WO2006019673A2

WO2006019673A2 - Jiadifenin analogs and uses thereof

Info

Publication number: WO2006019673A2
Application number: PCT/US2005/024483
Authority: WO
Inventors: Samuel J. Danishefsky; Young Shin Cho; David A. Carcache
Original assignee: Memorial Sloan Kettering Cancer Center
Current assignee: Memorial Sloan Kettering Cancer Center
Priority date: 2004-07-08
Filing date: 2005-07-08
Publication date: 2006-02-23
Anticipated expiration: 2007-01-08
Also published as: WO2006019673A3

Abstract

The present invention provides compounds having formula (I) and additionally provides methods for the synthesis thereof, compositions thereof, and methods for the use thereof in the treatment of neurodegenerative disorders, wherein R1-R6, m and n are as defined herein.

Description

JIADIFENIN ANALOGS AND USES THEREOF

PRIORITY

[0001] The present application claims priority to U.S. Provisional Application Serial No.: 60/586,302 filed July 8, 2004; which is hereby incorporated by reference in its entirety.

GOVERNMENT SUPPORT

[0002] The invention was supported in part by Grant No.: AI-16943-25 (now CA- 103823-25) from the National Institutes of Health. The U.S. government may have certain rights in this invention.

BACKGROUND OF THE INVENTION

[0003] Fukuyama and colleagues recently reported the isolation of jiadifenin (1) in 0.001% yield from the methanol extract of the pericarps of Illicium jiadifengpi) (2S)-Hydroxy-3,4-dehydroneomanjucin (2), also obtained from Illicium jiadifengpi, is a potential a biosynthetic precursor of 1. Indeed, Fukuyama and coworkers demonstrated that 2 could be converted to jiadifenin (1) through the intermediacy of ketones 3 and 4, another natural products isolated from Illicium majus. The chemical structure of 1 was determined, by extensive NMR analysis, to be a unique cage-like majucin-type sesquiterpene epimeric at the C(IO) acetal carbon.

[0004] Fukuyama et al. have shown that 1 promotes neurite outgrowth in the primary cultures of rat cortical neurons in concentrations as low as 0.1 μM.¹ [0005] Neurons are non-proliferating cells whose progressive or abrupt loss can result in diseases exemplified by Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic laterial sclerosis ("ALS" or "Lou Gehrig's disease"), and stroke. These diseases and disorders are individually or collectively referred to herein as "central neurodegenerative diseases." Selected symptoms resulting from these diseases include memory loss, loss of cognitive function, loss of gross and fine motor control, and blindness. Peripheral neuronal loss or neurite damage results in sensory loss exemplified by pain or discomfort, sensorimotor defects, and paralysis.

[0006] The incidence of central neurodegenerative diseases increases with age. For example, less than 5% of the population under the age of 65 displays signs of AD. An exponential increase is observed over the age of 65, with as much as 47% of the population displaying some form of AD over the age of 85. Many factors (etiological agents) are responsible for the initiation of neurodegenerative conditions, factors as varied as genetic DNA damage or loss in the mitochondria, abnormal amyloid processing, oxidative stress following ischemia and reperfusion, and loss of neurotrophic support for the nerve cells. The mode of action ultimately underlying such irreversible neuronal loss involves programmed cell death, or apoptosis. Preventing neuronal apoptosis and neurite disfunction represents a new, broad- spectrum, approach to the treatment of progressive central neurological disorders Various other neurodegenerative diseases related to the peripheral nervous system, herein referred to as "peripheral neuropathies", are characterized by the loss of feeling, experiencing pain, and even paralysis of or in the extremities. These peripheral neuropathies result from disease states such as ALS, Multiple Sclerosis, AIDS, diabetes, and various neuropathies induced by chemotherapeutic treatments such as cisplatin, vinblastine and taxane (Taxol.TM. and Taxotere.TM.) treatment for cancer therapy, and D4T for the treatment of HIV (Human Insufficiency Virus). In most of these cases, progressive loss of axonal finction occurs initially, resulting in severe symptoms, followed by the apoptotic loss of the neuron. In these cases, inhibiting neuronal apoptosis and or axonal degradation is a new approach to treating these diseases.

[0007] Many of the compounds previously shown to stimulate nerve regeneration have undesired side-effects, such as immunosuppression (FK506 and analogs that retain immunosuppressant activity) or androgenic or estrogenic stimulation. In addition, there is a paucity of pharmaceutical options for devastating ailments such as Alzheimer's, Parkinson's, Huntington's and Lou Gehrig's diseases. For example, there are currently no effective treatments for halting, preventing or reversing the progression of Alzheimer's disease; only treatments that palliate symptoms are thus far available. There is a need for compounds that induce regrowth of damaged neurons. SUMMARY OF THE INVENTION

[0008] In one aspect, the present invention provides a compound of general formula (I):

(D and pharmaceutically acceptable derivatives thereof; wherein n is 0 or 1 ; m is 1 or 2;

Xi and X₂ are independently O or NR^X1, wherein R^X1 is hydrogen, an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl moiety, or a nitrogen protecting group;

Ri is hydrogen, halogen, -OR^1A, -SR^1A, -NR^1AR^1B, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; wherein R^1A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; and R^1B is hydrogen, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety;

R₂ is hydrogen, halogen, -OR^2A, -SR^2A, -NR^2AR^2B, -CO₂R^2A, -CH₂OR^2A, - C(=O)H, -CH=CR^2CR^2D, -C(=O)R^2C, -C(=NR^2A)R^2C, -C(=NR^2A)R^2C, -C(=N- NR^2AR^2B)R^2C, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; wherein R^2A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; and R^2B is hydrogen, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; and R^2C and R^2D are indenpently hydrogen, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety;

R₃, R₄ and R₅ are independently hydrogen, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; R₆ is hydrogen, halogen, -OR^6Λ, -SR^6A, -NR^6ΛR^6B, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; wherein R^6A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; and R^6B is hydrogen, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety.

[0009] In yet another aspect, the present invention provides pharmaceutical compositions comprising an inventive compound and a pharmaceutically acceptable carrier, optionally further comprising an additional therapeutic agent. [0010] In a further aspect, the present invention provides methods for treating a neurodegenerative disorder/ or condition comprising administering to a subject in need thereof a therapeutically effective amount of the compound of the invention in an amount effective to promote neurite outgrowth. In another aspect, the present invention provides methods for treating Alzheimer's disease and/or Parkinson's disease.

DEFINITIONS

[0011] In accordance with the present invention and as used herein, the following terms, are defined with the following meanings, unless explicitly stated otherwise. [0012] Certain compounds disclosed in the present invention, and definitions of specific functional groups are also described in more detail below. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated herein by reference. Furthermore, it will be appreciated by one of ordinary skill in the art that the synthetic methods, as described herein, utilize a variety of protecting groups. By the term "protecting group", has used herein, it is meant that a particular functional moiety, e.g., O, S, or N, is temporarily blocked so that a reaction can be carried out selectively at another reactive site in a multifunctional compound. In preferred embodiments, a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group must be selectively removed in good yield by readily available, preferably nontoxic reagents that do not attack the other functional groups; the protecting group forms an easily separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group has a minimum of additional functionality to avoid further sites of reaction. As detailed herein, oxygen, sulfur, nitrogen and carbon protecting groups may be utilized. For example, in certain embodiments, as detailed herein, certain exemplary oxygen protecting groups are utilized. These oxygen protecting groups include, but are not limited to methyl ethers, substituted methyl ethers (e.g., MOM (methoxymethyl ether), MTM (methylthiomethyl ether), BOM (benzyloxymethyl ether), PMBM (p- methoxybenzyloxymethyl ether), to name a few), substituted ethyl ethers, substituted benzyl ethers, silyl ethers (e.g., TMS (trimethylsilyl ether), TES (triethylsilylether), TIPS (triisopropylsilyl ether), TBDMS (t-butyldimethylsilyl ether), tribenzyl silyl ether, TBDPS (t-butyldiphenyl silyl ether)), esters (e.g., formate, acetate, benzoate (Bz), trifluoroacetate, dichloroacetate, to name a few), carbonates, cyclic acetals and ketals. In certain other exemplary embodiments, nitrogen protecting groups are utilized. These nitrogen protecting groups include, but are not limited to, carbamates (including methyl, ethyl and substituted ethyl carbamates (e.g., Troc), to name a few) amides, cyclic imide derivatives, N-Alkyl and N-Aryl amines, imine derivatives, and enamine derivatives, to name a few. Certain other exemplary protecting groups are detailed herein, however, it will be appreciated that the present invention is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and utilized in the present invention. Additionally, a variety of protecting groups are described in "Protective Groups in Organic Synthesis" Third Ed. Greene, T. W. and Wuts, P.G., Eds., John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.

[0013] It is understood that the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term "substituted" whether preceded by the term "optionally" or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic, carbon and heteroatom substituents of organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. Furthermore, this invention is not intended to be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment and prevention, for example of disorders, as described generally above. Examples of substituents include, but are not limited to aliphatic; heteroaliphatic; alicyclic; heteroalicyclic; aromatic, heteroaromatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -NO₂; -CN; -CF₃; - CH₂CF₃; -CHCl₂; -CH₂OH; -CH₂CH₂OH; -CH₂NH₂; -CH₂SO₂CH₃; - or -GR^GI wherein G is -0-, -S-, -NR^G2-, -C(=0)-, -S(=0)-, -SO₂-, -C(=0)0-, -C(=0)NR^G2-, - 0C(=0)-, -NR^G2C(=0)-, -0C(=0)0-, -0C(=0)NR^G2-, -NR^G2C(=0)0-, - NR^G2C(=O)NR^G2-, -C(=S)-, -C(=S)S-, -SC(=S)-, -SC(=S)S-, -C(=NR^G2)-, - C(=NR^G2)0-, -C(=NR^G2)NR^G3-, -0C(=NR^G2)-, -NR^G2C(=NR^G3)-, -NR⁰²SO₂-, - NR^G2SO₂NR^G3-, or -SO₂NR⁰²-, wherein each occurrence of R^G1, R⁰² and R⁰³ independently includes, but is not limited to, hydrogen, halogen, or an optionally substituted aliphatic, alicyclic heteroaliphatic, heterocyclic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein. [0014] The term "stable", as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein. [0015] The term "aliphatic", as used herein, includes both saturated and unsaturated, straight chain (i.e., unbranched) or branched aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, "aliphatic" is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl moieties. Thus, as used herein, the term "alkyl" includes straight and branched alkyl groups. An analogous convention applies to other generic terms such as "alkenyl", "alkynyl" and the like. Furthermore, as used herein, the terms "alkyl", "alkenyl", "alkynyl" and the like encompass both substituted and unsubstituted groups. In certain embodiments, as used herein, "lower alkyl" is used to indicate those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms. [0016] In certain embodiments, the alkyl, alkenyl and alkynyl groups employed in the invention contain 1 -20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-4 carbon atoms. Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n- propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, which again, may bear one or more substituents. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1- propynyl and the like.

[0017] The term "alicyclic", as used herein, refers to compounds which combine the properties of aliphatic and cyclic compounds and include but are not limited to cyclic, or polycyclic aliphatic hydrocarbons and bridged cycloalkyl compounds, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, "alicyclic" is intended herein to include, but is not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, which are optionally substituted with one or more functional groups. Illustrative alicyclic groups thus include, but are not limited to, for example, cyclopropyl, -CH₂- cyclopropyl, cyclobutyl, -CH₂-cyclobutyl, cyclopentyl, -CH₂-cyclopentyl-n, cyclohexyl, -CH₂-cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norborbyl moieties and the like, which again, may bear one or more substituents. [0018] The term "alkoxy" (or "alkyloxy"), or "thioalkyl" as used herein refers to an alkyl or cycloalkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom or through a sulfur atom. In certain embodiments, the alkyl or cycloalkyl group contains 1-20 aliphatic or alicyclic carbon atoms. In certain other embodiments, the alkyl or cycloalkyl group contains 1-10 aliphatic or alicyclic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic or alicyclic carbon atoms. In still other embodiments, the alkyl group contains 1 -6 aliphatic or alicyclic carbon atoms. In yet other embodiments, the alkyl group contains 1-4 aliphatic or alicyclic carbon atoms. Examples of alkoxy, include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy. Examples of thioalkyl include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.

[0019] The term "alkylamino" refers to a group having the structure - NHR'wherein R' is alkyl or cycloalkyl, as defined herein. The term "dialkylamino" refers to a group having the structure -N(R')₂, wherein each occurrence of R' is independently alkyl or cycloalkyl, as defined herein. The term "aminoalkyl" refers to a group having the structure NH₂R'-, wherein R' is alkyl or cycloalkyl, as defined herein. In certain embodiments, the alkyl group contains 1-20 aliphatic or alicyclic carbon atoms. In certain other embodiments, the alkyl or cycloalkyl group contains 1- 10 aliphatic or alicyclic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic or alicyclic carbon atoms. In still other embodiments, the alkyl or cycloalkyl group contains 1 -6 aliphatic or alicyclic carbon atoms. In yet other embodiments, the alkyl or cycloalkyl group contains 1 -4 aliphatic or alicyclic carbon atoms. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, iso-propylamino and the like. [0020] In general, the terms "aryl" and "heteroaryl", as used herein, refer to stable mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted. It will also be appreciated that aryl and heteroaryl moieties, as defined herein may be attached via an alkyl or heteroalkyl moiety and thus also include - (alkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)aryl, and -(heteroalkyl)heteroaryl moieties. Thus, as used herein, the phrases "aryl or heteroaryl" and "aryl, heteroaryl, -(alkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)aryl, and -(heteroalkyl)heteroaryl" are interchangeable. Substituents include, but are not limited to, any of the previously mentioned substitutents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound. In certain embodiments of the present invention, "aryl" refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. In certain embodiements of the present invention, the term "heteroaryl", as used herein, refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.

[0021] It will be appreciated that aryl and heteroaryl groups (including bicyclic aryl groups) can be unsubstituted or substituted, wherein substitution includes replacement of one or more of the hydrogen atoms thereon independently with any one or more of the substituents generally described above. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0022] The term "cycloalkyl", as used herein, refers specifically to groups having three to seven, preferably three to ten carbon atoms. Suitable cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case of other alicyclic, heteroalicyclic or heterocyclic moieties, may optionally be substituted with one or more of the substituents generally described above. An analogous convention applies to other generic terms such as "cycloalkenyl", "cycloalkynyl" and the like. Additionally, it will be appreciated that any of the alicyclic or heteroalicyclic moieties described above and herein may comprise an aryl or heteroaryl moiety fused thereto. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0023] The term "heteroaliphatic", as used herein, refers to aliphatic moieties in which one or more carbon atoms in the main chain have been substituted with a heteroatom. Thus, a heteroaliphatic group refers to an aliphatic chain which contains one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms, e.g., in place of carbon atoms. Heteroaliphatic moieties may be branched or linear unbranched. In certain embodiments, heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more of the substituents generally described above. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0024] The term "heteroalicyclic", as used herein, refers to compounds which combine the properties of heteroaliphatic and cyclic compounds and include but are not limited to saturated and unsaturated mono- or polycyclic heterocycles such as morpholino, pyrrolidinyl, furanyl, thiofuranyl, pyrrolyl etc., which are optionally substituted with one or more functional groups, as defined herein.

[0025] Additionally, it will be appreciated that any of the alicyclic or heteroalicyclic moieties described above and herein may comprise an aryl or heteroaryl moiety fused thereto. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0026] The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.

[0027] The term "haloalkyl" denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.

[0028] The term "heterocycloalkyl" or "heterocycle", as used herein, refers to a non-aromatic 5-, 6- or 7- membered ring or a polycyclic group, including, but not limited to a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 1 double bonds and each 6- membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to a substituted or unsubstituted aryl or heteroaryl ring. Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. In certain embodiments, a "substituted heterocycloalkyl or heterocycle" group is utilized and as used herein, refers to a heterocycloalkyl or heterocycle group, as defined above, substituted by the independent replacement of one or more of the hydrogen atoms thereon with one or more of the substituents generally described above. Additional examples or generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0029] As used herein, the terms "aliphatic", "heteroaliphatic", "alkyl", "alkenyl", "alkynyl", "heteroalkyl", "heteroalkenyl", "heteroalkynyl", and the like encompass substituted and unsubstituted, saturated and unsaturated, and linear and branched groups. Similarly, the terms "alicyclic", "heteroalicyclic", "heterocycloalkyl", "heterocycle" and the like encompass substituted and unsubstituted, and saturated and unsaturated groups. Additionally, the terms "cycloalkyl", "cycloalkenyl", "cycloalkynyl", "heterocycloalkyl", "heterocycloalkenyl", "heterocycloalkynyl", "aryl", "heteroaryl" and the like encompass both substituted and unsubstituted groups. [0030] The phrase, "pharmaceutically acceptable derivative", as used herein, denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof. Pharmaceutically acceptable derivatives thus include among others pro-drugs. A pro-drug is a derivative of a compound, usually with significantly reduced pharmacological activity, which contains an additional moiety, which is susceptible to removal in vivo yielding the parent molecule as the pharmacologically active species. An example of a pro-drug is an ester, which is cleaved in vivo to yield a compound of interest. Pro-drugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs, are known and may be adapted to the present invention. Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below.

