WO2013026852A2

WO2013026852A2 - Derivatives of mecamylamine

Info

Publication number: WO2013026852A2
Application number: PCT/EP2012/066285
Authority: WO
Inventors: Michael Southern; David MANGAN
Original assignee: The Provost, Fellows, Foundation Scholars, And The Other Members Of Board, Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth, Near Dublin
Priority date: 2011-08-22
Filing date: 2012-08-21
Publication date: 2013-02-28
Also published as: WO2013026852A3

Abstract

Mecamylamine is a general nicotinic acetylcholine receptor (nAChR) antagonist that was one of the first anti-hypertensive agents. Since its demise as an anti-hypertensive drug, mecamylamine has been shown to aid smoking cessation (in humans), reduce cue induced craving in human ***e addicts and heavy drinkers. The present invention provides for novel derivatives of mecamylamine and inventive synthetic routes to these compounds.

Description

Title

Derivatives of Mecamylamine

Field of the Invention

[0001] The present invention relates to novel derivatives of mecamylamine [methyl-(2,3,3- trimethyl-bicyclo[2.2.1]hept-2-yl)-amine] and methods for the preparation of these compounds. Moreover, the present invention provides for pharmaceutical compositions comprising these compounds.

Background to the Invention

[0002] Mecamylamine (MA) or methyl-(2,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amine is a drug that was previously used to treat high blood pressure prior to the discovery and clinical use of beta-blockers.

mecamylamine

[0003] MA is a general nicotinic acetylcholine receptor (nAChR) antagonist that was one of the first anti-hypertensive agents and was employed from the 1950's onwards for a number of years before better drugs with fewer side-effects were discovered. Since its demise as an antihypertensive drug, MA has been shown to aid smoking cessation (in humans), reduce cue induced craving in human ***e addicts and reduce alcohol consumption in heavy drinkers. MA has also been shown to reduce self-administration of numerous drugs of abuse in animal models.

[0004] nAChRs are also implicated in depression and MA has been shown to outperform citalopram and riboxetin (Andreasen, J. T. et al. Journal of Psychopharmacology 2009, 23, 797- 804). International Patent Application No. WO2005067909 relates to the use of MA as an adjunct to traditional depression/mood disorder remedies. Currently, S-(+)-Mecamylamine is in Phase 3 trials as an adjunct to other anti-depressant drugs.

[0005] MA was reintroduced to the market for treatment of Tourette's in 1997 and is of interest for the treatment of ADHD, epilepsy, Alzheimer's, schizophrenia, anxiety, Parkinson's and pain.

[0006] Notwithstanding the potential therapeutic utility of MA synthetic methods for the preparation of novel and inventive derivatives of MA remain hitherto largely unexplored. [0007] One of the first syntheses of mecamylamine was from camphene and is disclosed in U.S. Patent. No. 2,831 ,027 and United Kingdom Patent No. GB804879. The method is shown in Scheme 1 below.

R ⁼ C-| - Cg

Scheme 1

[0008] Subsequent syntheses were disclosed in U.S. Patent. Nos. 2,885,428 and 5,986,142.

[0009] These methods suffer in that they leave little scope for the synthesis of derivatives. Optically pure camphene is available thus making enantiopure synthesis of MA a possibility via this route, however, methyl shifts caused by the reaction conditions may result in racemisation.

[0010] Stone, C. A. et al., J. Med. Pharm. Chem., 5: 665, 1962 disclose a number of possible routes to MA:

i) Camphene, racemic or isomeric, in an acidic medium can be reacted with a nitrogen source, such as cyanide. The intermediates so produced can be converted to mecamylamine, the racemate or either isomer; and

ii) Camphenilone, racemic or as either of its isomers, can be reacted with a methyl lithium or similar nucleophilic methyl to give an alcohol. The alcohol or its derivatives can be transformed into mecamylamine, racemic or as either of its isomers.

[0011] Suchocki et al., J. Med. Chem. 1991 , 34, 1003-1010 disclose a synthesis of endo-2- demethylmecamylamine via an imine intermediate.

[0012] Again, these methods suffer in that they leave little scope for the synthesis of derivatives. Accordingly, there remains a need for an alternative method for the synthesis of MA and derivatives thereof that allows for facile substitution of the molecule. Such a new synthetic method may provide for derivatives of MA having improved properties over MA itself. Summary of the Invention

[0013] The present invention provides for an inventive synthetic route facilitating the preparation of a library of mecamylamine derivatives that are inaccessible by prior art synthetic methods, such as those discussed above. The novel and inventive compounds prepared by the method of the present invention may find utility in the treatment of any condition responsive to the antagonism of nicotinic acetylcholine receptors.

[0014] Accordingly, in a first aspect the present invention provides for a method of synthesising a compound of formula (I),

the method comprising the steps of:

i) substituting a compound of formula (II) with R¹ and R² at position 6 to

produce a compound of formula III ; an

(ll) (III)

where X can be selected from O, NR⁴ and +N(R⁴)(R⁵);

ϋ) adding R³ to the carbon of the C=X group of the compound of formula (III) to provide a compound of the general formula (IV);

(IV),

wherein XZ is OH, NHR⁴ or N(R⁴)(R⁵), and

iii) if XZ is OH, replacing the OH group of the compound of formula (IV) with an amino group of the formula N(R⁴)(R⁵),

R¹ is selected from C1-C10 aliphatic, C₃-Ci₀ cycloaliphatic, C₂-Ci₀ aliphatic heterocycle, C₆-C₂o aromatic, C₂-C₂o heteroaromatic, and combinations thereof; R² is selected from C1-C1₀ aliphatic, C₃-Ci₀ cycloaliphatic, C₂-Ci₀ aliphatic heterocycle, C₆-C₂o aromatic, C₂-C₂o heteroaromatic, and combinations thereof; or

R¹ and R² together with the carbon atom to which they are attached may define a C₃- C1₀ cycloaliphatic ring or a C₂-Ci₀ aliphatic heterocycle;

R³ is selected from H, C1-C10 aliphatic, C3-C10 cycloaliphatic, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof;

R⁴ is selected from H, C1-C10 aliphatic, C3-C10 cycloaliphatic, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof;

R⁵ is selected from H, C1-C10 aliphatic, C3-C10 cycloaliphatic, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof; or

N, R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle or a Ci-C₂₀ heteroaromatic,

R⁶, R⁷, R⁸ and R⁹ are the same or different and may be independently selected from H, Ci-C₆ alkyl, and CrC₆ alkoxy;

L is selected from the group consisting of CR¹⁰R¹¹, CR¹⁰R¹¹CR¹²R¹³, and O, wherein R¹⁰, R¹¹, R¹² and R¹³ are the same or different and may be independently selected from H , and Ci-C₆ alkyl; and

wherein the dashed line indicates an optional double bond.

[0015] In one embodiment, X may be selected from NR⁴ and +N(R⁴)(R⁵).

[0016] The present invention may provide for a method of synthesising a compound of formula

(la),

the method comprising the steps of:

i) substituting a compound of formula (l la) with R¹ and R² at position 6 to

produce a compound of formula (I l ia); and

(l la) (I l ia)

where X can be selected from O, NR⁴ and +N(R⁴)(R⁵);

adding R³ to the carbon of the C=X group of the compound of formula (I l ia) to provide a compound of the general formula (IVa);

wherein XZ is OH, NHR⁴ or N(R⁴)(R⁵), and

iii) if XZ is OH , replacing the OH group of the compound of formula (IVa) with an amino group of the formula N(R⁴)(R⁵),

R¹ is selected from C1-C10 aliphatic, C₃-Ci₀ cycloaliphatic, C₂-Ci₀ aliphatic heterocycle, C₆-C₂o aromatic, C₂-C₂o heteroaromatic, and combinations thereof;

R² is selected from C1-C1₀ aliphatic, C₃-Ci₀ cycloaliphatic, C₂-Ci₀ aliphatic heterocycle, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof; or

[0017] R¹ may be selected from C1-C10 aliphatic, C3-C10 cycloaliphatic, C₂-Ci₀ aliphatic heterocycle, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic;

R² may be selected from C1-C10 aliphatic, C3-C10 cycloaliphatic, C₂-Ci₀ aliphatic heterocycle, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic; or

R³ may be selected from H , C1-C10 aliphatic, C3-C10 cycloaliphatic, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic;

R⁴ may be selected from H , C1-C10 aliphatic, C3-C10 cycloaliphatic, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic;

R⁵ may be selected from H , C1-C10 aliphatic, C3-C10 cycloaliphatic, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic; or

N, R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle or a Ci-C₂₀

heteroaromatic.

[0018] As used herein, +N(R⁴)(R⁵) refers to a moiety in which the nitrogen atom is positively charged. [0019] When XZ is NHR⁴, the method may further comprise the step of replacing the hydrogen of NHR⁴ with R⁵ (when R⁵ is not hydrogen) to give N(R⁴)(R⁵).

[0020] The step of substituting a compound of formula (II or I la) with R¹ and R² at position 6 to produce a compound of formula (III or Ilia) may be stereoselective.

[0021] When X is NR⁴ or +N(R⁴)(R⁵) the step of adding R³ to the carbon of the C=NR⁴ or C=N(R⁴)(R⁵)+ group of the compound of formula (III or Ilia) to provide a compound of the general formula (IV or IVa) may be stereoselective for the endo isomer. The stereoselectivity may arise from the picket effect of the bicyclic ring structure. The stereoselectivity may be improved if the addition of R³ is carried out at a temperature below room temperature, for example 0 °C or below. The stereoselectivity may be improved if the addition of R³ is carried out in the presence of a Lewis acid, for example BF₃. The stereoselectivity may be improved if the addition of R³ is carried out at a temperature below room temperature, for example for example 0 °C or below, and in the presence of a Lewis acid, for example BF₃.

[0022] The step of substituting a compound of formula (II or lla) with R¹ and R² at position 6 to produce a compound of formula (III or Ilia) may comprise removing an acidic proton at position 6, under basic conditions, and alkylating with one of R¹-X or R²-X, wherein X is a leaving group. Then resulting compound may be treated with base once again to remove the remaining proton at position 6 and subsequently alkylating with the other of R¹-X or R²-X. R¹ and R² can be added stereospecifically because of the picket effect of the bicyclic ring structure. The base utilised may be Sodium bis(trimethylsilyl)amide (NaHMDS).

[0023] The step of adding R³ to the carbon of the C=X group of the compound of formula (III or Ilia) to provide a compound of the general formula (IV or IVa) may be achieved using any synthetic equivalent of a nucleophilic R³ group. Suitable examples include organolithium reagents comprising R³ and grignard reagents comprising R³.

[0024] The step of replacing the OH group of the compound of formula (IV or IVa) with an amino group of the formula N(R⁴)(R⁵) may be achieved by any synthetic transformation known to a person skilled in the art. This replacing step may be a single step or multi-step

transformation. For example:

i) the OH group may be substituted by a nitrogen based nucleophile (for

example, azide, nitrite, or cyanide) which may be subsequently reduced to an amine, which may in turn be subjected to reductive amination to yield an alkylated amine;

ii) the OH group may be substituted by a heterocyclic nitrogen based nucleophile, for example triazole, tetrazole or imidazole whereupon no further reductive amination step is required; or iii) the OH group may be substituted by an azide, whereupon the azide is

subjected to a Huisgen 1 ,3-Dipolar Cycloaddition with an optionally substituted alkyne (Click Chemistry) to yield an optionally substituted triazole.

[0025] Advantageously, the synthetic method of the present invention allows for a vast array of possible substituents R¹ and R². Such diversity has hitherto been unavailable utilising synthetic methods of the prior art. Prior art synthetic methods effectively limit the substituents R¹ and R² to Me or H. In particular, any suitable electrophile R¹-X or R²-X, wherein X is a leaving group, can be added to the bicyclo[2.2.1 ]heptyl core in step i) above. This allows access to a huge variety of molecules which are unavailable through synthetic methods of the prior art.

[0026] As used herein, the term "leaving group" refers to species that depart with a pair of electrons in heterolytic bond cleavage.

[0027] The present invention also provides for an alternative method of synthesising a compound of formula (I),

the method comprising the steps of:

i) providing a compound of the general formula (V)

where X can be selected from O, NR⁴ and +N(R⁴)(R⁵)

adding R¹ to the three membered heterocyclic ring to provide a ring opened compound of the general formula (IV),

wherein XZ is OH, NHR⁴ or N(R⁴)(R⁵), and

wherein, R¹ is selected from C1-C10 aliphatic, C₃-Ci₀ cycloaliphatic, C₂-Ci₀ aliphatic heterocycle, C₆-C₂o aromatic, C₂-C₂o heteroaromatic, and combinations thereof;

N, R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle or a Ci-C₂₀ heteroaromatic;

L is selected from the group consisting of CR¹⁰R¹¹ , CR¹⁰R¹¹CR¹²R¹³, and O, wherein R¹⁰, R¹¹ , R¹² and R¹³ are the same or different and may be independently selected from H , and Ci-C₆ alkyl; and

wherein the dashed line indicates an optional double bond.

[0028] The present invention also provides for an alternative method of synthesising a compound of formula (la),

the method comprising the steps of:

i) providing a compound of the general formula (Va):

where X can be selected from O, NR⁴ and +N(R⁴)(R⁵)

adding R¹ to the three membered heterocyclic ring to provide a ring opened compound of the general formula (IVa),

wherein XZ is OH, NHR⁴ or N(R⁴)(R⁵), and

iii) if XZ is OH , replacing the OH group of the compound of formula (IV) with an amino group of the formula N(R⁴)(R⁵),

wherein,

[0029] R¹ may be selected from C1-C10 aliphatic, C3-C10 cycloaliphatic, C₂-Ci₀ aliphatic heterocycle, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic;

N, R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle or a Ci-C₂₀ heteroaromatic. [0030] When XZ is N HR⁴, the method may further comprise the step of replacing the hydrogen of NH R⁴ with R⁵ (when R⁵ is not hydrogen) to give N(R⁴)(R⁵).

[0031] Advantageously, the synthetic method of the present invention allows for a vast array of possible substituents R¹ and R² via ring opening of the three membered heterocyclic ring. Such diversity has hitherto been unavailable utilising synthetic methods of the prior art.

[0032] The step of adding R¹ to the three membered heterocyclic ring to provide a ring opened compound of the general formula (IV or IVa) may be achieved using any synthetic equivalent of a nucleophilic R¹ group. Suitable examples include organolithium reagents comprising R¹ and grignard reagents comprising R¹. Alternatively, the ring opening step could be carried out in acidic media, following by quenching of the cation by a nucleophilic R¹ compound.

[0033] The step of replacing the OH group of the compound of formula (IV or IVa) with an amino group of the formula N(R⁴)(R⁵) may be achieved by any synthetic transformation known to a person skilled in the art. This may be a single step or multi-step transformation. For example, the OH group may be substituted by a nitrogen based nucleophile (for example, azide, nitrite, or cyanide) which may be subsequently reduced to an amine, which may in turn be subjected to reductive amination to yield an alkylated amine. Alternatively, the nitrogen based nucleophile may be a heterocycle, for example triazole, tetrazole or imidazole whereupon no further reductive amination step is required.

[0034] The synthetic methods of the present invention may be carried out in a solvent selected from the group consisting of C1-C12 hydrocarbons, C₆-Ci₂ aromatic hydrocarbons, C3-C12 ketones (cyclic and acyclic), C2-C12 ethers (cyclic and acyclic), C₂ to C12 esters (cyclic and acyclic), C₂-C₅ nitriles and combinations thereof. As used herein, C1-C12 hydrocarbon solvents include halogenated variants thereof, such as chlorinated C1-C12 hydrocarbon solvents.

Suitable solvents may be selected from the group consisting of THF, and CH₂CI₂. In particular, for the steps involving nucleophilic addition the following solvents may be particularly preferred: TH F, dioxane, pentane, hexane, heptanes, octane, nonane, decane, undecane, dodecane, ethyl, propyl and butyl ethers, or benzene. For all other steps the following solvents may be preferred: THF, dioxane, pentane, hexane, heptanes, octane, nonane, decane, undecane, dodecane, ethyl, propyl and butyl ethers, benzene, acetonitrile, ethyl, propyl and butyl acetate, dimethyl sulfoxide, dimethyl formamide, /V-Methyl pyrrolidinone, acetone, butanone, pentanone, methanol, ethanol propanol, butanol, dichloromethane, chloroform, toluene, xylenes, or pyridine.

[0035] In a further aspect, the present invention provides for a compound of the general formula

(I):

a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, an amide thereof, or a prodrug thereof,

wherein: R¹ may be selected from C1-C10 aliphatic, C₃-Ci₀ cycloaliphatic, C₂-Ci₀

aliphatic heterocycle, C₆-C₂o aromatic, C₂-C₂o heteroaromatic, and combinations thereof;

R² may be selected from C1-C10 aliphatic, C₃-Ci₀ cycloaliphatic, C₂-Ci₀ aliphatic heterocycle, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof; or

R¹ and R² may together define a C3-C10 cycloaliphatic ring or a C₂-Ci₀ aliphatic heterocycle;

R³ may be selected from H, C1-C10 aliphatic, C3-C10 cycloaliphatic, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof;

R⁴ may be selected from H, C1-C10 aliphatic, C3-C10 cycloaliphatic, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof;

R⁵ may be selected from H, C1-C10 aliphatic, C3-C10 cycloaliphatic, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof; or

N, R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle or a Ci-

C₂₀ heteroaromatic,

provided that:

i) when R¹= R² = R⁴ = Me and R⁵ = H, R³ is not H or C C₃ alkyl;

ii) when R¹= R² = R³ = Me and R⁵ = H, R⁴ is not H, C(0)(C C₅ alkyl), C(0)CH₂Ph, C(0)CH₂CH₂Ph, C C₈ alkyl, CH(CH₃)₂, CH₂CH₂C(CH₃)₃, CH₂CH=CH₂, CH₂Ph, CH₂CH₂Ph or CH₂CH₂CH₂Ph; and

iii) when R¹= R² = R³ = Me and R⁵ = C C₂ alkyl, R⁴ is not C C₂ alkyl.

[0036] The compounds disclaimed from the above formula are disclosed in Stone, C. A. et al., J. Med. Pharm. Chem., 5: 665, 1962, U.S. 804879 and Suchocki et al., J. Med. Chem. 1991 , 34, 1003-1010. The compounds disclosed in Stone, C. A. et al., J. Med. Pharm. Chem., 5: 665, 1962, U.S. 804879 and Suchocki et al., J. Med. Chem. 1991 , 34, 1003-1010 are not embraced by the present invention.

[0037] R¹ may be C1-C10 aliphatic, R² may be C1-C10 aliphatic, R³ may be C1-C10 aliphatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic, provided that:

i) when R¹= R² = R⁴ = Me and R⁵ = H, R³ is not H or C C₃ alkyl;

ii) when R¹= R² = R³ = Me and R⁵ = H, R⁴ is not C(0)(C C₅ alkyl), C(0)CH₂Ph, C(0)CH₂CH₂Ph, d-Ce alkyl, CH(CH₃)₂, CH₂CH₂C(CH₃)₃, CH₂CH=CH₂, CH₂Ph, CH₂CH₂Ph or CH₂CH₂CH₂Ph; and iii) when R¹= R² = R³ = Me and R⁵ = C C₂ alkyl, R⁴ is not C C₂ alkyl.

[0038] The compound may be of the general formula (I):

R

N(R⁴)(R⁵)

(I) a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, an amide thereof, or a prodrug thereof,

wherein: R¹ may be selected from C1-C1₀ aliphatic, C₃-Ci₀ cycloaliphatic, C₂-Ci₀ aliphatic heterocycle, C₆-C₂o aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof;

R³ may be selected from H , C1-C10 aliphatic, C3-C10 cycloaliphatic, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof;

R⁴ may be selected from H , C1-C10 aliphatic, C3-C10 cycloaliphatic, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof;

R⁵ may be selected from H , C1-C10 aliphatic, C3-C10 cycloaliphatic, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof; or

provided that:

when R¹ and R² are the same they are not Me.

[0039] R¹ may be C1-C10 aliphatic, R² may be C1-C10 aliphatic, R³ may be C1-C10 aliphatic, and N, R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle.

[0040] R¹ may be C1-C10 aliphatic, R² may be C1-C10 aliphatic, R³ may be C1-C10 aliphatic, and N, R⁴ and R⁵ may together define a Ci-C₂₀ heteroaromatic.

[0041] R¹ may be C1-C10 aliphatic, R² may be C₆-C₂₀ aromatic, R³ may be C1-C10 aliphatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ may C1-C10 aliphatic, R² may be C₂-C₂₀ heteroaromatic, R³ may be C1-C10 aliphatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ may be C1-C10 aliphatic, R² may be C₆-C₂₀ aromatic, R³ may be d- C1₀ aliphatic, and N, R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle. R¹ may be C1-C10 aliphatic, R² may be C₂-C₂₀ heteroaromatic, R³ may be C1-C10 aliphatic, and N, R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle. R¹ may be C1-C10 aliphatic, R² may be C₆- C₂₀ aromatic, R³ may be C1-C1₀ aliphatic, and N, R⁴ and R⁵ may together define a Ci-C₂₀ heteroaromatic. R¹ may be C1-C10 aliphatic, R² may be C₂-C₂o heteroaromatic, R³ may be C C1₀ aliphatic, and N, R⁴ and R⁵ may together define a C1-C2₀ heteroaromatic.

[0042] R¹ may be C1-C10 aliphatic, R² may be C₆-C₂o aromatic, R³ may be H, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ may C1-C10 aliphatic, R² may be C₂-C₂o heteroaromatic, R³ may be H, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ may be C1-C1₀ aliphatic, R² may be C₆-C₂₀ aromatic, R³ may be H, and N , R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle. R¹ may be C1-C10 aliphatic, R² may be C₂-C₂₀ heteroaromatic, R³ may be H, and N , R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle. R¹ may be C1-C1₀ aliphatic, R² may be C₆-C₂₀ aromatic, R³ may be H, and N , R⁴ and R⁵ may together define a Ci-C₂₀ heteroaromatic. R¹ may be C1-C1₀ aliphatic, R² may be C₂- C₂₀ heteroaromatic, R³ may be H, and N, R⁴ and R⁵ may together define a Ci-C₂₀

heteroaromatic.

