Login| Sign Up| Help| Contact|

Patent Searching and Data


Title:
SPIROAMINOOXAZOLINE ANALOGUES AS ALPHA2C ADRENERGIC RECEPTOR MODULATORS
Document Type and Number:
WIPO Patent Application WO/2010/042475
Kind Code:
A1
Abstract:
In its many embodiments, the present invention provides a novel class of spiroaminooxazoline analogues as modulators of α2C adrenergic receptor, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more conditions associated with the α2C adrenergic receptors using such compounds or pharmaceutical compositions.

Inventors:
MCCORMICK KEVIN D (US)
DONG LI (US)
BOYCE CHRISTOPHER W (US)
DE LERA RUIZ MANUEL (US)
ZHENG JUNYING (US)
WON WALTER S (US)
Application Number:
PCT/US2009/059638
Publication Date:
April 15, 2010
Filing Date:
October 06, 2009
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
SCHERING CORP (US)
MCCORMICK KEVIN D (US)
DONG LI (US)
BOYCE CHRISTOPHER W (US)
DE LERA RUIZ MANUEL (US)
ZHENG JUNYING (US)
WON WALTER S (US)
International Classes:
C07D235/02; A61K31/4184; A61K31/4188; A61K31/423; A61K31/424; A61P7/12; A61P9/04; A61P11/02; A61P25/16; A61P25/28; C07D263/52; C07D265/12; C07D498/10
Domestic Patent References:
WO2006031676A22006-03-23
WO2008073251A12008-06-19
WO2007016087A22007-02-08
WO2004087649A22004-10-14
WO2004082602A22004-09-30
WO2008100456A22008-08-21
Foreign References:
EP0635495A21995-01-25
Other References:
MILLAN, MARK J. ET AL: "S18616, a highly potent, spiroimidazoline agonist at .alpha.2- adrenoceptors : I. Receptor profile, antinociceptive and hypothermic actions in comparison with dexmedetomidine and clonidine", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS , 295(3), 1192-1205 CODEN: JPETAB; ISSN: 0022-3565, 2000, XP002559983
Attorney, Agent or Firm:
RUSSELL, Mark W. (Patent Department K-6-1 19902000 Galloping Hill Roa, Kenilworth New Jersey, US)
Download PDF:
Claims:
CLAIMS

What is claimed is:

1. A compound represented by Formula I

<R3)»

I or a pharmaceutically acceptable salt.thereof wherein:

J1, J2, J3 and J4 are independently -N-, -N(O)-, or -C(R2 )-; X is -C(R6XR6')-, -N(R6')-, -O- or -S -;

W is -N(R15)-, -O- or-S-;

Z is independently selected from the group consisting of H, -OH1 halo, -CN, -NO2, -S(O)pR7, -NR7R7' , -[C(Ra)(Rb)]qYR7', -[C(Ra)(Rb)]qN(R7)YR7', - [C(Ra)(Rb)])=qOYR7', and -(CH2)qON=CR7Rr, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R5; wherein is a single or double bond provided that when W is -O- or -S-, the double bond is present between N and the 2-position, and when W is -N(R15)-, the double bond is present between the N and the 2-position or W and the 2-position, but cannot form 2 contigous double bonds;

R1 is selected from the group consisting of -[C(Ra)(Rb)]qYR7', - [C(Ra)(Rb)]qN(R7)YR7', -[C(Ra)(Rb)]qNR7R7', -[C(Ra)(Rb)]qOYR7', - [C(Ra)(Rb)]qN (YR7XYR7'), -[C(Ra)(Rb)]qON=CR7R7' and -[ C(Ra)(Rb)]qCN; Y is selected from the group consisting of -C(=O)-, -C(=O)NR7-,

-C(=0)0-, -C(=O)-[C(Ra)(Rb)]n-O-C(=O)-, -C(=O)N(RC)-O-, -C(=NR7)-, -C(=NOR7)-, - C(=NR7)NR7-, -C(=NR7)NR7O-, -C(=N-CN)-, -S(0)p-, -SO2NR7-, and -C(=S)NR7-; wherein Ra and Rb are independently selected from the group consisting of H, alkyl, alkoxy, and halo, and Rc is H or alkyl;

R2 is absent or independently selected from the group consisting of H, -OH, halo, -CN, -NO2, -S(O)PR7, -NR7R7', and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, aryloxy, arylalkyl, heteroarylalkyl, and heterocyclylalkyl groups optionally substituted with at least one R5;

R3 is independently selected from the group consisting of H, halo, -CN, and (=0), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R5, provided that when w is 3, no more than 2 of the R3 groups may be (=0);

R4 is independently selected from the group consisting of H, D, -OH1 halo, -CN, -S(O)PR7, -NR7R7' and -S(O)PNR7R7', and alkyl, deuterated alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R5;

R4 is independently selected from the group consisting of H, D, halo, -OH1, and alkyl, deuterated alkyl and alkoxy; or R4 and R4 may be taken together to form (=0), provided that when m >

1 , there is no more than 1 (=0) group;

R5 is independently selected from the group consisting of H, halo, -OH, -CN, -NO2, -NR7R7', and -S(O)PR7, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each of which is optionally substituted with at least one of halo, -OH, -CN, -NO2, -NR7R7', and -S(O)PR7 substituents and/or 1 or 2 (=0);

R6 is selected from the group consisting of H, -OH, halo, -CN, -NO2, -S(O)PR7, - NR7R7', -S(O)pNR7R7', -C(O)-R10, -C(O)-OR10, and -C(O)-N(R7JR10, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each of which is optionally substituted with at least one of halo, -OH, -CN, -NO2, -NR7R7', and -S(O)PR7 substituents and/or 1 or 2 (=0) groups, and -C(=O)R7, -C(=O)OR7, -C(=O)NR7R7', - SO2R7 and -SO2NR7R7'; R6' is selected from the group consisting of H, -S(O)PR7, -S(O)PNR7R7', -C(O)- R10, -C(O)-OR10, -C(O)-N(R7)R10 and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each of which is optionally substituted with at least one of halo, -OH, -CN, -NO2, -NR7R7', and -S(O)PR7 and/or 1 or 2 (=O) groups substituents, and -C(=0)R7, -C(O)OR7, -C(=O)NR7R7', -SO2R7 and -SO2NR7R7'; or

R6 and R6 may be taken together to form (=0);

R7 is independently selected from the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloclenyl, cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, hetrocyclenyl, hetrocyclenylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted one or more times by R12;

R7 is independently selected from the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloclenyl, cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, hetrocyclenyl, hetrocyclenylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted one or more times by R12; or a) when a variable is -NR7R7', -[C(Ra)(Rb)]qYR7>, -C[(Ra)(Rb)]qNR7R7', - [C(Ra)(Rb)]qOYR7V -(CH2JqNR7R7', -C(O)NR7R7' Or -SO2NR7R7', R7 and R7' together with the nitrogen atom to which they are attached independently form a 3- to 8-membered heterocyclyl, heterocyclenyl or heteroaryl ring having, in addition to the N atom, 1 or 2 additional hetero atoms independently selected from the group consisting of O, N, -N(R9)- and S, wherein said rings are optionally substituted by 1 to 5 independently selected R5 moieties and/or 1 or 2 (=0), or b) when a variable is -(CH2)qON=CR7R7' or -[C(Ra)(Rb)]qON=CR7R7', R7 and R7' together with the carbon atom to which they are attached independently form a 3- to 8-membered cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl or heteroaryl ring, wherein said heterocyclyl, heterocyclenyl or heteroaryl rings have 1-3 heteroatoms which are independently selected from the group consisting of O, N, -N(R9)- and S, wherein said rings are optionally substituted by 1 to 5 independently selected R5 moieties and/or 1 or 2 (=0); R9 is independently selected from the group consisting of H, -C(O)-R10, -C(O)- OR10, and -S(O)P-OR10 and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted with at least one of halo, -OH, -CN, -NO2, -N(R11)2, and -S(O)PR11 substituents and/or 1 or 2 (=0);

R10 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted with at least one of halo, -OH, -CN, -NO2, -N(R1V and - S(O)pR11 substituents and/or 1 or 2 (=0); R11 is a moiety independently selected from the group consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, each of which is optionally substituted by at least one substituent independently selected from the group consisting of halo, -OH, -CN, -NO2, -N(R11')2, and -S(O)PR11' substituents and/or 1 or 2 (=0);

R11 is independently selected from the group consisting of H, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R12 is independently selected from the group consisting of H, halo, -OH, -CN, -NO2, -N(R11J2 , -C(O)-OR14 , -N(R14)-C(O)-R14, -N(R14)-C(O)2-R14, -C(O)-N(R11J2, - N(R14J-S(O)2-R11, -S(O)2-N(R11)2 and -S(O)PR11 and/or 1 or 2 (=O) groups, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heterocyclyl, heterocyclenyl, heterocyclenyloxy, heterocyclylalkyl, heterocyclenylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy, and heterocyclenylalkoxy groups, each of which in turn is optionally substituted by at least once by a substituent selected from the group consisting of H, alkyl, haloalkyl, halo, -OH, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted cycloalkoxy, optionally substituted heteroaryloxy, optionally substituted heterocyclenyloxy, -CN, -NO2, -N(R11)2, and - S(O)pR11 and/or 1 or 2 (=O) groups, wherein said optionally substituted alkoxy, aryloxy, optionally substituted cycloalkoxy, optionally substituted heteroaryloxy, and heterocyclenyloxy when substituted are substituted one or more times by R11; R14 is independently H, alkyl, or aryl; R15 is absent or independently selected from the group consisting of H, -C(O)- R10, -C(O)-OR10, -C(O)-N(R7XR7'), and -S(O)P-R10, SO2-NR7R7' and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each of which is optionally substituted with at least one of halo, -OH, -CN, -NO2, -NR7R7', and -S(O)PR7 and/or 1 or 2 (=0) groups substituents, and -C(=0)R7, -C(=O)OR7, -C(=O)NR7R7', -SO2R7 and - SO2NR7R7'; n is independently an integer from 0-2; m is independently an integer from 1-3 p is independently an integer from 0-2; and w is an integer from 0-3; provided that when R1 is -[C(Ra)(Rb)]qYR7' and Y is -S(O)P-, p cannot be O. 2. The compound according to claim 1 wherein Z is H, -OH, halogen,-CN, -NO2, or NR7R7';

R1 is selected from the group consisting of -[C(Ra)(Rb)]qYR7', - [C(Ra)(Rb)]qN(R7)YR7', -[C(Ra)(Rb)]qNR7R7', -[C(Ra)(Rb)]qOYR7', and -[ C(Ra)(Rb)]qCN;

Y is selected from the group consisting of a bond, -C(=0)-, -C(=O)NR7-, -C(=0)0-, -C(=O)-[C(Ra)(Rb)]n-O-C(=O)-, -C(=O)N(RC)-O-, -C(=NR7)-, -C(=NOR7)-, - C(=NR7)NR7-, -C(=NR7)NR7O-, -C(=N-CN)-, -S(0)p-, -SO2NR7-, and -C(=S)NR7-; wherein Ra and Rb are independently selected from the group consisting of H, alkyl, alkoxy, and halo, and Rc is H or alkyl;

R2 is independently selected from the group consisting of H, -OH, halo, -CN, -NO2, -S(O)PR7, -NR7R7' , and alkyl and alkoxy groups optionally substituted with at least one R5;

R3 is independently selected from the group consisting of H, halo, and (=0), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R5, provided that when w is 3, no more than 2 of the R3 groups may be (=0);

R4 is independently selected from the group consisting of H, halo, -OH, halo, and -CN, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R5;

R4' is independently selected from the group consisting of halo and alkyl; R5 is independently selected from the group consisting of H, halo, -OH, -CN, -NO2, -NR7R7', and -S(O)PR7, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each of which is optionally substituted with at least one of halo, -OH, -CN, -NO2, -NR7R7', and -S(O)PR7 substituents and/or 1 or 2 (=0); R6 is selected from the group consisting of H and halo, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each of which is optionally substituted with at least one of halo, -OH, -CN, -NO2, -NR7R7', and -S(O)PR7 substituents and/or 1 or 2 (=0), and -C(=O)R7, -C(=0)OR7, -C(=O)NR7R7', -SO2R7 and -SO2NR7R7'; R7 is independently selected from the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloclenyl, cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, hetrocyclenyl, hetrocyclenylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted one or more times by R12; R7 is independently selected from the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloclenyl, cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, hetrocyclenyl, hetrocyclenylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted one or more times by R12; R11 is independently selected from the group consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, each of which is optionally substituted by at least one substituent independently selected from the group consisting of halo, -OH, -CN, -NO2, -N(R11')2, and -S(O)PR11 substituents and/or 1 or 2 (=0);

R11 is independently selected from the group consisting of H, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R12 is independently selected from the group consisting of H, halo, -OH, -CN, -NO2, -N(R11)2 , and -S(O)PR11, and/or 1 or 2 (=0), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heterocyclyl, heterocyclenyl, heterocyclenyloxy, heterocyclylalkyl, heterocyclenylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy, and heterocyclenylalkoxy groups, each of which in turn is optionally substituted by at least one by a substituent selected from the group consisting of H, alkyl, haloalkyl, halo, -OH, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted cycloalkoxy, optionally substituted heteroaryloxy, optionally substituted heterocyclenyloxy, -CN, -NO2, -N(R11)2, and - S(O)pR11 and/or 1 or 2 (=0), wherein said optionally substituted alkoxy, aryloxy, optionally substituted cycloalkoxy, optionally substituted heteroaryloxy, and heterocyclenyloxy when substituted are substituted one or more times by R11;

R14 is independently selected from the group consisting of H1 alkyl, halo, -CN, and alkoxy; and

R15 is absent or selected from the group consisting of H and alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted with at least one halo, -OH, -CN, -NO2, -N(R11)2, and -S(O)PR11 and/or 1 or 2 (=0); or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 2, which has the formula

or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 3, wherein R1 is -[C(Ra)(Rb)]qYRr, -[C(Ra)(Rb)]qN(R7)YRr, -[C(Ra)(Rb)]qOYR7' and -[ C(Ra)(Rb)]qCN, wherein q is 0 or 1 ; Y is -C(=O)-, -C(=O)NR7-, -C(=O)O-, -C(=NOR7)- -S(O)p-, and -SO2NR7-;

R7 and R7' are independently H. R12-alkyl or R12-aryl;

R15 is absent or H or alkyl or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 2, which has the formula

or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. 6. The compound according to claim 5 wherein

R1 is -[C(Ra)(Rb)]qYR7', -[C(Ra)(Rb)]qN(R7)YR7', -[C(Ra)(Rb)]qOYR7' and -[ C(Ra)(Rb)]qCN, wherein q is 0 or 1; Y is -C(=O)-, -C(=O)NR7-, -C(=O)O-, -C(=NOR7)-, -S(O)p-, and -SO2NR7-;

R7 and R7' are independently H, R12-alkyl or R12-aryl; R15 is absent or H or alkyl or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

7. The compound according to claim 1 , which is selected from the group consisting of

or a pharmaceutically acceptable salt of each of these compounds.

8. A pharmaceutical composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, adjuvant or vehicle, provided that when the compositon is a liquid, aqueous composition one or more solubility enhancing components are excluded with the exception of cyclodextrin.

9. The pharmaceutical composition of claim 8, further comprising one or more additional therapeutic agents. 10. The pharmaceutical composition of claim 9, further comprising one or more additional therapeutic agents, wherein said additional therapeutic agents are selected from the group consisting of steroids, glucocorticosteroids, PDE-4 inhibitors, anti- muscarinic agents, muscle relaxants, cromolyn sodium, Hi receptor antagonists, 5- HTi agonists, NSAIDs, angiotensiπ-converting enzyme inhibitors, angiotensin Il receptor agonists, β-blockers, long and short acting β-agonists, leukotriene antagonists, diuretics, aldosterone antagonists, ionotropic agents, natriuretic peptides, pain management/analgesic agents, anti-anxiety agents, anti-migraine agents, sedatives, NMDA receptor antagonists, alpha-adrenergics not including alpha-1 receptor antagonists, anticonvulsants , tachykinin (NK) antagonists, COX-2 inhibitors, neuroleptics, vanilloid receptor agonists or antagonists, beta-adrenergics, local anaesthetic, corticosteroids, serotonin receptor agonists or antagonists, PDEV inhibitors, alpha-2-delta ligands, canabinoids and therapeutic agents suitable for treating heart conditions, psychotic disorders, or glaucoma.

11. A method for treating one or more conditions associated with α2C adrenergic receptors, comprising administering to a mammal in need of such treatment a compound of claim 1 or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein the conditions are selected from the group consisting of allergic rhinitis, congestion, pain, diarrhea, glaucoma, congestive heart failure, chronic heart failure, cardiac ischemia, manic disorders, depression, anxiety, migraine, stress-induced urinary incontinence, neuronal damage from ischemia, schizophrenia, attention deficit hyperactivity disorder, and symptoms of diabetes.

13. The method of claim 12, wherein the condition is congestion.

14. The method of claim 13, wherein the congestion is associated with perennial allergic rhinitis, seasonal allergic rhinitis, non-allergic rhinitis, vasomotor rhinitis, rhinitis medicamentosa, sinusitis, acute rhinosinusitis, or chronic rhinosinusitis.

15. The method of claim 13, wherein the congestion is caused by polyps or is associated with the common cold.

16. The method of claim 11, wherein the condition is pain.

17. The method of claim 16, wherein the pain is associated with neuropathy, inflammation, arthritis, or diabetis.

18. The method of claim 11, wherein the condition is Alzheimer's disease, depression, anxiety or Parkinson's disease.

Description:
AL06896

1

Spiroaminooxazoline Analogues As Alpha2C Adrenergic Receptor Modulators

Related Applications

This application claims benefit to US provisional application USSN 61/103385, filed October 7, 2008, herein incorporated by reference

Field of the Invention

The present invention relates to spiroaminooxazoline analogues useful as alpha-2C (or "α2C") adrenergic receptor modulators, methods for making these compounds, pharmaceutical compositions containing the compounds, and methods of treatment and prevention using the compounds and compositions to treat disease states associated with the modulation of the alpha-2C receptor, such as congestion (including nasal), migraine, congestive heart failure, cardiac ischemia, glaucoma, stress-induced urinary incontinence, Alzheimer's disesase, Parkinson's disease, attention deficit hyperactivity disorder, pain and psychotic disorders (e.g., depression and schizophrenia).

Background of the Invention The initial classification of adrenergic receptors into α- and β-families was first described by Ahlquist in 1948 (Ahlquist RP, "A Study of the Adrenergic Receptors," Am. J. Physiol. 153:586-600 (1948)). Functionally, the α-adrenergic receptors were shown to be associated with most of the excitatory functions (vasoconstriction, stimulation of the uterus and pupil dilation), β-adrenergic receptors were implicated in vasodilation, bronchodilation and myocardial stimulation (Lands et al., "Differentiation of Receptor Systems Activated by Sympathomimetic amines," Nature 214:597-598 (1967)). Since this early work, α-adrenergic receptors have been subdivided into α1 - and α2-adrenergic receptors. Cloning and expression of α-adrenergic receptors have confirmed the presence of multiple subtypes of both α1 -(α1 A, α1 B, α1 D) and α2- (α2A, α2B, α2C) adrenergic receptors (Michel et al., "Classification of αi - Adrenoceptor Subtypes," Naunyn-Schmiedeberg's Arch. Pharmacol, 352:1-10 (1995); Macdonald et al., "Gene Targeting-Homing in on α 2 -Adrenoceptor-Subtype Function," TIPS, 18:211-219 (1997)).