[0031] As used herein the term "biological sample" includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from an animal (e.g., mammal) or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. For example, the term "biological sample" refers to any solid or fluid sample obtained from, excreted by or secreted by any living organism, including single-celled micro-organisms (such as bacteria and yeasts) and multicellular organisms (such as plants and animals, for instance a vertebrate or a mammal, and in particular a healthy or apparently healthy human subject or a human patient affected by a condition or disease to be diagnosed or investigated). The biological sample can be in any form, including a solid material such as a tissue, cells, a cell pellet, a cell extract, cell homogenates, or cell fractions; or a biopsy, or a biological fluid. The biological fluid may be obtained from any site (e.g. blood, saliva (or a mouth wash containing buccal cells), tears, plasma, serum, urine, bile, cerebrospinal fluid, amniotic fluid, peritoneal fluid, and pleural fluid, or cells therefrom, aqueous or vitreous humor, or any bodily secretion), a transudate, an exudate (e.g. fluid obtained from an abscess or any other site of infection or inflammation), or fluid obtained from a joint (e.g. a normal joint or a joint affected by disease such as rheumatoid arthritis, osteoarthritis, gout or septic arthritis). The biological sample can be obtained from any organ or tissue (including a biopsy or autopsy specimen) or may comprise cells (whether primary cells or cultured cells) or medium conditioned by any cell, tissue or organ. Biological samples may also include sections of tissues such as frozen sections taken for histological purposes. Biological samples also include mixtures of biological molecules including proteins, lipids, carbohydrates and nucleic acids generated by partial or complete fractionation of cell or tissue homogenates. Although the sample is preferably taken from a human subject, biological samples may be from any animal, plant, bacteria, virus, yeast, etc. The term animal, as used herein, refers to humans as well as non-human animals, at any stage of development, including, for example, mammals, birds, reptiles, amphibians, fish, worms and single cells. Cell cultures and live tissue samples are considered to be pluralities of animals. In certain exemplary embodiments, the non- human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig). An animal may be a transgenic animal or a human clone. If desired, the biological sample may be subjected to preliminary processing, including preliminary separation techniques.

BRIEF DESCRIPTION OF THE DRAWING

[0032] Figure 1 depicts results of neurite outgrowth experiments in PC 12 cells treated with inventive compounds. Pictures of neurons after treatment with DMSO and compounds of the invention are shown.

DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS OF THE INVENTION [0033] In recognition of the need to access novel Jiadifenin analogs, and this class of polycycles in general, the present invention provides novel polycyclic compounds, as described in more detail herein, which exhibit neurotrophic activity (e.g., promotion of neurite outgrowth). Therefore, the compounds may be useful as neurotrophic agents. In certain embodiments, compounds of the invention may find use in the treatment of Alzheimer's Disease (AD). [0034] 1) General Description of Compounds of the Invention [0035] The compounds of the invention include compounds of the general formula I as further defined below:

(I) and pharmaceutically acceptable derivatives thereof; wherein n is 0 or 1 ; m is 1 or 2;

Xi and X₂ are independently O or NR^XI, wherein R^xl is hydrogen, an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl moiety, or a nitrogen protecting group;

Ri is hydrogen, halogen, -OR^1A, -SR^{1 A}, -NR^1ΛR^1B, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; wherein R^1A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; and R^{1 B} is hydrogen, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety;

R₂ is hydrogen, halogen, -OR^2A, -SR^2A, -NR^2AR^2B, -CO₂R^2A, -CH₂OR^2A, - C(=O)H, -CH=CR^2CR^2D, -C(=O)R^2C, -C(=NR^2A)R^2C, -C(=NR^2A)R^2C, -C(=N- NR^2AR^2B)R^2C, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; wherein R^2A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; and R^2B is hydrogen, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; and R and R^2D are indenpently hydrogen, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety;

R₃, R₄ and R₅ are independently hydrogen, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety;

R₆ is hydrogen, halogen, -OR^6A, -SR^6A, -NR^6AR^6B, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; wherein R^6A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; and R is hydrogen, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety. [0036] In certain embodiments, compounds of the invention have the following stereochemistry:

[0037] In certain embodiments, compounds of formula (I) exclude compounds having the following structure:

[0038] In certain embodiments, the present invention defines particular classes of compounds which are of special interest. For example, one class of compounds of special interest includes those compounds of Formula I wherein: n is 0 or 1; m is 1 or 2;

Xi and X₂ are independently O or NR , wherein R is hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, acyl moiety, or a nitrogen protecting group;

Ri is hydrogen, halogen, -OR^1A, -SR^1Λ, -NR^1AR^1B, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein R^IA is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R^1B is hydrogen, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;

R₂ is hydrogen, halogen, -OR^2A, -SR^2A, -NR^2AR^2B, -CO₂R^2A, -CH₂OR^2A, - C(O)H, -CH=CR^2CR^2D, -C(=0)R^2C, -C(=NR^2A)R^2C, -C(=NR^2A)R^2C, -C(=N- NR^2ΛR^2B)R^2C, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein R^2A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R^2B is hydrogen, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R^2C and R^2D are indenpently hydrogen, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;

R₃, R₄ and R₅ are independently hydrogen, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;

R₆ is hydrogen, halogen, -0R^6A, -SR^6A, -NR^6AR^6B, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein R^6A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R^6B is hydrogen, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety.

[0039] Another class of compounds of special interest includes those compounds having the structure:

wherein R₁-R₆, X₁, X₂ and m are as described generally and in classes and subclasses herein. [0040] Another class of compounds of special interest includes those compounds having the structure:

wherein Ri-R₆, Xi, X₂ and m are as described generally and in classes and subclasses herein.

[0041] A number of important subclasses of each of the foregoing classes deserve separate mention; these subclasses include subclasses of the foregoing classes in which:

[0042] i) n is 0; [0043] ii) n is 1; [0044] iii) m is l; [0045] iv) m is 2; [0046] v) X₁ is O;

[0047] vi) X, is NR^XI wherein R^X1 is hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, acyl moiety, or a nitrogen protecting group; [0048] vii) X₁ is NR^X1 wherein R^X1 is hydrogen, alkyl, alkenyl, -C(=O)R^X, -

C(=O)OR^X, -SR^X, SO₂R^X, wherein R^x is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, -C(=O)R^A or-ZR^A, wherein Z is -O-, -S-, -NR^D, wherein each occurrence of R^Λ and R^B is independently hydrogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

[0049] viii) X] is NR^X1 wherein R^X1 is hydrogen, lower alkyl or acyl;

[0050] ix) X, is NH;

[0051] x) X₂ is O;

[0052] xi) X₂ is NR^X2 wherein R^X2 is hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, acyl moiety, or a nitrogen protecting group;

[0053] xii) X₂ is NR^ wherein R^ is hydrogen, alkyl, alkenyl, -C(=O)R^X, -

C(=O)OR^X, -SR^X, SO₂R^X, wherein R^x is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, -C(=O)R^A or-ZR^A, wherein Z is -O-, -S-, -NR^B, wherein each occurrence of R^A and R^B is independently hydrogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

[0054] xiii) X₂ is NR^ wherein R^x2 is hydrogen, lower alkyl or acyl;

[0055] xiv) X₂ is NH;

[0056] xv) R₁ is hydrogen, halogen, -OR^1A, -SR^{1 A}, -NR^1AR^{1 B}, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein R^1A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R^1B is hydrogen, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;

[0057] xvi) Ri is hydrogen, halogen, -OR^1A, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein R^1A is hydrogen, an oxygen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;

[0058] xvii) Ri is hydrogen or -OR^1A; wherein R^IA is hydrogen, an oxygen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;

[0059] xviii) Ri is hydrogen or -OR^1A; wherein R^1A is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, silyl, -C(=O)R^X, -

C(=S)R^X, -C(=NR^x)R^y, -SO₂R", wherein R^x and R^y are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, -C(=O)R^A or-

ZR^A, wherein Z is -O-, -S-, -NR^B, wherein each occurrence of R^A and R^B is independently hydrogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

[0060] xix) R₁ is hydrogen or -OH;

[0061] xx) Ri is hydrogen;

[0062] xxi) R₁ is OH;

[0063] xxii) R₂ is hydrogen, halogen, -OR^2A, -SR^2A, -NR^2AR^2B, -CO₂R^2A, -

CH₂OR^2A, -C(=O)H, -CH=CR^2CR^2D, -C(=O)R^2C, -C(=NR^2A)R^2C, -C(=NR^2A)R^2C, -

C(=N-NR^2AR^2B)R^2C, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein R^2A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R^2B is hydrogen, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R^2C and R^2D are indenpently hydrogen, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;

[0064] xxiii) R₂ is hydrogen, halogen, -OR^2A or -CO₂R^2A; wherein R^2A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R^2B is hydrogen, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R^2C and R^2D are indenpently hydrogen, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;

[0065] xxiv) R₂ is hydrogen, halogen, -OR^2Λ or -CO₂R^2A; wherein R^2Λ is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, silyl, -C(=O)R\ -C(=S)R^X, -C(=NR^x)R^y, -SO₂R^X, wherein R^x and R^y are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, -C(=O)R^Λ or-ZR^Λ, wherein Z is -O-, -S-, -NR , wherein each occurrence of R^A and R^B is independently hydrogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

[0066] xxv) R₂ is hydrogen or -CO₂R^2A; wherein R^2A is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, silyl, -C(=O)R^X, -

C(=S)R^X, -C(=NR^x)R^y, -SO₂R^X, wherein R^x and R^y are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl,. heterocycloalkynyl, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, -C(=O)R^A or-

ZR^A, wherein Z is -O-, -S-, -NR^D, wherein each occurrence of R^A and R^B is independently hydrogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;

[0067] xxvi) R₂ is hydrogen or -CO₂R^2A; wherein R^2A is hydrogen or lower alkyl;

[0068] xxvii) R₂ is hydrogen or -CO₂Me;

[0069] xxviii) R₂ is hydrogen;

[0070] xxix) R₂ is -CO₂R^2A; wherein R^2A is hydrogen or lower alkyl;

[0071] xxx) R₂ is -CO₂Me;

[0072] xxxi) R₃, R₄ and R₅ are independently hydrogen, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;

[0073] xxxii) R₃, R₄ and R₅ are independently hydrogen or lower alkyl;

[0074] xxxii) R₃, R₄ and R₅ are independently hydrogen or methyl; [0075] xxxiii) R₆ is hydrogen, halogen, -OR^6A, -SR^6Λ, -NR^6AR^6B, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein R^6Λ is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R^6B is hydrogen, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;

[0076] xxxiv) R₆ is hydrogen, halogen, -OR^6A, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein R^6A is hydrogen, an oxygen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;

[0077] xxxv) R₆ is hydrogen or -OR^6A; wherein R^6A is hydrogen, an oxygen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;

[0078] xxxvi) R₆ is hydrogen or -OR^6A; wherein R^6Λ is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, silyl, -C(=O)R^X, -

C(=S)R^X, -C(=NR^x)R^y, -SO₂R", wherein R^x and R^y are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, -C(=O)R^A or—

[0079] xxxvii) R₆ is hydrogen or -OR^6A; wherein R^6A is hydrogen or lower alkyl;

[0080] xxxviii) R₆ is hydrogen or -OR^6A; wherein R^6A is hydrogen or methyl;

[0081] xxxvii) R₆ is hydrogen;

[0082] xxxvii) R₆ is OH;

[0083] xxxvii) R₆ is OMe;

[0084] It will be appreciated that for each of the classes and subclasses described above and herein, any one or more occurrences of aliphatic, alicyclic heteroaliphatic, heterocyclic, alkyl, heteroalkyl may independently be substituted or unsubstituted, cyclic or acyclic, linear or branched and any one or more occurrences of aryl, heteroaryl, alicyclic, heteroalicyclic may be substituted or unsubstituted.

[0085] The reader will also appreciate that all possible combination of the variables described in i)- through xxxvii) above (e.g., Ri-R₆, m, n, Xi and X₂, among others) is considered part of the invention. Thus, the invention encompasses any and all compounds of formula I generated by taking any possible permutation of the variables described in i)- through xxxvii) above.

[0086] As the reader will appreciate, compounds of particular interest include, among others, those which share the attributes of one or more of the foregoing subclasses. Some of those subclasses are illustrated by the following sorts of compounds:

[0087] I) Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

[0088] wherein Ri-R₆, m and X₂ are as efined generally above and in classes and subclasses herein. In certain embodiments, the compounds have the following stereochemistry:

[0089] II) Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

[0090] wherein Ri-R₆, m and X₂ are as defined generally above and in classes and subclasses herein. In certain embodiments, the compounds have the following stereochemistry:

[0091] III) Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

[0092] wherein Ri-R₆ and m are as defined generally above and in classes and subclasses herein. In certain embodiments, the compounds have the following stereochemistry:

[0093] In certain embodiments, the compound has one of the following structures:

[0094] In certain embodiments, the compound has the structure:

[0095] IV) Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

[0096] wherein Ri-R₆ and m are as defined generally above and in classes and subclasses herein. In certain embodiments, the compounds have the following stereochemistry:

[0097] In certain embodiments, the compound has one of the following structures:

[0098] In certain embodiments, the compound has the structure:

[0099] V) Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

wherein Ri-R₆ and m are as defined generally above and in classes and subclasses herein. In certain embodiments, the compounds have the following stereochemistry:

[0100] In certain embodiments, the compound has the structure:

[0101] VI)Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

[0102] In certain embodiments, the compound has the structure:

[0103] VII) Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

[0104] wherein Ri-R₆, m and X₂ are as defined generally above and in classes and subclasses herein. In certain embodiments, the compounds have the following stereochemistry:

[0105] VIII) Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

[0106] w erein Ri-R₆, m and X₂ are as defined gen above and in classes and subclasses herein. In certain embodiments, the compounds have the following stereochemistry:

[0107] IX) Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

[0108] wherein RpR₆ and m are as defined generally above and in classes and subclasses herein. In certain embodiments, the compounds have the following stereochemistry:

[0109] In certain embodiments, the compound has the structure:

[0110] X) Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

[0111] wherein Ri-R₆ and m are as defined generally above and in classes and subclasses herein. In certain embodiments, the compounds have the following stereochemistry:

[0112] In certain embodiments, the compound has the structure:

[0113] XI)Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

[0114] wherein Ri-R₆ and m are as defined generally above and in classes and subclasses herein. In certain embodiments, the compounds have the following stereochemistry:

[0115] XII) Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

[0116] wherein Ri-R₆ and m are as defined generally above and in classes and subclasses herein. In certain embodiments, the compounds have the following stereochemistry:

[0117] In certain embodiments, for compounds of classes I-XII above, Ri is hydrogen or OH. In certain other embodiments, R₂ is hydrogen or -CO₂Me. In certain other embodiments, R₃ and R₄ are independently hydrogen or lower alkyl. In certain exemplary embodiments, R₃ and R₄ are independently hydrogen or methyl. In certain exemplary embodiments, R₃ is methyl and R₄ is hydrogen. In certain other embodiments, R₅ is hydrogen or lower alkyl. In certain other embodiments, R₅ is hydrogen or methyl. In certain embodiments, R₆ is hydrogen or OH. In certain embodiments, m is 1.

[0118] It will be appreciated that each of the compounds described herein and each of the subclasses of compounds described above (I-XII) may be substituted as described generally herein, or may be substituted according to any one or more of the subclasses described above and herein (e.g., i- xxxvii).

[0119] Some of the foregoing compounds can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., stereoisomers and/or diastereomers. Thus, inventive compounds and pharmaceutical compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the invention are enantiopure compounds. In certain other embodiments, mixtures of stereoisomers or diastereomers are provided. For example, a compound of the invention depicted as having the structure:

denotes that the compound exists as a mixture of the following stereoisomers:

which mixture may or may not be racemic. In certain embodiments, the mixture is racemic. [0120] More generally, compounds having the general formula:

exist as a mixture of the following stereoisomers:

which mixture may or may not be racemic. In certain embodiments, the mixture is racemic.

[0121] Furthermore, certain compounds, as described herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated. The invention additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of stereoisomers. In addition to the above-mentioned compounds per se, this invention also encompasses pharmaceutically acceptable derivatives of these compounds and compositions comprising one or more compounds of the invention and one or more pharmaceutically acceptable excipients or additives. [0122] Compounds of the invention may be prepared by crystallization of compound of formula (I) under different conditions and may exist as one or a combination of polymorphs of compound of general formula (I) forming part of this invention. For example, different polymorphs may be identified and/or prepared using different solvents, or different mixtures of solvents for recrystallization; by performing crystallizations at different temperatures; or by using various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffractogram and/or other techniques. Thus, the present invention encompasses inventive compounds, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and pharmaceutically acceptable compositions containing them.

[0123] As discussed above, this invention provides novel compounds with a range of biological properties. Preferred compounds of this invention have biological activities relevant for the treatment of neurodegenerative diseases and disorders. [0124] Compounds of this invention include those specifically set forth above and described herein, and are illustrated in part by the various classes, subgenera and species disclosed elsewhere herein. [0125] 1) Synthetic Methodology

[0126] Guidance for preparing compound useful for practicing the present invention can be found, for example, in Cho et al, "Total synthesis of (+/-)- jiadifenin, a non-peptidyl neurotrophic modulator" J Am Chem Soc. 2004;126(44): 14358-9, which is hereby incorporated by reference in its entirety. [0127] It will be appreciated that the methods as described therein can be applied to each of the compounds as disclosed herein and equivalents thereof. Additionally, the reagents and starting materials are well known to those skilled in the art. Although the schemes described in the above-cited references depict certain exemplary compounds, it will be appreciated that the use of alternate starting materials will yield other analogs of the invention.

