US20070203111A1

US20070203111A1 - Cycloalkylamines as monoamine reuptake inhibitors

Info

Publication number: US20070203111A1
Application number: US11/649,927
Authority: US
Inventors: Liming Shao; Fengjiang Wang; Scott Malcolm; Michael Hewitt; Larry Bush; Jianguo Ma; Mark Varney; Una Campbell; Sharon Engel; Larry Hardy; Patrick Koch; John Campbell
Original assignee: Sepracor Inc
Current assignee: Sunovion Pharmaceuticals Inc
Priority date: 2006-01-06
Filing date: 2007-01-05
Publication date: 2007-08-30
Also published as: CN101394847B; BRPI0706365A2; ZA200806145B; JP5432526B2; AU2007205114B2; RU2430913C2; US20180230120A1; KR101294014B1; IL192613A0; EP1976513A2; JP2009531277A; JP2013209390A; NZ569630A; US9868718B2; US20100190861A1; CA2636324A1; US10562878B2; KR20080083201A; AU2007205114A1; EP1976513A4

Abstract

The invention relates to novel cyclohexylamine derivatives and their use in the treatment and/or prevention of central nervous system (CNS) disorders, such as depression, anxiety, schizophrenia and sleep disorder as well as methods for their synthesis. The invention also relates to pharmaceutical compositions containing the compounds of the invention, as well as methods of inhibiting reuptake of endogenous monoamines, such as dopamine, serotonin and norepinephrine from the synaptic cleft and methods of modulating one or more monoamine transporter.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 60/756,550 filed Jan. 6, 2006, which application is incorporated herein by reference in its entirety for all purposes.

FIELD OF THE INVENTION

The invention relates to compounds and compositions for the treatment of central nervous system (CNS) disorders.

BACKGROUND OF THE INVENTION

Psychiatric disorders are pathological conditions of the brain characterized by identifiable symptoms that result in abnormalities in cognition, emotion, mood, or affect. These disorders may vary in severity of symptoms, duration, and functional impairment. Psychiatric disorders afflict millions of people worldwide resulting in tremendous human suffering and economic burden due to lost productivity and dependent care.
Over the past several decades, the use of pharmacological agents to treat psychiatric disorders has greatly increased, largely due to research advances in both neuroscience and molecular biology. In addition, chemists have become increasingly sophisticated at creating chemical compounds that are more effective therapeutic agents with fewer side effects, targeted to correct the biochemical alterations that accompany mental disorders.
Yet, despite the many advances that have occurred, many psychiatric diseases remain untreated or inadequately treated with current pharmaceutical agents. In addition, many of the current agents interact with molecular targets not involved with the psychiatric disease. This indiscriminate binding can result in side effects that can greatly influence the overall outcome of therapy. In some cases the side effects are so severe that discontinuation of therapy is required.
Depression is an affective disorder, the pathogenesis of which cannot be explained by any single cause or theory. It is characterized by a persistently low mood or diminished interests in one's surroundings, accompanied by at least one of the following symptoms: reduced energy and motivation, difficulty concentrating, altered sleep and appetite, and at times, suicidal ideation (American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed. 4. Washington, American Psychiatric Association, 1994). Major depression is associated with high rates of morbidity and mortality, with suicide rates of 10-25% (Kaplan H I, Sadock B J (eds): Synopsis of Psychiatry. Baltimore, Williams & Wilkins, 1998, p. 866). The compounds of the invention may also be used to reduce fatigue commonly associated with depression (see, for example, “Bupropion augmentation in the treatment of chronic fatigue syndrome with coexistent major depression episode” Schonfeldt-Lecuona et al., Pharmacopsychiatry 39(4):152-4, 2006; “Dysthymia: clinical picture, extent of overlap with chronic fatigue syndrome, neuropharmacological considerations, and new therapeutic vistas” Brunello et al., J. Affect. Disord. 52 (1-3):275-90, 1999; “Chronic fatigue syndrome and seasonal affective disorder: comorbidity, diagnostic overlap, and implications for treatment” Terman et al., Am. J. Med. 105 (3A):115S-124S, 1998).
Depression is believed to result from dysfunction in the noradrenergic or serotonergic systems, more specifically, from a deficiency of certain neurotransmitters (NTs) at functionally important adrenergic or serotonergic receptors.
Neurotransmitters produce their effects as a consequence of interactions with specific receptors. Neurotransmitters, including norepinephrine (NE) and/or serotonin (5-hydroxytryptamine, or 5-HT), are synthesized in brain neurons and stored in vesicles. Upon a nerve impulse, NTs are released into the synaptic cleft, where they interact with various postsynaptic receptors. Regional deficiencies in the synaptic levels of 5-HT and/or NE are believed to be involved in the etiology of depression, wakefulness, and attention.