SLIBSTITUTE SHEET (RULE 26) Current therapeutic uses of α-2 adrenergic receptor drugs involve the ability of those drugs to mediate many of the physiological actions of the endogenous catecholamines. There are many drugs that act on these receptors to control hypertension, intraocular pressure, eye reddening and nasal congestion and induce analgesia and anesthesia. α2 adrenergic receptors can be found in the rostral ventrolateral medulla, and are known to respond to the neurotransmitter norepinephrine and the antihypertensive drug clonidine to decrease sympathetic outflow and reduce arterial blood pressure (Bousquet et al., "Role of the Ventral Surface of the Brain Stem in the Hypothesive Action of Clonidine, " Eur. J. Pharmacol., 34:151-156 (1975); Bousquet et al.,

"Imidazoline Receptors: From Basic Concepts to Recent Developments," 26:S1-S6 (1995)). Clonidine and other imidazolines also bind to imidazoline receptors (formerly called imidazoline-guanidinium receptive sites or IGRS) (Bousquet et al., "Imidazoline Receptors: From Basic Concepts to Recent Developments," 26:S1-S6 (1995)). Some researchers have speculated that the central and peripheral effects of imidazolines as hypotensive agents may be related to imidazoline receptors (Bousquet et al., "Imidazoline Receptors: From Basic Concepts to Recent Developments," 26:S1-S6 (1995); Reis et al., "The Imidazoline Receptor: Pharmacology, Functions, Ligands, and Relevance to Biology and Medicine," Ann. N.Y. Acad. ScL, 763:1-703 (1995). Compounds having adrenergic activity are well-known in the art and are described in numerous patents and scientific publications. It is generally known that adrenergic activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having an adrenergic compound or compounds as the active ingredient are useful for treating, among other things, glaucoma, chronic pain, migraines, heart failure, and psychotic disorders (e.g., schizophrenia).

For example, published PCT application WO 02/076950 discloses compounds having α2 agonist activity of the following general formula:

Other publications disclosing similar compounds includes WO 01/00586, WO 99/28300, US 6,841 ,684 B2 and US 2003/0023098 Al

Another class of compounds having α2-agonist properties is disclosed in U.S. Patent No. 5,658,938, and has the following general formula:

wherein n=1-2, R 1 -R 3 represent hydrogen, halogen hydroxy, alkyl or alkoxy, and R 5 is hydrogen or alkyl.

Another class of compounds reported to have affinity for α2 receptors includes the following two compounds (Bagley et.al., Med. Chem. Res. 1994, 4:346-364):

It is also known that compounds having adrenergic activity, such as α2A agonists, may be associated with undesirable side effects. Examples of such side effects include hyper-and hypotension, sedation, locomotor activity, psychotic disorders (e.g., schizophrenia).

Another class of compounds reported to have affinity for α2 receptors includes the following two compounds (Miller et.al., J. Med. Chem. 1994, 37:2328-2333; J. Med. Chem. 1996, 39:3001-3013; J. Med. Chem. 1997, 37:3014-3024):

Another class of indane and tetrahyrdonaphthalene type compounds having α2- agonist properties is disclosed in PCT application WO 97/12874 and WO20040506356. This class has the following general formula: wherein n = 0-1 , X is 1 or 2 carbon units, R 4 is H, OH, alkyl, or alkoxy, R 5 may be taken together with R 4 to form a carbonyl, and R 6 -R 8 = H, OH, SH, alkyl, alkenyl, cycloalkyl, alkoxy, hydroxyalkyl, alkylthio, alkylthiol, halo, CF 3 , NO 2 , or alkylamino. This class specifically includes MPV-2426 (fadolmidine) and its prodrug esters: wherein R is optionally substituted lower alkyl, aryl, cycloalkyl, heteroaryl, lower alkylamino, and saturated 5- or 6-membered heterocyclic groups containing 1 or 2 N atoms. Further, other classes of compounds that exhibit functional selectivity for the alpha 2C receptor have been discovered. Application USSN 11/508,458, filed August 23, 2006, discloses indoline compounds that possess this activity and application USSN 11/508,467, filed on the same date, describes morpholine compounds that are functionally selective of the alpha 2C receptor. CIP applications of these applications have been filed; the Ser. Nos. are 11/705,673 and 11/705,683, both filed on February 13, 2009.

Additional applications that have been filed by Schering-Plough and disclose alpha2C receptor agonists include applications WO 2008/100480 (PCT/US2008/ 001808); WO 2008/100459 (PCT/US2008/001770) and WO 2008/100456 (PCT/ US2008/001765.

Compounds that act as antagonists of the alpha-2C receptor are also known in the art. Hoeglund ef a/, describe quinoline derivatives that are said to be potent and selective alpha 2C antagonists and said to be useful in treating "certain psychiatric disorders such as depression and schizophrenia" (Hoeglund et al., J. Med. Chem 49:6351-6363 (2006)). WO 2001/64645 to Orion Corp. also describes quinoline derivatives that are alpha-2C recptor antagonists and indicates that these compounds are useful for the treatment of conditions of the pheripheric or CNS system, including treating depression, anxiety, post traumatic stress disorder, schizophrenia, Parkinson's disease and other movement disorders, and dementias (e.g., Alzheimer's disease). WO 2003/082825, also to Orion Corp., indicates alpha-2C receptor antagonists have utility in treating symptoms of disorders and conditions with sensorimotor-gating deficits. Selliner et al., indicate that acridin-9-yl-[4-(4- methylpiperazinal-1-yl)-phenyl]amine is a highly selective alpha-2C adrenergic receptor antagonist and may be useful intreating neuropsychiatric disorders (Salliner et al., British J. Pharmacol. 150 :391-402 (2007)).

It is also known that compounds having adrenergic activity, such as α2A agonists, may be associated with undesirable side effects. Examples of such side effects include hyper-and hypotension, sedation, locomotor activity, and body temperature variations.

Cordi et al. in U.S. Patent Nos. 5,436,261, 5,486,532 and 5,648,374 describe benzospiroalkene heterocyclic compounds of the general formula

that are said to be useful as α2-adrenergic agonists; in the compounds described therein the definition of X includes -(CH 2 ) 2 -, -O-, -0-CH 2 -, and -S-CH 2 -; of Y includes - O-, -S-, and -N(R 6 )-; and of R 5 includes hydrogen or an amino group. Cordi et al. also disclose spiro[1, 3-diazacyclopent-1-ene)5,2'-(1', 2', 3',4'-tetrahydronaphthylene)] or spiro-imidazolines compounds such as

in J. Med. Chem. 1994, 38:4056-4069 as α-adrenergic agonists. WO 2006/080890 discloses that this compound may be used in combinations with other agents to prevent biofouling organisms. U.S. Patent 6,673,337 describes and claims an ophthalmic composition comprising an alpha-2C agonist component and a solubility enhancing component other than cyclodextrin. The patent does not specifically describe alpha-2C receptor agonists. It has been discovered in accordance with the present invention that the inventive compounds act as modulators of of the alpha-2C receptor (i.e., they can act as alpha-2C receptor agonists or as alpha-2C receptor antagonists) and are useful in treating disorders modulated by the alpha-2C receptor.

There is a need for new compounds, formulations, treatments and therapies to treat diseases and disorders associated with α2C adrenergic receptors. Further, there is a need for alpha-2C receptor modulators that minimize adverse side effects, such as those associated with the alpha-2A receptor subtype (viz., blood pressure or sedation). It is, therefore, an object of this invention to provide compounds useful in the treatment or prevention or amelioration of such diseases and disorders.

Summary of the Invention

In its many embodiments, the present invention provides a novel class of heterocyclic compounds that are modulators of the α2C adrenergic receptor, or metabolites, stereoisomers, salts, solvates or polymorphs thereof, methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more conditions associated with α2C receptors using such compounds or pharmaceutical compositions. In one aspect, the present application discloses a compound, or pharmaceutically acceptable salts or metabolites, solvates, prodrugs or polymorphs of said compound, said compound having the general structure shown in Formula I

(R 3 )w

I wherein:

J 1 , J 2 , J 3 and J 4 are independently -N-, -N(O)-, or -C(R 2 )-; X is -C(R 6 XR 6' )-, -N(R 6 )-, -O- or -S -;

W iS -N(R 15 K -O- Or -S-;

Z is independently selected from the group consisting of H, -OH, halo, -CN, -NO 2 , -S(O) P R 7 , -NR 7 R 7' , -[C(R a )(R b )] q YR 7' , -[C(R a )(R b )] q N(R 7 )YR 7' , - [C(R a )(R b )])= q OYR 7> , and -(CH 2 ) q ON=CR 7 R 7' , and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one (preferably 1 to 5, more preferably 1 to 3) R 5 ; wherein is a single or double bond provided that when W is -O- or -S-, the double bond is present between N and the 2-position, and when W is -N(R 15 )-, the double bond is present between the N and the

2-position or W and the 2-position, but cannot form 2 contiguous double bonds;

R 1 is selected from the group consisting of -[C(R a )(R b )] q YR 7> , - [C(R a )(R b )] q N(R 7 )YR 7' , -[C(R a )(R b )] q NR 7 R 7' , -[C(R a )(R b )] q OYR 7' , - [C(R a )(R b )] q N(YR 7 )(YR 7 '), -[C(R a )(R b )] q ON=CR 7 R 7' and -[ C(R a )(R b )] q CN;

Y is selected from the group consisting of -C(=0)-, -C(=O)NR 7 -, -C(=0)0-, -C(=O)-[C(R a )(R b )] n -O-C(=O)-, -C(=O)N(R C )-O-, -C(=NR 7 )-, -C(=NOR 7 )-, - C(=NR 7 )NR 7 -, -C(=NR 7 )NR 7 O-, -C(=N-CN)-, -S(0) p -, -SO 2 NR 7 -, and -C(=S)NR 7 -; wherein R a and R b are independently selected from the group consisting of H, alkyl, alkoxy, and halo, and

R c is H or alkyl;

R 2 is absent or independently selected from the group consisting of H, -OH, halo, -CN, -NO 2 , -S(O) P R 7 , -NR 7 R 7' , and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, aryloxy, arylalkyl, heteroarylalkyl, and heterocyclylalkyl groups optionally substituted with at least one (preferably 1 to 5, more preferably 1 to 3) R 5 ;

R 3 is independently selected from the group consisting of H, halo, -CN, and (=0), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one (preferably 1 to 5, more preferably 1 to 3) R 5 , provided that when w is 3, no more than 2 of the R 3 groups may be (=O);

R 4 is independently selected from the group consisting of H, D, -OH, halo, -CN, -S(O) p R 7 , -NR 7 R 7' and -S(O) P NR 7 R 7' , and alkyl, deuterated alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one (preferably 1 to 5, more preferably 1 to 3) R 5 ;

R 4' is independently selected from the group consisting of H, D, halo, -OH, and alkyl, deuterated alkyl and alkoxy; or R 4 and R 4' may be taken together to form (=0), provided that when m >

1 , there is no more than 1 (=0) group;

R 5 is independently selected from the group consisting of H, halo, -OH, -CN, -NO 2 , -NR 7 R 7' , and -S(O) P R 7 , and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each of which is optionally substituted with at least one (preferably 1 to 5, more preferably 1 to 3) of halo, -OH, -CN, -NO 2 , -NR 7 R 7' , and - S(O) P R 7 substituents and/or 1 or 2 (=0);

R 6 is selected from the group consisting of H, -OH, halo, -CN, -NO 2 , -S(O) P R 7 , - NR 7 R 7- , -S(O)pNR 7 R 7' , -C(O)-R 10 , -C(O)-OR 10 , and -C(O)-N(R 7 )R 10 and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each of which is optionally substituted with at least one (preferably 1 to 5, more preferably 1 to 3) of halo, -OH, - CN, -NO 2 , -NR 7 R 7' , and -S(O) P R 7 substituents and/or 1 or 2 (=0) groups, and - C(=0)R 7 , -C(=O)OR 7 , -C(=O)NR 7 R 7' , -SO 2 R 7 and -SO 2 NR 7 R 7' ; R 6' is selected from the group consisting of H, -S(O) P R 7 , -S(O) P NR 7 R 7' , -C(O)-

R 10 , -C(O)-OR 10 , -C(O)-N(R 7 )R 10 and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each of which is optionally substituted with at least one (preferably 1 to 5, more preferably 1 to 3) of halo, -OH, -CN, -NO 2 , -NR 7 R 7' , and - S(O) P R 7 and/or 1 or 2 (=O) groups substituents, and -C(=O)R 7 , -C(=O)OR 7 , - C(=O)NR 7 R 7' , -SO 2 R 7 and -SO 2 NR 7 R 7' ; or

R 6 and R 6' may be taken together to form (=0); R 7 is independently selected from the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloclenyl, cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, hetrocyclenyl, hetrocyclenylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted one or more times (preferably 1 to 5, more preferably 1 to 3) by R 12 ; R 7 is independently selected from the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloclenyl, cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, hetrocyclenyl, hetrocyclenylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted one or more times (preferably 1 to 5, more preferably 1 to 3) by R 12 ; or a) when a variable is -NR 7 R 7' , -[C(R a )(R b )] q YR 7' , -C[(R a )(R b )] q NR 7 R 7' , -

[C(R a )(R b )] q OYR 7 V -(CH 2 ) C1 NR 7 R 7' , -C(O)NR 7 R 7' Or -SO 2 NR 7 R 7' , R 7 and R 7' together with the nitrogen atom to which they are attached independently form a 3- to 8-membered heterocyclyl, heterocyclenyl or heteroaryl ring having, in addition to the N atom, 1 or 2 additional hetero atoms independently selected from the group consisting of O, N, -N(R 9 )- and S, wherein said rings are optionally substituted by 1 to 5 independently selected R 5 moieties and/or 1 or 2 (=0), or b) when a variable is -(CH 2 ) q ON=CR 7 R 7' or -[C(R a )(R b )] q ON=CR 7 R 7' , R 7 and R 7' together with the carbon atom to which they are attached independently form a 3- to 8-membered cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl or heteroaryl ring, wherein said heterocyclyl, heterocyclenyl or heteroaryl rings have 1-3 heteroatoms which are independently selected from the group consisting of O, N, -N(R 9 )- and S, wherein said rings are optionally substituted by 1 to 5 independently selected R 5 moieties and/or 1 or 2 (=0); R 9 is independently selected from the group consisting of H, -C(O)-R 10 , -C(O)-

OR 10 , and -S(O) P -OR 10 and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted with at least one (preferably 1 to 5, more preferably 1 to 3) of halo, -OH, -CN, -NO 2 , -N(R 11 ) 2 , and -S(O) p R 11 substituents and/or 1 or 2 (=0);

R 10 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted with at least one (preferably 1 to 5, more preferably 1 to 3) of halo, -OH, -CN, -NO 2 , -N(R 11 J 2 , and -S(O) P R 11 substituents and/or 1 or 2 (=0);

R 11 is a moiety independently selected from the group consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, each of which is optionally substituted by at least one (preferably 1 to 5, more preferably 1 to 3) substituent independently selected from the group consisting of halo, -OH, -CN, -NO 2 , -N(R 11' ) 2 , and -S(O) P R 11' substituents and/or 1 or 2 (=0);

R 11' is independently selected from the group consisting of H, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R 12 is independently selected from the group consisting of H, halo, -OH, -CN, -NO 2 , -N(R 11 ) 2 , -C(O)-OR 14 , -N(R 14 )-C(O)-R 14 , -N(R 14 J-C(O) 2 -R 14 , -C(O)-N(R 11 J 2 , - N(R 14 )-S(O) 2 -R 11 , -S(O) 2 -N(R 11 J 2 and -S(O) P R 11 and/or 1 or 2 (=0) groups, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heterocyclyl, heterocyclenyl, heterocyclenyloxy, heterocyclylalkyl, heterocyclenylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy, and heterocyclenylalkoxy groups, each of which in turn is optionally substituted by at least once (preferably 1 to 5, more preferably 1 to 3) by a substituent selected from the group consisting of H, alkyl, haloalkyl, halo, -OH, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted cycloalkoxy, optionally substituted heteroaryloxy, optionally substituted heterocyclenyloxy, -CN, -NO 2 , -N(R 11 ) 2 , and -S(O) P R 11 and/or 1 or 2 (=0) groups, wherein said optionally substituted alkoxy, aryloxy, optionally substituted cycloalkoxy, optionally substituted heteroaryloxy, and heterocyclenyloxy when substituted are substituted one or more (preferably 1 to 5, more preferably 1 to 3) times by R 11 , R 14 is independently H, alkyl, or aryl;

R 15 is absent (i.e., the nitrogen and the 2-position carbon atom forms -N=C(Z)- bond) independently selected from the group consisting of H, -C(O)-R 10 , -C(O)-OR 10 , -C(O)-N(R 7 XR 7' ), and -S(O) P -R 10 , SO 2 -NR 7 R 7' and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each of which is optionally substituted with at least one (preferably 1 to 5, more preferably 1 to 3) of halo, -OH, -CN, -NO 2 , - NR 7 R 7' , and -S(O) P R 7 and/or 1 or 2 (=0) groups substituents, and -C(O)R 7 , - C(=O)OR 7 , -C(=O)NR 7 R 7' , -SO 2 R 7 and -SO 2 NR 7 R 7' ; n is independently an integer from 0-2; m is independently an integer from 1-3 p is independently an integer from 0-2; and w is an integer from 0-3; provided that when R 1 is -[C(R a )(R b )] q YR 7' and Y is -S(0) p -, p cannot be O. The compounds of Formula I can be useful as α2C adrenergic receptor modulators and can be useful in the treatment or prevention of one or more conditions associated with the α2C receptor by administering at least one compound of Formula I to a mammal in need of such treatment. Conditions that my be treated by modulating the α2C receptor include allergic rhinitis, congestion (including congestion associated with perennial allergic rhinitis, seasonal allergic rhinitis, non-allergic rhinitis, vasomotor rhinitis, rhinitis medicamentosa, sinusitis, acute rhinosinusitis, or chronic rhinosinusitis, congestion caused by polyps, or caused by the common cold), pain (e.g., neuropathy, inflammation, arthritis, or diabetes), diarrhea, glaucoma, congestive heart failure, chronic heart failure, cardiac ischemia, manic disorders, depression, anxiety, migraine, stress-induced urinary incontinence, neuronal damage from ischemia, schizophrenia, attention deficit hyperactivity disorder, symptoms of diabetes, post traumatic stress disorder, Parkinson's disease or a dementia (e.g., Alzheimer's disease).

Another embodiment of this invention is the treatment or prevention of one or more conditions associated with the α2C receptor by administering at least one compound of Formula I to a mammal in need of such treatment by selectively modulating α2C adrenergic receptors in the mammal.

Another embodiment of this invention is the treatment or prevention of one or more conditions associated with the α2C receptor by administering an effective amount at least one compound of Formula I to a mammal in need of such treatment without modifying blood pressure at the therapeutic dose.

Another embodiment of the present invention is a method for selectively modulating α2C adrenergic receptors in a cell in a mammal in need thereof, comprising contacting said cell with a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt, ester, prodrug or salt thereof.

Another embodiment of the present invention is a method for the treatment of congestion in a mammal in need thereof without modifying the blood pressure at therapeutic doses which comprises administering to the mammal an effective dose of at least one compound having adrenergic activity wherein said compound is a selective agonist of the α2C receptor.

Detailed Description In an embodiment, the present invention discloses certain spiroaminooxazoline derivatives, which are represented by structural Formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein the various moieties are as described above.

In another embodiment, J 1 , J 2 , and J 3 are each -C(R 2 )-. In another embodiment, J 2 , J 3 and J 4 are each -CH-.

In another embodiment, J 2 and J 3 are -CH- and J 1 is -N-.

In another embodiment, J 1 and J 3 are -CH- and J 2 is -N-.

In another embodiment, J 1 , J 2 and J 3 are independently -CR 2 - or -N-.

In another embodiment, J 1 and J 2 are -CH- and J 3 is -N-. In another embodiment, J 1 and J 2 are -CH- and J 3 is -N-.

In another embodiment, n is 1.

In another embodiment, n is 2.

In another embodiment, n is 0.

In another embodiment, p is an integer from 0-2. In another embodiment, X is -CH 2 -.