[0128] In one aspect, the present invention provides methods for preparing novel polycycles having formula (I) a described above and in certain classes and subclasses herein. An overview of exemplary synthesic approaches to the inventive compounds is provided below, as detailed in Schemes 1-13, and in the Exemplification herein. It will be appreciated that the methods as described herein can be applied to each of the compounds as disclosed herein and equivalents thereof. Additionally, the reagents and starting materials are well known to those skilled in the art. Although the following schemes describe certain exemplary compounds, it will be appreciated that the use of alternate starting materials will yield other analogs of the invention. [0129] As disccused previously, Fukuyama et. al. recently reported the isolation and structural identification of a novel majucin-type prezizaane, jiadifenin (Scheme 1, 1), from the Illicium jiadifengpi species of China. The previously known (25)- hydroxy-3,4-dehydronemajucin (2), also isolatable from /. jiadifengpi, is a potential biosynthetic precursor to jiadifenin (1). Moreover, both jiadifenin and (25)-hydroxy- 3,4-dehydronemajucin (2) have been shown by Fukuyama and coworkers to promote neurite outgrowth in primary cultures of rat cortical neurons at levels as low as 0.1 to 10 μiM. Fukuyama and colleagues demonstrated that 2, the absolute configuration of which had been previously determined, could be converted to jiadifenin (1), as outlined below (Scheme 1). This series of manipulations served both to establish 2 as a potential biosynthetic precursor to jiadifenin and to verify the absolute configuration of jiadifenin. [0130] Scheme 1

Jiadifenin (1)

[0131] Key: (a) Dess-Martin reagent, CH₂Cl₂, rt, 81%; (b) DBU, benzene, 80 °C, 74%; (c) Dess-Martin reagent, dioxane, rt; (d) MeOH, rt, 9%.

[0132] An exemplary synthetic strategy is outlined in Scheme 2. Compound 6 should be readily obtained in racemic form from the commercially available 1,4- cyclohexanedione monoethylene ketal 5. From compound 6, we planned to install the C₉ quaternary carbon center through sequential alkylation reactions. We recognized that there could well be difficulties in achieving diastereocontrol in the conversion of 6 to 7. From intermediate 7, the requisite cyclopentenone functionality would be installed through an intramolecular Horner-Wadsworth-Emmons reaction and, following appropriate functional group transformations, intermediate 8 would be in hand. At this stage, we envisioned installing the lactone through an intramolecular Claisen-type condensation with a pendant carbonate moiety (cf. 8 to 9). We were optimistic that, with the tricyclic core structure in place, we would be able to achieve adequate diastereocontrol in the installation of the three remaining stereocenters at Ci, C₆, and C₇. Thus, a straightforward series of transformations should allow access to 10. Based on the earlier work of Fukuyama et. al. (Scheme 1), we anticipated that, upon oxidation of Ci₀, intermediate 10 would undergo ring contraction to produce jiadifenin (1).

[0134] Preparation of 10 was to be achieved through successive ring closing operations of α,α'-tetrasubstituted cyclohexanone obtained from the commercially available 1 ,4-cyclohexanedione monoethylene ketal (Scheme 3 or 4). [0135] Scheme 3.

[0136] Key: (a) LHMDS, THF, -78 °C; then MeI, -78 °C to rt; (b) 10% KOH, MeOH, HCHO (aq.), 0 °C; (c) TBSOTf, 2,6-lutidine, CH₂Cl₂, 0 °C, 64% for three steps; (d) LHMDS, THF, -78 °C, then allyl bromide, -78 °C to rt; (e) LHMDS, THF, -78 °C, then allyl bromide, -78 °C to rt; (f) NBS, THF, -45 °C, 66%.

[0137] Methylation of ketone 5, followed by hydroxymethylation under the thermodynamic conditions⁴ and protection of the resulting primary alcohol produced 11 (Scheme 3). Initial attempts to reach 14 from the desymmetrization of α,α'- diallycyclohexanone 12 were not fruitful. Bromoetherifϊcation reaction of 12 provided 13 in 66% yield and a mixture of other diastereomers in 24% yield. Di- tetrahydrofuran unit may be formed through the predominant attack of the carbonyl oxygen on an bromonium ion followed by hydrolysis and subsequent 5-membered cyclization.³ Therefore, we turned our attention to a sequential alkylation protocol to efficiently prepare the α,α'-tetrasubstituted cyclohexanone. In the event, the ketone 11 was mono-allylated, then alkylated with ethyl bromoacetate to generate tetrasubstituted ketones 14 and 15 in 73% and 24% yield for two steps, respectively (Scheme 4). [0138] Scheme 4.

14 (73%) + 15 (24%)

[0139] The moderate selectivity (3:1) is presumably a result of stereoelectronic effect in the enolate intermediate with the bulky TBS protected hydroxymethyl group configured in an pseudo-equatorial position.

[0140] We then initiated a series of cyclization operations to close the three remaining rings around the cyclohexanone core of 14. Conversion of the ester moiety to the β-ketophosphonate followed by intramolecular Horner-Emmons-Wadsworth reaction⁶ and global deprotection led to cyclopentenone 14a in 70% yield for three steps (Scheme 5). Conversion of 14a to the ethyl carbonate ester and subsequent cyclization to lactone 9 proceeded without difficulty. Oxidation of the β-keto lactone 9 with mCPBA furnished the desired α-hydroxy product in 90% yield as a single isomer, then which following stereoselective reduction gave trans-άιo\ 19. The relative configurations of the newly generated stereocenters were determined by single-crystal X-ray analysis of 19. [0141] Scheme 5 py , 93%

[0142] In certain embodiments, the C-I methyl group may be introduced at an earlier stage in the synthesis. For example, conversion of the ester moiety to the β- ketophosphonate followed by intramolecular Horner-Emmons-Wadsworth reaction⁶ led to cyclopentenone 16 in 91% yield (Scheme 6). At this stage, α-methylation at C₁ occurred primarily from the α-face, anti to the pendant allyl functionality to afford, upon deprotection, 17, as a 7:1 mixture of isomers. We initially sought to interpolate carbon 12 through a one-pot mixed orthoformate ester formation — cyclization sequence, as previously demonstrated in our synthesis of tazettine.⁷ Thus, intermediate 17 was first heated with trimethylorthoformate. When the alcohol had been consumed, the reaction was treated with polyphosphoric acid to afford, upon work-up, 18 as only a 2:1 mixture of Ci epimers. Unfortunately, various attempts to oxidize 18 to the requisite lactone were unsuccessful, resulting only in retro- Aldol decomposition products. [0143] Scheme 6

[0144] Key: (a) LiCH₂P(O)(OMe)₂, THF, -78 °C, 81% (99% based on recovered starting material); (b) NaH, THF, reflux, 91%; (c) LDA, THF, -20 ⁰C; then MeI, -30 °C; (d) 2N HCl, THF, 85% for two steps; (e) HC(OMe)₃, 105 °C; PPA, 105 ⁰C, 39% (18-C₁-(X) and 19% (18-C,-β).

[0145] Methylation of 19 via trianion formation followed by a two step oxidative cyclization generated lactone 10 setting the final stage of synthesis (Scheme 7). Stereoselective reduction of 10 under the Luche conditions and C(IO) hydroxyl incorporation with Davis' oxaziridine⁹ afforded α-hydroxy lactone 21 [6:1 at C(IO)].¹⁰ Next was attempted an oxidation of both C(2) and C(IO) hydroxyls and subsequent rearrangement of the β-keto lactone into hydroxytetrahydro- furancarboxlyate acetal moiety of jiadifenin. Surprisingly, even with the strong oxidant Jones reagent, the reaction would not progress to completion resulting in a mixture of (l/?^*,105^*)-2-oxo-3,4-dehydroneomajucin (22) and jiadifenin (1). After separation, 22 was submitted to oxidative ring contraction to yield 1 in 46% yield after a prolonged reaction time. The spectroscopic data of 22 and 1 were in accord with the published data.¹'² Further confirmation came from the identity of the NMR spectra of synthetic jiadifenin (±)-l with those of natural jiadifenin. [0146] Scheme 7 .

[0147] Key: (a) LDA, THF₃ -40 ⁰C to -15 °C; then MeI, HMPA, -35 °C, 64% (77% based on recovered starting material); (b) O₃, Sudan 7B Red, CH₂Cl₂-EtOH (1 :1), -78 °C; (c) Jones' reagent, acetone, 90% for two steps; (d) NaBH₄, CeCl₃-7H₂O, THF-MeOH (3: 1), -65 °C, 88%; (e) NaHMDS, THF, -78 °C; then Davis' oxaziridine, THF, -78 °C, 42% after one recycle; (f) Jones' reagent, acetone, MeOH, 22 (29%) and 1 (40%); (g) Jones' reagent, acetone, MeOH, 0 °C, 46%. [0148] The exemplary synthesis of 1 described herein, which follows an initial sequence of succesive alkylations in order to prepare α,α'-tetrasubstituted cyclohexanone 14, faced a significant selectivity problem during the last step, leading to a modest 3:1 selectivity for the desired product (14/15) (Scheme 4). Consequently, several approaches were investigated, such as desymmetrization of a α,α- diallylcyclohexanone by bromoetherification,¹¹ or intramolecular delivery of the electrophile during the final alkylation, in order to improve this selectivity but they all met the same unsuccessful outcome. Finally the solution came from a methodology developped at the same time by Tsuji and Trost in the mid-80s. In these original papers,¹² they showed that allyl cyclohexenol carbonate can be converted into α- allylcyclohexanone by a Pd-catalyzed reaction known today as the Tsuji-Trost allylation. More recently, an asymmetric version of this reaction was reported by Stoltz et al. ¹³

[0149] Even though only few examples of formation of all carbon quaternary center by this method were available at the time this work was performed, we examined the use of this reaction for the formation of α,α'-tetrasubstituted cyclohexanone intermediate. In our earliest attempts, trisubstituted cyclohexanone 24 was prepared by alkylation of the known compound 11 with ethyl bromoacetate (Scheme 8). Subsequent treatment of ketone 24 with /-BuOK, led to the selective formation of a cyclohexanolate moiety which was quenched with allylchloroformate to afford allyl vinylcarbonate 26.

[0150] With 26 in hand, the stage was now set for applying the palladium catalyzed allylation methodology on the real system. Upon exposure of carbonate 26 to [Pd(PPh₃)₄] in THF at room temperature, we were pleased to observed the formation of α,α'-tetrasubstituted cyclohexanone 14 and 15. Unfortunately, and not unexpectedly, the mixture obtained after purification exhibited a 14/15 ratio of 1 :5.6. The outcome of this reaction can be explained by the α«//-delivery of the allylic electrophile to the Pd-enolate intermediate, bearing the protected hydromethyl in a pseudo-equatorial orientation. We hypothesized that the improved selectivity of this alkylation might come from the intramolecular delivery of the allylic electrophile. Although not completely satisfying, the enhancement of the selectivity observed during the formation of the cc,α'-tetrasubstituted cyclohexanone system was encouraging. We decided to pursue the investigation of this reaction, having our minds convinced that if the selectivity could be further enhanced, the major product 15 could be used for the synthesis of jiadifenin. [0151] Scheme 8

11 R = TBS 24 R = TBS 26 R = = TBS 14 R = TBS 15 R = TBS

23 R = TBDPS 25 R = TBDPS 27 R = = TBDPS 28 R = TBDPS 29 R = TBDPS

Key: (a) LDA, BrCH₂CO₂Et, THF, -78 °C to rt, 64-81%; (b) t-BuOK, allylchloroformate, THF, -78 ⁰C, 80% - quant; (c) Pd(PPh₃)₄, THF, rt (26) or -40 °C (27), 62-65%, 14 : 15 (1 : 5.6), or 28 : 29 (1 : 8.7).

[0152] In order to further validate the hypothesis that the protected hydromethyl group has a directing effect on the selectivity, the bulkier TBDPS ether 23 was prepared under standard conditions. Alkylation to provide tri substituted cyclohexanone 25 and subsequent treatment with t-BuOK and allylchloroformate furnished allyl cyclohexenol carbonate 27 (Scheme 8). Upon exposure of carbonate 27 to [Pd(PPh₃)₄] in THF at -40 ⁰C, α,α'-tetrasubstituted cyclohexanone 28 and 29 were obtained in a 1 :8.7 ratio. Attempts to run the reaction at lower temperature led to poor conversion.

[0153] Having improved the selectivity for the synthesis of the of α,α'- tetrasubstituted cyclohexanone intermediate 15, and 29 respectively, we initiated a basic methodology study in order to determine the origin of the enhanced selectivity. The addition of an external source of deuterated π-allyl cation should permit to determine if the Pd-catalyzed allyation is an intramolecular process or not. Consequently, in a control experiment, allyl vinyl carbonate 27 was mixed with 10 equivalents of diallylcarbonate in THF and this solution was exposed to [Pd(PPh₃)₄]. After 15 minutes, a 6.5:1 mixture of ketone 29/28 was isolated after purification (Scheme 9). Deuterated Jio-diallylcarbonate 36 was prepared by reacting J₅-allyl alcohol and ΛζN-carbonyldiimidazole in DMF. A solution of carbonate 27 and 10 equivalents of 36 in THF was then treated with [Pd(PPh₃)₄] for 15 minutes. To our surprise, the mixture of α,α'-tetrasubstituted cyclohexanones, after purification, showed 67% of d₅-allyl incorporation. This result clearly invalidated the hypothesis that the enhanced selectivity observed during the formation of the 14/15, and 28/29 respectively, by Pd-catalyzed allylation originates from an intrmolecular process. A possible conclusion that can be drawn from this experiment is that the better selectivity observed with the Pd-catalysis methodology only stem from the tighter nature of the π-allyl-Pd enolate with regard to the Li-enolate species. Consequently, the pseudo-equatorial orientation of the protected hydroxymethyl group has a stonger influence on the selectivity observed during the Pd-catalyzed allylation than during standard alkylation with a lithium base such as LDA. [0154] Scheme 9.

28 29 = 1 6 5

(28 + d₅-28) (29 + d₅-29) = 1 6 6 (28 cf₅-28) = (29 d₅-29) = 1 2

[0155] Key: (a) diallylcarbonate (10 equiv.), Pd(PPh₃)₄, THF, rt, 77%; (b) J₅- diallylcarbonate (10 equiv.), Pd(PPh₃)₄, THF, rt, 90%.

[0156] With the selectivity issue having been addressed successfully, we then turned our attention to the conversion of 29 into a common intermediate of our previously discolosed total synthesis (Scheme 10). Therefore cyclohexanone 29 was subjected to Wacker oxidation conditions to afford methyl ketone 30. Intramolecular aldol condensation of 30 with t-BuOK in THF provided the bicyclic moiety 32, with concomittent participation of the methyl ester group to the cyclization reaction. [Note: the use of a milder base such as EtOK led to a mixture of desired 32 and tricycle product 31, as observed by Η-,¹³C-NMR, MS]. Thioester 33 was formed under standard procedure from carboxylic 31, and subsequently reduced by a mild Fukuyama reduction to give rise to aldehyde 34. Final treatment of 34 with methyl phosphonium bromide and NaHMDS led to Wittig olefination, furnishing the allyl intermediate 35 which correspond to an advanced intermediate of our total synthesis of (±)-jiadifenin.

[0157] In summary, we have reported herein our efforts addressing the selectivity issue encountered in the total synthesis of 1. We also emphasize some basic methodology investigations to identify the origin of the improved selectivity during the formation of α,α'-tetrasubstituted cyclohexanone 29 by Pd-catalyzed allylation of an allyl vinylcarbonate moiety. [0158] Scheme 10.

[0159] Key: (a) PdCl₂, Cu(OAc)₂, O₂, DMA/H₂0, rt, 69%; (b) t-BuOK, THF, 0 °C, 61%; (c) EtSH, DMAP, EDCI-HCl, CH₂Cl₂, 0 ⁰C to rt, 95%; (d) EtSiH, Pd/C, CH₂Cl₂, rt, 67%; (e) MePPh₃Br, NaHMDS, THF, rt, 72%. [0160] In certain embodiments, a similar strategy may be used to prepare normethyl jiadifenin (27) as depicted in Scheme 1 1. [0161] Scheme 11

[0162] For example, a two step oxidative cyclization of 19 generated lactone 23 setting the final stage of synthesis of normethyl jiadifenin. Stereoselective reduction of 23 and C(IO) hydroxyl incorporation with Davis' oxaziridine⁹ afforded α-hydroxy lactone 25. Next was attempted an oxidation of both C(2) and C(IO) hydroxyls and subsequent rearrangement of the β-keto lactone into hydroxytetrahydro- furancarboxlyate acetal moiety of normethyl jiadifenin. Oxidation with the Jones reagent afforded normethyl jiadifenin (27) in 36% yield. [0163] De-symmetrization was attempted as outlined in Scheme 12. [0164] Scheme 12

-78⁰C ratio -5.1:1 not much improved

In certain embodiments, the neurotrophic activity of 10, 22, 27 and 1 was examined (See Example 16). The ability of jiadifenin (1) to promote neurite outgrowth was measured in both the presence and absence of nerve growth factor (NGF). In the presence of NGF, jiadifenin enhanced neurite lengths by 162% (P < 0.05). However, in the absence of NGF, no neurite outgrowth was observed, indicating that jiadifenin operates by upregulating the action of NGF rather than functioning independently. [0165] In addition to jiadifenin itself, we evaluated the in vitro neurotrophic activity of several synthetic analogs of the natural product in order to establish an SAR profile (See Table 1 and Figure 1 - data shown for 22 and 1 only). Neurite lengths enhanced by 27, 22 and 1 were 181% (/^><0.01), 184% (PO.01) and 162% (P<0.05), respectively, relative to the DMSO control.