Norepinephrine is involved in regulating arousal, dreaming, and moods. Norepinephrine can also contribute to the regulation of blood pressure, by constricting blood vessels and increasing heart rate.
Serotonin (5-HT) is implicated in the etiology or treatment of various disorders. The most widely studied effects of 5-HT are those on the CNS. The functions of 5-HT are numerous and include control of appetite, sleep, memory and learning, temperature regulation, mood, behavior (including sexual and hallucinogenic behavior), cardiovascular function, smooth muscle contraction, and endocrine regulation. Peripherally, 5-HT appears to play a major role in platelet homeostasis and motility of the GI tract. The actions of 5-HT are terminated by three major mechanisms: diffusion; metabolism; and reuptake. The major mechanism by which the action of 5-HT is terminated is by reuptake through presynaptic membranes. After 5-HT acts on its various postsynaptic receptors, it is removed from the synaptic cleft back into the nerve terminal through an uptake mechanism involving a specific membrane transporter in a manner similar to that of other biogenic amines. Agents that selectively inhibit this uptake increase the concentration of 5-HT at the postsynaptic receptors and have been found to be useful in treating various psychiatric disorders, particularly depression.
Approaches to the treatment of depression over the years have involved the use of agents that increase the levels of NE and 5-HT, either by inhibiting their metabolism (e.g., monoamine oxidase inhibitors) or reuptake (e.g., tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRIs)).
There are more than twenty approved antidepressant drugs available in the United States. The classical tricyclic antidepressants (TCAs) currently available block primarily the uptake of NE and also, to varying degrees, the uptake of 5-HT, depending on whether they are secondary or tertiary amines. Tertiary amines such as imipramine and amitriptyline are more selective inhibitors of the uptake of 5-HT than of catecholamines, compared with secondary amines such as desipramine.
Selective serotonin reuptake inhibitors have been investigated as potential antidepressants. Fluoxetine (PROZAC®), sertraline (ZOLOFT®), and paroxetine (PAXIL®) are three examples of SSRIs currently on the U.S. market. These agents do not appear to possess greater efficacy than the TCAs, nor do they generally possess a faster onset of action; however, they do have the advantage of causing less side-effects. Of these three SSRIs, paroxetine is the most potent inhibitor of 5-HT uptake, fluoxetine the least. Sertaline is the most selective for 5-HT versus NE uptake, fluoxetine the least selective. Fluoxetine and sertraline produce active metabolites, while paroxetine is metabolized to inactive metabolites. The SSRIs, in general, affect only the uptake of serotonin and display little or no affinity for various receptor systems including muscarinic, adrenergic, dopamine, and histamine receptors.
In addition to treating depression, several other potential therapeutic applications for SSRIs have been investigated. They include treatment of Alzheimer's disease, aggressive behavior, premenstrual syndrome, diabetic neuropathy, chronic pain, fibromyalgia, and alcohol abuse. For example, fluoxetine is approved for the treatment of obsessive-compulsive disorder (OCD). Of particular significance is the observation that 5-HT reduces food consumption by increasing meal-induced satiety and reducing hunger, without producing the behavioral effects of abuse liability associated with amphetamine-like drugs. Thus, there is interest in the use of SSRIs in the treatment of obesity.
Venlafaxine (EFFEXOR®) is a dual-reuptake antidepressant that differs from the classical TCAs and the SSRIs chemically and pharmacologically in that it acts as a potent inhibitor of both 5-HT and NE uptake. Neither venlafaxine nor its major metabolite have a significant affinity for adrenergic alpha-1 receptors. Venlafaxine possesses an efficacy equivalent to that of the TCAs, and a benign side effect profile similar to those of the SSRIs.
Dopamine is hypothesized to play a major role in psychosis and certain neurodegenerative diseases, such as Parkinson's disease, where a deficiency in dopaminergic neurons is believed to be the underlying pathology. Dopamine affects brain processes that control movement, emotional response, and ability to experience pleasure and pain. Regulation of DA plays a crucial role in our mental and physical health. Certain drugs increase DA concentrations by preventing DA reuptake, leaving more DA in the synapse. An example is methylphenidate (RITALIN®), used therapeutically to treat childhood hyperkinesias and symptoms of schizophrenia. Dopamine abnormalities are believed to underlie some of the core attentional abnormalities seen in acute schizophrenics.
A therapeutic lag is associated with the use of these drugs. Patients must take a drug for at least three (3) weeks before achieving clinically meaningful symptom relief. Furthermore, a significant number of patients do not respond to current therapies at all. For example, it is currently estimated that up to thirty percent (30%) of clinically diagnosed cases of depression are resistant to all forms of drug therapy.

