US007576207B2

(12) United States Patent (10) Patent No.: US 7,576,207 B2 DOlle et al. (45) Date of Patent: Aug. 18, 2009

(54) SPIROCYCLIC HETEROCYCLIC 2004/0082612 A1 4/2004 Baxter et al...... 514,317 DERVATIVES AND METHODS OF THEIR 2004/0106652 A1 6/2004 Hamilton et al...... 514,355 USE 2005. O159438 A1 7/2005 Dolle et al...... 514,278 (75) Inventors: Roland E. Dolle, King of Prussia, PA 2006/027O695 A1 11, 2006 Dole et al. (US); Bertrand Le Bourdonnec, East 2008.0102031 A1 5/2008 Dolle et al. Fallowfield, PA (US); Guo-Hua Chu, 2008/01 19452 A1 5/2008 Dolle et al. Exton, PA (US) (73) Assignee: Adolor Corporation, Exton, PA (US) FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 CN 1390221 A1 1, 2003 U.S.C. 154(b) by 191 days. EP O 420 266 A3 4f1991 EP O 362 119 B1 7, 1993 (21) Appl. NO. 11/696,585 EP O 600 147 A1 6, 1994 (22) Filed: Apr. 4, 2007 EP O401958 B1 1, 1995 EP O 376 524 B1 3, 1995 (65) Prior Publication Data EP O 708 164 A3 4f1996 US 2007/O269374A1 Nov. 22, 2007 EP O 582338 B1 10, 1999 EP 1179 551 A1 2, 2002 Related U.S. Application Data EP O 864. 559 B1 6, 2002 (60) Provisional application No. 60/790.416, filed on Apr. JP 4-27.5288 A 9, 1992 6, 2006. JP 9-30 1973 11, 1997 WO 93.17026 A1 9, 1993 (51) Int. C. WO 93/19755 A1 10, 1993 C07D 401/00 (2006.01) WO 94, 17045 A1 8, 1994 AOIN 43/42 (2006.01) WO 95,04734 A1 2, 1995 U.S. Cl...... 54.6/17: 514/278 (52) WO 95.31464 A1 11, 1995 (58) Field of Classification Search ...... 546/17: 514/278 WO 96.22276 A1 T 1996 See application file for complete search history. WO 97.10216 A1 3, 1997 WO WO9828275 7, 1998 (56) References Cited U.S. PATENT DOCUMENTS 5,106,998 4, 1992 Tanaka et al...... 549,331 (Continued) 5,132,307 7, 1992 Baumgarth et al...... 514,247 5,349,065 9, 1994 Tanaka et al...... 546.15 OTHER PUBLICATIONS 5,354,863 10, 1994 Dappen et al...... 546,35 5,356,915 10, 1994 Almansa et al. . ... 514,357 Yang, Shuzang et al., “Structure-activity relationship of 5,387,587 2, 1995 Häusler et al...... 514,254 as 8 peptides.” Peptides, 2003, 24, 503-508. 5,403,846 4, 1995 Baldwin et al. . ... 514,278 5,628,935 5, 1997 Hughes et al...... 252/589 (Continued) 5,656,420 8, 1997 Chien ...... 435/12 5,705,102 1, 1998 Hughes et al...... 252/375 Primary Examiner D. Margaret Seaman 5,786,378 7, 1998 Hamilton et al. ... 514,423 Assistant Examiner Nizal S Chandrakumar 5.990,131 11, 1999 Hamilton et al. 514,330 (74) Attorney, Agent, or Firm Feldman Gale, P.A.; David A. 6,022,895 2, 2000 Zimmer et al. Cherry 6,031,115 2, 2000 Bell et al...... 549,362 6,040,308 3, 2000 Häusler et al...... 514,253 (57) ABSTRACT 6,153,627 11, 2000 Häusler et al...... 514,337 6,200,978 3, 2001 Maw et al...... 514,254.05 6,218,424 4, 2001 Hamilton et al...... 514,423 6,319,939 11, 2001 Mabire et al...... 514,381 Spirocyclic heterocyclic derivatives, pharmaceutical compo 6,417,209 T/2002 Hamilton et al...... 514,365 sitions containing these compounds, and methods for their 6,436,959 8, 2002 Carson et al...... 514/326 pharmaceutical use are disclosed. In certain embodiments, 6,596,758 T/2003 Brunet et al...... 514,450 the Spirocyclic heterocyclic derivatives are ligands of the 6,645,973 11, 2003 Gibson Ö- and may be useful, inter alia, for treating 7,226,933 6, 2007 Brown et al. and/or preventing pain, anxiety, gastrointestinal disorders, 7,338,962 3, 2008 Dolle et al...... 514,278 and other Ö-opioid receptor-mediated diseases, disorders, 2001/0056103 12, 2001 Hamilton et al...... 514,327 and/or conditions. 2002fO115653 8, 2002 Mabire et al...... 514,212 2002/0193420 12, 2002 Hamilton et al. ... 514,438 2003, OO69241 A1 4, 2003 Mchardy et al...... 514,241 62 Claims, No Drawings US 7,576,207 B2 Page 2

FOREIGN PATENT DOCUMENTS Dondio, et al., “Central & Peripheral Nervous Systems: Non-Peptide AOpioid And Antagonists.” Exp. Opin. Ther: Patents, 1997. WO 99.04795 A1 2, 1999 7(10), 1075-1098. WO 99.29674 A1 6, 1999 Dorland's Illustrated Medical Dictionary, 27" Ed., W.B. Saunders WO OOf 39113 A1 T 2000 co., Phila., 1988, p. 375. WO 01 3.6423 A1 5, 2001 Dourish, C.T. et al., “Enhancement Of Analgesia And WO Of 46.192 A1 6, 2001 Prevention Of Morphine Tolerance In The Rat By The WO 01f83476 A1 11, 2001 Cholecystokinin Antagonist L-364,718.” Eur: J. Pharmacol., 1988, WO WOO1851.45 11, 2001 147, 469-472. WO O2/48122 A2 6, 2002 Fraser, M.O., “Urinary Incontinence: Neuropharmacological WO 02/094782 A1 11 2002 Approaches.” Annual Reports in Medicinal Chemistry, 2003, Chap WO 02/094783 A1 11 2002 WO 02/094784 A1 11 2002 ter 6, 51-60. WO O2/O94785 A1 11, 2002 Galligan, J.J., et al., “Cerebral Delta Opioid Receptors Mediate Anal WO 02/094786 A1 11 2002 gesia But Not The Intestinal Motility Effects Of WO 02/094794 A1 11 2002 Intracerebroventricularly Administered .” J. Pharm. Exp. WO 02/094810 A1 11 2002 Ther:, 1984, 229(3), 641-648. WO 02/094811 A1 11 2002 Jain, K.K., “A guide to evaluation for chronic pain.” Emerging WO 02/094812 A1 11 2002 , 2000, 5(2), 241-257. WO O3,O292.15 A1 4/2003 Livingston, E.H., et al., “Postoperative Ileus.” Digestive Diseases WO 03/033486 A1 4/2003 and Sciences, 1990, 35(1), 121-132. WO 03/037342 A1 5, 2003 Lord, J.A.H., et al., “Endogenous opioid peptides: multiple agonists WO O3,057223 A1 T 2003 and receptors.” Nature, 1977,267,495-499. WO 93.15062 A1 8, 2003 Mao, J., et al., “Oral Administration Of Dextromethorphan Prevents WO 2004/026819 A2 4/2004 The Development Of Morphine Tolerance And Dependence In Rats.” WO 2004/035541 A1 4/2004 Pain, 1996, 67, 361-368. WO 2004/035574 A2 4/2004 Moreland, R.B., et al., “Emerging Pharmacologic Approaches For WO 2004/041 784 A1 5, 2004 The Treatment Of Lower Urinary Tract Disorders,” J. Pharm. Exp. WO 2004/041800 A1 5, 2004 Ther:, 2004, 308(3), 797-804. WO 2004/041801 A1 5, 2004 Moulin, D.E., et al., “The Efficacy Of Intrathecal D-Ala WO 2004/041802 A1 5, 2004 D-Leu-Enkephalin in Cancer Patients with Chronic Pain.” Pain, WO 2004/060321 A2 T 2004 1985, 23, 213-221. WO 2004/062562 A2 T 2004 Nichols, M.L., et al., “Enhancement of the antiallodynic and WO 2004/063157 A1 7, 2004 antinociceptive efficacy of spinal morphine by antisera to dynorphin WO 2004/063193 A1 T 2004 A (1-13) or MK-801 in a nerve-ligation model of peripheral WO 2004/082612 A1 9, 2004 neuropathy.” Pain, 1997, 69,317-322. WO WO2005O19157 3, 2005 Raynor, K., et al., “Pharmacological Characterization Of The Cloned WO 2005/033073 A2 4/2005 K-, A-, And M-Opioid Receptors.” Molecular , 1994, 45, 330-334. OTHER PUBLICATIONS Resnick, J., “Delayed gastric emptying and postoperative Ileus after Ennaceur, A. et al., “A new one-trial test for neurobiological studies nongastric abdominal Surgery: Part I. Am. J. of Gastroenterology, of memory in rats. 1: Behavioral data.” Behavioural Brain Research, 1997, 92(5), 751-762. 1988, 31, 47-59. Resnick, J., “Delayed gastric emptying and postoperative Ileus after Yang, Shuzhang, et al., “Effect on , a Ö opioid peptide nongastric abdominal Surgery: Part II. Am. J. of Gastroenterology, derived from Rubisco, on memory consolidation.” Peptides (2003), 1997, 92(6), 934-940. 24, 325-328. Schultz, J.J. etal, “Ischemic Preconditioning and Morphine-Induced U.S. Appl. No. 60/507,864, filed Oct. 1, 2003, Roland Dolle. Cardioprotection Involve the delta-Opioid Receptor in the Intact Rat Bhargava, H.N., et al., “Effect of nitric oxide synthase inhibition on Heart'. J. Mol. Cell. Cardiol., 1997, 29, 2187-2195. tolerance to the analgesic action of D-Pen, D-Penenkephalin and Schultz, J.J. et al., “Ischemic Preconditioning is Mediated by a morphine in the mouse.” Neuropeptides, 1996, 30(3), 219-223. Peripheral Opioid Receptor Mechanism in the Intact Rat Heart”. J. Bilsky, E.J., et al., “SNC 80, A Selective. Nonpeptidic And Systemi Mol. Cell. Cardiol., 1997, 29, 1355-1362. cally Active Opioid Delta .” J. of Pharmacology and Experi Tsung-Ping Su, “Delta Opioid Peptide D-Ala. D-Leu Enkephalin mental Therapeutics, 1995, 273(1), 359-366. Promotes Cell Survival.”.J. of Biomedical Science, 2000, 7, 195-199. Bilsky, E.J., et al., “Effects Of And D-Phe-Cys-Tyr-D-Trp Watson, M.J. et al., “ARD-353 4-((2R,5S)-4-(R)-(4- Arg-Thr-Pen-Thr-NH. And The Protein Kinase Inhibitors H7 And Diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl)-2,5- H8. On Acute Morphine Dependence And Antinociceptive Tolerance dimethylpiperazin-1-ylmethyl)benzoic Acid). A Novel Nonpeptide 8 In Mice.” J. of Pharmacol Exp. Ther:, 1996, 277(1), 484-490. Receptor Agonist, Reduces Myocardial Infarct Size without Central Borlongan, C.V., et al., “Delta opioid peptide (D-ALA 2, D-LEU 5) Effects.” J. Pharm. Exp. Ther:, 2006, 316(1), 423-430. enkephalin: linking hibernation and neuroprotection.” Frontiers in Xenopoulos, N.P. et al., “Morphine Mimics Ischemic Precondition Bioscience, Sep. 1, 2004, 9, 3392-3398. ing in Human Myocardium during PTCA'. J. Am. Coll. Cardiol. DeHaven R.N., et al., “Characterization Of Opioid Receptors.” Cur 1998, 31(Suppl. A), 65A-66A, Abstract No. 810-3. rent Protocols in Pharmacology, 2000, John Wiley & Sons, 1.4.1-1. 4.12. * cited by examiner US 7,576,207 B2 1. 2 SPROCYCLIC HETEROCYCLC Pharmacology and Experimental Therapeutics, 1995, 273 DERVATIVES AND METHODS OF THEIR (1), 359-366; WO93/15062, WO95/04734, WO95/31464, USE WO 96/22276, WO 97/10216, WO 01/.461.92, WO 02/094794, WO 02/094810, WO 02/094811, WO 02/094812, CROSS-REFERENCE TO RELATED WO 02/48122, WO 03/029215, WO 03/033486, JP-427.5288, APPLICATIONS EP-A-0,864,559, U.S. Pat. Nos. 5,354,863, 6,200,978, 6,436, 959, and US 2003/0069241. This application claims the benefit of U.S. Provisional While there are a large number of non-peptidic 6-opioid Application Ser. No. 60/790,416, filed Apr. 6, 2006, the dis receptor modulators, there is still an unfulfilled need for com closure of which is incorporated herein by reference in its 10 pounds with selective 8-opioid receptor activity that may be entirety. used in methods to provide beneficial pharmaceutical char acteristics while minimizing undesirable side effects. The FIELD OF THE INVENTION present invention is directed to these, as well as other impor tant ends. The invention relates to spirocyclic heterocyclic deriva 15 tives (including derivatives of spiro (2H-1-benzopyran-2,4'- SUMMARY OF THE INVENTION piperidines and spiro1.2.3,4-tetrahydronaphthalene-2,4'-pi peridines), pharmaceutical compositions containing these Accordingly, the present invention is directed, in part, to compounds, and methods for their pharmaceutical use. In novel spiro(2H-1-benzopyran-2,4'-piperidine and spiro1.2, certain embodiments, the spirocyclic heterocyclic derivatives 3,4-tetrahydronaphthalene-2,4'-piperidine compounds. In are ligands of the Ö-opioid receptor and are useful, interalia, preferred form, the novel compounds of the invention have for treating pain, anxiety, gastrointestinal disorders, and other the following formula I: Ö-opioid receptor-mediated conditions.