[0166] The most active compound was found to be intermediate 22, which is the direct precursor to the natural product. This analog was found to enhance neurite lengths by 184%. The normethyl jiadifenin analog, 27, also exhibits superior activity in comparison with jiadifenin, enhancing neurite lengths by 181%. Interestingly, intermediate 10, in which Ci₀ is unoxidized, exhibits no neurite length enhancement. [0167]

[0168] Diversification:

[0169] It will also be appreciated that each of the components used in the synthesis of jiadifenin analogues can be diversified either before synthesis or alternatively after the construction of the polycycle. As used herein, the term "diversifying" or "diversify" means reacting an inventive compound (I) or any of the precursor fragments as defined herein (or any classes or subclasses thereof) at one or more reactive sites to modify a functional moiety or to add a functional moiety (e.g., nucleophilic addition of a substrate). Described generally herein are a variety of schemes to assist the reader in the synthesis of a variety of analogues, either by diversification of the intermediate components or by diversification of the macrocyclic structures as described herein, and classes and subclasses thereof. It will be appreciated that a variety of diversification reactions can be employed to generate novel analogues. For additional guidance available in the art, the practitioner is directed to "Advanced Organic Chemistry", March, J. John Wiley & Sons, 2001, 5^th ed., the entire contents of which are hereby incorporated by reference. For example, analogs of the structure depicted below may be prepared:

CF₂

CF₂ n = 0 or 1, m = 1 or 2

Rl = H, OH, OR, alkyl, heteroalkyl, aryl, heteroaryl, amino, halogen, SH, SR¹.

R2 = H, -COOR, -COOH, -CH20H, -C(=O)H, -CH=CR¹R², -C(=0)R, -C(=NR')R², -

C(=N0R')R², -C(=N-NR'R²)R², alkyl, heteroalkyl, aryl, heteroaryl, OH, OR, amino, halogen, SH, SR¹.

R3, R4, R5 = H, alkyl, aryl, heteroalkyl

R6 = H, OH, OR, alkyl, heteroalkyl, aryl, heteroaryl, amino, halogen, SH, SR¹

[0170] 3) Pharmaceutical Compositions

[0171] As discussed above this invention provides novel compounds that have biological properties useful for the treatment of any disorder or condition that would benefit from promotion of neurite outgrowth.

[0172] Accordingly, in another aspect of the present invention, pharmaceutical compositions are provided, which comprise any one of the compounds described herein (or a prodrug, pharmaceutically acceptable salt or other pharmaceutically acceptable derivative thereof), and optionally comprise a pharmaceutically acceptable carrier. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. Alternatively, a compound of this invention may be administered to a patient in need thereof in combination with the administration of one or more other therapeutic agents. For example, additional therapeutic agents for conjoint administration or inclusion in a pharmaceutical composition with a compound of this invention may be an approved agent for the treatment of a neurodegenerative disease or disorder, or it may be any one of a number of agents undergoing approval in the Food and Drug Administration that ultimately obtain approval for the treatment of any disorder or condition that benefits from promotion of neurite outgrowth. It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or a pro-drug or other adduct or derivative of a compound of this invention which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

[0173] Optionally, the composition may include one or more additional inventive compounds.

[0174] When the composition is used to treat Alzheimer's disease, the composition optionally may contain therapeutically effective amount of one or more compounds that are used to treat cognitive symptoms of Alzheimer's disease including but not limited to: cholinesterase inhibitors (e.g., donepezil (Aricept®), rivastigmine (Exelon®), galantamine (Reminyl®) and Tacrine (Cognex®)) and N- methyl-D-aspartate (NMDA) receptor antagonists (e.g., Memantine (Namenda®)). [0175] In certain embodiments, when the composition is used to treat Alzheimer's disease, the composition optionally may contain therapeutically effective amount of vitamin E. Vitamin E supplements are often prescribed as a treatment for Alzheimer's disease, because they may help brain cells defend themselves from "attacks." Normal cell functions create a byproduct a called free radical, a kind of oxygen molecule that can damage cell structures and genetic material. This damage, called oxidative stress, may play a role in Alzheimer's disease.

[0176] Cells have natural defenses against this damage, including the antioxidants vitamins C and E, but with age some of these natural defenses decline. Research has shown that taking vitamin E supplements may offer some benefit to people with Alzheimer's.

[0177] When the composition is used to treat Parkinson's disease, the composition optionally may contain therapeutically effective amount of one or more compounds that are used to treat Parkinson's disease including but not limited to: Anticholinergics (e.g., Benztropine, Ethropropazine, Procyclidine and Trihexyphenidyl), COMT Inhibitors (such as Entacapone or Tolcapone), Dopamine Precursor (such as levodopa), Dopamine Receptor Agonists (e.g., Bromocriptine, Cabergoline, Pergolide, Pramipexole and Ropinirole) and MAO-B Inhibitors (e.g., Amantadine).

[0178] A wide variety of carriers may be selected of either polymeric or non- polymeric origin which may be biodegradable or non-biodegradable. Examples of suitable carriers are described in published U.S. Patent Application 2002/0128471, paragraphs [0111] through [0123] which are incorporated herein by reference. [0179] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below. For example, a free base function can be reacted with a suitable acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0180] Additionally, as used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

[0181] Furthermore, the term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the issues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

[0182] As described above, the pharmaceutical compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogenfree water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0183] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifϊers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. [0184] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0185] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0186] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension or crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include (poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

[0187] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0188] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar— agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. [0189] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. [0190] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose and starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

[0191] The present invention encompasses pharmaceutically acceptable topical formulations of inventive compounds. The term "pharmaceutically acceptable topical formulation", as used herein, means any formulation which is pharmaceutically acceptable for intradermal administration of a compound of the invention by application of the formulation to the epidermis. In certain embodiments of the invention, the topical formulation comprises a carrier system. Pharmaceutically effective carriers include, but are not limited to, solvents (e.g., alcohols, poly alcohols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffered solutions (e.g., hypotonic or buffered saline) or any other carrier known in the art for topically administering pharmaceuticals. A more complete listing of art-known carriers is provided by reference texts that are standard in the art, for example, Remington's Pharmaceutical Sciences, 16th Edition, 1980 and 17th Edition, 1985, both published by Mack Publishing Company, Easton, Pa., the disclosures of which are incorporated herein by reference in their entireties. In certain other embodiments, the topical formulations of the invention may comprise excipients. Any pharmaceutically acceptable excipient known in the art may be used to prepare the inventive pharmaceutically acceptable topical formulations. Examples of excipients that can be included in the topical formulations of the invention include, but are not limited to, preservatives, antioxidants, moisturizers, emollients, buffering agents, solubilizing agents, other penetration agents, skin protectants, surfactants, and propellants, and/or additional therapeutic agents used in combination to the inventive compound. Suitable preservatives include, but are not limited to, alcohols, quaternary amines, organic acids, parabens, and phenols. Suitable antioxidants include, but are not limited to, ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents like EDTA and citric acid. Suitable moisturizers include, but are not limited to, glycerine, sorbitol, polyethylene glycols, urea, and propylene glycol. Suitable buffering agents for use with the invention include, but are not limited to, citric, hydrochloric, and lactic acid buffers. Suitable solubilizing agents include, but are not limited to, quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates. Suitable skin protectants that can be used in the topical formulations of the invention include, but are not limited to, vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[0192] In certain embodiments, the pharmaceutically acceptable topical formulations of the invention comprise at least a compound of the invention and a penetration enhancing agent. The choice of topical formulation will depend or several factors, including the condition to be treated, the physicochemical characteristics of the inventive compound and other excipients present, their stability in the formulation, available manufacturing equipment, and costs constraints. As used herein the term " penetration enhancing agent " means an agent capable of transporting a pharmacologically active compound through the stratum corneum and into the epidermis or dermis, preferably, with little or no systemic absorption. A wide variety of compounds have been evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin. See, for example, Percutaneous Penetration Enhancers, Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., Boca Raton, FIa. (1995), which surveys the use and testing of various skin penetration enhancers, and Buyuktimkin et al. , Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh T. K., Pfϊster W. R., Yum S. I. (Eds.), Interpharm Press Inc., Buffalo Grove, 111. (1997). In certain exemplary embodiments, penetration agents for use with the invention include, but are not limited to, triglycerides (e.g., soybean oil), aloe compositions {e.g., aloe- vera gel), ethyl alcohol, isopropyl alcohol, octolyphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate) and N-methyl pyrrolidone.

[0193] In certain embodiments, the compositions may be in the form of ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. In certain exemplary embodiments, formulations of the compositions according to the invention are creams, which may further contain saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmito-oleic acid, cetyl or oleyl alcohols, stearic acid being particularly preferred. Creams of the invention may also contain a non-ionic surfactant, for example, polyoxy-40-stearate. In certain embodiments, the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are made by dissolving or dispensing the compound in the proper medium. As discussed above, penetration enhancing agents can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. [0194] It will also be appreciated that the compounds and pharmaceutical compositions of the present invention can be formulated and employed in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated with or administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another therapeutic agent useful for the treatment of a suitable neuridegenerative diseases or disorder), or they may achieve different effects (e.g., control of any adverse effects). [0195] For example, other therapies or therapeutic agents that may be used in combination with the inventive compounds of the present invention include [0196] In certain embodiments, the pharmaceutical compositions of the present invention further comprise one or more additional therapeutically active ingredients (e.g., neurotrophic agent and/or palliative). For purposes of the invention, the term "Palliative " refers to treatment that is focused on the relief of symptoms of a disease and/or side effects of a therapeutic regimen, but is not curative. For example, palliative treatment encompasses painkillers, antinausea medications and anti-sickness drugs.

[0197] 4) Research Uses, Pharmaceutical Uses and Methods of Treatment

[0198] Research Uses

[0199] According to the present invention, the inventive compounds may be assayed in any of the available assays known in the art for identifying compounds having neurotrophic activity. For example, the assay may be cellular or non-cellular, in vivo or in vitro, high- or low-throughput format, etc.

[0200] Thus, in one aspect, compounds of this invention which are of particular interest include those which:

• exhibit neurotrophic activity;

• promote neurite outgrowth; and/or

• exhibit a favorable therapeutic profile (e.g., safety, efficacy, and stability). [0201] As discussed above, certain of the compounds as described herein exhibit activity generally as neurotrophic agents. More specifically, compounds of the invention act as modulators of neurite outgrowth. As detailed in the exemplification herein, in assays to determine the ability of compounds to enhance neurite length certain inventive compounds exhibit neurite length enhancement > about 50% at a concentration between about 0.1 μM and 10 μM. In certain other embodiments, inventive compounds exhibit exhibit neurite length enhancement > about 70% at a concentration between about 0.1 μM and 10 μM. In certain other embodiments, inventive compounds exhibit exhibit neurite length enhancement > about 80% at a concentration between about 0.1 μM and 10 μM. In certain other embodiments, inventive compounds exhibit exhibit neurite length enhancement > about 90% at a concentration between about 0.1 μM and 10 μM. In certain other embodiments, inventive compounds exhibit exhibit neurite length enhancement > about 100% at a concentration between about 0.1 μM and 10 μM. In certain other embodiments, inventive compounds exhibit exhibit neurite length enhancement > about 120% at a concentration between about 0.1 μM and 10 μM. In certain other embodiments, inventive compounds exhibit exhibit neurite length enhancement > about 150% at a concentration between about 0.1 μM and 10 μM. In certain other embodiments, inventive compounds exhibit exhibit neurite length enhancement > about 160% at a concentration between about 0.1 μM and 10 μM. In certain other embodiments, inventive compounds exhibit exhibit neurite length enhancement > about 170% at a concentration between about 0.1 μM and 10 μM. In certain other embodiments, inventive compounds exhibit exhibit neurite length enhancement > about 180% at a concentration between about 0.1 μM and 10 μM. In certain embodiments, the following compounds exhibited the following neurite length enhancements at a concentration of 0.3 μM. neurite lengths enhanced relative to the DMSO-NGF control

184% 162% 181% 0 %

[0202] Pharmaceutical Uses and Methods of Treatment

[0203] In yet another aspect, the present invention provides methods for treating or lessening the severity of any disorder or condition that would benefit from promotion of neurite outgrowth.

[0204] In general, methods of using the compounds of the present invention comprise administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention. Diseases that may be treated with the compounds of the present invention are those that are associated with neurotrophic activity, such as neurodegenerative disorders. Illustrative examples of neurodegenerative disorders include, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease and Lou Gehrig's disease.

[0205] Accordingly, in another aspect of the invention, methods for the treatment of a neurodegenerative disorder are provided comprising administering a therapeutically effective amount of a compound of formula (I), as described herein, to a subject in need thereof, wherein the amount is effective to promote neurite outgrowth. In certain embodiments, a method for the treatment of a neurodegenerative disorder is provided comprising administering a therapeutically effective amount of an inventive compound, or a pharmaceutical composition comprising an inventive compound to a subject in need thereof, in such amounts and for such time as is necessary to achieve the desired result. [0206] In certain embodiments, the method involves the administration of a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or animal) in need of it. In certain embodiments, the inventive compounds as useful for the treatment of a neurodegenerative disorder (including, but not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease and Lou Gehrig's disease).

[0207] The compounds in accordance with the present invention may be used in combination with a supplementary active compound or as a substitution for treating a subject suffering from a neurodegenerative disease or disorder. For example, when the compound is used to treat or lessen to the severity of Alzheimer's disease, the compound may be used alone or combination with one or more supplementary active compounds such as cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine and Tacrine), N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., Memantine) and/or vitamin E supplements. In other embodiments, when the compound is used to treat or lessen to the severity of Parkinson's disease, the compound may be used alone or combination with one or more supplementary active compounds such as Anticholinergics (e.g., Benztropine, Ethropropazine, Procyclidine and Trihexyphenidyl), COMT Inhibitors (such as Entacapone or Tolcapone), Dopamine Precursor (such as levodopa), Dopamine Receptor Agonists (e.g., Bromocriptine, Cabergoline, Pergolide, Pramipexole and Ropinirole) and MAO-B Inhibitors (e.g., Amantadine). In certain embodiments, a compound of the invention may be used alone or in combination with another neurotrophic agent, or a second compound of the invention to treat, prevent or inhibit Alzheimer's disease. [0208] Moreover, treatment of a subject with a therapeutically effective amount of the compounds fo the invention can include a single treatment or, preferably, can include a series of treatments.

[0209] The inventive compoundscan be administered in any manner sufficient to achieve the above endpoints. Exemplary methods of administration include intravenous, oral, or subcutaneous, intramuscular or intrathecal injection. The inventive compounds can be administered as a chronic low dose therapy to prevent disease progression, prolong disease remission or decrease symptoms in active disease. Alternatively, the therapeutic agent can be administered in higher doses as a "pulse" therapy to induce remission in acutely active disease. The minimum dose capable of achieving these endpoints can be used and can vary according to patient, severity of disease, formulation of the administered agent, and route of administration. [0210] In certain embodiments, an effective therapy for Alzheimer's disease will accomplish one or more of the following: (i) decrease the severity of symptoms (e.g., forgetfulness, memory loss, decision making impairment, problems speaking, understanding, reading, or writing, anxiety, aggressivity); (ii) decrease the severity of clinical signs of the disease (e.g., beta-amyloid deposits in the brain, massive loss of cortical neurons and accumulation of paired helical filaments (PHFs) in the neurofibrillary tangles (NFTs)); (iii) increase the frequency and duration of disease remission/symptom-free periods; and (iv) prevent/attenuate chronic progression of the disease.

[0211] Another aspect of the invention relates to a method for promoting neurite outgrowth in a biological sample or a subject, which method comprises administering to the subject, or contacting said biological sample with a compound of formula I or a composition comprising said compound.

[0212] Another aspect of the invention relates to a method of treating or lessening the severity of a neurodegenerative disease or condition associated in a subject, said method comprising a step of administering to said subject, a compound of formula I or a composition comprising said compound.

[0213] It will be appreciated that the compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for the treatment of neurodegenerative disorders. For example, when using the inventive compounds for the treatment of Alzheimer's disease, the expression "effective amount" as used herein, refers to a sufficient amount of agent to promote neurite outgrowth, or refers to a sufficient amount to reduce the effects/symptoms of Alzheimer's disease. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the diseases, the particular compound, its mode of administration, and the like.

[0214] The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of therapeutic agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts (see, for example, Goodman and Gilman's, "The Pharmacological Basis of Therapeutics", Tenth Edition, A. Gilman, J.Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001, which is incorporated herein by reference in its entirety).

[0215] Furthermore, in certain embodiments, after formulation with an appropriate pharmaceutically acceptable carrier in a desired dosage, the pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, creams or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered at dosage levels of about 0.001 mg/kg to about 50 mg/kg, from about 0.01 mg/kg to about 25 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. It will also be appreciated that dosages smaller than 0.001 mg/kg or greater than 50 mg/kg (for example 50-100 mg/kg) can be administered to a subject. In certain embodiments, compounds are administered orally or parenterally.

TREATMENT KIT

[0216] In other embodiments, the present invention relates to a kit for conveniently and effectively carrying out the methods in accordance with the present invention. In general, the pharmaceutical pack or kit comprises one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Such kits are especially suited for the delivery of solid oral forms such as tablets or capsules. Such a kit preferably includes a number of unit dosages, and may also include a card having the dosages oriented in the order of their intended use. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered. Alternatively, placebo dosages, or calcium dietary supplements, either in a form similar to or distinct from the dosages of the pharmaceutical compositions, can be included to provide a kit in which a dosage is taken every day. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

EQUIVALENTS

[0217] The representative examples that follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. It should further be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the art. Throughput this document, various publications are referred to, each of which is hereby incorporated by reference in its entirety in an effort to more fully describe the state of the art to which the invention pertains.