SUMMARY OF THE INVENTION

The present invention relates to novel cycloalkylamines and salts thereof. It further relates to novel pharmaceutical compositions, and their use in the treatment of CNS disorders such as depression (e.g., major depressive disorder, bipolar disorder), fibromyalgia, pain (e.g., neuropathic pain), sleep apnea, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), restless leg syndrome, schizophrenia, anxiety, obsessive compulsive disorder, posttraumatic stress disorder, seasonal affective disorder (SAD), premenstrual dysphoria as well as neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease).
Hence, in a first aspect the invention provides a compound having a structure according to Formula (I):
In Formula (I), n is an integer from 0 to 2; s is an integer from 1 to 3. The integer m is selected from 0 to 12. When n is 0, m is preferably not greater than 8; when n is 1, m is preferably not greater than 10. Ar is a member selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and a fused ring system.
Each X is an independently selected alkyl group substitutent. In an exemplary embodiment, each X is a member independently selected from the group consisting of H, halogen, CN, CF₃, OR⁵, SR⁵, acyl, C(O)OR⁵, C(O)NR⁶R⁷, S(O)₂R⁵, S(O)₂NR⁶R⁷, NR⁶R⁷, NR⁶S(O)₂R⁵, NR⁶C(O)R⁵, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, wherein each R⁵, R⁶and R⁷is a member independently selected from the group consisting of H, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, wherein two of R⁵, R⁶and R⁷, together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring.
Each R¹and R²is an independently selected alkyl group substitutent. In an exemplary embodiment, each R¹and R²is a member independently selected from the group consisting of H, halogen, CN, CF₃, OR⁸, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, wherein R⁸is a member selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
R³and R⁴are members independently selected from the group consisting of H, OR⁹, acyl, C(O)OR⁹, S(O)₂R⁹, ═N═N, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl. When one member of R³and R⁴is ═N═N, the other member is preferably not present. R⁹is a member selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
At least two of R¹, R², R³, R⁴and any of the substitutents X, together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring.
Any pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemic mixture, enantiomerically enriched mixture, and enantiomerically pure form of the above described compounds falls within the scope of the invention.
In a second aspect, the invention provides a pharmaceutical composition including a compound of the invention or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
In a third aspect, the invention provides a method of inhibiting binding of a monoamine transporter ligand to a monoamine transporter, such as serotonin transporter, dopamine transporter and norepinephrine transporter. The method includes contacting the monoamine transporter and a compound of the invention. In an exemplary embodiment the monoamine transporter ligand is a monoamine, such as serotonin, dopamine and norepinephrine.
In a fourth aspect, the invention provides a method of inhibiting the activity of at least one monoamine transporter, such as serotonin transporter, dopamine transporter and norepinephrine transporter. The method includes contacting the monoamine transporter and a compound of the invention.
In another aspect, the invention provides a method of inhibiting uptake of at least one monoamine, such as serotonin, dopamine and norepinephrine, by a cell. The method includes contacting the cell with a compound of the invention. In an exemplary embodiment, the cell is a brain cell, such as a neuronal cell or a glial cell.
In yet another aspect, the invention provides a method of treating depression by inhibiting the activity at least one monoamine transporter. The method includes administering to a mammalian subject a compound of the invention. In a preferred embodiment, the compound of the invention inhibits the activity of at least two different monoamine transporters. In another preferred embodiment, the mammalian subject is a human.
In a further aspect, the invention provides a method of treating a central nervous system disorder. The method includes administering to a subject in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof. In a preferred embodiment, the subject is a human.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions
The term “alkyl,” by itself or as part of another substitutent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C₁-C₁₀means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The term “alkyl,” unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below, such as “heteroalkyl.” Alkyl groups that are limited to hydrocarbon groups are termed “homoalkyl”.
The term “alkylene” by itself or as part of another substitutent means a divalent radical derived from an alkane, as exemplified, but not limited, by —CH₂CH₂CH₂CH₂—, and further includes those groups described below as “heteroalkylene.” Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃and —CH₂—O—Si(CH₃)₃. Similarly, the term “heteroalkylene” by itself or as part of another substitutent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, —CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula —CO₂R′— represents both —C(O)OR′ and —OC(O)R′.
The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
The terms “halo” or “halogen,” by themselves or as part of another substitutent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C₁-C₄)alkyl” is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, substitutent that can be a single ring or multiple rings (preferably from 1 to 3 rings), which are fused together or linked covalently. The term “heteroaryl” refers to aryl groups (or rings) that contain from one to four heteroatoms selected from N, O, S, Si and B, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substitutents described below.
For brevity, the term “aryl” when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term “arylalkyl” is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).
Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and “heteroaryl”) are meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substitutents for each type of radical are provided below.
Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are generically referred to as “alkyl group substitutents,” and they can be one or more of a variety of groups selected from, but not limited to: substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and —NO₂in a number ranging from zero to (2m′+1), where m′ is the total number of carbon atoms in such radical. R′, R″, R′″ and R″″ each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″ and R″″ groups when more than one of these groups is present. When R′ and R″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substitutents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., —CF₃and —CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).
Similar to the substitutents described for the alkyl radical, substitutents for the aryl and heteroaryl groups are generically referred to as “aryl group substitutents.” The substitutents are selected from, for example: substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R′, R″, R′″ and R″″ are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″ and R″″ groups when more than one of these groups is present.
Two of the substitutents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substitutent of the formula -T-C(O)—(CRR′)_q—U—, wherein T and U are independently —NR—, —O—, —CRR′— or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substitutents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substitutent of the formula -A-(CH₂)_r-D-, wherein A and D are independently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substitutents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substitutent of the formula —(CRR′)_s—X″—(CR″R′″)_d—, where s and d are independently integers of from 0 to 3, and X″ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—. The substitutents R, R′, R″ and R′″ are preferably independently selected from hydrogen or substituted or unsubstituted (C₁-C₆)alkyl.
As used herein, the term “acyl” describes a substitutent containing a carbonyl residue, C(O)R′. Exemplary species for R include H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl.
As used herein, the term “fused ring system” means at least two rings, wherein each ring has at least 2 atoms in common with another ring. “Fused ring systems may include aromatic as well as non aromatic rings. Examples of “fused ring systems” are naphthalenes, indoles, quinolines, chromenes and the like.
As used herein, the term “heteroatom” includes oxygen (O), nitrogen (N), sulfur (S), silicon (Si) and boron (B).
The symbol “R” is a general abbreviation that represents a substitutent group that is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl groups.
The phrase “therapeutically effective amount” as used herein means that amount of a compound, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect (e.g., by inhibiting uptake of a monoamine from the synaptic cleft of a mammal, thereby modulating the biological consequences of that pathway in the treated organism) at a reasonable benefit/risk ratio applicable to any medical treatment.
The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The phrase “pharmaceutically acceptable carrier” as used herein means any pharmaceutically acceptable material, which may be liquid or solid. Exemplary carriers include vehicles, diluents, additives, liquid and solid fillers, excipients, solvents, solvent encapsulating materials. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.