BACKGROUND OF THE INVENTION 25 There are at least three different opioid receptors (u, 6, and K) that are present in both central and peripheral nervous systems of many species, including humans. Lord, J. A. H., et al., Nature, 1977,267,495. Activation of the 8-opioid recep 30 tors induces analgesia in various animal models. Moulin, et al., Pain, 1985, 23, 213. Some work suggests that the analge sics working at Ö-opioid receptors do not have the attendant side effects associated with Land Kopioid receptor activation. Galligan, et al., J. Pharm. Exp. Ther., 1985, 229, 641. The 35 Ö-opioid receptor has also been identified as having a role in circulatory systems. Ligands for the Ö-receptor have also been shown to possess immunomodulatory activities. Don wherein: dio, et al., Exp. Opin. Ther. Patents, 1997, 10, 1075. Further, W is alkylene; selective 6-opioid receptor agonists have been shown to pro 40 Z is alkoxy, NR mote organ and cell survival. Su, T-P, Journal of Biomedical - NRS(=O), alkyl: Science, 2000, 9(3), 195-199. The 8-opioid receptor was each R' is independently carboxy, hydroxy, alkoxy, halo, recently recognized to trigger and mimic ischemic precondi aminocarbonyl, N-alkylaminocarbonyl, or N,N-dialky tioning (Schultz, et al., “Ischemic Preconditioning and Mor laminocarbonyl: phine-Induced Cardioprotection Involve the delta-Opioid 45 Receptor in the Intact Rat Heart”. J. Mol. Cell. Cardiol., 29: R’ is NR'R' or alkoxy; 2187-2195, 1997: Schultz, et al., “Ischemic Preconditioning RandR are each independently H or alkyl: is Mediated by a Peripheral Opioid Receptor Mechanism in R is alkyl or NRR: the Intact Rat Heart, J. Mol. Cell. Cardiol., 29:1355-1362, Rand Rare each independently Horalkyl, or RandR 1997). An opioid role in human preconditioning was further 50 taken together with the nitrogen atom to which they are demonstrated by Xenopoulos, et al., “Morphine Mimics connected form a 3- to 8-membered heterocycloalkyl Ischemic Preconditioning in Human Myocardium during ring in which 1 or 2 of the heterocycloalkyl ring carbon PTCA’, J. Am. Coll. Cardiol. 65:65A 1998 with the appli atoms independently may each be optionally replaced cation of intracoronary morphine as a mimic for precondi by -O-, - S - N(R) , N(R)-C(=O) , or tioning. Other reported developments include the use of 55 - C(=O) N(R)–: Ö-opioid receptor agonists to reduce myocardial infarct size R. R. and Rare each independently H or alkyl: (Watson, et al., J. Pharm. Exp. Ther. 316: 423-430 (2006)) X is —CH2—, —S(=O), or —O—; and to reduce ischemic damage or provide cardioprotection A and B are each H, or taken together with the carbon for example, from myocardial infarction (WO 2004/060321 atoms through which they are connected form a double A2: WO99/04795). Ligands for the 8-opioid receptor may 60 bond; therefore find potential use as , antihypertensive each m is independently 0, 1, or 2: agents, immunomodulatory agents, and/or agents for the p and t are each independently 0, 1, or 2; and treatment of cardiac disorders. s is 1 or 2; provided that the sum of p--s is 1, 2, or 3: Numerous selective 6-opioid ligands are peptidic in nature or a pharmaceutically acceptable salt thereof. and thus are unsuitable for administration by Systemic routes. 65 In other embodiments, the present invention is directed to Several non-peptidic 6-opioid receptor ligands have been pharmaceutical compositions, comprising a pharmaceuti developed. See, for example, E. J. Bilsky, et al., Journal of cally acceptable carrier and a compound of formula I. US 7,576,207 B2 3 4 In certain other embodiments, the present invention is Subcombinations of ranges and specific numbers of carbon directed to methods of binding opioid receptors in a patient in atoms therein), wherein alkyl is as previously defined. need thereof, comprising the step of administering to said As used herein, “alkoxy' refers to an optionally substituted patient an effective amount of a compound of formula I. alkyl-O-group wherein alkyl is as previously defined. In These and other aspects of the invention will become more some preferred embodiments, the alkyl moieties of the alkoxy apparent from the following detailed description. groups have from about 1 to about 4, more preferably from about 1 to about 3, carbon atoms. Exemplary alkoxy groups DETAILED DESCRIPTION OF ILLUSTRATIVE include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, EMBODIMENTS and heptoxy. 10 As used herein, “aryl” refers to an optionally substituted, The invention relates to spirocyclic heterocyclic deriva mono-, di-, tri-, or other multicyclic aromatic ring system tives, pharmaceutical compositions containing these com having from about 5 to about 50 carbon atoms (and all com pounds, and methods for their pharmaceutical use. In certain binations and Subcombinations of ranges and specific num embodiments, the Spirocyclic heterocyclic derivatives are bers of carbon atoms therein), with from about 6 to about 10 ligands of the Ö-opioid receptor and may be useful, interalia, 15 carbons being preferred. Non-limiting examples include, for in methods for treating diseases, disorders, and/or conditions example, phenyl, naphthyl, anthracenyl, and phenanthrenyl. that may be mediated or modulated by the 6-opioid receptor As used herein, “aralkyl refers to an optionally substituted including, for example, pain, gastrointestinal disorders, uro moiety composed of an alkyl radical bearing an aryl Substitu genital tract disorders including incontinence and overactive ent, wherein the aralkyl moiety has from about 7 to about 50 bladder, immunomodulatory disorders, inflammatory disor carbon atoms (and all combinations and Subcombinations of ders, respiratory function disorders, anxiety, mood disorders, ranges and specific numbers of carbon atoms therein), with stress-related disorders, attention deficit hyperactivity disor from about 7 to about 11 carbon atoms being preferred. Non ders, sympathetic nervous system disorders, depression, tus limiting examples include, for example, benzyl, diphenylm sis, motor disorders, traumatic injuries, especially to the cen ethyl, triphenylmethyl, phenylethyl, and diphenylethyl. tral nervous system, stroke, cardiac arrhythmias, glaucoma, 25 As used herein, "heteroaryl refers to an optionally substi sexual dysfunctions, shock, brain edema, cerebral ischemia, tuted aryl ring system wherein in at least one of the rings, one cerebral deficits Subsequent to cardiac bypass Surgery and or more of the carbon atom ring members is independently grafting, systemic lupus erythematosus, Hodgkin's disease, replaced by a heteroatom group selected from the group con Sjogren's disease, epilepsy, rejections in organ transplants sisting of S, O, N, and NH, wherein aryl is as previously and skin grafts, and Substance addiction. In certain other 30 defined. Heteroaryl groups having a total of from about 5 to embodiments, the Spirocyclic heterocyclic derivatives are about 14 carbon atom ring members and heteroatom ring ligands of the 6-opioid receptor and may be useful in, inter members (and all combinations and Subcombinations of alia, methods for improving organ and cell Survival, methods ranges and specific numbers of carbon and heteroatom ring for providing cardioprotection, methods for reducing the members) are preferred. Exemplary heteroaryl groups need for anesthesia, methods for producing and/or maintain 35 include, but are not limited to, pyrryl, furyl, pyridyl, pyridine ing an anesthetic state, and methods of detecting, imaging, or N-oxide, 1,2,4-thiadiazolyl pyrimidyl, thienyl, isothiazolyl, monitoring degeneration or dysfunction of opioid receptors imidazolyl, tetrazolyl pyrazinyl, pyrimidyl, quinolyl, iso in a patient. quinolyl, thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl, As employed above and throughout the disclosure, the indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl. following terms, unless otherwise indicated, shall be under 40 Heteroaryl groups may be attached via a carbon or a heteroa stood to have the following meanings. tom to the rest of the molecule. As used herein, “alkyl refers to an optionally substituted, As used herein, “cycloalkyl refers to an optionally substi saturated Straight, or branched, hydrocarbon having from tuted, mono-, di-, tri-, or other multicyclic alicyclic ring sys about 1 to about 10 carbon atoms (and all combinations and 45 tem having from about 3 to about 20 carbon atoms (and all Subcombinations of ranges and specific numbers of carbon combinations and Subcombinations of ranges and specific atoms therein), preferably with from about 1 to about 6, more numbers of carbonatoms therein). In some preferred embodi preferably 1 to about 4, yet more preferably about 1 to about ments, the cycloalkyl groups have from about 3 to about 8 3, with about 2 to about 3 carbonatoms being most preferred. carbon atoms. Multi-ring structures may be bridged or fused Alkyl groups include, but are not limited to, methyl, ethyl, ring structures, wherein the additional groups fused or n-propyl, isopropyl. n-butyl, isobutyl, t-butyl, n-pentyl, iso 50 bridged to the cycloalkyl ring may include optionally Substi pentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, 2.2- tuted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl rings. dimethylbutyl, and 2,3-dimethylbutyl. Exemplary cycloalkyl groups include, but are not limited to, As used herein, “alkenyl refers to an optionally substi cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, tuted alkyl group having from about 2 to about 10 carbon 55 adamantyl, 2-4-isopropyl-1-methyl-7-Oxa-bicyclo[2.2.1 atoms and one or more double bonds (and all combinations heptanyl, and 2-1,2,3,4-tetrahydro-naphthalenyl. and Subcombinations of ranges and specific numbers of car As used herein, “alkylcycloalkyl refers to an optionally bon atoms therein), wherein alkyl is as previously defined. Substituted ring system comprising a cycloalkyl group having As used herein, “alkylene' refers to an optionally substi one or more alkyl Substituents, wherein cycloalkyl and alkyl tuted bivalent alkyl radical having the general formula 60 are each as previously defined. Exemplary alkylcycloalkyl —(CH), , where n is 1 to 10, preferably 1 to 6, with 1 to 4 groups include, for example, 2-methylcyclohexyl, 3.3-dim being most preferred. Non-limiting examples include meth ethylcyclopentyl, trans-2,3-dimethylcyclooctyl, and 4-meth ylene, dimethylene, trimethylene, pentamethylene, and hex yldecahydronaphthalenyl. amethylene. As used herein, "heteroaralkyl refers to an optionally As used herein, “alkynyl refers to an optionally substi 65 Substituted ring system composed of a heteroaryl Substituted tuted alkyl group having from about 2 to about 10 carbon alkyl radical where heteroaryl and alkyl are as previously atoms and one or more triple bonds (and all combinations and defined. Non-limiting examples include, for example, 2-(1H US 7,576,207 B2 5 6 pyrrol-3-yl)ethyl 3-pyridylmethyl, 5-(2H-tetrazolyl)methyl, hydroxyl ( OH), oxo (=O), nitro ( NO), cyano ( CN), and 3-(pyrimidin-2-yl)-2-methylcyclopentanyl. amino ( NH), N-substituted amino ( NHR"), N.N- As used herein, the term "heterocycloalkyl and "hetero disubstituted amino ( N(R")R"), carboxy (-COOH), cyclic ring each refers to an optionally Substituted ring sys - O C(=O)R", C(=O)R", OR", C(=O)CR", tem composed of a cycloalkyl radical wherein in at least one —NHC(=O)R", aminocarbonyl ( C(=O)NH), N-sub of the rings, one or more of the carbon atom ring members is stituted aminocarbonyl ( C(=O)NHR"), —N,N-disubsti independently replaced by a heteroatom group selected from tuted aminocarbonyl ( C(=O)N(R")R"), thiol, thiolato the group consisting of O, S, N, and NH, wherein cycloalkyl (—SR"), sulfonic acid ( SOH), phosphonic acid is as previously defined. Heterocycloalkyl ring systems hav ( POH), -P(=O)(OR")OR", S(=O)R", S(=O).R", ing a total of from about 3 to about 14 carbon atom ring 10 S(=O)NH, -S(=O)NHR", S(=O)NR"R", members and heteroatom ring members (and all combina NHS(=O).R", NR"S(=O).R", CF, CFCF tions and Subcombinations of ranges and specific numbers of NHC(=O)NHR", NHC(=O)NR"R", NR"C(=O) carbon and heteroatom ring members) are preferred. In other NHR", NR"C(=O)NR"R", NR"C(=O)R" and the like. preferred embodiments, the heterocyclic groups may be fused In relation to the aforementioned Substituents, each moiety to one or more aryl rings. In certain preferred embodiments, 15 R" can be, independently, any of H, alkyl, cycloalkyl, alkenyl, heterocycloalkyl moieties are attached via a ring carbonatom aryl, aralkyl, heteroaryl, or heterocycloalkyl, or when two R" to the rest of the molecule. Exemplary heterocycloalkyl groups are attached to the same nitrogen atom within a Sub groups include, but are not limited to, aziridinyl, azepanyl. stituent, as herein above defined, R" and R" can be taken tetrahydrofuranyl, hexahydropyrimidinyl, tetrahydrothienyl, together with the nitrogenatom to which they are attached to piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, form a 3- to 8-membered heterocycloalkyl ring, wherein one pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperazinyl, or two of the heterocycloalkyl ring carbon atoms indepen 2-oxo-morpholinyl, morpholinyl, 2-oxo-piperidinyl, piper dently may be optionally replaced by —O— —S——SO, adinyl, decahydroquinolyl, octahydrochromenyl, octahydro —SO. , —NH , —N(alkyl)-, - N(acyl)-, - N(aryl)-, or cyclopentacpyranyl, 1,2,3,4,-tetrahydroquinolyl, 1.2.3,4- —N(aroyl)- groups, for example. tetrahydroquinazolinyl, octahydro-2pyridinyl, decahydro 25 As used herein, “ligand’ or “modulator refers to a com cyclooctaclfuranyl, 1,2,3,4-tetrahydroisoquinolyl, 2-oxo pound that binds to a receptor to form a complex, and imidazolidinyl, and imidazolidinyl. In some embodiments, includes, agonists, partial agonists, antagonists and inverse two moieties attached to a heteroatom may be taken together agonists. to form a heterocycloalkyl ring, such as when R and R. As used herein, the term “antagonist” refers to a compound taken together with the nitrogen atom to which they are 30 that binds to a receptor to form a complex that preferably does attached, form a heterocycloalkyl ring. In certain of these not elicit any response, in the same manner as an unoccupied embodiments, 1 or 2 of the heterocycloalkyl ring carbon receptor, and does not alter the equilibrium between inactive atoms may be replaced by other moieties which contain either and active receptor. one ( O— —S— —N(R')—) or two ( N(R")—C As used herein, “agonist” refers to a ligand that produces a (=O)—, or —C(=O)—N(R")—) ring replacement atoms, 35 conformational change in the receptor and alters the equilib wherein each R' and R" may independently be, for example, rium of the receptor's active and inactive states, which in turn H or alkyl. When a moiety containing one ring replacement induces a series of events, resulting in a measurable biological atom replaces a ring carbon atom, the resultant ring, after response. Agonists include, for example, conventional ago replacement of a ring atom by the moiety, will contain the nists, which exhibit positive receptor activity, and inverse same number of ring atoms as the ring before ring atom 40 agonists, which exhibit a negative . replacement. When a moiety containing two ring replacement As used herein, “side effect” refers to a consequence other atoms replaces a ring carbon atom, the resultant ring after than the one(s) for which an agent or measure is used, as the replacement will contain one more ring atom than the ring adverse effects produced by a drug, especially on a tissue or prior to replacement by the moiety. For example, when a organ system other then the one sought to be benefited by its piperidine ring has one of its ring carbon atoms replaced by 45 administration. In the case, for example, of opioids, the term —N(R")—C(=O)—, the resultant ring is a 7-membered ring “side effect” may refer to such conditions as, for example, containing 2 ring nitrogenatoms and the carbon of a carbonyl constipation, nausea, vomiting, dyspnea and pruritus. group in addition to 4 other carbon ring atoms (CH groups) “Effective amount” refers to an amount of a compound as from the original piperidine ring. described herein that may be therapeutically effective to As used herein, the term “spiroalkyl refers to an option 50 inhibit, treat the symptoms of particular disease, disorder, ally substituted alkylene diradical, both ends of which are condition, or side effect. Such diseases, disorders, conditions, bonded to the same carbon atom of the parent group to form and side effects include, but are not limited to, those patho a spirocyclic group. The spirocyclic group, as herein defined, logical conditions associated with the binding of Ö-opioid has 3 to 20 ring atoms, preferably with 3 to 10 ring atoms. receptor (for example, in connection with the treatment of Exemplary spiroalkyl groups taken together with its parent 55 pain), wherein the treatment comprises, for example, agoniz group include, but are not limited to, 1-(1-methyl-cyclopro ing the activity thereof by contacting cells, tissues or recep pyl)-propan-2-one, 2-(1-phenoxy-cyclopropyl)-ethylamine, tors with compounds of the present invention. Thus, for and 1-methyl-spiro4.7dodecane. example, the term “effective amount, when used in connec As used herein, "halo' and “halogen each refers to a tion with compounds of the invention, opioids, or opioid fluoro, chloro, bromo, or iodo moiety with fluoro, chloro, or 60 replacements, for example, for the treatment of pain, refers to bromo moieties being preferred, and fluoro being more pre the treatment of the painful condition. The term “effective ferred. amount, when used in connection with compounds active Typically, Substituted chemical moieties include one or against gastrointestinal dysfunction, refers to the treatment of more Substituents that replace hydrogen. Exemplary Substitu symptoms, diseases, disorders, and conditions typically asso ents include, for example, halo (e.g., F. Cl, Br, I), alkyl, 65 ciated with gastrointestinal dysfunction. The term “effective cycloalkyl, alkylcycloalkyl, alkenyl, alkynyl, aralkyl, aryl, amount, when used in connection with compounds useful in heteroaryl, heteroaralkyl, spiroalkyl, heterocycloalkyl, the treatment of urogenital tract disorders, refers to the treat US 7,576,207 B2 7 8 ment of symptoms, diseases, disorders, and conditions typi cerebral ischemia, cerebral deficits Subsequent to cardiac cally associated with urogenital tract disorders and other bypass Surgery and grafting, systemic lupus erythematosus, related conditions. The term “effective amount, when used in Hodgkin’s disease, Sjogren's disease, epilepsy, and rejection connection with compounds useful in the treatment of immu in organ transplants and skin grafts and other related condi nomodulatory disorders, refers to the treatment of symptoms, tions. The term “effective amount, when used in connection diseases, disorders, and conditions typically associated with with compounds useful in the treatment of Substance addic immunomodulatory disorders and other related conditions. tion, refers to the treatment of symptoms, diseases, disorders, The term “effective amount, when used in connection with and conditions typically associated with Substance addiction compounds useful in the treatment of inflammatory disor and other related conditions. The term “effective amount.” ders, refers to the treatment of symptoms, diseases, disorders, 10 when used in connection with compounds useful in reducing and conditions typically associated with inflammatory disor the need for anesthesia or producing and/or maintaining an ders and other related conditions. The term “effective anesthetic state, refers to the production and/or maintenance amount, when used in connection with compounds useful in of a minimally-acceptable anesthetic state. the treatment of respiratory function disorders, refers to the As used herein, “pharmaceutically acceptable' refers to treatment of symptoms, diseases, disorders, and conditions 15 those compounds, materials, compositions, and/or dosage typically associated with respiratory function disorders and forms which are, within the scope of Sound medical judg other related conditions. The term “effective amount, when ment, Suitable for contact with the tissues of human beings used in connection with compounds useful in the treatment of and animals without excessive toxicity, irritation, allergic anxiety, mood disorders, stress-related disorders, and atten response, or other problem complications commensurate tion deficit hyperactivity disorder, refers to the treatment of with a reasonable benefit/risk ratio. symptoms, diseases, disorders, and conditions typically asso “In combination with.” “combination therapy,” and “com ciated with anxiety, mood disorders, stress-related disorders, bination products’ refer, in certain embodiments, to the con attention deficit hyperactivity disorder and other related con current administration to a patient of a compound of the ditions. The term “effective amount, when used in connec invention including, for example, a compound of formula I, tion with compounds useful in the treatment of sympathetic 25 II, III, IV, or V, and one or more additional agents including, nervous system disorders, refers to the treatment of symp for example, an opioid, an anesthetic agent (Such as for toms, diseases, disorders, and conditions typically associated example, an inhaled anesthetic, hypnotic, anxiolytic, neuro with sympathetic nervous system disorders and other related muscular blocker and opioid), an anti-Parkinson's agent (for conditions. The term “effective amount, when used in con example, in the case of treating a motor disorder, particularly nection with compounds useful in the treatment of tussis, 30 Parkinson's disease), an antidepressant (for example, in the refers to the treatment of symptoms, diseases, disorders, and case of treating a mood disorder, particularly depression), an conditions typically associated with tussis and other related agent for the treatment of incontinence (for example, in the conditions. The term “effective amount, when used in con case of treating a urogenital tract disorder), an agent for the nection with compounds useful in the treatment of motor treatment of pain, including neuralgias or neuropathic pain, disorders, refers to the treatment of symptoms, diseases, dis 35 cardioprotective agents, and/or other optional ingredients (in orders, and conditions typically associated with motor disor cluding, for example, antibiotics, antivirals, antifungals, anti ders and other related conditions. The term “effective inflammatories, anesthetics and mixtures thereof). When amount, when used in connection with compounds useful in administered in combination, each component may be the treatment of traumatic injuries of the central nervous administered at the same time or sequentially in any order at system, refers to the treatment of symptoms, diseases, disor 40 different points in time. Thus, each component may be ders, and conditions typically associated with the central administered separately but sufficiently closely in time so as nervous system and other related conditions. The term “effec to provide the desired therapeutic effect. tive amount, when used in connection with compounds use As used herein, “dosage unit refers to physically discrete ful in the treatment of stroke, cardiac arrhythmia or glaucoma, units Suited as unitary dosages for the particular individual to refers to the treatment of symptoms, diseases, disorders, and 45 be treated. Each unit may contain a predetermined quantity of conditions typically associated with stroke, cardiac arrhyth active compound(s) calculated to produce the desired thera mia, glaucoma and other related conditions. The term “effec peutic effect(s) in association with the required pharmaceu tive amount, when used in connection with compounds use tical carrier. The specification for the dosage unit forms of the ful in the treatment of sexual dysfunction, refers to the invention may be dictated by (a) the unique characteristics of treatment of symptoms, diseases, disorders, and conditions 50 the active compound(s) and the particular therapeutic typically associated with sexual dysfunction and other related effect(s) to be achieved, and (b) the limitations inherent in the conditions. The term “effective amount, when used in con art of compounding Such active compound(s). nection with compounds useful in improving organ and cell As used herein, “hydrate” refers to a compound of the Survival, refers to refers to the maintenance and/or improve present invention which is associated with water in the ment of a minimally-acceptable level of organ or cell Survival, 55 molecular form, i.e., in which the H-OH bond is not split, including organ preservation. The term “effective amount.” and may be represented, for example, by the formula R.H.O. when used in connection with compounds useful for provid where R is a compound of the invention. A given compound ing cardioprotection, including after myocardial infarction, may form more than one hydrate including, for example, refers to the minimum level of compound necessary to pro monohydrates (R.HO) or polyhydrates (R.nHO wherein n vide cardioprotection. The term “effective amount, when 60 is an integer> 1) including, for example, dihydrates (R.2H2O). used in connection with compounds useful in the treatment of trihydrates (R.3H2O), and the like, or hemihydrates, such as, shock, brain edema, cerebral ischemia, cerebral deficits sub for example, R.nH2O, R.nH2O, R.nH2O and the like sequent to cardiac bypass Surgery and grafting, systemic wherein n is an integer. lupus erythematosus, Hodgkin’s disease, Sjogren's disease, As used herein, “solvate” refers to a compound of the epilepsy, and rejection in organ transplants and skin grafts, 65 present invention which is associated with solvent in the refers to the treatment of symptoms, diseases, disorders, and molecular form, i.e., in which the solvent is coordinatively conditions typically associated with shock, brain edema, bound, and may be represented, for example, by the formula US 7,576,207 B2 10 R.(Solvent), where R is a compound of the invention. A given such damage. “Pain includes, but is not limited to, two broad compound may form more than one Solvate including, for categories of pain: acute and chronic pain (Buschmann, H.; example, monosolvates (R. (Solvent)) or polySolvates (R.n Christoph, T. Friderichs, E.; Maul, C.; Sundermann, B; eds.; (solvent)) wherein n is an integer>1) including, for example, Analgesics, Wiley-VCH, Verlag GMbH & Co. KgaA, Wein disolvates (R.2(solvent)), trisolvates (R.3(solvent)), and the heim; 2002: Jain, K. K. “A Guide to Drug Evaluation for like, or hemisolvates, such as, for example, Rn(solvent), Chronic Pain': Emerging Drugs, 5(2), 241-257 (2000)). Non R.n(solvent), R.na (solvent) and the like wherein n is an limiting examples of pain include, for example, nociceptive integer. Solvents herein include mixed solvents, for example, pain, inflammatory pain, visceral pain, Somatic pain, neural methanol/water, and as such, the Solvates may incorporate gias, neuropathic pain, AIDS pain, cancer pain, phantom one or more solvents within the solvate. 10 pain, and psychogenic pain, and pain resulting from hyperal As used herein, “acid hydrate” refers to a complex that may gesia, pain caused by rheumatoid arthritis, migraine, allo be formed through association of a compound having one or dynia and the like. more base moieties with at least one compound having one or As used herein, “gastrointestinal dysfunction” refers col more acid moieties or through association of a compound lectively to maladies of the stomach, Small and large intestine. having one or more acid moieties with at least one compound 15 Non-limiting examples of gastrointestinal dysfunction having one or more base moieties, said complex being further include, for example, diarrhea, nausea, emesis, post-opera associated with water molecules So as to form a hydrate, tive emesis, opioid-induced emesis, irritable bowel syn wherein said hydrate is as previously defined and R represents drome, opioid-bowel dysfunction, inflammatory bowel dis the complex herein described above. ease, colitis, increased gastric motility, increased gastric As used herein, “pharmaceutically acceptable salts' refer emptying, stimulation of Small intestinal propulsion, stimu to derivatives of the disclosed compounds wherein the parent lation of large intestinal propulsion, decreased amplitude of compound is modified by making acid or base salts thereof. non-propulsive segmental contractions, disorders associated Examples of pharmaceutically acceptable salts include, but with sphincter of Oddi, disorders associated with anal sphinc are not limited to, mineral or organic acid salts of basic ter tone, impaired reflex relaxation with rectal distention, residues such as amines; alkali or organic salts of acidic 25 disorders associated with gastric, biliary, pancreatic or intes residues such as carboxylic acids; and the like. The pharma tinal secretions, changes to the absorption of water from ceutically acceptable salts include the conventional non-toxic bowel contents, gastro-esophageal reflux, gastroparesis, salts or the quaternary ammonium salts of the parent com cramping, bloating, distension, abdominal or epigastric pain pound formed, for example, from non-toxic inorganic or and discomfort, non-ulcerogenic dyspepsia, gastritis, or organic acids. For example. Such conventional non-toxic salts 30 changes to the absorption of orally administered medications include those derived from inorganic acids such as hydro or nutritive Substances. chloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric As used herein, “urogenital tract disorders' refers collec and the like; and the salts prepared from organic acids such as tively to maladies of the urinary and genital apparati. Non acetic, propionic, Succinic, glycolic, Stearic, lactic, malic, limiting examples of urogenital tract disorders include incon tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phe 35 tinence (i.e., involuntary loss of urine) Such as stress urinary nylacetic, glutamic, benzoic, Salicylic, Sulfanilic, 2-acetoxy incontinence, urge urinary incontinence and benign prostatic benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane hyperplasia, overactive bladder disorder, urinary retention, disulfonic, oxalic, isethionic, and the like. These physiologi renal colic, glomerulonephritis, and interstitial cystitis. cally acceptable salts are prepared by methods known in the As used herein, “overactive bladder disorder” refers to a art, e.g., by dissolving the free amine bases with an excess of 40 condition with symptoms of urgency with or without incon the acid in aqueous alcohol, or neutralizing a free carboxylic tinence, and is typically associated with increased urinary acid with an alkali metal base Such as a hydroxide, or with an frequency and nocturia. Overactive bladder disorders are amine. typically associated with urodynamic finding of involuntary Compounds described herein throughout, can be used or bladder contractions, generally referred to as bladder insta prepared in alternate forms. For example, many amino-con 45 bility. taining compounds can be used or prepared as an acid addi tion salt. Often such salts improve isolation and handling As used herein, “immunomodulatory disorders' refers col properties of the compound. For example, depending on the lectively to maladies characterized by a compromised or reagents, reaction conditions and the like, compounds as over-stimulated immune system. Non-limiting examples of described herein can be used or prepared, for example, as 50 immunomodulatory disorders include autoimmune diseases their hydrochloride or tosylate salts. Isomorphic crystalline (such as arthritis, autoimmune disorders associated with skin forms, all chiral and racemic forms, N-oxide, hydrates, Sol grafts, autoimmune disorders associated with organ trans Vates, and acid salt hydrates, are also contemplated to be plants, and autoimmune disorders associated with Surgery), within the scope of the present invention. collagen diseases, allergies, side effects associated with the Certain acidic or basic compounds of the present invention 55 administration of an anti-tumor agent, side effects associated may exist as Zwitterions. All forms of the compounds, includ with the administration of an antiviral agent, multiple Sclero ing free acid, free base and Zwitterions, are contemplated to sis and Guillain-Barre syndrome. be within the scope of the present invention. It is well known As used herein, “inflammatory disorders' refers collec in the art that compounds containing both amino and carboxy tively to maladies characterized by cellular events in injured groups often exist in equilibrium with their Zwitterionic 60 tissues. Non-limiting examples of inflammatory disorders forms. Thus, any of the compounds described hereinthrough include arthritis, psoriasis, asthma, and inflammatory bowel out that contain, for example, both amino and carboxy disease. groups, also include reference to their corresponding Zwitte As used herein, “respiratory function disorders' refers to rions. conditions in which breathing and/or airflow into the lung is As used herein, “pain” refers to the perception or condition 65 compromised. Non-limiting examples of respiratory function of unpleasant sensory or emotional experience, associated disorders include asthma, apnea, tussis, chronic obstruction with actual or potential tissue damage or described interms of pulmonary disease, and lung edema. US 7,576,207 B2 11 12 As used herein, “lung edema’ refers to the presence of cytes to be resistant to ischemic and reperfusion damage. abnormally large amounts of fluid in the intercellular tissue Patients undergoing repeated balloon angioplasty have been spaces of the lungs. shown to experience significant protection through adapta As used herein, "anxiety” refers to the unpleasant emo tion of the myocardium to mild ischemic periods. tional state consisting of psychophysiological responses to As used herein, “myocardial infarction” refers to irrevers anticipation of real, unreal or imagined danger, ostensibly ible injury to heart muscle caused by a local lack of oxygen. resulting from unrecognized intrapsychic conflict. As used herein, “addiction” refers to a pattern of compul As used herein, "mood disorders' refers to disorders that sive Substance abuse (alcohol, nicotine, or drug) character have a disturbance in mood as their predominant feature, ized by a continued craving for the Substance and, in some including depression, bipolar manic-depression, borderline 10 cases, the need to use the substance for effects other than its personality disorder, and seasonal affective disorder. prescribed or legal use. As used herein, “depression” refers to a mental state of As used herein, “anesthetic state' refers to the state of the depressed mood characterized by feelings of sadness, despair loss of feeling or sensation, including not only the loss of and discouragement, including the blues, dysthymia, and tactile sensibility or of any of the other senses, but also to the major depression. 15 loss of sensation of pain, as it is induced to permit perfor As used herein, “stress-related disorders' refer collectively mance of Surgery or other painful procedures, and specifically to maladies characterized by a state of hyper- or hypoarousal including amnesia, analgesia, muscle relaxation and seda with hyper- and hypovigilance. Non-limiting examples of tion. stress-related disorders include post-traumatic stress disor As used herein, “improving organ and cell Survival” refers der, panic disorder, generalized anxiety disorder, Social pho to the maintenance and/or improvement of a minimally-ac bia, and obsessive-compulsive disorder. ceptable level of organ or cell survival. As used herein, “attention deficit hyperactivity disorder s As used herein, patient” refers to animals, including refers to a condition characterized by an inability to control mammals, preferably humans. behavior due to difficulty in processing neural stimuli. As used herein, prodrug” refers to compounds specifi As used herein, “sympathetic nervous system disorders s 25 cally designed to maximize the amount of active species that refer collectively to maladies characterized by disturbances reaches the desired site of reaction, which are of themselves of the autonomic nervous system. Non-limiting examples of typically inactive or minimally active for the activity desired, sympathetic nervous system disorders include hypertension, but through biotransformation are converted into biologically and the like. active metabolites. As used herein, 'tussis' refers to a coughing condition, and 30 As used herein, the term “stereoisomers' refers to com “antitussive' agents refer to those materials that modulate the pounds that have identical chemical constitution, but differas coughing response. regards the arrangement of the atoms or groups in space. As used herein, “motor disorders' refers to involuntary As used herein, “N-oxide' refers to compounds wherein manifestations of hyper or hypo muscle activity and coordi the basic nitrogen atom of either a heteroaryl ring or tertiary nation. Non-limiting examples of motor disorders include 35 amine is oxidized to give a quaternary nitrogen bearing a tremors, Parkinson's disease, Tourette's syndrome, parasom positive formal charge and an attached oxygenatom bearing nias (sleep disorders) including restless leg syndrome, post a negative formal charge. operative shivering and dyskinesia. The terms “treatment” and “treating as used herein As used herein, “traumatic injury of the central nervous include preventative (e.g., prophylactic), curative and/or pal system’ refers to a physical wound or injury to the spinal cord 40 liative treatment. or brain. When any variable occurs more than one time in any con As used herein, “stroke' refers to a condition due to the stituent or in any formula, its definition in each occurrence is lack of oxygen to the brain. independent of its definition at every other occurrence. Com As used herein, “cardiac arrhythmia' refers to a condition binations of substituents and/or variables are permissible characterized by a disturbance in the electrical activity of the 45 only if such combinations result in stable compounds. heart that manifests as an abnormality in heart rate or heart It is believed the chemical formulas and names used herein rhythm. Patients with a cardiac arrhythmia may experience a correctly and accurately reflect the underlying chemical com wide variety of symptoms ranging from palpitations to faint pounds. However, the nature and value of the present inven ing. tion does not depend upon the theoretical correctness of these As used herein, “glaucoma’ refers collectively to eye dis 50 formulae, in whole or in part. Thus it is understood that the eases characterized by an increase in intraocular pressure that formulas used herein, as well as the chemical names attrib causes pathological changes in the optic disk and typical uted to the correspondingly indicated compounds, are not defects in the field of vision. intended to limit the invention in any way, including restrict As used herein, “sexual dysfunction” refers collectively to ing it to any specific tautomeric form or to any specific optical disturbances, impairments or abnormalities of the function 55 or geometric isomer, except where such stereochemistry is ing of the male or female sexual organs, including, but not clearly defined. limited to premature ejaculation and erectile dysfunction. In certain preferred embodiments, the compounds, phar As used herein, "cardioprotection” refers to conditions or maceutical compositions and methods of the present inven agents, including, for example, ischemic preconditioning, tion may involve a peripheral Ö-opioid modulator compound. that reduce or combat ischemic damage, or protect or restore 60 The term “peripheral designates that the compound acts the heart from dysfunction, heart failure and/or reperfusion primarily on physiological systems and components external injury. to the central nervous system. In preferred form, the periph As used herein, “ischemic preconditioning refers to a eral Ö-opioid modulator compounds employed in the methods physiological method of reducing injury to the myocardium of the present invention exhibit high levels of activity with after short-term ischemia and reperfusion. Repeated cycling 65 respect to peripheral tissue. Such as, gastrointestinal tissue, of short episodes of ischemia induces changes in the myocar while exhibiting reduced, and preferably substantially no. dial cell signaling systems that appear to condition the myo CNS activity. The phrase “substantially no CNS activity, as US 7,576,207 B2 13 14 used herein, means that less than about 50% of the pharma In formula I above, A and B are each H or taken together cological activity of the compounds employed in the present with the carbonatoms through which they are connected form methods is exhibited in the CNS, preferably less than about a double bond. In preferred embodiments, A and Bare each H. 25%, more preferably less than about 10%, even more pref In other preferred embodiments, A and B are taken together erably less than about 5% and most preferably 0% of the pharmacological activity of the compounds employed in the with the carbon atoms through which they are connected to present methods is exhibited in the CNS. form a double bond. Furthermore, it is preferred in certain embodiments of the In the above formula I, X is —CH2— or —O—. In certain invention that the 6-opioid modulator compound does not preferred embodiments, X is —CH2—, while in other pre substantially cross the blood-brain barrier. The phrase “does 10 ferred embodiments, X is —O—. not substantially cross, as used herein, means that less than In formula I above, Z is alkoxy, —C(=O) R, NR— about 20% by weight of the compound employed in the C(=O) R', or NRS(=O)-alkyl. In preferred form, Z is present methods crosses the blood-brain barrier, preferably less than about 15% by weight, more preferably less than C(=O) R, NR C(=O ) R, or NRS(=O), about 10% by weight, even more preferably less than about 15 alkyl, with C(=O) R' or - NR C(=O) R' being 5% by weight and most preferably 0% by weight of the more preferred. Even more preferably, Z is —C(=O) R. compound crosses the blood-brain barrier. Selected com Each R' in formula I above is independently carboxy, pounds can be evaluated for CNS penetration, for example, by hydroxy, alkoxy, halo, aminocarbonyl, N-alkylaminocarbo determining plasma and brain levels following i.v. adminis nyl, or N,N-dialkylaminocarbonyl. In preferred embodi tration. ments, each R" is independently carboxy, hydroxy, alkoxy, Accordingly, in certain embodiments, the present inven halo, aminocarbonyl, or N-alkylaminocarbonyl, with tion is directed, in part, to novel spiro(2H-1-benzopyran-2,4'- piperidine and spiro1.2.3,4-tetrahydronaphthalene-2,4'-pip hydroxy, alkoxy, or halo being more preferred. A preferred eridine compounds of formula I: alkoxy group is methoxy, and a preferred halogen atom is 25 fluoro. In the above formula I, R is NR'R' or alkoxy. In certain

preferred embodiments, R is NRR. Each R and R' in formula I above is independently H or alkyl. In certain preferred embodiments, R is each H, while 30 in certain other preferred embodiments, R is alkyl. In pre ferred embodiments, R is H. In formula I above, R is alkyl or - NRR. In certain preferred embodiments, R is alkyl, while in other preferred 35 embodiments, R is NR'R''. RandR' informula I are eachindependently Horalkyl, or RandR taken together with the nitrogenatom to which they are connected form a 3- to 8-membered heterocycloalkyl ring 40 in which 1 or 2 of the heterocycloalkyl ring carbon atoms wherein: independently may each be optionally replaced by —O—, W is alkylene; S-, - N(R) - N(R) C(=O)—, or - C(=O) N Z is alkoxy, NR (R)-. In certain preferred embodiments, RandR are each - NRS(=O), alkyl: independently Horalkyl, with alkyl being more preferred. In each R" is independently carboxy, hydroxy, alkoxy, halo, 45 aminocarbonyl, N-alkylaminocarbonyl, or N,N-dialky other preferred embodiments, Rand Rare taken together laminocarbonyl: with the nitrogenatom to which they are connected to form a 3- to 8-membered heterocycloalkyl ring, more preferably a 3 R’ is NR'R' or alkoxy; to 5-membered heterocycloalkyl ring, in which 1 or 2 of the Rand Rare each independently H or alkyl: heterocycloalkyl ring carbon atoms independently may each R is alkyl or NRR: 50 RandR are each independently Horalkyl, or RandR be optionally replaced by —O , —S , N(R') , taken together with the nitrogen atom to which they are connected form a 3- to 8-membered heterocycloalkyl Informula I above, each m, p and t is independently 0, 1 or ring in which 1 or 2 of the heterocycloalkyl ring carbon 2. In certain preferred embodiments, p is 0 or 1, with 1 being atoms independently may each be optionally replaced 55 more preferred. Also in certain preferred embodiments, t is 0 by -O-, - S - N(R) , N(R)-C(=O)—, or or 1, more preferably 0. In certain other preferred embodi - C(=O) N(R)–: R. R. and Rare each independently H or alkyl: ments, m is 2. X is —CH2—, —S(=O), , or —O—; 60 In formula I above, s is 1 or 2, with 1 being preferred. A and B are each H, or taken together with the carbon atoms through which they are connected form a double In the above formula I, the sum of p--s is 1, 2, or 3. In bond; preferred form, the sum of p--s is 2 or 3, with 2 being more each m is independently 0, 1, or 2; preferred. p and t are each independently 0, 1, or 2; and 65 A preferred class of compounds useful in the practice of the s is 1 or 2; provided that the sum of p--s is 1, 2, or 3: present invention include those described by formula I which or a pharmaceutically acceptable salt thereof. have the following formula II: US 7,576,207 B2

II IV

10

15 where A, B, W, Z. R', p. s and t are as described above. wherein A, B, W. Z. R', p. sandt are as described above. An even more preferred class of compounds useful in the practice An even more preferred class of compounds useful in the of the present invention include those described by formulas practice of the present invention include those described by I and IV which have the following formula V: formulas I and II which have the following formula III:

25 III

30

N

35 wherein: Q' and Q are each independently H, carboxy, hydroxy, N alkoxy, halo, aminocarbonyl, N-alkylaminocarbonyl, or N.N- dialkylaminocarbonyl, and W. Z. p and S are as described 40 above. Informula V. Q' and Q are eachindependently H. carboxy, hydroxy, alkoxy, halo, aminocarbonyl, N-alkylaminocarbo nyl, or N,N-dialkylaminocarbonyl. In certain preferred embodiments, at least one of Q' and Q is Hand the other of wherein: 45 Q' and Q is carboxy, hydroxy, alkoxy, halo, aminocarbonyl, N-alkylaminocarbonyl, or N,N-dialkylaminocarbonyl. In Q' and Q are each independently H, carboxy, hydroxy, certain more preferred embodiments, at least one of Q' and alkoxy, halo, aminocarbonyl, N-alkylaminocarbonyl, or N.N- Q is H and the other of Q' and Q is carboxy, hydroxy, dialkylaminocarbonyl, and W. Z. p and S are as described alkoxy, halo, aminocarbonyl, or N-alkylaminocarbonyl. In above. 50 certain preferred embodiments, both Q' and Q are hydrogen In the above formula III, Q and Q are each independently while in other preferred embodiments, Q" is hydroxy or H, carboxy, hydroxy, alkoxy, halo, aminocarbonyl, N-alky alkoxy. laminocarbonyl, or N,N-dialkylaminocarbonyl. In certain In certain preferred embodiments, the compounds of the preferred embodiments, at least one of Q' and Q is Hand the invention are selected from the group consisting of: other of Q' and Q is carboxy, hydroxy, alkoxy, halo, ami 55 4-2-(N,N-diethylaminocarbonyl)ethyl-spiro2H, 1-ben nocarbonyl, N-alkylaminocarbonyl, or N,N-dialkylami Zopyran-2,4'-piperidine: 4-3-(N,N-diethylaminocarbonyl)propyl-spiro2H, 1-ben nocarbonyl. In certain more preferred embodiments, at least Zopyran-2,4'-piperidine: one of Q and Q is Hand the other of Q' and Q is carboxy, 4-2-(N,N-diethylaminocarbonyl)ethyl-spiro 3,4-dihydro hydroxy, alkoxy, halo, aminocarbonyl, or N-alkylaminocar 60 2H, 1-benzopyran-2,4'-piperidine; bonyl. In certain preferred embodiments, both Q' and Q are 4-3-(N,N-diethylaminocarbonyl)propyl-spiro 3,4-dihy hydrogen while in other preferred embodiments, Q' is dro-2H, 1-benzopyran-2,4'-piperidine; hydroxy or alkoxy. 4-3-(ethoxycarbonyl)propyl-spiro2H, 1-benzopyran-2,4'- Another preferred class of compounds useful in the prac 65 piperidine; tice of the present invention include those described by for 4-3-(N,N-diisopropylaminocarbonyl)propyl-spiro 3,4-di mula I which have the following formula IV: hydro-2H, 1-benzopyran-2,4'-piperidine:

US 7,576,207 B2 19 20 used herein, “prodrug is intended to include any covalently The Ö-agonist compounds of the present invention may be bonded carriers which release the active parent drug, for administered by any means that results in the contact of the example, as according to formula I or other formulas or com active agent with the agent's site of action in the body of a pounds as described herein, in vivo when such prodrug is patient. The compounds may be administered by any conven administered to a mammalian Subject. Since prodrugs are tional means available for use in conjunction with pharma known to enhance numerous desirable qualities of pharma ceuticals, either as individual therapeutic agents or in a com ceuticals (e.g., solubility, bioavailability, manufacturing, bination of therapeutic and/or prophylactic agents. For etc.), the compounds described herein may, if desired, be example, they may be administered as the Sole active agent in delivered in prodrug form. Thus, the present invention con a pharmaceutical composition, or they can be used in combi templates compositions and methods involving prodrugs. 10 nation with other therapeutically active ingredients including, Prodrugs of the compounds employed in the present inven for example, opioid analgesic agents. In Such combinations, tion, for example formula I, II, III, IV, or V. may be prepared selected compounds of the invention may provide equivalent by modifying functional groups present in the compound in or even enhanced therapeutic activity Such as, for example, Sucha way that the modifications are cleaved, either in routine pain ameliorization, while providing reduced adverse side manipulation or in Vivo, to the parent compound. 15 effects associated with opioids, such as addiction or pruritus, Accordingly, prodrugs include, for example, compounds by lowering the amount of opioid required to achieve a thera described herein in which a hydroxy, amino, or carboxy group peutic effect. is bonded to any group that, when the prodrug is administered Generally speaking, therapeutic compounds of this inven to a mammalian Subject, cleaves to form a free hydroxyl, free tion may be administered to a patient alone or in combination amino, or carboxylic acid, respectively. Examples include, with a pharmaceutically acceptable carrier. Accordingly, the but are not limited to, acetate, formate and benzoate deriva compounds of the invention, for example, compounds of tives of alcohol and amine functional groups; and alkyl, formulas I, II, III, IV, and/or V. are preferably combined with cycloalkyl, aryl, and alkylaryl esters such as methyl, ethyl, a pharmaceutical carrier selected on the basis of the chosen propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclo route of administration and standard pharmaceutical practice propyl, phenyl, benzyl, and phenethyl esters, and the like. 25 as described, for example, in Remington's Pharmaceutical Compounds described herein may contain one or more Sciences (Mack Publishing Co., Easton, Pa., 1980), the dis asymmetrically substituted carbon atoms, and may be iso closures of which are hereby incorporated herein by refer lated in optically active or racemic forms. Thus, all isomeric ence, in their entireties. The carrier(s) must be acceptable in forms of a structure, including all Stereogenic (such as enan the sense of being compatible with the other ingredients of the tiomeric, diastereomeric, and/or meso forms, whether chiral 30 composition and not deleterious to the recipient thereof. or racemic), all achiral, all geometric, and/or all conforma In addition to the pharmaceutical carrier, the compound of tional isomeric forms are intended, unless the specific stere the invention, for example, compounds of formula I, II, III, ochemical or other isomeric form is specifically indicated IV, and/or V, may be co-administered with at least one opioid, and/or achiral. It is well known in the art how to prepare and preferably ap opioid compound. In cer isolate such isomeric forms of a structure including those 35 tain embodiments, the combination of the compounds of having stereogenic centers including those stereogenic forms formula I, II, III, IV, or V, with at least one opioid, preferably wherein the structure is present in optically active form. For ap opioid receptor modulator compound, provides a syner example, mixtures of stereoisomers may be separated by gistic analgesic effect. The utility of such combination prod standard techniques including, but not limited to, resolution ucts may be determined by those skilled in the art using of racemic forms, normal, reverse-phase, and chiral chroma 40 established animal models. Suitable opioids include, without tography, preferential salt formation, recrystallization, and limitation, , allylprodine, alphaprodine, , the like, or by chiral synthesis either from chiral starting benzyl-morphine, , , , materials or by deliberate synthesis of target chiral centers. clonitaZene, , , , dextro The compounds of the present invention may be prepared moramide, , diampromide, diamorphone, dihydro in a number of ways well knownto those skilled in the art. The 45 codeine, , , dimepheptanol, compounds can be synthesized, for example, by the methods dimethylthiambutene, dioaphetylbutyrate, , epta described below, or variations thereon as appreciated by the Zocine, ethoheptazine, ethylmethylthiambutene, ethylmor skilled artisan. All processes disclosed in association with the phine, etonitaZene, , , , hydro present invention are contemplated to be practiced on any morphone, hydroxypethidine, , , Scale, including milligram, gram, multigram, kilogram, mul 50 , , levophenacylmorphan, , tikilogram or commercial industrial scale. , meperidine (), , , As will be readily understood, functional groups present , , morphine, myrophine, , may contain protecting groups during the course of synthesis. narceline, , norlevorphanol, normethadone, Protecting groups are known per se as chemical functional , normorphine, norpinanone, , , groups that can be selectively appended to and removed from 55 , papavereturn, , phenadoxone, functionalities, such as hydroxyl groups and carboxyl groups. phenomorphan, phanazocine, phenoperidine, , These groups are present in a chemical compound to render , propheptazine, promedol, properidine, propi Such functionality inert to chemical reaction conditions to ram, propoxyphene, Sulfentanil, , , diastere which the compound is exposed. Any of a variety of protect oisomers thereof, pharmaceutically acceptable salts thereof, ing groups may be employed with the present invention. 60 complexes thereof; and mixtures thereof. Preferred protecting groups include the benzyloxycarbonyl The pain ameliorating and/or opioid combination products group and the tert-butyloxycarbonyl group. Other preferred of the present compositions may further include one or more protecting groups that may be employed in accordance with other active ingredients that may be conventionally employed the present invention may be described in Greene, T. W. and in analgesic and/or cough-cold-antitussive combination Wuts, P. G. M., Protective Groups in Organic Synthesis 2nd. 65 products. Such conventional ingredients include, for Ed., Wiley & Sons, 1991, the disclosures of which are hereby example, aspirin, acetaminophen, phenylpropanolamine, incorporated herein by reference, in their entirety. phenylephrine, chlorpheniramine, caffeine, and/or guaifen US 7,576,207 B2 21 22 esin. Typical or conventional ingredients that may be peppermint, oil of wintergreen orcherry flavoring. When the included in the opioid component are described, for example, dosage unit form is a capsule, it may contain, in addition to in the Physicians' Desk Reference, 1999, the disclosure of materials of the above type, a liquid carrier. Various other which is hereby incorporated herein by reference, in its materials may be present as coatings or to otherwise modify entirety. the physical form of the dosage unit. For instance, tablets, In addition, the opioid component may further include one pills, or capsules may be coated with shellac, Sugar or both. A or more compounds that may be designed to enhance the syrup or elixir may contain the active compound. Sucrose as a analgesic potency of the opioid and/or to reduce analgesic Sweetening agent, methyl and propylparabens as preserva tolerance development. Such compounds include, for tives, a dye and flavoring, Such as cherry or orange flavor. Of example, dextromethorphan or other NMDA antagonists 10 course, any material used in preparing any dosage unit form is (Mao, M.J. et al., Pain 1996, 67,361), L-364,718 and other preferably pharmaceutically pure and Substantially non-toxic CCK antagonists (Dourish, C. T. et al., Eur: J. Pharmacol. in the amounts employed. In addition, the active compound 1988, 147, 469), NOS inhibitors (Bhargava, H. N. et al., may be incorporated into Sustained-release preparations and Neuropeptides 1996,30, 219), PKC inhibitors (Bilsky, E.J. et formulations. al., J. Pharmacol. Exp. Ther. 1996, 277, 484), and dynorphin 15 The active compound may also be administered parenter antagonists or antisera (Nichols, M. L. et al., Pain 1997, 69. ally or intraperitoneally. Solutions of the active compound as 317). The disclosures of each of the foregoing documents are a free base or a pharmacologically acceptable salt can be hereby incorporated herein by reference, in their entireties. prepared in water Suitably mixed with a Surfactant, Such as Other opioids, optional conventional opioid components, hydroxypropylcellulose. A dispersion can also be prepared in and optional compounds for enhancing the analgesic potency glycerol, liquid polyethylene glycols and mixtures thereof of the opioid and/or for reducing analgesic tolerance devel and in oils. Under ordinary conditions of storage and use, opment, that may be employed in the methods and composi these preparations may contain a preservative to prevent the tions of the present invention, in addition to those exemplified growth of microorganisms. above, would be readily apparent to one of ordinary skill in The pharmaceutical forms suitable for injectable use the art, once armed with the teachings of the present disclo 25 include, for example, Sterile aqueous solutions or dispersions SUC. and sterile powders for the extemporaneous preparation of Compounds of the present invention can be administered to sterile injectable solutions or dispersions. In all cases, the a mammalian host in a variety of forms adapted to the chosen form is preferably sterile and fluid to provide easy syringabil route of administration, e.g., orally or parenterally. Parenteral ity. It is preferably stable under the conditions of manufacture administration in this respect includes administration by the 30 and storage and is preferably preserved against the contami following routes: intravenous, intramuscular, Subcutaneous, nating action of microorganisms such as bacteria and fungi. rectal, intraocular, intrasynovial, transepithelial including The carrier may be a solvent or dispersion medium contain transdermal, ophthalmic, Sublingual and buccal; topically ing, for example, water, ethanol, polyol (for example, glyc including ophthalmic, dermal, ocular, rectal, and nasal inha erol, propylene glycol, liquid polyethylene glycol and the lation via insufflation aerosol. 35 like), suitable mixtures thereof, and vegetable oils. The The active compound may be orally administered, for proper fluidity can be maintained, for example, by the use of example, with an inert diluent or with an assimilable edible a coating, such as lecithin, by the maintenance of the required carrier, or it may be enclosed in hard or soft shell gelatin particle size in the case of a dispersion, and by the use of capsules, or it may be compressed into tablets, or it may be Surfactants. The prevention of the action of microorganisms incorporated directly with the food of the diet. For oral thera 40 may be achieved by various antibacterial and antifungal peutic administration, the active compound may be incorpo agents, for example, parabens, chlorobutanol, phenol, Sorbic rated with excipient and used in the form of ingestible tablets, acid, thimerosal and the like. In many cases, it will be pref buccal tablets, troches, capsules, elixirs, Suspensions, syrups, erable to include isotonic agents, for example, Sugars or wafers, and the like. Such compositions and preparations sodium chloride. Prolonged absorption of the injectable com should preferably contain at least 0.1% of active compound. 45 positions may be achieved by the use of agents delaying The percentage concentration of active compound in the com absorption, for example, aluminum monostearate and gelatin. positions and preparations may, of course, be varied, and the Sterile injectable solutions may be prepared by incorporat relative proportions of active ingredient and carrier may be ing the active compound in the required amount, in the appro determined, for example, by the solubility and chemical priate solvent, with various of the other ingredients enumer nature of the compound, chosen route of administration and 50 ated above, as required, followed by filtered sterilization. standard pharmaceutical practice. Generally speaking, the Generally, dispersions may be prepared by incorporating the concentration of active agent may be, for example, from sterilized active ingredient into a sterile vehicle that contains about 2 to about 6% of the weight of the unit. The amount of the basic dispersion medium and the required other ingredi active compound in Such therapeutically useful compositions ents from those enumerated above. In the case of sterile is preferably such that a suitable dosage will be obtained. 55 powders for the preparation of sterile injectable solutions, the Preferred compositions or preparations according to the preferred methods of preparation may include vacuum drying present invention may be prepared so that an oral dosage unit and the freeze-drying technique that yield a powder of the form contains from about 0.1 to about 1000 mg of active active ingredient, plus any additional desired ingredient from compound (and all combinations and Subcombinations of the previously sterile-filtered solution thereof. dosage ranges and specific dosage amounts therein). 60 The dosage of the compounds of the present invention that The tablets, troches, pills, capsules and the like may also will be most suitable for prophylaxis or treatment will vary contain one or more of the following: a binder, such as gum with the form of administration, the particular compound tragacanth, acacia, corn starch or gelatin; an excipient, Such chosen and the physiological characteristics of the particular as dicalcium phosphate; a disintegrating agent, such as corn patient under treatment. Generally, Small dosages may be starch, potato starch, alginic acid and the like; a lubricant, 65 used initially and, if necessary, increased by Small increments Such as magnesium Stearate; a Sweetening agent Such as until the desired effect under the circumstances is reached. Sucrose, lactose or saccharin; or a flavoring agent, such as The therapeutic human dosage, based on physiological stud US 7,576,207 B2 23 24 ies using rats, may generally range from about 0.01 mg to nations and Subcombinations of ranges therein) and about about 100 mg/kg of body weight per day, and all combina 0.001 to about 100 milligrams of other therapeutic com tions and Subcombinations of ranges and specific dosages pounds as described herein (and all combinations and Sub therein. Alternatively, the therapeutic human dosage may be combinations of ranges therein), per kilogram of patient body from about 0.4 mg to about 10 g or higher, and may be 5 weight. Preferably, a daily dosage may be about 0.1 to about administered in several different dosage units from once to 10 milligrams of the compound of the invention and about several times a day. Generally speaking, oral administration 0.01 to about 10 milligrams of other therapeutic compounds may require higher dosages. as described herein per kilogram of patient body weight. Even It will be further appreciated that the amount of the com more preferably, the daily dosage may be about 1.0 milli pound, or an active salt or derivative thereof, required for use 10 grams of the compound of the invention and about 0.1 milli in treatment will vary not only with the particular salt selected grams of other therapeutic compounds as described herein but also with the route of administration, the nature of the per kilogram of patient body weight. With regard to a typical condition being treated and the age and condition of the dosage form of this type of combination product, Such as a patient and will be ultimately at the discretion of the attendant tablet, the compound of the invention generally may be physician or clinician. 15 present in an amount of about 15 to about 200 milligrams, and The desired dose may conveniently be presented in a single the other therapeutic compounds as described herein in an dose or as divided doses administered at appropriate intervals, amount of about 0.1 to about 4 milligrams. for example, as two, three, four or more Sub-doses per day. Particularly when provided as a single dosage form, the The sub-dose itselfmay be further divided, e.g., into a number potential exists for a chemical interaction between the com of discrete loosely spaced administrations; such as multiple bined active ingredients (for example, a compound of the inhalations from an insufflator or by application of a plurality invention and other therapeutic compounds as described of drops into the eye. herein). For this reason, the preferred dosage forms of the Combination products of this invention, Such as pharma combination products of this invention are formulated Such ceutical compositions comprising the compounds of the that although the active ingredients are combined in a single present invention, for example, compounds of formulas I, II, 25 dosage form, the physical contact between the active ingre II, IV, and/or V. in combination with other therapeutic com dients is minimized (that is, reduced). pounds described herein may be in any dosage form, such as In order to minimize contact, one embodiment of this those described herein, and can also be administered in Vari invention where the product is orally administered provides ous ways, as described herein. In a preferred embodiment, the for a combination product wherein one active ingredient is combination products of the invention are formulated 30 enteric coated. By enteric coating one or more of the active together, in a single dosage form (that is, combined together ingredients, it is possible not only to minimize the contact in one capsule, tablet, powder, or liquid, etc.). When the between the combined active ingredients, but also, it is pos combination products are not formulated together in a single sible to control the release of one of these components in the dosage form, the compounds of the present invention and gastrointestinal tract such that one of these components is not other therapeutic compounds described herein may be admin 35 released in the stomach but rather is released in the intestines. istered at the same time (that is, together), or in any order. Another embodiment of this invention where oral adminis When not administered at the same time, preferably the tration is desired provides for a combination product wherein administration of a compound of the invention and other one of the active ingredients is coated with a Sustained-release therapeutic compounds as described herein occurs less than material that effects a Sustained-release throughout the gas about one hour apart, more preferably less than about 30 40 trointestinal tract and also serves to minimize physical con minutes apart, even more preferably less than about 15 min tact between the combined active ingredients. Furthermore, utes apart, and still more preferably less than about 5 minutes the Sustained-released component can be additionally enteric apart. Preferably, administration of the combination products coated Such that the release of this component occurs only in of the invention is oral, although other routes of administra the intestine. Still another approach would involve the formu tion, as described above, are contemplated to be within the 45 lation of a combination product in which the one component scope of the present invention. Although it is preferable that is coated with a Sustained and/or enteric release polymer, and the compound of the invention and other therapeutic com the other component is also coated with a polymer Such as a pounds as described herein are both administered in the same low-viscosity grade of hydroxypropyl methylcellulose fashion (that is, for example, both orally), if desired, they may (HPMC) or other appropriate materials as known in the art, in each be administered in different fashions (that is, for 50 order to further separate the active components. The polymer example, one component of the combination product may be coating serves to forman additional barrier to interaction with administered orally, and another component may be admin the other component. istered intravenously). The dosage of the combination prod Dosage forms of the combination products of the present ucts of the invention may vary depending upon various fac invention wherein one active ingredient is enteric coated can tors such as the pharmacodynamic characteristics of the 55 be in the form of tablets such that the enteric coated compo particular agent and its mode and route of administration, the nent and the other active ingredient are blended together and age, health and weight of the recipient, the nature and extent then compressed into a tablet or such that the enteric coated of the symptoms, the kind of concurrent treatment, the fre component is compressed into one tablet layer and the other quency of treatment, and the effect desired. active ingredient is compressed into an additional layer. Although the properdosage of the combination products of 60 Optionally, in order to further separate the two layers, one or this invention will be readily ascertainable by one skilled in more placebo layers may be present such that the placebo the art, once armed with the present disclosure, by way of layer is between the layers of active ingredients. In addition, general guidance, where one or more compounds of the dosage forms of the present invention can be in the form of present invention is combined with one or more other thera capsules wherein one active ingredient is compressed into a peutic compounds as described herein, for example, typically 65 tablet or in the form of a plurality of microtablets, particles, a daily dosage may range from about 0.01 to about 100 granules or non-perils, which are then enteric coated. These milligrams of the compound of the invention (and all combi enteric coated microtablets, particles, granules or non-perils US 7,576,207 B2 25 26 are then placed into a capsule or compressed into a capsule LincoSumides Such as Clindamycin and Lincomycin; along with a granulation of the other active ingredient. Macrollides such as Azithromycin, Carbomycin, Clarithro These as well as other ways of minimizing contact between mycin, Erythromycin(s) and Derivatives, Josamycin, Leuco the components of combination products of the present inven mycins, Midecamycins, Miokamycin, Oleandomycin, Pri tion, whether administered in a single dosage form or admin mycin, Rokitamycin, Rosaramicin, Roxithromycin, istered in separate forms but at the same time by the same Spiramycin and Troleandomycin; manner, will be readily apparent to those skilled in the art, Polypeptides Such as Amphomycin, Bacitracin, Capreo once armed with the present disclosure. mycin, Colistin, Enduracidin, Enviomycin, Fusafungine, The dose may also be provided by controlled release of the Gramicidin(s), Gramicidin S. Mikamycin, Polymyxin, Poly compound, by techniques well known to those in the art. 10 myxin B-Methanesulfonic Acid, Pristinamycin, Ristocetin, The compounds of the invention may also be formulated Teicoplanin, Thiostrepton, Tuberactinomycin, Tyrocidine, with other optional active ingredients, in addition to or instead Tyrothricin, Vancomycin, Viomycin(s), Virginiamycin and of the optional opioids, and in addition to the optional phar Zinc Bacitracin; maceutical-acceptable carriers. Other active ingredients Tetracyclines such as Spicycline, Chlortetracycline, Clo include, but are not limited to, antibiotics, antivirals, antifun 15 mocycline, Demeclocycline, Doxycycline, Guamecycline, gals, anti-inflammatories, including steroidal and non-steroi Lymecycline, Meclocycline, Methacycline, Minocycline, dal anti-inflammatories, anesthetics, cardioprotective agents, Oxytetracycline, Penimepicycline, Pipacycline, Rolitetracy and mixtures thereof. Such additional ingredients include any cline, Sancycline, Senociclin and Tetracycline; and of the following: others such as Cycloserine, Mupirocin, Tuberin. a. Antibacterial Agents b. Synthetic Antibacterials Aminoglycosides, such as Amikacin, Apramycin, Arbeka 2,4-Diaminopyrimidines such as Brodimoprim, TetroX cin, Bambermycins, Butirosin, Dibekacin, Dihydrostrepto oprim and Trimethoprim; mycin, Fortimicin(s), Fradiomycin, Gentamicin, Ispamicin, Nitrofurans such as Furaltadone, Furazolium, Nifuradene, Kanamycin, Micronomicin, Neomycin, Neomycin Unde 25 Nifuratel, Nifurfoline, Nifurpirinol, Nifurprazine, Nifurtoi cylenate, Netilmicin, Paromomycin, Ribostamycin, Sisomi nol and Nitrofurantoin: cin, Spectinomycin, Streptomycin, Streptonicozid and Quinolones and analogs thereof. Such as Amifloxacin, Tobramycin; Cinoxacin, Ciprofloxacin, Difloxacin, Enoxacin, Fleroxacin, Amphenicols, such as AZidamfenicol, Chloramphenicol, Flumequine, Lomefloxacin, Miloxacin, Nalidixic Acid, Nor Chloramphenicol Palmirate, Chloramphenicol Pantothenate, 30 floxacin, Ofloxacin, Oxolinic Acid, Perfloxacin, Pipemidic Florfenicol. Thiamphenicol; Acid, Piromidic Acid, Rosoxacin, Temafloxacin and Tosu Ansamycins, such as Rifamide, Rifampin, Rifamycin and floxacin: Rifaximin: Sulfonamides Such as Acetyl Sulfamethoxypyrazine, B-Lactams; Acetyl Sulfisoxazole, AZosulfamide, Benzylsulfamide, Carbapenems, such as Imipenem; 35 Chloramine-B, Chloramine-T, Dichloramine-T, Formosul Cephalosporins, such as 1-Carba (dethia) Cephalosporin, fathiazole, N-Formyl-sulfisomidine, N'-(B-D-Glucosylsul Cefactor, Cefadroxil, Cefamandole, Cefatrizine, Cefazedone, fanilamide, Mafenide, 4'-(Methyl-sulfamoyl)sulfanilanilide, Cefazolin, Cefixime, Cefnmenoxime, Cefodizime, Cefonicid, p-Nitrosulfathiazole, Noprylsulfamide, Phthalylsulfaceta CefoperaZone, Ceforanide, Cefotaxime, Cefotiam, Ce?pimi mide, Phthalylsulfathiazole, Salazosulfadimidine. Succinyl Zole, Ce?pirimide, Cefpodoxime Proxetil, Cefroxadine, Cef 40 sulfathiazole, Sulfabenzamide, Sulfacetamide, Sulfachlorpy Sulodin, Ceftazidime, Cefteram, Ceftezole, Ceftibuten, Cefti ridazine, Sulfachrysoidine, Sulfacytine, Sulfadiazine, Zoxime, Ceftriaxone, Cefuroxime, Cefuzonam, Cephacetrile Sulfadicramide, Sulfadimethoxine, Sulfadoxine, Sulfaethi Sodium, Cephalexin, Cephaloglycin, Cephaloridine, Cepha dole, Sulfaguanidine, Sulfaguanol, Sulfalene, Sulfaloxic losporin, Cephalothin, Cephapirin Sodium, Cephradine and Acid, Sulfamerazine, Sulfameter, Sulfamethazine, Sulfame 45 thizole, Sulfamethomidine, Sulfamethoxazole, Sul Pivcefalexin: famethoxypyridazine, Sulfametrole, Sulfamidochrysoidine, Cephamycins such as CefbuperaZone, Cefnetazole, Sulfamoxole, Sulfanilamide, Sulfanilamidomethanesulfonic Cefninox, Cefetan and Cefoxitin; Acid Triethanolamine Salt, 4-Sulfanilamidosalicyclic Acid, Monobactams such as Aztreonam, Carumonam and Tige N-Sulfanilylsulfanilamide, Sulfanillylurea, N-Sulfanilyl-3, monan, 50 4-xylamide, Sulfanitran, Sulfaperine, Sulfaphenazole, Sul Oxacephems such as Flomoxef and Moxolactam: faproxyline, Sulfapyrazine, Sulfapyridine, Sulfasomizole, Penicillins such as Amidinocillin, Amdinocillin, Pivoxil, Sulfasymazine, Sulfathiazole, Sulfathiourea, Sulfatolamide, Amoxicillin, Ampicillan, Apalcillin, Aspoxicillin, AZidocil Sulfisomidine and Sulfisoxazole; lan, AZlocillan, Bacampicillin, Benzylpenicillinic Acid, Ben Sulfones, such as Acedapsone, Acediasulfone, Acetosul Zylpenicillin, Carbenicillin, Carfecillin, Carindacillin, Clom 55 fone, Dapsone, Diathymosulfone, Glucosulfone, Solasul etocillin, Cloxacillin, Cyclacillin, Dicloxacillin, fone, Succisulfone, Sulfanilic Acid, p-Sulfanilylbenzy Diphenicillin, Epicillin, Fenbenicillin, Floxicillin, Hetacillin, lamine, pp'-sulfonyldianiline-N,N'-digalactoside, Sulfoxone Lenampicillin, Metampicillin, Methicillin, Mezlocillin, and Thiazolsulfone; Nafcillin, Oxacillin, Penamecillin, Penethamate Hydriodide, Others such as Clofoctol, Hexedine, Magainins, Meth Penicillin G Benethamine, Penicillin G BenZathine, Penicil 60 enamine, Methenamine Anhydromethylene-citrate, Meth lin G Benzhydrylamine, Penicillin G Calcium, Penicillin G enamine Hippurate, Methenamine Mandelate, Methenamine Hydragamine, Penicillin G Potassium, Penicillin G. Sulfosalicylate, Nitroxoline, Squalamine and Xibomol. Procaine, PenicillinN, Penicillin O, Penicillin V, Penicillin V Benzathine, Penicillin V Hydrabamine, Penimepicycline, c. Antifungal (Antibiotics) Phenethicillin, Piperacillin, Pivapicillin, Propicillin, 65 Polyenes such as Amphotericin-B, Candicidin, Dermosta Quinacillin, Sulbenicillin, Talampicillin, Temocillin and tin, Filipin, Fungichromin, Hachimycin, Hamycin, Lucenso Ticarcillin; mycin, Mepartricin, Natamycin, Nystatin, Pecilocin, Perimy US 7,576,207 B2 27 28 cin; and others, such as AZaserine, Griseofulvin, Nitrofurans such as Furazolidone, 2-(Methoxymethyl)-5- Oligomycins, Pyrrolnitrin, Siccanin, Tubercidin and Viridin. Nitrofuran, Nidroxy Zone, Nifuroxime, Nifurzide and Nitro furaZone; d. Antifungal (Synthetic) Phenols such as Acetomeroctol, Chloroxylenol, Hexachlo Allylamines such as Naftifine and terbinafine; rophene, 1-Naphthyl Salicylate, 2.4.6-Tribromo-m-cresol Imidazoles such as Bifonazole, Butoconazole, Chlordan and 3',4',5-Trichlorosalicylanilide; toin, Chlormidazole, Cloconazole, Clotrimazole, Econazole, Quinolines such as Aminoquinuride, Chloroxine, Chlo Enilconazole, Finticonazole, Isoconazole, Ketoconazole, rquinaldol, Cloxyquin, Ethylhydrocupreine, Halquinol, Miconazole, Omoconazole, Oxiconazole Nitrate, Sulcona Hydrastine, 8-Hydroxyquinoline and Sulfate; and Zole and Tioconazole; 10 others, such as Boric Acid, Chloroazodin, m-Cresyl Triazoles such as Fluconazole, Itraconazole, Terconazole; Acetate, Cupric Sulfate and Ichthammol. Others such as Acrisorcin, Amorolfine, Biphenamine, Bro h. Antivirals mosalicylchloranilide, Buclosamide, Chlophenesin, Ciclo Purines/Pyrimidinones, such as 2-Acetyl-Pyridine 5-((2- pirox, Cloxyquin, Coparaffinate, Diamthazole, Dihydrochlo pyridylamino)thiocarbonyl) ThiocarbonohydraZone, Acy ride. Exalamide, Flucytosine, Halethazole, Hexetidine, 15 Loflucarban, Nifuratel, Potassium Iodide, Propionic Acid, clovir, Dideoxyadenosine, Dideoxycytidine, Dideoxyi Pyrithione, Salicylanilide, Sulbentine, Tenonitrozole, Tolci nosine, Edoxudine, Floxuridine, Ganciclovir, Idoxuridine, clate, Tolindate, Tolnaftate, Tricetin, Ujothion, and Unde MADU, Pyridinone, Trifluridine, Vidrarbine and Zidovud cylenic Acid. line; others such as Acetylleucine Monoethanolamine, Acridi e. Antiglaucoma Agents namine, Alkylisooxazoles, Amantadine, Amidinomycin, Antiglaucoma agents, such as Dapiprazoke, Dichlorphe Cuminaldehyde Thiosemicarbzone, Foscamet Sodium, namide, Dipivefrin and Pilocarpine. Kethoxal, Lysozyme, Methisazone, Moroxydine, Podophyl lotoxin, Ribavirin, Rimantadine, Stallimycin, Statolon, Thy f. Anti-inflammatory Agents mosins, Tromantadine and Xenazoic Acid. Corticosteroids, aminoarylcarboxylic Acid Derivatives 25 such as Etofenamate, Meclofenamic Acid, Mefanamic Acid, i. Agents for Neuralgia/Neuropathic Pain Niflumic Acid; Mild OTC (over the counter) analgesics, such as aspirin, Arylacetic Acid Derivatives such as Acemetacin, Amfenac acetaminophen, and ibuprophen. Cinmetacin, Clopirac, Diclofenac, Fenclofenac, Fenclorac, Narcotic analgesics, such as codeine. Fenclozic Acid, Fentiazac, Glucametacin, ISOZepac, Lona 30 Anti seizure medications, such as carbamazepine, gabap Zolac, Metiazinic Acid, Oxametacine, Proglumetacin, Sulin entin, lamotrigine and phenyloin. dac, Tiaramide and Tolimetin: Anti-depressants, such as amitryptiline. Arylbutyric Acid Derivatives such as Butibufen and Fen j. Agents for the Treatment of Depression bufen; Selective serotonin re-uptake inhibitors (SSRIs), such as Arylcarboxylic Acids such as Clidanac, Ketorolac and 35 Fluoxetine, Paroxetine, Fluvoxamine, Citaprolam, and Ser Tinoridine; traline. Arylpropionic Acid Derivatives such as Bucloxic Acid, Tricyclics, such as , , Carprofen, Fenoprofen, Flunoxaprofen, Ibuprofen, Ibu , Protriptyline, Trimipramine, Doxepin, , and Clomipramine. proxam, Oxaprozin, Piketoprofen, Pirprofen, Pranoprofen, 40 Protizinic Acid and Tiaprofenic Add: Monoamine Oxidase Inhibitors (MAOIs), such as Tranyl Pyrazoles such as Mepirizole; cypromine, Phenelzine, and Isocarboxazid. Pyrazolones such as ClofeZone, Feprazone, Mofebuta Heterocyclics, such as Amoxipine, Maprotiline and TraZ Zone, Oxyphenbutazone, Phenylbutazone, Phenyl Pyrazoli odone. dininones, SuXibuZone and ThiazolinobutaZone; 45 others such as Venlafaxine, Nefazodone and . Salicylic Acid Derivatives such as Bromosaligenin, Fen k. Agents for the Treatment of Incontinence dosal, Glycol Salicylate, Mesalamine, 1-Naphthyl Salicylate, agents such as propantheline. Olsalazine and Sulfasalazine; Antispasmodic medications such as Oxybutynin, tolterod Thiazinecarboxamides Such as Droxicam, Isoxicam and ine, and flavoxate. Piroxicam, 50 Tricyclic antidepressants such as imipramine, and doxepin. Others such as e-Acetamidocaproic Acid, S-Adenosylme Calcium channel blockers such as tolterodine. thionine, 3-Amino-4-hydroxybutyric Acid, Amixetrine, Beta agonists such as terbutaline. Bendazac, Bucolome, Carbazones, Difenpiramide, Ditazol, 1. AntiParkinson's Agents GuaiaZulene, Heterocyclic Aminoalkyl Esters of Mycophe Deprenyl, Amantadine, Levodopa, and Carbidopa. nolic Acid and Derivatives, Nabumetone, Nimesulide, Orgot 55 ein, Oxaceprol, Oxazole Derivatives, Paranyline, Pifoxime, m. Agents for the Treatment of Cardiac Disorders 2-substituted-4,6-di-tertiary-butyl-s-hydroxy-1,3-pyrim Nitrates, beta- blockers, calcium channel idines, ProquaZone and Tenidap. antagonists, ACE inhibitors, non-peptide angiotension II antagonists, IIb/IIIa antagonists, and aspirin. g. Antiseptics 60 Pharmaceutical kits useful in, for example, the treatment of Guanidines such as Alexidine, Ambazone, Chlorhexidine pain, which comprise a therapeutically effective amount of a and Picloxydine: compound of the invention and/or opioid and/or other thera Halogens/Halogen Compounds such as Bomyl Chloride, peutic compounds described herein, in one or more sterile Calcium Iodate, Iodine, Iodine Monochloride, Iodine containers, are also within the ambit of the present invention. Trichloride, Iodoform, Povidone-Iodine, Sodium Hypochlo 65 Sterilization of the container may be carried out using con rite, Sodium Iodate, Symclosene, Thymol Iodide, Triclocar ventional sterilization methodology well known to those ban, Triclosan and Troclosene Potassium; skilled in the art. The sterile containers of materials may US 7,576,207 B2 29 30 comprise separate containers, or one or more multi-part con methods for providing and maintaining an anesthetic state, in tainers, as exemplified by the UNIVIALTM two-part container methods for improving organ and cell Survival, and in meth (available from Abbott Labs, Chicago, Ill.), as desired. The ods of detecting, imaging, or monitoring degeneration or compound of the invention and/or opioid and/or other thera dysfunction of opioid receptors in a patient. peutic compound as described herein may be separate, or Compounds of the invention may be useful as analgesic combined into a single dosage form as described above. Such agents for use during general anesthesia and monitored anes kits may further include, if desired, one or more of various thesia care. Combinations of agents with different properties conventional pharmaceutical kit components. Such as for are often used to achieve a balance of effects needed to main example, one or more pharmaceutically acceptable carriers, tain the anesthetic state (e.g., amnesia, analgesia, muscle additional vials for mixing the components, etc., as will be 10 relaxation and sedation). Included in this combination are readily apparent to those skilled in the art. Instructions, either inhaled anesthetics, hypnotics, anxiolytics, neuromuscular as inserts or as labels, indicating quantities of the components blockers and opioids. to be administered, guidelines for administration, and/or Thus, in accordance with preferred aspects of the inven guidelines for mixing the components, may also be included tion, there are provided methods of treating pain, comprising in the kit. 15 the step of administering to a patient an effective amount of a In certain embodiments, the pharmaceutical compositions compound of the invention including, for example, a com may further comprise an effective amount of at least one of pound of formula I, II, III, IV, and/or V. In certain preferred the group consisting of an opioid, an agent for the treatment embodiments, the method further comprises administering to of neuralgia/neuropathic pain, an agent for the treatment of the patient an effective amount of an opioid, the opioid pref depression, an agent for the treatment of incontinence, an erably selected from the group consisting of alfentanil, allyl anti-Parkinson's agent, and an agent for the treatment of , alphaprodine, anilleridine, benzyl-morphine, bezit cardiac disorders. Even more preferably, the pharmaceutical ramide, buprenorphine, butorphanol, clonitaZene, codeine, compositions may further comprise an antibiotic, antiviral, cyclazocine, desomorphine, , dezocine, antifungal, anti-inflammatory, anesthetic, or mixture thereof. diampromide, diamorphone, , dihydromor In certain aspects, the compounds of the invention are 25 phine, dimenoxadol, dimepheptanol, dimethylthiambutene, ligands of the Ö-opioid receptor. As such, the invention, in dioaphetylbutyrate, dipipanone, , ethoheptazine, part, is directed to methods of binding opioid receptors, pref ethylmethylthiambutene, , etonitaZene, fenta erably 6-opioid receptors, in a patient in need thereof, com nyl, heroin, hydrocodone, , hydroxypethi prising the step of administering to said patient an effective dine, isomethadone, ketobemidone, levallorphan, levorpha amount of a compound of the invention including, for 30 nol, levophenacylmorphan, lofentanil, loperamide, example, a compound of formula I, II, III, IV, and/or V. The meperidine, meptazinol, metazocine, methadone, metopon, Ö-opioid receptors may be located in the central nervous morphine, myrophine, nalbuphine, narceline, nicomorphine, system or located peripherally to the central nervous system. norlevorphanol, normethadone, nalorphine, normorphine, In certain preferred embodiments, the binding of the present norpinanone, opium, oxycodone, oxymorphone, papavere compounds modulates the activity, preferably as an agonist, 35 turn, pentazocine, phenadoxone, phenomorphan, phanaZo of said opioid receptors. In certain preferred embodiments, cine, phenoperidine, piminodine, piritramide, propheptazine, the compound of formula I, II, III, IV, or V does not substan promedol, properidine, , propoxyphene, Sulfentanil, tially cross the blood-brain barrier. Preferably, the com tilidine, and tramadol, or a mixture thereof. pounds of the present invention are peripherally selective. In other preferred aspects of the invention, there are pro The spirocyclic heterocyclic derivatives of the present 40 vided methods of treating gastrointestinal dysfunction, com invention and pharmaceutical compositions containing these prising the step of administering to a patient an effective compounds may be utilized in a number of ways. In certain amount of a compound of the invention including, for embodiments, the Spirocyclic heterocyclic derivatives are example, a compound of formula I, II, III, IV, and/or V. ligands of the 6-opioid receptor and are useful, interalia, in In some preferred aspects of the invention, there are pro methods for treating pain, gastrointestinal dysfunction, uro 45 vided methods of treating a urogenital tract disorder, the genital tract disorders including incontinence, for example, urogenital tract disorder preferably selected from overactive stress urinary incontinence, urge urinary incontinence and bladder and incontinence, wherein the incontinence is pref benign prostatic hyperplasia, and overactive bladder disorder erably stressurinary or urge urinary incontinence, more pref (see, e.g., R. B. Moreland et al., Perspectives in Pharmacol erably overactive bladder, comprising the step of administer ogy, Vol. 308(3), pp. 797-804 (2004) and M. O. Fraser, 50 ing to a patient an effective amount of a compound of the Annual Reports in Medicinal Chemistry, Chapter 6, pp. 51-60 invention including, for example, a compound of formula I, (2003), the disclosures of which are hereby incorporated II, III, IV, and/or V. Thus, in some preferred methods of herein by reference, in their entireties), immunomodulatory treating urogenital tract disorder, the method further com disorders, inflammatory disorders, respiratory function dis prises administering to the patient an effective amount of an orders, depression, anxiety, attention deficit hyperactivity 55 agent for the treatment of incontinence. disorder, mood disorders, stress-related disorders, sympa In certain preferred aspects of the invention, there are pro thetic nervous system disorder, tussis, motor disorder, trau vided methods of treating an immunomodulatory disorder, matic injury to the central nervous system, stroke, cardiac the immunomodulatory disorder preferably selected from the arrhythmia, glaucoma, sexual dysfunction, shock, brain group consisting of an autoimmune disease, a collagen dis edema, cerebral ischemia, cerebral deficits Subsequent to car 60 ease, an allergy, a side effect associated with the administra diac bypass Surgery and grafting, systemic lupus erythema tion of an anti-tumor agent, and a side effect associated with tosus, Hodgkin’s disease, Sjogren's disease, epilepsy, and the administration of an antiviral agent, comprising the step rejection in organ transplants and skin grafts, and Substance of administering to a patient an effective amount of a com addiction. In certain other embodiments, the spirocyclic het pound of the invention including, for example, a compound of erocyclic derivatives are ligands of the 6-opioid receptor and 65 formula I, II, III, IV, and/or V. Thus, in some preferred meth are useful, interalia, in methods for providing cardioprotec ods of treating an immunomodulatory disorder, the autoim tion, in methods for reducing the need for anesthesia, in mune disease treated is selected from the group consisting of US 7,576,207 B2 31 32 arthritis, an autoimmune disorder associated with a skin graft, tremors, the method further comprises the step of administer an autoimmune disorder associated with organ transplant, ing to said patient an effective amount of an anti-Parkinson's and an autoimmune disorder associated with Surgery. agent. In certain other preferred aspects of the invention, there are In certain other preferred aspects of the invention, there are provided methods of treating an inflammatory disorder, the 5 provided methods of treating a traumatic injury to the central inflammatory disorder preferably selected from the group nervous system, wherein the traumatic injury to the central consisting of arthritis, psoriasis, asthma, or inflammatory nervous system is preferably selected from the group consist bowel disease, comprising the step of administering to a ing of a traumatic injury to the spinal cord or brain, compris patient an effective amount of a compound of the invention ing the step of administering to a patient an effective amount including, for example, a compound of formula I, II, III, IV, 10 of a compound of the invention including, for example, a and/or V. compound of formula I, II, III, IV, and/or V. In yet other preferred aspects of the invention, there are In certain other preferred aspects of the invention, there are provided methods of treating a respiratory function disorder, provided methods of treating a stroke, comprising the step of the respiratory function disorder preferably selected from the administering to a patient an effective amount of a compound group consisting of asthma and lung edema, comprising the 15 of the invention including, for example, a compound of for step of administering to a patient an effective amount of a mula I, II, III, IV, and/or V. compound of the invention including, for example, a com In certain other preferred aspects of the invention, there are pound of formula I, II, III, IV, and/or V. provided methods of treating a cardiac arrhythmia, compris In certain other preferred aspects of the invention, there are ing the step of administering to a patient an effective amount provided methods of treating anxiety, comprising the step of of a compound of the invention including, for example, a administering to a patient an effective amount of a compound compound of formula I, II, III, IV, and/or V. of the invention including, for example, a compound of for In certain other preferred aspects of the invention, there are mula I, II, III, IV, and/or V. provided methods of treating glaucoma, comprising the step In certain other preferred aspects of the invention, there are of administering to a patient an effective amount of a com provided methods of treating a mood disorder, wherein the 25 pound of the invention including, for example, a compound of mood disorder is preferably selected from the group consist formula I, II, III, IV, and/or V. ing of depression, bipolar manic-depression, and seasonal In certain other preferred aspects of the invention, there are affective disorder, comprising the step of administering to a provided methods of treating sexual dysfunction, wherein the patient an effective amount of a compound of the invention sexual dysfunction is preferably premature ejaculation, com including, for example, a compound of formula I, II, III, IV, 30 prising the step of administering to a patient an effective and/or V. In certain of the methods herein provided for treat amount of a compound of the invention including, for ing a mood disorder, the method further comprises the step of example, a compound of formula I, II, III, IV, and/or V. administering to said patient an effective amount of an agent In certain other preferred aspects of the invention, there are for the treatment of depression. provided methods of treating Substance addiction, wherein In certain other preferred aspects of the invention, there are 35 the Substance addiction is preferably alcohol addiction, nico provided methods of treating a stress-related disorder, tine addiction, or drug addiction, more preferably drug addic wherein the stress-related disorder is preferably selected from tion, especially where the drugs are opioids, comprising the the group consisting of post-traumatic stress disorder, panic step of administering to a patient an effective amount of a disorder, generalized anxiety disorder, Social phobia, and compound of the invention including, for example, a com obsessive-compulsive disorder, comprising the step of 40 pound of formula I, II, III, IV, and/or V. administering to a patient an effective amount of a compound In certain other preferred aspects of the invention, there are of the invention including, for example, a compound of for provided methods of treating a condition selected from the mula I, II, III, IV, and/or V. group consisting of shock, brain edema, cerebral ischemia, In certain other preferred aspects of the invention, there are cerebral deficits Subsequent to cardiac bypass Surgery and provided methods of treating attention deficit hyperactivity 45 grafting, systemic lupus erythematosus, Hodgkin's disease, disorder, comprising the step of administering to a patient an Sjogren's disease, epilepsy, and rejection in organ transplants effective amount of a compound of the invention including, and skin grafts, comprising the step of administering to a for example, a compound of formula I, II, III, IV, and/or V. patient an effective amount of a compound of the invention In certain other preferred aspects of the invention, there are including, for example, a compound of formula I, II, III, IV, provided methods of treating a sympathetic nervous system 50 and/or V. disorder, preferably hypertension, comprising the step of In certain other preferred aspects of the invention, there are administering to a patient an effective amount of a compound provided methods for improving organ and cell Survival, of the invention including, for example, a compound of for comprising the step of administering to a patient an effective mula I, II, III, IV, and/or V. amount of a compound of the invention including, for In certain other preferred aspects of the invention, there are 55 example, a compound of formula I, II, III, IV, and/or V. provided methods of treating tussis, comprising the step of Techniques for evaluating and/or employing the present administering to a patient an effective amount of a compound compounds in methods for improving organ and cell Survival of the invention including, for example, a compound of for and organ preservation are described, for example, in C. V. mula I, II, III, IV, and/or V. Borlongan et al. Frontiers in Bioscience (2004), 9(Suppl.), In certain other preferred aspects of the invention, there are 60 3392-3398, Su, Journal of Biomedical Science (Basel) provided methods of treating a motor disorder, wherein the (2000), 7(3), 195-199, and U.S. Pat. No. 5,656,420, the dis motor disorder is preferably selected from the group consist closures of each of which are hereby incorporated herein by ing of tremors, Parkinson's disease, Tourette's syndrome, and reference in their entireties. dyskenesia, more preferably tremors, comprising the step of In certain other preferred aspects of the invention, there are administering to a patient an effective amount of a compound 65 provided methods for providing cardioprotection, compris of the invention including, for example, a compound of for ing the step of administering to a patient an effective amount mula I, II, III, IV, and/or V. In certain methods of treating of a compound of the invention including, for example, a US 7,576,207 B2 33 34 compound of formula I, II, III, IV, and/or V. In preferred form, The present invention will now be illustrated by reference the methods may be used in the treatment of ischemic dam to the following specific, non-limiting examples. Those age. skilled in the art of organic synthesis may be aware of still Accordingly, the methods and compositions of the present other synthetic routes to the invention compounds. The invention may be employed to protect against ischemia and reperfusion injuries. reagents and intermediates used herein are commercially In connection with preferred embodiments, the compound available or may be prepared according to standard literature of the invention may be administered prior to, during, or after procedures. the ischemic event. In embodiments involving patients who Methods of Preparation are to undergo heart Surgery, the compound of the invention 10 may preferably be administered before the surgery. Also in The synthesis of compounds 1A-1E is outlined in Scheme certain preferred embodiments, the methods may further 1. Palladium catalyzed Negishi-type coupling of 1.1 Dolle, comprise the co-administration of an agent for treating a R. E.; et al., WO2005033073 with zinc bromide reagents 1.2 cardiac disorder. or 1.3, conducted in tetrahydrofuran using tetrakistriph Techniques for evaluating and/or employing the present 15 enylphosphine palladium (0) as catalyst, provided the methyl compounds in methods for providing cardioprotection are esters 1.4a and 1.4b, respectively. The esters 1.4a and 1.4b described, for example, in Watson, et al., J. Pharm. Exp. Ther. were hydrolyzed under basic conditions to give carboxylic 316: 423-430 (2006), WO 2004/060321 A2 and WO acid derivatives 1.5a and 1.5b, respectively. Coupling of car 99/04795, the disclosures of each of which are hereby incor porated herein by reference in their entireties. boxylic acid derivatives 1.5a and 1.5b with diethylamine (1.6) In certain other preferred aspects of the invention, there are using O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium provided methods for reducing the need for anesthesia, com tetrafluoroborate (TBTU) as coupling agent afforded tertiary prising the step of administering to a patient an effective amides 1.7a and 1.7b, respectively. Treatment of the Boc amount of a compound of the invention including, for derivatives 1.7a, 1.7b and 1.4b with hydrochloric acid pro example, a compound of formula I, II, III, IV, and/or V. 25 vided the final compounds 1A, 1B, and 1E, respectively. In certain other preferred aspects of the invention, there are Palladium catalyzed hydrogenation of 1A and 1B provided provided methods for producing or maintaining an anesthetic the compounds 1C and 1D, respectively. state, comprising the step of administering to a patient an effective amount of a compound of the invention including, for example, a compound of formula I, II, III, IV, and/or V. In 30 some more preferred embodiments, the method further com Scheme 1: prises administering to the patient an anesthetic agent selected from the group consisting of an inhaled anesthetic, N-1 O sa.pi an hypnotic, an anxiolytic, a neuromuscular blocker, and an F3CN -O opioid, with co-administration of the anesthetic agent and the 35 S O compound of the invention being even more preferred. M \, n = 2: 1.2 Additional diseases and/or disorders which may be treated O O O n = 3: 1.3 with the compounds and pharmaceutical compositions of the present invention include those described, for example, in WO2004/062562 A2, WO 2004/063157 A1, WO 2004/ 40 063193 A1, WO 2004/041801 A1, WO 2004/041784A1, WO 2004/041800 A1, WO 2004/060321 A2, WO 2004/035541 A1, WO 2004/035574 A2, WO 2004041802 A1, US 2004082612 A1, WO 2004026819 A2, WO 2003057223 A1, WO 2003037342 A1, WO 2002094812 A1, WO 2002094810 45 A1, WO 2002094794 A1, WO 2002094786 A1, WO 2002094785 A1, WO 2002094784A1, WO 2002094782 A1, WO 2002094783 A1, WO 2002094811 A1, the disclosures of each of which are hereby incorporated herein by reference in their entireties. 50 In certain aspects, the present invention is directed to radio labeled derivatives and isotopically labeled derivatives of compounds of the invention including, for example, com pounds of formula I, II, III, IV, and/or V. Suitable labels include, for example, H, H, ''C, C, N, N, O, O, 55 LiOH, H2O, MeOH, THF, H2O 'F and S. Such labeled derivatives may be useful for bio He logical studies and/or diagnostic imaging including, for step 1.2 example, using positron emission tomography, for metabolite identification studies and the like. Such diagnostic imaging methods may comprise, for example, administering to a 60 patient a radiolabeled derivative or isotopically labeled derivative of a compound of the invention including, for example a compound of formula I, II, III, IV, and/or V, and imaging the patient, for example, by application of Suitable energy, Such as in positron emission tomography. Isotopi 65 = cally- and radio-labeled derivatives may be prepared utilizing = techniques well known to the ordinarily skilled artisan. US 7,576,207 B2 35 36