[0218] The following examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and the equivalents thereof.

EXEMPLIFICATION

[0219] The compounds of this invention and their preparation can be understood further by the examples that illustrate some of the processes by which these compounds are prepared or used. It will be appreciated, however, that these examples do not limit the invention. Variations of the invention, now known or further developed, are considered to fall within the scope of the present invention as described herein and as hereinafter claimed. [0220] 1) General Description of Synthetic Methods: [0221] The practitioner has a a well-established literature of polycycle chemistry to draw upon, in combination with the information contained herein, for guidance on synthetic strategies, protecting groups, and other materials and methods useful for the synthesis of the compounds of this invention.

[0222] Moreover, the practitioner is directed to the specific guidance and examples provided in this document relating to various exemplary compounds and intermediates thereof.

[0223] The compounds of this invention and their preparation can be understood further by the examples that illustrate some of the processes by which these compounds are prepared or used. It will be appreciated, however, that these examples do not limit the invention. Variations of the invention, now known or further developed, are considered to fall within the scope of the present invention as described herein and as hereinafter claimed.

[0224] According to the present invention, any available techniques can be used to make or prepare the inventive compounds or compositions including them. For example, a variety of solution phase synthetic methods such as those discussed in detail below may be used. Alternatively or additionally, the inventive compounds may be prepared using any of a variety combinatorial techniques, parallel synthesis and/or solid phase synthetic methods known in the art.

[0225] It will be appreciated as described below, that a variety of inventive compounds can be synthesized according to the methods described herein. The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Sigma (St. Louis, MO), or are prepared by methods well known to a person of ordinary skill in the art following procedures described in such references as Fieser and Fieser 1991, "Reagents for Organic Synthesis", vols 1-17, John Wiley and Sons, New York, NY, 1991; Rodd 1989 "Chemistry of Carbon Compounds", vols. 1-5 and supps, Elsevier Science Publishers, 1989; "Organic Reactions", vols 1-40, John Wiley and Sons, New York, NY, 1991; March 2001, "Advanced Organic Chemistry", 5th ed. John Wiley and Sons, New York, NY; and Larock 1990, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 2^nd ed. VCH Publishers. These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to a person of ordinary skill in the art having regard to this disclosure.

[0226] The starting materials, intermediates, and compounds of this invention may be isolated and purified using conventional techniques, including filtration, distillation, crystallization, chromatography, and the like. They may be characterized using conventional methods, including physical constants and spectral data. [0227] Analytical Equipment: ¹H and ¹³C NMR spectra were recorded on a Bruker AMX-400 MHz or a Bruker Advance DRX-500 MHz spectrometer in CDCl₃ [referenced to 7.26 ppm (δ) for ¹H NMR and 77.0 ppm for ¹³C NMR], CD₃COCD₃ [referenced to 2.05 ppm (δ) for ¹H NMR and 20.83 ppm for ¹³C NMR], CD₃OD [referenced to 3.30 ppm (δ) for ¹H NMR and 49.05 ppm for ¹³C NMR], and C₅D₅N- TMS [referenced to 0 ppm (δ) for ¹H NMR and 123.44 ppm for ¹³C NMR]. Low resolution mass spectra (ionspray, a variation of electrospray) were acquired on a Perkin-Elmer Sciex API 100 spectrometer. High resolution mass spectra (fast atom bombardment, FAB) were acquired on a Micromass 70-SE-4F spectrometer. Infrared spectra were obtained on a Perkin-Elmer 1600 FT-IR spectrophotometer with a NaCl plate.

[0228] Example 1

[0229] TBS ether 11. To a cooled (-78 ⁰C) solution of LHMDS (1.0 M in THF, 89.5 mL, 1.0 equiv) in THF (250 mL) was added a solution of ketone 5 (13.90 g, 89.00 mmol) in THF (40 mL) slowly over 15 min and the resulting mixture was stirred at -78 ⁰C for 34 min. Iodomethane (6.5 mL, 1.2 equiv) was added to the reaction mixture and the resulting solution was stirred at -78 ⁰C for 20 min and at room temperature for 2 h. The reaction mixture was quenched by addition of saturated NH₄Cl (250 mL) and extracted with ether (3 X 250 mL). Combined extracts were dried (MgSO₄), filtered, and concentreated in vacuo. Flash chromatography (pentane-ether 4:1 -> 3:1 -> 2:1) afforded α-methylcyclohexanone (11.16 g, 74% yield). The spectroscopic data of the product were in accord with the published data (Pfau, M.; Jabin, L; Revial, G. J. Chem. Soc, Perkin Trans. 1 1993, 1935). [0230] To a cooled (0 ⁰C) yellow solution of α-methylcyclohexanone (1.871 g, 10.67 mmol) in 10% KOH in MeOH (10 g) was added a solution of 37% aqueous formaldehyde (0.80 mL, 1.0 equiv) in MeOH (0.80 mL) dropwise over 31 min. The reaction mixture was stirred at 0 ⁰C for 15 min. The reaction mixture was quenched by addition of 1 N aqueous HCl (18 mL), diluted with saturated NH₄Cl (20 niL), and extracted with CH₂Cl₂ (4 X 100 mL). Combined extracts were dried (MgSO₄), filtered and concentrated in vacuo. Flash chromatography (hexanes-ether 1.5:1 — > 1 :1 →1 :2 → 1 :3) gave alcohol (1.508 g, 71% yield, 89% based on recovered starting material): IR (neat) 3475 (m, br), 2959 (m), 2933 (m), 2883 (m), 1706 (s), 1457 (w), 1432 (w), 1362 (w), 1308 (w), 1275 (w), 1151 (w), 1113 (m), 1078 (m), 1038 (m), 995 (w), 948 (m) cm^"1; ¹H NMR (400 MHz, CDCl₃) δ 4.07-3.93 (m, 4 H), 3.58 (dd, J

= 7.4, 11.3 Hz, 1 H), 3.37 (dd, J = 6.6, 11.4 Hz, 1 H), 2.75 (ddd, J = 6.1, 11.1, 15.0 Hz, 1 H), 2.59 (t, J = 7.0 Hz, 1 H), 2.40 (td, J= 5.5, 15.0 Hz, 1 H), 2.16 (d, J = 14.1 Hz, 1 H), 2.06-1.93 (m, 2 H), 1.74 (dd, J= 2.6, 14.1 Hz, 1 H), 1.55 (s, 1 H), 1.20 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 215.1, 107.3, 68.5, 64.4, 64.1, 49.4, 42.1, 36.2,

34.0, 21.4; high resolution mass spectrum m/z 223.0943 [(M+Na)⁺; calcd for Ci₀H₁₆O₄Na: 223.0946].

[0231] A solution of alcohol (2.800 g, 14 mmol) in CH₂Cl₂ (150 mL) was cooled to 0 ⁰C, treated with 2,6-lutidine (4.0 mL, 2.5 equiv) and TBSOTf (3.7 mL, 1.1 equiv) and stirred at 0 ⁰C for 15 min. The reaction mixture was quenched with saturated NH₄Cl (175 mL) and extracted with CH₂Cl₂ (3 X 150 mL). Combined extracts were dried (MgSO₄), filtered and concentrated in vacuo. Flash chromatography (hexanes- ether 4:1 → 3:1 → 2:1) gave TBS ether 7 (4.726 g, 97% yield): IR (neat) 2955 (s), 2930 (s), 2884 (s), 2859 (s), 1716 (s), 1472 (m), 1463 (m), 1433 (w), 1387 (w), 1361 (m), 1307 (w), 1255 (m), 1101 (m, br), 1035 (w), 1005 (w), 949 (w), 837 (m, br) cm^"1; ¹H NMR (400 MHz, CDCl₃) δ 3.98 (m, 4 H), 3.73 (d, J = 9.4 Hz, 1 H), 3.46 (d, J = 9.4 Hz, 1 H), 2.52 (tdd, J= 6.8, 15.6, 37.8 Hz, 2 H), 2.25 (d, J = 14.2 Hz, 1 H), 1.97 (t, J = 7.1 Hz, 2 H), 1.72 (d, J= 14.0 Hz, 1 H), 1.10 (s, 3 H), 0.84 (s, 9 H), 0.01 (s, 6 H); ¹³C NMR (125 MHz, CDCl₃) δ 213.2, 107.9, 68.3, 64.4, 64.3, 49.9, 41.6, 36.3, 33.9, 25.8, 21.8, 18.2, -5.58, -5.59; high resolution mass spectrum m/z 337.1808

[(M+Na)+; calcd for C₁₆H₃₀O₄NaSi: 337.181 1].

[0232] Example 2

[0233] Esters 14 and 15. To a cooled (-78 ⁰C) solution of TBS ether 11 (1.389 g,

4.42 mmol) in THF (45 mL) was added LHMDS (1.0 M in THF, 4.40 mL, 1.0 equiv) dropwise and the resulting mixture was stirred at -78 ⁰C for 23 min. The reaction mixture was treated with allyl bromide (0.57 mL, 1.5 equiv) and warmed to room temperature over 4 h. The reaction mixture was quenched with saturated NH₄Cl (100 mL) and extracted with ether (3 X 100 mL). Combined extracts were dried (MgSO₄), filtered and concentrated in vacuo. Flash chromatography (hexanes-ether 10: 1 — » 3:1) afforded a mixture (less polar compound:more polar compound = 1:1.3) of α- allylcyclohexanone (1.147 g, 73% yield, 99% based on recovered starting material); IR (neat) 2954 (s), 2929 (s), 2884 (s), 2857 (s), 1716 (s), 1641 (w), 1472 (m), 1463 (m), 1387 (w), 1361 (m), 1297 (w), 1257 (m), 1202 (w), 1177 (w), 1095 (s, br), 1031 (w), 1006 (w), 948 (w), 913 (w), 836 (m, br) cm^"1; less polar compound ¹H NMR (500 MHz, CDCl₃) δ 5.73 (m, 1 H), 5.01 (m, 2 H), 4.05 (m, 2 H), 3.96 (m, 2 H), 3.80

(d, J = 9.5 Hz, 1 H), 3.27 (d, J = 9.5 Hz, 1 H), 2.83 (m, 1 H), 2.51 (td, J = 6.2, 14.4 Hz, 1 H), 2.24 (d, J= 14.1 Hz, 1 H), 2.08-1.98 (m, 2 H), 1.81 (dd, J = 3.6, 14.1 Hz, 1 H), 1.65 (t, J = 13.6 Hz, 1 H), 1.19 (s, 3 H), 0.86 (s, 9 H), 0.03 (s, 6 H); ¹³C NMR (125 MHz, CDCl₃) δ 213.5, 136.1, 116.6, 107.9, 68.3, 64.7, 64.0, 49.6, 43.1, 41.8, 39.3, 33.2, 25.8, 22.5, 18.2, -5.5, -5.6; more polar compound ¹H NMR (500 MHz, CDCl₃) δ 5.76 (m, 1 H), 5.00 (m, 2 H), 4.02 (m, 2 H), 3.92 (t, J = 6.2 Hz, 2 H), 3.89

(d, J = 9.4 Hz, 1 H), 3.61 (d, J = 9.5 Hz, 1 H), 2.81 (m, 1 H), 2.51 (td, J = 6.1, 14.1 Hz, 1 H), 2.21 (dd, J= 2.8, 14.4 Hz, 1 H), 2.13 (ddd, J= 3.0, 5.4, 13.6 Hz, 1 H), 1.96 (td, J= 7.3, 14.4 Hz, 1 H), 1.68 (d, J= 14.3 Hz, 1 H), 1.65 (t, J= 13.7 Hz, 1 H), 1.06 (s, 3 H), 0.85 (s, 9 H), 0.01 (s, 6 H); ¹³C NMR (125 MHz, CDCl₃) δ 213.3, 136.2, 116.5, 107.6, 68.8, 64.6, 64.1, 50.0, 43.6, 42.7, 40.5, 33.4, 25.7, 21.0, 18.1, -5.61, -

5.64; high resolution mass spectrum m/z 377.2113 [(M+Na)⁺; calcd for C₁₉H₃₄O₄NaSi: 377.2124].

[0234] To a cooled (-78 ⁰C) solution of LDA (1.1 equiv) in THF (30 mL) was added a solution of α-allylcyclohexanone (3.036 g, 8.562 mmol) in THF (6 mL) dropwise and the resulting mixture was warmed to -20 ⁰C over 2 h. The reaction mixture was cooled to -78 ⁰C and treated with a mixture of ethyl bromoacetate (2.0 mL, 2.1 equiv) and HMPA (1.5 mL, 1.1 equiv). The resultant mixture was stirred at - 78 ⁰C for 21 h. The reaction mixture was quenched with saturated NH₄Cl (200 mL) and extracted with ether (3 X 250 mL). Combined extracts were dried (MgSO₄), filtered and concentrated in vacuo. Flash chromatography (hexanes-ether 10:1 — > 6:1 -> 3:1) afforded esters 14 (2.754 g, 73% yield) and 15 (0.905 g, 24% yield). [0235] 14: IR (neat) 2955 (s), 2929 (s), 2883 (s), 2857 (s), 1733 (s), 1710 (s), 1638 (w), 1472 (m), 1463 (m), 1407 (m), 1388 (m), 1370 (m), 1344 (m), 1254 (m), 1190 (m), 1 155 (m), 1098 (m, br), 1033 (m), 984 (m), 947 (m), 917 (m), 839 (m,br) cm^"1; ¹H NMR (400 MHz, CDCl₃) δ 5.65 (m, 1 H), 5.06 (m, 2 H), 4.04 (q, J= 7.2 Hz, 2 H), 4.00-3.88 (m, 4 H), 3.96 (d, J = 8.9 Hz, 1 H), 3.13 (d, J = 9.1 Hz, 1 H), 2.89 (d, J= 16.6 Hz, 1 H), 2.58 (d, J= 14.6 Hz, 1 H), 2.45 (dd, J= 7.5, 13.8 Hz, 1 H), 2.43 (d, J= 14.4 Hz, 1 H), 2.20 (d, J= 16.7 Hz, 1 H), 2.16 (dd, J= 7.3, 13.8 Hz, 1 H), 1.95 (d, J = 14.5 Hz, 1 H), 1.81 (d, J= 15.4 Hz, 1 H), 1.19 (t, J= 7.1 Hz, 3 H), 1.13 (s, 3 H), 0.84 (s, 9 H), 0.00 (s, 3H), -0.01 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 214.9, 171.5, 133.0, 119.2, 107.8, 68.4, 64.0, 63.8, 60.3, 49.5, 48.3, 41.2, 40.6, 39.6, 39.4, 25.8, 22.8, 18.2, 14.2, -5.6, -5.7; high resolution mass spectrum m/z 463.2478

[(M+Na)+; calcd for C₂₃H₄₀O₆NaSi: 463.2492].

[0236] 15: IR (neat) 2929 (s, br), 2883 (s), 2858 (s), 1732 (s), 1698 (s), 1638 (m), 1474 (m), 1408 (w), 1389 (w), 1370 (m), 1341 (m), 1304 (w), 1252 (m), 1187 (m), 1152 (m), 1094 (m), 1033 (m), 1013 (m), 972 (m), 948 (m), 918 (m), 836 (m, br) cm^' '; ¹H NMR (400 MHz, CDCl₃) δ 5.61 (m, 1 H), 5.06 (m, 2 H), 4.03 (q, J= 7.1 Hz, 2 H), 4.01-3.95 (m, 2 H), 3.90 (m, 2 H), 3.71 (d, J= 9.3 Hz, 1 H), 3.47 (d, J = 9.3 Hz, 1 H), 2.82 (d, J= 16.7 Hz, 1 H), 2.55 (dd, J= 7.6, 13.8 Hz, 1 H), 2.38 (dd, J= 7.2, 13.8 Hz, 1 H), 2.29 (d, J= 14.4 Hz, 1 H), 2.22 (d, J= 14.2 Hz, 1 H), 2.21 (d, J= 16.7 Hz, 1 H), 1.97 (dd, J = 2.6, 14.2 Hz, 1 H), 1.85 (dd, J= 2.6, 14.4 Hz, 1 H), 1.193 (s, 3 H), 1.185 (t, J= 7.1 Hz, 3 H), 0.85 (s, 9 H), 0.004 (s, 3 H), -0.002 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 215.9, 171.8, 133.7, 119.6, 108.2, 69.8, 65.0, 63.8, 60.7, 49.6, 49.5, 42.3, 41.6, 40.8, 39.9, 26.3, 23.4, 18.7, 14.6, -5.1, -5.2; high resolution mass spectrum m/z 463.2487 [(M+Na)⁺; calcd for C₂₃H₄₀O₆NaSi: 463.2492]. [0237] Example 3

[0238] Alcohol 12. IR (neat) 3501 (s, br), 3076 (m), 2934 (s, br), 1843 (w), 1699 (s), 1636 (m), 1456 (s), 1362 (m), 1262 (m), 1 150 (m), 1079 (m), 920 (m) cm^'1; ¹H NMR (400 MHz, CDCl₃) δ 5.60 (m, 2 H), 5.05 (m, 4 H), 3.95 (m, 4 H), 3.63 (dd, J =

7.6, 11.1 Hz, 1 H), 3.29 (dd, J = 6.0, 11.1 Hz, 1 H), 2.44 (m, 3 H), 2.27 (dd, J = 7.8, 13.9 Hz, 1 H), 2.23 (d, J= 14.6 Hz, 1 H), 2.14 (dd, J= 8.1, 13.9 Hz, 1 H), 2.02 (m, 2 H), 1.81 (d, J = 14.7 Hz, 1 H), 1.15 (s, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ 218.2, 133.5, 133.4, 1 19.0, 118.9, 107.6, 69.5, 64.3, 63.8, 50.6, 48.7, 41.4, 41.1, 40.9, 39.6,

