2-chlo dihydrochloride was prepared from 1-1-(1,1'-biphenyl-4- rothien-3-yl)-2-(1-hydroxycyclohexyl)ethylpiperazine-1- yl)-2-piperazin-1-ylethylcyclohexanol (see Example 157). carboxylate. MS (ESI) m/z 329/331 (M+H"); HRMS: calcd 25 MS (ESI) m/z. 379 (M+H"); HRMS: calcd for for CHCINOS.2.00 HCl, 400.0910; found (ESI), CHNO.HCl, 414.2438; found (ESI FT), 379.27468. 3.29.1442. Example 159 1-1-(5-chlorothien-3-yl)-2-(4-methylpiperazin-1-yl) 30 ethylcyclohexanol Dihydrochloride Example 157 1-1-(1,1'-biphenyl-4-yl)-2-piperazin-1-ylethylcy clohexanol Dihydrochloride 35 N

OH

40 S

In an analogous manner to Example 24, 1-1-(5-chlo 45 rothien-3-yl)-2-(4-methylpiperazin-1-yl)ethylcyclohexanol dihydrochloride was prepared from 1-1-(5-chlorothien-3- yl)-2-piperazin-1-ylethylcyclohexanol (see Example 144). MS (ES) m/z 343.2 (M+H+); HRMS: calcd for C.H.CINOS. 2.00 HCl, 414...1066: found (ESI),343.1596. 50 Example 160 1-1-(3-cyanophenyl)-2-piperazin-1-ylethylcyclo In an analogous manner to Example 1, Step 1 tert-butyl hexanol Dihydrochloride 4-1.1'-biphenyl-4-yl(1-hydroxycyclohexyl)acetylpipera Zine-1-carboxylate was prepared from (1-hydroxycyclo 55 hexyl)(1,1'-biphenyl-4-yl)acetic acid (Reference Example 1-ZZ) and tert-butyl 1-piperazinecarboxylate. MS (ESI) m/z. 479 (M+H+); Anal. Calcd for CHNO: C, 72.77; H, 8.00; N, 5.85. Found: C, 72.69; H, 8.39; N, 5.80. 60 O In an analogous manner to Example 13, step 2 1-1-(1,1'- OH biphenyl-4-yl)-2-piperazin-1-ylethylcyclohexanol dihydro chloride was prepared from tert-butyl 4-1,1'-biphenyl-4-yl (1-hydroxycyclohexyl)acetylpiperazine-1-carboxylate. MS 65 (ESI) m/z 365 (IM+H+) HRMS: calcd for CHNO. HCl, 400.2281; found (ESI FT), 365.25908. CN US 7,419,980 B2 113 114 Step 1: A mixture of tert-butyl 4-2-(3-bromophenyl)-2-(1- Step 1: A mixture oftert-butyl 4-2-(3-bromophenyl)-2-(1- hydroxycyclohexyl)ethylpiperazine-1-carboxylate (see hydroxycyclohexyl)ethylpiperazine-1-carboxylate (see Example 135, step 2) (467 mg, 1.00 mmol), Zinc cyanide (141 Example 135, step 2) (141 mg 0.300 mmol), tributyl (vinyl) mg, 1.20 mmol), tris(dibenzylideneacetone)dipalladium (46 tin (114 mg. 0.360 mmol. 1.2 equivalent), and tetrakis(triph mg, 0.0500 mmol), 1,1'-bis(diphenylphosphino) ferrocene enylphosphine)palladium (17 mg, 0.015 mmol. 5 mol%) in (55 mg 0.100 mmol), and zinc dust (16 mg, 0.25 mmol) in anhydrous N,N-dimethylformamide (5 mL) was heated at toluene (3 mL) was heated at reflux under nitrogen until all 125° C. under nitrogen until all starting material was con starting material was consumed and precipitation of black sumed (5 h). After cooling to room temperature, water (10 palladium occurred (1-2 h). Filtration through CeliteR) and mL) and a 2 Naqueous solution of ammonium hydroxide (5 10 purification via flash column chromatography (silica, gradi mL) were added and the mixture was extracted with ethyl ent from 0% ethyl acetate/hexane to 10% ethyl acetate/hex acetate (1x20 mL). The combined organic extracts were ane) yielded 111 mg (90%) tert-butyl 4-2-(1-hydroxycyclo washed with brine (15 mL), dried over sodium sulfate, fil hexyl)-2-(3-vinylphenyl)ethylpiperazine-1-carboxylate as a tered, and concentrated to give a brown solid, which was viscous colorless oil. MS (ES) m/z. 415.4 (IM+H"); HRMS: purified via flash column chromatography (silica, gradient 15 calcd for C.H.N.O., 414.2882; found (ESI), 415.2966. from 5% ethyl acetate/hexane to 30% ethyl acetate/hexane) to yield 345 mg (84%) tert-butyl 4-2-(3-cyanophenyl)-2-(1- Step 2: In an analogous manner to Example 135, step 4, hydroxycyclohexyl)ethylpiperazine-1-carboxylate as a yel 1-2-piperazin-1-yl-1-(3-vinylphenyl)ethylcyclohexanol low solid. MS (ESI) m/z. 414 (M+H"); HRMS: calcd for dihydrochloride was prepared from tert-butyl 4-2-(1-hy CHNO. 413.2678; found (ESI), 414.2745. droxycyclohexyl)-2-(3-vinylphenyl)ethylpiperazine-1-car Step 2: In an analogous manner to Example 135, step 4, boxylate. MS (ESI) m/z. 315 (IM+H"); HRMS: calcd for 1-1-(3-cyanophenyl)-2-piperazin-1-ylethylcyclohexanol CHNO-2.00 HCl, 386.1892; found (ESI), 315.242. dihydrochloride was prepared from tert-butyl 4-2-(3-cy anophenyl)-2-(1-hydroxycyclohexyl)ethylpiperazine-1- Example 163 carboxylate. MS (ESI) m/z. 314 (IM+H"); HRMS: calcd for 25 C.H.N.O.2.00 HCl, 385.1688; found (ESI), 314.2225. 1-2-piperazin-1-yl-1-(4-vinylphenyl)ethylcyclohex Example 161 anol Dihydrochloride 1-1-(3-cyanophenyl)-2-(4-methylpiperazin-1-yl) ethylcyclohexanol Dihydrochloride 30 ON N OH 35 OH

40 In an analogous manner to Example 1, Step 1 tert-butyl CN 4-(4-bromophenyl)(1-hydroxycyclohexyl)acetylpipera Zine-1-carboxylate was prepared from (4-bromophenyl)(1- In an analogous manner to Example 24, 1-1-(3-cyanophe hydroxycyclohexyl)acetic acid (Reference Example 1-h) and nyl)-2-(4-methylpiperazin-1-yl)ethylcyclohexanol dihydro 45 tert-butyl 1-piperazinecarboxylate. MS (ESI) m/z 481/483 chloride was prepared from 1-1-(3-cyanophenyl)-2-piper azin-1-ylethylcyclohexanol (see Example 160). MS (ES) (IM+H"); Anal. Calcd for CHBrNO: C, 57.38: H, 6.91; m/z 328.2 (M+H"); HRMS: calcd for CHNO.2.00 N, 5.82. Found: C, 57.06; H, 6.69; N, 5.73. HC1,399.1844; found (ESI), 328.2383. In an analogous manner to Example 135, step 2, tert-butyl 50 4-2-(4-bromophenyl)-2-(1-hydroxycyclohexyl)ethylpip Example 162 erazine-1-carboxylate was prepared from tert-butyl 4-(4- 1-2-piperazin-1-yl-1-(3-vinylphenyl)ethylcyclohex bromophenyl)(1-hydroxycyclohexyl)acetylpiperazine-1- anol Dihydrochloride carboxylate. MS (ESI) m/z 467/469 (M+H"). In an analogous manner to Example 162, step 1, tert-butyl 55 4-2-(1-hydroxycyclohexyl)-2-(4-vinylphenyl)ethylpipera Zine-1-carboxylate was prepared from tert-butyl 4-2-(4-bro mophenyl)-2-(1-hydroxycyclohexyl)ethylpiperazine-1-car ON boxylate. MS (ES) m/z 415.4 (IM+H"); HRMS: calcd for OH 60 C.H.N.O., 414.2882; found (ESI), 415.2975. In an analogous manner to Example 135, step 4, 1-2- piperazin-1-yl-1-(4-vinylphenyl)ethylcyclohexanol dihy drochloride was prepared from tert-butyl 4-2-(1-hydroxycy 65 clohexyl)-2-(4-vinylphenyl)ethylpiperazine-1-carboxylate. MS (ES) m/z. 315.3 (IM+H"); HRMS: calcd for CHNO.2.00 HCl, 386.1892; found (ESI), 315.2424.