[0043] R¹ may be C1-C10 aliphatic, R² may be C1-C10 aliphatic, R³ may be C₆-C₂₀ aromatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ may be C1-C10 aliphatic, R² may be C1-C10 aliphatic, R³ may be C₂-C₂₀ heteroaromatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ may be C1-C10 aliphatic, R² may be C1-C10 aliphatic, R³ may be C₆-C₂₀ aromatic, and N, R⁴ and R⁵ may together define a Ci-C₂₀ heteroaromatic or a C₂-Ci₀ aliphatic heterocycle. R¹ may be C1-C10 aliphatic, R² may be C1-C10 aliphatic, R³ may be C₂-C₂₀ heteroaromatic, and N , R⁴ and R⁵ may together define a Ci-C₂₀ heteroaromatic or a C₂-Ci₀ aliphatic heterocycle.

[0044] R¹ may be C₆-C₂₀ aromatic, R² may be C1-C10 aliphatic, R³ may be C₆-C₂₀ aromatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ may be C₂-C₂₀ heteroaromatic, R² may be C1-C10 aliphatic, R³ may be C₂-C₂₀ heteroaromatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ may be C₆-C₂₀ aromatic, R² may be C1-C10 aliphatic, R³ may be C₂-C₂₀ heteroaromatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ may be C₂-C₂₀ heteroaromatic, R² may be C1-C10 aliphatic, R³ may be C₆-C₂₀ aromatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic.

[0045] R¹ may be C₆-C₂₀ aromatic, R² may be C1-C10 aliphatic, R³ may be C₆-C₂₀ aromatic, and N, R⁴ and R⁵ may together define a Ci-C₂₀ heteroaromatic or a C₂-Ci₀ aliphatic heterocycle. R¹ may be C₂-C₂₀ heteroaromatic, R² may be C1-C10 aliphatic, R³ may be C₂-C₂₀ heteroaromatic, and N , R⁴ and R⁵ may together define a Ci-C₂₀ heteroaromatic or a C₂-Ci₀ aliphatic heterocycle. R¹ may be C₆-C₂₀ aromatic, R² may be C1-C10 aliphatic, R³ may be C₂-C₂₀ heteroaromatic, and N, R⁴ and R⁵ may together define a Ci-C₂₀ heteroaromatic or a C₂-Ci₀ aliphatic heterocycle. R¹ may be C₂-C₂₀ heteroaromatic, R² may be C1-C10 aliphatic, R³ may be C₆-C₂₀ aromatic, and N, R⁴ and R⁵ may together define a Ci-C₂₀ heteroaromatic or a C₂-Ci₀ aliphatic heterocycle.

[0046] R¹ may be C1-C10 aliphatic, R² may be C₆-C₂₀ aromatic, R³ may be C3-C10 cycloaliphatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ may C1-C10 aliphatic, R² may be C₂-C₂o heteroaromatic, R³ may be C3-C10 cycloaliphatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ may be C1-C10 aliphatic, R² may be C₆-C₂o aromatic, R³ may be C3-C10 cycloaliphatic, and N , R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle. R¹ may be C1-C10 aliphatic, R² may be C₂-C₂₀ heteroaromatic, R³ may be C3-C10 cycloaliphatic, and N , R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle. R¹ may be C1-C10 aliphatic, R² may be C₆-C₂₀ aromatic, R³ may be C3-C10 cycloaliphatic, and N , R⁴ and R⁵ may together define a Ci-C₂₀ heteroaromatic. R¹ may be C1-C10 aliphatic, R² may be C₂-C₂₀ heteroaromatic, R³ may be C3-C10 cycloaliphatic, and N , R⁴ and R⁵ may together define a Ci-C₂₀ heteroaromatic.

[0047] R¹ may be C3-C10 cycloaliphatic, R² may be C1-C10 aliphatic, R³ may be C₆-C₂₀ aromatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ may be C3-C10

cycloaliphatic, R² may be C1-C10 aliphatic, R³ may be C₂-C₂₀ heteroaromatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ may be C3-C10 cycloaliphatic, R² may be d- C10 aliphatic, R³ may be C₆-C₂₀ aromatic, and N , R⁴ and R⁵ may together define a Ci-C₂₀ heteroaromatic or a C₂-Ci₀ aliphatic heterocycle. R¹ may be C3-C10 cycloaliphatic, R² may be C1-C10 aliphatic, R³ may be C₂-C₂₀ heteroaromatic, and N , R⁴ and R⁵ may together define a Ci- C₂₀ heteroaromatic or a C₂-Ci₀ aliphatic heterocycle.

[0048] R¹ may be C₆-C₂₀ aromatic, R² may be C3-C10 cycloaliphatic, R³ may be C₆-C₂₀ aromatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ may be C₂-C₂₀

heteroaromatic, R² may be C3-C10 cycloaliphatic, R³ may be C₂-C₂₀ heteroaromatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ may be C₆-C₂₀ aromatic, R² may be C1-C10 aliphatic, R³ may be C₂-C₂₀ heteroaromatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ may be C₂-C₂₀ heteroaromatic, R² may be C3-C10 cycloaliphatic, R³ may be C₆-C₂₀ aromatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic.

[0049] R¹ may be C₆-C₂₀ aromatic, R² may be C3-C10 cycloaliphatic, R³ may be C₆-C₂₀ aromatic, and N , R⁴ and R⁵ may together define a Ci-C₂₀ heteroaromatic or a C₂-Ci₀ aliphatic heterocycle. R¹ may be C₂-C₂₀ heteroaromatic, R² may be C3-C10 cycloaliphatic, R³ may be C₂-C₂₀ heteroaromatic, and N , R⁴ and R⁵ may together define a Ci-C₂₀ heteroaromatic or a C₂-Ci₀ aliphatic heterocycle. R¹ may be C₆-C₂₀ aromatic, R² may be C3-C10 cycloaliphatic, R³ may be C₂-C₂₀ heteroaromatic, and N , R⁴ and R⁵ may together define a Ci-C₂₀ heteroaromatic or a C₂- C10 aliphatic heterocycle. R¹ may be C₂-C₂₀ heteroaromatic, R² may be C3-C10 cycloaliphatic, R³ may be C₆-C₂₀ aromatic, and N , R⁴ and R⁵ may together define a Ci-C₂₀ heteroaromatic or a C₂- C10 aliphatic heterocycle.

[0050] R¹ and R² may together define a C3-C10 cycloaliphatic ring, R³ may be C1-C10 aliphatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ and R² may together define a C3-C10 cycloaliphatic ring, R³ may be H , R⁴ may be C1-C10 aliphatic, and R⁵ may be H or d- C10 aliphatic. R¹ and R² may together define a C₃-C10 cycloaliphatic ring, R³ may be C3-C10 cycloaliphatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ and R² may together define a C3-C10 cycloaliphatic ring, R³ may be C₂-C₂o heteroaromatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C1₀ aliphatic. R¹ and R² may together define a C3-C1₀ cycloaliphatic ring, R³ may be C₆-C₂o aromatic, R⁴ may be C1-C1₀ aliphatic, and R⁵ may be H or C1-C10 aliphatic.

[0051] R¹ and R² may together define a C3-C1₀ cycloaliphatic ring, R³ may be C1-C1₀ aliphatic, and N , R⁴ and R⁵ may together define a C1-C2₀ heteroaromatic or a C2-C1₀ aliphatic heterocycle. R¹ and R² may together define a C3-C1₀ cycloaliphatic ring, R³ may be H , and N, R⁴ and R⁵ may together define a C1-C2₀ heteroaromatic or a C2-C1₀ aliphatic heterocycle. R¹ and R² may together define a C3-C1₀ cycloaliphatic ring, R³ may be C3-C1₀ cycloaliphatic, and N, R⁴ and R⁵ may together define a C1-C2₀ heteroaromatic or a C2-C1₀ aliphatic heterocycle. R¹ and R² may together define a C3-C1₀ cycloaliphatic ring, R³ may be C₂-C₂o heteroaromatic, and N, R⁴ and R⁵ may together define a Ci-C₂₀ heteroaromatic or a C₂-Ci₀ aliphatic heterocycle. R¹ and R² may together define a C3-C1₀ cycloaliphatic ring, R³ may be C₆-C₂₀ aromatic, and N, R⁴ and R⁵ may together define a Ci-C₂₀ heteroaromatic or a C₂-Ci₀ aliphatic heterocycle.

[0052] The compoun ntion may have the formula:

a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a prodrug thereof, or an amide thereof, wherein

R¹ may be selected from C1-C10 aliphatic, and C3-C10 cycloaliphatic;

R² may be selected from C1-C10 aliphatic, and C3-C10 cycloaliphatic;

R³ may be selected from H, C1-C10 aliphatic, and C3-C10 cycloaliphatic; R⁴ may be selected from H, C1-C10 aliphatic, and C3-C10 cycloaliphatic; R⁵ may be selected from H, C1-C10 aliphatic, and C3-C10 cycloaliphatic; or N, R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle or a Ci- C10 heteroaromatic,

provided that:

i) when R¹= R² = R⁴ = Me and R⁵ = H, R³ is not H or C C₃ alkyl;

ii) when R¹= R² = R³ = Me and R⁵ = H, R⁴ is not H, C(0)(C C₅ alkyl), C(0)CH₂Ph, C(0)CH₂CH₂Ph, d-Ce alkyl, CH(CH₃)₂, CH₂CH₂C(CH₃)₃, CH₂CH=CH₂, CH₂Ph, CH₂CH₂Ph or CH₂CH₂CH₂Ph; and

[0053] The compound of the present invention may have the formula: R

N(R⁴)(R⁵) a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a prodrug thereof, or an amide thereof, wherein

R¹ may be selected from C₁-C₁₀ aliphatic, and C₃-Ci₀ cycloaliphatic;

R² may be selected from C₁-C₁₀ aliphatic, and C₃-Ci₀ cycloaliphatic;

R³ may be selected from H, C₁-C₁₀ aliphatic, and C₃-Ci₀ cycloaliphatic; R⁴ may be selected from H, C₁-C₁₀ aliphatic, and C₃-Ci₀ cycloaliphatic; R⁵ may be selected from H, C₁-C₁₀ aliphatic, and C₃-Ci₀ cycloaliphatic; or N, R⁴ and R⁵ may together define a C₂-C₁₀ aliphatic heterocycle or a Ci- C10 heteroaromatic,

provided that:

when R¹ and R² are the same they are not Me.

[0054] R¹ may be C₃-Ci₀ cycloaliphatic, R² may be C1-C10 aliphatic, R³ may be C1-C10 aliphatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic.

[0055] R¹ may be C₃-Ci₀ cycloaliphatic, R² may be C1-C10 aliphatic, R³ may be C1-C10 aliphatic, and N, R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle. R¹ may be C₃-Ci₀ cycloaliphatic, R² may be C1-C10 aliphatic, R³ may be C1-C10 aliphatic, and N, R⁴ and R⁵ may together define a C₁-C₁₀ heteroaromatic.

[0056] R¹ may be C1-C10 aliphatic, R² may be C1-C10 aliphatic, R³ may be C₃-Ci₀ cycloaliphatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ may C1-C10 aliphatic, R² may be C₁-C₁₀ aliphatic, R³ may be C₃-Ci₀ cycloaliphatic, and N, R⁴ and R⁵ may together define a C2-C10 aliphatic heterocycle or a C1-C10 heteroaromatic.

[0057] R¹ may be C₃-Ci₀ cycloaliphatic, R² may be C1-C10 aliphatic, R³ may be C₃-Ci₀ cycloaliphatic, R⁴ may be C1-C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic. R¹ may C₃-Ci₀ cycloaliphatic, R² may be C₁-C₁₀ aliphatic, R³ may be C₃-Ci₀ cycloaliphatic, and N, R⁴ and R⁵ may together define a C₂-C₁₀ aliphatic heterocycle or a C₁-C₁₀ heteroaromatic.

[0058] R¹ may be C₃-Ci₀ cycloaliphatic, R² may be C1-C10 aliphatic, R³ may be H, R⁴ may be d- C10 aliphatic, and R⁵ may be H or C1-C10 aliphatic.

[0059] R¹ may be C₃-Ci₀ cycloaliphatic, R² may be C₁-C₁₀ aliphatic, R³ may be H, and N, R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle. R¹ may be C₃-Ci₀ cycloaliphatic, R² may be C1-C10 aliphatic, R³ may be H, and N, R⁴ and R⁵ may together define a C1-C10

heteroaromatic.

[0060] The compound of the present invention may have the formula: R

N(R⁴)(R⁵)

a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, an amide thereof, or a prodrug thereof, wherein

R¹ is selected from C1-C10 aliphatic;

R² is selected from C1-C10 aliphatic;

R³ is selected from H, and C1-C1₀ aliphatic;

R⁴ is selected from H, and C1-C1₀ aliphatic;

R⁵ is selected from H, and C1-C1₀ aliphatic; or

N, R⁴ and R⁵ may together define a C2-C1₀ aliphatic heterocycle or a Ci- C10 heteroaromatic,

provided that:

i) when R¹= R² = R⁴ = Me and R⁵ = H, R³ is not H or C C₃ alkyi;

ii) when R¹= R² = R³ = Me and R⁵ = H, R⁴ is not H, C(0)(C C₅ alkyi), C(0)CH₂Ph, C(0)CH₂CH₂Ph, d-Ce alkyi, CH(CH₃)₂, CH₂CH₂C(CH₃)_3! CH₂CH=CH₂, CH₂Ph, CH₂CH₂Ph or CH₂CH₂CH₂Ph; and

iii) when R¹= R² = R³ = Me and R⁵ = C C₂ alkyi, R⁴ is not C C₂ alkyi.

[0061] R¹ may be C1-C1₀ alkyi, R² may be C1-C1₀ alkyi, R³ may be C1-C1₀ alkyi, R⁴ may be C C1₀ alkyi and R⁵ may be C1-C1₀ alkyi, provided that when R¹= R² = R³ = Me and R⁵ = C C₂ alkyi, R⁴ is not Ci-C₂ alkyi. R¹ may be C1-C1₀ alkyi, R² may be C1-C1₀ alkyi, R³ may be C1-C1₀ alkyi, and N , R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle or a C1-C1₀ heteroaromatic.

[0062] R¹ may be C C₅ alkyi, R² may be C C₅ alkyi, R³ may be C C₅ alkyi, R⁴ may be C C₅ alkyi and R⁵ may be C1-C5 alkyi, provided that

when R¹= R² = R³ = Me and R⁵ = C C₂ alkyi, R⁴ is not C C₂ alkyi.

[0063] R¹ may be C C₅ alkyi, R² may be C C₅ alkyi, R³ may be C C₅ alkyi, and N , R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle or a C1-C1₀ heteroaromatic.

[0064] R¹ may be C1-C1₀ alkyi, R² may be C1-C1₀ alkyi, R³ may be C1-C1₀ alkyi, R⁴ may be C C1₀ alkyi and R⁵ may be H, provided that

i) when R¹= R² = R⁴ = Me, R³ is not C C₃ alkyi; and

ii) R¹= R² = R³≠ Me.

[0065] R¹ may be C C₅ alkyi, R² may be C C₅ alkyi, R³ may be C C₅ alkyi, R⁴ may be C C₅ alkyi and R⁵ may be H, provided that

i) when R¹= R² = R⁴ = Me, R³ is not C C₃ alkyi; and

ii) R¹= R² = R³≠ Me. [0066] R¹ may be C Ci₀ alkyi, R² may be C Ci₀ alkyi, R³ may be C Ci₀ alkyi, R⁴ may be H and R⁵ may be H, provided that R¹= R² = R³≠ Me.

[0067] R¹ may be C C₅ alkyi, R² may be C C₅ alkyi, R³ may be C C₅ alkyi, R⁴ may be H and R⁵ may be H, provided that R¹= R² = R³≠ Me.

[0068] R¹ may be C Ci₀ alkyi, R² may be C Ci₀ alkyi, R³ may be H, R⁴ may be C Ci₀ alkyi and R⁵ may be H or C Ci₀ alkyi provided that when R⁵ = H, R¹= R² = R⁴≠ Me. R¹ may be C C₅ alkyi, R² may be C C₅ alkyi, R³ may be H, R⁴ may be C C₅ alkyi and R⁵ may be H or C C₅ alkyi provided that when R⁵ = H, R¹= R² = R⁴≠ Me.

[0069] R¹ may be C Ci₀ alkyi, R² may be C Ci₀ alkyi, R³ may be H, and N , R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle or a C1-C10 heteroaromatic. R¹ may be C1-C5 alkyi, R² may be C1-C5 alkyi, R³ may be H, and N , R⁴ and R⁵ may together define a C2-C1₀ aliphatic heterocycle or a C1-C10 heteroaromatic.

[0070] The compound of the ay have the formula:

R¹ is selected from C1-C10 aliphatic;

R² is selected from C1-C10 aliphatic;

R³ is selected from H , and C1-C1₀ aliphatic;

R⁴ is selected from H , and C1-C1₀ aliphatic;

R⁵ is selected from H , and C1-C1₀ aliphatic; or

provided that:

when R¹ and R² are the same they are not Me.

[0071] The molecule of the present invention may be:

a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, an amide thereof, or a prodrug thereof. [0072] The compounds of the present invention may be the exo isomer of formula (la):

wherein any specific combination of R¹ to R⁵ as listed above is applicable to the exo isomer

[0073] The compounds of the present invention may be the endo isomer of formula (lb):

(lb) wherein any specific combination of R¹ to R⁵ as listed above is applicable to the endo isomer.

[0074] The compounds of the present invention make take the form of the exo isomer, the endo isomer, or a combination thereof.

[0075] In a further aspect the present invention provides for a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier.

[0076] The compounds of the present invention may find use in the treatment of a condition responsive to antagonism of a nicotinic acetylcholine receptor. The compounds of the present invention may find use as antagonists of nicotinic acetylcholine receptors.

[0077] The compounds of the present invention may find use in the treatment of a condition selected from behavioural addiction, substance addiction, aiding smoking cessation, treating weight gain associated with smoking cessation, attention deficit hyperactivity disorder (ADHD), psychosis, respiratory disorders, insomnia, alzheimer's disease, hypertension, hypertensive crisis, Tourette's Syndrome and other tremors, cancer, atherogenic profile, depression, anxiety, chronic fatigue syndrome, gastrointestinal disorders, inflammatory bowel disease, ulcerative colitis, Crohn's disease, autonomic dysreflexia, and spasmogenic intestinal disorders.

[0078] The compounds of the present invention may find use in the treatment of depression.

[0079] The compounds of the present invention may find use in the treatment of substance addiction. For example, the compounds of the present invention may find use in the treatment of an addiction to the following substances; nicotine, ***e, alcohol, amphetamines, opiates, or combinations thereof.

[0080] The invention further provides for a method of treating a condition responsive to antagonism of a nicotinic acetylcholine receptor in a patient in need thereof, the method comprising administering a compound according to the present invention to the patient.

Suitable conditions may be selected from behavioural addiction, substance addiction, aiding smoking cessation, treating weight gain associated with smoking cessation, attention deficit hyperactivity disorder (ADHD), psychosis, respiratory disorders, insomnia, alzheimer's disease, hypertension, hypertensive crisis, Tourette's Syndrome and other tremors, cancer, atherogenic profile, depression, anxiety, chronic fatigue syndrome, gastrointestinal disorders, inflammatory bowel disease, ulcerative colitis, Crohn's disease, autonomic dysreflexia, and spasmogenic intestinal disorders.

[0081] In yet a further aspect the present invention provides for a pharmaceutical composition comprising endo mecamylamine of the formula (Ic), a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a prodrug thereof, or an amide thereof,

and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is absent exo mecamylamine.

[0082] The pharmaceutical composition comprising endo mecamylamine and absent exo mecamylamine may find use in the treatment of a condition responsive to antagonism of a nicotinic acetylcholine receptor. Suitable conditions may be selected from behavioural addiction, substance addiction, aiding smoking cessation, treating weight gain associated with smoking cessation, attention deficit hyperactivity disorder (ADHD), psychosis, respiratory disorders, insomnia, alzheimer's disease, hypertension, hypertensive crisis, Tourette's

Syndrome and other tremors, cancer, atherogenic profile, depression, anxiety, chronic fatigue syndrome, gastrointestinal disorders, inflammatory bowel disease, ulcerative colitis, Crohn's disease, autonomic dysreflexia, and spasmogenic intestinal disorders.

[0083] As used herein, the term "C_x-C_y alkyi" embraces C_x-C_y unbranched alkyi, C_x-C_y branched alkyi and combinations thereof.

[0084] As used herein, the term C_x-C_y aliphatic refers to linear, branched, saturated and unsaturated hydrocarbon chains comprising C_x-C_y carbon atoms (and includes C_x-C_y alkyi, C_x-C_y alkenyl and C_x-C_yalkynyl).

[0085] Similarly, references to C_x-C_y alkyi, C_x-C_y alkenyl and C_x-C_yalkynyl include linear and branched C_x-C_y alkyi, C_x-C_y alkenyl and C_x-C_yalkynyl.

[0086] As used herein, the term "C_x-C_y cycloaliphatic" refers to unfused, fused, spirocyclic, polycyclic, saturated and unsaturated hydrocarbon rings comprising C_x-C_y carbon atoms (and includes C_x-C_ycycloalkyl, C_x-C_ycycloalkenyl and C_x-C_ycycloalkynyl). The carbon atoms of the hydrocarbon ring may optionally be replaced with at least one of O or S at least one or more times.

[0087] As used herein, the term aromatic refers to an aromatic carbocyclic structure in which the carbon atoms of the aromatic ring may optionally be substituted one or more times with at least one of a cyano group, a nitro group, a halogen, a C1-C10 ether, a C1-C10 thioether, a C1-C10 ester, C1-C10 ketone, C1-C10 ketimine, C1-C10 sulfone, C1-C10 sulfoxide, a C1-C10 primary amide or a C1-C20 secondary amide.

[0088] As used herein, the term heterocycle refers to cyclic compounds having as ring members atoms of at least two different elements.

[0089] As used herein, the term heteroaromatic refers to an aromatic heterocyclic structure having as ring members atoms of at least two different elements. The carbon atoms of the heteroaromatic ring may optionally be substituted one or more times with at least one of a cyano group, a nitro group, a halogen, a C1-C10 ether, a C1-C10 thioether, a C1-C10 ester, C1-C10 ketone, C1-C10 ketimine, C1-C10 sulfone, C1-C10 sulfoxide, a C1-C10 primary amide or a C1-C20 secondary amide

[0090] Where suitable, it will be appreciated that all optional and/or preferred features of one embodiment of the invention may be combined with optional and/or preferred features of another/other embodiment(s) of the invention.

Detailed Description of the Invention

[0091] It should be readily apparent to one of ordinary skill in the art that the examples disclosed herein below represent generalised examples only, and that other arrangements and methods capable of reproducing the invention are possible and are embraced by the present invention.

[0092] A general schematic for the preparation of compounds according to the present invention is given in Scheme 2.