21.9; low resolution mass spectrum 303.1 [(M+Na)⁺; calcd for Ci₆H₂₄O₄Na: 303.2 ]. [0239] Example 4 [0240] Bromoether 13. The alcohol 12 (22.6 mg, 0.0806 mmol) was azeotroped with anhydrous toluene (3 X 10 mL) and placed under high vacuum for 1 h. Then 12 was dissolved in THF (3 mL), cooled to -45 ⁰C, and treated with N-bromosuccinimde (34.6 mg, 2.4 equiv) in one portion. The resulting mixture was stirred at -40 ~ -45 ⁰C for 20 min. The reaction mixture was quenched by addition of saturated NaHCO₃ (30 mL) and extracted with ether (3 X 40 mL). Combined extracts were dried (MgSO₄), filtered and concentrated in vacuo. Flash chromatography (hexanes-ether 3:1 — » 1 :1 — »• 1 :2 — » 1 :4 — > ether) afforded bromoether 13 (24.3 mg, 66% yield) and a mixture of other isomers (8.8 mg, 24% yield). The structure of 13 was deduced from the 2D NMR studies. 13: IR (neat) 3543 (m, br), 2962 (s), 2879 (s), 1709 (m), 1458 (m), 1419 (m), 1361 (m), 1317 (w), 1223 (m), 1096 (s), 1017 (s), 880 (m) cm^"1; ¹U NMR (400 MHz, CDCl₃) δ 4.38 (m, 2 H), 3.90-3.83 (m, 4 H), 3.58 (dd, J= 5.0, 1 1.7 Hz, 1

H), 3.49-3.43 (m, 4 H), 3.37 (dd, J = 6.2, 10.4 Hz, 1 H), 2.60 (t, J = 6.7 Hz, 1 H), 2.18-2.02 (m, 5 H), 1.96 (m, 1 H), 1.92 (d, J = 15.0 Hz, 1 H), 1.64 (d, J= 15.1 Hz, 1 H), 1.06 (s, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ 119.2, 108.7, 77.4, 77.1, 68.1, 63.9, 63.8, 52.7, 46.1, 45.3, 44.0, 41.9, 40.2, 34.4, 34.3, 20.1; low resolution mass spectrum

476.9 [(M+Na)+; calcd for Ci₆H₂₄O₅Br₂Na: 477.0 ]. [0241] Example 5

[0242] Alcohol 14a. To a cooled (-78 ⁰C) solution of dimethyl methylphosphonate (0.51 mL, 20 equiv) in THF (3.0 mL) was added a solution of nBuLi (1.6 M in hexanes, 2.80 mL, 19 equiv) dropwise and the resulting cloudy mixture was stirred at -78 ⁰C for 22 min. A solution of ester 14 (104 mg, 0.237 mmol) in THF (1.0 mL) was added dropwise to the reaction mixture and the resulting mixture was stirred at -78 ⁰C for 1 h. The reaction mixture was quenched by water (40 mL) and extracted with EtOAc (3 X 45 mL). Combined extracts were dried (MgSO₄), filtered and concentrated in vacuo. Flash chromatography (hexanes-EtOAc 3:1 -» 1 :1) gave phosphonate (100 mg, 81% yield, 99% based on recovered starting material): IR (neat) 2954 (s), 2929 (s), 2856 (m), 1709 (s), 1462 (m), 1389 (w), 1361 (m), 1257 (s), 1182 (w), 1099 (m), 1030 (s), 983 (w), 948 (w), 917 (w), 838 (m) cm^"1; ¹H NMR (400 MHz, CDCl₃) δ 5.64 (m, 1 H), 5.07 (m, 2 H), 4.02-3.84 (m, 5 H), 3.733

(d, J = 11.3 Hz, 3 H), 3.726 (d, J= 11.3 Hz, 3 H), 3.15 (m, 2 H), 3.09 (dd, J = 13.8, 22.4 Hz, 1 H), 2.89 (dd, J= 13.8, 22.7 Hz, 1 H), 2.56 (d, J= 18.6 Hz, 1 H), 2.54 (d, J = 14.6 Hz, 1 H), 2.41 (dd, J= 7.9, 13.9 Hz, 1 H), 2.35 (d, J= 14.5 Hz, 1 H), 2.16 (dd, J= 7.2, 13.9 Hz, 1 H), 1.87 (d, J = 14.5 Hz, 1 H), 1.81 (d, J= 14.7 Hz, 1 H), 1.15 (s, 3 H), 0.83 (s, 9 H), -0.01 (s, 3 H), -0.02 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 215.2, 199.6 (d, J= 6.1 Hz), 133.0, 119.2, 107.7, 68.0, 64.1, 63.6, 53.1 (d, J= 6.8 Hz), 52.9 (d, J = 6.1 Hz), 51.1, 49.6, 48.2, 42.2, 40.9, 40.4, 39.2 (d, J = 16.5 Hz), 25.8, 23.0,

18.2, -5.6, -5.7; high resolution mass spectrum m/z 541.2355 [(M+Na)⁺; calcd for C₂₄H₄₃O₈NaSiP: 541.2363].

[0243] To a solution of phophonate (71.4 mg, 0.136 mmol) in THF (12 mL) was added NaH (60%, 28.7 mg, 5.2 equiv) in one portion and the resulting mixture was stirred at room temperature for 5 min until gas evolution ceased. The reaction mixture was heated at 60 ⁰C for 2 h. The reaction mixture was quenched with saturated NH₄Cl (55 mL) and extracted with ether (3 X 65 mL). Combined extracts were dried (MgSO₄), filtered and concentrated in vacuo. Flash chromatography (hexanes-EtOAc 1 :1) afforded cyclopentenone (48.9 mg, 91% yield): IR (neat) 2955 (s), 2928 (s), 2884 (s), 2856 (s), 1733 (m), 1716 (s), 1699 (s), 1604 (m), 1471 (m), 1418 (w), 1388 (w), 1361 (m), 1257 (m), 1202 (w), 1158 (w), 1098 (m, br), 1057 (w), 1026 (w), 1006 (w), 989 (w), 946 (w), 916 (w), 838 (m, br) cm^"1; ¹H NMR (400 MHz, CDCl₃) δ 6.00 (s, 1 H), 5.63 (m, 1 H), 5.01 (m, 2 H), 3.99 (m, 2 H), 3.89 (d, J = 9.6 Hz, 1 H), 3.85 (m, 2 H), 3.62 (d, J = 9.6 Hz, 1 H), 2.64 (dd, J = 6.0, 14.0 Hz, 1 H), 2.48 (d, J= 17.7 Hz, 1 H), 2.47 (dd, J= 6.6, 14.0 Hz, 1 H), 2.15 (dd, J = 2.3, 13.8 Hz, 1 H), 2.06 (d, J= 17.9 Hz, 1 H), 2.00 (dd, J= 2.3, 14.3 Hz, 1 H), 1.67 (d, J= 13.8 Hz, 1 H), 1.51 (d, J= 14.3 Hz, 1 H), 1.20 (s, 3 H), 0.85 (s, 9 H), 0.01 (s, 3 H), -0.005 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 206.9, 186.5, 134.3, 131.5, 118.7, 107.9, 67.6, 65.0, 63.3, 51.7, 47.5, 44.9, 43.0, 42.8, 42.5, 26.7, 25.7, 18.1, -5.6, -5.7; high resolution mass spectrum m/z 393.2469 (M+H+; calcd for C₂₂H₃₇O₄Si: 393.2461). [0244] A mixture of cyclopentenone (1.87 g, 4.77 mmol) and 2 N aqueous HCl (13 mL) in THF (20 mL) was stirred at room temperature for 3 d. The reaction mixture was poured into ice (60 mL)-saturated NaHCO₃ (100 mL) and extracted with EtOAc (3 X 200 mL, 2 X 130 mL). Combined extracts were dried (MgSO₄), filtered and concentrated in vacuo to give alcohol 14a (1.05 g, 95% yield): IR (neat) 3413 (m, br), 2969 (m), 2925 (m), 2873 (m), 1687 (s), 1602 (m), 1455 (w), 1414 (m), 1385 (w), 1315 (w), 1279 (m), 1212 (m), 1176 (w), 1058 (m), 1008 (w), 934 (m) cm^"1; ¹H NMR (400 MHz, CDCl₃) δ 6.21 (s, 1 H), 5.69-5.58 (m, 1 H), 5.18-5.10 (m, 2 H), 3.71 (dd, J = 5.8, 11.8 Hz, 1 H), 3.64 (dd, J= 5.7, 10.8 Hz, 1 H), 2.88 (d, J= 16.6 Hz, 1 H), 2.80 (d, J= 16.3 Hz, 1 H), 2.63 (d, J= 18.0 Hz, 1 H), 2.45 (d, J= 16.2 Hz, 1 H), 2.49-2.43 (m, 1 H), 2.40-2.35 (m, 1 H), 2.34 (d, J = 16.5 Hz, 1 H), 2.28 (d, J = 18.0 Hz, 1 H), 1.61 (t, J= 5.8 Hz, 1 H), 1.30 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 207.9, 205.6, 184.4, 132.5, 131.1, 120.3, 69.5, 53.4, 50.9, 50.0, 48.1, 47.5, 43.1, 27.6; high resolution mass spectrum m/z 257.1140 [(M+Na)⁺; calcd for Ci₄Hi₈O₃Na: 257.1 154]. [0245] Example 6

[0246] Lactone 9. To a cooled (0 ⁰C) solution of alcohol 14a (1.05 g, 4.50 mmol) in CH₂Cl₂ (90 mL) were added DMAP (1 1 mg, 0.02 equiv), pyridine (8.5 mL, 23 equiv) and ethyl chloroformate (5.2 mL, 12 equiv) and the resulting mixture was stirred at room temperature for 21 h. Another 2.6 mL of ethyl chloroformate was added and the reaction mixture was stirred for an additional 15 min. The reaction mixture was quenched with 2N aqueous HCl (200 mL) and extracted with EtOAc (3 X 200 mL). Combined extracts were dried (MgSO₄), filtered and concentrated in vacuo. Flash chromatography (hexanes-EtOAc 2:1 → 1 :1 → 1 :2 → 1 :5) gave the corresponding ethyl carbonate (1.32 g, 93% yield): IR (neat) 2979 (m), 2937 (w), 1746 (s), 1712 (s), 1606 (w), 1466 (w), 1399 (w), 1375 (m), 1255 (s), 1206 (m), 1180 (w), 1090 (w), 1007 (m), 962 (w), 927 (w), 873 (w) cm^"1; ¹H NMR (400 MHz, CDCl₃) δ 6.21 (s, 1 H), 5.58 (m, 1 H), 5.13 (m, 2 H), 4.22 (d, J= 10.9 Hz, 1 H), 4.18 (q, J= 7.1 Hz, 2 H), 4.07 (d, J= 10.9 Hz, 1 H), 2.87 (d, J= 16.8 Hz, 1 H), 2.81 (d, J= 16.9 Hz, 1 H), 2.60 (d, J= 18.0 Hz, 1 H), 2.40 (dd, J= 6.9, 14.3 Hz, 1 H), 2.38 (t, J = 16.3 Hz, 2 H), 2.32 (dd, J = 6.3, 14.4 Hz, 1 H), 2.21 (d, J = 17.9 Hz, 1 H), 1.32 (s, 3 H), 1.28 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 206.7, 205.2, 182.7, 154.7, 131.8, 131.2, 120.6, 72.5, 64.4, 49.6, 49.3, 47.8, 47.1, 43.0, 40.3, 28.1, 14.1; high resolution mass spectrum m/z 329.1362 [(M+Na)⁺; calcd for Ci₇H₂₂O₅Na: 329.1365].

[0247] To a solution of ethyl carbonate (1.29 g, 4.20 mmol) in THF (250 mL) was added NaH (60%, 1.99 g, 12 equiv) in one portion and the resulting mixture was heated to reflux for 12 h. The reaction mixture was quenched with saturated NH₄Cl (150 mL) and 4N aqueous HCl (75 mL), and after separation, further extracted with EtOAc (3 X 250 mL). Combined extracts were dried (MgSO₄), filtered and concentrated in vacuo. Flash chromatography (hexanes-EtOAc 2:1 — » 1:1 — » 1 :3 — > CH₂Cl₂-MeOH 20:1 → 10:1) gave lactone 9 (1.02 g, 94% yield): IR (neat) 2976 (m), 2917 (m), 1791 (s), 1716 (s, br), 1609 (m), 1455 (m), 1418 (m), 1391 (m), 1365 (m), 1337 (w), 1264 (m), 1 164 (m), 1101 (w), 1024 (m), 992 (w), 929 (w), 889 (w), 862 (w) cm^"1; ¹H NMR (500 MHz, CD₃COCD₃) δ 6.40 (s, 1 H), 5.57 (m, 1 H), 5.13 (m, 2

H), 4.45 (d, J= 9.5 Hz, 1 H), 4.25 (d, J = 9.5 Hz, 1 H), 3.63 (s, 1 H), 2.96 (d, J= 14.3 Hz, 1 H), 2.78 (d, J= 14.3 Hz, 1 H), 2.54 (d, J= 17.9 Hz, 1 H), 2.413 (d, J= 18.0 Hz, 1 H), 2.410 (dd, J = 7.4, 14.5 Hz, 1 H), 2.29 (dd, J= 6.5, 14.4 Hz, 1 H), 1.68 (s, 3 H); ¹³C NMR (125 MHz, CD₃COCD₃) δ 204.9, 200.3, 179.7, 171.3, 133.9, 133.4, 121.0, 76.6, 61.5, 51.5, 50.4, 49.9, 46.0, 43.5, 27.9; high resolution mass spectrum m/z

283.0935 [(M+Na)⁺; calcd for Ci₅H₁₆O₄Na: 283.0946]. [0248] Example 7

[0249] Diol 19. To a solution of lactone 9 (78.1 mg, 0.300 mmol) in CH₂Cl₂ (10 mL) was added mCPBA (-100%, 51.0 mg, 0.99 equiv) and the resulting mixture was stirred at room temperature for 15 min. The reaction mixture was quenched with a mixture of saturated Na₂S₂O₃ (35mL)-water (35 mL)-saturated NaHCO₃ (35 mL) and extracted with EtOAc (3 X 150 mL). Combined extracts were dried (MgSO₄), filtered and concentrated in vacuo. Flash chromatography (hexanes-EtOAc 1 :1) afforded the corresponding α-hydroxy lactone (74.4 mg, 90% yield); IR (film) 3340 (m, br), 2976 (w), 2923 (w), 1793 (s), 1715 (s), 1688 (s), 1604 (w), 1392 (w), 1364 (w), 1291 (w), 1250 (w), 1206 (w), 1159 (m), 1108 (m), 1021 (w), 1001 (m), 934 (w) cm^'1; ¹H NMR (400 MHz, CD₃OD) δ 6.39 (s, 1 H), 5.47 (m, 1 H), 5.13 (m, 2 H), 4.42 (d, J= 9.9 Hz, 1 H), 4.16 (d, J= 10.0 Hz, 1 H), 3.36 (d, J= 12.3 Hz, 1 H), 2.62 (d, J= 12.3 Hz, 1 H), 2.56 (d, J = 3.1 Hz, 2 H), 2.43 (d, J = 7.2 Hz, 2 H), 1.47 (s, 3 H); ¹³C NMR (100 MHz, CD₃OD) δ 207.1, 205.1, 178.1, 174.2, 136.3, 132.9, 121.0, 85.3, 72.5, 51.82, 51.75, 51.73, 48.2, 43.7, 19.9; high resolution mass spectrum m/z 299.0891 [(M+Na)+; calcd for Ci₅Hi₆O₅Na: 299.0895].

[0250] To a cooled (-78 ⁰C) solution of α-hydroxy lactone (1.16 g, 4.20 mmol) in THF (90 mL)-MeOH (90 mL) was added NaBH₄ (179 mg, 1.1 equiv) in one portion and the resulting mixture was stirred for 1 min. The reaction mixture was quenched with brine (175 mL) and extracted with EtOAc (3 X 300 mL). Combined extracts were dried (MgSO₄), filtered and concentrated in vacuo. Flash chromatography (hexanes-EtOAc 2:1) gave diol 19 (1.08 g, 93 % yield): IR (film) 3342 (m, br), 2919 (w), 1754 (s), 1678 (s), 1590 (w), 1449 (w), 1408 (w), 1361 (w), 1261 (w), 1226 (w), 1161 (m), 1114 (m), 1079 (m), 1020 (m), 991 (m) cm^'1; ¹H NMR (400 MHz, CD₃OD) δ 6.23 (s, 1 H), 5.58 (m, 1 H), 5.06 (m, 2 H), 4.87 (d, J= 8.5 Hz, 1 H), 3.99 (d, J= 8.4 Hz, 1 H), 3.32 (m, 1 H), 3.12 (dd, J= 7.0, 14.1 Hz, 1 H), 2.67 (dd, J = 7.8, 14.1 Hz, 1 H), 2.53 (d, J= 18.0 Hz, 1 H), 2.23 (dd, J= 2.8, 14.4 Hz, 1 H), 2.21 (d, J= 18.0 Hz, 1 H), 1.97 (dd, J = 3.0, 14.5 Hz, 1 H), 1.39 (s, 3 H); ¹³C NMR (100 MHz, CD₃OD) 5 209.2, 183.8, 179.5, 135.2, 134.9, 119.5, 83.7, 73.7, 72.8, 53.8, 48.3, 47.7, 45.5,

39.9, 22.0; high resolution mass spectrum m/z 279.1232 (M+H+; calcd for C₁₅Hi₉O₅: 279.1232).