US 7,419,980 B2 123 124 In an analogous manner to Example 1, step 2, 1-1-(4- Example 182 bromophenyl)-2-piperazin-1-ylethylcyclohexanol was pre pared from tert-butyl 4-(4-bromophenyl)(1-hydroxycyclo 1-1-(3'-chloro-1,1'-biphenyl-4-yl)-2-piperazin-1- hexyl)acetylpiperazine-1-carboxylate (see Example 163, ylethylcyclobutanol Dihydrochloride step 1). MS (ESI) m/z. 367/369 (IM+H"); HRMS: calcd for 5 CHBrNO.2.00 HC1,438,0840; found (ESI), 367.1365. In an analogous manner to Example 24, 1-1-(4-bro mophenyl)-2-(4-methylpiperazin-1-yl)ethylcyclohexanol was prepared from 1-1-(4-bromophenyl)-2-piperazin-1-yl 10 O ethylcyclohexanol. MS (ESI) m/z 381/383 (IM+H"): OH HRMS: calcd for CHBrNO, 380.1463; found (ESI), 381.1525. In an analogous manner to Example 135, step 3, 1-1-(4'- fluoro-1,1'-biphenyl-4-yl)-2-(4-methylpiperazin-1-yl)ethyl 15 Ort cyclohexanol dihydrochloride was prepared from 1-1-(4- bromophenyl)-2-(4-methylpiperazin-1-yl)ethyl O cyclohexanol using 4-fluorophenylboronic acid. Salt formation: A solution of 1-1-(4-fluoro-1,1'-biphenyl-4-yl)- C 2-(4-methylpiperazin-1-yl)ethylcyclohexanol, in diethyl In an analogous manner to Example 1, step 1, tert-butyl ether (2 mL) was treated with a 4 N solution of hydrogen 4-(4-bromophenyl)(1-hydroxycyclobutyl)acetylpipera chloride in dioxane (1 mL) and stored in the refrigerator for Zine-1-carboxylate was prepared from (4-bromophenyl)(1- 16 h. The resulting crystals were collected, washed with hydroxycyclobutyl)acetic acid (Reference Example 1-ww) diethyl ether, and dried in vacuo to yield 1-1-(4-fluoro-1,1'- and tert-butyl 1-piperazinecarboxylate. MS (ESI) m/z 453/ biphenyl-4-yl)-2-(4-methylpiperazin-1-yl)ethylcyclohex 455 (IM+H"). anol dihydrochloride. MS (ESI) m/z 397 (IM+H"); HRMS: In an analogous manner to Example 135, step 2, tert-butyl calcd for CHFN.O.2.00 HCl, 468.2110; found (ESI), 4-2-(4-bromophenyl)-2-(1-hydroxycyclobutyl)ethylpip 397.2639. 30 erazine-1-carboxylate was prepared from tert-butyl 4-(4- bromophenyl)(1-hydroxycyclobutyl)acetylpiperazine-1- Example 181 carboxylate. MS (ESI) m/z 439/441 (M+H"). In an analogous manner to Example 135, step 3. tert-butyl 1-1-(4-methyl-1,1'-biphenyl-4-yl)-2-(4-methylpip 4-2-(3'-chloro-1,1'-biphenyl-4-yl)-2-(1-hydroxycyclobutyl) erazin-1-yl)ethylcyclohexanol Dihydrochloride 35 ethylpiperazine-1-carboxylate was prepared from tert-butyl 4-2-(4-bromophenyl)-2-(1-hydroxycyclobutyl)ethylpip erazine-1-carboxylate using 3-chlorophenylboronic acid. MS (ES) m/z 471.3 (IM+H"); HRMS: calcd for CHCINO, H3C n 470.2336; found (ESI), 471.2405. N 40 In an analogous manner to Example 135, Step 4, 1-1-(3'- chloro-1,1'-biphenyl-4-yl)-2-piperazin-1-ylethylcyclobu N tanol dihydrochloride was prepared from tert-butyl 4-2-(3'- OH chloro-1,1'-biphenyl-4-yl)-2-(1-hydroxycyclobutyl)ethyl piperazine-1-carboxylate. MS (ES) m/z. 371.3 (M+H"): 45 HRMS: calcd for C.H.CINO.2.00 HCl, 442.1345; found (ESI), 371.1897. Example 183

HC 1-2-piperazin-1-yl-1-3'-(trifluoromethoxy)-1,1'- 50 biphenyl-4-yl)ethylcyclobutanol Dihydrochloride In an analogous manner to Example 135, step 3, 1-1-(4'- methyl-1,1'-biphenyl-4-yl)-2-(4-methylpiperazin-1-yl) ethylcyclohexanol dihydrochloride was prepared from 1-1- (4-bromophenyl)-2-(4-methylpiperazin-1-yl)ethyl 55 cyclohexanol (see Example 180, step 3) using 4-tolylboronic acid. Salt formation: A solution of 1-1-(4-methyl-1,1'-bi phenyl-4-yl)-2-(4-methylpiperazin-1-yl)ethylcyclohexanol, in diethyl ether (2 mL) was treated with a 4N solution of O hydrogen chloride in dioxane (1 mL) and stored in the refrig erator for 16 h. The resulting crystals were collected, washed with diethyl ether, and dried in vacuo to yield 1-1-(4-methyl 1,1'-biphenyl-4-yl)-2-(4-methylpiperazin-1-yl)ethylcyclo hexanol dihydrochloride. MS (ESI) m/z 393 (M+H"): 65 HRMS: calcd for CHNO.2.00 HCl, 464.2361; found OCF (ESI), 393.2913.

US 7,419,980 B2 145 146 Example 224 Reference Example 2-a 1-2-(3R)-3-aminopyrrolidin-1-yl)-1-3-(trifluo Alkylation Reaction: Preparation of Acid romethyl)phenylethylcyclohexanol Dihydrochlo Intermediates ride A solution of diisopropylamine (1.80 mL, 12.9 mmol) in dry tetrahydrofuran (6 mL) under nitrogen was cooled to -78° C. and treated dropwise with a solution of n-butyllithium (2.4 Min hexanes, 5.4 mL, 12.9 mmol). The resulting solution was 10 warmed to 0° C. and stirred for 15 min. The solution was re-cooled to -78°C. and treated, via cannula, with a solution of 3-chlorophenylacetic acid (1.0 g, 5.9 mmol) in tetrahydro furan (6 mL). The reaction was then allowed to warm to 25° C. where it was stirred for 45 minutes and was then re-cooled 15 to -78° C. Cyclopentyl bromide (0.76 mL, 7.1 mmol) was then added via Syringe, and the resulting mixture was stirred at -78° C. for 1 hour. The reaction mixture was allowed to warm to room temperature and then stirred overnight. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium chloride, and the tetrahydro furan was removed in vacuo. The resulting residue was dis solved in a 2Naqueous solution of sodium hydroxide (30 mL) In an analogous manner to Example 1, step 1, tert-butyl and washed with ethyl acetate (1x15 mL). The aqueous layer ((3R)-1-(1-hydroxycyclohexyl)-3-(trifluoromethyl)phenyl was then acidified to pH=1 with the addition of a 2 Naqueous acetylpyrrolidin-3-yl)carbamate was prepared from (1-hy 25 solution of hydrochloric acid. The product was extracted with droxycyclohexyl)3-(trifluoromethyl)phenyl)acetic acid ethyl acetate (3x15 mL), and the combined organic extracts (Reference Example 1 m) and (3R)-(-)-3-(tert-butoxycarbo were dried over magnesium Sulfate, concentrated in vacuo nylamino)pyrrolidine. MS (ES) m/z, 471.0. and the product was purified via Biotage Horizon (FLASH 25 M. silica, gradient from 0% EtOAc/hexane to 40% EtOAc/ In an analogous manner to Example 1, step 2, 1-2-((3R)- 30 hexane) to yield 1.08 g (79%) (3-chlorophenyl)(cyclohexyl) 3-aminopyrrolidin-1-yl)-1-3-(trifluoromethyl)phenyl acetic acid as a clear oil. HRMS: calcd for C13H15C1O2-H, ethylcyclohexanol dihydrochloride was prepared from tert 237,06823: found (ESI, M-H-), 237.0682 butyl ((3R)-1-(1-hydroxycyclohexyl)-3-(trifluoromethyl) SS) In an analogous manner, (3-chlorophenyl)(cyclohexyl) phenyl)acetylpyrrolidin-3-yl)carbamate MS (ES) m/z. acetic acid was prepared from 3-chlorophenylacetic acid 357.1; HRMS: calcd for CHFNO+H,357.21537; found 35 and cyclohexylbromide. HRMS: calcd for (ESI, M+H"),357.2154. CHCIO-H, 251.0817; found (ESI, M-HI), 251.0849. Example 225 tt) In an analogous manner, (3-chlorophenyl)(cycloheptyl) acetic acid was prepared from 3-chlorophenylacetic acid 40 and cycloheptylbromide. HRMS: calcd for 1-2-((3R)-3-(dimethylamino)pyrrolidin-1-yl)-1-3- CHCIO-H, 265.0974; found (ESI, M-HI), (trifluoromethyl)phenylethylcyclohexanol Dihy 265.0985. drochloride uu) In an analogous manner, (3-chlorophenyl)(2-hydroxy cyclohexyl)acetic acid was prepared from 3-chlorophe 45 nylacetic acid and cyclohexene oxide. HRMS: calcd for CHCIO-H, 267,0766; found (ESI, M-HI), 267.0779. Example 226 50 1-2-(3-chlorophenyl)-2-cyclopentylethylpiperazine Dihydrochloride