In another embodiment, X is -NH-.

In another embodiment, X is -O-.

In another embodiment, X is -S-. In another embodiment, X is -N(R 6 )

In another embodiment, R 1 is bonded to J 1 ; J 2 , J 3 and J 4 are -CH-; and X is - CH 2 -.

In another embodiment, R 1 is bonded to J 1 ; J 2 , J 3 and J 4 are -CH-; and X is - NH-.

In another embodiment, R 1 is bonded to J 1 ; J 2 , J 3 and J 4 are -CH-; and X is -O-.

In another embodiment, R 1 is bonded to J 1 ; J 2 , J 3 and J 4 are -CH-; and X is -S-.

In another embodiment, R 1 is bonded to J 4 ; J 1 , J 2 and J 3 are -CH-; and X is - CH 2 -. In another embodiment, R 1 is bonded to J 4 ; J 1 , J 2 and J 3 are -CH-; and X is -

NH-.

In another embodiment, R 1 is bonded to J 4 ; J 1 , J 2 and J 3 are -CH-; and X is -O-.

In another embodiment, R 1 is bonded to J 4 ; J 1 , J 2 and J 3 are -CH-; and X is -S-.

In another embodiment, R 1 is bonded to J 2 ; J 1 , J 3 and J 4 are -CH-; and X is - CH 2 -.

In another embodiment, R 1 is bonded to J 2 ; J 1 , J 3 and J 4 are -CH-; and X is - NH-.

In another embodiment, R 1 is bonded to J 2 ; J 1 , J 3 and J 4 are -CH-; and X is -O-.

In another embodiment, R 1 is bonded to J 2 ; J 1 , J 3 and J 4 are -CH-; and X is -S-. In another embodiment, R 1 is bonded to J 3 ; J 1 , J 2 and J 4 are -CH-; and X is -

CH 2 -.

In another embodiment, R 1 is bonded to J 3 ; J 1 , J 2 and J 4 are -CH-; and X is - NH-.

In another embodiment, R 1 is bonded to J 3 ; J 1 , J 2 and J 4 are -CH-; and X is -O-. In another embodiment, R 1 is bonded to J 3 ; J 1 , J 2 and J 4 are -CH-; and X is -S-.

In another embodiment, Z is -NR 7 R 7' , wherein R 7 and R 7 are independently H, alkyl, R 12 -aryl, and R 12 -cycloalkyl.

In another embodiment R 4 is H, -OH, halo, -CN, -NO 2 , -NR 7 R 7' , wherein R 7 and R 7 are independently H, alkyl, R 12 -aryl, and R 12 -cycloalkyl, alkyl, or haloalkyl In another embodiment, m is 1 and W is -O-.

In another embodiment, m is 1 and W is -S-.

In another embodiment, the spiro ring is:

In another embodiment, the spiro ring is:

In another embodiment R 15 is H, optionally substituted alkyl, optionally substituted cycloalkyl (e.g., cyclopropyl, cyclopentyl, or cyclohexyl) or, optionally substituted aryl (e.g., phenyl), wherein the optional substitutednts are halo, hydroxyl, amino, alkyl amino, dialkyl amino, nitro, or cyano.

In another embodiment Z is amino, alkyl amino or dialkyl amino. In another embodiment R 15 is H or alkyl. In another embodiment R 1 is -[C(R a )(R b )] q YR 7' , -[C(R a )(R b )] q N(R 7 )YR 7' , and -[

C(R a )(R b )] q CN, wherein q is 0 or 1 ; Y is -C(=O)-, -C(=O)NR 7 -, -C(=O)O-, -S(O) P -, and -SO 2 NR 7 -.

In another embodiment R 7 and R 7 are independently R 12 -alkyl (e.g., methyl, ethyl, propyl optionally substituted by halo, cyano, or alkoxy (e.g., methoxy)); and R 12 - aryl (e.g., phenyl optionally substituted by alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, hydroxyl or alkoxy).

In another embodiment, the present invention discloses compounds which are represented by structural formulae U-V or a pharmaceutically acceptable salt, solvate or ester thereof, wherein the various definitions are those described above for Formula I:

Formula

Formula IV Formula V

An embodiment of Formulae H-V is those compounds wherein:

R 1 is -[C(R a )(R b )] q YR 7' , -[C(R a )(R b )] q N(R 7 )YR r , -[C(R a )(R b )]qOYR 7 ', and -[ C(R a )(R b )] q CN, wherein q is 0 or 1 ; Y is -C(=O)-, -C(O)NR 7 -, -C(=0)0-, -C(=NOR 7 )-, -S(O) p -, and -SO 2 NR 7 -;

R 7 and R 7 are independently H, R 12 -alkyl (e.g., methyl, ethyl, propyl optionally substituted by halo, cyano, or alkoxy (e.g., methoxy)); and R 12 -aryl (e.g., phenyl optionally substituted by alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, hydroxyl or alkoxy);

X is CH 2 or O; and

R 15 is absent or is H or alkyl (e.g., methyl or ethyl).

An embodiment of the compounds of Formula I is compounds the formula

Vl or a pharmaceutically acceptable salt thereof, wherein the definitions are the same as those for Formula I. Another embodiment of compounds of Formula Vl is those compounds wherein

R 1 is -[C(R a )(R b )] q YR r , -[C(R a )(R b )] q N(R 7 )YR 7' , -[C(R a )(R b )] q OYR r and -[ C(R a )(R b )] q CN,

R 4 is H, D, alkyl or deuterated alkyl (e.g., -CH 2 D, CHD 2 or CD 3 );

R 4' is H, D, alkyl or deuterated alkyl (e.g., -CH 2 D, CHD 2 or CD 3 ); Y is a bond, -C(=O)-, -C(=O)NR 7 -, -C(=O)O-, -C(=NOR 7 ), -S(O) P -, and -

SO 2 NR 7 -; q is O or 1 ; and

R 7 and R 7 are independently H, R 12 -alkyl (e.g., methyl, ethyl, propyl optionally substituted by halo, cyano, or alkoxy (e.g., methoxy)); and R 12 -aryl (e.g., phenyl optionally substituted by alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, hydroxyl or alkoxy), or a pharmaceutically acceptable salt thereof.

Another embodiment of the compounds for Formula I

VII or a pharmaceutically acceptable salt thereof, wherein the definitions are the same as those for Formula I.

Another embodiment of compounds of Formula VII is those compounds wherein

R 1 is -[C(R a )(R b )] q YR 7 , -[C(R a )(R b )] q N(R 7 )YR 7' , -[C(R a )(R b )] q OYR 7' and -[ C(R a )(R b )] q CN,

R 4 is H, D, alkyl or deuterated alkyl (e.g., -CH 2 D, CHD 2 or CD 3 );

R 4' is H, D, alkyl or deuterated alkyl (e.g., -CH 2 D, CHD 2 or CD 3 ); Y is a bond, --C(=O)-, -C(=O)NR 7 -, -C(=O)O-, -C(=NOR 7 ), -S(O) P -, and - SO 2 NR 7 -; q is O or 1; and

R 7 and R 7' are independently H 1 R 12 -alkyl (e.g., methyl, ethyl, propyl optionally substituted by halo, cyano, or alkoxy (e.g., methoxy)); and R 12 -aryl (e.g., phenyl optionally substituted by alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, hydroxyl or alkoxy), or a pharmaceutically acceptable salt thereof.

Another embodiment of the compounds of Formula VIII is compounds of the formula

VIII or a pharmaceutically acceptable salt thereof, wherein the definitions are the same as those for Formula I.

Another embodiment of compounds of Formula VIII is those compounds wherein

R 1 is -[C(R a )(R b )] q YR r , -[C(R a )(R b )] q N(R 7 )YR 7' , -[C(R a )(R b )] q OYR 7' and -[ C(R a )(R b )] q CN,

R 4 is H, D, alkyl or deuterated alkyl (e.g., -CH 2 D, CHD 2 or CD 3 );

R 4' is H, D, alkyl or deuterated aikyl (e.g., -CH 2 D, CHD 2 or CD 3 );

Y is a bond, -C(=O)-, -C(=O)NR 7 -, -C(=O)O-, -C(=NOR 7 ), -S(O) P -, and - SO 2 NR 7 -; q is O or 1; and

R 7 and R 7' are independently H, R 12 -alkyl (e.g., methyl, ethyl, propyl optionally substituted by halo, cyano, or alkoxy (e.g., methoxy)); and R 12 -aryl (e.g., phenyl optionally substituted by alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, hydroxyl or alkoxy), or a pharmaceutically acceptable salt thereof.

Another embodiment of the compounds of Formula I is compounds of the formula

IX or a pharmaceutically acceptable salt thereof, wherein the definitions are the same as those for Formula I.

Another embodiment of compounds of Formula IX is those compounds wherein

R 1 is -[C(R a )(R b )] q YR 7> , -[C(R a )(R b )] q N(R 7 )YR 7' , -[C(R a )(R b )] q OYR 7' and -[ C(R a )(R b )] q CN,

R 4 is H, D, alkyl or deuterated alkyl (e.g., -CH 2 D, CHD 2 or CD 3 );

R 4' is H, D, alkyl or deuterated alkyl (e.g., -CH 2 D, CHD 2 or CD 3 );

Y is a bond, -C(=O)-, -C(=O)NR 7 -, -C(=O)O-, -C(=NOR 7 ), -S(O) P -, and - SO 2 NR 7 -; q is O or 1 ; and

R 7 and R 7' are independently H, R 12 -alkyl (e.g., methyl, ethyl, propyl optionally substituted by halo, cyano, or alkoxy (e.g., methoxy)); and R 12 -aryl (e.g., phenyl optionally substituted by alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, hydroxyl or alkoxy), or a pharmaceutically acceptable salt thereof.

A group of compounds falling within Formula I are those shown below: or a pharmaceutically acceptable salt of each of these compounds.

Another group of compounds falling within Formula I are those shown below:

as well as the pharmaceutically acceptable salts of each of these compounds.

In another embodiment the compound of Formula I or its pharmaceutically accept salt, solvate or ester thereof is present in its isolated and purified form.

One embodiment of the present invention is compounds that act as agonists of the α2C receptor. Alpha-2C receptor agonists can by used in the treatment or prevention of allergic rhinitis, congestion (including, but not limited to nasal congestion), migraine, congestive heart failure, chronic heart failure, cardiac ischemia, glaucoma, stress-induced urinary incontinence, attention deficit hyperactivity disorder, neuronal damage from ischemia and psychotic disorders. Further, alpha-2C receptor agonists can be useful in the treatment of pain (both chronic and acute), such as pain that is caused by inflammation, neuropathy, arthritis (including osteo and rheumatoid arthritis), diabetes (e.g., diabetes mellitus or diabetes insipidus) or pain of an unknown origin. Examples of neuropathic pain may include but not limited to; diabetic neuropathy, neuralgia of any etiology (e.g. post-herpetic, trigeminal), chemotherapy- induced neuropathy, HIV, lower back pain of neuropathic origin (e.g. sciatica), traumatic peripheral nerve injury of any etiology, central pain (e.g. post-stroke, thalamic, spinal nerve injury). Other pain that can be treated is nociceptive pain and pain that is visceral in origin or pain that is secondary to inflammation or nerve damage in other diseases or diseases of unknown origin. Further, alpha-2C receptor agonists can be useful in the treatment of symptoms of diabetes. Examples of symptoms of diabetes may include but are not limited to: hyperglycemia, hypertriglyceridemia, increased levels of blood insulin and hyperlipidemia.

A compound is defined to be an agonist of the alpha-2c receptor if the compound's efficacy at the α2C receptor is > 30% E max (GTPγS assay).

A further embodiment of the present invention are that act selectively, and preferably even specifically, as agonists of the α2C or the α2B/α2C (hereinafter referred to as α2C or α2B/2C) receptor subtypes in preference over the α2A receptor subtype and that act functionally selectively as agonists of the α2C or the α2B/2C receptor subtype in preference over the α2A receptor subtype possess desirable therapeutic properties associated with adrenergic receptors but without having one or more undesirable side effects such as changes in blood pressure or sedation. For the purposes of the present invention, a compound is defined to be a specific or at least functionally selective agonist of the α2C receptor subtype over the α2A receptor subtype if the compound's efficacy at the α2C receptor is > 30% E ma χ (GTPγS assay) and its efficacy at the α2A receptor is < 35% E ma x, (GTPγS assay). In another embodiment of the present invention the compound acts as an antagonist of the alpha-2C receptor. Alpha-2C receptor antagonists can be used in the treatment or prevention of disease states such as depression, schizophrenia, post tramautic stress disorder, Parkinson's disease, dementias (e.g., Alzheimer's disease and neuropathic disorders.

A compound is defined to be an antagonist of the alpha-2C receptor if the compounds's efficacy at the α2C receptor is < 30% E max (GTPYS assay) and the binding inhibition of at the α2C receptor (Kj) is < 500 nM, preferably < 200 nM, and most preferably < 20 nM. In a further embodiment of the present invention, the α2C receptor subtype antagonists possess desirable therapeutic properties associated with the α2C adrenergic receptor but without having one or more undesirable side effects associated with α2A agonism. For the purposes of this invention, compounds that act as antagonists at the α2C receptor subtype preferably do not possess an efficacy at the α2A receptor of 35% E max or more (GTPyS assay).

Alternatively, the present invention provides for a method for the treatment of congestion in a mammal in need thereof which comprises administering to a mammal an effective dose of at least one compound having adrenergic activity wherein said compound is a functionally selective agonist of the α2c receptor or the α2C/αB adrenergic receptor.

A further embodiment of the present invention is a method for the treatment of congestion in a mammal in need thereof which comprises administering to a mammal an effective dose of at least one compound having adrenergic activity wherein said compound is a functionally selective agonist of the α2C receptor or the α2C/αB adrenergic receptor, wherein the selective agonist of the α2c receptor or the α2C/αB adrenergic receptor has an efficacy that is greater than or equal to 35% E max when assayed in the GTPyS assay and its efficacy at the α2A receptor is < 35% E max (GTPγS assay). As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings: "Patient" includes both human and animals. "Mammal" means humans and other mammalian animals. "alpha-2C modulator" or "α2C modulator" means that a compound has affinity for (or binds to) the α2C receptor which provokes a biological response (i.e., either an agonistic or antagonistic response).

"alpha-2C receptor agonist or "a2C receptor agonist" is a compound that has affinity for the α2C receptor and elicits a biological response that mimics the response observed by the endrogenous ligand (e.g., neurotransmitter) that binds to the same receptor.

"alpha-2C receptor antagonist or "a2C receptor antagonist" is a compound that has affinity for the α2C receptor and elicits a biological response that blocks or dampens the response observed by the endrogenous ligand (e.g., neurotransmitter) that binds to the same receptor.

"Congestion" refers to all type of congestion including, but not limited to, congestion associated with perennial allergic rhinitis, seasonal allergic rhinitis, non- allergic rhinitis, vasomotor rhinitis, rhinitis medicamentosa, sinusitis, acute rhinosinusitis, or chronic rhinosinusitis or when the congestion is caused by polyps or is associated with the common cold.

"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. The term "substituted alkyl" means that the alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl) 2 , carboxy and -C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl. "Deuterated alkyl" means an alkyl group wherein at least on of the hydrogens in the aliphatic hydrocarbon group is replaced by a deuterium atom. Examples of deuterated alkyl groups include, for example, -CDH 3 , -CD 2 H, -CD 3 , -CH 2 CD 3 etc.

"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon- carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. "Alkenyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and -S(alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut- 2-enyl, n-pentenyl, octenyl and decenyl.

"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3- methylbutynyl. The term "substituted alkynyl" means that the alkynyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.

"Aryl" means an aromatic monocyclic or multicyclic ring system, in which at least one of the multicyclic rings is an aryl ring, comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. Non-limiting examples of aryl multicyclic ring systems include:

"Heteroaryl" means an aromatic monocyclic or multicyclic ring system, in which at least one of the multicyclic rings is aromatic, comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4- thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1 ,2,4-triazinyl, benzothiazolyl and the like.

Non-limiting examples of hetreroaryl multicyclic ring systems include:

"Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl. "Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.

"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms.

Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbomyl, adamantyl and the like. "Halogen" and "Halo" mean fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are fluorine and chlorine.

"Ring system substituent" means a substituent attached to an aromatic or non- aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, YiY 2 N-, YiY 2 N-alkyl-,

YiY 2 NC(O)- and Y 1 Y 2 NSO 2 -, wherein Yi and Y 2 may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl.

"Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protected moieties are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S 1 S- dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, and the like. Compounds of Formula I and salts, esters, solvates and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention. Non- limiting examples of tautomeric forms that are part of this invention are as follows:

It should be noted that in saturated heterocyclyl containing systems of this invention, there are no hydroxyl, amino, or thiol groups on carbon atoms adjacent to a N, O or S atom. Thus, for example, in the ring:

there is no -OH attached directly to carbons marked 2 and 5. It should also be noted that this definition does not preclude (=0), (=S), or (=N) substitutions, or their tautomeric forms, on C atoms adjacent to a N, O or S. Thus, for example, in the above ring, (=0) substitution on carbon 5, or its imino ether tautomer is allowed. Non-limiting examples which illustrate the present invention are as follows:

The following non-limiting examples serve to illustrate radicals not contemplated by the present invention:

"Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl. "Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.

"Heterocyclylalkyl" means a heterocyclyl-alkyl group in which the heterocyclyl and the alkyl are as previously described. Preferred heterocyclylalkyls contain a lower alkyl group. Non-limiting examples of suitable heterocyclylalkyl groups include piperidylmethyl, piperidylethyl, pyrrolidylmethyl, morpholinylpropyl, piperazinylethyl, azindylmethyl, azetidylethyl, oxiranylpropyl and the like. The bond to the parent moiety is through the alkyl group. "Heterocyclenyl" (or "heterocycloalkeneyl") means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon- nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic azaheterocyclenyl groups include 1 ,2,3,4- tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1 ,2,3,6- tetrahydropyridyl, 1 ,4,5,6-tetrahydropyrimidyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, 2-oxazolinyl, 2-thiazolinyl, and the like. Non-limiting examples of suitable oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like. Non-limiting example of a suitable multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl. Non-limiting examples of suitable monocyclic thiaheterocyclenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like.

"Heterocyclenylalkyl" means a heterocyclenyl-alkyl group in which the heterocyclenyl and the alkyl are as previously described. "Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined.

Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

"Acyl" means an organic acid group in which the -OH of the carboxyl group is replaced by some other substituent. Suitable non-limiting examples include H-C(O)-, alkyl-C(O)- , cycloalkyl-C(O)-, heterocyclyl-C(O)-, and heteroaryl-C(O)- groups in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.

"Aroyl" means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1-naphthoyl.

"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.

"Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.

"Aralkyloxy" or "arylalkyloxy" means an aralkyl-O- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.

"Heteroarylalkoxy" means a heteroarylalkyl-O-group in which the heteroarylalkyl group is as previously described. "Heterocyclylalkoxy" means a heterocyclylalkyl-O group in which the hetrocyclylalkyl group is as previously described.

"Heterocyclenylalkoxy" means a heterocyclenylalkyl-0 group in which the heterocyclenylalkyl group is as previously described. "Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur.

"Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.

"Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur. "Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

"Aryloxycarbonyl" means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.

"Aralkoxycarbonyl" means an aralkyl-O-C(O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.

"Alkylsulfonyl" means an alkyl-S(O 2 )- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.

"Arylsulfonyl" means an aryl-S(O 2 )- group. The bond to the parent moiety is through the sulfonyl.

The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

It is noted that carbons of Formula I can be replaced with 1-3 silicon atoms, provided all valency requirements are satisfied. The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

The straight line as a bond generally indicates a mixture of, or either of, the possible isomers, non-limiting example(s) include, containing (R)- and (S)- stereochemistry. For example,

means containing both and

A dashed line ( — ) represents an optional bond. Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of the substitutable ring atoms, non-limiting examples include carbon, nitrogen and sulfur ring atoms.