[0251] Example 8

[0252] Lactone 10. To a cooled (-45 ⁰C) solution of LDA (3.5 equiv) in THF (20 mL) was added a solution of diol 19 (153 mg, 0.548 mmol) in THF (2.5 mL) and the resulting mixture was warmed to -15 ⁰C over 55 min. The reaction mixture was cooled to -40 ⁰C, treated with a mixture of iodomethane (40 μL, 1.2 equiv) and HMPA (90 μL, 1.0 equiv), and stirred at -35 ⁰C for 18 h. The reaction mixture was quenched with saturated NH₄Cl (125 mL) and extracted with EtOAc (3 X 150 mL). Combined extracts were dried (MgSO₄), filtered and concentrated in vacuo. Flash chromatography (hexanes-EtOAc 2:1 → 1 :1 → CH₂Cl₂-MeOH 10:1) gave cyclopentenone (103 mg, 64% yield, 77% based on recovered starting material): IR (film) 3382 (m, br), 3265 (m, br), 1762 (s), 1686 (s), 1600 (m), 1456 (w), 1401 (w), 1371 (w), 1260 (w), 1164 (m), 1115 (m), 1056 (w), 1023 (w), 989 (m) cm^'1; ¹H NMR (400 MHz, CD₃OD) δ 6.18 (s, 1 H), 5.62 (m, 1 H), 5.06 (m, 2 H), 4.87 (d, J= 8.5 Hz, 1 H), 4.12 (t, J= 3.0 Hz, 1 H), 4.00 (d, J= 8.4 Hz, 1 H), 2.99 (dd, J= 6.9, 14.0 Hz, 1 H), 2.80 (dd, J = 7.8, 14.0 Hz, 1 H), 2.42 (q, J= 7.6 Hz, 1 H), 1.96 (dq, J= 3.0, 14.0 HZ, 2 H), 1.39 (s, 3 H), 1.01 (d, J = 7.7 Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 213.5, 183.5, 179.6, 135.3, 132.7, 119.7, 83.7, 73.9, 73.0, 54.1, 50.1, 48.3, 46.7,

33.5, 22.0, 13.9; high resolution mass spectrum m/z 293.1395 (M+H⁺; calcd for

[0253] A red solution of cyclopentenone (10 mg, 0.034 mmol) and Sudan Red 7B (trace) in CH₂Cl₂ (1.8 mL)-EtOH (1.8 m) was cooled to -78 ⁰C and a stream of ozone was bubbled through the solution until a red color turned into a yellow/orange. Argon was bubbled through the reaction mixture for 10 min. The mixture was treated with Me₂S (0.02 mL), warmed to room temperature, and concentrated in vacuo to give a mixture of lactols. The residue was diluted with acetone (1.7 mL), cooled to 0 ⁰C, and treated with Jones reagent (2.6 M, 0.25 mL, 19 equiv). The reaction mixture was stirred at 0 ⁰C for 7 min and quenched by addition of EtOH (1.5 mL). The resulting green mixture was diluted with EtOAc (20 mL) and washed with saturated NaHCO₃ (20 mL). The aqueous phase was combined with green solid residue and further extracted with EtOAc (3 X 20 mL). Combined extracts were dried (MgSO₄), filtered and concentrated in vacuo. Flash chromatography (hexanes-EtOAc 2:1 — > 1 :1 — > 1 :3) afforded lactone 15 (9 mg, 90% yield): IR (film) 3334 (m, br), 2975 (m), 2877 (m), 1784 (s), 1748 (s), 1710 (s), 1609 (m), 1491 (w), 1456 (m), 1367 (m), 1348 (w), 1327 (w), 1286 (w), 1251 (m), 1200 (m), 1159 (m), 1119 (m), 1063 (m), 1027 (m), 996 (m), 976 (w), 948 (w), 888 (w) cm^"1; ¹H NMR (400 MHz, CD₃OD) δ 6.27 (s, 1 H),

4.79 (dd, J= 1.8, 4.1 Hz, 1 H), 4.14 (d, J= 10.5 Hz, 1 H), 4.05 (d, J = 10.6 Hz, 1 H), 3.10 (d, J- 19.1 Hz, 1 H), 2.81 (dd, J= 2.7, 19.1 Hz, 1 H), 2.30 (dd, J= 4.1, 14.0 Hz, I H), 2.25 (q, J= 7.7 Hz, 1 H), 2.19 (td, J= 2.3, 14.4 Hz, 1 H), 1.44 (s, 3 H), 1.13 (d, J = 7.7 Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 207.3, 176.7, 175.9, 167.6, 131.9, 78.7, 78.4, 73.7, 52.4, 44.3, 43.2, 42.6, 27.7, 22.1, 11.6; high resolution mass spectrum m/z 293.1013 (M+H+; calcd for C₁₅H₁₇O₆: 293.1025). [0254] Example 10

[0255] α-Hydroxy Lactone 21. A solution of lactone 10 (40 mg, 0.0137 mmol) and CeCl₃*7H₂O (153 mg, 3.0 equiv) in THF (8.2 mL)-MeOH (2.8 mL) was cooled to -60 ⁰C and treated with a solution of NaBH₄ (0.82 mL, 3.0 equiv) in 2- methoxyethyl ether (0.5 M). The resulting mixture was stirred at -55-50 ⁰C for 35 min. The reaction mixture was quenched with IN aqueous HCl (0.23 mL), diluted with brine (50 mL), and extracted with EtOAc (5 X 100 mL). Combined extracts were dried (MgSO₄), filtered and concentrated in vacuo. Flash chromatography (hexanes-EtOAc 1 :1 → CH₂Cl₂-MeOH 40:1) gave alcohol 20 (35 mg, 88% yield). The configuration of the newly generated stereocenter was determined by NOE studies: IR (neat) 3384 (s, br), 2972 (s), 2935 (s), 2876 (m), 1784 (s), 1749 (s), 1456 (m), 1368 (m), 1325 (w), 1226 (m), 1162 (m), 1 117 (m), 1087 (m), 1064 (m), 1028 (m), 999 (m), 969 (w), 913 (w), 888 (w) cm^"1; ¹H NMR (400 MHz, CD₃OD) δ 5.80 (d, J = 1.3 Hz, 1 H), 4.89 (dd, J = 1.3, 6.6 Hz, IH), 4.72 (dd, J = 1.3, 4.3 Hz, 1 H), 4.00 (d, J= 10.1 Hz, 1 H), 3.80 (d, J= 10.1 Hz, 1 H), 2.85 (d, J= 18.8 Hz, 1 H), 2.67 (dd, J= 2.6, 18.9 Hz, 1 H), 2.17 (m, 2 H), 1.93 (dd, J= 4.4, 14.0 Hz, 1 H), 1.35 (s, 3 H), 0.92 (d, J = 7.3 Hz, 3 H); ¹³C NMR (100 MHz, CD₃OD) δ 178.6, 172.0, 147.5, 133.6, 81.4, 78.7, 76.6, 76.0, 50.3, 48.0, 44.4, 43.7, 28.3, 22.5, 9.1 ; high resolution mass spectrum m/z 295.1184 (M+H⁺; calcd for Ci₅Hi₉O₆: 295.1 182). [0256] Alcohol 20 (69.5 mg, 0.236 mmol) was azeotroped with anhydrous benzene (3 X 80 mL) and placed under high vacuum for 1 h. Then the alcohol was dissolved in THF (80 mL), cooled to -78 ⁰C, and treated with a solution of NaHMDS (0.93 mL, 3.9 equiv) in THF (1.0 M). The resultant mixture was stirred at -78 ⁰C for 6 min. A solution of 3-phenyl-2-(phenylsulfonyl)-l,2-oxaziridine (248 mg, 4.0 equiv) in THF (1.0 mL) was added to the reaction mixture and the resulting mixture was stirred at -78 ⁰C for 3 min. The reaction mixture was quenched with saturated NH₄Cl (5.0 mL), diluted with EtOAc (500 mL), dried (MgSO₄), filtered and concentrated in vacuo. Flash chromatography (hexanes-EtOAc 1 :1 → CH₂Cl₂-MeOH 30:1 → 20:1 — > 10:1) gave the unreacted alcohol starting material (51.2 mg, 73% recovered) and α-hydroxy lactone 21 [19.1 mg, 26% yield, 99% based on recovered starting material, 6:1 at C(IO)]. Recovered starting material (51.2 mg, 0.174 mmol) was engaged in a second hydroxylation reaction followed by flash chromatography to provide the unreacted starting material (28.3 mg, 56% recovered, total recovery: 41%) and α- hydroxy lactone 21 (11.3 mg, 21% yield, 42% overall yield): IR (neat) 3337 (m, br), 2975 (m), 2877 (m), 1783 (s), 1456 (m), 1369 (m), 1343 (w), 1228 (m), 1171 (m), 1111 (m), 1085 (m), 1051 (m), 1024 (m), 997 (m), 966 (w), 890 (w) cm^"1; ¹H NMR (400 MHz, CD₃OD) 5 5.89 (s, 1 H), 5.00* [dd, J = 1.6, 7.1 Hz, 1 H, minor diastereomer at C(IO)], 4.94 (dd, J= 1.3, 6.6 Hz, 1 H), 4.70 (dd, J= 1.2, 4.7 Hz, 1 H), 4.62* (dd, J= 1.7, 4.2 Hz, 1 H), 3.99 (d, J= 10.0 Hz, 1 H), 3.79 (d, J= 1.6 Hz, 1 H), 3.64 (d, J= 10.1 Hz, 1 H), 2.91 (quintet, J= 7.1 Hz, 1 H), 2.49* (quintet, J= 7.3 Hz, 1 H), 2.23 (dd, J= 4.7, 14.1 Hz, 1 H), 2.03 (td, J= 1.4, 14.0 Hz, 1 H), 1.36* (s, 3 H), 1.35 (s, 3 H), 0.91* (d, J = 7.5 Hz, 3 H), 0.85 (d, J = 7.3 Hz, 3 H); ¹³C NMR (100 MHz, CD₃OD) δ 178.8, 172.4, 144.3, 136.0, 81.3, 77.5, 76.6, 76.5, 73.3, 54.2, 44.6,

42.8, 23.2, 21.4, 9.5; high resolution mass spectrum m/z 333.0953 [(M+Na)⁺; calcd for Ci₅H₁₈O₇Na: 333.0950].

[0257] Example 11

[0258] (lR^*,10S^*)-2-Oxo-3,4-dehydroneomajucin 22 and Jiadifenin 1. To a solution of α-hydroxy lactone 21 (19.1 mg, 0.0615 mmol) in acetone (8.0 mL) was added Jones reagent (2.6 M, 1.0 mL, 42 equiv) and the resulting mixture was stirred at room temperature for 19 min. The reaction mixture was treated with MeOH (3.5 mL) and stirred at room temperature for 10 min. The reaction mixture was place into an ice bath, quenched with saturated NaHCO₃ (7 mL), diluted with EtOAc (450 m), dried (MgSO₄), filtered and concentrated in vacuo. Preparative TLC (250 μm X 20 cm X 20 cm, CH₂Cl₂-MeOH 25:1) afforded (17?^*,10S^*)-2-oxo-3,4-dehydroneomajucin 22 (5.6 mg, 29% yield) and jiadifenin 1 (8.5 mg, 40% yield).

[0259] (lR^*,10S>2-Oxo-3,4-dehydroneomajucin 22: IR (film) 3392 (m, br), 2933 (m), 1785 (s), 1751 (s), 1710 (s), 1608 (w), 1558 (w), 1456 (w), 1368 (w), 1289 (w), 1226 (w), 1158 (w), 11 14 (m), 1065 (m), 996 (m), 967 (w), 853 (w) cm⁴; ¹H NMR (500 MHz, C₅D₅N-TMS) δ 6.57 (s, 1 H), 5.29 (m, 1 H), 4.40 (brs, 1 H), 4.38 (d, J= 10.5 Hz, 1 H), 4.26 (d, J = 10.5 Hz, 1 H), 3.28 (q, J = 7.7 Hz, 1 H), 2.88 (dd, J = 4.3, 14.0 Hz, 1 H), 2.46 (d, J = 14.0 Hz, 1 H), 1.65 (brs, 3 H), 1.31 (d, J = 7.7 Hz, 3 H); ¹³C NMR (125 MHz, C₅D₅N-TMS) δ 208.6, 177.1, 176.1, 170.6, 133.6, 79.8, 79.4, 73.7, 73.4, 51.3, 49.0, 44.8, 23.0, 22.6, 13.1; high resolution mass spectrum m/z

331.0784 [(M+Na)⁺; calcd for C₁₅H₁₆O₇Na: 331.0794].

[0260] Jiadifenin 1: IR (film) 3402 (m, br), 2957 (m), 2876 (w), 1778 (s), 1746 (s), 1710 (s), 1610 (w), 1456 (w), 1398 (w), 1374 (w), 1257 (m), 1224 (w), 1192 (m), 1165 (w), 1104 (w), 1052 (m), 1036 (m), 998 (w), 938 (w), 895 (w) cm^"1; ¹H NMR (500 MHz, C₅D₅N-TMS) δ 6.57 (s, 1 H), 6.50* [s, 1 H, minor diastereomer at C(IO)], 5.87 (d, J= 8.5 Hz, 1 H), 5.12* (d, J= 6.2 Hz, 1 H), 5.05 (d, J= 6.2 Hz, 1 H), 4.43* (d, J = 9.0 Hz, 1 H), 4.20 (d, J = 8.4 Hz, 1 H), 4.16* (d, J = 9.0 Hz, 1 H), 3.68 (s, 3 H), 3.56* (s, 3 H), 3.51 * (q, J = 7.7 Hz, 1 H), 3.17* (dd, J= 6.3, 11.8 Hz, 1 H), 3.03 (dd, J= 6.2, 12.4 Hz, 1 H), 2.95 (q, J= 7.6 Hz, 1 H), 2.62* (d, J= 11.8 Hz, 1 H), 2.53 (d, J= 12.4 Hz, 1 H), 1.69 (s, 3 H), 1.64* (s, 3 H), 1.38* (d, J= 7.7 Hz, 3 H), 1.24 (d, J = 7.7 Hz, 3 H); ¹³C NMR (125 MHz, C₅D₅N-TMS) δ 209.6*, 208.7, 180.0, 178.8, 178.6*, 177.2*, 171.4, 169.0*, 131.1 *, 130.5, 105.8, 103.9*, 80.8, 80.4, 80.2*, 79.3*, 75.9, 75.2*, 61.3*, 60.1, 52.6, 51.9*, 45.1, 44.7*, 44.6*, 42.8, 31.5*, 31.3, 23.1,

23.0*, 14.4*, 12.9; high resolution mass spectrum m/z 339.1072 (M⁺; calcd for

[0261] Example 12 [0262] Compound 23: To a solution of 19 (266 mg, 0.956 mmol) in ¹BuOH-H₂O (45 mL, 2:1), were added OsO₄ (2.5 wt%, 0.11 mL) and NaIO₄ (922 mg, 4.31 mmol). The resulting mixture was stirred at room temperature overnight and quenched with brine (130 mL). The mixture was extracted with EtOAc (0.2 L x 6) and the combined extracts were washed with brine and dried over anhydrous MgSO₄. The solvent was evaporated under reduced pressure to give crude lactol (345 mg), which was used for next step without further purification.