55

N NH

In an analogous manner to Example 36, 1-2-((3R)-3- 60 (dimethylamino)pyrrolidin-1-yl)-1-3-(trifluoromethyl)phe C nyl)ethylcyclohexanol dihydrochloride was prepared from, 1-2-(3R)-3-aminopyrrolidin-1-yl)-1-3-(trifluoromethyl) phenylethylcyclohexanol (See Example 224). MS (ESI) 65 In an analogous manner to Example 1, step 1, tert-butyl m/z 385; HRMS: calcd for CHFNO+H, 385.24667; 4-(3-chlorophenyl)(cyclopentyl)acetylpiperazine-1-car found (ESI, M+H"), 385.2454. boxylate was prepared from (3-chlorophenyl)(cyclopentyl) US 7,419,980 B2 147 148 acetic acid (Reference Example 2-a) and tert-butyl 1-pipera Example 229 Zinecarboxylate. HRMS: calcd for CHCINO+H, 407.2123: found (ESI, M+H"), 407.2094. 1-2-(3-chlorophenyl)-2-cyclopentylethyl-N,N-dim In an analogous manner to Example 1, step 2, 1-2-(3- ethylpiperidin-4-amine Dihydrochloride chlorophenyl)-2-cyclopentylethylpiperazine dihydrochlo ride was prepared from tert-butyl 4-(3-chlorophenyl)(cyclo pentyl)acetylpiperazine-1-carboxylate HRMS: calcd for CHCIN+H, 293.17845; found (ESI, M+H"), 293.1776. 10 C Example 227 1-2-(3-chlorophenyl)-2-cyclopentylethyl-4-meth ylpiperazine Dihydrochloride 15

In an analogous manner to Example 36, 1-2-(3-chlorophe nyl)-2-cyclopentylethyl-N,N-dimethylpiperidin-4-amine dihydrochloride was prepared from, 1-2-(3-chlorophenyl)- N N 2-cyclopentylethyl-N-methylpiperidin-4-amine (See \ / Example 228). MS (ES) m/z 335.2; HRMS: calcd for CHCIN+H, 335.22540; found (ESI, M+H"), 335.2243. C 25 Example 230 1-2-(3-chlorophenyl)-2-cyclohexylethylpiperazine In an analogous manner to Example 24, 1-2-(3-chlorophe Dihydrochloride nyl)-2-cyclopentylethyl-4-methylpiperazine dihydrochlo 30 ride was prepared from, 1-2-(3-chlorophenyl)-2-cyclopen tylethylpiperazine (See Example 226). MS (ES) m/z 3.07.2: HRMS: calcd for C.H.CIN+H, 307. 19410; found (ESI, M+H"),307. 1935. 35

Example 228 N NH 1-2-(3-chlorophenyl)-2-cyclopentylethyl-N-meth C ylpiperidin-4-amine Dihydrochloride 40 In an analogous manner to Example 1, step 1, tert-butyl 4-(3-chlorophenyl)(cyclohexyl)acetylpiperazine-1-car boxylate was prepared from (3-chlorophenyl)(cyclohexyl) acetic acid (Reference Example 2-b) and tert-butyl 1-pipera 45 Zinecarboxylate. HRMS: calcd for CHCINO+H, 421.2280; found (ESI, M+H"), 421.2261. In an analogous manner to Example 1, step 2, 1-2-(3- chlorophenyl)-2-cyclohexylethylpiperazine dihydrochlo ride was prepared from tert-butyl 4-(3-chlorophenyl)(cyclo 50 hexyl)acetylpiperazine-1-carboxylate HRMS: calcd for C.H.CIN+H, 307. 19410; found (ESI, M+H"), N 3O7.1943. Example 231 In an analogous manner to Example 1, step 1, tert-butyl {1-(3-chlorophenyl)(cyclopentyl)acetylpiperidin-4- 55 1-2-(3-chlorophenyl)-2-cyclohexylethyl-4-meth y1}carbamate was prepared from (3-chlorophenyl)(cyclopen ylpiperazine Dihydrochloride tyl)acetic acid (Reference Example 2-a) and 4-N-Boc-ami nopiperidine. HRMS: calcd for CHCINO+H, 421.2280; found (ESI, M+H"), 421.2269. 60 In an analogous manner to Example 13, Step 2, 1-2-(3- chlorophenyl)-2-cyclopentylethyl-N-methylpiperidin-4- amine dihydrochloride was prepared from tert-butyl {1-(3- chlorophenyl)(cyclopentyl)acetylpiperidin-4-yl)carbamate 6s MS (ES) m/z 321.2: HRMS: calcd for CHCIN+H, 321.20975; found (ESI, M+H"), 321.2088. C US 7,419,980 B2 149 150 In an analogous manner to Example 24, 1-2-(3-chlorophe Example 234 nyl)-2-cyclohexylethyl-4-methylpiperazine dihydrochlo ride was prepared from, 1-2-(3-chlorophenyl)-2-cyclohexy 1-2-(3-chlorophenyl)-2-cycloheptylethylpiperazine lethylpiperazine (See Example 230). MS (ES) M/Z 321.2: Dihydrochloride HRMS: calcd for CHCIN+H, 321.20975; found (ESI, M+H"), 321.2108. Example 232 10 1-2-(3-chlorophenyl)-2-cyclohexylethyl-N-meth ylpiperidin-4-amine Dihydrochloride

N NH 15 C

In an analogous manner to Example 1, step 1, tert-butyl 4-(3-chlorophenyl)(cycloheptyl)acetylpiperazine-1-car C boxylate was prepared from (3-chlorophenyl)(cycloheptyl) acetic acid (Reference Example 2-c) and tert-butyl 1-pipera zinecarboxylate. MS m/z. 379. In an analogous manner to Example 1, step 2, 1-2-(3- chlorophenyl)-2-cycloheptylethylpiperazine dihydrochlo N ride was prepared from tert-butyl 4-(3-chlorophenyl)(cyclo 25 heptyl)acetylpiperazine-1-carboxylate MS (ES) m/z 32 1.2: In an analogous manner to Example 1, step 1, tert-butyl HRMS: calcd for CHCIN+H, 321.20975; found (ESI, {1-(3-chlorophenyl)(cyclohexyl)acetylpiperidin-4- M+H"), 321.2105. Example 235 y1}carbamate was prepared from (3-chlorophenyl)(cyclo 30 hexyl)acetic acid (Reference Example 2-b) and 4-N-Boc 1-2-(3-chlorophenyl)-2-cycloheptylethyl-4-meth aminopiperidine. HRMS: calcd for CHCINO+H, ylpiperazine Dihydrochloride 435.2436; found (ESI, M+H"), 435.2422. In an analogous manner to Example 13, Step 2, 1-2-(3- chlorophenyl)-2-cyclohexylethyl-N-methylpiperidin-4- 35 amine dihydrochloride was prepared from tert-butyl {1-(3- chlorophenyl)(cyclohexyl)acetylpiperidin-4-yl)carbamate MS (ES) m/z 335.3; HRMS: calcd for CHCIN+H, 335.22540; found (ESI, M+H"), 335.224.5. 40 Example 233 C 1-2-(3-chlorophenyl)-2-cyclohexylethyl-N,N-dim ethylpiperidin-4-amine Dihydrochloride 45 In an analogous manner to Example 24, 1-2-(3-chlorophe nyl)-2-cycloheptylethyl-4-methylpiperazine dihydrochlo ride was prepared from, 1-2-(3-chlorophenyl)-2-cyclohep tylethylpiperazine (See Example 234). MS (ES) m/z 335.2: HRMS: calcd for CHCIN+H, 335.22540; found (ESI, 50 M+HI), 335.2253. Example 236 C 1-2-(3-chlorophenyl)-2-cycloheptylethyl-N-meth ylpiperidin-4-amine Dihydrochloride 55