Scheme 2 General Experimental

[0093] Melting points were determined using a standard melting point apparatus and are uncorrected. Infrared spectra were obtained on a Perkin Elmer Spectrum 100 FT-IR spectrometer equipped with a universal ATR sampling accessory. Proton nuclear magnetic resonance (NMR) spectra were recorded on: Bruker Avance III 400 MHz, Bruker DPX400 400 MHz and Bruker Avance II 600 MHz spectrometers (¹H NMR spectra were recorded at 400.23 MHz, 400.13 MHz and 600.13 MHz respectively). Chemical shifts are reported in ppm relative to tetramethylsilane and coupling constants (J) are quoted in Hertz. Carbon NMR spectra were recorded on the previously mentioned instruments (100.64 MHz, 100.61 MHz & 150.9 MHz, respectively) with total proton decoupling. HSQC, HMBC, TOCSY and nOe NMR experiments were used to aid assignment of NMR peaks. A Waters micromass LCT-tof mass spectrometer was used in ES positive and ES negative modes for electrospray mass spectrometry. Electron impact mass spectra were determined on a Quatro-ll mass spectrometer in the El mode. Mass spectra were recorded in CSCB Trinity College Dublin. Flash chromatography was performed using Merk Kiesegel 60 (art. 9385) and aluminium oxide 90, standardized (activity ll-lll). Merk precoated Kiesegel 60F₂₅4 and alumina (neutral, type E) were used for thin-layer

chromatography and slides were visualised by UV irradiation, KMn0₄, or phosphomolybdic acid staining. Tetrahydrofuran and diethyl ether were distilled over sodium-benzophenone ketyl radical before use. Dichloromethane, toluene and triethylamine were distilled from calcium hydride.

Synthesis of mecamylamine

3-exo-Methylbicyclo[2.2.1]heptan-2-one (1 )

General procedure A

[0094] To a solution of freshly distilled diisopropylamine (1 .70 mL, 1.72 g, 1 1 .84 mmol) in anhydrous THF (1 1 mL) cooled to -78 °C, a solution of 2.5 M n-butyllithium in hexanes (4.60 mL, 1 1 .36 mmol) was added. The reaction mixture was allowed to warm to 0 °C. A solution of bicyclo[2.2.1 ]heptan-2-one x (1 .00 g, 9.08 mmol) in anhydrous THF (2mL) was then added dropwise. After stirring for 2 hours at 0 °C, iodomethane (1 .70 mL, 3.87 g, 27.30 mmol) was added dropwise. After stirring for 2 hours at room temperature, a solution of 1 M HCI (8 mL) was added. The product was extracted using diethyl ether (2 x 10 mL), washed with brine (10 mL) and dried over MgS0₄. The solvent was evaporated at reduced pressure to yield 3-exo- methylbicyclo[2.2.1 ]heptan-2-one 1 as a yellow oil. (0.95g, 84.4%). IR u_max (cm^"1): 2956, 2874, 1736, 1459, 1082, 937, 850; ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 1 .06 (d, J = 7.5 Hz, 3H, H8), 1.43-1 .56 (m, 3H, H5a, H6a, H7a), 1 .77-1 .91 (m, 4H, H5b, H6b, H3, H7b), 2.30-2.35 (m, 1 H, H4), 2.53-2.58 (m, 1 H, H1 ); ¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 13.7 (CH3, C8), 23.3 (CH2, C6), 27.5 (CH2, C5), 34.0 (CH2, C7), 41 .0 (CH, C3), 47.5 (CH, C4), 49.2 (CH, C1 ), 220.7 (q, C2). HRMS: {m/z - CI) calcd. for C₈H₁₃0 (M+H)⁺ 125.0966, found 125.0974.

[0095] 3,3-Dimethylbicyclo[2.2.1]heptan-2-one (2)

General procedure B

[0096] 3-exo-Methylbicyclo[2.2.1 ]heptan-2-one (1 .24 g, 10 mmol) was added to a solution of 1 M sodium bis(trimethylsilyl)amide in THF (15.00 mL, 15.00 mmol) in anhydrous THF (12 mL) cooled to -78 °C. After stirring for 2 hours at 0 °C, iodomethane (1 .93 mL, 4.40 g, 30.98 mmol) was added dropwise. After stirring for 2 hours at room temperature, a solution of 1 M HCI (8 mL) was added. The product was extracted using diethylether (2 x 10 mL), washed with brine (10 mL) and dried over MgS0₄. The solvent was evaporated at reduced pressure to provide a pale yellow oil which was purified by flash chromatography using 97:3 hexane:ethylacetate as the eluent to yield 3,3-dimethylbicyclo[2.2.1 ]heptan-2-one 2 as a pale yellow oil. (1 .15g, 83.1 %). IR Umax (cm^"1): 2967, 2874, 1739, 1464, 1290, 1 153, 949, 748. ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 1 .04 (s, 3H, H9), 1 .08 (s, 3H, H8), 1 .43-1 .53 (m, 2H, H6a, H7a), 1 .58-1 .72 (m, 1 H, H5a), 1 .76- 1 .93 (m, 2H, H5b, H6b), 1 .97-2.03 (m, 1 H, H7b), 2.30-2.35 (m, 1 H, H4), 2.53-2.58 (m, 1 H, H1 ). ¹³C NMR (CDCIs, 100 MHz): δ (ppm) 21 .5 (CH₃, C9), 23.26 (CH₃, C8), 23.31 (CH₂, C5), 24.6 (CH₂, C6), 35.1 (CH₂, C7), 46.2 (CH, C4), 47.2 (q, C3), 50.2 (CH, C1 ), 223.3 (q, C2). HRMS: (m/z+EI) calcd. for C₉H₁₄0 (M) 138.1045, found 138.1045.

[0097] 2-exo-,3,3-Trimethylbicyclo[2.2.1]heptan-2-ol (3)

General procedure C

[0098] 3,3-Dimethylbicyclo[2.2.1 ]heptan-2-one 2 (0.897 g, 6.50 mmol) was added dropwise to a solution of methyllithium (1.6 M in diethylether, 8.13 mL, 13.00 mmol) in anhydrous THF (20 mL) at -78 °C. The reaction mixture was allowed to warm to room temperature. After 3 hours, 10% NH₄CI (20 mL) was added. The product was extracted using diethylether (2 x 20 mL), washed with brine (20 mL) and dried over MgS0₄. The solvent was evaporated at reduced pressure to yield a pale yellow oil which was purified by flash chromatography using 98:2

hexane:ethylacetate as the eluent. 2-endo-,3,3-Trimethylbicyclo[2.2.1 ]heptan-2-ol 3 was obtained as a white solid (0.89g, 89%). M.p. 1 18-120 °C (lit, 1 13-1 15°C). IR u_max (cm^"1): 341 1 , 2929, 2871 , 1473, 1371 , 1295, 1087, 927; ¹H NMR (CDCI₃, 400 MHz): (ppm) 0.94 (s, 3H, H9), 0.97 (s, 3H, H8), 1 .19-1 .15 (m, 1 H, H7a), 1 .25 (s, 3H, H10), 1 .30-1 .36 (m, 2H, H5a, H6a), 1 .71 - 1 .78 (m, 3H, H7s, H4, H6b), 1 .85-1 .90 (m, 1 H, H5b), 1 .97-2.01 (m, 1 H, H1 ). ¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 21 .1 (CH₂, C5), 21 .8 (CH₃, C9), 24.0 (CH₂, C6), 26.3 (CH₃, C10), 27.0 (CH₃, C8), 34.6 (CH₂, C7), 42.0 (q, C3), 49.7 (CH, C4), 50.9 (CH, C1 ), 78.8 (q,C2). HRMS: (m/z - El) calcd. for Ci₀H₆O₄N₂S (M)⁺ 154.1358, found 154.1353.

[0099] 2-Azido-2-endo-,3,3,-trimethyl-bicyclo[2.2.1]heptane (4)

General Procedure E [00100] A solution of HN₃ was prepared by carefully adding a solution of 50% H₂S0₄ (10 mL) to a solution of NaN₃ (2.00 g, 30.77 mmol) in CHCI₃ (50 mL) at 0 °C. To this was added 2,3,3- trimethylbicyclo[2.2.1 ]heptan-2-ol 3 (1 .00 g, 6.49 mmol). After stirring for 4 hours at room temperature, ice-cold water (30 mL) was added. The product was extracted with CH₂CI₂ (3 x 30 mL). The combined organic extracts were washed with 5% NaHC0₃ solution (30 mL), dried over MgS0₄, and evaporated at reduced pressure to give a yellow oil which was purified by flash chromatography on silica gel using 100% hexane to yield 2-azido-2,3,3,

trimethylbicyclo[2.2.1 ]heptane 4 as pale yellow oil. (0.78 g, 67% yield). IR u_max (cm^"1): 2934, 2876, 2083, 1454, 1253, 1071 , 801 ; ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.94 (s, 3H, H9), 1.06 (s, 3H, H8), 1.12-1 .16 (m, 1 H, H7a), 1 .25-1 .35 (m, 4H, H 10, H5a), 1 .41 -1 .51 (m, 2H, H6), 1.55- 1 .63 (m, 1 H, H5b), 1 .75-1 .80 (m, 1 H, H4), 1.99-2.05 (m, 1 H, H7b), 2.1 1 -2.15( m, 1 H, H1 ). ¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 17.3 (CH₃, C10), 23.1 (CH₂, C6), 23.5 (CH₃, C9), 23.7 (CH₂, C5), 26.8 (CH₃, C8), 34.8 (CH₂, C7), 43.9 (q, C3), 48.8 (CH, C1 ), 49.8 (CH, C4), 72.6 (q, C2). HRMS: (m/z - ES) calcd. for CioH₁₈N (M+H-N₂)⁺ 152.1439, found 152.1443.

[00101] 2-endo-,3,3-Trimethyl-bicyclo[2.2.1]heptan-2 -amine (5)

Reduction using lithium aluminium hydride: General procedure F

[00102] To a solution of 2-azido-2-enc/o-,3,3-trimethylbicyclo[2.2.1 ]heptane 4 (179 mg, 1 mmol) in anhydrous THF (10 mL) under an argon atmosphere cooled to 0 °C, a solution of lithium aluminium hydride (2M in THF, 400 μί, 0.80 mmol) was added dropwise. The reaction was allowed to warm to room temperature over 2 hours. Effervescence was observed. After this time, TLC analysis showed that no starting material remained. The reaction was cooled to 0 °C and 2 M NaOH (10 mL) was added slowly. After stirring for 30 minutes at room temperature, the product was extracted using diethyl ether (2 x 10 mL), washed with brine (10 mL), dried over MgS0₄ and concentrated to give a clear viscous oil. The crude oil was further purified by flash chromatography on silica gel using a 50:50 hexane:ethyl acetate eluent to provide 2-endo-,3,3- trimethyl-bicyclo[2.2.1 ]heptan-2-amine. (107 mg, 70%) M.p. 1 10 °C -1 12 °C (Sublimes).

[00103] Reduction via Staudinger protocol: General procedure G

[00104] To a solution of 2-azido-2-enc/o-,3,3-trimethylbicyclo[2.2.1]heptane 4 (179mg, 1 mmol) in anhydrous THF (10 mL) under an argon atmosphere, tributylphosphine (375 μί, 304 mg, 1 .5 mmol) was added. The reaction was stirred for 4 hours at room temperature. H₂0 (180 μί, 10 mmol) was added and effervescence was observed. The reaction was stirred for a further 16 hours at room temperature. The organic solvent was evaporated to yield a pale yellow oil. This oil was redissolved in CH₂CI₂ (20 mL) and dried over MgS0₄. A 2 M solution of hydrogen chloride in diethyl ether (1 mL, 2 mmol) was added to form the hydrochloride salt of the amine. The CH₂CI₂ was removed under vacuum to give a pale yellow oil which was purified by flash chromatography on silica gel using a 100% ethyl acetate to 50:50 ethyl acetate:methanol eluent gradient. After removing the column solvent under vacuum, the hydrochloride salt was extracted from 1M NaOH (15 ml.) using CH₂CI₂ (2x15 ml_), dried over MgS0₄, filtered and concentrated to yield 2-enc/o-,3,3-trimethyl-bicyclo[2.2.1]heptan-2-amine. (88 mg, 58%) M.p.110 °C -112°C (Sublimes).

[00105] Reduction by hydrogenation: General Procedure H

[00106] A hydrogenation reaction vessel was charged with azido-2-enc/o-,3,3- trimethylbicyclo[2.2.1]heptane 4 (179 mg, 1 mmol), methanol (10 mL), and 10% Pd/C (20 mg). This mixture was reacted under an atmosphere of H₂ at 3 atm for 40 minutes. The catalyst was removed by filtration thourough celite and the celite was washed with CH₂CI₂ (30 mL). The hydrochloride salt was isolated by the addition of dry HCI and evaporation of solvent. M.p.233 °C (lit.,³⁶⁹243 °C) The free amine was obtained by the addition of NaOH (0.8 g, 20 mmol) and extraction with CH₂CI₂ (2 x 20 mL). The combined organic extracts were dried over MgS0₄ and concentrated to yield 2-enc/o-,3,3-trimethyl-bicyclo[2.2.1]heptan-2-amine 5 as a white solid (0.71 g, 83.3%). M.p.110°C-112°C (Sublimes). IRu_max (cm^"1): 2953, 2870, 1466, 1385, 1258, 1168, 806,743.¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.93 (s, 3H, H8), 0.99 (s, 3H, H9), 1.07-1.12 (m, 4H, H10, H7a), 1.23-1.32 (m, 1H, H5a), 1.34-1.44 (m, 1H, H6a), 1.50-1.66 (m, 2H, H5b, H6b), 1.71-1.76 (m,1H, H), 1.79-1.82 (m, 1H, H4), 1.89-1.96 (m, 1H, H7b).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 23.3 (CH₃, C10), 23.5 (CH₂, C6), 23.6 (CH₃, C8), 24.0 (CH₂, C5), 26.3 (CH₃, C9), 34.4 (CH₂, C7), 42.9 (q, C3), 50.2 (CH, C1), 52.6 (CH, C4), 59.5 (q, C2). HRMS: (m/z - El) calcd. for Ci₀H₂₀N (M+H)⁺ 154.1596, found 154.1590.

[00107] 2-endo-3,3-Trimethyl-yV-methylenebicyclo[2.2.1]heptan-2-amine

[00108] 2-enc/o-,3,3-trimethyl-bicyclo[2.2.1]heptan-2-amine 5 (1.00 g, 6.54 mmol) was dissolved in anhydrous CH₂CI₂ (20 mL). Paraformaldehyde (1.18 g, 39.25 mmol) and 4A molecular sieve pellets (1 g) were added. The reaction mixture was refluxed at 40 °C for 12 hours under an argon atmosphere. After this time, the molecular sieves and any unreacted paraformaldehyde were removed by filtration. The residue was washed with CH₂CI₂ (40mL). The washings were combined and the solvent evaporated at reduced pressure to yield 2-endo- 3,3-trimethyl-/V-methylenebicyclo[2.2.1]heptan-2-amine 6 as a clear oil (0.98g, 91%). IR u_max (cm^"1): 2934,2867, 1647, 1460, 1095,937,782, 1386, 1290, 1075, 971 , 878.¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.88 (s, 3H, H9), 0.94 (s, 3H, H8), 1.06 (s, 3H, H10), 1.09-1.13 (m, 1H, H7a), 1.32-1.40 (m, 1H, H5a), 1.42-1.50 (m, 1H, H6a), 1.53-1.63 (m, 1H, H6b), 1.65-1.74 (m, 1H, H5b), 1.77-1.82 (m, 1H, H4), 2.02-2.12 (m, 2H, H1, H7b), 7.32-7.45 (m, 2H, H11).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 18.3 (CH₃, C10), 23.1 (CH₃, C8), 23.3 (CH₂, C6) 23.57 (CH₃, C9), 23.62 (CH₂, C5), 27.6 (CH₃, C9), 33.9 (CH₂, C7), 43.2 (q, C3), 48.7 (CH, C4), 49.7 (CH, C1), 70.1 (q, C2), 146.5 (CH₂, C11). HRMS: (m/z - El) calcd. for CnH₂₀N (M+H)⁺ 166.1596, found 166.1597.

[00109] yV,2-endo-,3,3-Tetramethylbicyclo[2.2.1]heptan-2 -amine [00110] 2-endo-3,3-trimethyl-/V-methylenebicyclo[2.2.1 ]heptan-2-amine 6 (1 .00 g, 6.06 mmol) was added to a solution of NaBH₄ (345 mg, 9.09 mmol) in anhydrous CH₂CI₂ (20 mL) under an argon atmosphere at -78 °C. Anhydrous methanol (0.97 mL, 30.6 mmol) was added dropwise and the reaction allowed to warm to room temperature. After 1 hours, H₂0 (20 mL) was added and the product was extracted using CH₂CI₂ (2 x 20 mL). The organic extracts were combined and dried over MgS0₄. The solvent was removed under reduced pressure to yield N,2-endo- ,3,3-tetramethylbicyclo[2.2.1 ]heptan-2-amine as a clear viscous oil (0.82 g, 81 %).

[00111] Alkylation via quantitative deprotonation and subsequent alkylation:

[00112] A solution of n-butyllithium (2.5M in hexanes, 222 μί, 0.56 mmol) in anhydrous THF (2 mL) was prepared and cooled to 0 °C. To this was added a solution of 2-enc/o-,3,3-trimethyl- bicyclo[2.2.1 ]heptan-2-amine 10 (0.081 g, 0.53 mmol) in anhydrous THF (1 mL) dropwise. The reaction was cooled to -78 °C. Freshly distilled iodomethane (34 μί, 0.57 mmol) was added dropwise and the reaction allowed to warm to room temperature over 30 minutes. H₂0 (10 mL) was added and the product was extracted with CH₂CI₂ (2 x 20 mL). The organic extracts were combined and dried over MgS0₄. The solvent was evaporated at reduced pressure to yield Λ/,2- endo-,3,3-tetramethylbicyclo[2.2.1 ]heptan-2-amine 1 1 as a white solid (0.44 g, 49 %).

[00113] IR u_max (cm-¹): 2930, 2830, 1450, 1410, 1255, 1 1 10. ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.95 (s, 3H, H9), 1 .01 -1 .05 (m, 4H, H8, H7a), 1 .06 (s, 3H, H 10), 1 .23-1 .32 (m, 1 H, H5a), 1 .33-1 .47 (m, 2H, H6), 1.52-1 .65 (m, 1 H, H5b), 1 .65-1 .70 (m, 1 H, H1 ), 1.82-1 .90 (m, 1 H, H7b), 2.17-2.22 (m, 1 H, H4), 2.31 (s, 3H, H1 1 ). ¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 17.5 (CH₃, C10), 22.9 (CH₂, C6), 23.1 (CH₃, C9), 23.7 (CH₂, C5), 25.1 (CH₃, C8), 29.7 (CH₃, C1 1 ), 33.9 (CH₂, C7), 43.4 (q, C3), 44.5 (CH, C4), 50.0 (CH, C1 ), 63.3 (q, C2). HRMS: (m/z - ES) calcd. for CiiH₂₂N (M+H)⁺ 168.1752, found 168.1747.

[00114] Synthesis of 2- and 3-substituted MA analogues: Ketones

[00115] 3-exo-Ethylbicyclo[2.2.1]heptan-2-one (18)

[00116] Prepared as per general procedure A using freshly distilled diisopropylamine (1.70 mL, 1 .72 g, 1 1 .84 mmol), THF (1 1 mL), n-butyllithium (2.5M solution in hexanes, 4.6 mL, 1 1 .36 mmol), bicyclo[2.2.1 ]heptan-2-one (1.00 g, 9.08 mmol) in anhydrous THF (2 mL) and iodoethane (1 .7 mL, 3.32 g, 27.3 mmol) to yield 3-exo-ethylbicyclo[2.2.1 ]heptan-2-one 18 (0.93 g, 82.6 %). IR u_max (cm^"1): 2959, 2877, 1739, 1463, 1 173, 1095, 937. ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 1.0 (t, J = 7.2 Hz, 3H, H9), 1 .22-1 .31 (m, 1 H, H8a), 1 .37-1 .68 (m, 5H, H5a, H6a, H7a, H3_, H8b), 1 .77-1 .92 (3H, H5b, H6b, H7b), 2.43-2.46 (m, 1 H, H₄), 2.52-2.55 (m, 1 H, Hi). ¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 12.9 (CH₃, C9), 22.3 (CH₂, C8), 24.1 (CH₂, C5), 28.0 (CH₂, C6), 34.8 (CH, C7), 38.8 (CH, C4), 49.6 (CH, C1 ), 55.8 (CH, C3), 220.5 (q, C2). HRMS: (m/z - ES) calcd. for C₉H₁₅0 (M+H)⁺ 139.1 123, found 139.1 125.

[00117] 3-exo-Ethyl,3-methylbicyclo[2.2.1]heptan-2-one (2) [00118] Prepared as per general Procedure B using 3-exo-methylbicyclo[2.2.1]heptan-2-one (1.76 g, 14.20 mmol), 1 M sodium bis(trimethylsilyl)amide in THF (21.3 mL, 21.3 mmol), THF 25 mL and iodoethane (3.41 mL, 6.65 g, 42.62 mmol) to yield 3-exo-ethyl,3- methylbicyclo[2.2.1]heptan-2-one as a clear oil. (1.75 g, 81%). IR u_max(cm^"1): 2960, 2876, 1739, 1460, 1083, 938, 850.¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.89 (t, J = 7.2 Hz, 3H, H9), 0.97 (s, 3H, H10), 1.33-1.53 (m, 4H, H6a, H7a, H8), 1.56-1.66 (m, 1H, H5a), 1.68-1.77 (m, 1H, H5b), 1.79-1.90 (m, 1 H, H6b), 1.93-2.01 (m, 1 H, H7b), 2.36 (br s, 1 H, H4), 2.52-2.57 (m, 1 H, H1 ).¹³C NMR (CDCIs, 100 MHz): δ (ppm) 8.4 (CH₃, C10), 17.9 (CH₃, C9), 23.2 (CH₂, C5), 25.2 (CH₂, C6), 34.8 (CH₂, C7), 42.8 (CH, C4), 50.1 (q, C3), 50.2 (CH, C1), 223.3 (q, C2). HRMS:(m/z- ES) calcd. for Ci₀H₁₇O (M+H)⁺ 153.1279, found 153.1279.