[0263] To a solution of crude lactol (345 mg) in acetone (60 mL) at 0 ⁰C was added Jones reagent (3.2 mL). The resulting mixture was stirred at 0 ⁰C for 5 minutes before being treated with EtOH (4.5 mL). The mixture was diluted with EtOAc (200 mL) and washed with saturated aqueous NaHCO₃. The aqueous phase was extracted with EtOAc (200 mL x 5) and the combined organic layers were dried over anhydrous MgSO₄. The solvent was removed under reduced pressure and the crude product was purified with flash chromatography on silica gel (CH₂Cl₂-MeOH, 10:1) to afford compound 23 (140 mg, 53% for 2 steps): IR (neat) 3299 (m, br), 2975 (m), 2875 (m), 1785 (s), 1749 (s), 1698 (s), 1610 (m), 1456 (w), 1406 (w), 1367 (m), 1326 (w), 1290 (w), 1248 (w), 1225 (m), 1209 (m), 1160 (m), 1112 (m), 1046 (m), 1027 (w), 1005 (m), 987 (w), 965 (w), 885 (w) cm^"1; ¹H NMR (400 MHz, CD₃OD) δ 6.29 (s, IH), - 4.77 (dd, J = 1.7, 4.1 Hz, IH), 4.14 (d, J = 10.5 Hz), 4.02 (d, J = 10.6 Hz, IH), 3.11 (d, J = 19.1 Hz, IH), 2.85 (dd, J = 2.6, 19.1 Hz, IH), 2.63 (d, J = 18.6 Hz, IH), 2.42 (dd, J = 4.1, 14.1 Hz, IH), 2.39 (d, J = 18.5 Hz, IH), 2.31 (td, J = 2.1, 14.2 Hz, IH), 1.45 (s, 3H); ¹³C NMR (125 MHz, acetone-d6) δ 204.1, 178.9, 175.9, 168.2, 133.4, 79.3, 79.0, 73.5, 67.8, 50.7, 42.8, 31.5, 25.9, 22.1; HRMS (ESI) calcd. for Ci₄H₁₄O₆ [M+H]⁺ 279.0869, found 279.0863. [0264] Example 13

[0265] Compound 24: A mixture of lactone 23 (140 mg, 0.504 mmol) and CeCl₃»7H₂O (574 mg, 3.0 equiv) in THF-MeOH (40 mL, 3:1) was cooled to -60 ⁰C, to this solution was added a solution Of NaBH₄ in 2-methoxyethyl ether (0.5 M, 3.0 mL). The resulting mixture was stirred at -55 ~ -50 ⁰C for 7 minutes. The reaction mixture was quenched with IN aqueous HCl (0.5 mL), diluted with brine (75 mL), and extracted with EtOAc (150 mL x 6). The combined extracts were dried (MgSO₄), filtered and concentrated in vacuo. Flash chromatography (CH₂Cl₂-MeOH 30:1 → 20:1 → 10:1) gave alcohol 24 (114 mg, 81% and 88% brsm) and recovered lactone 23 (1 1.2 mg, 8.0%): IR (neat) 3310 (m, br), 2930 (w), 1799 (s), 1748 (m), 1718 (m), 1652 (w), 1456 (w), 1367 (m), 1339 (w), 1250 (w), 1224 (m), 1205 (m), 1 164 (m), 1108 (m), 1066 (m), 1021 (w), 1001 (m) cm^"1; ¹H NMR (400 MHz, acetone-d6) δ 5.91 (s, IH), 4.98 (t, J = 7.1 Hz, IH), 4.69 (dd, J = 1.3, 3.5 Hz, IH), 3.84 (brs, IH), 3.77 (d, J - 10.0 Hz, IH), 3.62 (t, J = 6.3 Hz, IH), 2.88 (d, J = 18.7 Hz, IH), 2.65 (dd, J =2.4, 18.7 Hz, IH), 2.27 (dd, J = 6.7, 12.6 Hz, IH), 2.18 (m, 2H), 1.76 (dd, J = 7.7, 12.7 Hz, IH), 1.37 (s, 3H); ¹³C NMR (100 MHz, acetone-d6) δ 177.0, 169.0, 146.9, 135.4, 79.9, 77.8, 74.9, 74.2, 51.0, 44.3, 44.1, 42.6, 32.2, 22.2; HRMS (ESI) calcd. for Ci₄Hi₆O₆ [M+H]⁺ 281.1025, found 281.1021. [0266] Example 14

[0267] Compound 25: Alcohol 24 (113.8 mg, 0.406 mmol) was azeotroped with anhydrous benzene (60 mL x 3) and placed under high vacuum for 1 h. Then the alcohol was dissolved in THF (110 mL) and cooled to -78 ⁰C. To this solution was added a solution of NaHMDS in THF (1.0 M, 0.93 mL). The resultant mixture was stirred at -78 ⁰C for 6 minutes. A solution of 3-phenyl-2-(phenylsulfonyl)-l,2- oxaziridine (318 mg, 1.470 mmol) in THF (1.0 mL) was added to this mixture and the resulting mixture was stirred at -78 ⁰C for 3 minutes. The reaction was quenched with saturated NH₄Cl (8.0 mL) and then diluted with EtOAc (700 mL). The solution was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Flash chromatography (hexanes-EtOAc 1 :1 → CH₂Cl₂-MeOH 30:1 → 20:1 → 10:1) gave the unreacted alcohol starting material 3 (71.5 mg, 63% recovered) and α-hydroxy lactone 25 (37.3 mg, 31% and 83% brsm): IR (neat) 3316 (s, br), 2976 (m), 2933 (m), 2876 (m), 1783 (s), 1749 (s), 1490 (w), 1453 (w), 1368 (m), 1341 (w), 1222 (m), 1170 (m), 1140 (w), 1109 (m), 1050 (m), 1000 (m), 965 (w), 925 (w), 889 (w), 847 (w) cm^" ¹J ¹H NMR (400 MHz, CD₃OD) δ 6.01 (s, IH), 4.88 (d, J = 6.9 Hz, IH), 4.66 (dd, J = 0.9, 3.9 Hz, IH), 3.98 (d, J = 10.1 Hz, IH), 3.77 (d, J = 1.3 Hz, IH), 3.66 (d, J = 10.1 Hz, IH), 2.90 (dd, J = 6.7, 12.8 Hz, IH), 2.47 (dd, J = 4.5, 14.1 Hz, IH), 1.93 (d, J = 14.1 Hz, IH), 1.43 (dd, J = 8.1, 12.8 Hz, IH), 1.36 (s, 3H); ¹³C NMR (100 MHz, CD₃OD) δ 178.7, 172.2, 146.3, 138.0, 81.1, 77.8, 76.1, 74.7, 73.4, 51.0, 45.5, 43.1, 26.9, 13.2; HRMS (ESI) calcd. for Ci₄H₁₆O₇ [M+H]⁺ 297.0974, found 297.0960. [0268] Example 15

[0269] Compound 26 and normethyl jiadifenin (27): To a solution of α-hydroxy lactone 25 (32.0 mg, 0.108 mmol) in acetone (10 mL) was added Jones reagent (2.6 M, 1.5 mL) and the resulting mixture was stirred at room temperature for 19 minutes. The reaction was quenched by addition of MeOH (5 mL). The mixture was placed into an ice bath before being stirred at room temperature for 10 minutes and then treated with saturated NaHCO₃ (10 mL). The mixture was diluted with EtOAc (1 L), dried over anhydrous MgSO₄, filtered and concentrated in vacuo. Preparative TLC (250 μm, 20 cm x 20 cm, 3:1 MeOH-EtOAc as eluant) afforded 26 (9.1 mg, 25% yield, decomposed in NMR solvent) and normethyl jiadifenin (27) (14.4 mg, 36% yield, - 3:2 mixture of diastereomers at C(IO)).

[0270] Compound 26: IR (neat) 3359 (m, br), 2977 (m), 2937 (m), 2877 (m), 1784 (s), 1749 (s), 1733 (s), 1715 (s), 1698 (s), 1607 (m), 1456 (w), 1394 (w), 1369 (m), 1342 (w), 1320 (w), 1293 (w), 1244 (m), 1227 (m), 1210 (m), 1162 (m), 1109 (m), 1084 (m), 1048 (m), 1024 (m), 999 (m), 979 (w), 954 (w), 913 (w); ¹H NMR (400 MHz, CD₃OD) δ 6.37 (s, IH), 4.74 (dd, J = 1.2, 3.4 Hz, IH), 4.10 (d, J = 8.7 Hz, IH), 3.92 (d, J = 1.4 Hz, IH), 3.89 (d, J = 8.7 Hz, IH), 3.00 (d, J = 15.2 Hz, IH), 2.69 (dd, J = 3.4, 11.4 Hz, IH), 2.37 (d, J = 15.2 Hz, IH), 2.16 (td, J = 1.2, 11.4 Hz, IH), 1.45 (s, 3H).

[0271] Normethyl jiadifenin (27): IR (neat) 3354 (m, br), 2957 (m), 2936 (m), 2877 (m), 1778 (s), 1747 (s), 1721 (s), 1688 (s), 1609 (m), 1456 (m), 1437 (w), 1403 (w), 1374 (w), 1275 (m), 1258 (m), 1228 (m), 1167 (m), 1103 (m), 1044 (s), 1016 (m), 968 (w), 934 9w), 901 (m) cm^"1; ¹H NMR (400 MHz, C₅D₃N-TMS) δ 6.57 (s, IH), 6.51^* [s, IH, minor diastereomer at C(IO)], 5.82 (d, J = 8.5 Hz, IH), 5.07 (d, J = 6.1 Hz, IH), 4.44^* (d, J = 9.0 Hz, IH), 4.20 (d, J = 8.4 Hz, IH), 4.16^* (d, J = 9.0 Hz, IH), 3.65 (s, 3H), 3.57^* (s, 3H), 3.52^* (d, J = 18.5 Hz, IH), 3.23^* (dd, J = 6.2, 11.8 Hz,, IH), 3.09 (dd, J = 6.0, 12.3 Hz, IH), 3.06 (d, J = 18.6 Hz, IH), 2.78^* (d, J = 18.5 Hz, IH), 2.69 ( d, J = 19.0 Hz, IH), 2.62^* (d, J = 12.4 Hz, IH), 1.69 (s, 3H), 1.63^* (s, 3H); ¹³C NMR (125 MHz, C₅D₃N-TMS) δ 205.9, 205.5^*, 180.6, 178.9^*, 178.7^*, 177.7, 171.5, 169.1^*, 132.8^*, 132.0, 105.8, 103.5^*, 80.6, 80.3^*, 80.1, 79.3^*, 76.1, 75.4^*, 57.4^*, 56.1, 52.6, 52.0^*, 45.0, 44.6^*, 42.0^*, 40.1, 34.9^*, 34.7, 23.2, 23.1^*; LRMS (ESI) calcd. for C₁₅H₁₆O₈ [M+Na]⁺ 347.1, found 347.2. [0272] Example 16 [0273] Assay Protocols:

[0274] Neurotrophic factors, which play an important role in neuronal survival, differentiation, growth, and apoptosis, have emerged as a potential therapy for Alzheimer's disease (AD) and other neurodegenerative disorders. Interventions that mimic NGF action in patients may facilitate the maintenance of neuronal function and could potentially be used to treat neurodegenerative diseases. However, due to poor pharmacokinetics and bioavailability of NGF and other neurotrophins, the use of these proteins as therapeutic agents is limited. Developing small molecules that enhance or mimic NGF function would be a practical and promising approach to treat AD and other human disorders.

[0275] The PC- 12 cell line was derived from a transplantable rat pheochromocytoma (Greene, L. A.; Tischler, A. S. P. Natl. Acad. Sci. U.S.A. 1976, 73, 2424). Since PC 12 cells can be induced to differentiate toward sympathetic neurons after treatment with nerve growth factor (NGF), it has been a useful model for the study of neuronal development. Therefore, the PC 12 cells were chosen to assay the activities of jiadifenin and its analogs.

[0276] The PC 12 cells were cultured in a 96- well collagen coated plate in

F12K medium supplemented with 0.5% fetal calf serum and 50 ng/mL of NGF (2.5 S) with or without each compound at various concentration for 48 h. Fresh media with the same supplements were placed on the cell for an additional 48 h. Following 96 hr treatment, media were removed; cells were fixed in 4% paraformaldehyde and imaged with ECLIPSE TE2000-S Nikon microscopy. Five regions with similar cell density for each treatment were selected for photographing by ECLIPSE TE2000-S Nikon microscope. For each treatment, more than 15 neurons were randomly selected to measure the length of neurites. Student T test was used to check the P value. [0277] Table 1. Effect of 1, 22 and 27 on the NGF-induced neurite outgrowth of PC 12 cells

Treatment³ DMSO 22** 1* 27**

Average neurite length 10.1 ± 1.6 18.6 ± 1.9 16.2 ± 2.1 18.1 ± 1.5 (mean ± SE, arbitrary unit)

^a duplicate Compounds 22, 27 and 1 were dissolved in DMSO at 0.3 μM concentration.

** P<0.01, * P<0.05 REFERENCES

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[0281] 4. Brieskom, C. H.; Schwack, W. Chem. Ber. 1981, 114, 1993.

[0282] 5. To the best of our knowledge, there is only one literature precedent of such a reaction. See: Heusler, K.; Ueberwasser, H.; Wieland, P.; Wettstein, A. HeIv.

Chim. Acta 1957, 40, 787.

[0283] 6. Halterman, R. L.; Vollhardt, P. C. Organometallics 1988, 7, 883.

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Soc. 1982, 104, 7591.

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[0287] 10. Incorporation of the C(IO) hydroxyl was hampered by decomposition of both starting compound and product under the reaction conditions. Nevertheless, suitable quantities of α-hydroxy lactone was obtained by keeping reaction time short and recycling the recovered starting material.

[0288] 11. Cho et al, "Total synthesis of (+/-)-jiadifenin, a non-peptidyl neurotrophic modulator" J. Am. Chem. Soc. 2004;126(44): 14358-9.

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Claims

CLAIMSWe claim:

1. An isolated compound having the structure:

(I) or pharmaceutically acceptable derivative thereof; wherein n is 0 or 1 ; m is 1 or 2;

Ri is hydrogen, halogen, -OR^1A, -SR^1A, -NR^1AR^1B, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; wherein R^1Λ is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; and R^1B is hydrogen, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety;

R₂ is hydrogen, halogen, -OR^2A, -SR^2A, -NR^2AR^2B, -CO₂R^2A, -CH₂OR^2A, - C(=O)H, -CH=CR^2CR^2D, -C(=0)R^2C, -C(=NR^2A)R^2C, -C(=NR^2A)R^2C, -C(=N- NR^2AR^2B)R^2C, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; wherein R^2A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; and R^2B is hydrogen, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; and R^2C and R^2D are indenpently hydrogen, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety;

R₃, R₄ and R₅ are independently hydrogen, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; R₆ is hydrogen, halogen, -OR^6A, -SR^0A, -NR^bAR^0B, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; wherein R^6A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; and R^6B is hydrogen, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; with the proviso that the compound does not have the following structure:

2. The compound of claim 1 having the structure:

wherein RpR₆, m and X₂ are as defined in claim 1.

3. The compound of claim 2 having the structure:

4. The compound of claim 1 having the structure:

wherein Ri -Re, m and X₂ are as defined in claim 1.

5. The compound of claim 4 having the structure:

6. The compound of any one of claims 1-5 wherein n is 0 or 1 ; m is 1 or 2;

Xi and X₂ are independently O or NR^XI, wherein R^X1 is hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, acyl moiety, or a nitrogen protecting group;

Ri is hydrogen, halogen, -OR^1A, -SR^1A, -NR^1AR^1B, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein R^1A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R^1B is hydrogen, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;

R₂ is hydrogen, halogen, -OR^2A, -SR^2A, -NR^2AR^2B, -CO₂R^2A, -CH₂OR^2A, - C(=O)H, -CH=CR^2CR^2D, -C(=0)R^2C, -C(=NR^2A)R^2C, -C(=NR^2A)R^2C, -C(=N- NR^2AR^2B)R^2C, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein R^2A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R^2B is hydrogen, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R and R^2D are indenpently hydrogen, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;

R₆ is hydrogen, halogen, -OR^6A, -SR^6A, -NR^6AR^6B, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein R^6A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R^6B is hydrogen, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety.

7. The compound of claim 1 or 2 wherein Xi and X₂ are independently O or NR^X wherein R^x is hydrogen, lower alkyl or acyl.

8. The compound of claim 1 or 2 wherein Xi and X₂ are independently O or NH.

9. The compound of any one of claims 1 -5 wherein m is 1.

10. The compound of any one of claims 1-5 wherein m is 2.

11. The compound of any one of claims 1-5 wherein Ri is hydrogen or -OR^1A; wherein R^1A is hydrogen, an oxygen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety.

12. The compound of claim 11 wherein Ri is hydrogen or OH.

13. The compound of any one of claims 1-5 wherein R₂ is hydrogen or -CO₂R^2A; wherein R^2A is hydrogen or lower alkyl.

14. The compound of claims 13 wherein R₂ is hydrogen or -CO₂Me.

15. The compound of any one of claims 1-5 wherein R₃, R₄ and R₅ are independently hydrogen or lower alkyl.

16. The compound of claims 15 wherein R₃, R₄ and R₅ are independently hydrogen or methyl.

17. The compound of any one of claims 1-5 wherein R₆ is hydrogen or -OR ^A; wherein R^6A is hydrogen or lower alkyl.

18. The compound of claims 15 wherein R₆ is hydrogen or -OR^6A; wherein R^6A is hydrogen or methyl.

19. The compound of claim 1 having one of the following structures:

20. A pharmaceutical composition comprising a compound of claim 1; and a pharmaceutically acceptable carrier or diluent.

21. A method for treating or lessening the severity of a neurodegenerative disease or disorder in a subject comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1; and a pharmaceutically acceptable carrier.

22. The method of claim 21 , wherein the neurodegenerative disease or disorder is Alzheimer's disease, Parkinson's disease, Huntington's disease or Lou Gehrig's disease.

23. The method of claim 22, wherein the neurodegenerative disease or disorder is Alzheimer's disease.

24. The method of claim 23 further comprising a step of administering to the subject one or more additional therapeutic agent selected from a cholinesterase inhibitor, an N-methyl-D-aspartate (NMDA) receptor antagonist and a vitamin E supplement, wherein: said additional therapeutic agent is appropriate for the disease being treated; and said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.

25. The method of claim 24, wherein the cholinesterase inhibitor is donepezil, rivastigmine, galantamine or Tacrine.

26. The method of claim 24, wherein the N-methyl-D-aspartate (NMDA) receptor antagonist is Memantine.

27. The method of claim 22, wherein the neurodegenerative disease or disorder is Parkinson's disease.

28. The method of claim 27 further comprising a step of administering to the subject one or more additional therapeutic agents selected from an Anticholinergic, a COMT Inhibitor, a Dopamine Precursor, a Dopamine Receptor Agonist and an MAO- B Inhibitor, wherein: said additional therapeutic agent is appropriate for the disease being treated; and said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.

29. The method of claim 28, wherein: the Anticholinergic is Benztropine, Ethropropazine, Procyclidine or Trihexyphenidyl; the COMT Inhibitor is Entacapone or Tolcapone; the Dopamine Precursor is levodopa; the Dopamine Receptor Agonist is Bromocriptine, Cabergoline, Pergolide, Pramipexole or Ropinirole); and the MAO-B Inhibitor is Amantadine.