As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise. For example:

represents

It should also be noted that any heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the hydrogen atom to satisfy the valences.

When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York. When any variable (e.g., aryl, heterocycle, R 2 , etc.) occurs more than one time in any constituent or formula, its definition on each occurrence is independent of its definition at every other occurrence.

Unless defined otherwise, all definitions for the variables follow the convention that the group to the right forms the point of attachement to the molecule; i.e., if a definition is arylalkyl, this means that the alkyl portion of the definition is attached to the molecule.

Further, all divalent variable are attached from left to right. For example when R 1 is -[C(R a )(R b )] q N(R 7 )YR r and Y is -C(=O)-, -C(=O)O- or -C(=O)NR 7 , then R 1 forms the group -[C(R a )(R b )] q N(R 7 )-C(=O)-R 7' , -[C(R a )(R b )] q N(R 7 )-C(=O)O-R r , or - [C(R a )(R b )] q N(R 7 )-C(=O)N(R 7 )(R 7 ).

In this application, unless otherwise indicated, whenever there is a structural formula provided, such as those of Formulae I to IX, this formula is intended to encompass all forms of a compound such as, for example, any solvates, hydrates, stereoisomers, tautomers, etc.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug", as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula I or a salt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S.

Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.

For example, if a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-C 8 )alkyl, (C 2 - C 12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarboπyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N > N-(C 1 -C 2 )alkylamino(C 2 -C 3 )alkyl (such as β-dimethylaminoethyl), carbamoyl-(Ci-C 2 )alkyl, N,N-di (Ci-C 2 )alkylcarbamoyl-(C1- C2)alkyl and piperidino-, pyrrolidino- or morpholino(C 2 -C3)alkyl, and the like.

Similarly, if a compound of of Formula I contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (CrC^alkanoyloxymethyl, 1-((C r C 6 )alkanoyloxy)ethyl, 1-methyl-1-((Ci-C 6 )alkanoyloxy)ethyl, (C 1 - C 6 )alkoxycarbonyloxymethyl, N^d-Cβjalkoxycarbonylaminomethyl, succinoyl, (d- C 6 )alkanoyl, α-amino(CrC 4 )alkanyl, arylacyl and α-aminoacyl, or α-aminoacyl-α- aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, -P(O)(OH) 2 , -P(O)(O(Ci-C 6 )alkyl) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.

If a compound of of Formula I incorporates -NH- functional group, such as in a primary or secondary amine or in a nitrogen-containing heterocycle, such as imidazole or piperazine ring, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'- carbonyl where R and R' are each independently (Ci-Cio)alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl, -C(OH)C(O)OY 1 wherein Y 1 is H, (C r C 6 )alkyl or benzyl, -C(OY 2 )Y 3 wherein Y 2 is (C r C 4 ) alkyl and Y 3 is (Ci-C6)alkyl, carboxy (Ci-C 6 )alkyl, amino(CrC 4 )alkyl or mono-N- or di-N,N-(Ci- C 6 )alkylaminoalkyl, -C(Y 4 ) Y 5 wherein Y 4 is H or methyl and Y 5 is mono-N- or di-N,N- (CrCeJalkylamino morpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of illustrative solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H 2 O.

One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et a/, J. Pharmaceutical ScL, 93(3). 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et a/, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et a/, Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

Metabolic conjugates, such as glucuronides and sulfates which can undergo reversible conversion to the compounds of of Formula I are contemplated in the present invention.

"Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect. The terms "purified", "in purified form" or "in isolated and purified form," as used herein, for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like) , in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan. "Capsule" is meant to describe a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients. Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.

"Tablet" is meant to describe a compressed or molded solid dosage form containing the active ingredients with suitable diluents. The tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction.

"Oral gels" is meant to describe to the active ingredients dispersed or solubilized in a hydrophillic semi-solid matrix.

"Powders for constitution" refers to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices. "Diluent" refers to substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potato; and celluloses such as microcrystalline cellulose. The amount of diluent in the composition can range from about 10 to about 90% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, even more preferably from about 12 to about 60%.

"D is integrants" refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments. Suitable disintegrants include starches; "cold water soluble" modified starches such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures. The amount of disintegrant in the composition can range from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight.

"Binders" refers to substances that bind or "glue" powders together and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose; starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate. The amount of binder in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight. "Lubricant" is meant to describe a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and d'l-leucine. Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press. The amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%, more preferably from about 0.3 to about 1.5% by weight.

"Glidents" means materials that prevent caking and improve the flow characteristics of granulations, so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the composition can range from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight.

"Coloring agents" refers to excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1%.

"Bioavailability" refers to the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed into the systemic circulation from an administered dosage form as compared to a standard or control. Conventional methods for preparing tablets are known. Such methods include dry methods such as direct compression and compression of granulation produced by compaction, or wet methods or other special procedures. Conventional methods for making other forms for administration such as, for example, capsules, suppositories and the like are also well known.

The compounds of Formula I can form salts which are also within the scope of this invention. Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of of Formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of Formula I or may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tarta rates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by S. Berge er a/, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et a/, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others. All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those which may exist due to asymmetric carbons or sulfurs on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. For example, if a compound of Formula I incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate" "prodrug" and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds. Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula I may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.

Polymorphic forms of the compounds of Formula I, and of the salts, solvates and prodrugs of the compounds of Formula I 1 are intended to be included in the present invention. The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.

Certain isotopically-labelled compounds of Formula I (e.g., those labeled with 3 H and 14 C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, lsotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.

The compounds according to the invention have pharmacological properties; in particular, the compounds of Formula I can be useful as α2C adrenoreceptor agonists. A preferred dosage is about 0.001 to 500 mg/kg of body weight/day of the compound of Formula I. An especially preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound. The compounds of this invention may also be useful in combination (administered together or sequentially) with one or more therapeutic agents such as, for example, glucocorticosteroids, PDE-4 inhibitors, anti-muscarinic agents, cromolyn sodium, Hi receptor antagonists, 5-HT 1 agonists, NSAIDs, angiotensin-converting enzyme inhibitors, angiotensin Il receptor agonists, β-blockers, β-agonists (including both long and short acting), leukotriene antagonists, diuretics, aldosterone antagonists, ionotropic agents, natriuretic peptides, pain management/analgesic agents, anti-anxiety agents, anti-migraine agents, and therapeutic agents suitable for treating heart conditions, psychotic disorders, and glaucoma. Suitable steroids include prednisolone, fluticasone (including all ester such as the propionate or furoate esters), triamcinolone, beclomethasone, mometasone (including any ester form such as mometasone furoate), budasamine, ciclesonide betamethasone, dexamethasone, prednisone, flunisolide, and cortisone.

Suitable PDE-4 inhibitors include roflumilast, theophylline, rolipram, piclamilast, cilomilast and CDP-840.

Suitable antiimuscarinic agents include ipratropium bromide and tiatropium bromide.

Suitable Hi antagonists include astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratidine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizeine, fexofenadine, hydroxyzine, ketotifen, loratidine, levocabastine, meclizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine or triprolidine.

Suitable anti-inflammatory agents include aspirin, diclofenac, diflunisal, etodolac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, and tolmetin.

Suitable aldosterone antagonists include spironolactone. Suitable ionotropic agents include digitalis.

Suitable angiotensin Il receptor agonists include irbesartan and losartan. Suitable diuretics include spironolactone, methyclothiazide, bumetanide, torsemide, hydroflumethiazide, trichlormethiazide, hydroclorothiazide, triamterene, ethacrynic acid, methyclothiazide, hydrochlorothiazide, benzthiazide, hydrochlorothiazide, quinethazone, hydrochlorothiazide, chlorthalidone, furosemide, indapamide, hydroclorothiazide, triamterene, trichlormethiazide, hydrochlorothiazide, amiloride HCI, amiloride HCI 1 metolazone, trichlormethiazide, bendroflumethiazide, hydrochlorothiazide, polythiazide, hydroflumethiazide, chlorthalidone, and metolazone.

Suitable pain management/analgesic agents include Celecoxib, amitriptyline, ibuprofen, naproxen, gabapentin, tramadol, rofecoxib, oxycodone HCI, acetaminophenoxycodone HCI, carbamazepine, amitriptyline, diclofenac, diclofenac, etodolac, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac tromethamine, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin sodium, valdecoxib, diclofenac/ misoprostol, oxycontin, vicodin, darvocet, percocet, morphine sulfate, dilaudid, stadol, stadol NS, acetaminophen with codeine, acetaminophen with codeine #4, Lidoderm ® patches, ziconotide, duloxetine, roboxetine, gabapentin and pregabalin. Suitable β-blockers include acebutolol, atenolol, atenolol/chlorthalidone, betaxolol, bisoprolol fumarate, bisoprolol/HCTZ, labetolol, metoprolol tartrate, nadolol, pindolol, propranolol, propranolol/HCTZ, sotalol, and timolol.

Suitable β-agonists include dobutamine, ritodrine, salbutamol, levalbuterol, metaproternol, formoterol, fenoterol, bambuterol, brocaterol, clenbuterol, terbutaline, tulobuterol, epinephrine, isopreπalin, and hexoprenalin.

Suitable leucotriene antagonists include levamisole.

Suitable anti-migraine agents include rovatriptan succinate, naratriptan HCI 1 rizatriptan benzoate, sumatriptan succinate, zolmitriptan, almotriptan malate, methysergide maleate, dihydroergotamine mesylate, ergotamine tartrate, ergotamine tartrate/caffeine, Fioricet ® , Fiorninal ® , Depakene ® , and Depakote ® .

Suitable anti-anxiety and anti-depressant agents include amitriptyline HCI, bupropion HCI, citalopram hydrobromide, clomipramine HCI, desipramine, fluoxetine, fluvoxamine maleate, maprotiline HCI, mirtazapine, nefazodone HCI, nortriptyline, paroxetine HCI 1 protriptyline HCI, sertraline HCI, doxepin, and trimipramine maleate. Suitable angiotensin converting enzyme inhibitors include Captopril, enalapril, enalapril/HCTZ , lisinopril, lisinopril/HCTZ, and Aceon ® . The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays. The exemplified pharmacological assays which are described later have been carried out with the compounds according to the invention and their salts. This invention is also directed to pharmaceutical compositions which comprise at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and at least one pharmaceutically acceptable carrier.

For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18 th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.

Liquid form preparations include solutions, suspensions and emulsions. When preparing a liquid preparation, the inclusion of one or more solubility enhancing components is excluded. Solubility enhancing components are described, for example, in U.S. 6,673,337 in column 2, line 50 to column 3, line 17 and in column 6, line 49 to line 31 ; US 6,673,337 is expressly incorporated by reference. Specific solubility enhancing agents that are excluded in the liquid form preparations include metal carboxymethylcelluloses, metal carboxymethylhydroxyethylcelloses, hydroxypropylmethyl celluloses derivative of these compounds, and cyclodextrins. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions or suspensions for intranasal administration.

An aspect of this invention is that the pharmaceutical composition is in a solid dosage form comprising a compound of Formula I or a pharmaceutical acceptable salt, ester, solvate or prodrug thereof and a least one pharmaceutically acceptable carrier, adjuvant or vehicle.

Another aspect of this invention is a liquid, aqueous pharmaceutical composition is comprising a compound of Formula I or a pharmaceutical acceptable salt, ester, solvate or prodrug thereof and a least one pharmaceutically acceptable carrier, adjuvant or vehicle provided that the adjuvant is not a solubility enhancing component, such as those described in US 6,673,337 (discussed above).

Another aspect of this invention is a liquid, aqueous pharmaceutical composition is comprising a compound of Formula I or a pharmaceutical acceptable salt, ester, solvate or prodrug thereof and a least one pharmaceutically acceptable carrier, adjuvant or vehicle wherein if a solubility enhancement component is present it is cyclodextrin.

Another aspect of this invention is a pharmaceutical formulation that is a nasal spray wherein the pH is equal to or less that about 6.5, more preferably between about 6.1 to 6.2.

Another aspect of this invention the formulation is a nasal spray wherein the adjuvants include a suspending agent (e.g., AVICEL (such as AVICIL RC-581 , RC- 591 and CL-611), which are microcrystalline cellulose and carboxymethylcellulose sodium; hydroxypropylmethyl cellulose; methyl cellulose; polyvinyl alcohol; or CARBOPOL) and a humectant (e.g., glycerin, propylene glycol; polyethylene glycol; povidone; or dextrose).

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions or suspensions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. The compounds of this invention may also be delivered subcutaneously.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required. The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.

Another aspect of this invention is a kit comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.

Yet another aspect of this invention is a kit comprising an amount of at least one compound of Formula I 1 or a pharmaceutically acceptable salt or solvate of said compound and an amount of at least one therapeutic agent listed above, wherein the amounts of the two or more ingredients result in desired therapeutic effect.

In general, the compounds in the invention may be produced by a variety of processes know to those skilled in the art and by know processes analogous thereto. The invention disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art. The practitioner is not limited to these methods.

One skilled in the art will recognize that one route will be optimized depending on the choice of appendage substituents. Additionally, one skilled in the art will recognize that in some cases the order of steps has to be controlled to avoid functional group incompatibility.

The prepared compounds may be analyzed for their composition and purity as well as characterized by standard analytical techniques such as, for example, elemental analysis, NMR, mass spectroscopy and IR spectra.

One skilled in the art will recognize that reagents and solvents actually used may be selected from several reagents and solvents well known in the art to be effective equivalents. Hence, when a specific solvent or reagent is mentioned, it is meant to be an illustrative example of the conditions desirable for that particular reaction scheme and in the preparations and examples described below.

Where NMR data are presented, 1 H spectra were obtained on either a Varian VXR-400 (400 MHz, 1 H), Varian Gemini-300 (300 MHz), Varian Mercury VX-400 (400MHz), or Bruker-Biospin AV-500 (500MHz), and chemical shifts are reported as ppm with number of protons and multiplicities indicated parenthetically. Where LC/MS data are presented, analyses was performed using an Applied Biosystems API-100 mass spectrometer and C18 column, 10-95% CH 3 CN-H 2 O (with 0.05% TFA) gradient. The observed parent ion is given.

The following solvents and reagents may be referred to by their abbreviations in parenthesis: Me = methyl; Et = ethyl; Pr = propyl; Bu = butyl; t-Bu = tert-butyl; Ph = phenyl, and Ac = acetyl μl = microliters AcOEt or EtOAc = ethyl acetate AcOH or HOAc = acetic acid

ACN = acetonitrile aq = aqueous atm = atmosphere Bn = benzyl

Boc or BOC = tert-butoxycarbonyl

BINAP = 2,2'-bis(diphenylphosphino)-1 ,1'-bisnaphthyl

Bz = benzoyl cat = catalyst or catalytic Cbz = benyzloxycarbonyl

DEA = diethylamine

DEAD = diethylazodicarboxylate

DCM or CH 2 CI 2 : dichloromethane:

DMAP = 4-dimethylaminopyridine DIBAL = diisobutylaluminum hydride

DIPEA = diisopropylethylamine

DME = 1,2-dimethoxyethane

DMF = dimethylformamide

DMS = dimethylsulfide DMSO = dimethyl sulfoxide

Dppf = 1,1 '-bis(diphenylphosphino)ferrocene

EDCI or DEC = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

Eq = equivalents g = grams h or hr = hour

HATU = 0-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

HOBt = 1-hydroxybenzotriazole

IPA = isopropyl alchohol Im = imidazole

LAH = lithium aluminum hydride

LDA = lithium diisopropylamide

LCMS = liquid chromatography mass spectrometry M = molar mCPBA = m-chloroperoxybenzoic acid min = minute mg = milligrams mL = milliliters mmol = millimoles

MeOH: methanol

MS = mass spectrometry

N = normal NBS = N-bromosuccimide

NMO =N-methylmorpholine N-oxide

NMR = nuclear magnetic resonance spectroscopy

PG = protecting group

Pyr = pyridine rac or (±) = racemic mixture or enantiomers

RT or rt = room temperature (ambient, about 25 0 C) sat = saturated

SFC = supercritical fluid chromatography

SM = starting material TBSCI = t-butyldimethylsilyl chloride

TBS = t-butyldimethyl silyl

TEA = triethylamine (Et 3 N)

TEMPO = 2,2,6,6-Tetramethylpiperidine-i-oxyl

TFA = trifluoroacetic acid THF = tetrahydrofuran

TLC = thin layer chromatography

TMS = trimethylsilyl

Tos or Ts = p-toluenesulfonyl (tosyl)

ToI = toluene TosMIC = Toluenesulfonylmethyl isocyanide

TPAP = tetrapropylammonium perruthenate

Tr = triphenylmethyl EXAMPLES

The compounds of this invention can be prepared through the general approach outlined in the following schemes. These schemes are being provided to illustrate the present invention. While the schemes depict J 1 -J 4 as -CH-, wherein the hydrogen may be replaced by A, this is for exemplary purposes only and one of ordinary skill in the art would be able to prepare compounds containing the other definitions for J 1 -J 4 by modifying these schemes using other procedures known to one in the art. To assist in one in this endeavor the ordinary practitioner would have full knowledge of literature sources such as Chemical Abstracts, Beilstein, etc. Scheme 1 shows an approach in which S1 (X = -CH 2 - and n = 0-2; or X = -O-, -

NH- or substituted N and n = 1-2) is converted to hydantoin S2 by reaction with ammonium carbonate and a cyanide source (such as KCN , NaCN or TMSCN; or related conditions such as CO 2 /NH 4 OH/NaCN/ H 2 O 2 ). Subsequent hydrolysis to the amino acid S3a with base (LiOH, NaOH, Ba(OH) 2 , or the like) is followed by conversion to the amino ester S3b and reduction to the alcohol S4 (with reagents such as as DIBAL, NaBH 4 , borane, or LAH). Alternatively, the amino acid S3a is directly reduced to S4. In various embodiments, the amino alcohol (S4) is then cyclized to provide the following moieties:

-substitued 2-aminooxazoline S5a (Z = NHC(O)R), with an isothiocyanate (such as benzoyl isothiocyanate);

-2-aminooxazoline S5b (Z = NH 2 via treatment with, for example, cyanogen bromide with or without a base (such as diisopropylethylamine) or by treatment with an thioisocyanate, such as (EtO 2 C)NCS or BzNCS, followed by treatment with a base or acid or catalyst such as Hg(O),

Hg(OAc) 2 or 2-chloro-3-ethylbenzoxazolium tetrafluoroborate and hydrolysis with LiOH); -oxazoline S5c (Z = H, by treatment with, for example, methyl formate/DAST, trialkoxyformate, dimethylformamide dimethyl acetal or other similar reagent);

-oxazolidinone (S5d, Z = OH) by treatment with reagents known in the literature (e.g., carbonyldiimidazole, triosgene, or related carbonates or chloroformates etc.); -oxazolidinethione (S5e, Z = SH, by treatment with a known reagent such as

EtOCS 2 H, Im 2 CS, CS 2 , CI 2 CS, NaSCH, or MeSC(S)OEt etc.); and -an oxazoline S5f with a carbon linkage at Z (by numerous literature methods such as treatment with RC(=NH)OEt, RCN/ZnCI 2 , RCO 2 H, an anhydride, RCHO with an appropriate oxidant or other methods).

2-aminooxazoline S5b (Z = NH 2 ) may also be obtained from S5a (Z = NHC(O)R), by treatment with a hydroxide source such as LiOH. Oxazolidinethione S5e (Z = SH) may also be obtained from 5d (Z = OH) by treatment with a sulfur reagent (such as Lawesson's reagent). The oxazolidinone (S5d, Z = OH) or oxazolidinethione (S5β, Z = SH) may be further substituted by alkylation or acylation chemistry known in the literature (to Z =0R or Z = SR respectively). An alkylated oxazolidinethione (S5e, Z = SR, where R = alkyl or the like) is optionally oxidized to provide Z = S(O) P R (where p = 1 or 2).