As set out above, certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term “pharmaceutically acceptable salts” in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification. Representative salts include the hydrobromide, hydrochloride, sulfate, sulfamate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, tosylate, citrate, maleate, ascorbate, palmitate, fumarate, succinate, tartrate, napthylate, mesylate, hydroxymaleate, phenylacetate, glutamate, glucoheptonate, salicyclate, sulfanilate, 2-acetoxybenzoate, methanesulfonate, ethane disulfonate, oxalate, isothionate, lactobionate, and laurylsulphonate salts and the like. See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19.
The term “pharmaceutically acceptable salts” includes salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substitutents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., Journal of Pharmaceutical Science, 66: 1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
In addition to salt forms, the present invention provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention. “Compound or a pharmaceutically acceptable salt or solvate of a compound” intends the inclusive meaning of “or”, in that a material that is both a salt and a solvate is encompassed.
Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the present invention. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr, J. Chem. Ed., 62: 114-120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but not implying any absolute stereochemistry; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration.
The terms “enantiomeric excess” and “diastereomeric excess” are used interchangeably herein. Compounds with a single stereocenter are referred to as being present in “enantiomeric excess,” those with at least two stereocenters are referred to as being present in “diastereomeric excess.”
The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
The term “monoamine transporter ligand” refers to any compound, which binds to a monoamine transporter. Ligands include endogenous monoamines, which are the natural ligands for a given monoamine transporter as well as drug molecules and other compounds, such as synthetic molecules known to bind to a particular monoamine transporter. In one example, the ligand includes a radioisotope, such as tritium or is otherwise (e.g., fluorescently) labeled. It is within the abilities of a skilled person to select an appropriate ligand for a given monoamine transporter. For example, known ligands for the dopamine transporter include dopamine and WIN35428, known ligands for the serotonin transporter include 5-hydroxytryptamine (serotonin) and citalopram, and ligands for the norepinephrine transporter include norepinephrine and nisoxetine.
The term “central nervous system disorder” refers to any abnormal condition of the central nervous system of a mammal. Central nervous system disorder includes neurodegenerative diseases such Alzheimer's disease and Parkinson's disease, neuropsychiatric diseases (e.g. schizophrenia), anxieties, sleep disorders, depression, dementias, movement disorders, psychoses, alcoholism, post-traumatic stress disorder and the like. “Central nervous system disorder” also includes any condition associated with the disorder, such as loss of memory and/or loss of cognition. For instance, a method of treating a neurodegenerative disease would also include treating or preventing loss of neuronal function characteristic of such disease. “Central nervous system disorder” also includes any disease or condition that is implicated, at least in part, in monoamine (e.g., norepinephrine) signaling pathways (e.g., cardiovascular disease).
The term “pain” refers to all categories of pain, including pain that is described in terms of stimulus or nerve response, e.g., somatic pain (normal nerve response to a noxious stimulus) and neuropathic pain (abnormal response of a injured or altered sensory pathway, often without clear noxious input); pain that is categorized temporally, e.g., chronic pain and acute pain; pain that is categorized in terms of its severity, e.g., mild, moderate, or severe; and pain that is a symptom or a result of a disease state or syndrome, e.g., inflammatory pain, cancer pain, AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiac ischaemia, and diabetic neuropathy (see, e.g., Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al., eds., 12th ed. 1991); Williams et al., J. of Med. Chem. 42: 1481-1485 (1999), herein each incorporated by reference in their entirety). “Pain” is also meant to include mixed etiology pain, dual mechanism pain, allodynia, causalgia, central pain, hyperesthesia, hyperpathia, dysesthesia, and hyperalgesia.
The term “depression” includes all forms of depression, which include major depressive disorder (MDD), bipolar disorder, seasonal affective disorder (SAD) and dysthymia. “Major depressive disorder” is used herein interchangeably with “unipolar depression” and “major depression. “Depression” also includes any condition commonly associated with depression, such as all forms of fatigue (e.g., chronic fatigue syndrome) and cognitive deficits.
II. Introduction
One strategy to develop effective therapies is the use of broad spectrum antidepressants that simultaneously inhibit the reuptake of more than one biogenic amine, such as serotonin (5-HT), norepinephrine (NE) and dopamine (DA). The rationale for this approach is based upon clinical and preclinical evidence showing that deficiencies in dopaminergic function can be correlated with anhedonia, which is a core symptom of depression. Baldessarini, R. J., “Drugs and the Treatment of Psychiatric Disorders: Depression and Mania, in Goodman and Gilman's The Pharmacological Basis of Therapeutics 431-459 (9^thed 1996) Hardman et al. eds.
An advantage of the compounds and compositions of the present invention is their ability to increase synaptic availability of at least two neurotransmitters (e.g., NE, 5-HT and DA) by inhibiting their (re)uptake from the synaptic cleft. Skolnick and coworkers report on a body of preclinical evidence suggesting that the therapeutic profile of an antidepressant concurrently increasing the synaptic availability of DA, NE and 5-HT will differ from a compound inhibiting only NE and/or 5-HT. Skolnick, P. et al., “Antidepressant-like actions of DOV-21,947: a “triple” reuptake inhibitor,” Eur. J. Pharm. 2003, 461, 103.
For example, Skolnick and coworkers have reported that a compound, DOV 21,947 ((+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane), inhibits the reuptake of serotonin, norepinephrine, and dopamine in human embryonic kidney (HEK293) cells expressing the corresponding human recombinant transporters (IC₅₀values of 12, 23 and 96 nM, respectively). Skolnick, P. et al., “Antidepressant-like actions of DOV-21,947: a “triple” reuptake inhibitor,” Eur. J. Pharm. 2003, 461, 99. In addition, DOV 21,947 reduces the duration of immobility in the forced swim test (in rats) and also produces a dose-dependent reduction in immobility in the tail suspension test. Additional evidence can be found in preclinical data for new triple reuptake inhibitors such as DOV 21,947 in, e.g., U.S. Pat. No. 6,372,919, wherein DOV 21,947 was disclosed as having a significantly greater affinity for the norepinephrine and serotonin uptake sites than the racemic compound, (±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.
Taken together, the preclinical data for compounds such as DOV 21,947 indicate that dual or triple reuptake inhibitors may hold potential as novel treatments for depression in the clinic.
III. Compositions
A. Cycloalkyl Amines
In a first aspect, the invention provides a compound having a structure according to Formula (I):
In Formula (I), n is an integer from 0 to 2. Hence, in one embodiment, the invention provides cyclopentyl-, cyclohexyl- and cycloheptylamines. The integer s is selected from 0 to 3, preferably from 1 to 2. In a particularly preferred embodiment, s is 1. The integer m is selected from 0 to 12. When n is 0, m is preferably not greater than 8; when n is 1, m is preferably not greater than 10. Ar is a member selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and a fused ring system.
Each X is a member independently selected from an alkyl group substitutent. In an exemplary embodiment, each X is a member independently selected from the group consisting of H, halogen, CN, CF₃, OR⁵, SR⁵, acyl, C(O)OR⁵, C(O)NR⁶R⁷, S(O)₂R⁵, S(O)₂NR⁶R⁷, NR⁶R⁷, NR⁶S(O)₂R⁵, NR⁶C(O)R⁵, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl. Each R⁵, R⁶and R⁷is a member independently selected from the group consisting of H, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, wherein two of R⁵, R⁶and R⁷, together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring.
Each R¹and R²is an independently selected alkyl group substitutent. In an exemplary embodiment, each R¹and R²is a member independently selected from the group consisting of H, halogen, CN, CF₃, OR⁸, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, wherein R⁸is a member selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
In one embodiment, R³and R⁴are members independently selected from the group consisting of H, OR⁹, acyl, C(O)OR⁹, S(O)₂R⁹, ═N═N, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl. When one member of R³and R⁴is ═N═N, the other member is preferably not present. R⁹is a member selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.
At least two of R¹, R², R³, R⁴and any substitutent X, together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring. In an exemplary embodiment, two substitutents X, together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring. In another exemplary embodiment, R³and R⁴are joined to form a ring, such as a morpholine, N-methyl-piperazine and the like. In another exemplary embodiment, R¹and R³are joined to form a ring, such as a pyrrolidine ring. In yet another exemplary embodiment, at least one of R¹, R², R³and R⁴is optionally joined with the Ar group or a substitutent on the Ar group to form a 5- to 7-membered ring. An exemplary structure, in which Ar-s substituted phenyl and R³is joined with Ar to form a 6-membered ring is provided below:

wherein Y and Z are as defined below.
In an especially preferred embodiment, the integer s in Formula (I) is 1. Exemplary compounds according to this embodiment have a Formula, which is a member selected from Formula (II) and Formula (III):
In an exemplary embodiment, the cycloalkyl ring is mono- or disubstituted at either the 2-, 3-, or 4-position. Exemplary compounds according to this embodiment have a Formula, which is a member selected from the group consisting of:

wherein X¹and X²are alkyl group substitutents. In an exemplary embodiment, X¹and X²are each defined as the substitutent X, above. In another exemplary embodiment, X¹and X²are members independently selected from the group consisting of H, OR⁵, SR⁵, halogen, CN, CF₃, S(O)₂R⁵, NR⁶R⁷, NR⁶S(O)₂R⁵, NR⁶C(O)R⁵, acyl, substituted or unsubstituted C₁-C₄alkyl and substituted or unsubstituted C₁-C₄heteroalkyl, wherein at least two of R¹, R³, R⁴, X¹and X², together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring.
In a preferred embodiment, X¹and X²are members independently selected from H, methyl, ethyl, propyl, OR⁵(e.g., OH, OMe, OEt, OPh), CH₂OR⁵(e.g., CH₂OH), halogen substituted alkyl (e.g., CF₃, CH₂F), halogen (e.g., F or Cl) and CN. In another preferred embodiment, R¹is a member selected from H and substituted or unsubstituted C₁-C₄alkyl. In yet another preferred embodiment, R³and R⁴are members independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl, such as substituted or unsubstituted C₁-C₄alkyl or substituted or unsubstituted C₁-C₄heteroalkyl. In one example, R³and R⁴, together with the nitrogen atom to which they are attached, are joined to form a 3- to 7-membered ring, such as a morpholine, piperidine, pyrrolidine or N-alkyl-piperazine moiety.
In another embodiment, the compound of the invention includes a cyclobutyl ring. An exemplary structure is provided below in Formula (IV):

wherein the integer q is selected from 0 to 6.
Aryl Group Substituent (Ar)
In one embodiment, Ar is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and a fused ring system. Preferably, Ar is a member selected from substituted or unsubstituted phenyl and substituted or unsubstituted naphthyl, including 1-naphthyl and 2-naphthyl analogs. Hence, in one embodiment, Ar is a member selected from:

wherein Y, Z, Y¹and Z¹are members independently selected from aryl group substitutents. In an exemplary embodiment, Y, Z, Y¹and Z¹are members independently selected from H, halogen, CF₃, CN, OR¹¹, SR¹¹, NR¹²R¹³, NR¹²S(O)₂R¹¹, NR¹²C(O)R¹¹, S(O)₂R¹¹, acyl, C(O)OR¹¹, C(O)NR¹²R¹³, S(O)₂NR¹²R¹³, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl. Each R¹¹, R¹²and R¹³is a member independently selected from the group consisting of H, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, wherein two of R¹¹, R¹²and R¹³, together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring.
Two of Y, Z, Y¹and Z¹, together with the atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring, such as a dioxolyl ring. In another exemplary embodiment, Y, Z, Y¹and Z¹are members independently selected from the group consisting of H, halogen, CN, halogen substituted C₁-C₄alkyl (e.g., CF₃) and C₁-C₄alkoxy (e.g., OMe, OEt, OCF₃).
In yet another exemplary embodiment, Ar is a 3,4-disubstituted phenyl moiety and has the structure:
In a preferred embodiment, Y and Z, in the structure above, are members independently selected from H, halogen, CN, CF₃and OR¹⁶(e.g., OMe, OEt, OCF₃). In a particular preferred embodiment, Y and Z are both halogen. In an exemplary embodiment, Ar in any of the structures above is 3,4-dichlorophenyl.
Exemplary compounds according to the above described embodiments are provided below:
In an exemplary embodiment, in the structures above, R¹, R³and R⁴are independently selected from H and C₁to C₄alkyl (e.g., methyl) and X¹and X²are independently selected from H, OH, OMe, methyl, ethyl, CH₂OH, halogen (e.g., Cl and F), CN and CF₃.
The compounds of the invention include an amine moiety (e.g., a primary, secondary or tertiary amino group) and as such can be converted into a salt form by contacting the compound (e.g., the free base) with an acid. In an exemplary embodiment, the salt form is generated to convert an otherwise oily or viscous compound into a solid substance for easier handling. In another exemplary embodiment, converting the free base of a compound of the invention into a corresponding salt increases solubility of the compound in aqueous media, which can effect biological characteristics, such as bioavailability, pharmacokinetics and pharmacodynamics. Hence, any salt forms, such as pharmaceutically acceptable salts, including salts of inorganic acids (e.g., hydrochloride salts) or organic acids, of the compounds of the invention are within the scope of the current invention. Also within the scope of the invention are any prodrugs of the compounds of the invention. For example, R³and R⁴can be any group, which is cleavable in vivo to result in an amine, such as a primary or secondary amine.
In another embodiment, the invention provides synthetic precursors for the cycloalkylamines of the invention. For example, a large subset of the currently provided amines can be synthesized via the corresponding nitrile (e.g., by reduction) or the corresponding aldehyde (e.g., by reductive amination). Thus, the invention provides compounds having a structure selected from the following Formulae:

wherein p is an integer selected from 0 to 2. Ar, R¹, R², X and the integers m and n are as defined above. In a preferred embodiment p is 0.
In another embodiment, the invention provides cycloalkylamines, wherein the cycloalkyl ring includes one or more double bonds. Exemplary compounds are shown below:

wherein the integer r is selected from 0 to 8 and t is selected from 0 to 6.
B. Compositions Including Stereoisomers
The compound of the invention can include one or more stereocenter and may exist in particular geometric or stereoisomeric forms. Compounds can be chiral, racemic or be present in a composition including one or more stereoisomer. The current invention encompasses any enantiomer, diastereomer, racemic mixtures, enantiomerically enriched mixtures, and diastereomerically enriched mixture as well as any enantiomerically or diastereomerically (essentially) pure forms of the compounds of the invention. The invention contemplates cis- and trans-isomers, (−)- and (+)-enantiomers, (D)-isomers, (L)-isomers, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substitutent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as an amino group, or an acidic functional group, such as a carboxyl group, diastereomeric salts may be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers. In addition, separation of enantiomers and diastereomers is frequently accomplished using chromatography employing chiral, stationary phases, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).
As used herein, the term “enantiomerically enriched” or “diastereomerically enriched” refers to a compound having an enantiomeric excess (ee) or a diastereomeric excess (de) greater than about 50%, preferably greater than about 70% and more preferably greater than about 90%. In general, higher than about 90% enantiomeric or diastereomeric purity is particularly preferred, e.g., those compositions with greater than about 95%, greater than about 97% and greater than about 99% ee or de.
The terms “enantiomeric excess” and “diastereomeric excess” are used interchangeably herein. Compounds with a single stereocenter are referred to as being present in “enantiomeric excess”, those with at least two stereocenters are referred to as being present in “diastereomeric excess”.
For example, the term “enantiomeric excess” is well known in the art and is defined as: ${ee}_{a} = (\frac{conc . of a - conc . of b}{conc . of a + conc . of b}) \times 100$
The term “enantiomeric excess” is related to the older term “optical purity” in that both are measures of the same phenomenon. The value of ee will be a number from 0 to 100, zero being racemic and 100 being enantiomerically pure. A compound which in the past might have been called 98% optically pure is now more precisely characterized by 96% ee. A 90% ee reflects the presence of 95% of one enantiomer and 5% of the other(s) in the material in question.
Hence, in one embodiment, the invention provides a composition including a first stereoisomer and at least one additional stereoisomer of a compound of the invention. The first stereoisomer may be present in a diastereomeric or enantiomeric excess of at least about 80%, preferably at least about 90% and more preferably at least about 95%. In a particularly preferred embodiment, the first stereoisomer is present in a diastereomeric or enantiomeric excess of at least about 96%, at least about 97%, at least about 98%, at least about 99% or at least about 99.5%. Enantiomeric or diastereomeric excess may be determined relative to exactly one other stereoisomer, or may be determined relative to the sum of at least two other stereoisomers. In an exemplary embodiment, enantiomeric or diastereomeric excess is determined relative to all other detectable stereoisomers, which are present in the mixture. Stereoisomers are detectable if a concentration of such stereoisomer in the analyzed mixture can be determined using common analytical methods, such as chiral HPLC.
C. Synthesis of the Compounds

1. General

Compounds of the invention may be synthesized as a racemic mixture, a mixture of cis and trans isomers, or a mixture of two or more diastereomers. Stereoisomers may be separated at an appropriate synthetic stage, for example, by chiral column chromatography, such as HPLC to give enantiomerically/diastereomerically enriched or enantiomerically or diastereomerically pure forms of the respective stereoisomers. Cis and trans assignments may be made on the basis of NMR coupling patterns optionally in conjunction with literature values. Absolute configurations can be determined by synthesis from chiral precursor of known configuration, or by X-ray crystallographic determination using crystallized materials.
Numbering of the positions within the cycloalkyl ring structure is based on the following Scheme:
Cis- and trans-configurations are defined according to the relative configuration of the amine-bearing side chain and the substitutent on the cyclalkyl ring. When more than one substitutent is present, the higher order (IUPAC) substitutent is used for the determination of cis- and trans-configuration. Examples are Outlined Below

(a) 2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclohexanol

(b) 3-(aminomethyl)-3-(3,4-dichlorophenyl)-1-methylcyclohexanol

Compounds of the invention may be synthesized according to Schemes 1 to 23, below. It is within the abilities of a person skilled in the art to select appropriate alternative reagents replacing the exemplary reagents shown in Schemes 1-23 in order to synthesize a desired compound of the invention. It is also within the abilities of a skilled artisan to omit or add synthetic steps when necessary. As a non-limiting example, Ar in Schemes 1 to 23 is selected from substituted or unsubstituted phenyl. In an exemplary embodiment, Ar is 3,4-dichlorophenyl.

2. General Synthesis of Cycloalkylamines

In one embodiment, the compounds of the invention are synthesized from the corresponding nitrile C as shown in Scheme 1, below.
Synthesis of the nitrile C and the carboxylic acid intermediate E can, for example, be accomplished as described by Calderon et al., J. Med. Chem. 1994, 37, 2285, which is incorporated herein by reference. In addition, the reduction of the nitrile C to the corresponding primary amine D can be accomplished by borane reduction, for example, as described by Nagarathnam et al., J. Med. Chem. 1998, 41, 5320, which is also incorporated herein by reference.
Referring to Scheme 1, alkylation of the acetonitrile A with dibromoalkane B (e.g., with NaH in DMSO) gives the nitrile C, which is subsequently converted to acid E (e.g., NaOH, 1,3-propanediol). The dibromoalkane can optionally be substituted to afford a substituted cycloalkane analog of the invention. The integer n may be selected from 0 to 2, resulting in cyclopentyl, cyclohexyl and cycloheptyl intermediates, respectively. Alternatively, substituted or unsubstituted 1,3-dibromopropane may be used to prepare a cyclobutyl analog of the invention.
Coupling of acid E with either a primary amine (R⁴═H) or a secondary amine is performed using peptide coupling reagents known in the art resulting in the corresponding amide (not shown). In an exemplary embodiment the amide is formed using EDCI and HOBt in DMF as the coupling reagents. In another exemplary embodiment, the amide is formed using PyBOP in DMF as the coupling reagent. Exemplary coupling procedures are described in General Procedures G to G3.
Referring to Scheme 1, the amide is then reduced using a reducing agent, such as borane. Exemplary borane reagents include BH₃.THF and borane.dimethylsulfide complexes. The resulting amine may be converted to the corresponding salt form. For example, treatment of the amine with HCl in Et₂O affords the HCl salt, which may be recrystallized to give the amine F as a solid.
Alternatively, the nitrile C can be reduced to the primary amine D using a reducing agent, such as borane (e.g., BH₃.THF). The amine may be converted to the corresponding salt form. For example, treatment of the amine with HCl in Et₂O affords the HCl salt, which may be recrystallized to give a pure solid. The primary amine may be converted to a secondary or tertiary amine by alkylation of the amino group as described below.
Alternatively, the carboxylic acid intermediate E can be activated by formation of an acid chloride, which may then be reacted with a primary or secondary amine to give the amide, as outlined for an exemplary cyclopentylamine in Scheme 2, below.
In another approach, the nitrile C can be converted to the corresponding aldehyde G using a reducing agent, such as DIBAL (Scheme 3). The aldehyde can then be converted to an amine, for example, through reductive amination. This synthetic route is particularly useful for the preparation of secondary amines of the invention (R⁴═H), as the amination of the aldehyde with a secondary amine to form a tertiary amine may be sluggish.