60 In an analogous manner to Example 36, 1-2-(3-chlorophe C nyl)-2-cyclohexylethyl-N,N-dimethylpiperidin-4-amine dihydrochloride was prepared from, 1-2-(3-chlorophenyl)- 2-cyclohexylethyl-N-methylpiperidin-4-amine (See Example 232). HRMS: calcd for CHCIN+H,349.24105; 65 found (ESI, M+H"),349.2422. N US 7,419,980 B2 151 152 In an analogous manner to Example 1, step 1, tert-butyl Step 2: A solution of 3-(3-chlorophenyl)hexahydro-1-ben {1-(3-chlorophenyl)(cycloheptyl)acetylpiperidin-4- Zofuran-2(3H)-one (540 mg, 2.19 mmol) in dry tetrahydro y1}carbamate was prepared from (3-chlorophenyl)(cyclohep furan (7 mL) was cooled to -78°C. under nitrogen and was tyl)acetic acid (Reference Example 2-c) and and 4-N-Boc treated dropwise with a solution of DiBAL (1.0 M in toluene, aminopiperidine. MS m/z. 449. 5 In an analogous manner to Example 13, Step 2, 1-2-(3- 3.07 mL, 3.07 mmol). The resulting solution was stirred at chlorophenyl)-2-cycloheptylethyl-N-methylpiperidin-4- -78°C. for 2 h, after which time the reaction was treated a 1 amine dihydrochloride was prepared from tert-butyl {1-(3- Maqueous solution of Sulfuric acid to dissolve precipitated chlorophenyl)(cycloheptyl)acetylpiperidin-4-yl)carbamate salts. The reaction mixture was allowed to warm to room MS (ES) m/z 349.2; HRMS: calcd for CHCIN+H, 10 temperature and was partitioned between diethyl ether and 349.24105; found (ESI, M+H"),349.2412. water. The organic layer was washed with a saturated aqueous Solution of sodium bicarbonate, water, and brine and was Example 237 dried over magnesium sulfate and concentrated Invacuo. The 1-2-(3-chlorophenyl)-2-cycloheptylethyl-N,N-dim crude product was purified via Biotage Horizon (FLASH 25 ethylpiperidin-4-amine Dihydrochloride 15 M, silica, gradient from 0% EtOAc/hexane to 35% EtOAc/ hexane) to yield 0.38 g (69%) the lactol, 3-(3-chlorophenyl) octahydro-1-benzofuran-2-ol as a white foam. HRMS: calcd for CHCIO-H, 251.0817; found (ESI, M-HI), 251.0835. Step 3: A solution of 3-(3-chlorophenyl)octahydro-1-ben C Zofuran-2-ol (175 mg, 0.69 mmol) and tert-butyl 1-piperazi necarboxylate (128 mg, 0.69 mmol) in dichloroethane (3 mL) was treated with sodium trisacetoxyborohydride (220 mg. 25 1.04 mmol). The reaction was allowed to stir at room tem perature for 16 h. The reaction was then diluted with meth ylene chloride and washed with a saturated aqueious Solution of ammonium chloride (3 times). The organic layer was dried 30 over magnesium sulfate and concentrated in vacuo and the In an analogous manner to Example 36, 1-2-(3-chlorophe product was purified via Biotage Horizon (FLASH 25 M, nyl)-2-cycloheptylethyl-N,N-dimethylpiperidin-4-amine silica, gradient from 0% EtOAc/hexane to 30% EtOAc/hex dihydrochloride was prepared from, 1-2-(3-chlorophenyl)- ane). This material was dissolved in methanol (0.5 mL) and 2-cycloheptylethyl-N-methylpiperidin-4-amine (See treated with a saturated methanolic solution of hydrochloric Example 236). MS (ES) m/z. 363.3: 35 acid (0.5 mL) followed by diethyl ether. After crystallizing in HRMS: calcd for CHCIN+H,363.25670; found (ESI, the refrigerator for 16 h, the resulting solid was collected, M+HI), 363.2578. washed with diethyl ether and dried in vacuo to yield 250 mg Example 238 (83%) 2-1-(3-chlorophenyl)-2-piperazin-1-ylethylcyclo 40 hexanol dihydrochloride as a white solid. HRMS: calcd for 2-1-(3-chlorophenyl)-2-piperazin-1-ylethylcyclo C.H.CINO+H, 323.18901; found (ESI, M+H"), hexanol Dihydrochloride 323.1891. Example 239 45 2-2-(4-aminopiperidin-1-yl)-1-(3-chlorophenyl) HO ethylcyclohexanol Dihydrochloride

50 N NH C HO Step 1: A solution of (3-chlorophenyl)(2-hydroxycyclo hexyl)acetic acid (Reference Example 2-d) (1.25 g, 4.66 55 mmol), benzotriazol-1-yloxytris(dimethylaminop)phospho nium hexafluorophosphate (3.1 g, 7.0 mmol), and tert-butyl 1-piperazinecarboxylate (0.87 g, 4.66 mmol) in methylene C O)- NH2 chloride (12 mL) was treated with triethylamine (0.98 mL, 7.0 mmol). The reaction was stirred at 25°C. for 16 h, after 60 which time the solvent was removed in vacuo and the product In an analogous manner to Example 238, step 3 2-2-(4- was purified via Biotage Horizon (FLASH 40 M, silica, gra aminopiperidin-1-yl)-1-(3-chlorophenyl)ethylcyclohexanol dient from 0% EtOAc/hexane to 25% EtOAc/hexane) to yield dihydrochloride was prepared from 3-(3-chlorophenyl)oc 0.97g (83%) the lactone, 3-(3-chlorophenyl)hexahydro-1- tahydro-1-benzofuran-2-ol (see Example 238, Step 2) and benzofuran-2(3H)-one as a clear oil. HRMS: calcd for 65 N-Boc-4-aminopiperidine. HRMS: calcd for CHCINO+ CHClO+H, 251.0861; found (ESI, M+H"), 251.0844. H, 337.20467: found (ESI, M+H"), 337.2031. US 7,419,980 B2 153 154 Example 240 Example 242 1-2-(1-hydroxycyclohexyl)-2-3-(trifluoromethoxy) 1-1-4-(benzyloxy)-3-chlorophenyl-2-(4-methox phenylethylpiperidin-4-ol Hydrochloride ypiperidin-1-yl)ethylcyclohexanol Hydrochloride

O)- OH 10 OH OH

15 F

C In an analogous manner to Example 1, step 1, 1-(1-hy droxycyclohexyl)3-(trifluoromethoxy)phenyl acetylpiperidin-4-ol was prepared from (1-hydroxycyclo hexyl)3-(trifluoromethoxy)phenyl)acetic acid (Reference Example 1-f) and 4-hydroxypiperidine. MS (ES) m/z 402.0. In an analogous manner to Example 1, step 1, 1-1-4- 25 (benzyloxy)-3-chlorophenyl-2-(4-methoxypiperidin-1-yl)- In an analogous manner to Example 1, step 2, 1-2-(1- 2-oxoethylcyclohexanol was prepared from 4-(benzyloxy)- hydroxycyclohexyl)-2-3-(trifluoromethoxy)phenyl 3-chlorophenyl(1-hydroxycyclohexyl)acetic acid ethylpiperidin-4-olhydrochloride was prepared from 1-(1- (Reference Example leee) and 4-methoxypiperidine (Baker, hydroxycyclohexyl)3-(trifluoromethoxy)phenyl W. R.; Fung, A. K. I. Kleinhart, H. Det. Al. J. Med. Chem. acetylpiperidin-4-ol MS (ES) m/z 388.0; HRMS: calcd for 30 1992, 35 (10), 1722-1734.) MS m/z. 379. CHFNO+H, 388.20995; found (ESI, M+H"), In an analogous manner to Example 1, Step 2, 1-1-4- 388.2103. (benzyloxy-3-chlorophenyl-2-(4-methoxypiperidin-1-yl) Example 241 ethylcyclohexanol hydrochloride was prepared from 1-1- 35 4-(benzyloxy)-3-chlorophenyl-2-(4-methoxypiperidin-1- 1-2-4-(benzyloxy)-3-chlorophenyl-2-(1-hydroxy yl)-2-oxoethylcyclohexanol HRMS: calcd for cyclohexyl)ethylpiperidin-4-ol Hydrochloride CHCINO+H, 458.24620; found (ESI, M+H"), 458,2443. 40 Example 243 1-(1S)-2-piperazin-1-yl-1-3-(trifluoromethoxy) phenylethylcyclohexanol Dihydrochloride 45

50

OH In an analogous manner to Example 1, step 1, 1-4-(ben Zyloxy)-3-chlorophenyl(1-hydroxycyclohexyl)acetylpip eridin-4-ol was prepared from (4-(benzyloxy)-3-chlorophe 55 nyl(1-hydroxycyclohexyl)acetic acid (Reference Example 1-eee) and 4-hydroxypiperidine. MS (ES) m/z. 458.0.

In an analogous manner to Example 1, step 2, 1-2-4- 60 F (benzyloxy)-3-chlorophenyl-2-(1-hydroxycyclohexyl) ethylpiperidin-4-ol hydrochloride was prepared from 1-4- (benzyloxy)-3-chlorophenyl(1-hydroxycyclohexyl)acetyl Racemic tert-butyl 4-(1-hydroxycyclohexyl)-3-(trifluo piperidin-4-ol MS (ES) m/z 444.1; HRMS: calcd for 65 romethoxy)phenyl)acetylpiperazine-1-carboxylate (see CHCINO+H, 444.23055; found (ESI, M+H"), Example 23, step 1) was dissolved in methanol at a concen 444.2316. tration of approximately 50 mg/mL. The resulting Solution US 7,419,980 B2 155 156 was injected onto the Supercritical Fluid Chromatography (see Example 243). MS (ES) m/z. 373.1; HRMS: calcd for instrument with an injection volume of 750DL. The baseline CHFNO+H, 373.21029; found (ESI, M+H"), resolved enantiomers, using the conditions described below, 373.2102. were collected. The enantiomeric purity of each enantiomer was determined under the same Supercritical Fluid Chroma Example 245 tography conditions using a Chiralpak AD-H 5u, 250 mmx4.6 mm ID column at 2.0 mL/min flow rate using Ana lytical Supercritical Fluid Chromatography (Berger Instru 1-(1S)-2-(4-methylpiperazin-1-yl)-1-3-(trifluo ments, Inc. Newark, Del. USA). romethoxy)phenylethylcyclohexanol Dihydrochlo 10 ride