In various embodiments, group A may be functionalized to the various definitions of R 1 at different stages in the sequence from a precursor group (such as A = halogen, optionally protected alcohol, nitro group, or optionally protected amine). Alternatively, the functionalized A group may exist in the starting material S1 or its precursor. In the cases where A = halogen or alcohol, functionalization may occur a metal catalyzed or metal-faciliated process (with copper, palladium, or other metals). The functionalized R 2 and R 3 groups may exist in the starting material S1 or its precursor. Alternatively, S1 or its precursor may be functionalized with R 2 and R 3 groups at various stages in the sequence.

SCHEME 1 :

S(O) P R substituent

According to another embodiment (Scheme 2), compound S1 is converted to S6 by a Strecker reaction (with a cyanide source and an amine such as NhUCI/KCN or alkylamine/NaCN). The nitrile is reduced (with LAH or a similar reagent) to S7, which may be cyclized to provide S8 or S9. In another embodiment, compound S6 is converted to amino acid S3a (Scheme 1) by hydrolysis.

SCHEME 2:

According to another embodiment (Scheme 3), compound S5d or S5e is converted to S10 (via chlorination with SOCI 2 , POCI 3 , PCI 3 , PCI 5 , Cl 2 or the like). In various embodiments, intermediate S10 is displaced with an amine, oxygen or carbon nucleophile or alternatively reacted in a metal catalyzed or metal-facilitated process (such as a palladium-catalyzed Suzuki or Stille coupling) to provide S5 (in which Z is a carbon, oxygen or nitrogen linked substituent). SCHEME 3

Scheme 4 shows an approach in which amino alcohol S4 is reacted with an acid under standard coupling conditions (with reagents such as EDCI, HOBt etc.) or with an acid chloride to provide the amide S11 (wherein R is defined as Z in Formula I or a group that may be converted into Z). In one embodiment, compound S11 is then treated with sulfur reagent such as Lawesson's Reagent, P 2 S 5 , or Deoxy-Fluor to affect incorporation of S with concomitant cyclization to S12. Alternatively, S4 may be converted to thioamide or thiourea S13 (by reaction with a thioester, thioacid, or thioisocyanate) and then cyclized to S12 (under a variety of conditions including treatment with HCI, SOCI 2 , Deoxy-Fluor, DAST, Hg(O), Hg(OAc) 2 or 2-chloro-3- ethylbenzoxazolium tetrafluoroborate or other reagents). In another embodiment, S11 is first converted to S13 (by treatment with a sulfur reagent such as Lawesson's Reagent , DAST or the like) and then cyclized to S12 in a step-wise fashion.

SCHEME 4

According to another embodiment (Scheme 5), aminoester S3b (optionally protected) is sequentially treated with an organometallic reagent (such as a RMgBr, a Grignard reagent, or RLi, an alkyllithium compound, to give a ketone S15), followed by reduction to afford S17 (wherein R is defined as R 4 in Formula I or a group that may be converted into R 4 ). The subsituted aminoalcohol S17 is then cyclized to a substituted oxazoline S18 as previously described. Alternatively, this general approach may be taken starting with the amino nitrile S6 or Weinreb amide S14 (accessed from aminoacid S3a by amide coupling with HN(Me)OMe or from aminoester S3b reaction with HN(Me)OMe/AIMe 3 ). In another embodiment, S3b, S6, or S14 are reduced (or reduced/oxidized) to aldehyde S16 which is then subsequentially reacted with an organometallic reagent to provide S17. The reduction of ketone S15 may optionally be undertaken in a stereoselective manner to preferentially provide one stereoisomeric alcohol S17. Reagents for a stereoselective reduction are well known in the art, and include, but are not limited to the CBS- oxazaborolidine/borane reagent, LAH/N-methylephedrine, BINAL-H, IpC 2 BCI, DIBAL- H, Li-selectride, NaBH_(/CeCl3, and enzymatic catalysis.

SCHEME 5

According to another embodiment (Scheme 6), ketone S15 (optionally protected) undergoes an olefination (Wittig, Horner-Emmons, Tebbe reaction etc.) hydroboration sequence to provide alcohol S20 (wherein R is defined as R 4 in Formula I or a group that may be converted into R 4 ), which is then cyclized to S21.

SCHEME 6

According to another embodiment (Scheme 7), ketone S15 (optionally protected) undergoes an olefination (Wittig, Horner-Emmons etc.) to a 1 ,2- disubstituted olefin. Hydroboration of S22 (wherein R and R' are independently defined as R 4 in Formula I or a group that may be converted into R 4 ) provides alcohol S23, which is then cyclized to S24.

SCHEME 7

According to another embodiment (Scheme 8), alcohol S20 (optionally protected) is sequentially oxidized and treated with an organometallic reagent to provide S23 (wherein R and R' are independently defined as R 4 in Formula I or a group that may be converted into R 4 ). Compound S23 is then cyclized to provide S24.

SCHEME 8

According to another embodiment (Scheme 9), chiral alcohol S28 is prepared by the addition of the anion of a chiral sulfoxide S27 onto ketone S26. An intramolecular SN2 reaction provides epoxides S29, which are opened using nitrogen nucleophiles such as ammonia or by addition of NH precursors such as azides, phthalimides, benzyl amines or benzhydryl amines to give aldehyde S30. Alcohols S31 and S32 are prepared by addition of an organometallic compound (such as an organomagnesium) and amine deprotection. SCHEME 9

In another embodiment (Scheme 10), chiral sulfoxide S33 contains an alkyl group R'. Following an approach similar to Scheme 9, epoxide opening provides ketone S36. Alcohols S31 and S32 are obtained by reduction of the ketone by known methods (such as treatement with as NaBH 4 ) and amine deprotection. Alternatively, the ketone is reduced in an asymmetrical fashion using chiral reduction methods known for those skilled in the art (such as CBS reduction).

SCHEME 10

According to another embodiment (Scheme 11), compound S1 is treated with a chiral amine (such as ( " Rj-phenylglycine or other chiral amine) and then treated with a cyanide source (such of KCN, NaCN or TMSCN) to provide converted to S6 as a pure enantiomer or in enantiomerically enriched form. Reduction of the nitrile, cleavage of the chiral auxiliary, and cyclization provides imidazoline S8 as previously described. Alternatively, S6 is converted to S3b by hydrolysis (with MeOH/HCI or other approach) and cleavage of the chiral auxiliary.

SCHEME 11

According to another embodiment (Scheme 12), the ester S3b is converted to amide S3c (by treatment with ammonia or an amine) and then reduced (with LAH, BH3 or a similar reagent) to diamine S38, which may be cyclized to provide: -S39a, via treatment with amidine reagents such as formamidine, acetamidine, or benzamidine);

-S39b, via treatment with diphenyl cyanocarbonimidate; -S39c, via treatment with cyanogen bromide; and -S39d, via treatment with carbonyldiimidazole, triphosgene, or related carbonates or chloroformates etc.).

SCHEME 12

According to another embodiment (Scheme 13), a functionlized xylene 40b (R = LG such as Br, synthesized from S40a with NBS or similar) is condensed with a N- protected glycine ester (such as N-(diphenylmethylene)glycine ethyl ester or N- benzylideneglycine ethyl ester) to provide S41 which is further elaborated to S42. Use of chiral N-protectected glycine ester or use of a chiral phase-transfer catalyst with a nonchiral N-protected glycine ester provides enantioselective enhancement in the condensation.

Alternatively, S40b is condensed with a maloπate ester (such as dimethyl malonate) to provide S43. Selective enzymatic hydrolysis of one ester (by an esterase or similar enzyme) provides S44 which is converted to S45 by a Curtuis rearrangement and then further elaborated to S42.

SCHEME 13

The starting materials, including compound S1, S26, and S40, and reagents used in preparing compounds described are either available from commercial suppliers such as Aldrich Chemical Co. (Wisconsin, USA) and Acros Organics Co. (New Jersey, USA) or were prepared by literature methods known to those skilled in the art. When unavailable from commercial suppliers, compound S1 (optionally substituted with R 2 and R 3 , or with substituents that are converted into R 2 and R 3 ) is synthesized from S46, S47, S48, S49, or other starting materials according to methods known in the literature.

Compounds of formulae S5, S8, S9, S10, S12, S18, S21, S24, S39, S42 and S45 can be prepared by the general methods outlined above. Exemplary compounds were prepared as described in the examples below or from starting materials known in the art. These examples are being provided to further illustrate the present invention. They are for illustrative purposes only; the scope of the invention is not to be considered limited in any way thereby. PREPARATIVE EXAMPLE 1

1E 1F (±)-1

Step i

A mixture of 8-bromo-2-tetralone (5.Og, 22.2 mmol), (NH 4 J 2 CO 3 (15.Og, 156 mmol), and KCN (2.16g, 33.3 mmol) in 1:1 EtOH-H 2 O (50 mL) was heated in a sealed tube overnight at 85 0 C. The reaction was then cooled to RT, diluted with water (-400 mL) and stirred for 2h. The precipitate was filtered and dried in vacuo overnight to provide hydantoin 1A (5.95g, 91%). LCMS m/z 295/297 (MH+).

Steps 2-3 A mixture of 1A (4.46 g, 15.1 mmol) and LiOH-H 2 O (3.18g, 75.6 mmol) in H 2 O

(100 mL) was refluxed overnight. The reaction was then cooled to 0 0 C, acidified with 12 N HCI, and concentrated to give the amino acid as a solid. LCMS m/z 270 (MH+). Thionyl chloride (9 mL) was carefully added to MeOH (300 m L) at 0 0 C. The resulting mixture was then added to a flask charged with the amino acid product. The reaction was heated to reflux overnight and then cooled and concentrated. The residue was taken up in sat. aq. NaHCO 3 and extracted EtOAc (2x). The combined organic layers were dried over Na 2 SO 4 and concentrated. Chromatography (0-50% EtOAc/hex) provided 1B as a red oil. LCMS m/z 284/286 (MH+). Steps 4-5

Compound 1B (8.16g, 28.7 mmol) was dissolved in anhydrous MeOH and then treated with NaBH 4 (2.72g, 71.8mmol, bubbling and heat generation noted). A second portion of NaBH 4 (2.72g, 71.8mmol) was added after 15 min. The reaction was concentrated after TLC indicated consumption of 1B (-15 min). THF (100 mL) was added to the residue and then removed in vacuo to give the yellow foam 1C, which was used in the next step without purification or aqueous workup. LCMS m/z 256/258 (MH+).

The crude aminoalcohol 1C (~28.7 mmol) was dissolved in anhydrous THF (250 mL) and treated with benzoyl isothiocyanate (8.5 mL, 63 mmol). After stirring for 20 min at RT, additional benzoyl isothiocyanate (4.3 mL, 32 mmol) was added. The reaction was concentrated after TLC and MS indicated consumption of 1C (~20 min). The residue was diluted with water and extracted with DCM (3x). The combined organic layers were dried over Na 2 SO 4 , concentrated and chromatographed (20-40% EtOAc/hex) to provide provided 1D as a yellow foam. LCMS m/z 385/387 (MH+). Step 6

A mixture of 1D (-38.7 mmol) and LiOH-H 2 O (6.03g, 144 mmol) in 1 :1 MeOH- H 2 O (200 mL) was refluxed for 1.5h. The reaction was concentrated to one-half volume and extracted with DCM (4x). The combined organic layers were dried over Na 2 SO 4 , concentrated and chromatographed (2% of NH 3 -MeOH/DCM) to give the desired product 1E (white solid 2.49g, -38% for 3-steps, LCMS m/z 281/283 MH+) and a small amount of a byproduct from Step 5 (1G, LCMS m/z 298/300 MH+).

(±)-1G Step 7

A mixture of compound 1E, EtNH 2 (2.0N/THF, 3 eq), CuI (0.5 eq), K 3 PO 4 (2 eq), and N.N'-Dimethyl^i R^RJ-cyclohexanediamine (1.6 eq) in DMF is heated at 100 0 C overnight in a sealed tube. The mixture is cooled, diluted with water and extracted with DCM (3x). The combined organic layers are washed with brine, dried over Na 2 SO 4 , and concentrated. Chromatography (NH 3 -MeOH in DCM) provides 1F. Step 8

A mixture of the ethyl aniline 1F in DCM is treated with CICO 2 Me (1.1 eq) and DIPEA (2 eq). The reaction is stirred overnight at RT, concentrated, and chromatographed to provide the title (±)-1. Alternative to Steps 4-6

Compound 1B is dissolved in anhydrous MeOH and then treated with NaBH 4 (3 eq). A second portion of NaBH 4 (3 eq) is added after 15 min. The reaction is concentrated after TLC indicated consumption of 1B and then directly purified by flash chromatography to provide purified 1C.

A mixture of 1C and cyanogen bromide (1.1 eq) in DCM is stirred for 4h at RT and concentrated. Chromatography provides compound 1E and recovered starting material 1C. The racemic mixtures of 1 E or 1 (or their CBz protected derivatives) are optionally separated on a preperative Chiralpak AD column with isopropanol-hexanes to provide the pure enantiomers.

In a manner similar to that described above, 1F (optionally protected with CBz) is reacted with the reagent indicated and, if protected, then hydrogenated, to provide the following compounds:

In a manner similar to that described above, 1E is sequentially reacted with Cul/MeNH 2 and CICO 2 Me to provide the compound (±)-1L.

(±)-1L

PREPARATIVE EXAMPLE 2

1E 2A 2B

Step i

A mixture of compound 1E, CbzCI (2.5 eq), TEA (2.5 eq), and DMAP (0.2 eq) in DCM is stirred at RT for 30 min. Additional portions of CbzCI and TEA are added if necessary. The reaction is concentrated, treated with water and extracted with DCM (4x). The organic layer is dried over Na 2 SO 4 , filtered, concentrated and chromatographed to provide 2A. Step 2

A mixture of compound 2A, Pd 2 (OAc) 2 (0.1 eq), BINAP (0.15 eq) and Cs 2 CO 3 (2.0 eq) in toluene (20 ml.) is treated with benzophenone imine (1.5 eq) and then stirred at 100 0 C overnight. After cooling to RT, the precipitate is filtered and washed with DCM. The combined filtrate is concentrated and chromatographed to provide 2B. Step 3

A mixture of 2B, NaOAc (5 eq), and NH 2 OH-HCI (3 eq) in MeOH is stirred at RT overnight. The reaction is then treated with aqueous NaOH (1 N) and extracted DCM (2x). The combined organic extracts are dried over Na 2 SO 4 , filtered and chromatographed to provide 2C. Steps 4-5

In a manner similar to that described in Example 1 (Step 8), compound 2C is treated with CICO 2 Me to provide 2D.

Compound 2D is subjected to hydrogenation with Pd/C and H 2 (40psi, overnight, MeOH), followed by chromatography (NH 3 -MeOH/DCM) to provide the title (±)-2.

PREPARATIVE EXAMPLE 3 1

3C 3D (±)-3

6-bromo-3-chromanone 3B was prepared from 6- bromo-4-chromanone in a 4 step sequence as outlined in Synthesis, 1980, 621: reduction with NaBH 4 (1.2 eq, MeOH-DCM, O 0 C to RT, 2h), elimination with pTsOH (cat., toluene, reflux, 3h, 90% for 2-steps), osmylation (cat. OsO 4 , 1 eq. NMO, water-acetone-tBuOH, RT, overnight) and final treatment with pTsOH (cat., toluene, reflux, 15min, 86% for 2-steps). Compound (±)-3 is prepared compound from 3B following essentially the same procedures as described in Example 1. Alternatively, compound 3C was reacted with 1.2 eq. cyanogen bromide (4h, RT, EtOH). The reaction was concentrated and purified to directly provide (±)-3D (LCMS m/z 283/285, MH+) in ~50% yield with ~40% recovered starting material 3C.

3C 3D

Alternatively, compound (±)-3 is prepared from 6-nitro-3-chromanone (prepared from 6-nitro-4-chromanone) in a manner similar to that described in Example 4.

PREPARATIVE EXAMPLE 4

4A 4B

4C 4D

Steps 1-2

In a manner similar to that described in Examples 1 and 2, 7-nitro-2-tetralone is converted to CBz-protected compound 4A.

A solution of compound 4A in EtOH is treated with SnCI 2 -2H 2 O (4 eq). The reaction is refluxed at 90 0 C and then concentrated. The residue is diluted with sat. aq. NaHCO 3 and extracted with EtOAc. The combined organic layer is dried (Na 2 SO 4 ), filtered and evaporated to give a brown solid 4B. Steps 3-5

Compound 4B is treated with CICO 2 Me (1.1 eq) and DIPEA (2 eq). The reaction is stirred overnight at RT and then concentrated. The resulting compound 4C is taken up in acetone and treated with CS 2 CO 3 (6 eq) and EtI (2 eq). The reaction mixture is stirred at 50°C and cooled to RT. The mixture is diluted with DCM, filtered through a pad of celite and concentrated in vacuo to provide 4D.

Compound 4D is subjected to hydrogenaticn with Pd/C and H 2 (40psi, overnight, MeOH), followed by chromatography (NH 3 -MeOH/DCM) to provide the title (±K

PREPARATIVE EXAMPLE 5

(±)-5

Step i

KCN

To a solution of 8-methoxy-2-tetralone (600 mg, 3.4 mmol) in EtOH-H 2 O (1:1, 12 mL) in a sealed tube was added ammonium carbonate (2.28 g, 23.8 mmol) and KCN (420 mg, 6.8 mmol) in one portion. The mixture was heated at 80 0 C for 12 h before it was cooled to RT. Water (20 mL) was added to precipitate the product 5A. The light grey solid was collected by filtration and washed with water and dried in air (835 mg, 100%, LCMS m/z 247, MH+).

Steps 2-3

5A 5B A suspension of 5A (200 mg, 0.813 mmol) and Ba(OH) 2 (460 mg, 3.25 mmol) in water (2 mL) was heated in a sealed tube at 120 0 C for 36 h. The mixture was acidified with 6 N H 2 SO 4 , and filtered and the filter pad was washed with MeOH repeatedly. The combined filtrate was concentrated under reduced pressure to yield the amino acid as an off-white solid. The crude product was added to a mixture of SOCI 2 (145 mg, 1.219 mmol) and MeOH (10 mL). The mixture was stirred at reflux for 3 h, cooled to RT and concentrated under reduced pressure. The methyl ester HCI salt was suspended in EtOAc (20 mL) and neutralized with sat. NaHCO 3 . The aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (80% EtOAc/Hexanes) to give 5B as a pale yellow oil (105 mg, 55%, LCMS m/z 236, MH+).

Step 4

5B 5C

To a stirred solution of 5B (3.17 g, 13.5 mmol) in THF (50 mL) was added LiAIH 4 (1.02 g, 27 mmol) in small portions at 0 0 C. The mixture was stirred at RT overnight and quenched with slow addition of water (1 mL), 1 N NaOH (3 mL) and water (1 mL). The grey suspension was filtered and the filtrate was dried (Na 2 SO.ι), filtered and concentrated under reduced pressure to yield compound 5C (2.79 g, 100%, LCMS m/z 208, MH+) as a white solid.

Step 5

5C 5D

To a stirred solution of 5C (2.79 g, 13.5 mmol) in DCM (25 mL) was added BBr 3 (1M DCM solution, 32.5 mL) at 0 0 C. The bright yellow solution was stirred at this temperature for 3 h and quenched with addition of sat. NaHCO 3 until pH reached 7. The mixture was concentrated under reduced pressure to give an off-white solid. To a solution of the crude phenol in dioxane-H 2 O (1 :1 , 25 mL) was added BoC 2 O (5.9 g, 27 mmol) and NaHCθ 3 (1.7 g, 20.25 mmol). The mixture was stirred overnight, acidified with 1 N HCI, and extracted with EtOAc (4 x 60 mL). The combined organic layers were washed with brine (10 mL), dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (50% EtOAc/Hexanes) to give compound 5D as pale yellow oil (2.555 g, 64%, LCMS m/z 294, MH+).