[00119] 3-endo-Ethyl,3-methylbicyclo[2.2.1]heptan-2-one

[00120] Prepared as per general procedure B using 3-exo-ethylbicyclo[2.2.1]heptan-2-one (2.32 g, 16.81 mmol), 1 M sodium bis(trimethylsilyl)amide in THF (25.21 mL, 25.21 mmol), THF 30 mL and iodomethane (3.14 mL, 7.16 g, 50.43 mmol) to yield 3-exo-methyl,3-ethyl- bicyclo[2.2.1]heptan-2-oneasaclearoil(1.99g, 79%). IR u_max (cm^"1): 2960,2926, 1739, 1456, 1257, 1012, 791.¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.91 (t, J = 7.50 Hz, 3H, H10), 1.02 (s, 3H, H8), 1.31-1.39 (m, 1H, H9a), 1.43-1.56 (m, 3H, H6a, H7a, H9b), 1.58-1.66 (m, 1H, H5a), 1.68-1.75 (m, 1H, H5b), 1.80-1.89 (m, 1H, H6b), 1.93-1.98 (m, 1H, H7b), 2.29-2.32 (m, 1H, H4), 2.57-2.60 (m, 1H, H1).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 8.3 (CH₃, C10), 18.7 (CH₃, C8), 23.1 (CH₂, C5), 24.9 (CH₂, C6), 27.0 (CH2, C9), 34.8 (CH₂, C7), 43.6 (CH, C4), 50.2 (CH, C1),

50.1 (q, C3), 223.1 (q, C2). HRMS: (m/z - ES) calcd. for Ci₀H₁₇O (M+H)⁺ 153.1279, found 153.1283.

[00121] 3, 3-Diethylbicyclo[2.2.1]heptan-2-one

[00122] Prepared as per general procedure B using 3-exo-ethylbicyclo[2.2.1]heptan-2-one (1.15 g, 8.32 mmol), 1 M sodium bis(trimethylsilyl)amide in THF (12.48 mL, 12.48 mmol), THF 15 mL and iodoethane (2.00 mL, 3.90 g, 24.96 mmol) to yield 3-exo-methyl, 3-enc/o-ethyl- bicyclo[2.2.1]heptan-2-oneasaclearoil(1.01 g, 75%). IR u_max (cm^"1): 2954, 2872, 1731, 1460, 1382, 1056.¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.88 (t, 3H, H11), 0.92 (t, 3H, H9), 1.30-1.30 (m, 1H, H10), 1.41-1.79 (m, 7H, H5, H6, H7, H8, H10), 1.80-1.90 (m, 1H, H6), 1.98-2.04 (m, 1H, H7s), 2.30 (brs, 1H, H4), 2.52-2.57 (m, 1H, H1).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 7.83 (CH₃, C11), 8.19 (CH₃, C9), 22.2 (CH2, C10), 22.6 (CH₂, C5), 23.06 (CH2, C8), 25.1 (CH₂, C6),

34.2 (CH₂, C7), 43.1 (CH, C4), , 50.1 (CH, C1), 52.5 (q, C3), 222.0 (q, C2). HRMS: (m/z - CI) calcd. for CnH₁₉0 (M+H)⁺ 167.1436, found 167.1428.

[00123] Alcohols

[00124] 3-exo-Ethyl-2-exo-,3-dimethylbicyclo[2.2.1]heptan-2-ol [00125] Prepared as per general procedure C using 3-exo-ethyl,3-methylbicyclo[2.2.1]heptan- 2-one (4.25g, 27.92 mmol), methyllithium (1.6M in diethylether, 34.9 mL, 55.84 mmol) and THF (80 mL) to yield 3-exo-ethyl-2-enc/o-,3-dimethylbicyclo[2.2.1]heptan-2-ol as a clear oil. (4.32 g, 92%). IRu_max(cm-¹): 3455,2953,2875, 1454, 1370, 1292, 1199, 1148, 1003, 899, 876.¹H NMR (CDCIs, 400 MHz): δ (ppm) 0.86 (t, J = 7.50Hz, 3H, H9), 0.89 (s, 3H, H10), 1.11-1.16 (m, 1H, H7a), 1.25 (s, 3H, H11 ), 1.26-1.36 (m, 2H, H5a, H6a), 1.38 (q, J = 7.5 Hz, 2H, H8), 1.60-1.69 (m, 2H, H7b, H6b), 1.81-1.90 (m, 1H, H5b), 1.94-1.98 (m, 1H, H4), 2.02-2.06 (m, 1H, H1).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 9.7 (CH₃, C9), 17.0 (CH₃, C10), 20.6 (CH₂, C5), 23.7 (CH₂, C6), 25.3 (CH₃, C11), 29.5 (CH₂, C8), 34.1 (CH₂, C7), 43.7 (CH, C4), 44.4 (q, C3), 50.7 (CH, C1), 79.2 (q, C2). HRMS: (m/z - CI) calcd. for CnH₂₁0 (M+H)⁺ 169.1592, found 169.1592.

[00126] 3-encfo-Ethyl-2-exo-, 3-dimethyl-bicyclo[2.2.1]heptan-2-ol

[00127] Prepared as per general procedure C using 3-endo-ethyl,3-methylbicyclo[2.2.1]heptan- 2-one (3.83 g, 25.11 mmol), methyllithium (1.6 M in diethylether, 31.41 mL, 50.22 mmol) and THF (75 mL) to yield 3-enc/o-ethyl-2-exo-,3-dimethylbicyclo[2.2.1]heptan-2-ol as a clear oil. (3.59 g, 85%). IRu_max (cm^"1): 3468,2961,2936,2876, 1462, 1375, 1089,941.¹H NMR (CDCI₃, 400 MH): δ (ppm) 0.86 (t, J = 7.5 Hz, 3H, H10), 0.92 (s, 3H, H8), 1.13-1.20 (m, 1H, H7a), 1.24 (s, 3H, H11), 1.25-1.34 (m, 3H, H5a, H6a, H9), 1.48-1.58 (m, 1H, H9), 1.58-1.66 (m, 1H, H6b), 1.66-1.73 (m, 1H, H7b), 1.77-1.90 (m, 2H, H5b, H4), 1.94-2.00 (m, 1H, H1).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 9.3 (CH₃, C10), 20.9 (CH₂, C5), 21.4 (CH₃, C8), 23.1 (CH₂, C6), 26.0 (CH₂, C9), 26.5 (CH₃, C11), 34.1 (CH₂, C7), 46.88 (CH, C4), 44.6 (q, C3), 50.9 (CH, C1), 79.3 (q, C2). HRMS:(m/z - CI) calcd. for CnH₂₁0 (M+H)⁺ 169.1592, found 169.1602.

[00128] 2-exo-Ethyl-3,3-dimethylbicyclo[2.2.1]heptan-2-ol

General Procedure D

[00129] A solution of ethyl lithium in THF was prepared by slowly adding ief-butyllithium (1.7 M in pentane, 34.12 mL, 58.00 mmol) to a solution of ethylbromide (2.17 mL, 3.16 g, 29.0 mmol) in anhydrous THF (45 mL) cooled to -78 °C under an argon atmosphere. To this, a solution of 3,3- diethylbicyclo[2.2.1]heptan-2-one (2.00 g, 14.49 mmol) in THF (5 mL) was added and the reaction was allowed to warm to room temperature. After 3 hours, 10% NH₄CI (80 mL) was added. The product was extracted using diethylether (2 x 80 mL), washed with brine (80 mL) and dried over MgS0₄. The solvent was evaporated at reduced pressure to yield a pale yellow oil which was purified by flash chromatography using 98:2 hexane:ethylacetate as the eluent.2- exo-Ethyl-3,3-dimethylbicyclo[2.2.1]heptan-2-ol was obtained as a clear oil (2.05g, 87%). IR u_max (cm^"1): 3512, 2957, 2875, 1459, 1372, 1190, 1027.¹H NMR (CDCI₃, 400 MHz): δ (ppm)0.946 (s, 3H, H9), 0.948 (t, J = 7.53 Hz, 3H, H11), 0.99 (s, CH3, 3H, H8), 1.10-1.15 (m, 1H, H7a), 1.26- 1.37 (m, 2H, H5a, H6a), 1.53-1.76 (m, 5H, H5b, H10, H7b, H4), 1.78-1.86 (m, 1 H, H6b) 2.22 (br s, 1H, H1).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 8.4 (CH₃, C11), 20.8 (CH₂, C6), 21.4 (CH₃, C9), 23.5 (CH₂, C5), 25.9 (CH₃, C8), 28.9 (CH₂, C10), 34.0 (CH₂, C7), 42.5 (q, C3), 45.1 (CH, C1), 49.4 (CH, C4), 80.2 (q, C2). HRMS: (m/z - CI) calcd. for CnH210 (M+H)⁺ 169.1592, found 169.1592.

[00130] 3,3-Dimethylbicyclo[2.2.1]heptan-2-endo-ol

[00131] Prepared as per general procedure C using 3,3-dimethylbicyclo[2.2.1]heptan-2-one (2.50 g, 18.66 mmol), ethylmagnesium bromide (3 M in diethylether, 15.00 mL, 45.00 mmol) and THF (30 mL) to unexpectedly yield 3,3-dimethylbicyclo[2.2.1]heptan-2-enc/o-ol as a white solid following purification by flash chromatography on silica gel using 95:5 hexane ethyl acetate as eluent. (3.16 g, 82%). None of the expected 2-exo-ethyl-3,3-dimethylbicyclo[2.2.1]heptan-2-ol was obtained. IR u_max (cm^"1): 3412, 2932, 2873, 1476, 1372, 1129, 1081.¹H NMR (CDCI3, 400 MHz): δ (ppm) 0.86 (s, 3H, H9), 0.99 (s, 3H, H8), 1.14-1.20 (m, 1 H, H7a), 1.25-1.40 (m, 2H, H5a, H6a), 1.56-1.71 (m, 3H, H5b, H6b, H7b), 1.79 (m, 1H, H4), 2.25-2.32 (m, 1H, H1), 3.67 (d, J = 4.03 Hz, 1H, H1).¹³C NMR (CDCI3, 100 MHz): δ (ppm) 18.2 (CH₂, C6), 20.1 (CH₃, C9), 24.7 (CH₂, C5), 30.6 (CH₃, C8), 33.8 (CH₂, C7), 38.1 (q, C3), 44.1 (CH, C1), 48.4 (CH, C4), 80.4 (CH,C2). HRMS: (m/z - CI) calcd. for C₉H₁₇0 (M) 141.1279, found 141.1272.

[00132] 2-exo-Methyl-3,3-diethyl-bicyclo[2.2.1]heptan-2-ol

[00133] Prepared as per general procedure C using 3,3-diethylbicyclo[2.2.1]heptan-2-one (3.51 g, 21.14 mmol), methyllithium (1.6 M in diethylether, 2.43 mL, 42.28 mmol) and THF (75 mL) to yield 2-exo-methyl-3,3-diethylbicyclo[2.2.1]heptan-2-ol as a clear oil. (3.16 g, 82%). IR u_max (cm^" ¹): 3434, 2936, 2746, 1480, 1428, 1327, 1112, 1072.¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.846 (t, J = 7.48 Hz, 3H, H11), 0.853 (t, J = 7.52 Hz, 3H, H9), 1.09-1.16 (m, 1H, H7a), 1.23-1.35 (m, 7H, H6a, H5a, H8a, H10a, H12), 1.58-1.71 (m, 4H, H5b, H10b, H9b, H7b), 1.83-1.88 (m, 1H, H6b), 1.91-1.93 (m, 1H, H1), 1.97-1.99 (m, 1H, H4).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 9.8 (CH₃, C9), 10.2 (CH₃, C11), 21.1 (CH₂, C6), 22.0 (CH₃, C10), 23.3 (CH₂, C5), 25.4 (CH₂, C8), 26.8 (CH₃, C12), 34.7 (CH₂, C7), 45.6 (CH, C4), 47.2 (q, C3), 51.9 (CH, C1), 80.0 (q, C2). HRMS: (m/z -El) calcd. for Ci₂H₂₁0 (M-H)^" 181.1592, found 181.1592.

[00134] 2-exo-,3,3-triethylbicyclo[2.2.1]heptan-2-ol

[00135] Prepared as per general procedure D using 3,3-diethylbicyclo[2.2.1]heptan-2-one x (2.50 g, 15.06 mmol), ethyl bromide (2.25 mL, 3.29 g, 30.14 mmol), ie/f-butyllithium solution (1.7 M in pentane, 35.44 mL, 60.24 mmol) to yield the desired alcohol as a clear oil (2.89 g, 97%). IR Umax (cm^"1): 3456, 2953, 2876, 1464, 1370, 1128.¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.840 (t, J = 7.36 Hz, 3H, H11), 0.844 (t, J = 7.46 Hz, 3H, H9), 0.94 (t, J = 7.42 Hz, 3H, H13), 1.06-1.11 (m, 1H, H7a), 1.22-1.36 (m, 4H, H5a, H6a, H8a, H10a), 1.59-1.74 (m, 6H, H5b, H7b, H8b, H10b, H12), 1.75-1.83 (m, 1H, H6b), 1.98-2.02 (m, 1H, H4), 2.18-2.23 (m, 1H, H4).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 8.5 (CH₃, C13), 9.5 (CH₃, C9), 9.8 (CH₃, C11 ), 20.1 (CH₂, C6), 21.7 (CH₂, C8), 22.7 (CH₂, C5), 24.0 (CH₂, C10), 29.1 (CH₂, C12), 34.1 (CH₂, C7), 45.0 (CH, C4), 45.4 (CH, C1 ), 47.8 (q, C3), 81.4 (q, C2). HRMS: (m/z - CI) calcd. for Ci₃H250 (M+H)⁺

197.1905, found 197.1901. [00136] 2-exo-Butyl-3,3-dimethylbicyclo[2.2.1]heptan-2-ol

[00137] Prepared as per general procedure C using 3,3-dimethylbicyclo[2.2.1]heptan-2-one x (2.00 g, 14.49 mmol), n-butyllithium (2.5 M in hexanes, 11.20 mL, 29.00 mmol) and THF (50 mL) to yield 2-exo-butyl-3,3-dimethylbicyclo[2.2.1]heptan-2-ol as a clear oil. (1.85 g, 65%).¹H NMR(CDCI₃, 400 MHz): δ (ppm) 0.91-0.96 (m, 6H, H9, H13), 0.99 (s, 3H, H8), 1.10-1.16 (m, 1H, H7a), 1.29-1.41 (m, 6H, H5a, H6a, H10a, H11a, H12), 1.47-1.56 (m, 2H, H10b, H11b), 1.65-1.72 (m, 2H, H5b, H7b), 1.72-1.75 (m, 1H, H4), 1.78-1.85 (m, 1H, H6b), 2.20-2.23 (m, 1H, H1).¹³C NMR (CDCIs, 100 MHz): δ (ppm) 14.3 (CH₃, C13), 21.4 (CH₂, C6), 22.0 (CH₃, C9), 23.6 (CH₂, C12), 23.9 (CH₂, C5), 26.4 (CH₃, C8), 27.1 (CH₂, C11), 34.5 (CH₂, C7), 37.1 (CH₂, C10), 43.0 (q, C3), 46.4 (CH, C1), 50.0 (CH, C4) , 80.4 (q, C2). HRMS: (m/z - CI) calcd. for Ci₃H₂₅0 (M) 197.1905, found 197.1898.

[00138] 2-exo-Butyl-3-exo-ethyl-3-methylbicyclo[2.2.1]heptan-2-ol

[00139] Prepared as per general procedure C using 3-exo-ethyl,3-methylbicyclo[2.2.1]heptan- 2-one x (200 mg, 1.266 mmol), n-butyllithium (2.5 M in hexanes, 1.01 mL, 2.53 mmol) and THF (6 mL) to yield 2-exo-butyl-3-exo-ethyl-3-methylbicyclo[2.2.1]heptan-2-ol as a clear oil. (241 mg, 91%).¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.86 (t, J = 7.42 Hz, 3H, H9), 0.89 (s, 3H, H10), 0.94 (t, J = 7.16 Hz, 3H, H14), 1.07-1.11 (m, 1H, H7a), 1.28-1.41 (m, 7H, H5a, H6a, H8a, H12, H13), 1.42 (q, J = 7.42, 2H, H8), 1.50-1.68 (m, 4H, H5b, H7b, H11 ), 1.78-1.89 (m, 1 H, H6b), 2.04-2.07 (m, 1H, H4), 2.21-2.24 (m, 1H, H1).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 10.3 (CH₃, C9), 14.3 (CH₃, C14), 17.5 (CH₃, C10), 21.5 (CH₂, C6), 23.6 (CH₂, C13), 24.0 (CH₂, C₅), 27.1 (CH₂, C12), 29.0 (CH₂, C8), 34.3 (CH₂, C7), 36.4 (CH₂, C11), 44.1 (CH, C4), 45.9 (q, C3), 46.1 (CH, C1) , 77.2 (q, C2). HRMS: (m/z - CI) calcd. for Ci₄H₂₇0 (M+H)⁺ 211.2062, found 211.2070.

[00140] 2-exo-Butyl-3-endo-ethyl-3-methylbicyclo[2.2.1]heptan-2-ol

[00141] Prepared as per general procedure C using 3-endo-ethyl,3-methylbicyclo[2.2.1]heptan- 2-one x (200 mg, 1.266 mmol), n-butyllithium (2.5 M in hexanes, 1.01 mL, 2.53 mmol) and THF (6 mL) to yield 2-exo-butyl-3-enc/o-ethyl-3-methylbicyclo[2.2.1]heptan-2-ol as a clear oil. (198 mg, 75%).¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.87 (t, J = 7.41 Hz, 3H, H10), 0.93 (t, J = 7.10 Hz, 3H, H14), 0.94 (s, 3H, H8), 1.11-1.16 (m, 1H, H7a), 1.19-1.44 (m, 7H, H5a, H6a, H9a, H12, H13), 1.49-1.69 (m, 5H, H5b, H7b, H9b, H11), 1.77-1.85 (m, 2H, H4, H6b), , 2.19-2.23 (m, 1H, H1).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 9.8 (CH₃, C10), 14.3 (CH₃, C14), 21.45 (CH₃, C8), 21.48 (CH₂, C6), 23.3 (CH₂, C5), 23.6 (CH₂, C13), 26.5 (CH₂, C9), 27.1 (CH₂, C12), 34.4 (CH₂, C7), 37.7 (CH₂, C11), 45.6 (q, C3), 46.7 (CH, C1), 47.6 (CH, C4), 80.9 (q, C2). HRMS: (m/z - CI) calcd. for Ci₄H₂₇0 (M+H)⁺ 211.2062, found 211.2056.

[00142] 2-exo-Butyl-3,3-diethylbicyclo[2.2.1]heptan-2-ol

[00143] Prepared as per general procedure C using 3,3-diethylbicyclo[2.2.1]heptan-2-one x (200 mg, 1.205 mmol), n-butyllithium (2.5 M in hexanes, 0.96 mL, 2.41 mmol) and THF (6 mL) to yield 2-exo-butyl-3,3-diethylbicyclo[2.2.1]heptan-2-ol as a clear oil. (215 mg, 80%).¹H NMR (CDCIs, 400 MHz): δ (ppm) 0.84 (t, J = 7.37 Hz, 3H, H11 ), 0.85 (t, J = 7.06 Hz, 3H, H9), 0.94 (t, J = 7.10 Hz, 3H, H15), 1.06-1.11 (m, 1H, H7a), 1.22-1.44 (m, 7H, H5a, H6a, H8a, H10a, H13, H14a), 1.55-1.84 (m, 8H, H5b, H6b, H7b, H8b, H10b, H12, H14b), 1.98-2.02 (m, 1H, H4, 2.18- 2.23 (m, 1H, H1).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 9.9 (CH₃, C9), 10.3 (CH₃, C11), 14.3 (CH₃, C15), 21.3 (CH₂, C6), 22.1 (CH₂, C8), 23.1 (CH₂, C5), 23.6 (CH₂, C13), 24.5 (CH₂, C10), 27.0 (CH₂, C14), 34.5 (CH₂, C7), 37.3 (CH₂, C12), 45.3 (q, C4), 46.7 (CH, C1), 48.2 (q, C3),

81.8 (q, C2). HRMS: (m/z - CI) calcd. for Ci₅H₂₉0 (M+H)⁺ 225.2218, found 225.2223.

[00144] Azides

[00145] 2-Azido-3-exo-ethyl-2-endo-,3-dimethylbicyclo[2.2.1]heptane

[00146] Prepared as per general procedure E using 3-exo-ethyl-2-exo-,3- dimethylbicyclo[2.2.1]heptan-2-ol x (500 mg, 2.98 mmol), 50% H₂S0₄ (10 ml_), NaN₃ (2.40 g,

36.9 mmol) and CHCI₃ (50 mL) with a reaction time of 8 hours to yield 2-azido-3-exo-ethyl-2,3- dimethylbicyclo[2.2.1]heptane. (304 mg, 53%) and a related azide tentatively assigned as 2- azido-2-endo-,3-dimethylbicyclo[2.2.1]heptane (140 mg, 28%).¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.87 (s, 3H, H10), 0.88 (t, J = 7.38 Hz, 3H, H9), 1.11-1.14 (m, 1H, H7a), 1.28-1.35 (m, 4H, H5a, H11), 1.39-1.60 (m, 5H, H8, H6, H5b), 1.94-1.97 (m, 1H, H4), 1.98-2.02 (m, 1H, H7b), 2.15-2.18 (m, 1H, H1).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 10.1 (CH₃, C9), 17.7 (CH₃, C11), 19.3 (CH₃, C10), 23.0 (CH₂, C6) 24.2 (CH₂, C5), 30.7 (CH₂, C8), 34.9 (CH₂, C7), 46.1 (CH, C4), 46.5 (q, C3), 48.7 (CH, C1 ), 73.7 (q, C2). HRMS: (m/z - ES) calcd. for CnH₂₀N (M+H-N₂)⁺ 166.1596, found 166.1596.

[00147] 2-Azido-2-endo-,3-dimethylbicyclo[2.2.1]heptane:

[00148] ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.92 (d, J = 7.41 Hz, 3H, H8), 1.25 (s, 3H, H9), 1.26-1.48 (m, 5H, H7a, H5, H6), 1.77-1.83 (m, 1H H7b), 1.91-2.00 (m, 1H, H3), 2.11-2.17 (m, 2H, H4, H1).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 12.13 (CH₃, C8), 17.6 (CH₃, C9), 20.1 (CH₂, C5), 24.0 (CH₂, C6), 37.2 (CH₂, C7), 42.7 (CH, C4), 44.6 (CH, C3), 48.0 (CH, C1), 69.6 (q, C2).