-continued -continued

EtNH (1.6), TBTU, iPrEtN, CH3CN He anh. HC step 1.3 dioxane, CHCl2 step 1.6

anh. HCl, dioxane,CHCl2 N1 O Her 25 step 1.4

30 N

The synthesis of compounds 2A-2G is outlined in Scheme 35 2. Palladium catalyzed hydrogenation of 1.4b provided the provided the ester 2.1. The ester 2.1 was hydrolyzed under basic conditions to give the carboxylic acid derivative 2.2. Coupling of the carboxylic acid 2.2 with the amines 2.3a, 40 2.3b, 2.3c or 2.3d, using 2-chloro-1-methylpyridinium iodide (Mukaiyama acylating reagent) as coupling agent afforded the corresponding aminocarbonyl derivatives 2.5, which were converted to the compounds 2A-D under acidic condi H2, Pd/C, MeOH tions. Palladium catalyzed Negishi-type coupling of 1.1 with - I - 45 Zinc bromide reagent 2.6, conducted in tetrahydrofuran using tetrakistriphenylphosphine palladium (0) as catalyst, pro vided the ester 2.7, which was converted to 2.8 by hydroge nation. The ester 2.8 was hydrolyzed under basic conditions to give the carboxylic acid derivative 2.9. Coupling of the 50 carboxylic acid 2.9 with diethylamine (1.6), using 2-chloro 1-methylpyridinium iodide (Mukaiyama acylating reagent) as coupling agent afforded the corresponding aminocarbonyl derivative 2.10, which was converted to the compound 2E 55 under acidic conditions. Palladium catalyzed Negishi-type coupling of 1.1 with Zinc bromide reagent 2.11, conducted in N-N pi tetrahydrofuran using tetrakistriphenylphosphinepalladium (O) as catalyst, provided the ester 2.12, which was converted O O to 2.13 by hydrogenation. The ester 2.13 was hydrolyzed " under basic conditions to give the carboxylic acid derivative 2.14. Coupling of the carboxylic acid 2.14 with the amines 1.6 or 2.3a, using 2-chloro-1-methylpyridinium iodide (Mu N kaiyama acylating reagent) as coupling agent afforded the 2 65 corresponding aminocarbonyl derivatives 2.15, which were 3 converted to the compounds 2F-G, respectively, under acidic conditions.

US 7,576,207 B2 39

-continued -continued

HO 5 Et2NH (1.6) or anh. HCl, iPrNH (2.3a), EtO, CHCl2 O O Et3N, CHCl2 Hostep 2.9 r 2 N Nt C

-k Oluk O .2.4 15 step 2.13 2.10 2.14

R 5 R 1. 2 anh. HCl, 25 O O EtO, CHCl2 --step 2.14 N 30 N -k N1 O sa,5 es 2.15 O 2.11 1.1 -- 2.15a: R = R2 = Et Pd(P(C6H5)3)4, THF 35 step 2.10

40 R 5 H2, Pd/C, EtOAc He step 2.11 O O 45

N al-k H 2F-G 2.12 50

LiOHHO, MeOH, 55 The synthesis of compounds 3A-3C is outlined in Schemes O THF, H2O 3(a-c). Palladium catalyzed Negishi-type coupling of 3.1 Hesstep 2.12 with Zinc bromide reagent 2.6, conducted in tetrahydrofuran using tetrakistriphenylphosphinepalladium (O) as catalyst, provided the ester 3.2, which was hydrolyzed under basic 60 conditions to give the carboxylic acid derivative 3.3. Cou N -k pling of carboxylic acid derivative 3.3 with diethylamine 1s. (1.6) using O-benzotriazol-1-yl-N,N,N',N'-tetramethyluro 2.13 nium tetrafluoroborate (TBTU) as coupling agent afforded 65 the tertiary amide 3.4, which was converted to 3.5 by hydro genation. Treatment of the Boc derivative 3.5 with hydrochlo ric acid provided the final compound 3A. US 7,576,207 B2

-continued Scheme 3a. O F F

O O

F. C1W-O SV 1n O --~~ ZnBr HCl, Et2O, O CHCl2 O O 2.6 10 He Pd(P(C6H5)3)4, THF step 3.5 step 3.1 N -k 1so 15 esN -k 3.1 O F 3.5 1No

LiOH·H2O, O F MeOH, O THF, HO step 3.2 25

O esN u 30 3.2 N H O F 35 3A HO EtNH (1.6), TBTU, Palladium catalyzed Negishi-type coupling of 3.6 with iPrEtN, CH3CN He Zinc bromide reagent 2.6, conducted in tetrahydrofuran using step 3.3 O 40 tetrakistriphenylphosphinepalladium (0) as catalyst, pro vided the ester 3.7, which was hydrolyzed under basic con ditions to give the carboxylic acid derivative 3.8. Coupling of the carboxylic acid derivative 3.8 with diethylamine (1.6) using O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium 45 tetrafluoroborate (TBTU) as coupling agent afforded the ter 1s.N -k tiary amide 3.9, which was converted to 3.10 by hydrogena tion. Treatment of the Boc derivative 3.10 with hydrochloric 3.3 acid provided the final compound 3B (Scheme 3b). O F 50 1S Scheme 3b H2, Pd/C, EtOAc He O step 3.4 55 O O O FC1V-O SV 1n O --~~ ZnBr O O 2.6 Pd(P(C6H5)3)4, THF 60 N -k step 3.6 1s. alsoN -k 3.4 65 3.6 US 7,576,207 B2 43 44

-continued -continued O 1S O -

---step 3.7 10

N 15 3B

Palladium catalyzed Negishi-type coupling of 3.11 with Zinc bromide reagent 2.6, conducted in tetrahydrofuran using tetrakistriphenylphosphinepalladium (0) as catalyst, pro vided the ethyl ester 3.12, which was hydrolyzed under basic EtNH (1.6), TBTU, iPrEtN, CHCN conditions to give the carboxylic acid derivative 3.13. Cou --step 3.8 pling of carboxylic acid derivative 3.13 with diethylamine 25 (1.6) using O-benzotriazol-1-yl-N,N,N',N'-tetramethyluro nium tetrafluoroborate (TBTU) as coupling agent afforded the tertiary amide 3.14, which was converted to 3.15 by hydrogenation. Treatment of the N-Boc, O-MOM derivative 3.15 with hydrochloric acid provided the final compound 3C. 30

Scheme 3c 35 N O H2, Pd/C, O O MeOH step 3.9 40 FC1V S V -O 1n O--~~ ZnBr O O 2.6 Pd(P(C6H5)3)4, THF step 3.11 45 alsoN -k 3.11

50 O O

1n O O 55 HCl, EtO, LiOH·H2O, CHCl2 MeOH, --- step 3.10 O THF, H2O step 3.12 60

65 3.12 US 7,576,207 B2 45 46

-continued -continued O 1N HO

HO - EtNH (1.6), TBTU, iPrEtN, CH3CN 10 Hestep 3.13

N 15

The synthesis of compounds 4A-4E is outlined in Schemes 3.13 4(a-c). The Negishi coupling of the enol triflate 1.1 with zinc bromide reagent 4.1 in tetrahydrofuran in the presence of tetrakistriphenylphosphinepalladium (0) gave the nitrile 4.2, which was converted to 4.3 by hydrogenation. Treatment of 4.3 with borane-dimethyl sulfide complex afforded the pri 25 mary amine 4.4. Coupling of 4.4 with diethylcarbamoyl chlo ride (4.5) afforded the urea 4.6, which was converted to 4A under acidic conditions.

30 Scheme 4a H2, Pd/C, MeOH ---step 3.14 FC n1 O 35 S ZnBr O O O 4.1 He Pd(P(C6H5)3)4, THF step 4.1 1s.N -k 40 3.14 1s.N -k 1.1 45

50

NC 55 HCl, dioxane, O H2, Pd/C, MeOH MeOH --- Hestep 3.15 step 4.2 -k 60 -k 4.2 3.15 65 US 7,576,207 B2 47 48

-continued -continued

NC O 1) BHMeS/THF O 2) MeOH --step 4.3 ---, 10 u " O

l-k N 15 4.3 4A O HN ---, u 4.5 He EtN, CHCl2 25 Coupling of 4.4 with 2-ethylbutanoyl chloride (4.7) pro 1. -k step 4.4 vided the amide 4.8, which was converted to 4B under acidic O O

4.4 conditions. Treatment of 4.8 with methyl iodide (4.9) in the 30 O presence of sodium hydride afforded the tertiary amide ---, derivative 4.10, which was converted to 4C under acidic con H anh. HCl, O EtO, MeOH dition. Coupling of 4.4 with ethanesulfonyl chloride (4.11) - Hostep 4.5 35 provided the sulfonamide 4.12, which was converted to 4D under acidic conditions. Treatment of 4.12 with methyl iodide esN -k 40 (4.9) in the presence of sodium hydride afforded the tertiary sulfonamide derivative 4.13, which was converted to 4E 4.6 under acidic condition.

O

C

4.7 4.4 Hestep 4.6 EtN, CHCl2

US 7,576,207 B2 51 52

-continued V / 'V' N-1 Sn N H N-1 ns O O

N N H H

The synthesis of compounds 5A and 5B is outlined in Schemes. 5a and 5b. Wittig olefination of 5.1 with ethyl 2-(di -continued ethoxyphosphoryl)acetate (5.2) in the presence of sodium hydride, provided a mixture of the olefins 5.3, 5.4 and 5.5. Hydrogenation of this mixture provided the ethyl ester 5.6, N which was hydrolyzed under basic conditions to give the -- carboxylic acid derivative 5.7. Coupling of the carboxylic O O acid derivative 5.7 with diethylamine (1.6) using O-benzot riazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate 25 (TBTU) as coupling agent afforded the tertiary amide 5.8, which was converted to 5A under acidic conditions. Coupling r of the carboxylic acid derivative 5.7 with glycine methyl ester (5.9) using O-benzotriazol-1-yl-N,N,N',N'-tetramethyluro 30 -k nium tetrafluoroborate (TBTU) as coupling agent afforded 5.4 the amide 5.10, which was hydrolyzed under basic conditions to give the carboxylic acid derivative 5.11. Coupling of 5.11 with diethylamine (1.6) provided the diethylcarboxamide O derivative 5.12, which was converted to 5B under acidic con 35 N-19 ditions.

Scheme 5 a. H2, Pd/C, EtOAC ---step 5.2 40 O O O C2H5O-NC.H.O1 Nulls 1N 5.N O 5.2 45 -k NaH, THF es step 5.1 5.5 esN -k 50 5.1 N-9 O 55 LiOH·H2O, MeOH, N THF, HO --- -- step 5.3 O

60

65 US 7,576,207 B2 53

-continued -continued

O 5 HO EtNH (1.6), ulus EtNH (1.6), iPrEtN, TBTU, HO iPrEtN, TBTU, CH3CN CH3CN O O Hess -- Step 5.4 O O step 5.8

10 esN -k -k 15 5.7 5.11

N N1 anh. HCl, EtO, CHCl2 He step 5.5 25 1n N lus anh.EtO, HCl, CHCl2 O O step 5.9 -k 30 5.8

5.12 35

40 N 5A 45

H2NCH2COCH (5.9), 50 iPrEtN, TBTU, CHCN N 5.7 -ss step 5.6

O 55 LiOH·H2O, No ulus MeOH, THF, HO The synthesis of compound 6A is outlined in Scheme 6. O O Hestep 5.7 Treatment of the ethyl ester 5.6 with lithium borohydride afforded the primary alcohol 6.1 which reacted with ethyl 60 diazoacetate (6.2) in the presence of rhodium(II) acetate dimer to give the ethyl ester 6.3. Basic hydrolysis of 6.3 N provided the carboxylic acid 6.4. Coupling of the carboxylic acid derivative 6.4 with diethylamine (1.6) using O-benzot O1. O -k 65 riazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate 5.10 (TBTU) as coupling agent afforded the tertiary amide 6.5, which was converted to 6A under acidic conditions. US 7,576,207 B2 55

-continued O 5 --- EtNH (1.6), HO iPrEtN, TBTU, O CH3CN LiBH, THF step 6.4 step 6.1 10 esN -k -k 6.4

anh. HCl, 25 1n O EtO, N CHCl2 - O Hestep 6.5

30

O HO

EtO ---21 4N 6.2 35 Rh2(OAc)4, CHCl2 step 6.2

-k 40

45

50 6A N

The synthesis of compounds 7A and 7B is outlined in LiOH·H2O, 55 Scheme 7. Palladium catalyzed Negishi-type coupling of 7.1 MeOH, with Zinc bromide reagent 2.6, conducted in tetrahydrofuran THF, HO O He using tetrakistriphenylphosphinepalladium (O) as catalyst, step 6.3 provided the ethyl ester 7.2, which was converted to 7.3 by hydrogenation. The ester 7.3 was hydrolyzed under basic 60 conditions to give the carboxylic acid derivatives 7.4. Cou N pling of the carboxylic acid derivative 7.4 with diethylamine (1.6) using O-benzotriazol-1-yl-N,N,N',N'-tetramethyluro O1. O -k nium tetrafluoroborate (TBTU) as coupling agent afforded 6.3 65 the tertiary amide 7.5. Treatment of the Boc derivatives 7.4 and 7.5 with hydrochloric acid provided the final compounds 7A and 7B, respectively.

US 7,576,207 B2 59 60

-continued O F 1n u

N N 7A

The synthesis of compounds 8A-8C is outlined in Schemes -continued 8a and 8b. Palladium catalyzed Negishi-type coupling of 8.1 O with Zinc bromide reagent 2.6, conducted in tetrahydrofuran using tetrakistriphenylphosphinepalladium (0) as catalyst, 1no provided the ethyl ester 8.2, which was hydrolyzed under O 25 basic conditions to give the carboxylic acid derivative 8.3.