SFC Instrument: Berger MultiGram PrepSFC (Berger Instruments, Inc. Newark, DE 19702. Column: Chiralpak AD-H; 5u: 250 mm Lx 20 mm ID (Chiral Technologies, Inc, Exton, PA, USA) 15 Column 35o C. temperature: SFC Modifier: 10%. EtOH Flow rate: 50 mL/min Outlet Pressure: 100 bar r Detector: UV at 220 mm -N - OH tert-butyl 4-(2R)-2-(1-hydroxycyclohexyl)-2-3-(trifluo romethoxy)phenyl)acetylpiperazine-1-carboxylate was iso O lated at peak 1. MS (ES) m/z. 487.2; HRMS: calcd for CHFNO+H, 487.2442+H: found (ESI, M+H"), 25 487.2428; C–+23° (c=0.00116 G/ML, EtOH). F tert-butyl 4-(2S)-2-(1-hydroxycyclohexyl)-2-3-(trifluo romethoxy)phenyl)acetylpiperazine-1-carboxylate was iso In an analogous manner to Example 24, 1-(1S)-2-(4-me lated at peak 2. MS (ESI) m/z 487; HRMS: calcd for thylpiperazin-1-yl)-1-3-(trifluoromethoxy)phenyl CHFNO+H, 487.2442; found (ESI, M+H"), 30 ethylcyclohexanol dihydrochloride was prepared from, 1 ol--19° (c=0.01 12 G/ML, MeOH). (1S)-2-piperazin-1-yl-1-3-(trifluoromethoxy)phenyl In an analogous manner to Example 1, step 2 1-(1S)-2- ethylcyclohexanol (See Example 243). MS (ES) m/z 387.2: piperazin-1-yl-1-3-(trifluoromethoxy)phenyl ethylcyclohexanol dihydrochloride was prepared from tert HRMS: calcd for CHFNO+H,387.22594; found (ESI, butyl 4-(2R)-2-(1-hydroxycyclohexyl)-2-3- 35 M+H"), 387.2249. (trifluoromethoxy)phenyl)acetylpiperazine-1-carboxylate. Example 246 MS (ES) m/z. 373.2; HRMS: calcd for CHFNO+H, 373.21029; found (ESI, M+HI), 373.2094; C-42.2° 1-(1R)-2-(4-methylpiperazin-1-yl)-1-3-(trifluo (c=0.0099 G/ML, MeOH). 40 romethoxy)phenylethylcyclohexanol Dihydrochlo Example 244 ride 1-(1R)-2-piperazin-1-yl-1-3-(trifluoromethoxy) phenylethylcyclohexanol Dihydrochloride 45 N Cl "Ol 50 OH : OH 55 x"

x" 60 In an analogous manner to Example 24, 1-(1R)-2-(4- methylpiperazin-1-yl)-1-3-(trifluoromethoxy)phenyl In an analogous manner to Example 1, step 2 1-(1R)-2- ethylcyclohexanol dihydrochloride was prepared from, 1 piperazin-1-yl-1-3-(trifluoromethoxy)phenyl (1R)-2-piperazin-1-yl-1-3-(trifluoromethoxy)phenyl ethylcyclohexanol dihydrochloride was prepared from tert 65 ethylcyclohexanol (See Example 244). HRMS: calcd for butyl 4-(2S)-2-(1-hydroxycyclohexyl)-2-3- CHFNO+H, 387.22594; found (ESI, M+H"), (trifluoromethoxy)phenyl)acetylpiperazine-1-carboxylate 387.2269.

US 7,419,980 B2 163 164 Example 260 resulted in the isolation of 1.3 g (67%) of 2-(2,2-Dibromo vinyl)-benzobthiophene as a yellow oil, which was used as 1-1-(5-chloro-1-benzothien-3-yl)-2-piperazin-1- Such in the next step. ylethylcyclohexanol Dihydrochloride Step 2: A 50 mL round bottom flask was charged with 2-(2,2-dibromo-vinyl)-benzobthiophene (1.0 g, 3.17 mmol), tert-butyl 1-piperazinecarboxylate (0.09 g, 4.76 mmol) and potassium hydroxide (0.71 g, 12.5 mmol). A solu tion of tetrahydrofuran:water (4:1) was added and the solu tion was heated to 70° C. for 18 hours. At the end of this time 10 the solution was concentrated and the residue was diluted OH with a 2N aqueious solution of hydrochloric acid and extracted 3 times with ethyl acetate. The ethyl acetate was dried and concentrated and the residue subjected chromatog 15 raphy via Biotage (FLASH 40 M, silica, 60% ethyl acetate/ hexane) to yield 0.75 g (65%) of tert-butyl 4-2-(1-ben Zothien-2-yl)-1-hydroxyethylpiperazine-1-carboxylate as Step 1: In an analogous manner to Example 1 step 1. an off white solid. MS (ES) m/z 3.05.1; HRMS: calcd for tert-butyl 4-(5-chloro-1-benzothien-3-yl)acetylpiperazine C19H26N2O3S,362.1664; found (ESI, M+H+),361.1569. Step 3: In an analogous manner to Example 141 step 3. 1-carboxylate was prepared from 5-chlorobenzothiophene-3- tert-butyl 4-(1-benzothien-2-yl)-2-(1-hydroxycyclohexyl) acetic acid and tert-butyl 1-piperazinecarboxylate. MS (ES) acetylpiperazine-1-carboxylate was prepared from tert-butyl m/z 395.0; HRMS: calcd for C19H23CIN2O3S, 394.1118; 4-2-(1-benzothien-2-yl)-1-hydroxyethylpiperazine-1-car found (ESI, M+H+), 395.1201. boxylate and used as such in the next step. Step 2: In an analogous manner to Example 141 step 3. 25 Step 4: In an analogous manner to Example 135, Step 2. tert-butyl 4-(5-chloro-1-benzothien-3-yl)-2-(1-hydroxycy tert-butyl 4-(1-benzothien-2-yl)-2-(1-hydroxycyclohexyl) clohexyl)acetylpiperazine-1-carboxylate was prepared from ethylpiperazine-1-carboxylate was prepared from tert-butyl tert-butyl 4-(5-chloro-1-benzothien-3-yl)acetylpiperazine 4-(1-benzothien-2-yl)-2-(1-hydroxycyclohexyl)acetylpip 1-carboxylate. erazine-1-carboxylate. Step 3: In an analogous manner to Example 135 Step 2. 30 Step 5: In an analogous manner to Example 135 step 4, tert-butyl 4-(5-chloro-1-benzothien-3-yl)-2-(1-hydroxycy 1-1-(1-benzothien-2-yl)-2-piperazin-1-ylethylcyclohex clohexyl)ethylpiperazine-1-carboxylate was prepared from anol dihydrochloride was prepared from tert-butyl 4-(1-ben tert-butyl 4-(5-chloro-1-benzothien-3-yl)-2-(1-hydroxycy Zothien-2-yl)-2-(1-hydroxycyclohexyl)ethylpiperazine-1- clohexyl)acetylpiperazine-1-carboxylate. carboxylate. MS (ES) m/z 345.2; HRMS: calcd for Step 4: In an analogous manner to Example 135 Step 4, 35 C20H28N2OS+H, 345.20006; found (ESI, M+H+), 1-1-(5-chloro-1-benzothien-3-yl)-2-piperazin-1-ylethylcy 345-199. clohexanol dihydrochloride was prepared from tert-butyl 4-(5-chloro-1-benzothien-3-yl)-2-(1-hydroxycyclohexyl) Example 262 ethylpiperazine-1-carboxylate and isolated as a colorless powder. MS m/z. 379; HRMS: calcd for C20H27CIN2OS+H, 40 1-(2-piperazin-1-yl-1-quinolin-3-ylethyl)cyclohex 379. 16108; found (ESI, M+H+),379. 1607. anol Dihydrochloride Example 261

1-1-(1-benzothien-2-yl)-2-piperazin-1-ylethylcy 45 clohexanoldihydrochloride

50

OH 55 Step 1: In an analogous manner to Example 261 step 1. 3-(2,2-Dibromo-vinyl)-quinoline was prepared from quino line-3-carboxaldehyde. Step 2: In an analogous manner to Example 261 step 2. 60 tert-butyl 4-(quinolin-3-ylacetyl)piperazine-1-carboxylate Step 1: A solution of benzobthiophene-2-carbaldehyde was prepared from 3-(2,2-Dibromo-vinyl)-quinoline. MS (1.0 g. 6.17 mmol) and carbon tetrabromide (3.1 g, 9.25 m/z. 356; HRMS: calcd for C20H25N3O3, 355.1896; found mmol) in methylene chloride (50 mL) was cooled to 0°C. A (ESI, M+H+), 356.1963. solution of triphenylphosphine (4.86 g. 18.3 mmol) in meth Step 3: In an analogous manner to Example 261 step 3. ylene chloride (20 mL) was added dropwise. After /2 hour the 65 tert-butyl 4-(2-quinoline-3-yl)-2-(1-hydroxycyclohexyl) Solution was placed on a plug of silica gel and eluted with acetylpiperazine-1-carboxylate was prepared from tert-butyl 20% ethyl acetate:hexane. Concentration of the eluent 4-(quinolin-3-ylacetyl)piperazine-1-carboxylate. US 7,419,980 B2 165 166 Step 4: In an analogous manner to Example 261 step 4, Step 6: In an analogous manner to Example 135 step 3. tert-butyl 4-(2-quinoline-3-yl)-2-(1-hydroxycyclohexyl) tert-butyl 4-2-4-(benzyloxy)-3-(trifluoromethyl)phenyl-2- ethylpiperazine-1-carboxylate was prepared from tert-butyl (1-hydroxycyclohexyl)ethylpiperazine-1-carboxylate was 4-(2-quinoline-3-yl)-2-(1-hydroxycyclohexyl)acetylpip prepared from tert-butyl 4-4-(benzyloxy)-3-(trifluorom erazine-1-carboxylate. ethyl)phenyl(1-hydroxycyclohexyl)acetylpiperazine-1- Step 5: In an analogous manner to Example 261 step 5. 1-(2-piperazin-1-yl-1-quinolin-3-ylethyl)cyclohexanol dihy carboxylate. MS (ES) m/z 563.1; HRMS: calcd for drochloride was prepared from tert-butyl 4-(2-quinoline-3- C31H41F3N2O4, 562.3018; found (ESI, M+H+), yl)-2-(1-hydroxycyclohexyl)ethylpiperazine-1-carboxy 563.3096. late. MS m/z 340; HRMS: calcd for C21H29N3O+H, 10 Step 7: In an analogous manner to Example 135 step 4, 340.23889; found (ESI, M+H+), 340.2402. 1-1-4-(benzyloxy)-3-(trifluoromethyl)phenyl-2-piper azin-1-ylethylcyclohexanol dihydrochloride was prepared Example 263 from tert-butyl 4-2-4-(benzyloxy)-3-(trifluoromethyl)phe nyl-2-(1-hydroxycyclohexyl)ethylpiperazine-1-carboxy 1-1-4-(benzyloxy)-3-(trifluoromethyl)phenyl-2- 15 late. MS (ES) m/z 463.0; HRMS: calcd for piperazin-1-ylethylcyclohexanol Dihydrochloride C26H33F3N2O2+H, 463.25724; found (ESI, M+H+), 463,2554. Example 264 1-1-4-(benzyloxy)-3-(trifluoromethyl)phenyl-2-(4- O methylpiperazin-1-yl)ethylcyclohexanol Dihydro OH chloride