[00149] 2-Azido-3-endo-ethyl-2-en o-3-dimethylbicyclo[2.2.1]heptaneX

[00150] Prepared as per general procedure E using 3-enc/o-ethyl-2-exo, 3-dimethyl- bicyclo[2.2.1]heptan-2-ol x (2.00 g, 11.90 mmol), H₂S0₄ (55%, 40 mL), NaN₃ (7.00 g, 107.7 mmol) and CHCI₃ (200 mL) with reaction time of 6 hours to yield 2-azido-3-enc/o-ethyl-2-endo- ,3-dimethylbicyclo[2.2.1]heptane (390 mg, 17%), 2-azido-2-enc/o-ethyl-3,3- dimethylbicyclo[2.2.1]heptane (140 mg, 6%) and 2-azido-3-exo-ethyl-2-enc/o-,3- dimethylbicyclo[2.2.1]heptane (210 mg, 10%) after multiple column chromatography separations on silica gel using 100% hexane as eluent. IR u_max (cm^"1): 2958, 2875, 2096, 1458, 1373, 1189, 1028.¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.87 (t, 3H, H10), 1.04 (s, 3H, H8), 1.12-1.18 (m, 1H, H7a), 1.21-1.32 (m, 2H, H9a, H5a), 1.35 (s, CH3, H11), 1.41-1.52 (m, 4H, H6, H5b, H9b), 1.86- 1.91 (m, 1H, H4), 1.96-2.02 (m, 1H, H7s), 2.11 ( brs, 1H, H1).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 10.0 (CH₃, C10), 16.9 (CH₃, C11 ), 21.4 (CH₃, C8), 23.25 (CH₂, C6), 23.34 (CH₂, C5), 27.8 (CH₂, C9), 34.7 (CH₂, C7), 46.6 (CH, C4), 47.6 (q, C3), 49.2 (CH, C1), 73.8 (q, C2). HRMS: (m/z - ES) calcd. for CnH₂₀N (M+H-N₂)⁺ 166.1596, found 166.1590.

[00151] 2-Azido-2-endo-ethyl-3,3-dimethylbicyclo[2.2.1]heptane

[00152] IRu_max(crn¹): 2962, 2083, 1456, 1377, 1254, 1112, 1072.¹H NMR (CDCI₃, 400 MHz): 5(ppm) 0.96 (s, 3H, H8), 0.98 (t, J = 7.38 Hz, 3H, H11), 1.13 (s, 3H, H9), 1.16-1.21 (m, 1H, H7a), 1.30-1.83 (m, 7H, H5, H6, H10, H4), 1.93-2.00 (m, 1H, H7b), 2.21-2.25 (m, 1H, H1).¹³C NMR (CDCIs, 100 MHz): δ (ppm) 9.6 (CH₃, C11), 23.0 (CH₃, C8), 22.6 (CH₂, C6), 23.7 (CH₂, C5), 23.9 (CH₂, C10), 27.0 (CH₃, C9), 34.6 (CH₂, C7), 45.2 (CH, C1), 46.0 (q, C3), 49.8 (CH, C4), 76.2 (q, C2). HRMS: (m/z - ES) calcd. for CnH₂₀N (M+H-N₂)⁺ 166.1596, found 166.1589.

[00153] 2-Azido-3,3-diethyl-2-endo-methylbicyclo[2.2.1]heptane

[00154] Prepared as per general procedure E was followed using 3,3-diethyl-2-exo- methylbicyclo[2.2.1]heptan-2-ol x (9.19 g, 50.49 mmol), NaN₃ (20.00 g, 307.69 mmol), CHCI₃ (200 mL), H₂S0₄ (52.5%, 200 mL) with a reaction time of 8 hours to yield 2-azido-3,3-diethyl-2- enc/o-methylbicyclo[2.2.1]heptane (1.04 g, 10%), 2-azido-2-enc/o-,3-enc/o-diethyl-3- methylbicyclo[2.2.1]heptane (0.91 g, 9%) and 2-azido-2-enc/o-,3-exo-diethyl-3- methylbicyclo[2.2.1]heptane (1.25 g, 12 %) after multiple column chromatography separations on silica gel using 100% hexane as eluent. IR u_max (cm^"1): 2964, 2881, 2084, 1459, 1261, 1109, 1079, 742.¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.79 (t, J = 7.50 Hz, 3H, H11), 0.84 (t, J = 7.53 Hz, 3H, H9), 1.10-1.15 (m, 1H, H7a), 1.20-1.56 (m, 10H, H12, H5, H6, H10, H8a), 1.67-1.79 (m, 1H, H8b), 1.87 (br s, 1H, H1), 1.98-2.03 (m, 1H, H7b), 2.17-2.21 (m, 1H, H4).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 9.4 (CH₃, C9), 9.9 (CH₃, C11), 17.9 (CH₃, C12), 22.5 (CH₂, C10), 23.0 (CH₂, C5), 24.0 (CH₂, C6), 26.4 (CH₃, C8), 34.5 (CH₂, C7), 46.8 (CH, C1), 48.7 (q, C3), 48.8 (CH, C4), 73.7 (q, C2). HRMS: (m/z - El) calcd. for Ci₂H₂₁N (M-N₂) 179.1674, found 179.1669.

[00155] 2-Azido-2-endo-,3-en o-diethyl-3-methylbicyclo[2.2.1]heptane

[00156] IRu_max(crrf¹):2965, 2880, 2091, 1465, 1379, 1269, 1076,901.¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.98 (t, J = 7.65 Hz, 3H, H12), 0.87 (t, J = 7.51 Hz, 3H, H10), 1.06 (s, 3H, H8), 1.14-1.19 (m, 1H, H7a), 1.20-1.59 (m, 6H, H9, H5, H6), 1.61-1.72 (m, 1H, H11a), 1.78-1.88 (m, 1H, H11b), 1.88-1.95 (m, 2H, H7b, H4), 2.19-2.24 (m, 1H, H1).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 9.5 (CH₃, C12), 9.9 (CH₃, C10), 21.5 (CH₃, C8), 22.7 (CH₂, C6), 23.0 (CH₂, C11), 23.3 (CH₂, C5), 27.3 (CH₂, C9), 34.4 (CH₂, C7), 45.2 (CH, C1), 46.5 (CH, C4), 49.7 (q, C3), 77.2 (q, C2). HRMS: (m/z - ES) calcd. for Ci₂H₂₂N (M+H-N₂)⁺ 180.1752, found 180.1759.

[00157] 2-azido-2-endo-,3-exo -diethyl-3-methylbicyclo[2.2.1]heptane

[00158] IRu_max(crrf¹):2965, 2880,2090, 1463, 1263, 1075, 931.¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.88 (t, J = 7.60 Hz, 3H, H9), 0.90 (s, 3H, H10), 0.99 (t, J = 7.50 Hz, 3H, H12), 1.13-1.18 (m, 1H, H7a), 1.27-1.68 (m, 7H, H6, H5, H8, H11a), 1.77-1.88 (m, 1H, H11b), 1.88-1.94 (m, 1H, H7b), 1.98-2.02 (m, 1H, H4), 2.26-2.30 (m, 1H, H1).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 9.6 (CH₃, C12), 10.2 (CH₃, C9), 18.7 (CH₃, C10), 22.5 (CH₂, C6), 23.9 (CH₂, C5), 24.7 (CH₂, C11), 30.7 (CH₂, C8), 34.6 (CH₂, C7), 45.1 (CH, C1 ), 45.3 (CH, C4), 48.1 (q, C3), 77.1 (q, C2). HRMS: (m/z - ES) calcd. for C12H22N3 (M+H)⁺ 208.1814, found 208.1801 .

[00159] 2-azido-2-endo-,3,3-triethylbicyclo[2.2.1]heptanes

[00160] Prepared as per general procedure E using 2-exo-,3,3-triethylbicyclo[2.2.1 ]heptan-2-ol x (500 mg, 2.55 mmol), 60% H₂S0₄ (10 ml_), NaN₃ (2.50 g, 38.46 mmol) and CHCI₃ (50 mL) with a reaction time of 5 hours to yield 2-azido-2-endo-,3,3-triethylbicyclo[2.2.1]heptane (290 mg, 51 %) after purification by flash chromatography on silica gel using 100% hexane as eluent.

[00161] IR u_max (cm^"1): 2964, 2881 , 2091 , 1464, 1270, 957, 881 . ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.80 (t, J = 7.48 Hz, 3H, H 1 1 ), 0.84 (t, J = 7.48 Hz, 3H, H9), 0.98 (t, J = 7.48 Hz, 3H, H13), 1 .16-1 .21 (m, 1 H, H_7a), 1 .25-1 .65 (m, 8H, H5, H6, H8a, H 10, H 12a), 1 .70-1 .94 (m, 4H, H8b, H7b, H4, H12b), 2.36-2.41 (m, 1 H, H1 ). ¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 9.0 (CH₃, C1 1 ), 9.1 (CH₃, C13), 9.6 (CH₃, C9), 21 .5 (CH₂, C10), 21.9 (CH₂, C6), 23.4 (CH₂, C5), 25.1 (CH₂, C12), 26.3 (CH₂, C8), 33.8 (CH₂, C7), 44.3 (CH, C1 ), 46.0 (CH, C4), 50.2 (q, C3), 76.7 (q, C2). HRMS: (m/z - ES) calcd. for d₃H₂₄N (M+H-N₂)⁺ 194.1909, found 194.1908.

[00162] Amines

[00163] 3-exo-Ethyl-2-endo-,3-dimethylbicyclo[2.2.1]heptan-2 -amine

[00164] Prepared as per general procedure F using 2-Azido-3-exo-ethyl-2-enc/o-,3- dimethylbicyclo[2.2.1 ]heptane x (150 mg, 0.78 mmol), lithium aluminium hydride solution (2 M in THF, 500 μΙ_, 1 mmol) and anhydrous THF (5 mL) to yield 3-exo-ethyl-2-enc/o-,3- dimethylbicyclo[2.2.1 ]heptan-2-amine as a clear oil (1 10 mg, 84%). ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.83 (s, 3H, H10), 0.86 (t, J = 7.31 Hz, 3H, H9), 1 .02-1 .10 (m, 4H, H 1 1 , H7a), 1 .21 -1 .58 (m, 6H, H5, H6, H8), 1.73-1 .79 (m, 1 H, H1 ), 1.82-1 .90 (m, 1 H, H7b), 1.92 (br s, 1 H, H4). ¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 10.6 (CH₃, C9), 19.3 (CH₃, C10), 23.6 (CH₃, C1 1 ), 23.7 (CH₂, C6), 23.9 (CH₂, C5), 29.7 (CH₃, C8), 34.4 (CH₂, C7), 45.2 (q, C3), 45.5 (CH, C4), 52.7 (CH, C1 ), 60.6 (q, C2). HRMS: (m/z - ES) calcd. for CnH₂₂N (M+H)⁺ 168.1752, found 168.1751 .

[00165] 3-endo-Ethyl-2-endo-,3-dimethylbicyclo[2.2.1]heptan-2 -amine

[00166] Prepared as per general procedure F using 2-azido-3-endo-ethyl-2-enc/o-,3- dimethylbicyclo[2.2.1]heptane x (100 mg, 0.52 mmol), lithium aluminium hydride solution (2 M in THF, 200 μί, 0.40 mmol) and anhydrous THF (5 mL) to yield 3-enc/o-ethyl-2-enc/o-,3- dimethylbicyclo[2.2.1 ]heptan-2-amine as a clear oil (71 mg, 82%). ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.84 (t, J = 7.25 Hz, 3H, H10), 0.97 (s, J = 7.31 Hz, 3H, H8), 1 .12 (s, 3H, H 1 1 ), 1 .08-1 .14 (m, 1 H, H7a), 1.16-1 .57 (m, 6H, H5, H6, H9), 1 .81 -1 .86 (m, 2H, H1 , H4), 1.89-1 .96 (m, 1 H, H7b). ¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 10.1 (CH₃, C10), 20.7 (CH3, C8), 22.2 (CH₃, C1 1 ), 23.1 (CH₂, C5), 24.1 (CH₂, C6), 27.6 (CH₂, C9), 34.3 (CH₂, C7), 45.9 (q, C3), 47.0 (CH, C4), 52.3 (CH, C1 ), 60.9 (q, C2). HRMS: (m/z - ES) calcd. for CnH₂₀N (M-H)^" 166.1596, found 166.1598. [00167] 2-endo-Ethyl-3,3-dimethylbicyclo[2.2.1]heptan-2 -amine

[00168] Prepared as per general procedure F using 2-azido-2-enc/o-ethyl-3,3- dimethylbicyclo[2.2.1]heptanes x (100 mg, 0.52 mmol), lithium aluminium hydride solution (2 M in THF, 200 μΙ_, 0.40 mmol) and anhydrous THF (5 mL) to yield 2-azido-2-enc/o-ethyl-3,3- dimethylbicyclo[2.2.1]heptan-2-amine as a clear oil (63 mg, 72%).¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.88 (t, J = 7.57 Hz, 3H, H11), 0.91 (s, 3H, H9), 0.99 (s, 3H, H8), 1.05-1.11 (m, 1H, H7a), 1.77-1.45 (m, 4H, H6, H5a, H10a), 1.54-1.62 (m, 1H, H5b), 1.62-1.74 (m, 2H, H4, H10b), 1.86-1.96 (m, 2H, H1, H7b).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 8.9 (CH₃, C11), 22.4 (CH₃, C9), 23.0 (CH₃, C6), 23.1 (CH₂, C5), 26.2 (CH₃, C8), 27.0 (CH2, C10), 33.8 (CH₂, C7), 43.0 (q, C3), 48.5 (CH, C1), 50.1 (CH, C4), 61.5 (q, C2). HRMS: (m/z - El) calcd. for CnH₂₀N (M-H)^" 166.1596, found 166.1594.

[00169] 2-endo-,3-exo-Diethyl-3-methylbicyclo[2.2.1]heptan-2-amine

[00170] Prepared as per general procedure F using 2-azido-2-enc/o-,3-exo-diethyl,3- methylbicyclo[2.2.1]heptan x (400 mg, 1.93 mmol), lithium aluminium hydride solution (2 M in THF, 900 μί, 1.80 mmol) and anhydrous THF (12 mL) to yield 2-enc/o-,3-exo-diethyl-3- methylbicyclo[2.2.1]heptan-2-amine as a clear oil (310 mg, 89%).¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.878 (t, J = 7.36 Hz, 3H, H₁₂), 0.880 (s, 3H, H₁₀), 0.92 (t, J = 7.25 Hz, 3H, H₉), 1.05-1.10 (m, 1H, H7a), 1.22-1.59 (m, 7H, H₆, H5, H8, H11a), 1.71-1.82 (m, 1H, H11), 1.85-1.97 (m, 3H, H1, H4, H7b).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 9.3 (CH₃, C9), 10.6 (CH₃, C12), 18.6 (CH₃, C10), 23.1 (CH₂, C6), 23.9 (CH₂, C5), 27.8 (CH₂, C11), 30.0 (CH₂, C8), 34.3 (CH₂, C7), 45.9 (q, C3), 46.0 (CH, C1 ), 49.2 (CH, C4), 62.8 (q, C2). HRMS: (m/z - ES) calcd. for Ci₂H₂₄N (M+H)⁺ 182.1909, found 182.1911.

[00171] 2-endo-,3-endo-Diethyl-3-methylbicyclo[2.2.1]heptan-2-amine

[00172] Prepared as per general procedure F using 2-azido-2-endo-,3-enc/o-diethyl-3- methylbicyclo[2.2.1]heptane (1.00 g, 4.83 mmol), lithium aluminium hydride solution (2 M in THF, 1.70 mL, 3.38 mmol) and anhydrous THF (20 mL) to yield a clear oil which was purified by precipitation of the hydrochloride salt in anyhydrous diethyl ether and subsequent filtration to yield the hydrochloride salt of 2-enc/o-,3-enc/o-diethyl-3-methylbicyclo[2.2.1]heptan-2-amine as white solid (655 mg, 75%). IR u_max (cm^"1): 3361,2960,2844, 1457, 1379, 1150,882.¹H NMR (CDCI3, 400 MHz): δ (ppm) 0.84 (t, J = 6.20 Hz, 3H, H10), 1.14, (t, J = 6.30 Hz, 3H, H12), 1.19- 1.26 (m, 1H, H7a), 1.27, (s, 3H, H8), 1.28-1.64 (m, 6H, H5, H6, H9), 1.66-1.98 (m, 3H, H4, H11), 2.32-2.42 (m, 2H, H1, H7b).¹³C NMR (CDCI3, 100 MHz): δ (ppm) 9.5 (CH3, C12), 9.8 (CH3, C10), 20.8 (CH3, C8), 22.6 (CH2, C6), 23.0 (CH2, C5), 24.0 (CH2, C11), 26.8 (CH2, C9), 34.0 (CH2, C7), 46.0 (CH, C1), 46.8 (CH, C4), 46.9 (q, C3), 69.8 (q, C2). HRMS: (m/z - ES) calcd. for Ci₂H₂₄N (M+H)⁺ 182.1909, found 182.1909.

[00173] 3,3-Diethyl-2-endo-methylbicyclo[2.2.1]heptan-2-amine [00174] Prepared as per general procedure F using 2-azido 3,3-diethyl-2-enc/o- methylbicyclo[2.2.1 ]heptane x (85 mg, 0.41 mmol), lithium aluminium hydride solution (2 M in THF, 210 μΙ_, 0.41 mmol) and anhydrous THF (5 mL) to yield 3,3-diethyl-2-enc/o- methylbicyclo[2.2.1 ]heptan-2-amine as a clear oil (70 mg, 94%). IR u_max (cm^"1): 2936, 2746, 1480, 1428, 1327, 1 1 12, 1072. ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.79 (t, J = 7.33 Hz, 3H, H9), 0.87 (t, J = 7.34 Hz, 3H, H1 1 ), 1 .03-1 .8 (m, 1 H, H7a), 1 .43 (s, 3H, H12), 1 .19-1 .57 (m, 7H, H6, H5, H8, H 10a), 1 .67-1 .77 (m, 2H, H 1 , H 10b), 1 .80-1 .85 (m, 1 H, H4), 1.88-1 .95 (m, 1 H, H7b). ¹³C NMR (CDCIs, 100 MHz): δ (ppm) 9.4 (CH₃, C9), 10.6 (CH₃, C1 1 ), 23.3 (CH₃, C12), 22.5 (CH₂, C8), 22.9 (CH₂, C6), 23.3 (CH₂, C5), 25.1 (CH₂, C10), 33.7 (CH₂, C7), 46.5 (CH, C4), 47.9 (q, C3), 52.9 (CH, C1 ), 60.5 (q, C2). HRMS: (m/z - ES) calcd. for Ci₂H₂₄N (M+H)⁺

182.1909, found 182.1907.

[00175] 2-endo-,3,3-triethylbicyclo[2.2.1]heptan-2-amine

[00176] Prepared as per general procedure H using 2-azido-2-enc/o-,3,3

triethylbicyclo[2.2.1 ]heptane x (450 mg, 2.03 mmol), 10% Pd/C (60 mg) and 10:1

methanokisopropanol (35 mL) with a reaction time of 5 hour to 2-endo-,3,3- triethylbicyclo[2.2.1 ]heptan-2-amine as a clear oil (279 mg, 70%). ¹H NMR (CDCI3, 400 MHz): δ (ppm) 0.80 (t, J = 7.34 Hz, 3H, H9), 0.86 (t, J = 7.34 Hz, 3H, H1 1 ), 0.93 (t, J- 7.54 Hz, 3H, H13), 1 .03-1 .12 (m, 1 H, H7a), 1 .17-1 .70 (m, 8H, H5, H6, H8, H 10a, H12a), 1 .72-1 .91 (m, 4H, H1 , H4, H 10b, H12b), 1 .91 -2.007 (m, 1 H, H7). ¹³C NMR (CDCI3, 100 MHz): δ (ppm) 9.2 (CH₃, C13), 9.7 (CH₃, C9), 1 1 .1 (CH₃, C1 1 ), 22.1 (CH₂, C8), 22.7 (CH₂, C5), 23.9 (CH₂, C6), 25.7 (CH₂, C10), 27.7 (CH₂, C12), 33.9 (CH₂, C7), 47.1 (CH, C1 ), 49.2 (q, C3), 49.3 (CH, C4), 63.5 (q, C2). HRMS: (m/z - ES) calcd. for Ci₃H₂₆N (M+H)⁺ 196.2065, found 196.2066.

[00177] W-Methyl amine MA analogues

[00178] 3-endo-Ethyl-yV,2-en o-,3-trimethylbicyclo[2.2.1]heptan-2 -amine EMM

[00179] General Procedure I

[00180] Into an oven dried RBF under an argon atmosphere fitted with a reflux condenser, 3- enc/o-ethyl-2-enc/o-,3-dimethylbicyclo[2.2.1 ]heptan-2-amine x (1 10 mg, 0.67 mmol),

paraformaldehyde (60 mg, 2.0 mmol) and activated molecular sieves (1 10 mg) were added. Anhydrous CH₂CI₂ (10 mL) was then added and the reaction refluxed for 16 hours. After this time, an in situ ¹H nmr sample was taken to confirm quantitative conversion to the imine was complete. The reaction was cooled to -10 °C and sodium borohydride (101 mg, 2.67 mmol) was added. Anhydrous methanol (0.5 mL) was added dropwise and the reaction was allowed to warm to room temperature with contiuous stirring over 1 hour and then stirred at room temperature for a further 2 hours. The reaction mixture was filtered to remove the molecular sieves and the unreacted paraformaldehyde. The residue was washed with CH₂CI₂ (30 mL) and the combined filtrate extracted with 2 M NaOH (30 mL). The organic solvent was dried over MgS0₄ and removed under vacuum to give the N-methylated amine as a tacky solid. This product was redissolved in anhydrous diethyl ether (2 mL) and a solution of hydrogen chloride (2 M in diethyl ether, 1 .0 mL, 2.0 mmol) was added. The hydrochloride salt was removed by filtration and dried under vacuum to yield the desired product as a white solid (72 mg, 50%). IR Umax (cm^"1): 3360, 2953, 2884, 1458, 1381 , 1342, 1 1 12, 915. ¹H NMR (CD₃OD, 400 MHz): δ (ppm) 0.93 (t, J = 7.48 Hz, 3H, H10), 1 .15 (s, 3H, H8), 1 .31 -1 .46 (m, 6H, H1 1 , H7a, H5a, H9a), 1 .54-1 .75 (m, 4H, H6, H5b, H9b), 1 .94-2.00 (m, 1 H, H7b), 2.00-2.05 (m, 1 H, H4), 2.45 (br s, 1 H, H1 ), 2.66 (s, 3H, H12). ¹³C NMR (CD₃OD, 100 MHz): δ (ppm) 8.2 (CH₃, Ci₀), 14.0 (CH₃, Cn), 18.0 (CH₃, C₈), 21 .5 (CH₂, C6), 22.7 (CH₂, C₅), 26.5 (CH₂, C9), 27.3 (CH₃, C₁₂), 32.8 (CH₂, C₇), 43.7 (CH, C1 ), 46.88 (CH, C₄), 46.92 (C3,q), 70.0 (q, C2). HRMS: (m/z - ES) calcd. for Ci₂H₂₄N (M+H)⁺ 182.1909, found 182.1916.