C Hs Coupling of the carboxylic acid derivative 8.3 with diethy step 8.2 lamine (1.6) using O-benzotriazol-1-yl-N,N,N',N'-tetram ethyluronium tetrafluoroborate (TBTU) as coupling agent 30 afforded the tertiary amide 8.4. Hydrogenation of 8.4 under 1. acidic conditions provided the final compound 8A. Palladium catalyzed Negishi-type coupling of 8.5 with zinc bromide r 8.2 35 reagent 2.6, conducted intetrahydrofuran using tetrakistriph O enylphosphinepalladium (O) as catalyst, provided the ethyl ester 8.6, which was hydrolyzed under basic conditions to O give the carboxylic acid derivative 8.7. Coupling of the car 40 boxylic acid derivative 8.7 with diethylamine (1.6) using EtNH (1.6), TBTU, iPrEtN, CHCN O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tet He step 8.3 rafluoroborate (TBTU) as coupling agent afforded the tertiary N amide 8.8. Hydrogenation of 8.8 provided the final compound 45 8B. Treatment of 8.8 with boron tribromide afforded the phenolic derivative 8.9, which was converted to 8C by hydro genation. 50

55 O dioxane, EtOAc O step 8.4 2.6 Pd(P(C6H5)3)4, THF 60 N step 8.1 ro O l O 8.1 65 8.4

US 7,576,207 B2 64

N -continued O O

HO

EtNH (1.6), TBTU, iPrEtN, CHCN He step 8.7 esN

8.7

O No

H2, Pd/C, MeOH He step 8.8 esN N

8.8 BBr, cities 8.9

O OH O OH 1n

H2, Pd/C, MeOH - Hestep 8.10

N H N 8.9

The synthesis of compounds 9A-9D is outlined in Scheme 1.1'-bis(diphenylphosphino)propane (dppp), and carbon 9. Treatment of 8.9 with di-tert-butyl dicarbonate (7.7) pro 60 monoxide, provided the methyl ester 9.4, which was hydro vided the Boc derivative 9.1, which was converted to 9.2 by lyzed under basic conditions to give the carboxylic acid derivative 9.5. Coupling of the carboxylic acid 9.5 with vari hydrogenation. Conversion of the phenol 9.2 to the triflate ous amines (9.6a; 9.6b or 2.3c) using O-benzotriazol-1-yl-N, derivative 9.3 was achieved using N-phenylbis(trifluo N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) as romethanesulphonimide) 7.9 as triflating reagent. Palladium 65 coupling agent afforded the amides 9.7. Treatment of the Boc catalyzed carbonylation of 9.3, conducted in a mixture N,N- derivatives of carboxylic acid 9.5 and the three 9.7 amides dimethylformamide/methanol using palladium (II) acetate, with hydrochloric acid provided the final compounds 9A-9D.