25

BO CF 30 O OH Step 1: A solution of 2-trifluoromethyl phenyl (5.0 g, 30.86 mmol) and hexamethylenetetramine (8.64 g. 61.72 mmol) in trifluoracetic acid (50 mL) was heated at 65° C. for 18 h. At the end of this time the solution was concentrated and diluted 35 with a 2N aqueious solution of hydrochloric acid. The acid phase was extracted twice with ethyl acetate and the com BO CF bined organic extract dried over magnesium sulfate and con centrated. The residue was subjected to chromatography via Biotage (FLASH 40 M, silica, 20% ethyl acetate/hexane) to 40 In an analogous manner to Example 24, 1-1-4-(benzy yield 2.1 g (36%) of 4-hydroxy-3-(trifluoromethyl)benzalde loxy)-3-(trifluoromethyl)phenyl-2-(4-methylpiperazin-1- hyde. MS (ES) m/z 188.9; HRMS: calcd for C8H5F3O2, yl)ethylcyclohexanol dihydrochloride was prepared from 190.0242; found (ESI, M+H+), 191.0324. tert-butyl 4-2-4-(benzyloxy)-3-(trifluoromethyl)phenyl-2- Step 2: A solution of 4-hydroxy-3-(trifluoromethyl)ben (1-hydroxycyclohexyl)ethylpiperazine-1-carboxylate. MS Zaldehyde (1.5 g, 8.0 mmol), benzyl bromide (1.51 g, 8.8 45 (ES) m/z 477.1; HRMS: calcd for C27H35F3N2O2+H, mmol) and potassium carbonate (1.66 g, 12.0 mmol) in dim 477.27289; found (ESI, M+H+), 477.2711. ethyl formamide (20 mL) was stirred water (100 mL) and extracted 3 times with ethyl acetate. The ethyl acetate extracts Example 265 were combined and washed 2 times with water and dried over magnesium Sulfate. Concentration in vacuo yielded 1.7 g of 50 1-1-4-(benzyloxy)-3-bromophenyl-2-(4-meth 4-benzyloxy-3-trifluoromethyl-benzaldehyde which was ylpiperazin-1-yl)ethylcyclohexanol Dihydrochloride used as Such in the next step. Step 3: In an analogous manner to Example 261 step 1. 1-benzyloxy-4-(2,2-dibromo-vinyl)-2-trifluoromethyl-ben Zene was prepared from 4-benzyloxy-3-trifluoromethyl-ben 55 Zaldehyde. Step 4: In an analogous manner to Example 261, Step 2. tert-butyl 4-4-(benzyloxy)-3-trifluoromethylphenyl acetylpiperazine-1-carboxylate was prepared 1-benzyloxy OH 4-(2,2-dibromo-vinyl)-2-trifluoromethyl-benzene. 60 Step 5: In an analogous manner to Example 135 Step 2. tert-butyl 4-4-(benzyloxy)-3-(trifluoromethyl)phenyl(1- hydroxycyclohexyl)acetylpiperazine-1-carboxylate was prepared from tert-butyl 4-4-(benzyloxy)-3-trifluorometh BO Br ylphenyl)acetylpiperazine-1-carboxylate. MS (ESI) m/z. 65 577; HRMS: calcd for C31H39F3N2O5, 576.2811; found (ESI, M+H+), 577.2901. US 7,419,980 B2 167 168 Step 1: In an analogous manner to Example 263 step 2. Example 267 4-benzyloxy-3-bromo-benzaldehyde was prepared from 3-bromo-4-hydroxy-benzaldehyde. 2-(benzyloxy)-5-1-(1-hydroxycyclohexyl)-2-(4- Step 2: In an analogous manner to Example 261 step 1. methylpiperazin-1-yl)ethylbenzonitrile Dihydro 1-benzyloxy-4-(2,2-dibromo-vinyl)-2-bromo-benzene was chloride prepared from 4-benzyloxy-3-bromo-benzaldehyde. Step 3: In an analogous manner to Example 261 step 2. tert-butyl 4-4-(benzyloxy)-3-bromophenyl acetylpiperazine-1-carboxylate was prepared from 1-benzy 10 loxy-4-(2,2-dibromo-vinyl)-2-bromo-benzene. MS (ES) m/z. 432.9; HRMS: calcd for C24H29BrN2O4, 488.1311; found (ESI, M+H+), 489.1394. OH Step 4: In an analogous manner to Example 135 Step 2. tert-butyl 4-4-(benzyloxy)-3-bromophenyl(1-hydroxycy 15 clohexyl)acetylpiperazine-1-carboxylate was prepared from, tert-butyl 4-4-(benzyloxy)-3-bromophenyl acetylpiperazine-1-carboxylate. MS (ES) m/z 587.0; BO CN HRMS: calcd for C30H39BrN2O5, 586.2042; found (ESI, M+H+), 587.2139. In an analogous manner to Example 24, 2-(benzyloxy)-5- Step 5: In an analogous manner to Example 135 Step 3. 1-(1-hydroxycyclohexyl)-2-(4-methylpiperazin-1-yl)ethyl tert-butyl 4-4-(benzyloxy)-3-bromophenyl(1-hydroxycy benzonitrile dihydrochloride was prepared from 2-(benzy clohexyl)ethylpiperazine-1-carboxylate was prepared from loxy)-5-1-(1-hydroxycyclohexyl)-2-piperazin-1-ylethyl tert-butyl 4-4-(benzyloxy)-3-bromophenyl(1-hydroxycy 25 benzonitrile dihydrochloride (See Example 267). MS m/z. clohexyl)acetylpiperazine-1-carboxylate. 434; HRMS: calcd for C27H35N3O2+H, 434.28075; found Step 6: In an analogous manner to Example 24, 1-1-4- (ESI, M+H+), 434.2821. (benzyloxy)-3-bromophenyl-2-(4-methylpiperazin-1-yl) Example 268 ethylcyclohexanol dihydrochloride was prepared from tert butyl 4-4-(benzyloxy)-3-bromophenyl(1- 30 1-1-4-(benzyloxy)-3-(trifluoromethoxy)phenyl-2- hydroxycyclohexyl)ethylpiperazine-1-carboxylate. MS piperazin-1-ylethylcyclohexanol Dihydrochloride (ES) m/z 487.0; HRMS: calcd for C26H35BrN2O2+H, 487. 19601; found (ESI, M+H+), 487. 1978. Example 266 35 2-(benzyloxy)-5-1-(1-hydroxycyclohexyl)-2-piper C azin-1-ylethylbenzonitrile Dihydrochloride OH 40

BO O O 45 W OH FC

Step 1: Inananalogous manner to Example 263 step 14-hy 50 droxy-3-(trifluoromethoxy)benzaldehyde. was prepared from 2-trifluoromethoxyphenyl. MS (ES) m/z. 204.9; HRMS: BO CN calcd for C8H5F3O3, 206.0191; found (ESI, M+H+), 2O7.0279. Step 2: In an analogous manner to Example 263 step 2. Step 1: In an analogous manner to Example 160, step 1. 55 4-benzyloxy-3-trifluoromethoxy-benzaldehyde was pre tert-butyl 4-4-(benzyloxy)-3-cyanophenyl(1-hydroxycy pared from 4-hydroxy-3-(trifluoromethoxy)benzaldehyde. clohexyl)ethylpiperazine-1-carboxylate was prepared from Step 3: In an analogous manner to Example 261 step 1. tert-butyl 4-4-(benzyloxy)-3-bromophenyl(1-hydroxycy 1-benzyloxy-4-(2,2-dibromo-vinyl)-2-(trifluoromethoxy)- clohexyl)ethylpiperazine-1-carboxylate (See Example 265, benzene was prepared from 4-benzyloxy-3-trifluo step5). 60 romethoxy-benzaldehyde. HRMS: calcd for Step 2: In an analogous manner to Example 135, step 4, C16H11 Br2F3O2, 449.9078; found (EI, M+.), 449.9079. 2-(benzyloxy)-5-1-(1-hydroxycyclohexyl)-2-piperazin-1- Step 4: In an analogous manner to Example 261, Step 2. ylethylbenzonitrile dihydrochloride was prepared from tert tert-butyl 4-4-(benzyloxy)-3-trifluoromethoxyphenyl butyl 4-4-(benzyloxy)-3-cyanophenyl(1-hydroxycyclo acetylpiperazine-1-carboxylate was prepared 1-benzyloxy hexyl)ethylpiperazine-1-carboxylate. MS (ES) m/z 420.1; 65 4-(2,2-dibromo-vinyl)-2-(trifluoromethoxy)-benzene. HRMS: calcd for C26H33N3O2+H,420.26510; found (ESI, Step 5: In an analogous manner to Example 135 step 2. M+H+), 420.263. tert-butyl 4-4-(benzyloxy)-3-(trifluoromethoxy)phenyl(1-