[00181] 3-exo-Ethyl-yV,2-endo-,3-trimethylbicyclo[2.2.1]heptan-2 -amine MEM

[00182] Prepared as per general procedure I using 3-exo-ethyl-2-enc/o-,3- dimethylbicyclo[2.2.1 ]heptan-2-amine x (120 mg, 0.62 mmol), paraformaldehyde (70 mg, 2.33 mmol), molecular sieves (200 mg), CH₂CI₂ (5 mL) and sodium borohydride (1 10 mg, 2.91 mmol) to yield the desired amine as a viscous oil. This oil was dissolved in anhydrous diethyl ether (1 .0 mL) and hydrogen chloride solution (2 M in diethylether, 800 micL, 1 .6 mmol) was added. The desired HCI salt was obtained by filtration and dried under vacuum to yield a white solid (80 mg, 59%). IR u_max (cm^"1): 3359, 2953, 1457, 1370, 1 150, 1 1 12, 914, 892. ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.94 (t, J = 6.95 Hz, 3H, H9), 0.98 (s, 3H, H10), 1 .23-1 .27 (m, 1 H, H7a), 1 .36 (s, 3H, H1 1 ), 1 .37-1 .60 (m, 4H, H5, H6), 1 .78-1 .90 (m, 1 H, H8a), 2.03-2.14 (m, 1 H, H8b), 2.20-2.23 (m, 1 H, H4), 2.32-2.39 (m, 1 H, H7b), 2.39-2.43 (m, 1 H, H1 ), 2.69 (br s, 3H, H12), 8.40 (br s, 1 H, H13a), 9.04 (br s, 1 H, H13b). ¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 9.9 (CH₃, C₉), 16.1 (CH₃, C1 1 ), 19.07 (CH₃, C10), 23.1 1 (CH₂, C5), 23.5 (CH₃, C6), 28.0 (CH₂, C8), 29.1 (CH₃, C12), 34.5 (CH₂, C7), 44.1 (CH, C4), 44.8 (CH, C1 ), 47.6 (q, C3), 71 .5 (q, C2). HRMS: (m/z - ES) calcd. for Ci₂H₂₄N (M+H)⁺ 182.1909, found 182.1901 .

[00183] 2-endo-Ethyl-yV,2,3-trimethylbicyclo[2.2.1]heptan-2 -amine MME

[00184] Prepared as per general procedure I using 2-enc/o-ethyl-3,3- dimethylbicyclo[2.2.1 ]heptan-2-amine e x (60 mg, 0.36 mmol), paraformaldehyde (32.3 mg, 1 .07 mmol), molecular sieves (100 mg), CH₂CI₂ (5 mL) and sodium borohydride (41 mg, 1 .07 mmol) to yield the desired amine as a viscous oil. This oil was dissolved in anhydrous diethyl ether (0.5 mL) and hydrogen chloride solution (2 M in diethylether, 400 μί, 0.8 mmol) was added. The desired HCI salt was obtained by filtration and dried under vacuum to yield a white solid (34 mg, 44%). IR u_max (cm^"1): 3360, 2950, 2761 , 1596, 1513, 1381 , 1370, 1092, 1000, 860. ¹H NMR (CD₃OD, 400 MHz): δ (ppm) 1.00 (t, J = 6.81 Hz, 3H, H1 1 ), 1.15 (s, 3H, H8), 1.27 (s, 3H, H9), 1 .30-1 .74 (m, 5H, H5, H6, H7a), 1 .75-2.01 (m, 3H, H10, H4), 2.06-2.14 (m, 1 H, H7b), 2.43 (br s, 1 H, H1 ), 2.69 (s, 3H, H12). ¹³C NMR (CD₃OD, 100 MHz): δ (ppm) 8.1 (CH₃, C1 1 ), 21.5 (CH₂, C10), 22.27 (CH₃, C8), 22.30 (CH₂, C5), 23.3 (CH₂, C6), 25.0 (CH₃, C9), 29.1 (CH₃, C12), 33.7 (CH₂, C7), 44.9 (q, C3), 45.7 (CH, C1 ), 51 .9 (CH, C4), 73.2 (q, C2).

[00185] 2-endo-,3-endo-Diethyl-A/,3-dimethylbicyclo[2.2.1]heptan-2 -amine EME

[00186] Prepared as per general procedure I using 2-enc/o-,3-enc/o-diethyl-3- methylbicyclo[2.2.1 ]heptan-2-amine x (400 mg, 2.2 mmol), paraformaldehyde (198 mg, 6.6 mmol, molecular sieves (400 mg), anhydrous CH₂CI₂ (15 mL) and sodium borohydride (304 mg, 8.0 mmol) to yield the free amine as a viscous oil. This was purified by flash chromatography on silica gel using a 100% ethyl acetate to 95:5 ethyl acetate:methanol eluent gradient. The HCI salt was formed on addition of a solution of hydrogen chloride (2 M in diethylether, 2.2 mL, 4.4 mmol). The diethyl ether was removed under vacuum to yield the desired HCI salt as a white solid (290 mg, 57%). IR u_max (cm^"1): 3361 , 2953, 2885, 2744, 1459, 1381 , 1 151 , 1 1 13, 916. ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.93 (t, J = 7.51 Hz, 3H, H10), 1 .01 (s, 3H, H8), 1 .14 (t, J = 7.39 Hz, 3H, H12), 1 .20-1 .25 (m, 1 H, H7a), 1 .31 -1 .53 (m, 4H, H5, H6), 1 .54-1 .65 (m, 1 H, H9a), 1 .65-1 .89 (m, 2H, H 1 1 ), 2.17-2.21 (m, 1 H, H4), 2.21 -2.32 (m, 1 H, H9b), 2.52-2.60 (m, 2H, H1 , H7b), 2.67 (app t, 3H, H13), 8.51 -8.97 (m, 2H, H14). ¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 9.4 (CH₃, C₁₂), 10.1 (CH3, C10), 19.2 (CH₃, C₈), 22.3 (CH₃, Cn), 22.7 (CH2, C5), 23.6 (CH₂, C₆), 28.7 (CH2, C9), 29.6 (CH₃, Ci₃), 34.5 (CH₂, C₇), 44.7 (CH, C4), 45.5 (CH, C1 ), 48.1 (q, C3), 74.5 (q, C2). HRMS: (m/z - ES) calcd. for Ci₃H₂₆N (M+H)⁺ 196.2065, found 196.2065.

[00187] 2-endo-,3-exo-Diethyl-A/,3-dimethylbicyclo[2.2.1]heptan-2 -amine MEE

[00188] Prepared as per general procedure I using 2-enc/o-,3-exo-diethyl-3- methylbicyclo[2.2.1 ]heptan-2-amine x (400 mg, 2.2 mmol), paraformaldehyde (198 mg, 6.6 mmol, molecular sieves (400 mg), anhydrous CH₂CI₂ (15 mL) and sodium borohydride (304 mg, 8.0 mmol) to yield the free amine as a low melting solid. This was purified by flash

chromatography on silica gel using a 100% ethyl acetate to 95:5 ethyl acetate:methanol eluent gradient. The HCI salt was formed on addition of a solution of hydrogen chloride (2 M in diethyl ether, 2.2 mL, 4.4 mmol). The diethyl ether was removed under vacuum to yield the desired HCI salt as a white solid (310 mg, 61 %). IR u_max (cm^"1): 3360, 2954, 1597, 1458, 1381 , 1 1 13, 916, 886. ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.89 (t, J = 7.22 Hz, 3H, H9), 1 .15 (t, 3H, H12), 1 .26- 1 .57 (m, 9H, H 10, H5, H6, H8a, H7a), 1 .59-1 .85 (m, 3H, H 1 1 , H8b), 1 .95-2.00 (m, 1 H, H4), 2.52-2.61 (m, 1 H, H7b), 2.61 -2.76 (m, 4H, H13, H1 ), 8.51 -8.77 (br s, 1 H, H 14a), 8.87-9.10 (br s, 1 H, H14b). ¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 8.9 (CH₃, C12), 9.3 (CH₃, C9), 20.9 (CH₂, C1 1 ), 21.3 (CH₃, C10), 21.8 (CH₂, C6), 23.3 (CH₂, C5), 27.0 (CH₂, C8), 29.1 (CH₃, C13), 33.8 (CH₂, C7), 45.3 (CH, C1 ), 47.5 (CH, C4), 47.9 (q, C3), 73.8 (q, C2).

[00189] 3,3-Diethyl-A/,2-endo-dimethylbicyclo[2.2.1]heptan-2-amine EEM

[00190] Prepared as per general procedure I was followed using 3,3-diethyl-2-enc/o- methylbicyclo[2.2.1 ]heptan-2-amine x (410 mg, 2.23 mmol), paraformaldehyde (356 mg, 1 1 .86 mmol, molecular sieves (400 mg), anhydrous CH₂CI₂ (15 mL) and sodium borohydride (350 mg, 10.52 mmol) to yield the free amine as a low melting solid. This was purified by flash chromatography on silica gel using a 100% ethyl acetate to 95:5 ethyl acetate:methanol eluent gradient. The HCI salt was formed on addition of a solution of hydrogen chloride (2 M in diethyl ether, 2.25 ml_, 4.4 mmol). The diethyl ether was removed under vacuum to yield the desired HCI salt as a white solid (310 mg, 61 %). IR u_max (cm^"1): 3359, 2953, 2844, 2744, 1458, 1369, 1 150. ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.92-1 .00 (m, 6H, H9, Hn), 1 .19-1 .26 (m, 1 H, H_7a), 1 .27-1 .65 (m, 9H, H5, H6, H 10, H12), 1 .91 -2.05 (m, 2H, H8), 2.18-2.22 (m, 1 H, H4), 2.34-2.41 (m, 2H, H1 , H7b), 2.69 (br s, 3H, H13), 8.43 (br s, 1 H, H 14a), 8.98 (br s, 1 H, H14b). ¹³C NMR (CDCIs, 100 MHz): δ (ppm) 9.41 (CH₃, C9), 9.44 (CH₃, C1 1 ), 16.2 (CH₃, C12), 21.6 (CH₂, C5), 22.8 (CH₂, C6), 23.1 CH₂, C8), 23.6 (CH₂, C10), 28.7 (CH₃, C13), 34.3 (CH₂, C7), 45.3 (CH, C4), 45.6 (CH, C1 ), 49.9 (q, C3), 71.0 (q, C2). HRMS: (m/z - ES) calcd. for Ci₃H2₆N (M+H)⁺ 196.2065, found 196.2062.

[00191] 2-endo-,3,3-Triethyl-yV-methylbicyclo[2.2.1]heptan-2-amine EEE

[00192] Prepared as per general procedure I was followed using 2-endo-,3,3- triethylbicyclo[2.2.1 ]heptan-2-amine x (120 mg, 0.61 mmol), paraformaldehyde (1 10 mg, 3.66 mmol, molecular sieves (100 mg), anhydrous CH₂CI₂ (5 mL) and sodium borohydride (152 mg, 4.00 mmol) to yield the free amine as a low melting solid. The HCI salt was formed on addition of a solution of hydrogen chloride (2 M in diethyl ether, 0.75 mL, 1 .5 mmol). The diethyl ether was removed under vacuum to yield the desired HCI salt as a white solid (82 mg, 55%). IR u_max (cm^"1): 3360, 2952, 2886, 1457, 1343, 1 150, 1 1 12, 915. ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.90 (t, J = 7.48 Hz, 3H, H13), 0.96 (t, J = 7.05 Hz, 3H, H1 1 ), 1 .15 (t, J = 7.26 Hz, 3H, H9), 1 .19- 1 .26 (m, 1 H, H7a), 1 .26-1 .96 (m, 9H, H5, H6, H8, H 10a, H12), 2.12-2.24 (m, 2H, H4, H10b), 2.48-2.56 (m, 1 H, H7b), 2.65-2.77 (m, 4H, H1 , H14), 8.39 (br s, 1 H, H15a), 9.01 (br s, 1 H, H15b). ¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 9.6 (CH3, C9), 10.0 (CH3, C1 1 ), 10.1 (CH3, C13), 21.4 (CH2, C8), 21 .7 (CH2, C5), 23.1 (CH2, C12), 23.9 (CH2, C6), 24.0 (CH2, C10), 30.6 (CH3, C14), 34.6 (CH2, C7), 46.18 (CH, C4), 46.24 (CH, C1 ), 51 .3 (q, C3), 75.6 (q, C2). HRMS: (m/z - ES) calcd. for Ci₄H₂₈N (M+H)⁺ 210.2222, found 210.2204.

[00193] A/-(3,3-Dimethylbicyclo[2.2.1]heptan-2-ylidene)methanamine

[00194] Methylamine hydrochloride (640 mg, 9.48 mmol) was ground into a fine powder and heated to 100 °C in an RBF under high vacuum to remove all traces of H₂0. A reflux condenser was fitted to the flask and the system flushed with argon. 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (19.24 mmol, 1 .406 mL, 1 .434 g) was added and the reaction stirred for 5 minutes.

Triethylamine (4.545 mL, 3.30 g, 32.61 mmol) was added. Titanium tetrachloride solution (1 M in CH₂CI₂, 3.60 mL, 3.60 mmol) was added and the reaction was stirred for 20 minutes at 40 °C. 3,3-dimethylbicyclo[2.2.1 ]heptan-2-one x (1 .00 g, 7.25 mmol) was added slowly and the reaction turned from bright red to dark brown. After stirring at 40 °C for 16 hours, the reaction mixture was poured into diethyl ether (200 mL) and filtered thourough celite to remove triethylamine hydrochloride. The organic solvent was dried over MgS0₄ and evaporated at reduced pressure to yield /V-(3,3-dimethylbicyclo[2.2.1 ]heptan-2-ylidene)methanamine as a clear oil (663 mg, 61 %) without the need for further purification. IR u_max (cm^"1): 2965, 2869, 1686, 1463, 1379, 1 105, 1066. ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 1.08 (s, 3H, H9), 1 .09 (s, 3H, H8), 1.23-1 .33 (m, 1 H, H6a), 1.41 -1 .46 (m, 1 H, H7a), 1 .53-1 .63 (m, 1 H, H5a), 1 .74-1 .88 (m, 3H, H5b, H6b, H7b), 2.08-2.1 1 (m, 1 H, H4), 3.1 1 (s, 3H, H10), 3.19-3.24 (m, 1 H, H1 ). ¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 22.6 (CH₃, C9), 22.9 (CH₂, C5), 24.6 (CH₂, C6), 24.7 (CH₃, C8), 35.4 (CH₂, C7), 38.3 (CH₃, C10), 40.1 (CH, C1 ), 44.3 (q, C3), 46.8 (CH, C4), 189.8 (q, C2). HRMS: (m/z - ES) calcd. for CioH₁₈N (M+H)⁺ 152.1439, found 152.1444.

[00195] yV,2-exo-,3,3-Tetramethylbicyclo[2.2.1]heptan-2 -amine

[00196] /V-(3,3-Dimethylbicyclo[2.2.1 ]heptan-2-ylidene)methanamine x (250 mg, 1 .66 mmol) was placed in a RBF with a stirring bar in the absence of any solvent under an argon atmosphere. To this, boron trifluoride diethyl etherate (316 μΙ_, 354 mg, 2.49 mmol) was added dropwise. A crystalline solid formed. The reaction mixture was cooled to 0 °C and methyllithium solution (1 .6 M in diethyl ether, 10.00 mL, 16.00 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 1 hour. Ammonium hydroxide solution (30% in H₂0, 10 mL was added and the product extracted with diethyl ether (2 x 10 mL), washed with brine (10 mL) and dried over MgS0₄. The organic solvent was evaporated under vacuum to yield the desired amine as a viscous oil. This product was redissolved in anhydrous diethyl ether (2 mL) and a solution of hydrogen chloride (2 M in diethyl ether, 1 .0 mL, 2.0 mmol) was added. The hydrochloride salt was isolated by filtration and dried under vacuum to yield the desired product as a white solid (191 mg, 56%). ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 1.00 (s, 3H, H8), 1 .1 1 (CH3, 3H, H9), 1 .18-1 .23 (m, 1 H, H7a), 1 .24 (s, 3H, H10), 1 .30-1 .47 (m, 2H, H5a, H6a), 1 .50-1 .68 (m, 2H, H5b, H6b), 1 .73-1 .77 (m, 1 H, H4), 1.82-1 .89 (m, 1 H, H7b), 2.14-2.18 (m, 1 H, H1 ), 2.47 (t, J = 5.34 Hz, 3H, H1 1 ), 7.81 (br s, 1 H, H 12a), 8.98 (br s, 1 H, H12b). ¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 18.6 (CH₃, C10), 21.3 (CH₃, C9), 21 .4 (CH₂, C6), 23.0 (CH₂, C5), 27.0 (CH₃, C8), 28.5 (CH₃, C1 1 ), 34.3 (CH₂, C7), 42.5 (q, C3), 46.0 (CH, C1 ), 49.2 (CH, C4), 68.0 (q, C2). HRMS: {m/z - ES) calcd. for CnH_22N (M+H)⁺ 168.1752, found 168.1751 .

[00197] 4-Pentyl-1 -(2-endo-,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)-1 H-1 ,2,3-triazole

[00198] A microwave reaction vessel was charged with 2-azido,2-enc/o-,3,3- trimethylbicyclo[2.2.1 ]heptane (100 mg, 0.55 mmol), heptyne (79 μί, 58 mg, 0.61 mmol), 0.08 M sodium ascorbate solution (2.8 mL, 0.224 mmol) and 0.04 M copper sulphate solution (2.8 mL, 0.1 12 mmol). The reaction mixture was heated to 100 °C and stirred vigorously for 10 minutes in the microwave. After this time, the reaction mixture was diluted with H₂0 (60 mL) and concentrated acqueous ammonia (1 mL) was added. The product was extracted using diethyether (2 x 60 mL) which was dried over MgS0₄. The organic solvent was removed under vacuum to yield a brown oil. This was further purified on silica gel using 100% ethyl acetate as eluent to yield 4-Pentyl-1 -(2-endo-,3,3-trimethylbicyclo[2.2.1 ]heptan-2-yl)-1 H-1 ,2,3-triazole as a pale yellow oil. (124 mg, 82%).

Spiro-compounds

Spiro[bicyclo[2.2.1]heptane-3,1 '-cyclopentan]-2-one

[00199] To a solution of norcamphor (2.00 g, 18.16 mmol), and 1 ,4-dibromobutane (6.50 mL, 54.49 mmol), in anhydrous diethyl ether (40 ml_) was added sodium amide (1.77 g, 45.36 mmol). The reaction mixture was heated to reflux and stirred for 24 hrs. The mixture was allowed to cool to r.t. and was diluted with cold H₂0 (100 mL). The product was extracted with diethyl ether (2 x 50 mL), washed with brine (50 mL) and dried over MgS0₄ before being filtered. The solvent was removed at reduced pressure to yield a pale yellow oil which was subsequently purified via column chromatography (9:1 hexane: diethyl ether, R_f= 0.53) to yield

spiro[bicyclo[2.2.1 ]heptane-3,1 '-cyclopentan]-2-one as a clear colourless oil. (2.84 g, 95.3 %). Ref - K. Hori, N. Takaishi, Y. Inamoto, Bull. Chem. Soc. Jpn., 1988, 61 , 2669. ¹H NMR (CDCI₃, 600 MHz): δ (ppm) 1.44-1 .67 (H, m, H_7a, H_6a, H_6b, H_5a, H_{1 a}, H _b, H_{2 a}, H_{2 b}), 1 .67-1 .80 (4H, m, H _c, H _d H_{2 c,} H_{2 d}), 1 .80-1 .92 (2H, m, H_7b, H_5b), 2.25-2.27 (1 H, m, H₄), 2.56-2.59 (1 H, m, Hi). ¹³C NMR (CDCIs, 100 MHz): δ (ppm) 23.8 (C₅), 25.5 (C₆), 26.4 (C₂ ), 26.8 (C₂ ), 32.8 (C ), 36.0 (C₇), 36.5 (Cr), 46.5 (C₄), 49.9 (Ci), 59.0 (q, C₃), 224.5 (q, C₂). IR u_max(cm^"1): 2951 , 2873, 1736 (C=0), 1449, 91 1 . HRMS:(m/z - ESI) Calculated for CnH₁₇0 (M+H)⁺ 165.1279, found 165.1279. 3-Methylspiro[bicyclo[2.2.1]heptane-3,1 '-cyclopentan]-2-ol

[00200] To a solution of spiro[bicyclo[2.2.1 ]heptane-3,1 '-cyclopentan]-2-one (2.30 g, 14.0 mmol) in anhydrous THF (40mL) at 0°C was added slowly a solution of

methylmagnesiumbromide (3M in diethyl ether, 28.0 mL, 84.14 mmol). The reaction was allowed to warm to r.t. and stirred for 19hrs. 10% NH₄CI (15 mL) was added. The product was extracted using diethylether (2 x 30 mL), washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate before being filtered. The solvent was evaporated at reduced pressure and the resultant yellow oil which was purified via column chromotography (3:7 diethyl ether: hexane, R_f = 0.35) to yield 3-methylspiro[bicyclo[2.2.1 ]heptane-3,1 '-cyclopentan]-2-ol as a clear colourless oil. (2.27 g, 90.2%). ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 1.21 -1 .26 (4H, m, H_7a, H₈), 1 .26-1 .42 (3H, m, H_6a, H_5a, H_{1 a}), 1 .42-1 .54 (3H, m, H _b, H_{1 c}, H_{2 a}), 1 .55-1 .72 (6H, m, H_5b, H_7b, H _d, H_{2 b}, H_{2 c}, H_{2 d}), 1 .82-1 .90 (2H, m, H₄, H_6b), 1 .99-2.03 (1 H, m, Hi). ¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 21 .6 (C₆), 23.4 (C₂ ), 23.5 (C₂ ), 23.8 (C₅), 26.9 (C₈), 30.4 (C_r), 35.4 (C), 35.4 (C₇), 46.0 (C₄), 50.7 (Ci), 55.8 (q, C₃), 78.8 (q, C₂). IR u_max(Neat)/crTf¹ : 3451 (OH), 2951 , 2872, 1464, 1372, 1097, 940. HRMS: (m/z - El) Calculated for Ci₂H₂₀O (M) 180.1514, found 180.1523. 2-Azido-2-methylspiro[bicyclo[2.2.1]heptane-3,1 '-cyclopentane]

[00201] To a suspension of 3-methylspiro[bicyclo[2.2.1 ]heptane-3,1 '-cyclopentan]-2-ol (0.50 g, 2.78 mmol) and NaN₃ (1 .26 g, 19.38 mmol) in chloroforom (60mL) was carefully added a solution of H₂S0₄ (50%, 10 mL) at r.t. The reaction mixture was stirred vigorously for 2 hrs at which time ice cold H₂0 was added (50mL). The product was extracted with DCM (2 x 30 mL), and the combined organic extracts were washed with 5% NaHC0₃ solution (30 mL), dried over magnesium sulfate, filtered, and evaporated at reduced pressure to give a yellow oil. This was purified via column chromotography (100% hexane, R_f = 0.66) to yield 2-azido-2- methylspiro[bicyclo[2.2.1 ]heptane-3,1 '-cyclopentane] as a clear colourless liquid. (0.21 g, 35.8%). The reaction was terminated before full conversion to prevent the formation of a side product (R_f80.2%), 60.6% of the starting material was recovered. ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 1 .19 (1 H, dt, J = 1 .4, 9.9 Hz, H_7a), 1 .30-1 .55 (1 1 H, m, H₈, H_{1 a}, H _b, H_5a, H_5b, H_{1 c}, H_{2 a}, H₂'b, H_{2 c}) 1 .55-1 .68 (3H, m, H_6a, H_6b, H_{2 d}) 1 .74-1 .84 (1 H, m, H _d), 1 .87-19.1 (1 H, m, H₄), 1.94 (1 H, dt, J =2.1 , 9.9 Hz, H_7b), 2.18-2.22 (1 H, m, Hi ). ¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 18.7 (C₈), 22.6 (C₆), 23.4 (C₂ ), 23.5 (C₂ ), 23.6 (C₅), 31 .8 (C ), 35.3 (C₇), 35.5 (C ), 45.8 (C₄), 48.4 (CO, 57.1 (q, C₃), 72.1 (q, C₂). IR u_max cm^"1: 2957, 2875, 2080, 1456, 1254, 1071 . HRMS: (m/z - El) Calculated for d₂H₁₉N₃ (M) 205.1579, found 205.1584.