US 7,576,207 B2 68 mmol. 4 eq.) in one portion. The reaction mixture was stirred -continued at room temperature for 10 hours. The volatiles were removed R under reduced pressure and the remaining aqueous Solution o, was acidified with 1N hydrochloric acid until pH 2-3. The O YR, product was extracted with dichloromethane (3x100 mL) and the combined organics were dried over sodium sulfate, fil 1n HCl, Et2O, tered, and concentrated under reduced pressure. The product N CHCl2 --- was used for the next step without further purification. Yield: step 9.8 98% 10 H NMR (400 MHz, DMSO-d) & 12.17 (s, 1H), 7.24 (m, 1H), 7.16 (m, 1H), 6.92 (m, 1H), 6.86 (m. 1H), 5.56 (s, 1H), 3.65 (m, 2H), 3.20 (m, 2H), 2.61 (m, 2H), 2.43 (m, 2H), 1.76 (m. 2H), 1.56 (m. 2H), 1.40 (s, 9H). Mass Spectral Analysis m/z–371.9 (M-H) 15 N Preparation of 1.7a: To a solution of 1.5a (0.65g, 1.74 mol. 1 eq.) in acetonitrile 9.7 1. uk (30 mL) was slowly added diisopropylethylamine (0.73 mL, O O 4.18 mmol. 2.4 eq.), diethylamine 1.6 (0.54 mL, 5.22 mmol. 9.7a: R R2 = H 3 eq.) at room temperature and 10 minutes later at 0°C., 9.7b; R = methyl R2 = H O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tet 9.7c: R = Ethyl R2 = H rafluoroborate (TBTU) (0.67 g, 2.09 mmol. 1.2 eq.) portion R wise. The reaction mixture was slowly warmed to room tem o perature and stirred at room temperature for 10 hours. The O YR, volatiles were removed under reduced pressure and the resi 25 due was dissolved in ethyl acetate (200 mL). The organic solution was washed with 1M aqueous sodium bicarbonate (3x50 mL), brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: hexane/ethyl 30 acetate mixture of increasing polarity). Yield: 91% H NMR (400 MHz, CDC1) & 7.23 (m, 1H), 7.15 (m, 1H), 6.94-6.84 (m, 2H), 5.39 (s, 1H), 3.83 (m, 2H), 3.38 (q, 2H), 3.33-3.20 (m, 4H), 2.78 (m, 2H), 2.49 (m, 2H), 1.93 (m, 2H), 1.61-1.41 (m. 11H), 1.11 (m, 6H). Mass Spectral Analysis N 35 H m/Z-429.0 (M+H)" Preparation of 1A: To a solution of 1.7a (0.52g, 1.2 mmol. 1 eq.) in dichlo romethane (30 mL) was slowly added 4.0 M hydrogen chlo EXPERIMENTAL PROCEDURES 40 ride in dioxane (1.5 mL, 6 mmol. 5 eq.). The mixture was stirred at room temperature for 10 hours and two regioisomers Example 1A were detected by LC/MS. The reaction mixture was concen trated under reduced pressure and 100 mg of the isomers were Preparation of 1.4a: purified by preparative liquid chromatography to provide 65 To a solution of 1.1 (2.25 g, 5 mmol. 1 eq.) in dry tetrahy 45 mg of the pure product 1A as its trifluoroacetic acid salt. drofuran (40 mL) was added tetrakis(triphenylphosphine) "H NMR (400 MHz, CDC1,) & 9.52 (s, 1H), 9.07 (s, 1H), palladium(0) (290 mg, 0.25 mmol, 0.05 eq.) followed by 7.33-7.16 (m, 2H), 6.97 (m, 1H), 6.89 (m, 1H), 5.38 (s, 1H), (3-ethoxy-3-oxopropyl)Zinc(II) bromide 1.2 (0.5M solution 3.40 (m, 4H), 3.27 (m, 4H), 2.80 (m, 2H), 2.53 (m, 2H), 2.18 in THF, 16 mL, 8 mmol. 1.6 eq.) dropwise. The reaction (m. 2H), 1.98 (m. 2H), 1.14 (m, 6H). Mass Spectral Analysis mixture was stirred at room temperature for 10 hours and then 50 m/z-329.0 (M+H)" quenched with aqueous ammonium chloride (50 mL). The Example 1B product was extracted with diethyl ether (3x100 mL) and the combined extracts were washed with brine, dried over sodium Sulfate, filtered, and concentrated under reduced pressure. Preparation of 1.4b: The crude product was purified by column chromatography 55 To a solution of 1.1 (2.25 g, 5 mmol. 1 eq.) in dry tetrahy (eluent: hexane/ethyl acetate mixture of increasing polarity). drofuran (40 mL) was added tetrakis(triphenylphosphine) Yield: 62.5% palladium(0) (290 mg, 0.25 mmol, 0.05 eq.) followed by H NMR (400 MHz, CDC1) & 7.23-7.12 (m, 2H), 6.95 (5-ethoxy-5-oxopentyl)Zinc(II) bromide 1.3 (0.5M solution 6.83 (m, 2H), 5.36 (s, 1H), 4.14 (q, 2H), 3.82 (m,b, 2H), 3.27 in THF, 16 mL, 8 mmol. 1.6 eq.) dropwise. The reaction (m,b, 2H), 2.74 (m, 2H), 2.54 (m, 2H), 1.93 (m, 2H), 1.60 60 mixture was stirred at room temperature for 10 hours and then 1.45 (m. 11H), 1.26 (t, 3H). Mass Spectral Analysis quenched with aqueous ammonium chloride (50 mL). The m/Z-402.0 (M+H)" product was extracted with diethyl ether (3x100 mL) and the combined extracts were washed with brine, dried over sodium Preparation of 1.5a: Sulfate, filtered, and concentrated under reduced pressure. To a solution of 1.4a (0.92 g, 2.3 mol. 1 eq.) in a mixture 65 The crude product was purified by column chromatography methanol (20 mL)/tetrahydrofuran (20 mL)/water (20 mL) (eluent: hexane/ethyl acetate mixture of increasing polarity). was added lithium hydroxide monohydrate (0.39 g, 9.2 Yield: 58% US 7,576,207 B2 69 70 "H NMR (400 MHz, CDC1) & 7.20 (dd. 1H), 7.14 (m, 1H), Step 1.5:1B was replaced by 1A. 6.90 (m. 1H), 6.86 (dd. 1H), 5.35 (s, 1H), 4.14 (q, 2H), 3.82 H NMR (400 MHz, DMSO-d) & 8.94 (m, 2H), 7.31 (m, (m. 2H), 3.28 (m, 2H), 2.43 (m, 2H), 2.36 (t, 2H), 1.99-1.83 1H), 7.11 (m. 1H), 6.90 (m, 1H), 6.83 (m. 1H), 3.32-3.20 (m, (m, 4H), 1.63-1.51 (m, 2H), 1.47 (s, 9H), 1.26 (t, 3H). Mass 6H), 3.11 (m, 1H), 2.90 (m, 2H), 2.31 (m,3H), 2.03 (m. 1H), Spectral Analysis m/z 416.0 (M--H)" 1.88 (m,3H), 1.68 (m, 2H), 1.50 (m. 1H), 1.08 (t,3H), 1.00 (t, Preparation of 1.5b: 3H) To a solution of 1.4b (1.05 g, 2.5 mol. 1 eq.) in a mixture Mass Spectral Analysis m/z 33 1.0 (M+H)" methanol (20 mL)/tetrahydrofuran (20 mL)/water (20 mL) was added lithium hydroxide monohydrate (0.42g, 10 mmol. Example 1D 4 eq.) in one portion. The reaction mixture was stirred at room 10 temperature for 10 hours. The volatiles were removed under Preparation of 1D: reduced pressure and the remaining aqueous solution was To a solution of the regioisomers from step 1.4 of the acidified with 1N hydrochloric acid until pH 2-3. The prod preparation of 1B (0.42 g, 1.1 mmol. 1 eq.) in methanol (20 uct was extracted with dichloromethane (3x100 mL) and the 15 mL) was added palladium 84 mg, 10 wt.% (dry basis) on combined organics were dried over sodium sulfate, filtered, activated carbon, 20% wt. eq.). The reaction mixture was and concentrated under reduced pressure. The product was stirred under hydrogen atmosphere using a hydrogen balloon used for the next step without further purification. Yield: 96% at room temperature for 10 hours. The palladium on activated "H NMR (400 MHz, DMSO-d) & 12.07 (s, 1H), 7.26 (m, carbon was filtered off using a celite pad and the filtrate was 1H), 7.14 (m, 1H), 6.91 (m, 1H), 6.86 (m. 1H), 5.54 (s, 1H), concentrated under reduced pressure to give 1D as hydrochlo 3.68 (m, 2H), 3.20 (m, 2H), 2.38 (m, 2H), 2.28 (t, 2H), 1.78 ric acid salt. Yield: 100% (m. 2H), 1.68 (m. 2H), 1.58 (m. 2H), 1.41 (s, 9H). Mass H NMR (400 MHz, DMSO-d) & 8.91 (m, 2H), 7.28 (m, Spectral Analysis m/z 386.0 (M-H) 1H), 7.10 (m. 1H), 6.89 (m, 1H), 6.83 (m. 1H), 3.32-3.18 (m, Preparation of 1.7b: 6H), 3.11 (m, 1H), 2.89 (m, 2H), 2.31 (m, 2H), 2.05-1.82 (m, To a solution of 1.5b (0.73 g, 1.88 mol. 1 eq.) in acetonitrile 25 5H), 1.72 (m. 1H), 1.51 (m, 4H), 1.10 (t, 3H), 1.00 (t, 3H) (30 mL) was slowly added diisopropylethylamine (0.8 mL, Mass Spectral Analysis m/z 345.0 (M+H)" 4.52 mmol. 2.4 eq.), diethylamine 1.6 (0.59 mL, 5.65 mmol. 3 eq.) at room temperature and 10 minutes later at 0°C., Example 1E O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tet 30 rafluoroborate (TBTU) (0.73 g, 2.26 mmol. 1.2 eq.) portion Preparation of 1 E: wise. The reaction mixture was slowly warmed to room tem perature and stirred at room temperature for 10 hours. The To a solution of 1.4b (0.3 g, 0.72 mol. 1 eq.) in dichlo volatiles were removed under reduced pressure and the resi romethane (50 mL) was slowly added 4.0M hydrogen chlo due was dissolved in ethyl acetate (200 mL). The organic ride in dioxane (0.9 mL, 3.6 mmol. 5 eq.). The mixture was solution was washed with 1M aqueous sodium bicarbonate 35 stirred at room temperature for 10 hours and then concen (3x50 mL), brine, dried over sodium sulfate, filtered, and trated under reduced pressure. The resulting solids were col concentrated under reduced pressure. The crude product was lected by filtration and washed with ether (2x10 mL) to give purified by column chromatography (eluent: hexane/ethyl 1E as hydrochloric acid salt. Yield: 95% acetate mixture of increasing polarity). Yield: 90% H NMR (400 MHz, DMSO-d) & 8.91 (m, 2H), 7.30 (m, "H NMR (400 MHz, CDC1) & 7.23 (m, 1H), 7.13 (m, 1H), 40 1H), 7.19 (m, 1H), 6.94 (m, 2H), 5.59 (s, 1H), 4.06 (q, 2H), 6.90 (m. 1H), 6.85 (m, 1H), 5.37 (s, 1H), 3.82 (m, 2H), 3.38 3.16 (m, 4H), 2.58-2.33 (m, 4H), 1.99 (m, 2H), 1.87(m, 2H), (q, 2H), 3.34-3.20 (m, 4H), 2.45 (m, 2H), 2.35 (t, 2H), 1.92 1.73 (m, 2H), 1.17 (t,3H) Mass Spectral Analysis m/z. 316.0 (m, 4H), 1.56 (m, 2H), 1.47 (s.9H), 1.15 (t,3H), 1.11 (t,3H). (M+H)" Mass Spectral Analysis m/z. 443.0 (M+H)" 45 Example 2A Preparation of 1B: To a solution of 1.7b (0.65g, 1.47 mmol. 1 eq.) in dichlo Preparation of 2.1: romethane (30 mL) was slowly added 4.0M hydrogen chlo ride in dioxane (1.8 mL, 7.2 mmol. 5 eq.). The mixture was Compound 1.4b (9.0g, 21.7 mmol) was dissolved in ethyl stirred at room temperature for 10 hours and two regioisomers 50 acetate (500 mL), and the solution was hydrogenated in the were detected by LC/MS. The reaction mixture was concen presence of 10% Pd/C (2.7 g) at atmospheric pressure. After trated under reduced pressure and 100 mg of the isomers were 2 days at room temperature, the reaction mixture was filtered purified by preparative liquid chromatography to provide 78 and the filtrate was concentrated in vacuo to give the Saturated mg of the pure product 1B as trifluoroacetic acid salt. ester 2.1. Yield: 100% "H NMR (400 MHz, CDC1) & 9.48 (s, 1H), 9.04 (s, 1H), 55 H NMR (400 MHz, CDC1) & 7.21 (d. 1H), 7.10 (m, 1H), 7.32-7.14 (m, 2H), 6.95 (m, 1H), 6.88 (m, 1H), 5.38 (s, 1H), 6.88 (m. 1H), 6.81 (d. 1H), 3.84 (m, 2H), 3.35 (m, 1H), 3.01 3.46–3.22 (m, 8H), 2.52-2.35 (m, 4H), 2.17 (m, 2H), 2.03 (m. 1H), 2.90 (m. 1H), 2.35 (m, 2H), 2.0-1.40 (m. 10H), 1.48 1.84 (m, 4H), 1.25-1.09 (m, 6H). Mass Spectral Analysis (s, 9H), 1.25 (t, 3H). m/z 343.0 (M+H)" 60 Preparation of 2.2: Example 1C Lithium hydroxide monohydrate (5.04 g. 120 mmol) was added to the solution of ester 2.1 (8.34g, 20 mmol) in a mixed solvent of methanol (150 mL), tetrahydrofuran (150 mL) and Preparation of 1C: water (150 mL). The reaction mixture was stirred at room 1C (hydrochloric acid salt) was obtained according to a 65 temperature overnight, concentrated in vacuo, and then procedure similar to the one described for 1D (hydrochloric washed with diethyl ether. The aqueous layer was acidified acid salt) with the following exceptions: with 1 NHCl to pH-4, and extracted with methylene chloride. US 7,576,207 B2 71 72 The combined organic extracts were dried over Sodium Sul (m. 2H), 3.08 (m, 3H), 2.89 (m, 2H), 2.10-1.75 (m, 8H), 1.50 fate and concentrated in vacuo to give the carboxylic acid 2.2. (m, 4H), 1.0 (t, 3H). Mass Spectral Analysis m/z. 317.3 Yield: 93.8% (M+H)" "H NMR (400 MHz, DMSO d) & 12.03 (brs, 1H), 7.26 (d. 1H), 7.08 (t, 1H), 6.87 (m, 1H), 6.78 (d. 1H), 3.70 (m, 2H), Example 2D 3.27 (m. 1H), 2.90 (m, 2H), 2.25 (m, 2H), 1.98 (m, 2H), 1.66-1.45 (m, 8H), 1.40 (s, 9H). Preparation of 2D: Preparation of 2.5: 2D (hydrochloric acid salt) was obtained according to a To a solution of the carboxylic acid 2.2 (778 mg, 2.0 mmol) procedure similar to the one described for 2A (hydrochloric in methylene chloride (60 mL) was added diisopropylamine 10 acid salt) with the following exceptions: Step 2.3: 2.3a was (2.3a) (0.56 mL, 4 mmol), followed by triethylamine (1.12 replaced by 2.3d. ml. 8 mmol) and the Mukaiyama acylating reagent, H NMR (400 MHz, DMSO d) & 9.10 (brd, 2H), 7.81 (t, 2-chloro-1-methylpyridinium iodide (2.4) (614 mg, 2.4 1H), 7.23 (d. 1H), 7.10 (t, 1H), 6.90 (t, 1H), 6.84 (d. 1H), 3.20 mmol). The reaction mixture was stirred at room tempera 15 (m. 2H), 3.04 (m, 3H), 2.89 (m, 2H), 2.10-1.75 (m, 8H), ture for 2 days and washed with Saturated aqueous sodium 1.50-1.28 (m, 8H), 0.88 (t, 3H). Mass Spectral Analysis bicarbonate, and dried over sodium sulfate. Evaporation of m/z–317.3 (M+H)" the solvent and purification of the residue by column chro matography on silica gel using hexane:ethyl acetate (2:1) as Example 2E eluent, yielded the amide 2.5a. Yield: 53% "H NMR (400 MHz, CDC1) & 7.22 (d. 1H), 7.10 (t, 1H), Preparation of 2.7: 6.85 (m, 2H), 3.96-3.78 (m, 3H), 3.40 (m, 2H), 2.98 (m, 2H), To a solution of 1.1 (1.85 g, 4.12 mmol) in anhydrous 2.30 (m, 2H), 2.05-1.40 (m. 10H), 1.48 (s.9H), 1.38 (m, 6H), tetrahydrofuran (50 mL) at room temperature was added 1.19 (m, 6H). under nitrogen atmosphere a 0.5M solution of 5-ethoxy-5- Preparation of 2A: 25 oxopentylzinc bromide (2.6) in tetrahydrofuran (13 mL, 6.5 To a solution of compound 2.5a (480 mg, 1.02 mmol) in mmol) followed by tetrakis(triphenylphosphine)palladium methylene chloride (6 mL) was added a 2.0M anhydrous (0) (232 mg, 0.2 mmol). The reaction mixture was stirred at solution of hydrogen chloride in diethyl ether (20 mL, 40 50° C. overnight and concentrated in vacuo. The residue was mmol). The reaction mixture was stirred at room temperature partitioned in diethyl ether and Saturated aqueous ammonium overnight. Diethyl ether (50 mL) was then added to the reac 30 chloride. The organic layer was separated, washed with water, tion mixture, which was stirred for an additional 2 hours at brine and dried over sodium sulfate. Evaporation of the sol room temperature. The clear upper solution was decanted, vent and purification of the residue by column chromatogra and the product was washed with diethyl ether. The product phy on silica gel using hexane/ethyl acetate (10:1) as eluent, was then dissolved in methylene chloride. The resulting solu yielded the desired product 2.7. Yield: 49%. tion was concentrated and the resulting product was dried in 35 H NMR (400 MHz, CDC1) & 7.15 (m, 2H), 6.90 (m, 2H), vacuo to furnished 2A isolated as its hydrochloric acid salt. 5.32 (s, 1H), 4.12(q, 2H), 3.81 (m, 2H), 3.29 (m, 2H), 2.41 (t, Yield: 90% 2H), 2.31 (t, 2H), 1.95 (m, 2H), 1.70- 1.58 (m, 6H), 1.48 (s, "H NMR (400 MHz, DMSO d) & 9.12 (brd, 2H), 7.26 (d. 9H), 1.28 (t, 3H). 1H), 7.08 (m. 1H), 6.84 (m, 2H), 3.96 (m, 1H), 3.83 (m. 1H), 40 Preparation of 2.8: 3.20 (m, 2H), 3.10 (m. 1H), 2.89 (m, 2H), 2.29 (m, 2H), Compound 2.7 (830 mg, 1.9 mmol) was dissolved in ethyl 1.95-1.73 (m, 6H), 1.50 (m, 4H), 1.29 (m, 6H), 1.15 (m, 6H). acetate (60 mL) and hydrogenated in the presence of 10% Mass Spectral Analysis m/z. 373.4 (M+H)" Pd/C (162 mg) at room temperature overnight. The reaction Example 2B mixture was filtered and the filtrate was concentrated in vacuo 45 to yield the saturated ester 2.8. Yield: 98.3%. "H NMR (400 MHz, CDC1,) & 7.22 (d. 1H), 7.10 (t, 1H), Preparation of 2B: 6.90 (t, 1H), 6.83 (d. 1H), 4.10 (q, 2H), 3.88 (m, 2H), 3.38 (m, 2B (hydrochloric acid salt) was obtained according to a 1H), 2.97 (m, 2H), 2.32 (t, 2H), 2.0-1.38 (m, 12H), 1.48 (s, procedure similar to the one described for 2A (hydrochloric 9H), 1.29 (t, 3H). acid salt) with the following exceptions: 50 Preparation of 2.9: Step 2.3: 2.3a was replaced by 2.3b. To a solution of 2.8 (820 mg, 1.9 mmol) in a mixture of "H NMR (400 MHz, DMSO d) & 9.13 (brd, 2H), 7.30 (m, methanol (15 mL)/tetrahydrofuran (15 mL)/water (15 mL) 5H), 7.10 (m. 1H), 6.85 (m, 2H), 4.88 (d. 1H), 4.80 (d. 1H), was added lithium hydroxide monohydrate (504 mg, 12 4.68 (d. 1H), 4.60 (d. 1H), 3.20 (m, 2H), 3.10 (m, 1H), 2.90 mmol). The reaction mixture was stirred at room temperature (m. 2H), 2.40 (m, 2H), 2.00- 1.50 (m, 10H). Mass Spectral 55 overnight, concentrated in vacuo and washed with diethyl Analysis m/z 391.3 (M+H)" ether. The aqueous layer was acidified with 1N HCl to pH~4 and extracted with methylene chloride. The combined Example 2C organic extracts were dried over Sodium Sulfate and concen trated to give the carboxylic acid 2.9. Yield: 100%. 60 Preparation of 2C: "H NMR (400 MHz, DMSO-d) 812.0 (s, 1H), 7.29 (d. 2C (hydrochloric acid salt) was obtained according to a 1H), 7.08 (t, 1H), 6.88 (t, 1H), 6.79 (d. 1H), 3.70 (m, 2H), 3.30 procedure similar to the one described for 2A (hydrochloric (m. 1H), 2.90 (m, 1H), 2.12 (t, 2H), 1.98 (m, 2H), 1.62-1.30 acid salt) with the following exceptions: Step 2.3: 2.3a was (m. 10H), 1.40 (s.9H). replaced by 2.3c. 65 Preparation of 2.10: H NMR (400 MHz, DMSOd) & 9.20 (brs, 2H), 7.84 (brs, To a solution of 2.9 (806 mg, 2.0 mmol) in methylene 1H), 7.26 (d. 1H), 7.10 (t, 1H), 6.90 (t, 1H), 6.81 (d. 1H), 3.20 chloride (60 mL) was added diethylamine (1.6) (0.43 mL, 4 US 7,576,207 B2 73 74 mmol), followed by triethylamine (1.12 ml, 8 mmol) and temperature overnight, concentrated in vacuo and washed Mukaiyama acylating reagent, 2-chloro-1-methylpyri with diethyl ether. The aqueous layer was acidified with 1N dinium iodide (2.4) (614 mg, 2.4 mmol). The reaction mix HCl to pH-4 and extracted with methylene chloride. The ture was stirred at room temperature overnight, washed with combined organic extracts were dried over Sodium sulfate and saturated aqueous sodium bicarbonate, and dried over sodium 5 concentrated in vacuo to give the carboxylic acid 2.14. Yield: sulfate. Evaporation of the solvent and purification of the -100%. residue by column chromatography on silica gel using hex "H NMR (400 MHz, DMSOd) & 12.00 (brs, 1H), 7.28 (d. ane/ethyl acetate (1:1) as eluent, yielded the amide 2.10. 1H), 7.06 (t, 1H), 6.88 (t, 1H), 6.79 (d. 1H), 3.70 (m, 2H), 3.30 Yield: 83.7%. (m. 1H), 2.90 (m, 2H), 2.20 (t, 2H), 1.98 (m, 2H), 1.65-1.30 "H NMR (400 MHz, CDC1) & 7.22 (d. 1H), 7.10 (t, 1H), 10 (m. 12H), 1.40 (s.9H). 6.88 (t, 1H), 6.80 (d. 1H), 3.85 (m, 2H), 3.38-3.28 (m, 5H), Preparation of 2.15a: 2.95 (m, 2H), 2.30 (t, 2H), 2.05-1.40 (m, 12H), 1.47 (s, 9H), To the solution of 2.14 (700 mg, 1.68 mmol) in methylene 1.19 (t, 3H), 1.10 (t, 3H). chloride (50 mL) was added diethylamine (1.6) (0.36 mL, Preparation of 2E: 3.36 mmol), followed by triethylamine (0.94 ml, 6.72 mmol) To a solution of 2.10 (740 mg, 1.62 mmol) in methylene 15 and the Mukaiyama acylating reagent, 2-chloro-1-meth chloride (10 mL) was added a 2.0M anhydrous solution of ylpyridinium iodide (2.4) (516 mg, 2.02 mmol). The reaction hydrogen chloride in diethyl ether (30 mL, 60 mmol). The mixture was stirred at room temperature overnight, washed reaction mixture was stirred at room temperature overnight. with Saturated aqueous sodium bicarbonate, and dried over Diethyl ether (80 mL) was added to the reaction mixture, sodium sulfate. Evaporation of the solvent and purification of which was stirred for an additional 2 hours at room tempera the residue by column chromatography on silica gel using ture. The clear upper Solution was decanted, and the product hexane/ethyl acetate (1:1) as eluent, yielded the amide 2.15a. was washed with diethyl ether. The residue was dissolved in Yield: 75.7%. methylene chloride. The resulting solution was concentrated "H NMR (400 MHz, CDC1,) & 7.25 (d. 1H), 7.10 (t, 1H), and the product was dried in vacuo to furnish the 2E isolated 6.87 (t, 1H), 6.80 (d. 1H), 3.86 (m, 2H), 3.40-3.30 (m, 5H), as its hydrochloric acid salt. Yield: 95.8%. 25 2.95 (m, 2H), 2.30 (t, 2H), 2.0-1.4 (m, 14H), 1.48 (s.9H), 1.19 "H NMR (400 MHz, DMSO d) & 9.09 (brs, 2H), 7.30 (d. (t, 3H), 1.10 (t, 3H). 1H), 7.10 (t, 1H), 6.90 (t, 1H), 6.81 (d. 1H), 3.22 (m, 6H), 3.10 Preparation of 2F: (m. 1H), 2.89 (m, 2H), 2.29 (t, 2H), 2.0-1.30 (m, 12H), 1.10 (t, 3H), 1.0 (t,3H). Mass Spectral Analysis m/z. 359.4 (M+H)" To a solution of compound 2.15a (550 mg, 1.17 mmol) in 30 methylene chloride (10 mL) was added a 2.0M anhydrous Example 2F solution of hydrogen chloride in diethyl ether (30 mL, 60 immol). The reaction mixture was stirred at room temperature overnight. Diethyl ether (80 mL) was added to the reaction Preparation of 2.12: mixture, which was stirred for an additional 2 hours at room To a solution of enol triflate 1.1 (5.84 g, 12 mmol) in 35 temperature. The clear upper Solution was decanted, and the anhydrous tetrahydrofuran (150 mL) at room temperature product was washed with diethyl ether. The product was was added under nitrogen atmosphere a 0.5M solution of dissolved in methylene chloride and the resulting solution 6-ethoxy-6-oxohexylzinc bromide (2.11) in tetrahydrofuran was concentrated in vacuo. The product was dried in vacuo to (13 mL, 6.5 mmol) followed by tetrakis(triphenylphosphine) furnish the 2F isolated as its hydrochloric acid salt. Yield: palladium(0) (925 mg, 0.8 mmol). The reaction mixture was 40 -100%. stirred at 50° C. overnight and then cooled to room tempera H NMR (400 MHz, DMSO d) & 9.06 (brs, 2H), 7.29 (d. ture. The reaction mixture was quenched with water and 1H), 7.10 (m. 1H), 6.90 (t, 1H), 6.81 (d. 1H), 3.22 (m, 6H), extracted with ethyl acetate. The combined organic extracts 3.10 (m. 1H), 2.89 (m, 2H), 2.25 (t, 2H), 1.96-1.70 (m, 6H), were dried over Sodium sulfate and concentrated in vacuo. 1.50-1.30 (m, 8H), 1.10 (t, 3H), 1.0 (t, 3H). Mass Spectral The residue was purified by column chromatography on silica 45 Analysis m/z. 373.5 (M+H)" gel using hexane/ethyl acetate (8:1) as eluent. Yield: 31%. H NMR (400 MHz, CDC1) & 7.12 (m, 2H), 6.88 (m, 2H), Example 2G 5.30 (s, 1H), 4.12 (q, 2H), 3.81 (m, 2H), 3.28 (m, 2H), 2.38 (t, 2H), 2.30 (t, 2H), 1.92 (m, 2H), 1.65-1.40 (m, 8H), 1.48 (s, Preparation of 2G: 9H), 1.26 (t, 3H). 50 2G (hydrochloric acid salt) was obtained according to a Preparation of 2.13: procedure similar to the one described for 2F (hydrochloric Compound 2.12 (1.6 g., 3.61 mmol) was dissolved in ethyl acid salt) with the following exception: Step 2.13: 1.6 was acetate (120 mL), and hydrogenated in the presence of 10% replaced by 2.3a. Pd/C (480mg) using a hydrogenballoon. After 2 days at room H NMR (400 MHz, DMSO d) & 9.12 (brs, 2H), 7.29 (d. temperature, the reaction mixture was filtered and the filtrate 55 1H), 7.10 (m. 1H), 6.90 (t, 1H), 6.81 (d. 1H), 4.30 (m, 1H), was concentrated in vacuo to give the Saturated ester 2.13. 3.98 (m. 1H), 3.20 (m, 2H), 3.10 (m, 1H), 2.86 (m, 2H), 2.22 Yield: -100%. (t, 2H), 1.98-1.72 (m, 6H), 1.48-1.32 (m, 8H), 1.29 (d. 6H), "H NMR (400 MHz, CDC1) & 7.21 (d. 1H), 7.10 (t, 1H), 1.12 (d. 6H). 6.88 (t, 1H), 6.82 (d. 1H), 4.11 (q, 2H), 3.84 (m, 2H), 3.36 (m, Mass Spectral Analysis m/z 401.5 (M+H)" 1H), 2.92 (m, 2H), 2.30 (t, 2H), 2.0-1.38 (m. 14H), 1.48 (s, 60 9H), 1.29 (t, 3H). Example 3A Preparation of 2.14: Lithium hydroxide monohydrate (924 g. 22 mmol) was Preparation of 3.2: added to a solution of ester 2.13 (1.58 g, 3.55 mmol) in a 65 To a solution of 3.1 (4.67 g. 10 mmol. 1 eq.) in dry tetrahy mixture of methanol (30 mL), tetrahydrofuran (30 mL) and drofuran (100 mL) was added tetrakis(triphenylphosphine) water (30 mL). The reaction mixture was stirred at room palladium(0) (580 mg. 0.5 mmol, 0.05 eq.) followed by a US 7,576,207 B2 75 76 0.5M solution of (5-ethoxy-5-oxopentyl)Zinc(II) bromide 2.6 5H), 1.57-1.31 (m, 14H), 1.17 (t, 3H), 1.11 (t, 3H). Mass in tetrahydrofuran (32 mL, 16 mmol. 1.6 eq.) dropwise. The Spectral Analysis m/z. 477.86 (M+H)" reaction mixture was stirred at 45° C. for 10 hours and quenched with aqueous ammonium chloride (100 mL) at Preparation of 3A: room temperature. The product was extracted with ether 5 To a solution of 3.5 (1.25 g, 2.6 mmol. 1 eq.) in dichlo (3x100 mL) and the combined extracts were washed with romethane (50 mL) was slowly added a 2.0M anhydrous water, brine, dried over sodium sulfate, filtered, and concen solution of hydrogen chloride in diethyl ether (7.8 mL, 15.6 trated under reduced pressure. The crude product was purified mmol. 6 eq.). The mixture was stirred at room temperature for by column chromatography (eluent: hexane/ethyl acetate 10 hours and then concentrated under reduced pressure. The mixture of increasing polarity). Yield: 46% 10 crude was purified by column chromatography (eluent: "H NMR (400 MHz, CDC1) & 6.89-6.76 (m,3H), 5.39 (s. methanol/dichloromethane mixture of increasing polarity) to 1H), 4.13 (q, 2H), 3.83 (m, 2H), 3.25 (m, 2H), 2.34 (m, 4H), give 3A isolated as its hydrochloric acid salt. Yield: 85% 1.92 (m, 2H), 1.70 (m, 2H), 1.62-1.44 (m, 13H), 1.25 (t,3H). 'HNMR (400 MHz, DMSO-d) 88.93 (s, b, 2H), 7.15 (dd. Mass Spectral Analysis m/z 448.8 (M+H)" 1H), 6.94 (m, 1H), 6.84 (dd. 1H), 3.32-3.15 (m, 6H), 3.09 (m, Preparation of 3.3: 15 1H), 2.87 (im, 2H), 2.28 (t, 2H), 2.03-1.80 (m, 5H), 1.70 (m, To a solution of 3.2 (2.08 g. 4.6 mmol. 1 eq.) in a mixture 1H), 1.63-1.39 (m, 4H), 1.32 (m, 2H), 1.09 (t, 3H), 0.99 (t, of methanol (20 mL), tetrahydrofuran (20 mL) and water (20 3H) mL) was added lithium hydroxide monohydrate (0.78 g. 18.6 Mass Spectral Analysis m/z. 377.45 (M+H)" mmol. 4 eq.) in one portion. The reaction mixture was stirred at room temperature for 10 hours. The volatiles were removed Example 3B under reduced pressure and the remaining aqueous Solution was acidified with 1N hydrochloric acid until pH 2-3. The product was extracted with dichloromethane (3x100 mL) and Preparation of 3.7: the combined extracts were dried over sodium sulfate, fil To a solution of 3.6 (74.20 g, 153.2 mmol. 1 eq.) in dry tered, and concentrated under reduced pressure. The product 25 tetrahydrofuran (700 mL) under nitrogen was added tetrakis was used for the next step without further purification. Yield: (triphenylphosphine)palladium(0) (8.85 g, 7.66 mmol, 0.05 98% eq.) and then a 0.50M solution of 5-ethoxy-5-oxopentylzinc "H NMR (400 MHz, CDC1,) & 6.88-6.77 (m,3H), 5.39 (s. bromide (2.6) intetrahydrofuran (460 mL. 230 mmol. 1.5 eq.) 1H), 3.83 (m, 2H), 3.25 (m, 2H), 2.38 (m, 4H), 1.92 (m, 2H), 30 over a 20 minute period. The mixture was stirred at 45° C. for 1.72 (m, 2H), 1.64-1.51 (m, 4H), 1.47 (s, 9H) 10 hours. Additional amount of a 0.50M solution of 5-ethoxy Mass Spectral Analysis m/z 418.84 (M-H) 5-oxopentylzinc bromide (2.6) in tetrahydrofuran (150 mL. 75 mmol, 0.5eq.) was added to the mixture, which was stirred Preparation of 3.4: at 45° C. for another 10 hours. The volatiles were removed To a solution of 3.3 (1.4g, 3.3 mmol. 1 eq.) in acetonitrile under reduced pressure and the crude product was partitioned (50 mL) was slowly added diisopropylethylamine (1.38 mL, 35 between diethyl ether (800 mL) and saturated ammonium 7.92 mmol. 2.4 eq.), diethylamine 1.6 (0.68 mL, 6.6 mmol. 2 chloride (500 mL). The two phases were separated and the eq.) at room temperature and 10 minutes later at 0°C., O-ben organics were washed with water (3x150 mL), brine, dried Zotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluorobo over sodium sulfate, filtered, and concentrated under reduced rate (TBTU) (1.27 g, 3.96 mmol. 1.2 eq.) portionwise. The pressure. The crude product was purified by column chroma reaction mixture was slowly warmed to room temperature 40 tography (eluent: ethyl acetate/hexane mixture of increasing and stirred at room temperature for 10 hours. The volatiles polarity). Yield: 54% were removed under reduced pressure and the residue was dissolved in ethyl acetate (200 mL). The resulting solution 'HNMR (400 MHz, CDC1,) & 7.08 (m, 1H), 6.55 (dd. 1H), was washed with 1M aqueous sodium bicarbonate (5x100 6.48 (dd. 1H), 5.30 (s, 1H), 4.10 (q, 2H), 3.80 (s.3H), 3.75 (m, mL), brine, dried over Sodium sulfate, filtered, and concen 45 2H), 3.27 (m, 2H), 2.59 (m, 2H), 2.28 (t, 2H), 1.90 (m, 2H), trated under reduced pressure. The crude product was purified 1.69-1.37 (m. 15H), 1.24 (t, 3H). Mass Spectral Analysis by column chromatography (eluent: hexane/ethyl acetate m/z–460.51 (M+H)" mixture of increasing polarity). Yield: 80% Preparation of 3.8: "H NMR (400 MHz, CDC1) & 6.90-6.76 (m,3H), 5.40 (s, To a solution of 3.7 (38.4g, 83.6 mmol. 1 eq.) in a mixture 1H), 3.82 (m, 2H), 3.37 (q, 2H), 3.33–3.16 (m, 4H), 2.34 (m, 50 of methanol (200 mL), tetrahydrofuran (200 mL) and water 4H), 1.91 (m, 2H), 1.73 (m, 2H), 1.63-1.51 (m, 4H), 1.46 (s, (200 mL) was added lithium hydroxide monohydrate (14.0 g, 9H), 1.16 (t, 3H), 1.11 (t, 3H). Mass Spectral Analysis 334 mmol. 4 eq.) portionwise. The mixture was stirred at m/z-475.85 (M+H)" room temperature for 10 hours. The volatiles were removed Preparation of 3.5: 55 under reduced pressure. Water (500 mL) was added to the To a solution of 3.4 (1.25g, 2.6 mmol. 1 eq.) in ethylacetate mixture, which was washed with diethyl ether (300 mL). The (30 mL) was added palladium 250 mg, 10 wt.% (dry basis) aqueous phase was acidified with 1N hydrochloric acid until on activated carbon, 20% wt. eq.). The reaction mixture was pH 4. The product was then extracted with dichloromethane stirred under hydrogen atmosphere using a hydrogen balloon (1x500 mL, 3x150 mL) and the combined extracts were dried at room temperature for 10 hours. The palladium on activated 60 over sodium sulfate, filtered, and concentrated under reduced carbon was filtered off on a celite pad and the filtrate was pressure. The product was used for the next step without concentrated under reduced pressure. The crude product was further purification. Yield: 95% purified by column chromatography (eluent: ethyl acetate/ H NMR (400 MHz, CDC1) & 7.08 (m. 1H), 6.55 (dd. 1H), hexane mixture of increasing polarity). Yield: 100% 6.48 (dd. 1H), 5.31 (s, 1H), 3.80 (s.3H), 3.76 (m, 2H), 3.28 "H NMR (400 MHz, CDC1) & 6.92 (dd. 1H), 6.83-6.78 (m, 65 (m. 2H), 2.60 (m, 2H), 2.34 (t, 2H), 1.90 (m, 2H), 1.70-1.40 2H), 4.01-3.69 (m, 2H), 3.43-3.25 (m, 5H), 3.08-2.80 (m, (m. 15H). 2H), 2.32 (m, 2H), 1.95 (m. 1H), 1.86 (m, 1H), 1.82-1.60 (m, Mass Spectral Analysis m/z 430.54 (M-H) US 7,576,207 B2 77 78 Preparation of 3.9: reduced pressure and the crude product was partitioned To a solution of 3.8 (34.45 g, 79.8 mmol. 1 eq.) in aceto between diethyl ether (300 mL) and saturated ammonium nitrile (200 mL) was added N,N-diisopropylethylamine chloride (200 mL). The two phases were separated and the (34.76 mL, 199.6 mmol. 2.5 eq.), and diethylamine 1.6 (16.52 organics were washed with water (3x50 mL), brine, dried mL, 159.7 mmol. 2 eq.). The mixture was cooled to 0°C. and over sodium sulfate, filtered, and concentrated under reduced O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tet pressure. The crude product was purified by column chroma rafluoroborate (TBTU) (28.20 g, 87.82 mmol. 1.1 eq.) was tography (eluent: ethyl acetate/hexane mixture of increasing added portionwise. The reaction was gradually warmed at polarity). room temperature and stirred at room temperature for 10 Yield: 49% hours. The volatiles were removed under reduced pressure 10 'HNMR (400 MHz, CDC1,) & 7.06(m, 1H), 6.71 (dd. 1H), and the residue was dissolved in diethyl ether (800 mL). The 6.59 (dd. 1H), 5.33 (s, 1H), 5.17 (s.2H), 4.10 (q, 2H), 3.76 (m, mixture was washed with Saturated sodium bicarbonate and 2H), 3.49 (s.3H), 3.27 (m, 2H), 3.62 (m, 2H), 3.28 (t, 2H), with 1N hydrochloric acid (4x100 mL). The organics were 1.91 (m, 2H), 1.69-141 (m, 15H), 1.23 (t,3H). Mass Spectral dried over sodium sulfate, filtered and then concentrated. The Analysis m/z 490.50 (M+H)" product was used for the next step without further purifica 15 tion. Yield: 98% Preparation of 3.13: H NMR (400 MHz, CDC1) & 7.07 (m, 1H), 6.55 (dd. 1H), To a solution of 3.12 (2.2g, 4.49 mmol. 1 eq.) in a mixture 6.48 (dd. 1H), 5.32 (s, 1H), 3.80 (s.3H), 3.74 (m, 2H), 3.36 (q, of methanol (30 mL), tetrahydrofuran (30 mL) and water (30 2H), 3.32-3.21 (m, 4H), 2.62 (m, 2H), 2.27 (t, 2H), 1.90 (m, mL) was added lithium hydroxide monohydrate (0.75 g, 2H), 1.73-1.37 (m, 15H), 1.14 (t, 3H), 1.11 (t, 3H) 18.87 mmol. 4 eq.). The mixture was stirred at room tempera Mass Spectral Analysis m/z 487.54 (M--H) ture for 10 hours. The organic solvents were removed under reduced pressure and the remaining aqueous solution was Preparation of 3.10: acidified with 1N hydrochloric acid until pH 4. The product To a solution of 3.9 (38 g., 78 mmol. 1 eq.) in methanol (300 was then extracted with dichloromethane (3x100 mL) and the mL) was added palladium 5.78 g. 10 wt.% (dry basis) on 25 combined extracts were dried over sodium sulfate, filtered, activated carbon, 15% wt. eq.). The reaction mixture was and concentrated under reduced pressure. The product was stirred under hydrogen atmosphere using a hydrogen balloon used for the next step without further purification. at room temperature for 10 hours. The palladium on activated Yield: 96% carbon was filtered off on a celite pad and the filtrate was 'HNMR(400 MHz, CDC1) & 7.06 (m. 1H), 6.70 (dd. 1H), concentrated under reduced pressure. The product was used 30 6.59 (dd. 1H), 5.34 (s, 1H), 5.16 (s.2H), 3.76 (m, 2H), 3.49 (s. for the next step without further purification. Yield: 100% 3H), 3.27 (m, 2H), 2.63 (m, 2H), 2.34 (t, 2H), 1.91 (m, 2H), 'HNMR (400 MHz, CDC1,) & 7.05 (m, 1H), 6.49 (dd. 1H), 1.70-1.40 (m. 15H). Mass Spectral Analysis m/z 460.60 6.44 (dd. 1H), 3.95-3.65 (m, 5H), 3.41-3.24 (m, 5H), 2.95 (m, (M-H) 2H), 2.29 (m, 2H), 2.05 (m. 1H), 1.92 (m, 1H), 1.85-1.27 (m, 19H), 1.16 (t, 3H), 1.10 (t, 3H). Mass Spectral Analysis 35 Preparation of 3.14: m/z-489.54 (M+H)" To a solution of 3.13 (2 g, 4.33 mmol. 1 eq.) in acetonitrile Preparation of 3B: (50 mL) was added N,N-diisopropylethylamine (2.26 mL, 13 To a solution of 3.10 (38.0 g, 77.8 mmol. 1 eq.) in methyl mmol. 3 eq.), and diethylamine 1.6 (0.9 mL, 8.66 mmol. 2 ene chloride (500 mL) was added a 2.0Manhydrous solution eq.). The mixture was cooled to 0°C. and O-benzotriazol-1- of hydrogen chloride in diethyl ether (230 mL, 460 mmol. 6 40 yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) eq.) dropwise. The mixture was stirred at room temperature (1.53 g, 4.76 mmol. 1.1 eq.) was added portionwise. The for 10 hours. The organic solvents were removed under reaction was gradually warmed to room temperature and reduced pressure and the residue was dried in vacuo. The stirred at room temperature for 10 hours. The volatiles were crude product was purified by column chromatography (elu removed under reduced pressure and the residue was dis 45 solved in diethyl ether (200 mL). The organic solution was ent: methanol/dichloromethane mixture of increasing polar washed with saturated sodium bicarbonate (4x100 mL). The ity) to give 3 f isolated as its hydrochloric acid salt. organics were then dried over Sodium Sulfate and concen "H NMR (400 MHz, DMSO-d) & 8.91 (s, b, 2H), 7.06 (m, trated in vacuo. The crude product was purified by column 1H), 6.6.55 (dd. 1H), 6.48 (dd. 1H), 3.76 (s, 3H), 3.31-3.02 chromatography (eluent: ethyl acetate/hexane mixture of (m, 7H), 2.85 (m, 2H), 2.25 (m, 2H), 2.05-1.86 (m, 4H), 50 increasing polarity). Yield: 90% 1.80-1.61 (m, 3H), 1.57-1.37 (m, 3H), 1.25 (m, 2H), 1.08 (t, 3H), 0.98 (t,3H) 'HNMR(400 MHz, CDC1) & 7.05 (m. 1H), 6.71 (dd. 1H), Mass Spectral Analysis m/z 389.4 (M+H)" 6.59 (dd. 1H), 5.35 (s, 1H), 5.17 (s.2H), 3.76 (m, 2H), 3.49 (s. 3H), 3.35 (q, 2H), 3.32-3.21 (m, 4H), 2.64 (m, 2H), 2.27 (t, Example 3C 2H), 1.90 (m, 2H), 1.72-1.42 (m, 15H), 1.14 (t, 3H), 1.11 (t, 55 3H) Mass Spectral Analysis m/z 517.62 (M--H)" Preparation of 3.12: To a solution of 3.11 (4.72 g, 9.27 mmol. 1 eq.) in dry Preparation of 3.15: tetrahydrofuran (70 mL) under nitrogen was added tetrakis To a solution of 3.14 (2g, 3.87 mmol. 1 eq.) in methanol (triphenylphosphine)palladium(0) (0.53 g, 0.46 mmol, 0.05 60 (40 mL) was added palladium 0.4g, 10 wt.% (dry basis) on eq.) and then a 0.50M solution of 5-ethoxy-5-oxopentylzinc activated carbon, 20% wt. eq.). The reaction mixture was bromide (2.6) in tetrahydrofuran (37 mL, 18.5 mmol. 2 eq.) stirred under hydrogen atmosphere using a hydrogen balloon slowly. The mixture was stirred at 45° C. for 10 hours. Addi at room temperature for 10 hours. The palladium on activated tional amount of a 0.50M solution of 5-ethoxy-5-oxopentylz carbon was filtered off on a celite pad and the filtrate was inc bromide (2.6) in tetrahydrofuran (18.54 mL, 9.27 mmol. 65 concentrated under reduced pressure. The crude product was 1 eq.) was added to the mixture, which was stirred at 45° C. purified by column chromatography (eluent: ethyl acetate/ for an additional 10 hours. The volatiles were removed under hexane mixture of increasing polarity). Yield: 98% US 7,576,207 B2 79 80 "H NMR (400 MHz, CDC1) & 7.02 (m, 1H), 6.65 (dd. 1H), methanol (100 mL). The mixture was heated under reflux for 6.53 (dd. 1H), 5.17 (q, 2H), 3.98-3.65 (m, 2H), 3.48 (s.3H), 1 hour and then concentrated to provide the crude product 3.40-3.25 (m, 5H), 3.99 (m, 2H), 2.29 (m, 2H), 2.06 (m, 1H), used for the next step without further purification. 1.92 (m, 1H), 1.86-1.54 (m, 7H), 1.46 (s, 9H), 1.44-1.31 (m, Mass Spectral Analysis m/z. 361.83 (M--H)" 3H), 1.16 (t, 3H), 1.10 (t, 3H). Mass Spectral Analysis Preparation of 4.6: m/z =519.65 (M+H)" To a solution of 4.4 (0.90 g, 1.25 mmol. 1 eq.) in methylene Preparation of 3C: chloride (30 mL) at 0°C. was added triethylamine (1.68 mL, To a solution of 3.15 (1.98g, 3.82 mmol. 1 eq.) in methanol 12.5 mmol) and N,N-diethylcarbamoyl chloride 4.5 (0.64 (40 mL) was added a 4.0M anhydrous solution of hydrogen 10 mL, 5 mmol. 4 eq.) dropwise. The reaction mixture was chloride in dioxane (9.5 mL, 38 mmol. 10 eq.) slowly. The stirred at room temperature for 10 hours and then concen mixture was stirred at room temperature for 10 hours. The trated under reduced pressure. The residue was dissolved in organic solvents were removed under reduced pressure and ethyl acetate (200 mL). The organic solution was washed with the crude product was purified by column chromatography 0.5N hydrochloric acid (3x100 mL), brine, and then concen (eluent: methanol/dichloromethane mixture of increasing trated in vacuo. The crude product was purified by column polarity) to give 3C isolated as its hydrochloric acid salt. 15 chromatography (eluent: hexane/ethyl acetate mixture of Yield: 94% increasing polarity). Yield: 30% "H NMR (400 MHz, DMSO-d) & 9.48 (s, 1H), 8.90-8.70 H NMR (400 MHz, CDC1) & 7.22 (m, 1H), 7.10 (m, 1H), (m. 2H), 6.87(m, 1H), 6.39 (dd. 1H), 6.30 (dd. 1H), 3.31-3.03 6.88 (m. 1H), 6.83 (m, 1H), 4.37 (m. 1H), 4.00-3.69 (m, 2H), (m, 7H), 2.90-2.76 (m, 2H), 2.25 (m, 2H), 2.11 (m. 1H), 1.99 3.43-3.18 (m, 7H), 3.11-2.87 (n, 2H), 2.03-1.34 (m. 19H), (m. 1H), 1.93-1.35 (m, 8H), 1.27 (m,2H), 1.08 (t,3H), 0.98 (t, 1.13 (t, 6H). 