Step 6

To a solution of 5D (30 mg, 0.102 mmol) in DCM (1 mL) was added phenylboronic acid (37.3 mg, 0.306 mmol), TEA (0.071 mL, 0.51 mmol), 4 A molecular sieves (20 mg), and Cu(OAc) 2 (18.5 mg, 0.102 mmol). The dark green suspension was stirred at RT overnight and concentrated under reduced pressure. The residue was purified by column chromatography (20% EtOAc/Hexanes) to give compound 5E as a white solid (30.2 mg, 80%).

Steps 7-8

5E (±)-5 To a solution of 5E (30.1 mg, 0.0816 mmol) in DCM (1 mL) was added TFA

(0.5 mL). After being stirred for 1 h, the mixture was concentrated under reduced pressure and used for next step. The crude material was suspended in DCM (0.6 mL) followed by addition of BrCN (3 M in DCM, 0.033 ml_, 0.098 mmol). The mixture was stirred at RT for 3 h and purified by HPLC (0-50% CH 3 CN/H 2 O) to give compound (±)- 5 as a white solid (6.4 mg, 27%, LCMS m/z 295 MH+) and recovered 5E (15 mg,

The following compound was synthesized in a manner analogous to that described above:

PREPARATIVE EXAMPLE 6

Based on a literature procedure (J. Med. Chem. 2007, 50, 1958), a mixture of compound 3D (28 mg, 0.10 mmol), zinc cyanide (35 mg, 0.30 mmol), zinc dust (19 mg, 0.30 mmol), and Pd(dppf)CI 2 (20 mg, 0.024 mmol) in DMF (3 mL) was heated at 120 0 C overnight. The mixture was cooled, diluted with water (10 mL) and extracted with DCM (3x). The combined organic layers were washed with brine, dried over Na 2 SO 4 , and concentrated. Chromatography (0-10% NH 3 -MeOH in DCM) provided (±)-6 (16 mg, 71%, LCMS m/z 230 MH+).

PREPARATIVE EXAMPLE 7

CuI, MeCONH 2 A mixture of compound 3D (30 mg, 0.11 mmol), acetamide (32 mg, 0.53 mmol), N,N'-Dimethyl-(1R,2R)-cyclohexanediamine (27 μl_, 0.17 mmol), K 3 PO 4 (135 mg, 0.64 mmol) and CuI (24 mg, 0.13 mmol) in DMF (3.2 mL) was heated at 100 0 C overnight in a sealed tube. The mixture was cooled, diluted with water (10 mL) and extracted with DCM (3x). The combined organic layers were washed with brine, dried over Na 2 SO 4 , and concentrated. Chromatography (0-10% NH 3 -MeOH in DCM) provided (±)-7. LCMS m/z 262 (MH+).

Compound (±)-7A was synthesized in a similar manner by the following procedure:

To a solution of 1E (60 mg, 0.214 mmol) and acetamide (18.9 mg, 0.32 mmol) in DMF (2 mL) was added CuI (49 mg, 0.256 mmol), N,N'-Dimethyl-(1 R,2R)- cyclohexanediamine (0.051 mL, 0.32 mmol), and K 3 PO 4 (54.3 mg, 0.256 mmol) in a sealed tube. The mixture was heated at 100 0 C for 12 h and treated with water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic phase was dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure. The residue was purified by prep TLC (10% MeOH/methylene chloride) to give compound (±)-7A as a pale yellow solid (9.6 mg, 35%). LCMS m/z 260 (MH+).

PREPARATIVE EXAMPLE 8

To a solution of compound 1E (45 mg, 0.16 mmol) in DMF (1 mL) in a sealed tube was added copper (I) cyanide (28.7 mg, 0.32 mmol) in one portion. The mixture was heated at 150 0 C for 24 h before it was cooled to RT. The mixture was treated with EtOAc and filtered through a pad of celite. After concentration, the residue was purified by prep-HPLC to give the title compound (±)-8 as a clear glass (6 mg, 17%). LCMS m/z 228 (MH+).

PREPARATIVE EXAMPLE 9

Step i

9A 9B

In a manner similar to that described previously (Example 1, Steps 1-4), 5- bromo-2-tetralone was converted into the amino alcohol 9B . Step 2

9B 9C

To a stirred solution of 9B (380 mg, 1.48 mmol) in THF (7 mL) was added EtOCONCS (0.168 g, 1.48 mmol) at RT. The mixture was stirred at RT for 1 h and concentrated under reduced pressure. The residue was dissolved in EtOH (10 mL) and Hg(OAc) 2 (471.6 mg, 1.48 mmol) was added. After 1 h, the mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (60% EtOAc/Hexanes) to yield compound (±)-9C (339 mg, 65%, LCMS m/z 353/355, MH+) as a white solid. Steps 3-4

To a stirred solution of (±)-9C (305 mg, 0.864 mmol) in THF (4 mL) was added n-BuLi (2.9M solution in hexanes, 0.745 mL, 2.16 mmol) at -78 0 C. The light yellow solution was stirred at this temperature for 15 min and followed with addition of dry ice. The white suspension was stirred at this temperature for 30 min before warming to RT. The mixture was quenched with the addition of sat. NH 4 CI and extracted with EtOAc. The combined organic layers were washed with brine (10 mL), dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by prep TLC (5% MeOH/CH 2 CI 2 ) to give compound (±)-9D as a white solid (70.1 mg, 26%, LCMS m/z 319, MH+).

To a mixture of the crude (±)-9D in MeOH/water (1 :1) was added LiOH (10 eq). The mixture was refluxed for 2 hr and concentrated to remove most of MeOH. The mixture was extracted with EtOAc (20 mL), dried, and concentrated under reduced pressure. The crude product was purified by prep HPLC to give compound (±)-9 as a white solid. LCMS m/z 347, MH+

In a similar manner to that described above, compound (±)-9C was treated with nBuLi and then quenched with CICO 2 Me to provide (±)-9E, which was then selectively deprotected with LiOH to afford (±)-9F. LCMS m/z 261 (MH+)

PREPARATIVE EXAMPLE 10

To a solution of (±)-9 (7 mg, 0.022 mmol) in DMF (20 mL) was added HATU (12.6 mg, 0.033 mmol) and MeNH 2 (2 M in THF, 0.022 mL, 0.044 mmol). The solution was stirred at RT overnight and worked up with EtOAcZH 2 O. The organic layers were dried and concentrated under reduced pressure. The residue was purified by column chromatography (80% EtOAc/Hexanes) to give compound (±)-10A as a white solid (6.5 mg, 93%).

In a manner similar to that described in Example 9, (±)-10A was deprotected with LiOH to give (±)-10 as a white solid. LCMS m/z 260 (MH+).

The following compounds were synthesized from (±)-9 in a similar manner as described above:

PREPARATIVE EXAMPLE 11

Step i

(±)-9C (±)-11A

In a similar manner to that described in Example 9 (Step 3), compound (±)-9C was treated with nBuLi and then quenched with DMF to provide (±)-11A. LCMS m/z 303 (MH+)

Steps 2-3

To a solution of (±)-11A (32 mg, 0.106 mmol) in EtOH (2 mL) was added hydroxylamine (50% solution in water, 0.026 mL, 0.424 mmol) at RT. The mixture changed to white suspension after 2 hr and was concentrated under reduce pressure. The white solid was hydrolyzed with LiOH in a manner similar to that described in Example 9 to give compound (±)-11 as a white solid (11.6 mg, 46%). LCMS m/z 246 (MH+). In a similar manner, compound (±)-11A was treated with methoxyamine and then deprotected to provide (±)-11 B. (LCMS m/z 260, MH+).

PREPARATIVE EXAMPLE 12

In a manner similar to that previously described, compound (±)-12 (LCMS m/z

281/283, MH+) was synthesized from 6-bromo-2-tetralone.

Compound (±)-12A was synthesized from (±)-12 by the following procedure:

(±)-12 <±)-12A

To a solution of (±)-12 (100 mg, 0.36 mmol) in DMF (10 mL) was added Zn(CN) 2 (125 mg, 1.07 mmol), Zn powder (70 mg, 1.07 mmol), and 1 ,1'- Bis(diphenylphosphino)ferrocene (73 mg, 0.09 mmol). The reaction mixture was stirred in a sealed tube at 120 0 C for 12 h. Then the reaction mixture was diluted with H 2 O and the organic layer was extracted multiple times with CH 2 CI 2 . The combined organic layers were dried (MgSO 4 ), filtered, and concentrated under reduced pressure. The residue was purified by Prep TLC (10% 7N NH 3 in MeOH / CH 2 CI 2 ) to give the desired product (±)-12A (18 mg, 22%). LCMS m/z 228 (MH+) Compound (±)-12C was synthesized from (±)-12 by the following procedure:

(±)-12 (±)-12B (±)-12C

To a solution of (±)-12 (300 mg, 1.07 mmol) in DMF (30 ml.) was added ethylamine (3.0M in THF, 2.14 mL, 6.43 mmol), K 3 PO 4 (680 mg, 3.21 mmol), CuI (203 mg, 1.07 mmol), and 2-acetyl-1 -cyclohexanone (243 mg, 1.71 mmol). The reaction mixture was stirred in a sealed tube at 100 0 C for 12 h. Then the reaction mixture was diluted H 2 O and the organic layer was extracted with CH 2 CI 2 . The organic layer was washed with H 2 O three times, then dried (MgSO 4 ), filtered, and concentrated under reduced pressure. The residue was purified by Prep TLC (6% 7N NH 3 in MeOH / CH 2 CI 2 ) to give the desired product (±)-12B (30 mg, 9%).

To a solution of the aniline (±)-12B (21 mg, 0.086 mmol) in DCM (3 mL) was added MeNCO (15 mg, 0.257 mmol). The mixture was stirred at RT for 30 min. MeOH (1 mL) was added and the mixture was concentrated under reduced pressure. The residue was purified by Prep TLC (10% 7N NH 3 in MeOH / CH 2 CI 2 ) to give the desired product (±)-12C (5 mg). LCMS m/z 303 (MH+)

Compound (±)-12D was synthesized from (±)-12 by the following procedure:

(±)-12 (±)-12D

To a solution of (±)-12 (300 mg, 1.07 mmol) in DMF (30 mL) was added acetamide (189 mg, 5.34 mmol), K 3 PO 4 (1.36 g, 6.41 mmol), CuI (244 mg, 1.28 mmol), and (1 R,2R)-N1 ,N2-dimethylcyclohexane-1 ,2-diamine (243 mg, 1.71 mmol). The reaction mixture was stirred in a sealed tube at 100 0 C for 12 h. Then the reaction mixture was diluted H 2 O and the organic layer was extracted with CH 2 CI 2 . The organic layer was washed with H O three times, then dried (MgSO 4 ), filtered, and concentrated under reduced pressure. The residue was purified by Prep TLC (10% 7N NH 3 in MeOH / CH 2 CI 2 ) to give (±)-12D (14 mg, 5%). LCMS m/z 260 (MH+)

Compound (±)-12E was synthesized from (±)-12B by the following procedure:

(±)-12B (±)-12E

To a solution of 12B (15 mg, 0.06 mmol) in CH 2 CI 2 was added DIPEA (30 μL, 0.18 mmol) and Ac 2 O (12 μL, 0.12 mmol). The reaction mixture was stirred at RT until the starting material was consumed and then was quenched with NaHCO 3 (sat). The mixture was extracted with CH 2 CI 2 . The organic extracts were then dried (MgSO 4 ), filtered, and concentrated under reduced pressure. The residue was purified by Prep TLC (10% 7N NH 3 in MeOH / CH 2 CI 2 ) to give the desired product (±)-12E (13 mg, 65%). LCMS m/z 330 (MH+).

Alternatively, (±)-12 is protected (e.g. with CBzCI), reacted in the coupling reactions described above and then deprotected (e.g. Pd-C, H 2 ) to provide the final compounds. PREPARATIVE EXAMPLE 13

HEWBr,

13A 13B Steps 1-2

In a manner similar to that described in Example 1 (Step 1), 2-indanone was treated with (NH 4 ^COa and KCN to provide hydantoin 13A. The hydantoin was subjected to bromination (HBr/Br 2 ) as described in WO2004/082602 to provide 13B. Steps 3-6

In a manner similar to that described in Example 1 (Steps 2-4), compound 13B was sequentially treated with LiOH, SOCI 2 -MeOH, and NaBH 4 to provide 13C. In a manner similar to that described in Example 3, compound 13C was cyclized with cyanogen bromide to provide (±)-13.

The following compounds are prepared from (±)-13 in a manner similar to that previously described:

(±)-13D (±)-13E (±)-13F

(±)-13M (±)-13N (±)-130

(±)-13P PREPARATIVE EXAMPLE 14

14A 14B

14C (±)-14

Compound (±)-14 was prepared from 7-bromo-2-tetralone in a manner similar to that described in Example 1 : hydantoin formation with (NhU) 2 CCVKCN, hydrolysis with LiOH, methyl ester formation with SOCI 2 /Me0H, reduction with NaBH 4 , cyclization with benzoyl isothiocyanate, and hydrolysis with LiOH to provide (±)-14 (LCMS m/z 281/283, MH+).

14E 14G

The racemic mixture (±)-14B was separated on a preperative Chiralpak AD column (SFC Chromatography with 20% MeOH-0.2% DEA) to provide the pure enantiomers 14D and 14E (> 99% ee), which were separately advanced to provide compound 14F (LCMS m/z 281/283, MH+) and compound 14G (LCMS m/z 281/283, MH+). Alternatively, compound 14E is prepared as described in Example 15.

PREPARATIVE EXAMPLE 15

14E Step i

15A 15B

LDA 2.0 M (0.62 ml_, 1.14 mmol) was dropwise added to a solution of sulfoxide 15A (J. Org. Chem. 1989, 54, 3130; 0.197 g, 1.039 mmol) in dry THF (4 mL) at -75 0 C under nitrogen. The mixture was stirred for 10 min and a solution of 7-bromo-2- tetrolone (242 mg, 1.044 mmol) in dry THF (2 mL) was added dropwise over a period of 3 min. The resulting mixture was stirred for 30 min at -75 "C and then TFA was added (0.40 mL). The mixture was warmed to RT, diluted with water, and extracted with DCM. The combined organic phase was dried and the solvent removed in vacuo to give an orange oil. Et 2 O was added and the title compound 15B precipitated as a white solid (205 mg, 47%, 3:1 mixture of diastereomers).

Step 2

15B 15C

KOtBu (39 mg, 0.35 mmol) was added to a solution of a mixture of diastereomeric alcohols 15B (120 mg, 0.29 mmol) in a 1:1 mixture of dry tBuOH and dry THF (20 mL) at RT. The resulting mixture was stirred for 1.5 h and KOtBu (13 mg, 0.12 mmol) was added. The mixture was stirred for another 30 min and the solvent evaporated. Water was added and the mixture was extracted with DCM. The combined organic phase was dried and the solvent removed in vacuo to give an orange oil which was purified by column chromatography (AcOEt: hexanes 1 % to 100%) to afford major epoxide 15C (104 mg, 95% considering isolation of 16 mg of minor epoxide). Step 3

15C 15D

Diphenylamino methane (0.185 ml_, 1.06 mmol) was added to a solution of epoxide 15C (80 mg, 0.212 mmol) in IPA (3 mL) at RT. The resulting mixture was heated at 90 0 C for 17 h then cooled at RT. The solvent was evaporated and the residue was purified by column chromatography (AcOEt hexanes 1% to 10%) to afford the title compound 15D (38 mg, 43%) as a pale brown glass. Step 4

15D 15E

A solution of KOH (136 mg, 2.17 mmol) in dry MeOH (2 mL) was added to a solution of iodine (242 mg, 0.95 mmol) in dry MeOH (2 mL) and stirred for 10 min. The resulting mixture was added to a solution of aldehyde 15D (57 mg, 0.136 mmol) in MeOH (3 mL). The mixture was stirred for 25 min, quenched with aq sat Na 2 S 2 Os and extracted with DCM. The combined organic phase was dried and the solvent evaporated in vacuo to give a brown glass that was purified by column chromatography (AcOEt: hexanes 1 % to 10%) to afford the title compound 15E (37 mg, 61%) as a colorless glass. Step 5

15E 14E

A solution of benzhydryl-protected aminoester 15E (37 mg, 0.082 mmol) in tπfluoroacetic acid (3 mL) was heated in a 15 mL sealed tube at 90 0 C for 1 h and 20 min. The mixture was cooled to RT 1 the solvent was removed and the residue quenched with NH 3 in MeOH solution (0.4 N). The solvent was evaporated and the residue was purified by column chromatography (AcOEt: hexanes 1 % to 100%) to afford the title compound 14E (23 mg, 100%) as a pale brown glass.

PREPARATIVE EXAMPLE 16

In a manner similar to that described in Example 1 (Step 1), 5-methoxy-2- tetralone was treated with ammonium carbonate and KCN.

A solution of the resulting hydantoin (7.02 g, 28.5 mmol) in DMF (80 mL) was treated with NBS (5.58g, 31.4 mmol) at RT. The mixture was stirred for 30 min and poured into water (200 mL). The slurry was filtered and washed with water. The beige solid was dried in air to give 16A (quantitative yield). Compound 16A was converted into (±)-16B using procedures described in Example 1.

In a manner similar to that described in Examples 1 and 3, compound (±)-16B is then subjected to coupling with Cul/EtNH 2 , reaction with CICO 2 Me, and deprotection with LiOH to provide the title compound (±)-16.

PREPARATIVE EXAMPLE 17

Compound 5A was brominated (as described in Example 16) to provide 17A, which was further advanced to compound 17C in a manner similar to that previously described.

To a stirred solution of 17C (1.53 g, 5.33 mmol) in THF (20 ml.) was added EtOCONCS (0.7 g, 5.33 mmol). The mixture was stirred at RT for 2 h and concentrated under reduced pressure. The residue was dissolved in EtOH (40 mL) and then treated with Hg(OAc) 2 (1.698 g, 5.33 mmol) in one portion. After stirred for 2 h, the dark suspension was filtered through a pad of celite and concentrated under reduced pressure. The crude material was purified by column chromatography (55% hexanes/EtOAc) and then Chiralpak AD HPLC (12% IPA/hexanes) to give compound 17D (LCMS m/z 383/385, MH+) and 17E (LCMS m/z 383/385, MH+) as white solid (total 1.02 g, 50%).

Compound 17D and 17E are then individually converted to 17 and 17F in a manner similar to that previously described.

PREPARATIVE EXAMPLE 18

In a manner similar to that described previously (Example 1), 5-bromo-2- tetralone was converted into the amino ester (±)-18A. The racemic mixture was then separated on a preperative Chiralpak OD column (30% EtOH-hexanes with 0.2% DEA) to provide the pure enantiomers 18B and 18C (> 95% ee).

Alternatively, 18B and 18C were synthesized by an asymmetric approach outlined below: Step i

A mixture of 5-bromo-2-tetralone (2.0 g, 8.89 mmol), (R)-phenylglycinol (1.22 g, 8.89 mmol, 1.0 eq), and 4A molecular sieves in CHCI 3 (50 ml_) was refluxed until the starting material disappeared (monitored by 1 H NMR). After filtering the molecular sieves the solvent was removed under reduced pressure, the residual oil 18D was used for the next step without further purification.