2-Methylspiro[bicyclo[2.2.1]heptane-3,1 '-cyclopentan]-2-amine (nmn 364x)

[00202] To a solution of 2-azido-2-methylspiro[bicyclo[2.2.1 ]heptane-3,1 '-cyclopentane] (0.13 g, 0.63 mmol) in methanol (20mL) was added Palladium on charcoal (0.013 g, 10% w/w). The reaction mixture was stirred vigorously under a hydrogen atmosphere for approximately 16hrs at atmospheric pressure. The reaction mixture was filtered through celite, dried over magnesium sulfate and filtered before the solvent was removed at reduced pressure. The free amine hydrochloride salt was isolated by the addition of NaOH. It was extracted with DCM (2 x 20 mL) and dried over magnesium sulfate and filtered before the solvent was removed under reduced pressure to yield 2-methylspiro[bicyclo[2.2.1 ]heptane-3,1 '-cyclopentan]-2-amine as a clear colourless oil. (0.1 1 g, 97.5%). ¹H NMR (CDCI₃, 600 MHz): δ (ppm) 1.09 (3H, s, H₈), 1 .17 (1 H, app d, J = 10.1 Hz, H_7a), 1 .28-1 .68 (1 1 H, m, H6_a, H6_b, H_5a, H_5b, Hr_a, Hr_b, Hr_c, H_{2 a}, H_{2 b}, H_{2 c}, H_{2 d}), 1 .71 -1 .78 (1 H, m, H _d), 1 .82-1 .88 (3H, m, Hi , H₄, H_7b). ¹³C NMR (CDCI₃, 150 MHz): δ (ppm) 22.6 (C₅), 23.1 (C₂ ), 23.4 (C₂ ), 24.0 (C₆), 24.2 (C₈), 31 .4 (C ), 33.9 (C ), 34.8 (C7), 45.5 (C₄), 52.3 (CO, 56.7 (q, C₃), 58.9 (q, C₂). IR u_max cm^"1: 2949, 2872, 1456, 1372, 804. HRMS: (m/z - ESI) Calculated for Ci₂H₂₂N (M+H)⁺ 180.1752, found 180.1753.

N,2-dimethylspiro[bicyclo[2.2.1]heptane-3,1 '-cyclopentan]-2-amine

[00203] Into an oven dried RBF under an argon atmosphere fitted with a reflux condenser, 2- methylspiro[bicyclo[2.2.1 ]heptane-3,1 '-cyclopentan]-2-amine (0.32 g 1 .79 mmol),

paraformaldehyde (0.29 g, 9.66 mmol) and activated molecular sieves (0.40 g) were added. Anhydrous CH₂CI₂ (30 mL) was then added and the reaction refluxed for 16 hrs. After this time, an in situ ¹H nmr sample was taken to confirm quantitative conversion to the imine was complete. The reaction was cooled to -10 °C and sodium borohydride (0.30 g, 8.10 mmol) was added. Anhydrous methanol (2 mL) was added dropwise and the reaction was allowed to warm to room temperature with contiuous stirring over 1 hr and then stirred at room temperature for a further 2 hrs. The reaction mixture was filtered to remove the molecular sieves and the unreacted paraformaldehyde. The residue was washed with CH₂CI₂ (50 mL) and the combined filtrate extracted with 2 M NaOH (30 mL). The organic solvent was dried over MgS0₄ and removed under vacuum to give the /V-methylated amine as a tacky solid. This product was redissolved in anhydrous diethyl ether (5 mL) and a solution of hydrogen chloride (2 M in diethyl ether, 1.5 mL, 3.0 mmol) was added. Filtration afforded the HCI salt of N,2- dimethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclopentan]-2-amine as a white solid (0.25g, 60.8%). M.p.170-175 °C (decomposes).¹H NMR (CDCI₃, 600 MHz): δ (ppm) 1.27-1.43 (5H, m, H₈, H_7a, H_5a), 1.44-1.57 (5H, m, H_6a, H_6b, H_2a, H_2b, H_1a), 1.62-1.86 (4H, m, H_5b, H_2c, H_2d, H _b), 1.94-1.17 (3H, m, H₄, H _c, H _d), 2.29-2.37 (1H, m, H_7b), 2.39-2.46 (1H, m, H , 2.61-2.71 (3H, br s, H₉), 8.24 (1H, brs, H_10a), 9.15 (1H, br s, H_10b).¹³C NMR (CDCI₃, 150 MHz): δ (ppm) 17.4 (C₈), 22.0 (C₂), 22.1 (C₅), 22.5 (C₆), 23.4 (C₂), 28.6 (C₉), 31.6 (C ), 33.4 (C ), 34.8 (C₇), 43.8 (Ci), 44.5 (C₄), 57.3 (q, C₃), 69.2 (q, C₂). IR u_max cm^"1: 2955, 2733, 1462, 1431, 1398, 1108, 1036.

HRMS: (m/z -ESI) Calculated for Ci₃H₂₄N (M+H)⁺ 194.1909, found 194.1915.

Spiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]-2-one

[00204] Prepared by the method employed for spiro[bicyclo[2.2.1]heptane-3,1'-cyclopentan]-2- one using norcamphor (2.00 g, 18.16 mmol), 1 ,5-dibromopentane (7.40 mL, 54.49 mmol), sodium amide (1.77 g, 45.36 mmol) and anhydrous diethyl ether (50 mL) with a reaction time of 24hrs to yield a pale yellow oil which was subsequently purified via column chromatography (9:1 hexane: diethyl ether, R_f= 0.47) to yield spiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]-2-one as a clear colourless oil. (2.76 g, 85.5%). Ref- K. Hori, N. Takaishi, Y. Inamoto, Bull. Chem. Soc. Jpn., 1988, 61, 2669.¹H NMR (CDCI₃, 600 MHz): δ (ppm) 1.22-1.40 (2H, m, H_2a, H_3a), 1.40- 1.56 (7H, m, H_7a, H_6a, H _a, H _b, H _c, H _d, H_2¾), 1.59-1.71 (4H, m, H_5a, H_3¾, Η_2¾, H_2b), 1.72-1.79 (1H, m, H_5b), 1.82-1.90 (1H, m, H_6b), 1.90-1.95 (1H, m, H_7b), 2.55-2.58 (1H, m, Hi), 2.59-2.62 (1H, m, H₄).¹³C NMR (CDCI₃, 150 MHz): δ (ppm) 22.3 (C₂), 22.4 (C₂), 22.7 (C₅), 24.7 (C₆), 25.8 (C₃), 30.3 (Cr), 30.4 (d), 34.9 (C₇), 40.9 (C₄), 50.3 (d), 51.6 (q, C₃), 222.1 (q, C₂). IR u_maxcm-¹: 2928, 2856, 1736 (C=0), 1448, 1091, 768. HRMS: (m/z - El) Calculated for Ci₂H₁₈0 (M) 178.1358, found 178.1355.

2-Methylspiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]-2-ol

[00205] Prepared by the method employed for 3-methylspiro[bicyclo[2.2.1]heptane-3,1'- cyclopentan]-2-ol using spiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]-2-one (3.30 g, 16.83 mmol), a solution of methylmagnesiumbromide (3M in diethyl ether, 33.7 mL, 100.97 mmol) and anhydrous THF (50 mL) with a reaction time of 16 hrs at r.t. to yield a yellow oil which was purified via column chromatography (9:1 hexane: diethyl ether, R_f= 0.20) to yield 2- methylspiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]-2-ol as a clear colourless oil. (3.12 g, 95.5%).¹H NMR (CDCI₃, 400 MHz): δ (ppm) 1.08 (1 H, dt, J = 2.9, 12.9 Hz, H_1a), 1.12-1.26 (6H, m, H_2a, H_2b,H_8! H_7a), 1.30-1.39 (3H, m, H_6a, H_5a, H _b), 1.40-1.53 (2H, m, H _c, H_2c), 1.56-1.65 (5H, m, H_5b! H_7b! H_2d! H_2e, H_2f) 1.69-1.74 (1H, m, H _d), 1.79-1.84 (1H, m, H_6b), 1.95-1.98 (1H, m, Hi), 2.30-2.33 (1 H, m, H₄).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 21.1 (C₆), 23.3 (C₅), 23.7 (C₂), 24.1 (C₂), 25.3 (Ce), 26.2 (C₂), 30.2 (C ), 33.2 (C ), 34.4 (C₇), 41.2 (C₄), 44.8 (q, C₃), 50.8 (d),

79.8 (q, C₂). IR u_maxcrrf¹: 3451, 2925, 2854, 1447, 1124, 923. HRMS: (m/z - El) Calculated for Ci₃H₂₂0 (M) 194.1671, found 194.1662.

2-Azido-2-methylspiro[bicyclo[2.2.1]heptane-3,1 '-cyclohexane]

[00206] Prepared by the method employed for 2-azido-2-methylspiro[bicyclo[2.2.1]heptane- 3,1'-cyclopentane] using 2-Methylspiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]-2-ol (2.97 g, 15.30 mmol), NaN₃ (6.96 g, 107.06 mmol), 50% H₂S0₄ (15 mL) and chloroform (100 mL) with a reaction time of 6 hours to yield a yellow oil was purified via column chromotography (100% hexane, R_f= 0.49) to yield 2-azido-2-methylspiro[bicyclo[2.2.1]heptane-3,1 '-cyclohexane] as a clear colourless liquid. (0.95 g, 28.3 %). The reaction was terminated before full conversion to prevent the formation of a side product, 2.0 g of the starting material was recovered.¹H NMR (CDCI₃, 400 MHz): δ (ppm) 1.11-1.21 (4H, m, H_7a, H_1a, H_2a, H_2b), 1.22-1.43 (6H, m, H _b, H_5a, H6a,H8)1.44-1.53 (2H, m, H_5b, H_6b), 1.54-1.70 (6H, m, H _c, H_rd, H_2c, H_2d, H_2e, H_2f), 1.90-1.96 (1H, m, H_7b), 2.09-2.13 (1H, m, Hi), 2.32-2.36 (1H, m, H₄).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 16.6 (Ce), 23.1 (C₆), 23.2 (C₅), 23.7 (C₂), 24.1 (C₂), 25.9 (C₂), 32.1 (C ), 32.8 (C ), 34.6 (C₇),

41.9 (C₄), 47.1 (q, C₃), 48.6 (Ci), 74.2 (q, C₂). IR u_max cm^"1: 2926, 2857, 2082, 1448, 1260, 1102. HRMS: (m/z- ESI) Calculated for Ci₃H₂₂N (M+H - N₂)⁺ 192.1752, found 192.1754

2-Methylspiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]-2 -amine

[00207] Prepared by the method employed for 2-methylspiro[bicyclo[2.2.1]heptane-3,1'- cyclopentan]-2-amine using 2-azido-2-methylspiro[bicyclo[2.2.1]heptane-3,1 '-cyclohexane] (0.80 g, 3.65 mmol), Palladium on charcoal (0.08 g, 10% w/w) and a 1:6 solution of methanoLTHF (30 mL) with a reaction time of 14 hours under a hydrogen atmosphere at atmospheric pressure to yield 2-methylspiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]-2-amine as a clear colourless oil. (0.69 g, 97.5%).¹H NMR (CDCI₃, 600 MHz): δ (ppm) 1.59 (3H, s, H₈), 1.08-1.42 (H, m, H_5a, H_6a, H_7a, H-Ta, H , H_2a, H₂ ), 1.46-1.59 (5H, m, H₅ , H_6b, H _c, H_2c, H_2d), 1.60-1.68 (3H, m, H _d, H_2c, H_2d), 1.77-1.80 (1H, m, Hi), 1.81-1.85 (1H, m, H_7b), 2.30-2.33 (1H, m, H₄).¹³C NMR (CDCI₃, 150 MHz): δ (ppm) 22.5 (C₈), 22.9 (C₆), 23.7 (C₅), 23.9 (C₂), 25.4 (C₂), 26.1 (C₂), 32.0 (C ), 32.1 (Cr), 34.2 (C₇), 41.9 (C₄), 45.6 (q, C₃), 52.3 (Ci), 64.4 (q, C₂). IR u_maxcm^"1: 2921, 2856, 1447, 1374, 829. HRMS: {m/z - ESI) Calculated for Ci₃H₂₄N (M+H)⁺ 194.1909, found 194.1919.

N,2-dimethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]-2-amine

[00208] Prepared by the method employed for N,2-dimethylspiro[bicyclo[2.2.1]heptane-3,1'- cyclopentan]-2-amine using 2-methylspiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]-2-amine (0.50 g 2.59 mmol), paraformaldehyde (0.50 g, 16.66 mmol), activated molecular sieves (0.96 g) anhydrous CH₂CI₂ (40 mL), sodium borohydride (0.34 g, 9.07 mmol) and anhydrous methanol (2 mL) to yield a colourless oil. This product was re-dissolved in anhydrous diethyl ether (5 mL) and a solution of hydrogen chloride (2 M in diethyl ether, 1.5 mL, 3.0 mmol) was added.

Filtration afforded the HCI salt of N,2-dimethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]-2- amine as a white solid (0.43 g, 68.0%). M.p.175-180 °C (decomposes).¹H NMR (CDCI₃, 600 MHz): δ (ppm) 1.14-1.39 (7H, m, H₈, H_7a, H_1a, H_2a, H_2b), 1.36-1.72 (9H, m, H_5a, H_5b, H_6a, H_6b, H _b, H_2c, H_2d, H_2e, H_2f), 1.77-1.85 (1H, m, H_1c), 2.14-2.21 (1H, m, H _d), 2.29-2.36 (1H, m, H_7b), 2.38-2.42 (1 H, m, H , 2.52-2.55 (1 H, m, H₄), 2.64-2.72 (3H, br s, H₉), 8.24 (1 H, br s, H_10a), 9.00 (1 H, br s, H_10b).¹³C NMR (CDCI₃, 150 MHz): δ (ppm) 15.5 (C₈), 22.5 (C₅), 23.3 (C₆), 23.5 (C₂), 23.9 (C₂), 25.5 (C₂), 29.0 (C₉), 31.2 (C ), 31.8 (C ), 34.5 (C₇), 41.7 (C₄), 44.5 (Ci), 47.8 (q, C₃), 71.8 (q, C₂). IRu_maxcrrf¹: 2926, 2748, 1593, 1465, 1386, 1117, 996. HRMS: {m/z - ESI) Calculated for Ci₄H₂₆N (M+H)⁺ 208.2065, found 208.2069.

2-Ethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclopentan]-2-ol

[00209] To a solution of bromoethane (1.20 mL, 1.59 mmol) in anhydrous THF (20 mL) was added 1.7M tBuLi (18.70 mL, 31.72 mmol) at -78°C. The reaction mixture was stirred for ten minutes before a solution of spiro[bicyclo[2.2.1]heptane-3,1'-cyclopentan]-2-one (1.30 g, 7.93 mmol), in anhydrous THF (5 mL) was added. The reaction mixture was allowed to warm to r.t. and was stirred for 3hrs upon which time a saturated solution of sodium bicarb was added. The product was extracted with diethyl ether (2 x 40 mL), washed with brine (35 mL) and dried over MgS0₄ before being filtered. The solvent was removed at reduced pressure to afford a pale yellow oil which was purified via column chromotography (1:9 diethyl ether: hexane, R_f= 0.25) to yield 2-ethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclopentan]-2-ol as a clear colourless oil.

(1.17g, 76.2%).¹H NMR (CDCI₃, 600 MHz): δ (ppm) 0.94 (3H, t, J= 7.5 Hz, H₉), 1.16-1.21 (1H, m, H_7a), 1.24-1.29 (1H, m, H_1a), 1.30-1.39 (2H, m, H_5a, H_6a), 1.40-1.38 (2H, m, H_2a, H _b), 1.49- 1.67 (8H, m, H_8a, H_8b, H_1c, H_2b, H_2c, H_2d, H_7b, H_5b), 1.68-1.75 (1H, m, H _d), 1.78-1.86 (2H, m, H₄, H_6b), 2.23-2.26 (1H, m, Hi).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 8.7 (C₉), 21.9 (C₆), 23.3 (C₂),

23.4 (C₂), 23.7 (C₅), 30.2 (C₈), 30.6 (C ), 34.2 (C ), 35.1 (C₇), 45.1 (Ci), 46.0 (C₄), 56.8 (q, C₃),

80.5 (q, C₂). IR u_maxcm^"1: 3485, 2954, 2873, 1462, 1291, 982. HRMS: (m/z - El) Calculated for Ci₃H₂₂0 (M)⁺ 194.1671, found 194.1674.

2-Azido-2-ethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclopentane]

[00210] Prepared by the method employed for 2-azido-2-methylspiro[bicyclo[2.2.1]heptane- 3,1'-cyclopentane] using 2-ethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclopentan]-2-ol (0.33 g, 1.72 mmol), NaN₃ (0.56 g, 8.62 mmol), 50% H₂S0₄ (5 mL) and chloroform (30 mL) with a reaction time of 2hrs to yield a yellow oil was purified via column chromatography (100% hexane, R_f = 0.56) to yield 2-azido-2-ethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclopentane] as a clear colourless liquid. (0.16 g, 42.7%) and an elimination side product 2-ethylidenespiro[bicyclo[2.2.1]heptane- 3,1'-cyclopentane] (0.16g, 42.7%).¹H NMR (CDCI₃, 600 MHz): δ (ppm) 0.98 (3H, t, J = 7.5 Hz, H₉), 1.23 (1H, appd, J= 10.1 Hz, H_7a), 1.27-1.69 (13H, m, H_1a, H _b, H_1c, H_5a, H_5b, H_6a, H_6b, H_2a, H₂'b, H₂._C! H_2d, H₈), 1.73-1.80 (1H, m, H _d), 1.86 (1H, app d, J = 10.1 Hz, H_7b), 1.89-1.92 (1H, m, H₄), 2.29-2.31 (1H, m, Hi).¹³C NMR (CDCI₃, 150 MHz): δ (ppm) 9.3 (C₉), 22.1 (C₂), 23.0 (C₆), 23.1 (C₂), 23.3 (C₅), 25.4 (C₈), 31.0 (C ), 35.0 (C₇), 35.2 (C ), 44.4 (Ci), 44.9 (C₄), 58.8 (q, C₃), 75.3 (q, C₂). IRu_maxcrrf¹: 2963, 2876, 2091, 1454, 1258, 881. HRMS: {m/z- ESI) Calculated for Ci₃H₂₂N (M+H-N₂)⁺ 192.1752, found 192.1759.

2-Ethylidenespiro[bicyclo[2.2.1]heptane-3,1 '-cyclopentane]

[00211] ¹H NMR (CDCI₃, 400 MHz): δ (ppm) 1.17-1.33 (2H, m, H_6a, H_7a), 1.38-1.48 (2H, m, H_5a, Hra), 1.49-1.74 (13H, m, H_5b, H_6b ,H_7b, H9, H _b, H _c, H _d, H₂._a, H_2¾, Η_2¾, H₂._d), 1.91-1.95 (1H, m, H₄), 2.93-2.97 (1H, m, Hi), 5.02 (1 H quartet, J = 6.6 Hz, H₈).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 14.4 (C₉), 24.1 (C₅), 25.6 (C₂), 26.2 (C₂), 28.9 (C₆), 36.5 (C ), 38.1 (C₇), 40.7 (Ci), 42.1 (Cr), 47.3 (C₄), 54.8 (q, C₃), 109.1 (C₈), 157.6 (q, C₂). IRu_maxcrrf¹: 2951, 2866, 1452, 1289, 811. HRMS: (m/z - El) Calculated for Ci₃H₂₀ (M)⁺ 176.1565, found 176.1557.