3H) Mass Spectral Analysis m/z 460.95 (M--H)" Mass Spectral Analysis m/z. 375.8 (M+H)" Preparation of 4A: Example 4A To a solution of 4.6 (200 mg, 0.43 mmol. 1 eq.) in methanol 25 (15 mL) was added a 2.0M anhydrous solution of hydrogen Preparation of 4.2: chloride in diethylether (2.2 mL, 4.4 mmol. 10 eq.) dropwise. To a solution of 1.1 (20g, 44.5 mmol. 1 eq.) in dry tetrahy The reaction was stirred at room temperature for 10 hours and drofuran (300 mL) was added tetrakis(triphenylphosphine) then concentrated under reduced pressure. The crude product palladium(0) (2.56 g, 2.22 mmol, 0.05 eq.) followed by a 30 was purified by column chromatography (eluent: methanol/ 0.5M solution of (2-cyanoethyl)Zinc(II) bromide 4.1 in tet dichloromethane mixture of increasing polarity) to give the rahydrofuran (133.5 mL, 66.75 mmol, 1.5 eq.) dropwise. The 4A isolated as its hydrochloric acid salt. Yield: 83.5% reaction mixture was stirred at 45° C. for 10 hours. Additional H NMR (400 MHz, DMSO-d) & 8.92 (m, 2H), 7.28 (m, amount of a 0.5M solution of (2-cyanoethyl)Zinc(II) bromide 1H), 7.10 (m, 1H), 6.89 (m, 1H), 6.82 (dd. 1H), 6.20 (s. b. 1H), 4.1 intetrahydrofuran (45 mL, 22.5 mol, 0.5eq.) was added to 35 3.26-2.82 (m, 11H), 2.05-1.81 (m, 5H), 1.71 (m. 1H), 1.45 the reaction mixture, which was stirred at 45° C. for an addi (m, 4H), 1.10 (t, 6H). Mass Spectral Analysis m/z 360.4 tional 10 hours. The reaction mixture was quenched with (M+H)" saturated aqueous ammonium chloride (300 mL) and the product was extracted with diethyl ether (3x300 mL). The Example 4B combined organics were washed with water, brine, dried over 40 Sodium sulfate, filtered, and concentrated under reduced pres Preparation of 4.8: Sure. The crude product was purified by column chromatog To a solution of 4.4 (1.80g, 2.75 mmol. 1 eq.) in methylene raphy (eluent: hexane/ethyl acetate mixture of increasing chloride (50 mL) at 0°C. was added triethylamine (1.68 mL, polarity). Yield: 78% 12.5 mmol. 4.5 eq.) and 2-ethylbutyrylchloride 4.7 (1.06 mL, "H NMR (400 MHz, CDC1) & 7.13 (m, 1H), 7.08 (dd. 1H), 45 7.5 mmol. 2.7 eq.) dropwise. The reaction mixture was stirred 6.91 (m, 2H), 5.47 (s, 1H), 3.84 (m, 2H), 3.28 (m, 2H), 2.76 at room temperature for 10 hours and then concentrated under (m. 2H),2.59 (t, 2H), 1.97 (m, 2H), 1.60 (m, 2H), 1.47 (s.9H). reduced pressure. The residue was dissolved in ethyl acetate Mass Spectral Analysis m/z. 355.36 (M+H)" (200 mL). The organic solution was washed with 0.5N hydro Preparation of 4.3: chloric acid (3x100 mL), brine, and concentrated in vacuo. To a solution of 4.2 (12.5g, 35 mmol. 1 eq.) in methanol 50 The crude product was purified by column chromatography (200 mL) was added palladium 3.75 mg, 10 wt.% (dry basis) (eluent: hexane/ethyl acetate mixture of increasing polarity). on activated carbon, 20% wt. eq.). The reaction mixture was Yield: 87% stirred under hydrogen atmosphere using a hydrogen balloon H NMR (400 MHz, CDC1) & 7.20 (m, 1H), 7.10 (m, 1H), at room temperature for 10 hours. The palladium on activated 6.88 (m. 1H), 6.83 (m, 1H), 5.46 (m. 1H), 4.01-3.70 (m, 2H), carbon was filtered off on a celite pad and the filtrate was 55 3.32 (m, 3H), 2.96 (m, 2H), 2.01 (m. 1H), 1.89-1.71 (m, 4H), concentrated under reduced pressure. The crude product was 1.69-1.35 (m. 19H), 0.89 (m, 6H). Mass Spectral Analysis used for the next step without further purification. Mass Spec m/z–459.95 (M+H)" tral Analysis m/z. 357.42 (M+H)" Preparation of 4B: Preparation of 4.4: 60 To a solution of 4.8 (300 mg, 0.65 mmol. 1 eq.) in methanol To a solution of 4.3 (11 g, 30.8 mmol. 1 eq.) in dry tetrahy (20 mL) was added a 2.0M anhydrous solution of hydrogen drofuran (200 mL) under nitrogen was added a 2.0M solution chloride in diethylether (3.3 mL, 6.6 mmol. 10 eq.) dropwise. of borane-methyl sulfide in tetrahydrofuran (154 mL, 308 The reaction mixture was stirred at room temperature for 10 mmol. 10 eq.) dropwise at 0°C. The reaction mixture was hours and then concentrated under reduced pressure. The stirred at room temperature for 15 minutes and then slowly 65 crude product was triturated with diethyl ether and collected heated to reflux for 90 minutes. The volatiles were removed by filtration to give 4B isolated as its hydrochloric acid salt. under reduced pressure and the residue was dissolved in Yield: 80% US 7,576,207 B2 81 82 "H NMR (400 MHz, DMSO-d) & 8.86 (m, 2H), 7.85 (t, Mass Spectral Analysis m/z 453.48 (M--H)" 1H), 7.27 (m. 1H), 7.10 (m, 1H), 6.89 (m, 1H), 6.82 (m. 1H), Preparation of 4D: 3.22 (m, 2H), 3.10 (m,3H), 2.88 (m, 2H), 2.03-1.81 (m, 6H), To a solution of 4.12 (0.42g, 0.84 mmol. 1 eq.) in methanol 1.71 (m, 1H), 1.51-1.27 (m, 8H), 0.78 (m, 6H). (15 mL) was added a 2.0M anhydrous solution of hydrogen Mass Spectral Analysis m/z. 359.4 (M+H)" chloride in diethylether (4.2 mL, 8.4 mmol. 10 eq.) dropwise. Example 4C The reaction mixture was stirred at room temperature for 10 hours and then concentrated under reduced pressure. The crude product was purified by column chromatography (elu Preparation of 4.10: ent: methanol/dichloromethane mixture of increasing polar To a solution of 4.8 (0.820 g, 1.79 mmol. 1 eq.) in dry 10 ity) to give 4D isolated as its hydrochloric acid salt. Yield: tetrahydrofuran (50 mL) at 0°C. was added sodium hydride 74% (60% in mineral oil, 143 mg, 3.58 mmol. 2 eq.) in one portion. H NMR (400 MHz, DMSO-d) & 8.98 (m, 2H), 7.31 (m, The mixture was stirred at 0°C. for 1 hour and then methyl 1H), 7.09 (m, 2H), 6.90 (m, 1H), 6.83 (m. 1H), 3.26-3.06 (m, iodide 4.9 (0.15 mL, 2.4 mmol. 1.3 eq.) was added dropwise. 3H), 3.02-2.82 (m, 6H), 2.08-1.82 (m, 5H), 1.73 (m, 1H), The reaction mixture was stirred at 0° C. for another 30 15 1.56-1.39 (m, 4H), 1.13 (t, 3H). Mass Spectral Analysis minutes before slowly heated at 70° C. for 10 hours. The m/z–353.3 (M+H)" volatiles were removed under reduced pressure and the resi due was partitioned between dichloromethane (100 mL) and Example 4E water (100 mL). The aqueous phase was extracted with dichloromethane (3x50 mL) and the combined organics were dried over sodium sulfate, filtered, and concentrated under Preparation of 4.13: reduced pressure. The crude product was purified by column To a solution of 4.12 (0.80 g, 1.6 mmol. 1 eq.) in dry chromatography (eluent: hexane/ethyl acetate mixture of tetrahydrofuran (50 mL) at 0°C. was added sodium hydride increasing polarity). (60% in mineral oil, 130 mg, 3.2 mmol. 2 eq.) in one portion. Yield: 86% 25 The mixture was stirred at 0°C. for 1 hour and then methyl "H NMR (400 MHz, CDC1) & 7.20 (m, 1H), 7.10 (m, 1H), iodide 4.9 (0.13 mL, 2.1 mmol. 1.3 eq.) was added dropwise. 6.92-6.80 (m, 2H), 3.92 (m. 1H), 3.79 (m, 1H), 3.55-3.29 (m, The reaction mixture was stirred at 0° C. for another 30 3H), 3.10-2.86 (m, 5H), 2.55-2.37 (m, 1H), 2.03-1.35 (m, minutes before slowly heated at 70° C. for 10 hours. The 23H), 0.87 (n, 6H). Mass Spectral Analysis m/z 473.56 volatiles were removed under reduced pressure and the resi 30 due was partitioned between dichloromethane (100 mL) and (M+H)" water (100 mL). The aqueous phase was extracted with Preparation of 4C. dichloromethane (3x50 mL) and the combined organics were To a solution of 4.10 (0.72g, 1.5 mmol. 1 eq.) in methanol dried over sodium sulfate, filtered, and concentrated under (15 mL) was added a 2.0M anhydrous solution of hydrogen reduced pressure. The crude product was purified by column chloride in diethyl ether (7.5 mL, 15 mmol. 10 eq.) dropwise. 35 chromatography (eluent: hexane/ethyl acetate mixture of The reaction mixture was stirred at room temperature for 10 increasing polarity). hours and then concentrated under reduced pressure. The Yield: 96% crude product was purified by column chromatography (elu H NMR (400 MHz, CDC1) & 7.23 (m, 1H), 7.10 (m, 1H), ent: methanol/dichloromethane mixture of increasing polar 6.89 (m, 1H), 6.83 (dd. 1H), 3.93 (m. 1H), 3.79 (m. 1H), 3.36 ity) to give 4C isolated as its hydrochloric acid salt. Yield: 40 (m. 1H), 3.22 (m, 2H), 3.98 (m, 4H), 2.86 (s.3H), 2.00 (m, 770, 1H), 1.89-1.73 (m,3H), 1.70-1.52 (m, 5H), 1.46 (s.9H), 1.41 "H NMR (400 MHz, DMSO-d) & 8.98 (m, 2H), 7.27 (m, (m. 1H), 1.35 (t, 3H) 1H), 7.10 (m. 1H), 6.88 (m, 1H), 6.83 (m. 1H), 3.41-3.28 (m, Mass Spectral Analysis m/z 467.41 (M--H)" 5H), 3.22 (m, 2H), 3.10 (m, 1H), 3.01 & 2.81 (2s, 1H), 2.90 Preparation of 4E: (m. 2H), 2.06-1.81 (m, 5H), 1.73 (m. 1H), 1.60- 1.29 (m, 8H), 45 0.83-0.70 (m, 6H) To a solution of 4.13 (0.72g, 1.5 mmol. 1 eq.) in methanol Mass Spectral Analysis m/z. 373.4 (M+H)" (30 mL) was added a 2.0M anhydrous solution of hydrogen chloride in diethyl ether (7.6 mL, 15.2 mmol. 10 eq.) slowly. Example 4D The reaction mixture was stirred at room temperature for 10 50 hours and then concentrated under reduced pressure. The Preparation of 4.12 crude product was purified by column chromatography (elu To a solution of 4.4 (4.70 g. 6.52 mmol. 1 eq.) in methylene ent: methanol/dichloromethane mixture of increasing polar chloride (100 mL) at 0°C. was added pyridine (2.64 mL, 32.6 ity) to give 4E isolated as its hydrochloric acid salt. Yield: mmol. 5 eq.) and ethanesulfonyl chloride 4.11 (1.85 mL, 19.6 91% mmol. 3 eq.) dropwise. The reaction mixture was stirred at 55 H NMR (400 MHz, DMSO-d) & 8.76 (m, 2H), 7.29 (m, room temperature for 10 hours and then concentrated under 1H), 7.10 (m. 1H), 6.90 (m, 1H), 6.83 (m, 1H), 3.23 (m, 2H), reduced pressure. The residue was dissolved in ethyl acetate 3.18-3.02 (m, 5H), 2.90 (m, 2H), 2.77 (s.3H), 2.08-1.81 (m, (500 mL). The organic solution was washed with 0.5N hydro 5H), 1.76-1.37 (m, 5H), 1.19 (t, 3H). Mass Spectral Analysis chloric acid (3x100 mL), brine, and concentrated in vacuo. m/z =367.7 (M+H)" The crude product was purified by column chromatography 60 (eluent: hexane/ethyl acetate mixture of increasing polarity). Example 5A Yield: 37% "H NMR (400 MHz, CDC1,) 87.21 (m. 1H), 7.11 (m, 1H), Preparation of 5.6: 6.89 (m. 1H), 6.84 (m, 1H), 4.10 (m. 1H), 4.0-3.67 (m, 2H), To a suspension of NaH (2.53 g, 95%, 0.1 mol) in THF (300 3.36 (m. 1H), 3.15 (m, 2H), 3.08-2.90 (m, 4H), 2.02 (m, 1H), 65 mL) at 0°C. was added dropwise triethyl phosphonoacetate 1.88-1.72 (m, 3H), 1.69-1.52 (m, 6H), 1.46 (s, 9H), 1.37 (t, (5.2) (20 mL, 0.1 mol). The reaction mixture was then stirred 3H) at room temperature for 45 minutes and then the Spiroketone US 7,576,207 B2 83 84 5.1 (12.68 g., 0.03995 mol) was added in small portions to the Example 5B mixture. The reaction mixture was stirred at ~50° C. for 16 days. The reaction was quenched with water and extracted Preparation of 5.10: with ethyl acetate. The combined extracts were washed with To a solution of the carboxylic acid 5.7 (866mg, 2.4 mmol) brine, dried over Sodium Sulfate and concentrated in vacuo. 5 The residue was chromatographed using ethyl acetate/hexane in acetonitrile (40 mL) was added N,N-diisopropylethy (1:3) as eluent to give 14 g of a mixture of three very close lamine (2.6 mL, 15 mmol) and glycine methyl ester hydro spots corresponding to the three isomeric olefins 5.3, 5.4 and chloride (5.9) (480 mg, 3.8 mmol). The reaction mixture was 5.5. The mixture of olefins (14 g) in ethyl acetate (450 mL) cooled with ice-bath and TBTU (930 mg, 2.9 mmol) was was hydrogenated in the presence of 10% Pd/C (4.2 g) at 10 added in Small portions to the reaction mixture. The reaction room temperature for 3 days. Filtration followed by evapora mixture was stirred at room temperature overnight. The reac tion of the solvent gave the saturated ester 5.6. Yield: 90% (2 tion mixture was concentrated and dissolved in ethyl acetate. steps) The organic solution was washed with Saturated aqueous sodium bicarbonate and dried over sodium sulfate. Evapora "H NMR (400 MHz, CDC1) & 7.17 (m, 2H), 6.90 (m, 2H), tion of the solvent provided the crude product, which was 4.20 (q, 2H), 3.88 (m, 2H), 3.40 (m, 2H), 3.08 (m. 1H), 3.00 15 chromatographed using ethyl acetate/hexane (2:1) as eluent (dd. 1H), 2.40 (dd. 1H), 2.00 (m. 1H), 1.86-1.63 (m, 4H), 1.46 to yield the product 5.10. (s+m, 10H), 1.29 (t,3H). Yield: 94%. Preparation of 5.7: H NMR (400 MHz, CDC1) & 7.20 (m, 1H), 7.12 (m, 1H), To a solution of ester 5.6 (2.0 g, 5.1 mol) in a mixture of 6.90 (m, 2H), 6.00 (brs, 1H), 4.09 (d. 2H), 3.90 (m. 1H), 3.78 methanol (30 mL), tetrahydrofuran (30 mL) and water (30 (s+m, 4H), 3.48 (m, 1H), 3.33 (m, 1H), 3.03 (m. 1H), 2.96 (dd. mL) was added lithium hydroxide monohydrate (1.35 g, 32 1H), 2.29 (dd. 1H), 2.03 (m. 1H), 2.83-2.57 (m, 4H), 1.48 mmol). The reaction mixture was stirred at room temperature (s+m, 10H). overnight, then concentrated in vacuo, and the aqueous phase Preparation of 5.11: was washed with diethyl ether. The aqueous layer was acidi 25 To a solution of 5.10 (970 mg, 2.2 mmol) in a mixture of fied with 1N HCl to pH ~4 and extracted with methylene methanol (15 mL), tetrahydrofuran (15 mL) and water (15 chloride. The combined organic extracts were dried over mL) was added lithium hydroxide monohydrate (588 mg, 14 Sodium sulfate, filtered and concentrated in vacuo to give the mmol). The reaction mixture was stirred at room temperature desired carboxylic acid. Yield: 100%. overnight, concentrated in vacuo, and extracted with diethyl "H NMR (400 MHz, DMSO d) 87.26 (m, 1H), 7.10 (m, 30 ether. The aqueous layer was acidified with 1N HCl to pH~4. 1H), 6.86 (m. 1H), 6.90 (m, 1H), 3.75 (m, 1H), 3.63 (m. 1H), and extracted with methylene chloride. The combined 3.22 (m, 2H), 2.93 (m, 2H), 2.32 (dd. 1H), 2.0 (m. 1H), organic extracts were dried over Sodium Sulfate and concen 2.68-2.52 (m, 4H), 1.40 (s+m, 10H). trated in vacuo to give the desired carboxylic acid. Yield: 100%. Preparation of 5.8: 35 To a solution of the carboxylic acid 5.7 (433 mg, 1.2 mmol) H NMR (400 MHz, DMSO d) 812.58 (s, 1H), 8.36 (t, in acetonitrile (15 mL) was added N,N-diisopropylethy 1H), 7.30 (m. 1H), 7.09 (m, 1H), 6.80 (m, 2H), 3.80–3.60(m, lamine (0.86 mL, 4.9 mmol) and diethylamine (1.6) (0.36 4H), 3.30 (m, 2H), 3.02 (m. 1H), 2.86 (dd. 1H), 2.19 (dd. 1H), mL, 3.5 mmol). The reaction mixture was cooled with ice 2.05 (m. 1H), 2.65 (m, 3H), 1.40 (s+m, 11H). bath and TBTU (463 mg, 1.44 mmol) was added portionwise 40 to the reaction mixture. The reaction mixture was stirred at Preparation of 5.12: room temperature overnight. The reaction mixture was con To a solution of the carboxylic acid 5.11 (920 mg, 2.2 centrated, dissolved in ethylacetate. The organic solution was mmol) in acetonitrile (30 mL) was added N,N-diisopropyl washed with Saturated aqueous Sodium bicarbonate and dried ethylamine (1.6 mL, 9.0 mmol) and diethylamine (1.6) (0.66 over sodium sulfate. Evaporation of the solvent gave the mL, 6.4 mmol). The reaction mixture was cooled with ice crude product, which was chromatographed using ethyl 45 bath and TBTU (850 mg, 2.6 mmol) was added in small acetate/hexane (1:1) as eluent. Yield: 80%. portions to the reaction mixture. The reaction mixture was "H NMR (400 MHz, CDC1) & 7.20 (m, 1H), 7.10 (m, 1H), stirred at room temperature overnight. The reaction mixture 6.88 (m, 2H), 3.81 (m, 2H), 3.56-3.30 (m, 6H), 3.08 (m, 1H), was concentrated and dissolved in ethylacetate. The resulting 2.92 (dd. 1H), 2.40 (dd. 1H), 2.12 (m. 1H), 1.83-1.62 (m,3H), organic solution was washed with Saturated aqueous sodium 1.48 (s+m, 11H), 1.20 (t, 3H). 50 bicarbonate and dried over sodium sulfate. Evaporation of the solvent provided the crude product, which was chromato Preparation of 5A: graphed using acetone/hexane (1:2) as eluent. Yield: 87%. To the solution of 5.8 (380 mg. 0.91 mmol) in methylene H NMR (400 MHz, CDC1) & 7.20 (m, 1H), 7.10 (m, 1H), chloride (5 mL) was added a 2.0M anhydrous solution of 6.89 (m, 2H), 6.76 (m, 1H), 4.15 (d. 1H), 4.08 (d. 1H), 3.80 hydrogen chloride in diethyl ether (15 mL). The reaction 55 (m. 2H), 3.40-3.30 (m, 6H), 3.0 (m, 2H), 2.28 (dd. 1H), 2.0 mixture was stirred for 6 hours at room temperature. Diethyl (m. 1H), 1.78 (m. 2H), 1.58 (m, 2H), 1.47 (s+m, 10H), 1.21 (t, ether (80 mL) was added to the reaction mixture, which was stirred at room temperature for 2 days. The upper clear Solu 3H), 1.12 (t,3H). tion was decanted, the residue was washed with diethyl ether Preparation of 5B: three times and dissolved in methylene chloride. The result 60 To a solution of compound 5.12 (880 mg, 1.8 mmol) in ing Solution was concentrated in vacuo. The residue was dried methylene chloride (10 mL) was added a 2.0M anhydrous in vacuo to yield 5A isolated as its hydrochloric acid salt. solution of hydrogen chloride in diethyl ether (30 mL). The Yield: 93%. reaction mixture was stirred for 6 hours at room temperature. "H NMR (400 MHz, DMSO d) 89.08 (brs, 2H), 7.28 (m, Diethyl ether (120 ml) was added to the reaction mixture, 1H), 7.10 (m, 1H), 6.85 (m, 2H), 3.32-2.95 (m, 10H), 2.40 (m, 65 which was stirred at room temperature for 2 days. The upper 1H), 2.02-1.72 (m, 5H), 1.50 (m. 1H), 1.10 (m, 6H). clear solution was decanted and the residue was washed with Mass Spectral Analysis m/z. 317.3 (M+H)" diethyl ether three times and dissolved in methylene chloride. US 7,576,207 B2 85 86 The resulting Solution was concentrated in vacuo. The prod residue was dissolved in ethyl acetate and the resulting solu uct was then dried in vacuo to yield 5B isolated as its hydro tion was washed with Saturated aqueous Sodium bicarbonate chloric acid salt. Yield: 96%. and dried over sodium sulfate. Evaporation of the solvent "H NMR (400 MHz, DMSO d) 89.10 (brs, 2H), 8.18 (t, provided the crude product, which was chromatographed 1H), 7.31 (m. 1H), 7.10 (m, 1H), 6.88 (m, 2H), 3.98 (m, 2H), using ethyl acetate/hexane (1:1) as eluent. Yield: 68%. 3.50-3.10 (m, 8H), 2.90 (m, 2H), 2.20 (dd. 1H), 2.0-1.70 (m, H NMR (400 MHz, CDC1) & 7.26 (m, 1H), 7.10 (m, 1H), 5H), 1.52 (t, 1H), 1.12 (t, 3H), 1.02 (t, 3H). Mass Spectral 6.85 (m, 2H), 4.07 (d. 1H), 4.0 (d. 1H), 3.86 (m, 2H), 3.62 (m, Analysis m/z. 374.3 (M+H)" 2H), 3.40-3.30 (m, 5H), 3.05 (m, 2H), 2.42 (m, 1H), 1.98 (m, 1H), 1.77 (m, 3H), 1.56 (t, 1H), 1.43 (s+m, 1H), 1.20 (t,3H), Example 6A 10 1.13 (t, 3H). Preparation of 6A: Preparation of 6.1: To a solution of ester 5.6 (2.5 g. 6.4 mmol) in tetrahydro To a solution of 6.5 (450 mg, 0.98 mmol) in methylene furan (120 mL) was added lithium tetrahydroborate (450 mg. chloride (6 mL) was added a 2.0M anhydrous solution of 15 hydrogen chloride in diethyl ether (20 mL). The reaction was 20 mmol). The reaction mixture was refluxed overnight and stirred for 6 hours at room temperature. Diethyl ether (80 mL) quenched with water followed by 1N HCl in order to adjust was added to the reaction mixture, which was stirred at room the pH to 3-4. The mixture was extracted with ethyl acetate. temperature for 2 days. The upper clear Solution was decanted The combined organic extracts were dried over Sodium Sul and the residue was washed with diethyl ether three times, fate and concentrated to give the alcohol 6.1 used for the next dissolved in methylene chloride and the resulting solution step without further purification. Yield: 100%. was concentrated and dried in vacuo to yield 6A isolated as its "H NMR (400 MHz, CDC1) & 7.24 (m, 1H), 7.10 (m, 1H), hydrochloric acid salt. Yield: 94%. 6.83 (m, 2H), 3.90-3.80 (m, 4H), 3.37 (m. 1H), 3.18 (m, 2H), 2.33 (m. 1H), 1.96-1.58 (m, 6H), 1.47 (s+m, 11H). "H NMR (400 MHz, DMSO d) & 9.04 (brs, 2H), 7.30 (m, "H NMR (400 MHz, DMSOd) & 7.51 (s, 1H), 7.29 (t, 1H), 1H), 7.10 (m, 1H), 6.90 (m, 1H), 6.80 (m, 1H), 4.15 (d. 1H), 7.22 (s, 4H), 7.10 (d. 1H), 7.05 (d. 1H), 6.97 (s, 1H), 5.90 (s, 25 4.1 (d. 1H), 3.53 (m, 2H), 3.22-2.90 (m, 9H), 2.36 (m. 1H), 1H), 3.63 (m, 2H), 3.41 (m, 2H), 3.32 (m, 2H), 3.20 (m, 2H), 2.13 (m. 1H), 1.90-1.50 (m, 6H), 1.10 (t,3H), 1.02 (t, 3H). 1.80 (m, 4H), 1.42 (s, 9H), 1.10 (m, 6H). Mass Spectral Analysis m/z. 361.4 (M+H)" Preparation of 6.3: Example 7A A solution of ethyl diazoacetate (6.2) (1.22 mL, 11.6 30 mmol) in methylene chloride (10 mL) was added dropwise to a solution of the alcohol 6.1 (1.15g, 3.31 mmol) and rhodium Preparation of 7.2: (II) acetate dimer (16 mg, 0.036 mmol) in methylene chloride To a solution of 7.1 (4.g., 8.6 mmol. 1 eq.) in dry tetrahy (20 mL) at room temperature. The reaction mixture was drofuran (90 mL) was added tetrakis(triphenylphosphine) stirred at room temperature overnight. The reaction mixture 35 palladium(0) (497 mg, 0.43 mmol, 0.05 eq.) followed by a was concentrated in vacuo and the residue was purified by 0.5M solution of (5-ethoxy-5-oxopentyl)Zinc(II) bromide 2.6 column chromatography using ethyl acetate/hexane (1:4) as in tetrahydrofuran (27.5 mL, 13.7 mmol, 1.6 eq.) dropwise. eluent, yielding the ester 6.3. Yield: 60%. The reaction mixture was stirred at 45° C. for 10 hours and "H NMR (400 MHz, CDC1,) & 7.26 (m. 1H), 7.10 (m, 1H), then quenched with aqueous ammonium chloride (100 mL) at 6.86 (m. 2H), 4.21 (q, 2H), 4.11 (d. 1H), 4.04 (d. 1H), 3.88 (m, 40 room temperature. The product was extracted with diethyl 2H), 3.65 (m, 2H), 3.38 (m. 1H), 3.10 (m, 2H), 2.43 (m, 1H), ether (3x100 mL) and the combined extracts were washed with brine, dried over sodium sulfate, filtered, and concen 2.01 (dd. 1H), 1.83-1.58 (m, 4H), 1.48 (s+m, 1H). trated under reduced pressure. The crude product was purified Preparation of 6.4: by column chromatography (eluent: hexane/ethyl acetate To a solution of the ester 6.3 (1.12 g, 2.58 mmol) in a 45 mixture of increasing polarity). mixture of methanol (20 mL), tetrahydrofuran (20 mL) and Yield: 58%. water (20 mL) was added lithium hydroxide monohydrate (672 mg, 16 mmol). The reaction mixture was stirred at room H NMR (400 MHz, CDC1) & 7.06 (m, 1H), 6.92 (m, 1H), temperature overnight, concentrated in vacuo and extracted 6.83 (m. 1H), 5.79 (s, 1H), 4.13 (q, 2H), 3.64-3.28 (m, 4H), with diethyl ether. The aqueous layer was acidified with 1N 2.64 (s. 2H), 2.41 (t, 2H), 2.33 (t, 2H), 1.74-1.35 (m, 17H), HCl to pH ~4, and extracted with methylene chloride. The 50 1.25 (t, 3H). combined organic extracts were dried over Sodium sulfate and Mass Spectral Analysis m/z 446.85 (M--H)" concentrated in vacuo to give the carboxylic acid 6.4 used for Preparation of 7.3: the next step without further purification. Yield: 99.3%. To a solution of 7.2 (2.2g, 4.9 mmol. 1 eq.) in ethyl acetate "H NMR (400 MHz, DMSO d) 812.60 (s, 1H), 7.30 (m, 55 (50 mL) was added palladium 440 mg, 10 wt.% (dry basis) 1H), 7.08 (m, 1H), 6.88 (m, 1H), 6.79 (m, 1H), 4.07 (d. 1H), on activated carbon, 20% wt. eq.). The reaction mixture was 3.99 (d. 1H), 3.70 (m, 1H), 3.58 (m,3H), 3.30 (m, 1H), 3.0 (m, stirred under hydrogen atmosphere using a hydrogen balloon 2H), 2.32 (m. 1H), 2.15 (m. 1H), 1.60 (m, 4H), 1.40 (s+m, at room temperature for 10 hours. The palladium on activated 11H). carbon was filtered off on a celite pad and the filtrate was Preparation of 6.5: 60 concentrated under reduced pressure. The crude product was To a solution of the carboxylic acid 6.4 (609 mg, 1.5 mmol) purified by column chromatography (eluent: ethyl acetate/ in acetonitrile (25 mL) was added N,N-diisopropylethy hexane mixture of increasing polarity). Yield: 73% lamine (1.1 mL, 6.2 mmol) and diethylamine (1.6) (0.45 mL, "H NMR (400 MHz, CDC1) & 7.01-6.92 (m, 2H), 6.80 (m, 4.4 mmol). The reaction mixture was cooled with ice-bath 1H), 4.13 (q, 2H), 3.52 (m, 1H), 3.41 (m, 2H), 3.29 (m, 1H), and TBTU (580 mg, 0.0018 mol) was added in small portions. 65 2.79 (m. 1H), 2.66 (m, 1H), 2.47 (m, 1H), 2.32 (m, 2H), 1.89 The reaction mixture was stirred at room temperature over (m. 2H), 1.76-1.29 (m. 19H), 1.25 (t, 3H). night. The reaction mixture was concentrated in vacuo; the Mass Spectral Analysis m/z 448.86 (M--H)" US 7,576,207 B2 87 88 Preparation of 7.4: hours. The palladium on activated carbon was filtered off on To a solution of 7.3 (1.6 g., 3.6 mmol. 1 eq.) in a mixture of a celite pad and the filtrate was concentrated under reduced methanol (20 mL), tetrahydrofuran (20 mL) and water (20 pressure. The crude product was purified by column chroma mL) was added lithium hydroxide monohydrate (0.61 g, 14.5 tography (eluent: ethyl acetate/hexane mixture of increasing mmol. 4 eq.) in one portion. The reaction mixture was stirred 5 polarity) to give 8A isolated as its hydrochloric acid salt. at room temperature for 10 hours. The volatiles were removed Yield: 53% under reduced pressure and the remaining aqueous Solution 'HNMR (400 MHz, CDC1,) & 6.92 (dd. 1H), 6.83-6.78 (m, was acidified with 1N hydrochloric acid until pH 2-3. The 2H), 4.01-3.69 (m, 2H), 3.43-3.25 (m, 5H), 3.08-2.80 (m, product was extracted with dichloromethane (3x100 mL) and 2H), 2.32 (m, 2H), 1.95 (m. 1H), 1.86 (m, 1H), 1.82-1.60 (m, the combined organics were dried over sodium sulfate, fil 10 5H), 1.57-1.31 (m, 14H), 1.17 (t, 3H), 1.11 (t, 3H). Mass tered, and concentrated under reduced pressure. The product Spectral Analysis m/z. 357.4 (M+H)" was used for the next step without further purification. Yield: 80% Example 8B "H NMR (400 MHz, CDC1) & 7.00-6.89 (m, 2H), 6.78 (m, 1H), 3.49 (m. 1H), 3.39 (m, 2H), 3.28 (m, 1H), 2.75 (m. 1H), 15 Preparation of 8.6: 2.64 (m. 1H), 2.46 (m. 1H), 2.31 (m. 2H), 1.87 (n, 2H), To a solution of the enol triflate 8.5 (40.0 g, 78.2 mmol) in 1.73-1.12 (m. 19H). Mass Spectral Analysis m/z 418.87 tetrahydrofuran (300 mL) at room temperature was added a (M-H) 0.5M solution of 5-ethoxy-5-oxopentylzinc bromide (2.6) in Preparation of 7A: tetrahydrofuran (200 mL, 100 mmol) followed by tetrakis To a solution of 7.4 (0.3 g, 0.7 mmol. 1 eq.) in dichlo (triphenylphosphine)palladium(0) (4.1 g, 3.5 mmol). The romethane (15 mL) was slowly added a 2.0M anhydrous reaction mixture was stirred at 50° C. overnight. Additional solution of hydrogen chloride in diethyl ether (2.1 mL, 4.2 amount of a 0.5M solution of 5-ethoxy-5-oxopentylzinc bro mmol. 6 eq.). The mixture was stirred at room temperature for mide (2.6) in tetrahydrofuran (160 mL, 80 mmol) was added 10 hours and additional amount of a 2.0Manhydrous solution 25 to the reaction mixture, which was stirred at 50° C. for an of hydrogen chloride in diethyl ether (2 mL, 4 mmol. 5.7 eq.) additional 24 hours. The reaction mixture was cooled to room was added to the reaction mixture. The mixture was stirred at temperature, quenched with water and extracted with ethyl room temperature for another 10 hours and then concentrated acetate. The combined organic extracts were dried over under reduced pressure to give the crude product as the acid. Sodium Sulfate and concentrated in vacuo. The residue was The crude acid was purified by column chromatography (elu 30 chromatographed using ethyl acetate:hexane (1:3) as eluent. ent: methanol/dichloromethane mixture of increasing polar Yield: 78.3%. ity). During the purification and drying steps, the acid con "H NMR (400 MHz, CDC1) & 7.26 (m, 7.35 (m, 5H), 7.02 verted to the methyl ester, 7A, isolated as its hydrochloric acid (d. 1H), 6.80 (d. 1H), 6.68 (dd. 1H), 5.72 (s, 1H), 5.13 (s. 2H), salt. Yield: 81% 4.10 (q, 2H), 3.80 (s.3H), 3.58 (m, 2H), 3.43 (m, 2H), 2.60 (s, "H NMR (400 MHz, DMSO-d) & 8.60 (s, b, 2H), 7.10 (m, 35 2H), 2.43 (t, 2H), 2.30 (t, 2H), 1.70-1.40 (m,8H), 1.23 (t,3H). 2H), 6.93 (m. 1H), 3.58 (s.3H), 3.11 (m, 2H), 2.98 (m, 2H), 2.75 (m, 2H), 2.48 (m. 1H), 2.33 (m, 2H), 1.88 (m, 2H), Preparation of 8.7: 1.65-1.13 (m. 10H). Mass Spectral Analysis m/z 334.3 To a solution of 8.6 (30.0 g, 61.02 mmol) in a mixture of (M+H)" methanol-tetrahydrofuran-water (300 mL-300 mL-300 mL) was added lithium hydroxide monohydrate (16 g., 38 mmol). Example 7B 40 The reaction mixture was stirred at room temperature over night, concentrated in vacuo and extracted with diethyl ether. The aqueous layer was acidified with 1N HCl to pH ~4. Preparation of 7.5: extracted with methylene chloride. The combined organic To a solution of 7.4 (1.2g, 2.86 mmol. 1 eq.) in acetonitrile extracts were dried over sodium sulfate and concentrated to (30 mL) was slowly added diisopropylethylamine (1.09 mL, 45 give the carboxylic acid 8.7, used for the next step without 6.3 mmol. 2.2 eq.), diethylamine 1.6 (0.6 mL, 5.72 mmol. 2 further purification. eq.) at room temperature and 10 minutes later at 0°C., O-ben Zotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluorobo Yield: 98.8%. rate (TBTU) (1.01 g, 3.15 mmol. 1.1 eq.) portionwise. The H NMR (400 MHz, DMSO d) & 12.0 (brs, 1H), 7.32 (m, reaction mixture was slowly warmed to room temperature 50 5H), 7.10 (d. 1H), 6.80 (d. 1H), 6.71 (dd. 1H), 5.82 (s, 1H), and stirred at room temperature for 10 hours. The volatiles 5.08 (s. 2H), 3.73 (s, 3H), 3.48-3.38 (m, 4H), 2.60 (s. 2H), were removed under reduced pressure and the residue was 2.40 (t, 2H), 2.25 (t, 2H), 1.53-1.32 (m, 8H). dissolved in ethyl acetate (200 mL). The resulting solution To a solution of the carboxylic acid 8.7 (27.96 g. 60.32 was washed with 1M aqueous sodium bicarbonate (3x50 mol) in acetonitrile (600 mL) was added N,N-diisopropyl mL), brine, dried over Sodium sulfate, filtered, and concen 55 ethylamine (41.0 mL. 233 mmol) and diethylamine (17.0 mL. trated under reduced pressure. The crude product was purified 163.5 mmol). The reaction mixture was cooled with ice-bath by column chromatography (eluent: hexane/ethyl acetate and TBTU (25.2g, 78.5 mol) was added in small portions to mixture of increasing polarity). Yield: 88% the reaction mixture. The reaction mixture was stirred at room "H NMR (400 MHz, CDC1) & 6.97 (m, 2H), 6.79 (m, 1H), temperature overnight. The reaction mixture was concen 60 trated and dissolved in ethyl acetate. The resulting solution 3.57-3.24 (m, 8H), 2.79 (m, 1H), 2.65 (m. 1H), 2.48 (m, 1H), was washed with Saturated aqueous Sodium bicarbonate and 2.31 (m, 2H), 1.90 (m, 2H), 1.80-1.53 (m,3H), 1.50-1.19 (m, dried over sodium sulfate. Evaporation of the solvent pro 16H), 1.17 (t, 3H), 1.11 (t, 3H). Mass Spectral Analysis vided the crude product, which was chromatographed using m/z-475.53 (M+H)" ethyl acetate/hexane (2:1) as eluent to yield the amide 8.8. Preparation of 7B: 65 Yield: 96.5%. The reaction mixture was stirred under hydrogen atmo H NMR (400 MHz, CDC1) & 7.33 (m, 5H), 7.03 (d. 1H), sphere using a hydrogen balloon at room temperature for 10 6.82 (d. 1H), 6.70 (dd. 1H), 5.72 (s, 1H), 5.12 (s. 2H), 3.80 (s, US 7,576,207 B2 89 90 3H), 3.60 (m, 2H), 3.42-3.30 (m, 6H), 2.60 (s. 2H), 2.45 (t, reduced pressure. The crude product was purified by chroma 2H), 2.30 (t, 2H), 2.70 (m, 2H), 1.58-142 (m, 6H), 1.15 (t, tography using ethyl acetate:hexane (1:1) as eluent. Yield: 3H), 1.10 (t,3H). 95%. H NMR (400 MHz, CDC1) & 6.98 (d. 1H), 6.87 (d. 1H), Preparation of 8B: 6.73 (s, 1H), 6.68 (dd. 1H), 6.92 (s, 1H), 6.88 (d. 1H), 6.82 (d. Compound 8.8 (569 mg, 1.1 mmol) was dissolved in 1H), 6.62 (dd. 1H), 3.50 (m, 1H), 3.35 (m, 7H), 2.72 (m. 1H), methanol (30 mL) and the solution was hydrogenated in the 2.60 (d. 1H), 2.40 (d. 1H), 2.31 (t, 2H), 1.85-1.56 (m, 6H), presence of 10% Pd/C (180 mg) at room temperature for 2 1.46 (s, 9H), 1.40-1.30 (m, 6H), 1.20 (t, 3H), 1.12 (t, 3H). days. The reaction mixture was filtered and the filtrate was Preparation of 9.3: concentrated in vacuo. The residue was purified by column 10 chromatography using methylene chloride/methanol/ammo To a solution of the phenol 9.2 (3.21 g, 6.8 mmol) in nium hydroxide (10:1:1) as eluent to give 8B. Yield: 100%. methylene chloride (100 mL) was added triethylamine (2.37 mL, 17 mmol), 4-dimethylaminopyridine (DMAP) (83 mg, "H NMR (400 MHz, CDC1) & 6.97 (d. 1H), 6.80 (d. 1H), 0.68 mol), followed by N-phenylbis(trifluoromethane 6.68 (dd. 1H), 3.79 (s.3H), 3.38 (q, 2H), 3.30 (q, 2H), 2.90 sulphonimide) (7.9) (3.3 g, 9.2 mmol). The reaction mixture 2.70 (m, 6H), 2.42 (d. 1H), 2.30 (m, 2H), 1.92 (m, 2H), 1.68 15 was stirred at room temperature overnight. The reaction mix (m, 4H), 1.38 (m, 7H), 1.18 (t, 3H), 1.10 (t, 3H). ture was washed with aqueous saturated Sodium bicarbonate, Mass Spectral Analysis m/z 387.4 (M+H)" dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed using ethyl acetate:hexane Example 8C (1:1) as eluent, yielding the triflate 9.3. Yield: 92.5%. Preparation of 8C: H NMR (400 MHz, CDC1) & 7.10 (m, 1H), 7.0 (dd. 1H), To a solution of compound 8.8 in methylene chloride at 3.50-3.27 (m, 8H), 2.82 (m, 1H), 2.70 (d. 1H), 2.50 (d. 1H), -50°C. was added dropwise a 1.0M solution of borontribro 2.30 (m, 2H), 1.90 (m, 2H), 1.62 (m, 4H), 1.45 (s, 9H), mide in methylene chloride (12 mL, 12 mmol). The reaction 25 1.38-1.28 (m, 6H), 1.20 (t, 3H), 1.10 (t, 3H). mixture was stirred between -50° C. to -10°C. for 1 hour and Preparation of 9.4: then at room temperature overnight. The reaction mixture was To a solution of the triflate 9.3 (3.75 g. 6.2 mmol) in cooled to 0°C., quenched with 1N HCl and the mixture was N,N-dimethylformamide (25 mL) was added methanol (10 extracted with diethyl ether. The aqueous layer was basified mL), triethylamine (1.4 mL, 10 mol), 1,3-bis(diphenylphos with 3N sodium hydroxide to pH -9, and extracted with 30 phino)propane (207 mg, 0.502 mmol) followed by palladium methylene chloride. The organic extracts were combined, acetate (113 mg 0.503 mol). The reaction mixture was heated dried over sodium sulfate, and concentrated in vacuo. The to -65° C. and carbon monoxide was bubbled through the crude compound 8.9 was dissolved in methanol (50 mL) and reaction solution for 4 hours. The reaction mixture was then the solution was hydrogenated in the presence of 10% Pd/C cooled to room temperature, diluted with diethyl ether and (200mg) for 2 days. The reaction mixture was filtered and the 35 washed with water, brine, dried over sodium sulfate, and filtrate was concentrated in vacuo. The residue was purified concentrated in vacuo. The residue was purified by column by column chromatography using methylene chloride/metha chromatography using ethyl acetate:hexane (2:1) as eluent to nol/ammonia hydroxide (8:1:1) as eluent to yield 8C. Yield: give the methyl ester 9.4. Yield: 84.6%. 53.5% (two steps). H NMR (400 MHz, CDC1) & 7.93 (d. 1H), 7.73 (dd. 1H), H NMR (400 MHz, CDC1) & 6.90 (d. 1H), 6.78 (d. 1H), 40 7.10 (d. 1H), 3.90 (s.3H), 3.50-3.30 (m, 8H), 2.85 (m, 1H), 6.60 (dd. 1H), 4.70 (brs, 1H), 3.38 (q, 2H), 3.30 (q, 2H), 2.90 2.72 (d. 1H), 2.58 (d. 1H), 2.31 (m, 2H), 2.00 (m, 2H), 1.68 (m. 2H), 2.77 (m,3H), 2.63 (d. 1H), 2.40 (d. 1H), 2.30 (t, 2H), (m, 4H), 1.45 (s.9H), 1.40-1.28 (m, 6H), 1.19 (t,3H), 1.11 (t, 1.90 (m, 2H), 1.65 (m, 3H), 1.40 (m, 6H), 1.18-1.10 (m, 8H). 3H). Mass Spectral Analysis m/z. 373.4 (M+H)" Preparation of 9.5: 45 To a solution of compound 9.4 (2.6 g. 5.05 mmol) in a Example 9A mixture of methanol (40 mL), tetrahydrofuran (40 mL) and water (40 mL) was added lithium hydroxide monohydrate Preparation of 9.1: (1.35 g, 32 mmol). The reaction mixture was stirred at room temperature overnight, concentrated in vacuo and extracted Crude 8.9 prepared from 8.8 (30.2 g, 58.2 mmol) was 50 dissolved in methylene chloride (600 mL) and to this solution with diethyl ether. The aqueous layer was acidified with 1N was added triethylamine (13 mL. 93 mmol) followed by HCl to pH ~4, and extracted with methylene chloride. The di-tert-butyldicarbonate (12.8 g. 58.8 mmol). The reaction combined organic extracts were dried over Sodium sulfate and mixture was stirred for 1 hour at room temperature and con concentrated to give the carboxylic acid 9.5 used for the next centrated in vacuo. The residue was chromatographed using 55 step without further purification. Yield: 93.7%. ethyl acetate/methylene chloride (1:1) as eluent to yield the H NMR (400 MHz, CDC1) & 8.0 (d. 1H), 7.8 (dd. 1H), phenol 9.1. Yield: 66.4% (two steps). 7.10 (d. 1H), 3.50-3.30 (m, 8H), 2.82 (m, 1H), 2.71 (d. 1H), "H NMR (400 MHz, CDC1) & 6.98 (d. 1H), 6.87 (d. 1H), 2.58 (d. 1H), 2.35 (m, 2H), 2.00 (m, 2H), 1.70 (m, 4H), 1.44 6.73 (s, 1H), 6.68 (dd. 1H), 5.70 (s, 1H), 3.46–3.30 (m, 8H), (s, 9H), 1.40-1.28 (m, 6H), 1.20 (t, 3H), 1.10 (t, 3H). 2.60 (s. 2H), 2.40 (t, 2H), 2.32 (t, 2H), 1.73 (m,2H), 1.58-1.40 60 Preparation of 9A: (m. 15H), 1.18 (t, 3H), 1.10 (t, 3H). To a solution of the compound 9.5 (420 mg. 0.84 mmol) in methylene chloride (5 mL) was added a 2.0M anhydrous Preparation of 9.2: solution of hydrogen chloride in diethyl ether (15 mL). The A solution of compound 9.1 (15.0 g, 31.87 mmol) in ethyl reaction was stirred at room temperature overnight and acetate (600 mL) was hydrogenated in the presence of 10% 65 diluted with diethyl ether. The upper clear solution was Pd/C (4.5 g) at room temperature for 2 days. The mixture was decanted and the residue was washed with diethyl ether three filtered through celite. The filtrate was evaporated under times and dissolved in methylene chloride. The resulting US 7,576,207 B2 91 92 Solution was concentrated in vacuo to yield 9A isolated as its Example 9D hydrochloric acid salt. Yield: 100%. "H NMR (400 MHz, DMSO d) & 12.80 (s, 1H), 8.78 (brs, Preparation of 9D: 2H), 7.89 (d. 1H), 7.69 (dd. 1H), 7.20 (d. 1H), 3.28 (m, 4H), 9D (hydrochloric acid salt) was obtained according to a 3.10 (m, 2H), 3.0 (m, 2H), 2.81 (m, 2H), 2.60 (d. 1H), 2.30 (t, procedure similar to the one described for 9B (hydrochloric 2H), 1.91 (m, 2H), 1.60-1.20 (m, 10H), 1.10 (t,3H), 1.10 (t, acid salt) with the following exception: Step 9.7: 9.6a was 3H). Mass Spectral Analysis m/z 401.5 (M+H)" replaced by 2.3c. Example 9B 10 "H NMR (400 MHz, DMSO d) & 8.80 (brs, 2H), 8.40 (t, 1H), 7.80 (d. 1H), 7.60 (dd. 1H), 7.12 (d. 1H), 3.28 (m, 6H), 3.10 (m, 2H), 3.0 (m, 2H), 2.80 (m, 2H), 2.56 (d. 1H), 2.30 (t, Preparation of 9.7a: 2H), 1.98 (m, 2H), 1.60-1.20 (m, 10H), 1.10 (m, 6H), 1.0 (t, To a solution of the carboxylic acid 9.5 (500 mg, 1.0 mmol) 3H). in acetonitrile (35 mL) was added N,N-diisopropylethy 15 Mass Spectral Analysis m/z 428.5 (M+H)" lamine (1.18 mL, 6.71 mmol) and a 0.5M solution of ammo nia in 1,4-dioxane (9.6a) (20 mL, 10 mmol). The reaction TABLE A mixture was cooled with ice-bath and TBTU (389 mg, 0.00121 mol) was added in small portions. The reaction mix Ex- M+ ture was stirred at room temperature overnight and concen ample Structure H]" trated in vacuo. The residue was dissolved in ethyl acetate. The Solution was washed with Saturated aqueous sodium 1A 329.0 bicarbonate and dried over sodium sulfate. Evaporation of the O solvent provided the crude product, which was chromato graphed using acetone/hexane (1:1) as eluent to yield the 25 1n amide 9.7a. Yield: 90%. O "H NMR (400 MHz, CDC1) & 7.80 (d. 1H), 7.60 (dd. 1H), 7.10 (d. 1H), 7.0 (brs, 1H), 5.56 (brs, 1H), 3.46-3.30 (m, 8H), 2.88 (m. 1H), 2.72 (d. 1H), 2.57 (d. 1H), 2.37 (t, 2H), 1.89 (m, 30 3H), 1.70 (m, 2H), 1.46 (s, 9H), 1.40-1.28 (m, 7H), 1.18 (t, N 3H), 1.09 (t,3H). H Preparation of 9B: 1B N 343.0 To a solution of amide 9.7a (450 mg. 0.9 mmol) in meth 35 ylene chloride (5 mL) was added a 2.0M anhydrous solution N-N of hydrogen chloride in diethyl ether (15 mL). The reaction was stirred for 6 hours at room temperature. Diethyl ether (80 O O mL) was added to the reaction mixture, which was stirred at room temperature for 2 days. The upper clear Solution was 40 decanted and the residue was washed with diethyl ether three N times and dissolved in methylene chloride. The resulting H solution was concentrated in vacuo to yield 9B isolated as its hydrochloric acid salt. Yield: 93%. 1C 331.0 "H NMR (400 MHz, DMSO d) & 8.80 (brs, 2H), 7.92 (s, 45 O 1H), 7.80 (d. 1H), 7.60 (dd. 1H), 7.29 (s, 1H), 7.12 (d. 1H), 3.30 (m, 4H), 3.15 (m, 2H), 3.0 (m, 2H), 2.80 (m, 2H), 2.58 (d. 1n 1H), 2.30 (t, 2H), 1.98 (m, 2H), 1.60-1.20 (m. 10H), 1.10 (t, O 3H), 1.0 (t, 3H). 50 Mass Spectral Analysis m/z 400.5 (M+H)"