Step 2

18D 18E

To a solution of 18D in 10 mL CH 2 CI 2 at 0 0 C was added TMSCN (1.67 ml_, 13.34 mmol, 1.5 eq) followed by MeOH (3.5 mL). The cooling bath was removed and the reaction mixture was stirred at RT for 24 h. The solution was concentrated at reduced pressure and the residue 18E was used for the next step without any purification. Step 3

The oily residue 18E was dissolved in 10 mL MeOH and cooled in an ice-water bath. Anhydrous HCI (g) was bubbled through the solution until saturation. After stirring for 1 h, the MeOH was evaporated and the residue was diluted with 100 mL of EtOAc. The organic layer was washed with 10% aq NaHCθ 3 , brine and dried over Na 2 SO 4 . After removal of the solvent, the amino ester was purified by SFC chromatography to yield 18F (1.75 g) and 18G (0.43 g). Step 4

18F 18C

To a solution of 18F (330 mg, 0.82 mmol) in DCM (3.5 mL) and MeOH (1.8 mL) was added lead tetraacetate (362 mg, 0.82 mmol, 1.0 eq) at 0 0 C. After the resultant mixture was stirred for 30 min, 10 mL of phosphate buffer (pH 7) was added to quench the reaction. The mixture was filtered through celite, and the organic layer was separated, washed with water, and concentrated to dryness. The residual oil was purified by flash chromatography (1% MeOH/CH 2 CI 2 ) to yield 111 mg of the R- amino ester 18C.

In a manner similar to that described previously, the individual enantiomers 18B and 18C are converted to the following compounds:

PREPARATIVE EXAMPLE 19

Step i

KCN

19A

To a solution of 8-methoxy-2-tetralone (600 mg, 3.4 mmol) in EtOH-H 2 O (1 :1 , 12 mL) in a sealed tube was added ammonium carbonate (2.28 g, 23.8 mmol) and KCN (420 mg, 6.8 mmol) in one portion. The mixture was heated at 80 0 C for 12 h before it was cooled to RT Water (20 mL) was added to precipitate the product 19A The light grey solid was collected by filtration and washed with water and dried in air (835 mg, 100%, LCMS m/z 247, MH+). Steps 2-3

19A 19B

A suspension of 19A (200 mg, 0.813 mmol) and Ba(OH) 2 (460 mg, 3.25 mmol) in water (2 mL) was heated in a sealed tube at 120 0 C for 36 h. The mixture was acidified with 6 N H 2 SO 4 , and filtered and the filter pad was washed with MeOH repeatedly. The combined filtrate was concentrated under reduced pressure to yield the amino acid as an off-white solid. The crude product was added to a mixture of SOCI 2 (145 mg, 1.219 mmol) and MeOH (10 mL). The mixture was stirred at reflux for 3 h, cooled to RTand concentrated under reduced pressure. The methyl ester HCI salt was suspended in EtOAc (20 mL) and neutralized with sat. NaHCO 3 . The aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (80% EtOAc/Hexanes) to give 19B as a pale yellow oil (105 mg, 55%, LCMS m/z 236, MH+).

Step 4

19B 19C To a stirred solution of 19B (3.17 g, 13.5 mmol) in THF (50 mL) was added

LiAIH 4 (1.02 g, 27 mmol) in small portions at 0 0 C. The mixture was stirred at RT overnight and quenched with slow addition of water (1 mL), 1 N NaOH (3 mL) and water (1 mL). The grey suspension was filtered and the filtrate was dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to yield compound 19C (2.79 g, 100%, LCMS m/z 208, MH+) as a white solid. Step 5

19C 19D

In a manner similar to that described in Example 5 (Step 5), compound 19C was treated with BoC 2 O. To a solution of the resulting product (1.767 g, 5.756 mmol) in CH 2 CI 2 (30 mL) was added Dess-Martin periodinate (3.66 g, 8.634 mmol) at RT. The mixture was stirred for 1 h and quenched with addition of NaS 2 Os solution (1 M, 20 mL). The organic layer was separated and washed with saturated NaHCθ3 solution and brine. The organic phase was dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (15% EtOA/hexanes) to give aldehyde 19D as a white solid (1.637 g, 95%).

Step 6

19D 19E

To a solution of compound 19D (1.673 g, 5.485 mmol) in CH 2 CI 2 (30 mL) was added MeMgBr (3 M solution in THF, 4.2 mL, 12.6 mmol) at -78 0 C. The mixture was stirred at this temperature for 1 h and quenched with addition of saturated NH 4 CI solution (20 mL) and EtOAc (80 mL). The organic layer was separated, washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure. The crude material (white solid, 1.756 g, 97%) was deprotected with TFA in a manner similar to that described in Example 5 (Step 7) to provide 19E.

Step 7

In a manner similar to that previously described in Examples 9 and 16, compound 19E was cyclized and brominated to provide 19G.

In a manner similar to that previously described (e.g. Example 2), compound 19G is converted to the title compound to provide (±)-19.

PREPARATIVE EXAMPLE 20

Steps 1-3

A mixture of 5-bromotetralone (5.5 g, 24.4 mmol) and pyrrolidine (2.6 g, 36.6 mmol) in toluene (100 mL) was heated at reflux with a Dean Stark trap for 48 h. The reaction was then concentrated to give 2OA as a dark foam. LCMS m/z 278/280 (MH+).

The enamine 2OA was dissolved in 100 mL of 1 ,4-dioxane, tread with 15 mL of MeI and heated at reflux overnight. The reaction was cooled down in an ice bath and then treated with 40 mL H 2 O and 1.5 mL AcOH. After heating at reflux for 3 h, the reaction was concentrated and chromatographed (5% to 15% ether/hexanes) to give a light yellow oil 2OB (2.85g, 49% for 2 steps). Steps 4-10

In a manner similar to that described in Example 1 , compound 2OB was advanced to (±)-20D (LCMS m/z 295/297, MH+).

In a manner similar to that previously described, (±)-20D is converted to the title compound (±)-20.

PREPARATIVE EXAMPLE 21

In a manner similar to that described in Example 1 , 18A was reduced with NaBD 4 and then cyclized with PhC(O)NCS. Chiral separation (OD Column, 25% EtOH-hexanes) and hydrolysis with LiOH provided the S-enantiomer 21 C. LCMS m/z 283/285 (MH+). Compound 21 C is then converted to 21 as previously described.

Likewise, the fi-enantiomer 21 D was also synthesized. LCMS m/z 283/285 (MH+). Compound 21 D is then converted to 21 E as previously described.

PREPARATIVE EXAMPLE 22

A solution of compound 18A (0.92 g, 3.24 mmol) in THF (15 mL) was treated slowly with MeMgBr (6 mL of a 3.0M solution/Et 2 0) and then stirred overnight at RT. The reaction was cooled in an ice bath, quenched with sat. aq. NH 4 CI, and stirred for 30 min. The mixture was then treated with 1.0 M NaOH (~10 mL) and then extracted with DCM (3x), dried over Na 2 SO 4 , and concentrated to give 22A as a brown foam (0.92g).

In a manner similar to that described in Example 17, 22A was cyclized with PhC(O)NCS/Hg(OAc) 2 , and hydrolyzed to provide (±)-22C. LCMS m/z 309/311 (MH+).

Compound (±)-22C is converted to (±)-22 as previously described.

PREPARATIVE EXAMPLE 23

Steps 1-5

8-Bromochroman-3-one 23B was prepared from 2-bromophenol in a manner similar to that described in the literature (J. Med. Chem., 1988, 689):

Reaction of 2-bromophenol with paraformadehyde (MgCfe, NEt 3 , THF, 75 0 C, 4h), followed by treatment with acrylonitrile (neat, Dabco, 95 0 C, 18h),and hydrolysis with 10% NaOH (100 0 C, 4h) afforded 23A. Compound 23A was reacted with DPPA (NEt 3 , toluene, 110 0 C, 2h) followed by treatment with 6N HCI (85 0 C, 2h) to afford 8- bromochroman-3-one 23B.

Steps 6-11

Compound 23D was prepared from 23B in a manner similar to that described in Example 1 : hydantoin formation with (NH 4 J 2 CO 3 ZKCN, hydrolysis with LiOH, methyl ester formation with SOC^/MeOH, and reduction with NaBH 4 . The reaction of compound 23D with cyanogen bromide provided 23E (THF, RT, 3h).

The title compound (±)-23 is prepared from 23E in a manner similar to that previously described. PREPARATIVE EXAMPLE 24

Step i

24A

A solution of 5-bromo-2-tetralone (1.5 g, 6.66 mmol) in a 1:1 mixture of EtOH/H 2 O (50 mL) was treated with KCN (1.3 g, 19.99 mmol, 3.0 eq) and NH 4 CI (1.78 g, 33.3 mmol, 5.0 eq). The reaction mixture was heated to 60 0 C for 16 h after which it cooled to RT. Saturated NaHCO 3 (40 mL) was added and extracted with CH 2 CI 2 (3 x 50 mL). The combined organic layer was dried over Na 2 SO 4 , filtered, and concentrated to yield crude 24A which was carried to the next step without purification.

Step 2

A solution of the crude amino nitrile 24A in HCO 2 H (20 mL) was cooled to 0 0 C and saturated with anhydrous HCI (g). After 10 min, the excess formic acid was evaporated and the residue was taken up in acetone (25 mL). Filtration of the white solid afforded compound 24B (1.25 g). Steps 3-4

24B (±)-24C

To a suspension of compound 24B (500 mg, 1.86 mmol) in CH 2 CI 2 (10 ml.) was added Et 3 N (0.52 mL, 3.72 mmol, 2.0 eq). Acetyl chloride (0.16 mL, 2.23 mmol, 1.2 eq) was slowly added and the reaction was left to stir at RT overnight. After the reaction was complete, aq. NaHCC> 3 (15 mL) was added. Extraction with CH 2 CI 2 (2 x 20 mL), drying over Na 2 SO 4 , and evaporation under reduced pressure gave a crude mixture which was purified by flash chromatography using a gradient of DCM/MeOH (98/2) to yield (+)-24C (525 mg). LCMS m/z 293/295 (MH+).

Compound (±)-24C is converted into (±)-24 in a manner similar to that described in Example 12.

PREPARATIVE EXAMPLE 25

A solution of 24B (100 mg, 0.37 mmol) and trimethyl orthoformate (0.049 mL, 0.44 mmol, 1.2 eq) in 1 mL DMF was microwaved at 140 0 C for 40 min. Upon cooling, H 2 O (5 mL) was added and the mixture was extracted with EtOAc (2 x 10 mL), dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography by eluting with 2-4% MeOH/ CH 2 CI 2 to yield 30 mg of compound (±)-25. LCMS m/z 279/281 (MH+).

In a manner similar to that described in Example 2, (±)-25 is converted to (±)- 25A.

PREPARATIVE EXAMPLE 26

In a manner similar to that described in Example 6, compound 23E is treated with zinc cyanide, zinc dust, and Pd(dppf)Cl 2 in DMF and was heated at 120 0 C overnight to provide (±)-26.

PREPARATIVE EXAMPLE 27

14C 27A 27B

(±)-14

In a manner similar to that previously described, a solution of compound 14C is treated with EtOC(O)NCS (1.2 eq) in THF, stirred for 3h at RT, and then concentrated to provide 27 A.

Crude compound 27A is taken up in CH 3 CN, cooled in an ice bath, and treated with 2-chloro-3-ethylbenzoxazolium tetrafluoroborate (1.2 eq) portionwise. The reaction is stirred for 1.5h and then sequentially quenched with TEA and water. The mixture is extracted with DCM (2x) and concentrated to provide 27B.

Compound 27B is then deprotected with LiOH in a manner similar to that previously described to provide (±)-14.

PREPARATIVE EXAMPLE 28

Step i

28A 28B

A 3-neck round bottom flask fitted with a condenser was charged with AICb (41.6 g, 0.31 mol) and then heated to 75 0 C. 1-Benzosuberone (20 g, 0.13 mol) was added dropwise to the hot AICI 3 . To the resulting brown slurry was added Br 2 (24 g, 0.15 mol) dropwise. The reaction mixture was stirred for 5 min before it was cooled to 0 0 C. The reaction mixture was quenched with ice chips. Concentrated HCI was added slowing with stirring to get the mixture into solution. The mixture was diluted with H 2 O and extracted the organic layer with Et20 (2X). The combined organic layers were dried (MgSO 4 ), filtered and concentrated under reduced pressure to give a mixture of 6- bromocyclohepta-1-one 28A and 8- bromocyclohepta-1-one 28B (in a 1:2 ratio)

Step 2

To a 1 :2 mixture of 28A and 28B in MeOH (20 mL) and THF (40 mL) was added NaBH 4 at 0 0 C. The reaction mixture was stirred at RT for 1 h, neutralized with 1 N HCI, diluted with H 2 O and extracted the organic layer with Et 2 O. The combined organic layers were dried (MgSO 4 ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (5-10% EtOAc/Hexanes) to give i-hydroxy-δ-bromo-benzocycloheptane 37C (9.1 g) and 1-hydroxy-6-bromo- benzocycloheptane 28D (19.7 g). Step 3

28C 28E

To a solution of 28C (4.4 g, 0.02 mol) in toluene (50 mL) was added molecular sieves and p-toluenesulfonic acid monohydrate (347 mg, 1.82 mmol). The reaction mixture was refluxed for 3 h, cooled to RT, quenched with sat. NaHCO 3 solution and extracted with CH 2 CI 2 (2X). The combined organic layers were dried (MgSO 4 ), filtered and concentrated under reduced pressure to give the alkene 28E (used directly in next step).

Step 4

28E 28F

To a solution of 28E in toluene (50 mL) was added mCPBA (4.4 g, 0.03 mol) in

3 portions. The reaction mixture was stirred at RT for 1 h, quenched with aq sodium sulfite (10%), extracted with CH 2 CI 2 . The organic layer was washed with 1 N NaOH, dried (MgSO 4 ), filtered and concentrated under reduced pressureto give the epoxide 28F (used directly in next step). Step 5

28F 28G

To a solution of 28F in toluene (50 mL) was added ZnI 2 (7.31 g, 0.02 mol) at 0 0 C. The reaction mixture was stirred at RT for 1.5 h, diluted with H 2 O. The mixture was extracted with CH 2 CI 2 . The combined organic layer was dried (MgSO 4 ), filtered and concentrated under reduced pressure. Flash chromatography (EtOAc/Hexanes, 1 :9) afforded the desired product 28G (2.3 g, 53%).

Steps 6-10

28G (±)-28H

In a manner similar to that described previously (e.g. Example 1), compound 28G was subjected to the following sequence: hydantoin formation with (NH 4 ) 2 Cθ3/KCN, hydrolysis with LiOH, methyl ester formation with SOCI 2 /MeOH, reduction with NaBH 4 , and cyclization with BrCN to provide (±)-28H (LCMS m/z 295/297, MH+).

Compound (±)-28H is converted into the title compound (±)-28 in a manner similar to that descrived in Example 12.

Compounds 28I and (±)-28K (LCMS m/z 295/297, MH+) were synthesized from 28D in a similar manner.

Compound (±)-28K is converted to the title compound (±)-28L in a manner similar to that described in Example 12.

PREPARATIVE EXAMPLE 29

Step

29A 29B

In a sealed tube 5-bromo-2-tetralone (2.00 g, 8.88 mmol) was dissolved in EtOH (40.0 ml_, 685 mmol) and water (33.0 ml_, 1830 mmol). KCN (1.157 g, 17.77 mmol) followed by NH 4 CI (1.901 g, 35.54 mmol) were added. The reaction was heated to 60 0 C and stirred overnight. The mixture was diluted with DCM and sat. NaHCU3. The biphasic solution was separated and the aqueous layer was extracted with DCM in three portions. The combined organic phase was dried over anhydrous sodium sulfate and concentrated to dryness to provide 29A (2.3 g, 100%).

A solution of 29A (2.20 g, 8.76 mmol) in THF (20.0 ml_, 246 mmol) was treated with LAH (2.0 M/THF, 6.57 mL) and stirred at RT for 30 min. The reaction was cooled in an ice/water bath and slowly quenched with water (dropwise) followed by 10% NaOH. The mixture was warmed to RT and stirred for 3 h. The material was filtered through celite, washed with a solution of 1 :1 MeOH/DCM in three portions and concentrated to dryness to provide 29B (2.14 g, 96%). Steps 3-4

29B (±)-29C

A mixture of 29B (200 mg, 0.78 mmol) and formamidine acetate (106 mg, 1.02 mmol) in EtOH (10 ml_, 171 mmol) under Ar was stirred for 1 h at RT. The mixture was diluted with DCM and sat. sodium bicarbonate. The biphasic solution was separated and the aqueous layer was extracted with DCM in three portions. The combined organic phase was dried over anhydrous sodium sulfate and concentrated to provide (±)-29C (201 mg, 97%). LCMS m/z 265/267 (MH+).

Compound (±)-29C is converted to the title compound (±)-29 in a manner similar to that described in Example 12. Steps 5-6

Alternatively, compound 29B was synthesized from 18A by the following two- step procedure:

A solution of 18A (190 mg, 0.67 mmol) in NH 3 -MeOH (7N, 12 ml.) was heated to 105 C C overnight in a sealed tube. The reaction mixture was concentrated to provide 29D (191 mg, 106%).

A solution of compound 29D (180 mg, 0.67 mmol) in THF (10 ml_) in a sealed tube was treated slowly with BH 3 -SMe 2 (2M/THF, 1 ml_). The reaction mixture was heated to 105 0 C for 2 h, then cooled to 0 0 C in an ice/water bath and quenched with EtOH followed by K 2 CO 3 . The mixture was warmed to RT and stirred for 2 h. The material was filtered through celite, washed with EtOH in three portions and concentrated. The crude mixture was diluted with DCM and sat. sodium bicarbonate. The biphasic solution was separated and the aqueous layer was extracted with DCM in three portions. The combined organic phase was dried over anhydrous sodium sulfate and concentrated to provide 29B (161 mg, 94%). PREPARATIVE EXAMPLE 30

29B (±)-30A (+)-30

A solution of 29B (20O.mg, 0.78 mmol) in THF (10 ml.) was treated with diphenyl cyanocarbonimidate (280 mg, 1.18 mmol) and then heated to 85 0 C for 1 h..

The mixture was diluted with DCM and sat. sodium bicarbonate. The biphasic solution was separated and the aqueous layer was extracted with DCM in three portions. The combined organic phase was dried over anhydrous sodium sulfate and concentrated to provide (±)-30A (228 mg, 95%). LCMS m/z 305/307 (MH+).

Compound (±)-30A is converted to the title compound (±)-30 in a manner similar to that described in Example 12.

PREPARATIVE EXAMPLE 31

29B (±)-31A (±)-31

A solution of 29B (200 mg, 0.78 mmol) in THF (10 mL) was treated with BrCN (5M/MeCN, 204 uL) and then stirred at RT for 1 h. The mixture was diluted with DCM and sat. sodium bicarbonate. The biphasic solution was separated and the aqueous layer was extracted with DCM in three portions. The combined organic phase was dried over anhydrous sodium sulfate and concentrated to provide (±)-31A (224 mg, 100%). LCMS m/z 280/282 (MH+).

Compound (±)-31A is converted to the title compound (±)-30 in a manner similar to that described in Example 12. PREPARATIVE EXAMPLE 32

29B (±)-32A (±)-32

In a manner similar to that described in Example 29, compound 29B was reacted with acetamidine hydrochloride (EtOH, RT, 2h) to provide (±)-32A. LCMS m/z

279/281 (MH+).

Compound (±)-32A is converted to the title compound (±)-32 in a manner similar to that described in Example 12.

PREPARATIVE EXAMPLE 33

18A 33A 33B

In a manner similar to that described in Example 29, compound 18A was sequentially reacted with methylamine (2M/MeOH, 105 0 C overnight in a sealed tube), BH 3 -SMe 2 , and formamidine acetate to provide (±)-33C. LCMS m/z 279/281 (MH+).

Compound (±)-33C is converted to the title compound (±)-33 in a manner similar to that described in Example 12.

Likewise, reaction of 18A with ethylamine followed by reduction with BH 3 -SMe 2 , provided 33E, which was cyclized with formamidine acetate to provide (±)-33F and acetamidine hydrochloride to provide (±)-33G (LCMS m/z 307/309, MH+), respectively. In a manner similar to that previously described (e.g. Example 12), compound (±)-33F is converted to (±)-33H. Likewise, compound (±)-33G is converted to (±)-33l.

PREPARATIVE EXAMPLE 34

In a manner similar to that previously described (e.g. Example 1), 4-bromo-1- indanone was converted to 4-bromo-2-indanone (34A) and then further to (±)-34F (LCMS m/z 267/269, MH+).