US 7,419,980 B2 171 172 Example 273 In an analogous manner to Example 1, step 1, tert-butyl 4-(4-aminopiperidin-1-yl)-3-(3-chlorophenyl)-2- 4-2-(3-chlorophenyl)-3-hydroxy-3-methylbutanoylpipera methylbutan-2-ol Dihydrochloride Zine-1-carboxylate was prepared from 2-(3-chlorophenyl)-3- hydroxy-3-methylbutanoic acid (Reference Example 1-ggg) HN and tert-butyl 1-piperazinecarboxylate. MS (ESI) m/z 397.0. In an analogous manner to Example 1, step 2, 3-(3-chlo rophenyl)-2-methyl-4-piperazin-1-ylbutan-2-ol dihydro chloride was prepared from 1 tert-butyl 4-2-(3-chlorophe 10 nyl)-3-hydroxy-3-methylbutanoylpiperazine-1- carboxylate. MS (ES) m/z 283.0; HRMS: calcd for HO C15H23CIN2O+H, 283.15772: found (ESI, M+H+), 283.1581.

C 15 In an analogous manner to Example 1, Step 1 tert-butyl Example 276 {1-2-(3-chlorophenyl)-3-hydroxy-3-methylbutanoylpip 3-(3-chlorophenyl)-2-methyl-4-(4-methylpiperazin eridin-4-yl)carbamate was prepared from 2-(3-chlorophe 1-yl)butan-2-ol Dihydrochloride nyl)-3-hydroxy-3-methylbutanoic acid (Reference Example 1-ggg) and 4-N-boc-aminopiperidine. MS (ESI) m/z. 411.0. In an analogous manner to Example 1, Step 24-(4-aminopi peridin-1-yl)-3-(3-chlorophenyl)-2-methylbutan-2-ol dihy ON drochloride was prepared from tert-butyl {1-2-(3-chlo rophenyl)-3-hydroxy-3-methylbutanoylpiperidin-4- y1}carbamate. MS (ESI) m/z 297; HRMS: calcd for 25 C16H25CIN2O+H, 297.17337; found (ESI, M+H+), HO 297.1734.

Example 274 C 3-(3-chlorophenyl)-4-4-(dimethylamino)piperidin 30 In an analogous manner to Example 24, 3-(3-chlorophe 1-yl)-2-methylbutan-2-ol Dihydrochloride nyl)-2-methyl-4-(4-methylpiperazin-1-yl)butan-2-ol dihy drochloride was prepared from 3-(3-chlorophenyl)-2-me thyl-4-piperazin-1-ylbutan-2-ol dihydrochloride (See N 1 35 Example 275). MS (ES) m/z 297.0; HRMS: calcd for C16H25CIN2O+H, 297.17337; found (ESI, M+H+), O 297.1719. Example 277 40 1-1-(3-chlorophenyl)-2-piperazin-1-ylethyl-3,3,5,5- tetramethylcyclohexanol Dihydrochloride

cxC In an analogous manner to Example 24, 3-(3-chlorophe 45 nyl)-4-4-(dimethylamino)piperidin-1-yl)-2-methylbutan-2- ON ol dihydrochloride was prepared from 4-(4-aminopiperidin 1-yl)-3-(3-chlorophenyl)-2-methylbutan-2-ol dihydrochloride (See Example 273). MS (ESI) m/z 325: HRMS: calcd for C18H29CIN2O+H, 325.20467: found 50 HO (ESI, M+H+), 325.2063.

Example 275 C 3-(3-chlorophenyl)-2-methyl-4-piperazin-1-ylbutan In an analogous manner to Example 1, step 1, tert-butyl 2-ol Dihydrochloride 55 4-(3-chlorophenyl)(1-hydroxy-3,3,5,5-tetramethylcyclo hexyl)acetylpiperazine-1-carboxylate was prepared from 3-chlorophenyl)(1-hydroxy-3,3,5,5-tetramethylcyclohexyl) acetic acid (Reference Example 1-hhh) and tert-butyl 1-pip N erazinecarboxylate. O 60 In an analogous manner to Example 1, step 2, 1-1-(3- chlorophenyl)-2-piperazin-1-ylethyl-3,3,5,5-tetramethylcy clohexanol dihydrochloride was prepared from tert-butyl HO 4-(3-chlorophenyl)(1-hydroxy-3,3,5,5-tetramethylcyclo 65 hexyl)acetylpiperazine-1-carboxylate. MS (ES) m/z. 379.3: HRMS: calcd for C22H35CIN2O+H, 379,25161; found C (ESI, M+H+), 379.2527. US 7,419,980 B2 173 174 Example 278 Example 280 1-1-(3-chlorophenyl)-2-(4-methylpiperazin-1-yl) 1-2-(4-aminopiperidin-1-yl)-1-(5-methoxy-1-ben ethyl-3,3,5,5-tetramethylcyclohexanol Dihydrochlo Zothien-3-yl)ethylcyclohexanol Dihydrochloride ride

NH2 O 10

15 HO HO

C In an analogous manner to Example 1, step 1, tert-butyl 4-(1-hydroxycyclohexyl)(5-methoxy-1-benzothien-3-yl) In an analogous manner to Example 24, 1-1-(3-chlorophe acetylpiperidine-4-yl carbamate was prepared from (1-hy nyl)-2-(4-methylpiperazin-1-yl)ethyl-3,3,5,5-tetramethyl droxy-cyclohexyl)-(5-methoxy-benzobthiophen-3-yl)- cyclohexanol dihydrochloride was prepared from 1-1-(3- acetic acid (Reference Example 1-iii) and 4-N-boc chlorophenyl)-2-piperazin-1-ylethyl-3,3,5,5- 25 aminopiperidine. tetramethylcyclohexanol dihydrochloride (See Example In an analogous manner to Example 1, step 2, 1-2-(4- 277). MS (ESI) m/z 393; HRMS: calcd for C23H37CIN2O+ aminopiperidin-1-yl)-1-(5-methoxy-1-benzothien-3-yl) H, 393.26727; found (ESI, M+H+), 393.2653. ethylcyclohexanol dihydrochloride was prepared from, tert 30 butyl 4-(1-hydroxycyclohexyl)(5-methoxy-1-benzothien-3- yl)acetylpiperidine-4-yl carbamate. MS (ES) m/z. 389.0: HRMS: calcd for C22H32N2O2S+H, 389.22627; found Example 279 (ESI, M+H+), 389.2262. 1-1-(5-methoxy-1-benzothien-3-yl)-2-piperazin-1- 35 Example 281 ylethylcyclohexanol Dihydrochloride 1-1-(4-bromothien-2-yl)-2-piperazin-1-ylethylcy clohexanol Dihydrochloride 40 No C N

45

OH HO

In an analogous manner to Example 1, step 1, tert-butyl 50 4-(1-hydroxycyclohexyl)(5-methoxy-1-benzothien-3-yl) acetylpiperazine-1-carboxylate was prepared from (1-hy droxy-cyclohexyl)-(5-methoxy-benzobthiophen-3-yl)- Step 1: In an analogous manner to Example 261 step 1. acetic acid (Reference Example 1-iii) and tert-butyl 55 4-bromo-2-(2,2-dibromovinyl)thiophene was prepared from 1-piperazinecarboxylate. MS (ES) m/z. 489.0. 4-bromo-2-thiophenecarboxaldehyde. Step 2: In an analogous manner to Example 261 step 2. tert-butyl 4-(4-bromothien-2-yl)acetylpiperazine-1-car boxylate was prepared from 4-bromo-2-(2,2-dibromovinyl) In an analogous manner to Example 1, step 2, 1-1-(5- 60 methoxy-1-benzothien-3-yl)-2-piperazin-1-ylethylcyclo thiophene. hexanol dihydrochloride was prepared tert-butyl 4-(1-hy Step 3: In an analogous manner to Example 135 step 2. droxycyclohexyl)(5-methoxy-1-benzothien-3-yl)acetyl tert-butyl 4-2-(4-Bromo-thiophen-2-yl)-2-(1-hydroxy-cy clohexyl)-acetyl-piperazine-1-carboxylate was prepared piperazine-1-carboxylate. MS (ES) m/z. 375.1; HRMS: calcd 65 for C21H3ON2O2S+H, 375.21062; found (ESI, M+H+), from tert-butyl 4-(4-bromothien-2-yl)acetylpiperazine-1- 375.2117. carboxylate.