2-Ethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclopentan]-2 -amine

[00212] Prepared by the method employed for 2-methylspiro[bicyclo[2.2.1]heptane-3,1'- cyclopentan]-2-amine using 2-azido-2-ethylspiro[bicyclo[2.2.1]heptane-3,1 '-cyclopentane] (0.11 g, 0.50 mmol), Palladium on charcoal (0.012 g, 10% w/w) and methanol (10 mL) with a reaction time of 14 hrs under an atmosphere of hydrogen at atmospheric pressure to 2- ethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclopentan]-2-amine as a clear colourless oil. (0.06 g, 64.0%).¹H NMR(CDCI₃, 400 MHz): δ (ppm) 0.93 (3H, t, J= 7.5Hz, H₉), 1.18 (1H, app d, J = 10.0 Hz, H_7a), 1.25-1.75 (12H, m, H_5a, H_5b, H6_a, H6d, H _a, Hr_b, Hr_c, Hr_d, H_2a, H_2b, H_2c, H_2d, H_8a, H_8b), 1.83-1.90 (3H, m, Hi, H₄, H_7b).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 9.2 (C₉), 22.3 (C₅), 23.3 (C₈), 23.4 (C₆), 23.8 (C₂), 23.8 (C₂), 30.6 (C ), 34.0 (C ), 34.6 (C₇), 45.3 (Ci), 45.3 (C₄), 48.3 (q, C₃), 57.5 (q, C₂). IR u_maxcm^"1: 2948, 2873, 1463, 1377, 947, 806. HRMS: (m/z- El) Calculated for Ci₃H₂₃N (M)⁺ 193.1830, found 193.1828.

2-Ethyl-N-methylspiro[bicyclo[2.2.1]heptane-3,1'-cyclopentan]-2 -amine

[00213] Prepared by the method employed for N,2-dimethylspiro[bicyclo[2.2.1]heptane-3,1'- cyclopentan]-2-amine using 2-ethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclopentan]-2-amine (0.07 g 0.36 mmol), paraformaldehyde (0.40 g, 1.26 mmol), activated molecular sieves (0.15 g), anhydrous CH₂CI₂ (15 mL), sodium borohydride (0.06 g, 1.62 mmol) and anhydrous methanol (0.5 mL) to yield a pale yellow oil This product was re-dissolved in anhydrous diethyl ether (5 mL) and a solution of hydrogen chloride (2 M in diethyl ether, 0.5 mL, 1.0 mmol) was added. Filtration afforded the HCI salt of 2-ethyl-N-methylspiro[bicyclo[2.2.1]heptane-3,1'-cyclopentan]- 2-amine as a white solid - purification was difficult due to some degree of decomposition.¹H NMR(CDCI₃, 600 MHz): δ (ppm) 1.16 (3H, t, J= 7.3 Hz, H₉), 1.32 (1H, app d, J= 11.5 Hz, H_7a), 1.35-1.86 (H, m, H_5a, H_5b, H_6a, H6_b, H₈, Hr_a, Hr_b, Hr_c, H_2a, H_2b, H_2c, Η₂¾), 1.99 (1H, br s, H₄), 2.04-2.12 (1 H, m, H _d), 2.52 (1 H, app d, J = 11.5 Hz, H_7b), 2.65 (3H, app t, J = 5.7 Hz, H₁₀), 2.70 (1 H, br s, H .¹³C NMR (CDCI₃, 150 MHz): δ (ppm) 9.6 (C₉), 22.2 (C₅), 22.4 (C₂), 22.6 (C₂), 23.1 (Ce), 23.9 (C₆), 29.5 (do), 31.4 (C ), 34.0 (C ), 34.6 (C₇), 44.8 (Ci), 45.8 (C₄), 57.9 (q, C₃), 72.3 (q, C₂). IR Umax cm-¹: 2950, 1594, 1456, 1416, 1107, 1101, 907. HRMS: {m/z - ESI) Calculated for Ci₄H₂₆N (M+H)⁺ 208.2065, found 208.2051.

2-Ethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]-2-ol

[00214] Prepared by the method employed for 2-ethylspiro[bicyclo[2.2.1]heptane-3,1'- cyclopentan]-2-ol using of spiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]-2-one (0.80 g, 4.49 mmol), bromoethane (0.65 ml_, 8.97 mmol), a solution of tBuLi (1.7M in pentane, 10.5 ml_, 17.96 mmol) and anhydrous THF (65 mL) to yield a pale yellow oil which was purified via column chromotography (1:9 diethyl ether: hexane, R_f= 37.5%) to yield 2- ethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]-2-ol as a clear colourless oil. (0.42g, 40.9 %). ¹H NMR (CDCIs, 400 MHz): δ (ppm) 0.95 (3H, t, J = 7.4Hz, H₉), 0.98-1.07 (1 H, m, H_1a), 1.09- 1.32 (3H, m, H_7a, H_2a, H_2b), 1.32-1.48 (4H, m, H_5a, H_6a, H _b, H_1c), 1.49-1.69 (8H, m, H_5b, H_8a, H_8b, H_7b, H_2c, H_2d, H_2e, Η_2ΐ), 1.74-1.82 (2H, m, H_6b, H _d), 2.23-2.26 (1H, m, H , 2.32-2.26 (1H, m, H₄).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 9.0 (C₉), 21.4 (C₆), 23.2 (C₅), 23.8 (C₂), 24.0 (C₂), 26.3 (C₂), 28.3 (Ce), 30.3 (C ), 32.2 (C ), 34.3 (C₇), 41.8 (C₄), 45.1 (Ci), 45.9 (q, C₃), 81.7 (q, C₂). IR u_maxcm^"1: 3494 (OH), 2926, 2854, 1466, 1128, 966. HRMS: (m/z - El) Calculated for Ci₄H₂₄0 (M)⁺ 208.1827, found 208.1822.

2-Azido-2-ethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclohexane]

[00215] Prepared by the method employed for 2-azido-2-methylspiro[bicyclo[2.2.1]heptane- 3,1'-cyclopentane] using 2-ethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]-2-ol (0.42 g, 2.02 mmol), NaN₃ (0.91 g, 13.99 mmol), 50% H₂S0₄ (5 mL) and chloroform (50 mL) with a reaciton time of 6 hrs to yield a yellow oil was purified via column chromotography (100% hexane, R_f = 0.46) to yield 2-azido-2-ethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclohexane] as a clear colourless liquid. (0.28 g, 59.4 %).¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.95 (3H, t, J = 7.4 Hz, H₉), 1.12- 1.25 (4H, m, H_7a, H_1a, H_2a, H_2b), 1.26-1.39 (3H, m, H_5a, H_6a, H _b), 1.41-1.70 (8H, m, H_5b, H_6b, H_8a, Hr_c, H_2c, H_2d, H_2e, Η_2ΐ ), 1.73-1.88 (3H, m, H_7b, H_8b, H _d), 2.21-2.24 (1H, m, H^, 2.37-2.41 (1H, m, H₄).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 9.5 (C₉), 22.6 (C₆), 23.0 (C₈), 23.1 (C₅), 23.6 (C₂), 24.1 (C₂), 26.0 (C₂), 31.2 (C ), 32.8 (C ), 34.3 (C₇), 41.4 (C₄), 44.7 (d), 49.1 (q, C₃), 77.8 (q, C₂). IRu_maxcrrf¹: 2926, 2858, 2091 (N₃), 1452, 1270, 1135, 878. HRMS: {m/z - ESI) Calculated for Ci₄H₂₄N (M+H-N₂)⁺ 206.1909, found 206.1903.

2-Ethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]-2 -amine

[00216] Prepared by the method employed for 2-methylspiro[bicyclo[2.2.1]heptane-3,1'- cyclopentan]-2-amine using 2-azido-2-ethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclohexane] (0.24 g, mmol), Palladium on charcoal (0.02 g, 10% w/w) and methanol (10 mL) with a reaction time of 12 hours under a hydrogenated atmosphere at atmospheric pressure to yield 2- ethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]-2-amine as a clear colourless oil. (0.15 g, 65.7 %).¹H NMR (CDCI₃, 400 MHz): δ (ppm) 0.92 (3H, t, J = 7.5 Hz, H₉), 1.05-1.43 (8H, m, H_5a, H_6a, H_7a, H-i'a, H-i'b, H2'_a, ^2b, ^2c), 1.44-1.78 (9H, ΓΠ , H₅b, H6b, Hsa, Hsb, Hie H d, H2'd, H2'e, H2'f), 1.79-

1.85 (1H, m, H_7b), 1.89 (1H, br s, H₄), 2.34 (1H, br s, Hi).¹³C NMR (CDCI3, 100 MHz): δ (ppm) 9.1 (C₉), 23.1 (C₅), 23.2 (C₂), 23.8 (C₆), 24.3 (C₂), 26.2 (C₂), 26.7 (C₈), 31.1 (C ), 32.1 (C ),

34.2 (C₇), 41.8 (Ci), 48.4 (C₄), 46.4 (q, C₃), 62.5 (q, C₂). IR u_max cm^"1: 2923, 2857, 1451 , 831. HRMS: {m/z - ESI) Calculated for Ci₄H₂₆N (M+H)⁺ 208.2065, found 208.2067.

2-Ethyl-N-methylspiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]-2 -amine

[00217] Prepared by the method employed for N,2-dimethylspiro[bicyclo[2.2.1]heptane-3,1'- cyclopentan]-2-amine using 2-ethylspiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]-2-amine (0.13 g 0.63 mmol), paraformaldehyde (0.70 g, 2.19 mmol), activated molecular sieves (0.20 g), anhydrous CH₂CI₂ (20 ml_), sodium borohydride (0.11 g, 2.84 mmol) and anhydrous methanol (1 mL) to yield a clear colourless oil. This product was redissolved in anhydrous diethyl ether (3 mL) and a solution of hydrogen chloride (2 M in diethyl ether, 0.5 mL, 1.0 mmol) was added. Filtration afforded the HCI salt of 2-ethyl-N-methylspiro[bicyclo[2.2.1]heptane-3,1'-cyclohexan]- 2-amine as a white solid. (0.47g, 33.7 %). M.p.170-180 °C Decomp.¹H NMR (CDCI₃, 400 MHz): δ (ppm) 1.16 (3H, t, J= 7.3 Hz, H₉), 1.18-1.28 (4H, m, H_6a, H_7a, H_1a, H_2a), 1.35-1.84 (12H, m, H_5a, H₅b, H6b, H_3a, H₃b, H b, H _c, H2b, H2C ^d, H2f), 2.36-2.41 (1H, m, H d), 2.50- 2.56 (2H, m, H₄, H_7b), 2.63-2.66 (1 H, m, Hi), 2.69 (3H, app t, J = 5.4 Hz, H₁₀), 8.56 (1 H, br s, Hue), 8.91 (1H, brs, H_11b).¹³C NMR (CDCI₃, 100 MHz): δ (ppm) 9.4 (C₉), 21.0 (C₈), 22.1 (C₅), 23.4 (C₂), 23.5 (C₆), 23.7 (C₂), 25.7 (C₂), 30.0 (C10), 31.6 (C ), 31.7 (C ), 34.3 (C₇), 42.1 (C₄),

45.3 (Ci), 48.5 (q, C₃), 74.8 (q, C₂). IRu_maxcrrf¹: 2931, 1586, 1452, 1411, 922. HRMS: (m/z- ESI) Calculated for Ci₄H₂₃ (M-NH₂CH₃)⁺ 191.1800, found 191.1808.

Biological Testing

Xenopus oocyte expression and electrophysiological recordings

[00218] Stage V and VI Xenopus oocytes were prepared as previously described (Moroni et al., Mol Pharmacol 70:755-768, 2006 and J. Neurosci., 28(27): 6884-6894, 2008). Wild-type oc4 or β2 subunit cDNAs, ligated into the pCI (Promega) expression vector, were dissolved in distilled water at a concentration of 1 μgμl (spectrophotometric and agarose gel electrophoresis determinations). Mixtures of wild-type oc4 and β2 cDNA at 1:1 ratios were injected into the nuclei of oocytes in a volume of 18.4 nl/oocyte, using a Nanoject Automatic Oocyte Injector (Drummond, Broomall, PA, U.S.A.). The total amount of cDNA injected per oocyte was kept constant at 2 ng. After injection oocytes were incubated at 18 °C for 2-5 days in a modified Barth's solution containing 88 mM NaCI, 1 mM KCI, 2.4 mM NaHC0₃, 0.3 mM Ca(N0₃)₂, 0.41 mM CaCI₂, 0.82 mM MgS0₄, 15 mM Hepes and 5 mg/l neomycin (pH 7.6). Recordings were performed 3-5 days post-injection.

[00219] Oocytes were placed in a 0.1 ml recording chamber and perfused with modified Ringer solution (in mM: NaCI 150, KCI 2.8, Hepes 10, BaCI₂1.8; pH 7.2, adjusted with NaOH)ata rate of 10 ml/min. A nominally Ca²⁺ free solution was chosen in order to minimise the contribution to the response of Ca²⁺-gated chloride channels which are endogenous to the Xenopus oocyte and may be activated by Ca²⁺ entry through the nAChRs, as previously reported (Moroni et al., 2006, supra).

[00220] Oocytes were impaled by two agarose-cushioned microelectrodes filled with 3 M KCI (0.5-2.0 ΜΩ) and voltage-clamped at -60 mV using a Geneclamp 500B amplifier (Axon Instruments, CA, U.S.A.). All experiments were carried out at room temperature. A minimum interval of 4 minutes was allowed between acetylcholine applications as this was found to be sufficient to ensure reproducible recordings. The sensitivity of the receptors to inhibition by the novel nAChR antagonists was tested by first superfusing the antagonist for 2 min and then coapplying it with an EC₅₀ of ACh (α4β2 nAChR EC₅₀:100 μΜ).

Results

Mecamylamine

Derivatives Encfo-mecamylamine

Table 1 : Novel derivatives prepared

[00221] Preliminary testing of the library given in Table 1 was performed by electrophysiological measurements at a single concentration (3μΜ) employing oocytes expressing the low sensitivity α4β2 nAChR. The activity in the presence of each compound was compared to the control, the control was the response elicited by activity of 100 μΜ ACh alone. The results are tabulated in Table 2. Noteably, compound 8 resulted in a complete blockade of the α4β2 nAChR showing very promising antagonist activity. Table 2

[00222] The words "comprises/comprising" and the words "having/including" when used herein with reference to the present invention are used to specify the presence of stated features, integers, steps or components but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

[00223] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Claims

1 . A method of synthesising a compound of formula (la),

the method comprising the steps of:

i) substituting a compound of formula (l la) with R¹ and R² at position 6 to produce a compound of formula (I l ia); and

(lla) (Ilia)

where X can be selected from O, NR⁴ and +N(R⁴)(R⁵);

wherein XZ is OH, NHR⁴ or N(R⁴)(R⁵), and

i) if XZ is OH , replacing the OH group of the compound of formula (IVa) with an amino group of the formula N(R⁴)(R⁵),

R³ is selected from H , C1-C10 aliphatic, C3-C10 cycloaliphatic, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof;

R⁴ is selected from H, C1-C10 aliphatic, C3-C10 cycloaliphatic, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof; R⁵ is selected from H, C1-C10 aliphatic, C₃-Ci₀ cycloaliphatic, C₆-C₂o aromatic, C₂-C₂o heteroaromatic, and combinations thereof; or

N, R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle or a Ci-C₂₀ heteroaromatic.

2. A method of synthesising ),

(I)

the method comprising the steps of:

i) substituting a compound of formula (II) with R¹ and R² at position 6 to

produce a compound of formula III ; an

(II) (III)

where X can be selected from O, NR⁴ and +N(R⁴)(R⁵);

(IV),

wherein XZ is OH, NHR⁴ or N(R⁴)(R⁵), and

R¹ is selected from C1-C10 aliphatic, C₃-Ci₀ cycloaliphatic, C₂-Ci₀ aliphatic heterocycle, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof;

R² is selected from C₁-C₁₀ aliphatic, C₃-Ci₀ cycloaliphatic, C₂-Ci₀ aliphatic heterocycle, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof; or R¹ and R² together with the carbon atom to which they are attached may define a C₃- Cio cycloaliphatic ring or a C₂-Ci₀ aliphatic heterocycle;

R³ is selected from H, C1-C10 aliphatic, C3-C10 cycloaliphatic, C₆-C₂o aromatic, C₂-C₂o heteroaromatic, and combinations thereof;

L is selected from the group consisting of CR¹⁰R¹¹, CR¹⁰R¹¹CR¹²R¹³, and O, wherein R¹⁰, R¹¹, R¹² and R¹³ are the same or different and may be independently selected from H, and Ci-C₆ alkyl; and

wherein the dashed line indicates an optional double bond.

3. A method according to Claim 1 or Claim 2 wherein when X is NR⁴ and R⁵ is not H, the method further comprises the step of replacing the hydrogen of NHR⁴ with R⁵ to give N(R⁴)(R⁵).

4. A method according to Claim 1 wherein the step of substituting a compound of formula (lla) with R¹ and R² at position 6 to produce a compound of formula (Ilia) is stereoselective.

5. A method according to Claim 2 wherein the step of substituting a compound of formula (II) with R¹ and R² at position 6 to produce a compound of formula (III) is stereoselective.

6. A method according to Claim 1 or Claim 2 wherein X is selected from NR⁴ and +N(R⁴)(R⁵).

7. A method according to anyone of Claims 1 to 6 wherein when X is NR⁴ or +N(R⁴)(R⁵) the step of adding R³ to the carbon of the C=NR⁴ or C=N(R⁴)(R⁵)+ group of the compound of formula (III) to provide a compound of the general formula (IV) is stereoselective for the endo isomer.

8. A compound of the general formula (I): R

N(R⁴)(R⁵)

(I)

wherein: R¹ is selected from C1-C1₀ aliphatic, C₃-Ci₀ cycloaliphatic, C₂-Ci₀ aliphatic heterocycle, C₆-C₂o aromatic, C₂-C₂o heteroaromatic, and combinations thereof;

provided that

i) when R¹= R² = R⁴ = Me and R⁵ = H, R³ is not H or C C₃ alkyl;

ii) when R¹= R² = R³ = Me and R⁵ = H, R⁴ is not H, C(0)(C C₅ alkyl), C(0)CH₂Ph, C(0)CH₂CH₂Ph, C C₈ alkyl, CH(CH₃)₂, CH₂CH₂C(CH₃)₃,

CH₂CH=CH₂, CH₂Ph, CH₂CH₂Ph or CH₂CH₂CH₂Ph; and

9. A compound according to Claim 8

R¹ is selected from C1-C10 aliphatic, and C₃-Ci₀ cycloaliphatic;

R² is selected from C1-C10 aliphatic, and C₃-Ci₀ cycloaliphatic;

R³ is selected from H, C1-C10 aliphatic, and C₃-Ci₀ cycloaliphatic; R⁴ is selected from H, C₁-C₁₀ aliphatic, and C₃-Ci₀ cycloaliphatic;

R⁵ is selected from H, C₁-C₁₀ aliphatic, and C₃-Ci₀ cycloaliphatic; or N, R⁴ and R⁵ may together define a C₂-C₁₀ aliphatic heterocycle or a C10 heteroaromatic,

provided that

i) when R¹= R² = R⁴ = Me and R⁵ = H, R³ is not H or C C₃ alkyl;

10.A compound according to Claim 8 of the formula:

R¹ is selected from C1-C10 aliphatic;

R² is selected from C1-C10 aliphatic;

R³ is selected from H, and C₁-C₁₀ aliphatic;

R⁴ is selected from H, and C₁-C₁₀ aliphatic;

R⁵ is selected from H, and C₁-C₁₀ aliphatic; or

N, R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle or a C C10 heteroaromatic,

provided that

i) when R¹= R² = R⁴ = Me and R⁵ = H, R³ is not H or C C₃ alkyl;

1 1.A compound according to any one of Claims 8 to 10, wherein when R¹ and R² are the same they are not Me.

12. A compound according to any one of Claims 8 to 1 1 , wherein the compound is the exo isomer of formula (la), the endo isomer of general formula (lb), or a combination thereof:

13. A pharmaceutical composition comprising a compound according to any one of Claims 8 to 12 and a pharmaceutically acceptable carrier.

14. A compound according to any one of Claims 8 to 12 for use in the treatment of a condition responsive to antagonism of a nicotinic acetylcholine receptor.

15. A compound according to any one of Claims 8 to 12 for use in the treatment of a condition selected from substance addiction, aiding smoking cessation, treating weight gain associated with smoking cessation, attention deficit hyperactivity disorder (ADHD), psychosis, respiratory disorders, insomnia, alzheimer's disease, hypertension, hypertensive crisis, Tourette's Syndrome and other tremors, cancer, atherogenic profile, depression, anxiety, chronic fatigue syndrome, gastrointestinal disorders, inflammatory bowel disease, ulcerative colitis, Crohn's disease, autonomic dysreflexia, and spasmogenic intestinal disorders.

16. A compound according to any one of Claims 8 to 12 for use in the treatment of depression.

17. A pharmaceutical composition comprising endo mecamylamine of the formula (lc), a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, an amide thereof, or a prodrug thereof,

18. A method of synthesising a compound of formula (I),

the method comprising the steps of:

i) providing a compound of the general formula (V):

where X can be selected from O, NR⁴ and +N(R⁴)(R⁵)

ii) adding R¹ to the three membered heterocyclic ring to provide a ring

opened compound of the general formula (IV),

wherein XZ is OH, NHR⁴ or N(R⁴)(R⁵), and

wherein,

R¹ is selected from C1-C10 aliphatic, C₃-Ci₀ cycloaliphatic, C₂-Ci₀ aliphatic

heterocycle, C₆-C₂o aromatic, C₂-C₂o heteroaromatic, and combinations thereof;

R⁵ is selected from H, C1-C10 aliphatic, C3-C10 cycloaliphatic, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof; or N, R⁴ and R⁵ may together define a C₂-Ci₀ aliphatic heterocycle or a C₁-C₂₀ heteroaromatic;

wherein the dashed line indicates an optional double bond.

19. A method of synthesising (la),

the method comprising the steps of:

i) providing a compound of the general formula (Va),

where X can be selected from O, NR⁴ and +N(R⁴)(R⁵);

wherein XZ is OH, NHR⁴ or N(R⁴)(R⁵); and

iii) if XZ is OH, replacing the OH group of the compound of formula (IVa) with an amino group of the formula N(R⁴)(R⁵),

wherein,

R² is selected from C₁-C₁₀ aliphatic, C₃-Ci₀ cycloaliphatic, C₂-Ci₀ aliphatic heterocycle, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof; or

R¹ and R² together with the carbon atom to which they are attached may define a C₃- C₁₀ cycloaliphatic ring or a C₂-Ci₀ aliphatic heterocycle; R³ is selected from H, C1-C10 aliphatic, C₃-Ci₀ cycloaliphatic, C₆-C₂o aromatic, C₂-C₂o heteroaromatic, and combinations thereof;

R⁴ is selected from H, C1-C10 aliphatic, C₃-Ci₀ cycloaliphatic, C₆-C₂o aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof;

R⁵ is selected from H, C1-C10 aliphatic, C₃-Ci₀ cycloaliphatic, C₆-C₂₀ aromatic, C₂-C₂₀ heteroaromatic, and combinations thereof; or