Compound (±)-34F is converted to the title compound (±)-34 in a manner similar to that described in Example 12. An alternative conversion of 34A to 34B is described below:

To a solution of compound 34A (0.047 mol, prepared from 10 g 4-bromo-1- indanone) in EtOAc/water (220 mU220 ml.) was added NaHCO 3 (19.74 g, 0.235 mol) and acetone (34.5 ml_, 0.47 mol) at RT. To the above mixture was added dropwise over 1 hr a solution of Oxone (57.8 g, 0.094 mol) in water (220 ml_). The reaction mixture was stirred vigorously overnight before the layers were separated. The organic phase was washed with brine (20 ml_), dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure to give crude compound 34G.

To a solution of the crude 34G in THF/CH 2 CI 2 (65 mL/130 mL) was added IrCI 3 hydrate (158 mg, 0.47 mmol) at RT. The suspension was stirred for 2 hrs and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (15% EtOAc/hexanes) to give compound 34B as an off-white solid (6.65 g, 67% over four steps from 4-bromo-1-indanone). Another alternative conversion of 34A to 34B is described below: To an ice-cooled mixture of the 34A (crude, 22g, 0.113 mol) in DCM (360 mL) was added sodium bicarbonate (28.5g, 0.339 mol) followed by mCPBA (35.4g, 0.16 mol) portionwise. The reaction was slowly warmed to RT and vigorously stirred for 4 h. The mixture was quenched/washed with 10% solution of aq sodium sulfite followed by a final wash with brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness to provide 34G (100%). In a dry round-bottom flask under an atmosphere of nitrogen the crude epoxide

34G (0.113 mol) was dissolved in benzene (360 mL). The flask was cooled to 0 0 C in an ice/water bath and anhydrous zinc diiodide (43.4g, 0.136 mol) was gradually added. The resulting mixture was stirred at 0 °C for 10 min before it was warmed to RT and stirred for 4 h. The mixture washed with water in two portions followed by a final wash with brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness to provide 34B (99%). Another alternative preparation of 34E is described below:

A mixture of 3-bromo-o-xylene (2Og, 0.108 mol) in CCI 4 (200 mL) was treated with NBS (38.5 g, 2.0 eq) and benzoyl peroxide (263 mg, 0.01 eq) and refluxed overnight. The reaction was then cooled to 0 0 C and filtered. The filtrate was concentrated and purified (silica gel, hexanes) to give 34H as a colorless oil (which solidified to a white solid upon cooling and sitting).

In a manner similar to those described in the literature (Tetrahedon, 1999, 55, 14281 and Tetrahedron Letters, 1992, 33, 1565), a mixture of N-(diphenylmethylene)- glycine ethyl ester (267 mg, 1 mmol) in THF at -78 0 C was treated with NaHMDS

(1.0N/ THF, 1.1 mL, 1.1 eq) and stirred 30 min. A solution of compound 34H (343 mg) in THF was added and the reaction was stirred 1h at -78 0 C and then 2h at RT. The mixture was again cooled to -78 0 C and treated with NaHMDS (1.0N/ THF, 1.1 mL, 1.1 eq). The reaction was slowly warmed to RT, stirred overnight, quenched with sat. aq. NH 4 CI and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was taken up in ethyl ether, treated with 1 N HCI, and stirred vigorously for 2h. The benzophenone byproduct was removed from reaction mixture by extracting with diethyl ether. The product was isolated by cooling the aqueous layer in an ice bath, neutralizing with 1 N NaOH, and extracting with diethyl ether. The ether extract was concentrated to provide 34I.

In a manner similar to that previously described (e.g. Example 1), compound 34I is reduced with NaBH 4 to provide 34E.

PREPARATIVE EXAMPLE 35

Steps 1-2

A mixture of 9B (1.Og, 3.9 mmol) in THF-water (1 :1 , 40 ml.) was treated with BoC 2 O (1.28 g, 1.5 eq) and Na 2 CO 3 (491 mg, 1.5 eq), stirred at RT, and then extracted with EtOAc. The organic layers were combined and concentrated to give the protected product (1.25 g, 90%) as a cream colored solid.

A mixture of the Boc protected alcohol (660 mg, 1.85 mmol) in DCM (20 ml.) was treated with TPAP (65 mg, 0.1 eq) and NMO (282 mg, 1.3 eq) and stirred at RT for 3h. The reaction was then diluted with hexane (20 ml), stirred 10 min, and filtered. The filtrate was concentrated and purified by silica gel chromatography to provide 35A (490 mg).

Steps 3-4 A solution of 35A (430 mg, 1.21 mmol) in THF (15 mL) was cooled to -78 0 C and treated with MeMgBr (3.0 N/THF, 0.93 mL, 2.3 eq) dropwise. The mixture was allowed to warm to RT slowly and then was quenched with sat. aq. NH 4 CI at 0 0 C. The reaction was extracted with DCM. The combined organic extracts were dried over Na 2 SO 4 , concentrated and purified to provide a mixture of 35B (minor product) and 35C (major product).

Compound 35C was converted to 35B by the following procedure: A mixture of 35C (145 mg, 0.5 mmol) and Ba(OH) 2 in dioxane-water (1:1, 30 mL) was heated at 100 0 C until LCMS analysis indicatd consumption of the SM. The mixture was cooled and diluted with EtOAc and water. The organic layer was separated, dried over over Na 2 SO 4 , concentrated and purified to provide a mixture of 35B (110 mg, 81%).

Alternatively, compound 35A was converted directly to compound 35B by use of DCM as solvent: A mixture of 35A (3.49g, 9.8 mmol) in DCM (50 mL) was cooled to -78 0 C and treated with MeMgBr (3.0 N/THF, 8.2 ml_, 2.5 eq) dropwise. The mixture was allowed to warm to RT, stirred 1h, and then was quenched with sat. aq. NH 4 CI at 0 0 C. The reaction was extracted with DCM. The organic layer was dried over Na 2 SO 4 , concentrated and purified to provide 35B (3.61 g) as a white foam.

Steps 5-6

A mixture of the amino alcohol 35B (100 mg, 0.37 mmol) and BrCN (5.0 N/MeCN, 0.09 ml_) in EtOH (7 ml.) was stirred at RT for 4h. The mixture was concentrated and purified by column chromatography (7N NH 3 -MeOH in DCM) to provide (±)-35D.

Compound (±)-35D is converted to the title compound (±)-35 in a manner similar to that described in Example 12.

PREPARATIVE EXAMPLE 36

MeMgBr

36C (±)-36D, R = = CO 2 Et (+)-3S (+)-36E, R = = H

In a manner similar to that described in Example 35, compound 34E was sequentially protected with BoC 2 O, oxidized with TPAP/NMO or Dess-Martin reagent, and treated with MeMgBr (in DCM, -78 0 C to RT overnight or in THF, 1h, -78 0 C ) to provide 36C. In a manner similar to that previously described, 36C was deprotected with TFA, cyclized with EtOC(O)NCS/Hg(OAc) 2 , and hydrolyzed with LiOH to provide (±)-36E.

Compound (±)-36E is converted to the title compound (±)-36 in a manner similar to that described in Example 12. The enantiomers of compound 34D and 36A were separated by SFC (OD column with 10% MeOH and AD with 20% MeOH, respectively). The diastereomers of alcohols (36F and 36G) were separated by silica chromatography (2-25% EtOAc/hexanes).

PREPARATIVE EXAMPLE 37

To the mixture of 9B (93 mg, 0.360 mmol) and DIPEA (78 μL, 0.432 mmol) in DMF (3 ml.) was added trimethylorthoacetate (55 μL, 0.432 mmol). The mixture was kept stirring at 115 0 C for 16h. The mixture was diluted H 2 O (5 mL) and then extracted with EtOAc (2 x 10 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous MgSO 4 , and concentrated. The residue was purified (silica gel, 1 :1 EtOAc-Hexane) to obtain (±)-37A as a white solid (50mg). LCMS m/z 280/282, (MH+).

Compound (±)-37A is converted to the title compound (±)-37 in a manner similar to that described in Example 12.

PREPARATIVE EXAMPLE 38

Step i

2.5M n-BuLi in hexane (260 μL, 0.650 mmol) was added to a suspension of methyltriphenylphosphonium bromide (211 mg, 0.600 mmol) in THF (3 ml_). The mixture turned into an orange suspension. After stirring at RT for 30 min, the solution of aldehyde 35A (200 mg, 0.565 mmol) in THF (1 ml.) was added dropwise. The resultant mixture was kept stirring at RT for 1h and a white precipitate formed. The mixture was diluted with sat. aq. NH 4 CI (3 mL) and extracted with EtOAc (2 x 1OmL). The combined organic was washed with brine (10 mL), dried over anhydrous MgSO 4 , and concentrated. The residue was purified (silica gel, 1 :10 EtOAc-Hexane) to obtain 38A as a white solid (120 mg). LCMS m/z 352/354 (MH+).

Step 2

A solution of 38A in THF (1 mL) solution at 0 0 C was treated with BH 3 -THF (1M, 1.56mL, 1.56mmol) and stirred at 0 0 C for 1h. The reaction was treated with 1 N NaOH (1.5 mL), immediately followed by H 2 O 2 (30%). The ice bath was removed, and the reaction mixture was kept stirring at RT for 1h. The reaction was extracted with EtOAc (2 x 10 mL). The combined organic was washed with H 2 O (10 mL), dried over anhydrous MgSO 4 , and concentrated. The residue was purified (silica gel, 1 :2 EtOAc- Hexane) to obtain 38B as a white solid (31 mg). LCMS m/z 370/372 (MH+). Step 3:

TFA (1 ml.) was added to the solution of compound 38B (120 mg, 0.324 mmol) in CH 2 CI 2 (2 ml_). The reaction was kept stirring at RT for 2h. The mixture was diluted with CH 2 CI 2 (10 ml.) and basified with 50% NH 4 OH (v/v, 6 ml_). The aqueous layer was extracted once more with CH 2 CI 2 (10 ml_). The combined organic was dried over anhydrous MgSO 4 , and concentrated to obtain compound 38C as a white solid (67 mg). LCMS m/z 270/272 (MH+).

Steps 4-5

A solution of 38C (67 mg, 0.248 mmol) in EtOH (1 mL) at 0 0 C was treated with BrCN (5M/CH 3 CN, 60 μL, 0.3mmol) and then stirred at RT for 16 h. The mixture was concentrated, diluted with CH 2 CI 2 (10 mL), and basified with sat. aq. NaHCθ 3 (5 mL). The aqueous layer was extracted once more with CH 2 CI 2 (10 mL). The combined organic layers were dried over anhydrous MgSO 4 , and concentrated. The residue was purified (PTLC eluting with DCM-MeOH (2N NH 3 ) = 10:1) to obtain (±)-38D as a white foam (15 mg). LCMS m/z 295/297 (MH+).

Compound (±)-38C is converted to the title compound (±)-38 in a manner similar to that described in Example 12. PREPARATIVE EXAMPLE 39 I) O 3

2) NaOH-H 2 O 2

In a manner similar to that described in Example 35, vinylmagnesium bromide is added to compound 36B. In a manner similar to that previously described, the resulting product 39A is deprotected, cyclized, and hydrolyzed to give (±)-39B.

Ozone is bubbled through a mixture of compound (±)-39B in DCM at -78 0 C for 30 min. Air is then bubbled in for 10 min. The reaction is then treated with dimethylsulfide (10 eq), allowed to warm to RT, concentrated and purified by flash chromatography to provide (±)-39C. Compound (±)-39C is reduced with NaBH 4 in a manner similar to that previously described (e.g. Example 1). A solution of the resulting alcohol in DCM is treated with Deoxy-Fluor (F 3 S-N(CH 2 CH 2 OMe) 2 ) and refluxed until the starting material is consumed. The reaction is cooled to RT, poured onto sat. aq. NaHCO 3 and extracted with DCM (2x). The organic layers are dried over Na 2 SO 4 , concentrated and chromatographed on silica gel to provide the product (±)-39D. Alternatively, DAST (F 3 S-NEt 2 ) is used as the fluorinating reagent.

Compound (±)-39D is converted to the title compound (±)-39 in a manner similar to that described in Example 12.

PREPARATIVE EXAMPLE 40

In a manner similar to that described in Example 35, compound 36B is treated with CD 3 MgBr (prepared from CD 3 Br, see J. Am. Chem. Soc. 1989, 111 , 3897) and then advanced to (±)-40B.

Compound (±)-40B is converted to the title compound (±)-40 in a manner similar to that described in Example 12.

PREPARATIVE EXAMPLE 41

41C (±)-41 D (±)-41

A solution of 34D in THF is treated with LiAID 4 at RT for 1 h to provide 41 A, which is further progressed to (±)-41 in a manner similar to that outlined in Example 36.

PREPARATIVE EXAMPLE 42

1) BOC 2 O 2) TMSCH 2 Li Step i

A suspension of 3-bromo-o-xylene (8Og, 432 mmol), NBS (154g, 864 mmol) and AIBN (2,2'-azobis(2-methylpropionitrile, 2.Og, 12.3 mmol) in anhydrous CCI 4 (400 ml.) was gradually warmed to boiling and then refluxed for 2h. The mixture was cooled to RT and filtered. The filtrate was concentrated and filtered through a silica pad, eluting with 10% EtOAc-hexanes. The resulting product was concentrated, cooled in the freezer and then triturated with cold hexanes to obtain 42A (110 g). Additional product could be obtained from the mother liquor.

Steps 2-3

A solution of NaHMDS (1.0M/THF, 200 mL, 1.05 eq) in THF was cooled to -78 0 C and treated dropwise with a solution of N-(diphenylmethylene)glycine ethyl ester (50.68g, 1.0 eq) in THF. The reaction was stirred 30 min at -78 0 C and then treated with tribromide 42A (65g, 1.0 eq) in THF dropwise. The reaction was allowed to slowly warm to RT overnight. The mixture was then cooled to -78 0 C and treated dropwise with NaHMDS (1.0M/THF, 209 mL, 1.1 eq). The reaction was again allowed to slowly warm to RT overnight. The mixture was quenched with ice and extracted with Et 2 O.

The organic layer was treated with HCI (2N, 1 L) and stirred vigorously until analysis indicated complete conversion of the intermediate imine to 42B. The layers were then separated, discarding the organic layer. The aqueous layer was cooled in an ice-bath and neutralized with 5% NaOH (or aq. NH4OH) and extracted with DCM. The DCM layer was dried over Na 2 SO 4 , concentrated and chromatographed (5-50% EtOAc/hex) to give 42B. Steps 4-5

Compound 42B was treated with BoC 2 O as previously described. The resulting protected amino ester (0.14g, 0.364 mmol) was taken up in anhydrous pentane (3 mL) and treated with TMS-methyllithium (1.0 M/pentane, 1.1 mL, 3.0 eq) at 0 0 C. The reaction was stirred 2.5h at 0 0 C, quenched with MeOH (1 mL), and stirred at RT for 1h. The mixture was diluted with water and extracted with ether (3 x 50 mL). The ether layer was dried over Na 2 SO 4 , concentrated and chromatographed to give 42C. Compound 42C is reduced with NaBH 4 to give alcohol 36C. Alternatively, 42C is reduced in a steroselective manner with (S)-2-methyl-CBS-oxazaborolidine/borane or (R)-2-methyl-CBS-oxazaborolidine/borane as described in Example 66.

PREPARATIVE EXAMPLE 43

A solution of compound 43A (995mg, 2.79 mmol, prepared from 36G as described in Example 36) in DCM (25 mL) was treated with the Dess-Martin periodinane reagent (1.78 g, 4.19 mmol) and stirred for 3h at RT. The reaction was then quenched with a solution of Na 2 S 2 U 3 in water and stirred at RT. The organic layer was separated, washed with aqueous Na 2 S 2 θ 3 . The aqueous layer was further extracted with EtOAc. The combined organic layers were sequentially washed with sat. aq. NaHCθ 3 (2x), brine and water. The organic layer was then dried over Na SCu, concentrated and chromatographed (5-20% EtOAc/hex) to give 43B as a light yellow foam. LCMS m/z 352/354 (MH+)

A mixture of BH 3 -DMS (2.54 mL of 2.0N solution/THF) and (S)-2-methyl-CBS- oxazaborolidine (5.08 mL of 2.0N solution/THF) in THF (30 min) was stirred for 10 min at RT. The reaction was cooled to 0 0 C and then slowly treated with a solution of compound 43B (1.63 g, 4.62 mmol) in THF (30 mL) via addition funnel. The reaction was allowed to warm to RT slowly, stirred overnight, quenched with water, and stirred an additional 2h. The mixture was then extracted with EtOAc, dried over Na 2 SO 4 , concentrated and chromatographed (5-20% EtOAc/hex) to give 43C as a white solid (1.45 g). LCMS m/z 356/358 (MH+).

PREPARATIVE EXAMPLE 44 .Ph In aBH 4

Step i A mixture of 3-bromo-6-fluoro-o-xyleπe (25.37g, 432 mmol) in anhydrous CCI 4

(250 mL) was treated with NBS (44.5g, 864 mmol) and benzoyl peroxide (310 mg) and then heated at reflux overnight. The mixture was cooled to 0 °C and filtered, washing with hexanes. The filtrate was concentrated and chromatographed (hexanes) to give 44A as an colorless oil (41.57g, with minor mono-bromo impurities). Steps 2-4

In a manner similar to that described previously (Example 42, Steps 2-3 and Example 1, Step 4), compound 44A was sequentially treated with N- (diphenylmethylene)glycine ethyl ester, HCI 1 and NaBH 4 to provide 44C. Steps 5-6 A mixture of amino alcohol 44C (671 mg, 2.6 mmol) in anhydrous acetonitrile

(14 mL) was treated with BrCN (3M/DCM, 1.06 mL, 1.24 eq) and JPr 2 NEt (0.53 mL, 1.19 eq). The reaction was stirred at RT for 18h and then quenched with aq. NH 3 and extracted with DCM. The organic extracts were concentrated to give 44D (730 mg) as a white crystalline solid. In a manner similar to that previously described in Example 6, 44D is converted to (±)-44.

The following compounds are synthesized in a manner analogous to that described above, starting from the appropriately subsituted nitro-2-tetralone, nitro-1- tetralone, bromo-2-tetralone, bromo-1-tetralone, nitro-2-chromanone, nitro-1- chromanone, bromo-2-chromanone, or bromo-1-chromanone:

ASSAY:

Efficacy agonist activity values (Emax, GTPyS assay) for α2A and α2C were determined by following the general procedure detailed by Umland et. a/ ("Receptor reserve analysis of the human α 2C -adrenoceptor using [ 35 S]GTPyS and cAMP functional assays" European Journal of Pharmacology 2001, 411, 211-221). For the purposes of the present invention, a compound is defined to be active agonist of the α2C receptor subtype if the compound's efficacy at the α2C receptor is ≥ 30% Emax (GTPγS assay). For the purposes of the present invention, a compound is defined to be a specific or at least functionally selective agonist of the α2C receptor subtype if the compound's efficacy at the α2C receptor is ≥ 30% Emax (GTPγS assay) and its efficacy at the α2A receptor is ≤ 35% Emax (GTPγS assay). Additionally, for the purposes of this invention, a compound is defined to be an antagonist of the α2C receptor subtype if the compound's efficacy at the α2C receptor is < 30% Emax (GTPγS assay) and the Kj at the α2C receptor subtype is < 500 nM, preferentially < 200 nM, and most preferentially < 20 nM.

The following compounds were evaluated to be active or functionally selective agonists of the α2C receptor subtype based on the previously defined definition: (±)- 8, (±)-10, (±)-10B, (±)-11, (±)-11B and (±)-12c. The following compound was evaluated to be an antagonist of the α2C receptor subtype based on the previously defined definition (K 1 < 200 nM): (±)-5, and (±)-9. While the present invention has been described with in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.