3. Synthesis of Substituted Cyclopentyl Amines

Substituted cyclopentyl amines (n=0) can be synthesized according to the route outlined in Scheme 4, below. The nitrile H may be synthesized from dibromobutene and an appropriate aryl acetonitrile and can be converted to the racemic cis and trans hydroxylamines I and J via reduction of the nitrile and hydroboration of the alkene with BH₃/H₂O₂, NaOH. Alternatively, reduction of H to the aldehyde K, followed by reductive amination affords the ene-amine L. The double bond of L may be used to introduce a substitutent (X) into the 5-membered ring structure.

4. Synthesis of Secondary and Tertiary Amines

The synthesis of secondary amines from primary amines can, for example, be accomplished using the method described by De Luca et al., Synlett 2004, 2570, which is incorporated herein by reference. The method is outlined in Scheme 5, below. The primary amine is converted to the N-formylated intermediate M, which may be reduced to the corresponding methyl amine. Typically, N-formylation followed by borane reduction led to clean mono-methylated products.
Dialkylamine analogs of the invention can be synthesized according to Scheme 6 below. In this method, a secondary amine is reacted with formaldehyde and concentrated formic acid to form a methylated tertiary amine.
In an exemplary embodiment, reaction of a methyl amine analog (R³=Me) with a 1:1 mixture of concentrated formic acid and 37% aqueous formaldehyde at 100° C. for 1 h, typically gives the dimethyl amine in good yield.
Another method useful for the synthesis of N,N-dimethyl and N-methyl amines is shown in Scheme 7, below. Treatment of a primary amine with diisopropylethylamine (DIEA) and methyl iodide (e.g., in CH₂Cl₂) leads to the formation of both the N-methyl amine and the N,N-dimethyl amine, which can be separated chromatographically. Selectivity for either the mono- or dimethylated product can be controlled by altering the ratio of methyl iodide to the amine as well as the reaction time. For example, mono-methylated analogs may be obtained selectively by keeping the concentration of methyl iodide low and reaction times short.

5. Synthesis of 2-Substituted Cycloalkylamines

In an exemplary embodiment, cycloalkylamines of the invention are substituted at the 2-position. Such compounds may be synthesized according to Scheme 8, below.
The method, outlined above for an exemplary 3,4-diphenyl cyclohexylamine of the invention, is applicable to the synthesis of 2-substituted cycloalkylamines. Reaction of ethyl 2-oxocyclohexanecarboxylate N with an aryl-lead triacetate (e.g., 3,4-dichlorophenyllead triacetate) affords the ethyl 1-aryl)-2-oxocyclohexanecarboxylate O. NaBH₄mediated reduction of the keto-ester yields the alcohol P, which is subsequently saponified to afford the acid Q as a mixture of diastereomers. Amide coupling and reduction of the resulting amide group affords the amine S. Chiral HPLC can be used to separate enantiomers/diastereomers. The hydroxyl group of S may be functionalized (e.g., alkylation) or replaced by another substitutent (X), such as a halogen atom (e.g., Cl or F) to yield compound T. Alternatively the hydroxyl group may be converted to a leaving group, which can subsequently be replaced with a selected nucleophile.
Corresponding dialkylamines of S or another hydroxyamine can be prepared from the corresponding primary amine or mono-alkylated analog (R⁴═H) when using an appropriate base, such as DIEA. For example, synthesis of the N,N-dimethyl amino-alcohols is prepared via alkylation of the N-methyl amines with methyl iodide and DIEA in acetone, as shown in Scheme 9, below.
In another exemplary embodiment, the invention provides compounds, which include a substituted alkyl-substitutent within in the cycloalkyl ring structure. For example, hydroxymethyl analogs may be synthesized according to Scheme 10 below. The hydroxyl group may optionally be replaced with another substitutent, such as a halogen atom.
Referring to Scheme 10, the cycloalkyl lactone U is converted to the aryl derivative V. The lactone is then reacted with a lithium salt of a selected amine (e.g., dimethylamine) to give the amido-alcohol W, which is subsequently reduced to the amine. For certain amides W (e.g., dichlorophenyl analogs) it may be preferable to use LAH as the reducing agent instead of borane.

6. Synthesis of 3-Substituted Cycloalkylamines

In another exemplary embodiment, the compounds of the invention are substituted at the 3-position of the cycloalkyl ring. Exemplary synthetic approaches for the preparation of such compounds are outlined below. Referring to Scheme 11, treatment of ketone X with an aryl Grignard reagent, followed by acidic hydrolysis and Michael addition of the cyanide (e.g., following the procedure described by Callis et al., J. Org. Chem. 1996, 61, 4634) gives the cyano-ketone Y. Addition of an alkyl lithium reagent to the carbonyl group affords the alcohol Z. In one example, this addition is stereoselective and racemic cis Z is formed selectively. The cyano group of the alcohol Z can be reduced with a reducing agent, such as borane, and the resulting amine can be N—BOC protected to give the racemic alcohol AA. Chiral chromatography followed by removal of the BOC group (e.g., by TFA) gives the enantiomeric cis amino-alcohols BB and CC. The amines can then be converted to the corresponding alkyl amines (e.g., N-Me and NMe₂derivatives) as described herein, above.
Alternatively, the ketone Y can be treated with sodium borohydride to afford DD as a mixture of cis- and trans-diastereomers (Scheme 12). In an exemplary embodiment, in which Ar is 3,4-dichlorophenyl, the cis-diastereomer of DD was formed primarily. Reduction of the nitrile and BOC protection of the resulting amino group affords the amine EE. The stereoisomers may be separated by chiral chromatography to give two pairs of enantiomers derived from cis EE and trans EE.
In addition, the hydroxyl group of any of the above analogs (e.g., compound DD) can be functionalized or replaced to generate further 3-substituted cyclohexyl amine analogs. For example, alkylation of the hydroxyl group of DD with methyl iodide gave the methoxy nitrile FF as described in Scheme 13, below. Stereoisomers of FF may be isolated through chiral chromatography. The nitrile is further processed to generate an amine. For example, the nitrile group is reduced (e.g., borane reduction) to afford the corresponding amine, which may then be converted to the corresponding alkylamine (e.g., methylamine or dimethylamine) as described above.
In another exemplary embodiment, 3,3-difunctionalized cycloalkylamine derivatives are synthesized from the ketonitrile Y according to the procedure outlined in Scheme 14, below. For example, the 3,3-difluoro-cyclohexylamine GG is synthesized by treatment of the ketonitrile Y with diethylaminosulfur trifluoride (DAST), followed by reduction of the nitrile group. Treatment of GG with methyl iodide and Hunig's base leads to a separable mixture of the corresponding N-methyl amine HH and N,N-dimethyl amine II. The enantiomers of both HH and II can be resolved by chiral chromatography.