Example 9C N H 55 Preparation of 9C: 1D 345.0 9C (hydrochloric acid salt) was obtained according to a procedure similar to the one described for 9B (hydrochloric N-N acid salt) with the following exception: Step 9.7: 9.6a was 60 replaced by 9.6b. O O H NMR (400 MHz, DMSOd) 88.88 (brs, 2H), 8.40 (brs, 1H), 7.79 (d. 1H), 7.58 (dd. 1H), 7.12 (d. 1H), 3.28 (m, 4H), 3.11 (m, 2H), 3.0 (m, 2H), 2.80 (m, 5H), 2.60 (d. 1H), 2.30 (t, N 2H), 1.98 (m, 2H), 1.60- 1.20 (m. 10H), 1.10 (t, 3H), 1.0 (t, 65 H 3H). Mass Spectral Analysis m/z. 414.5 (M+H)" US 7,576,207 B2 93 94

TABLE A-continued TABLE A-continued

Ex- M+ Ex- M+ ample Structure H]" ample Structure H' 2E 359.4 1E 316.0

N-19 10 1n

O O

15

N H 373.5 2A 373.4 N- 2O

25

N H 30 401.5 2B 391.3 in N

N r 35 O O OO

40 N H 3A 377.4

2C 317.3

H 45 N-N

O O

50

N H

3B 389.4 2D 345 55 ( H N-1a-N

O O 60

N H 65 OOOOO NNN OOFNNO US 7,576,207 B2 95 96

TABLE A-continued TABLE A-continued

Ex- IM+ Ex- M+ ample Structure H]" ample Structure H]"

3C HO 375.8 4E 367.7 O O 10 N1insn 1n Ö - O O

15

N H N

4A 360.4 2O SA 317.3 O

1)N ls N N-N H O O O 25

N NH H 30 5B 374.3 4B 359.4 O O H 1n N lu N O u lul

N N 40 H H

6A 361.4 4C 373.4 O O 45 1N O N O O

50 N N H H

7A F 334.3 4D 353.3 O 55 | O Y-1N H No O 60

N H 65 N US 7,576,207 B2 97 98

TABLE A-continued TABLE A-continued Ex- M+ Ex ample Structure H]" ample Structure 9A 401.5

F 375.4

10 O 1S

15

N H 9B O NH 400.5 2O

O

8A 357.4 O 25 1n

30 N H

9C 414.5 N H O NH 35

O

8B 1 387.4 40 1)N

O

1n 45 N H 9D N 428.5 N 50

8C OH 373.4

55 O 1n

60

N H as E. Biological Methods The potencies of the final compounds found in Examples 1A-9D were determined by testing the ability of a range of US 7,576,207 B2 99 100 concentrations of each compound to inhibit the binding of the preparations used to measure receptor binding. Assays are non-selective , Hdiprenorphine, to the carried out in 96-well FlashPlates(R (Perkin Elmer Life Sci cloned humanu, 6and 8 opioid receptors, expressed in sepa ences, Inc, Boston, Mass.). Membranes prepared from CHO rate cell lines. ICso values were obtained by nonlinear analy cells expressing the appropriate receptor (50-100 g of pro sis of the data using GraphPad Prism version 3.00 for Win- 5 tein) are added to assay mixtures containing agonist with or dows (GraphPad Software, San Diego). K values were without antagonists, 100 pM SIGTPYS (approx. 100,000 obtained by Cheng-Prusoff corrections of ICs values. dpm), 3.0 uM GDP. 75 mM NaCl, 15 mM MgCl, 1.0 mM Receptor Binding ethylene glycol-bis(B-aminoethyl ether)-N.N.N',N'-tetrace The receptor binding method (DeHaven and DeHaven tic acid, 1.1 mM dithiothreitol, 10ug/mL leupeptin, 10ug/mL Hudkins, 1998) was a modification of the method of Raynor 1 0 pepstatin A, 200g/mL bacitracin, and 0.5 g/mL aprotinin in etal. (1994). After dilution in buffer A and homogenization as 50 mM Tris-HCl buffer, pH 7.8. After incubation at room before, membrane proteins (10-80 ug) in 250 uL were added temperature for one hour, the plates are sealed, centrifuged at to mixtures containing test compound and HIdiprenorphine 800xg in a swinging bucket rotor for 5 minutes and bound (0.5 to 1.0 nM, 40,000 to 50,000 dpm) in 250 uL of buffer A radioactivity determined with a TopCount microplate scintil in 96-well deep-well polystyrene titer plates (Beckman). 15 lation counter (Packard Instrument Co., Meriden, Conn.). After incubation at room temperature for one hour, the ECso values for agonists are determined from nonlinear samples were filtered through GF/B filters that had been regression fits of 8- or 12-point titration curves to the 4-pa presoaked in a solution of 0.5% (w/v) polyethylenimine and rameter equation for a sigmoidal dose-response with a slope 0.1% (w/v) bovine serum albumin in water. The filters were factor of 1.0 using GraphPad Prism(R) version 3.00 for Win rinsed 4 times with 1 mL of cold 50 mM Tris HCl, pH 7.8 and dows (GraphPad Software, San Diego, Calif.). radioactivity remaining on the filters determined by scintilla To determine ICso values, the concentrations to give half tion spectroscopy. Nonspecific binding was determined by maximal inhibition of agonist-stimulated SIGTPYS bind the minimum values of the titration curves and was confirmed ing, the amount of SIGTPYS bound in the presence of a by separate assay wells containing 10LM naloxone. K values fixed concentration of agonist and various concentrations of were determined by Cheng-Prusoff corrections of ICs values 25 antagonist was measured. The fixed concentration of agonist derived from nonlinear regression fits of 12 point titration was the ECso, the concentration to give 80% of the relative curves using GraphPad Prism(R) version 3.00 for Windows maximum stimulation of SIGTPYS binding. The agonists (GraphPad Software, San Diego, Calif.). loperamide (100 nM), U50,488 (50 nM), and BW373U86 To determine the equilibrium dissociation constant for the (2.0 nM) were used to stimulate SIGTPYS binding via the inhibitors (K), radioligand bound (cpm) in the presence of L., 8, and K opioid receptors, respectively. The ICso value was various concentrations of test compounds was measured. The determined from a best nonlinear regression fit of the data to concentration to give half-maximal inhibition (ECs) of the 4-parameter equation for a sigmoidal dose-response with radioligand binding was determined from a best nonlinear a slope factor of 1.0 using GraphPad Prism(R) version 3.00 for Windows. regression fit to the following equation, 35 F. Biological Results (Top - Bottom) The potencies of the compounds were determined by test Y = Bottom- 1 ox-logEC50 ing the ability of a range of concentrations of each compound to inhibit the binding of the non-selective opioid antagonist, 40 HIdiprenorphine, to the cloned human u, K, and 8 opioid where Y is the amount of radioligand bound at each concen receptors, expressed in separate cell lines. All the compounds tration of test compound. Bottom is the calculated amount of tested (Examples 1A-9D) bind with high affinity to the human radioligand bound in the presence of an infinite concentration cloned 8 opioid receptor. These compounds display high of test compound, Top is the calculated amount of radioligand selectivity Ö/K and Ö/L. The potencies of the ligands were bound in the absence of test compound, X is the logarithm of 45 assessed by their abilities to stimulated SIGTPYS binding the concentration of test compound, and LogECso is the log of to membranes containing the cloned human Ö opioid recep the concentration of test compound where the amount of tors. All the compounds tested were agonists at 8 opioid radioligand bound is half-way between Top and Bottom. The receptor with ECso values in the nanomolar range. Example nonlinear regression fit was performed using the program 9D (ADC02066447) (Table 1) binds to the u, 8 and K opioid Prism R (GraphPad Software, San Diego, Calif.). The K val- 50 receptors with affinity (expressed as K value) of 632 nM, 0.47 ues were then determined from the ECs values by the fol nM and 696nM, respectively. Furthermore, Example 9D dis lowing equation, played potent in vitro 8 agonist activity (ECso-8.1 nM). When ranges are used herein, Such as carbon ranges or 55 dosage ranges, all combinations and Subcombinations of EC50 K = ligand ranges and specific embodiments therein are intended to be 1 + included. The disclosures of each patent, patent application and pub lication cited or described in this document are hereby incor 60 porated herein by reference, in their entirety. where ligand is the concentration of radioligand and K is Those skilled in the art will appreciate that numerous the equilibrium dissociation constant for the radioligand. changes and modifications can be made to the preferred Receptor-mediated SIGTPYS Binding embodiments of the invention and that such changes and The potency and efficacy of compounds at each of the modifications can be made without departing from the spirit receptors are assessed by modifications of the methods of 65 of the invention. It is, therefore, intended that the appended Selley, et al., 1997 and Traynor and Nahorski, 1995 using claims cover all such equivalent variations as fall within the receptor-mediated SIGTPYS binding in the same membrane true spirit and scope of the invention. US 7,576,207 B2 101 102 What is claimed is: 1. A compound of formula I: II

Z 21 Yw -H(R'); A N B X 10

N H

N 15 14. A compound according to claim 13, wherein A and B Ra are taken together with the carbon atoms through which they are connected to form a double bond. wherein: 15. A compound according to claim 14, wherein Z is W is alkylene; C(=O) R, NR C(=O) R, or NRS(=O), Z is alkoxy, C(=O) R, NR C(=O) R', or alkyl. - NRS(=O), alkyl: 16. A compound according to claim 15, wherein Z is each R" is independently carboxy, hydroxy, alkoxy, halo, C(=O) R. aminocarbonyl, N-alkylaminocarbonyl, or N,N-dialky 17. A compound according to claim 16, wherein R is laminocarbonyl: NRR. 25 18. A compound according to claim 17, wherein RandR R’ is NR'R' or alkoxy; are each independently C-alkyl. R and Rare each independently H or alkyl: 19. A compound according to claim 18, whereint is 0. R is alkyl or NRR: 20. A compound according to claim 13, wherein A and B RandR are each independently Horalkyl, or RandR are each H. taken together with the nitrogen atom to which they are 30 21. A compound according to claim 20, having the formula connected form a 3- to 8-membered heterocycloalkyl III: ring in which 1 or 2 of the heterocycloalkyl ring carbon atoms independently may each be optionally replaced by -O-, - S - N(R) , N(R)-C(=O)—, or III - C(=O) N(R)–: 35 R. R. and Rare each independently H or alkyl: X is —CH2—, or —O—; A and B are each H, or taken together with the carbon atoms through which they are connected form a double bond; and 40 t is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein A and B are each H. 45 3. A compound according to claim 1, wherein A and B are N taken together with the carbon atoms through which they are connected to form a double bond. wherein: 4. A compound according to claim 1, wherein X is —O—. Q' and Q are each independently H, carboxy, hydroxy, 5. A compound according to claim 1, wherein X is 50 alkoxy, halo, aminocarbonyl, N-alkylaminocarbonyl, or —CH2—. N,N-dialkylaminocarbonyl. 6. A compound according to claim 1, wherein R is H. 22. A compound according to claim 21, wherein Z is 7. A compound according to claim 1, wherein Z is C(=O) R, NR C(=O) R, or NRS(=O), C(=O) R. alkyl. 8. A compound according to claim 7, wherein R is 55 23. A compound according to claim 22, wherein Z is NRR. C(=O) R. 24. A compound according to claim 23, wherein R is 9. A compound according to claim8, wherein RandR are NRR. each independently H or alkyl. 25. A compound according to claim 24, wherein RandR 10. A compound according to claim 9, wherein R and R' 60 are each independently C-alkyl. are each independently H or Calkyl. 26. A compound according to claim 25, wherein at least 11. A compound according to claim 10, wherein RandR one of Q' and Q is H. are each independently Calkyl. 27. A compound according to claim 26, wherein Q' and Q 12. A compound according to claim 11, wherein RandR are each H. are each independently C-alkyl. 65 28. A compound according to claim 26, wherein one of Q' 13. A compound according to claim 6, having the formula and Q is carboxy, hydroxy, alkoxy, halo, aminocarbonyl, or II: N-alkylaminocarbonyl. US 7,576,207 B2 103 104 29. A compound according to claim 28, wherein the halo is 43. A compound according to claim 42, wherein R is fluoro and the N-alkylaminocarbonyl is N-Cl alkylami NRSR. nocarbonyl. 44. A compound according to claim 43, wherein RandR 30. A compound according to claim 29, wherein Q is are each independently C-alkyl. carboxy, hydroxy, alkoxy, fluoro, aminocarbonyl, or N-C- 45. A compound according to claim 44, wherein at least 3alkylaminocarbonyl. one of Q' and Q is H. 31. A compound according to claim 28, wherein Q' is 46. A compound according to claim 45, wherein Q' and Q hydroxy or alkoxy. are each H. 32. A compound according to claim 6, having the formula 47. A compound according to claim 45, wherein one of Q' IV: 10 and Q is carboxy, hydroxy, alkoxy, halo, aminocarbonyl, or N-alkylaminocarbonyl. 48. A compound according to claim 46, wherein the halo is IV fluoro and the N-alkylaminocarbonyl is N C-alkylami z (1 nocarbonyl. W +-(R'). 15 49. A compound according to claim 47, wherein Q is A N carboxy, hydroxy, alkoxy, fluoro, aminocarbonyl, or N—C. 3alkylaminocarbonyl. B 50. A compound according to claim 47, wherein Q' is O hydroxy or alkoxy. 51. A compound according to claim 1, selected from the group consisting of: N 4-2-(N,N-diethylaminocarbonyl)ethyl-spiro2H, 1-ben H Zopyran-2,4'-piperidine; 4-3-(N,N-diethylaminocarbonyl)propyl-spiro2H, 1 33. A compound according to claim 32, wherein A and B 25 benzopyran-2,4'-piperidine; are taken together with the carbonatoms through which they 4-2-(N,N-diethylaminocarbonyl)ethyl-spiro 3,4-dihy are connected to form a double bond. dro-2H, 1-benzopyran-2,4'-piperidine: 34. A compound according to claim 33, wherein Z is 4-3-(N,N-diethylaminocarbonyl)propyl-spiro 3,4-dihy C(=O) R, NR C(=O) R, or NRS(=O), dro-2H, 1-benzopyran-2,4'-piperidine: alkyl. 30 4-3-(ethoxycarbonyl)propyl-spiro2H, 1-benzopyran-2, 35. A compound according to claim 34, wherein Z is 4'-piperidine; C(=O) R. 4-3-(N,N-diisopropylaminocarbonyl)propyl-spiro 3,4- 36. A compound according to claim 35, wherein R is dihydro-2H, 1-benzopyran-2,4'-piperidine: NRSR. 4-3-(1-(isoindolin-2-yl)carbonyl)propyl-spiro 3,4-dihy 37. A compound according to claim 36, wherein RandR 35 dro-2H, 1-benzopyran-2,4'-piperidine: are each independently C-alkyl. 4-3-(N-ethylaminocarbonyl)propyl-spiro 3,4-dihydro 38. A compound according to claim 37, whereint is 0. 2H, 1-benzopyran-2,4'-piperidine; 39. A compound according to claim 32, wherein A and B 4-3-(N-butylaminocarbonyl)propyl-spiro 3,4-dihydro are each H. 2H, 1 -benzopyran-2,4'-piperidine: 40. A compound according to claim39, having the formula 40 4-4-(N,N-diethylaminocarbonyl)butyl-spiro[3,4-dihy V: dro-2H, 1 -benzopyran-2,4'-piperidine; 4-5-(N,N-diethylaminocarbonyl)pentyl-spiro 3,4-dihy dro-2H, 1-benzopyran-2,4'-piperidine: 4-5-(N,N-diisopropylaminocarbonyl)pentyl-spiro 3,4- Q2 V 45 dihydro-2H, 1-benzopyran-2,4'-piperidine: 4-4-(N,N-diethylaminocarbonyl)butyl-spiro 6-fluoro-3, Q 4-dihydro-2H, 1-benzopyran-2,4'-piperidine: ^w 4-4-(N,N-diethylaminocarbonyl)butyl-spiro5-meth A oxy-3,4-dihydro-2H, 1-benzopyran-2,4'-piperidine: 50 4-4-(N,N-diethylaminocarbonyl)butyl-spiro5-hydroxy B 3,4-dihydro-2H, 1-benzopyran-2,4'-piperidine: 4-3-(N,N-diethylaminocarbonylamino)propyl-spiro.3, 4-dihydro-2H, 1-benzopyran-2,4'-piperidine: 4-3-(N-(2-ethylbutanoyl)amino)propyl-spiro[3,4-dihy 55 dro-2H, 1-benzopyran-2,4'-piperidine: N 4-(3-(N-methyl-N-(2-ethylbutanoyl)amino)propyl-spiro 3,4-dihydro-2H, 1-benzopyran-2,4'-piperidine: wherein: 4-(3-(ethylsulfonylamino)propyl-spiro 3,4-dihydro-2H, Q' and Q are each independently H, carboxy, hydroxy, 60 1-benzopyran-2,4'-piperidine; alkoxy, halo, aminocarbonyl, N-alkylaminocarbonyl, or 4-(3-(N-methyl-N-(ethylsulfonyl)amino)propyl-spiro[3. N,N-dialkylaminocarbonyl. 4-dihydro-2H, 1-benzopyran-2,4'-piperidine: 41. A compound according to claim 40, wherein Z is 4-(N,N-diethylaminocarbonyl)methyl]-spiro 3,4-dihy C(=O) R, NR C(=O) R, or NRS(=O), dro-2H, 1-benzopyran-2,4'-piperidine: alkyl. 65 4-(N,N-diethylaminocarbonylmethylaminocarbonyl)me 42. A compound according to claim 41, wherein Z is thyl-spiro[3,4-dihydro-2H, 1-benzopyran-2,4'-piperi C(=O) R. dine;

US 7,576,207 B2 107 108 60. A compound according to claim 56 which is 4-4-(N, 62. A compound according to claim 56 which is 4-4-(N, N-diethylaminocarbonyl)-butyl-spiro 3,4-dihydro-2H, 1- N-diethylaminocarbonyl)-butyl-spiro5-hydroxy-3,4-dihy benzopyran-2,4'-piperidine or a pharmaceutically accept- dro-2H, 1-benzopyran-2,4'-piperidine or a pharmaceutically able salt thereof. acceptable salt thereof. 61. A compound according to claim 56 which is 4-4-(N, 5 N-diethylaminocarbonyl)-butyl-spiro 6-fluoro-3,4-dihy dro-2H, 1-benzopyran-2,4'-piperidine or a pharmaceutically acceptable salt thereof. k . . . .