US 7,419,980 B2 183 184 Example 298 In an analogous manner to Example 24, 1-1-(3-ethy nylphenyl)-2-(4-methylpiperazin-1-yl)ethylcyclohexanol 1-1-(3-ethynylphenyl)-2-piperazin-1-ylethylcyclo dihydrochloride was prepared from 1-1-(3-ethynylphenyl)- hexanol Dihydrochloride 2-piperazin-1-ylethylcyclohexanol (Example 298). MS (ESI) m/z 327 (M+H"); HRMS: calcd for CHNO+H, 327.2436; found (ESI, M+H"), 327.2425. Example 300 O 10 1-2-piperazin-1-yl-1-(3-prop-1-ynylphenyl)ethyl OH cyclohexanol Dihydrochloride

15 "O OH

In an analogous manner to Example 162, step 1, tert-butyl 4-(2-(1-hydroxycyclohexyl)-2-3-(trimethylsilyl)ethynyl phenyl)ethyl)piperazine-1-carboxylate was prepared from tert-butyl 4-2-(3-bromophenyl)-2-(1-hydroxycyclohexyl) ethylpiperazine-1-carboxylate (Example 135, step 2) using (trimethylsilylethynyl)tributyltin. MS (ESI) m/z. 485 (IM+ 25 HI"); HRMS: calcd for CHNOSi+H, 485.3200; found (ESI, M+H"), 485.3202. In an analogous manner to Example 162, step 1, tert-butyl To a solution of tert-butyl 4-(2-(1-hydroxycyclohexyl)-2- 4-2-(1-hydroxycyclohexyl)-2-(3-prop-1-ynylphenyl)ethyl {3-(trimethylsilyl)ethynylphenylethyl)piperazine-1-car piperazine-1-carboxylate was prepared from tert-butyl 4-2- boxylate (104 mg. 0.215 mmol) in methanol (3 mL) was 30 (3-bromophenyl)-2-(1-hydroxycyclohexyl)ethylpiperazine added potassium carbonate (300 mg, 2.17 mmol) and the 1-carboxylate (Example 135, step 2) using (1-propynyl) mixture was stirred for 30 min at room temperature. The tributyltin. MS (ESI) m/z 427 (M+H"); HRMS: calcd for reaction mixture was quenched with aqueous ammonium chloride (5 mL) and extracted with ethyl acetate. The organic CHsNO+H, 427.2961; found (ESI, M+H"), 427.2967. layer was washed with water, brine, dried (sodium sulfate), 35 In an analogous manner to Example 135, step 4, 1-2- filtered and concentrated to give a crude oil, which was puri piperazin-1-yl-1-(3-prop-1-ynylphenyl)ethylcyclohexanol fied via silica gel flash chromatography (gradient from 10% dihydrochloride was prepared from tert-butyl 4-2-(1-hy ethyl acetate/hexane to 30% ethyl acetate/hexane) to yield 70 droxycyclohexyl)-2-(3-prop-1-ynylphenyl)ethylpiperazine mg (80%) tert-butyl 4-2-(3-ethynylphenyl)-2-(1-hydroxy 1-carboxylate. MS (ESI) m/z 327 (M+H"); HRMS: calcd cyclohexyl)ethylpiperazine-1-carboxylate as a white solid. 40 for CHNO+H, 327.2436; found (ESI, M+H"), MS (ESI) m/z 413 (M+H"); HRMS: calcd for 327.2421. CHNO+H, 413.2804; found (ESI, M+H"), 413.2809. In an analogous manner to Example 135, step 4, 1-1-(3- Example 301 ethynylphenyl)-2-piperazin-1-ylethylcyclohexanol dihy 1-2-(4-methylpiperazin-1-yl)-1-(3-prop-1-ynylphe drochloride was prepared from tert-butyl 4-2-(3-ethynylphe 45 nyl)-2-(1-hydroxycyclohexyl)ethylpiperazine-1- nyl)ethylcyclohexanol Dihydrochloride carboxylate. MS (ESI) m/z. 313 (M+H"); HRMS: calcd for CHNO+H, 313.2280; found (ESI, M+H"), 313.2280. Example 299 50

1-1-(3-ethynylphenyl)-2-(4-methylpiperazin-1-yl) OH ethylcyclohexanol Dihydrochloride

55

OH 60 In an analogous manner to Example 24, 1-2-(4-meth ylpiperazin-1-yl)-1-(3-prop-1-ynylphenyl)ethylcyclohex anol dihydrochloride was prepared from 1-2-piperazin-1-yl 65 1-(3-prop-1-ynylphenyl)ethylcyclohexanol (Example 300). HRMS: calcd for CHNO+H, 341.2593; found (ESI, M+H"), 341.2585. US 7,419,980 B2 185 186 Example 302 Example 304 1-2-(4-benzyl-1,4-diazepan-1-yl)-1-4(trifluo 1-2-piperazin-1-yl-1-4-(trifluoromethoxy)phenyl romethoxy)phenylethylcyclohexanol Dihydrochlo ethylcyclobutanol Dihydrochloride ride

10 C O OH OH

15 FCO FCO In an analogous manner to Example 1, Step 1 tert-butyl In an analogous manner to Example 1, step 1 1-2-(4- benzyl-1,4-diazepan-1-yl)-1-4-(trifluoromethoxy)phenyl 4-(1-hydroxycyclobutyl)-4-(trifluoromethoxy)phenyl 2-oxoethylcyclohexanol was prepared from (1-hydroxycy acetylpiperazine-carboxylate was prepared from (1-hy clohexyl)-4-(trifluoromethoxy)phenyl)acetic acid doxycyclobutyl)4-trifluoromethoxy)phenyl)acetic acid (Reference Example 1-g) and 1-benzyl-homopiperazine. (Reference Example 1-aaa) and tert-butyl 1-piperazincar MS(ESI) m/z 491 (M+H". 25 boxylate. MS(ESI) m/z 459 (IM+H"). In an analogous manner to Example 1 step 2 1-2-(4- In an analogous manner to Example 1, step 21-2-piper benzyl-1,4-diazepan-1-yl)-1-4-(trifluoromethoxy)phenyl azin-1-yl-1-4-(trifluoromethoxy)phenyl ethylcyclohexanol dihydrochloride was prepared from ethylcyclobutanol dihydrochloride was prepared from 1 1-2-(4-benzyl-1,4-diazepan-1-yl)-1-4-(trifluoromethoxy) tert-butyl 4-(1-hydroxycyclobutyl)4-(trifluoromethoxy) phenyl)-2-oxoethylcyclohexanol. 30 phenyl)acetylpiperazine-carboxylate. MS(ESI) m/z 345 MS(ESI) m/z 477 (IM+H"). Anal Calcd for (IM+H"). Anal Calcd for CHFNO2HCl 0.5H2O: C, CHFNO2HCl 1HO: C, 57.14; H, 6.93: N, 4.94. 47.90; H, 6.15: N, 6.57. Found: C, 47.81; H, 5.92: N, 6.43. Found: C, 57.02; H, 7.44; N, 4.98. 35 Example 305 Example 303 1-2-(4-aminopiperidin-1-yl)-1-4-(trifluo 1-2-(4-aminopiperidin-1-yl)-1-4-(trifluo romethoxy)phenylethylcyclobutanol Dihydrochlo romethoxy)phenylethylcyclohexanol Dihydrochlo ride ride 40

HN HN 45

OH OH

50 FCO FCO In an analogous manner to Example 1, Step 1 tert-butyl In an analogous manner to Example 1, Step 1 tert-butyl (1-(1-hydroxycyclohexyl)-4-(trifluoromethoxy)phenyl 55 (1-(1-hydoxycyclobutyl)4-(trifluoromethoxy)phenyl acetylpiperidin-4-yl)carbamate was prepared from (1-hy acetylpiperidin-4-yl)carbamate was prepared from (1-hy droxycyclohexyl)-4-(trifluoromethoxy)phenyl)acetic acid doxycyclobutyl)4-trifluoromethoxy)phenyl)acetic acid (Reference Example 1-g) and 4-N-BOC-aminopiperidine. (Reference Example 1-aaa) and 4-N-BOC-aminopiperidine. MS(ESI) m/z 501(M+H"). 60 MS(ESI) m/z 473 (M+H"). In an analogous manner to Example 1, step 2 1-2-(4- aminopiperidin-1-yl)-1-4-(trifluoromethoxy)phenyl In an analogous manner to Example 1, step 2 1-2-(4- ethylcyclohexanol dihydrochloride was prepared from 1 aminopiperidin-1-yl)-1-4-(trifluoromethoxy)phenyl tert-butyl (1-(1-hydroxycyclohexyl)4-(trifluoromethoxy) ethylcyclobutanol dihydrochloride was prepared from tert phenyl)acetylpiperidin-4-yl)carbamate. MS(ESI) m/z 387 65 butyl (1-(1-hydoxycyclobutyl)-4-(trifluoromethoxy) (M+H"). Anal Calcd for CHFNO2HCl: C, 52.29; H, phenyl)acetylpiperidin-4-yl)carbamate. MS(ESI) m/z. 359 6.80: N, 6.10. Found: C, 52.22; H, 6.98: N, 5.98. (IM+H").