7. Synthesis of 4-Substituted Cycloalkylamines

The invention further provides cycloalkylamines, in which the 4-position of the cycloalkyl ring is derivatized. An exemplary method for the synthesis of 4-substituted cycloalkyl amines was adapted from a procedure described in WO 03/063797, which is incorporated herein by reference in its entirety for all purposes. The method is outlined in Scheme 15, below.
Referring to Scheme 15, above, the acetonitrile JJ is condensed with methyl acrylate to give the di-ester KK, which is cyclized via Dieckmann condensation to give the cyclic hydroxy ester LL. Conversion of LL to the key intermediate MM can, for example, be affected by heating the compound in the microwave to about 160° C. Addition of an alkyl nucleophile (such as MeLi or EtLi) gives a mixture of the hydroxynitriles cis NN and trans NN, which may be separated by silica gel column chromatography. In an exemplary embodiment, in which Ar=3,4-dichlorophenyl and in which propylmagnesium chloride is used as the nucleophile, only the cis analog NN was obtained. Reduction of the nitrile group (e.g., borane) affords the corresponding amines cis OO and trans OO. Subsequent alkylation of the amines as described herein give corresponding alkyl amines, such as methyl- and dimethyl amines.
Alternatively, the intermediate nitrile alcohol NN can be reacted with an alkyl lithium reagent (such as MeLi/NaBH₄) to add an R¹group (e.g., a methyl group) before further processing as shown in Scheme 16, below, to afford the racemic amine PP. The enantiomers of PP can be separated by chiral chromatography.
In another exemplary embodiment, the ketonitrile MM is converted to chiral 4-hydroxy cyclohexylamines as shown in Scheme 17, below. Reduction of the carbonyl group (e.g., NaBH₄), followed by reduction of the nitrile group (e.g., borane) affords the primary amine QQ, which typically has cis configuration. Alternatively, the keto group of the ketonitrile MM is reduced (e.g., NaBH₄) and the stereocenter carrying the resulting hydroxyl group is inverted under Mitsonobu conditions to afford the hydroxynitrile RR, which is further processed to the corresponding primary amine SS or to the respective alkyl amine as described herein, above.
In an exemplary embodiment, the hydroxyl group of the intermediate hydroxynitrile RR is replaced or functionalized before further processing to the amine. For example, synthesis of O-alkylated or O-arylated species is accomplished through alkylation of the hydroxynitrile as shown in Scheme 18, below. Alkylation with methyl iodide followed by borane reduction of the nitrile provides the primary amine TT. A Mitsonobu protocol utilizing an alcohol, such as phenol, followed by borane reduction can be used to convert RR to the trans-analog UU, with inverted stereochemistry at the 4-position.
In another exemplary embodiment, the intermediate hydroxyl nitrile RR can be monofluorinated, for example, with morpholino sulfurtrifluoride or DAST to give the 4-fluoro species W, which may be obtained along with the elimination product WW (Scheme 19), which can be separated chromatographically. Both, the 4-fluoro nitrile VV and the alkene WW can be converted to the corresponding primary amines or alkyl amine species as described herein, above. The double bond can optionally be used to introduce a substitutent in to the cycloalkyl ring (e.g., by hydroboration).
In yet another exemplary embodiment, the ketonitrile MM is converted to a 4,4-disubstituted cycloalkylamine. For example, synthesis of the 4,4-difluoro amine XX could be affected via the action of morpholino sulfurtrifluoride or diethylamino trifluoride (DAST), followed by reduction of the nitrile group (e.g., by borane) as outlined in Scheme 19, below. The resulting primary amine may be converted to the corresponding alkyl amines as described herein.
The 4-position of the present cycloalkylamines can also be derivatized via the formation of an intermediate epoxide, as shown in Scheme 21, below. For example, epoxidation of the ketonitrile MM using trimethylsulfonium iodide/KO^tBu affords diastereomeric epoxides, which may be separated by column chromatography. The epoxide ring can be opened in a regioselective reaction with an appropriate nucleophile, such as TBAF/HF to give the corresponding hydroxyl derivative and subsequent reduction of the nitrile group affords the primary amine, such as the fluoromethyl analog YY. The primary amine is optionally converted to corresponding alkylamine species as described herein.
In another embodiment, the invention provides cycloalkylamines with an additional amino group substitutent in the cycloalkyl ring structure. In one example, the amine substitutent is located at the 4-position of the cycloalkyl ring. For instance, the ketonitrile MM can be converted to a 4-amino-cyclohexylamine using the exemplary synthetic conversions outlined in Scheme 22, below. Protection of the keto group of MM (e.g., through formation of a dioxolane), reduction of the nitrile group (e.g., with borane), alkylation of the primary amine (e.g., methylation with methyl iodide) and deprotection of the ketone functionality affords the analog ZZ. Reductive amination of the keto group (e.g., using methyl amine and sodium cyanoborohydride) affords a mixture of diastereomers, which may be separated by preparative HPLC to give the corresponding analogs cis- and trans AAA.

8. Introduction of R¹and/or R²

The invention further provides cycloalkylamines, in which the amine-bearing side chain is substituted with substitutents R¹and R². In an exemplary embodiment, R¹is a short alkyl group, such as C₁- to C₄-alkyl. Introduction of a R¹group can, for example, be accomplished using the synthetic procedure outlined in Scheme 23, below.
For example, addition of an alkyl lithium reagent to the aryl nitrile C, followed by reduction of the resulting imine affords the racemic primary amines BBB. The corresponding enantiomeric primary amines may be obtained by chiral HPLC chromatography.

9. Synthesis of Cycloalkylamines, in which R¹and R³are Joined in a Ring

The invention further provides cycloalkylamines, in which the amine nitrogen is part of a ring. In an exemplary embodiment, R¹and R³, together with the atoms to which they are attached, are joined to form a 3- to 7-membered ring, such as a substituted or unsubstituted pyrrolidine or piperidine ring. An exemplary synthetic method for the preparation of pyrrolidine analogs according to this embodiment is outlined in Scheme 24, below.
For example, addition of an acetal Grignard reagent to an aryl (e.g. 3,4-dichlorophenyl or 2-naphthyl) (R)-sulfinamine leads to the corresponding sulfinamide CCC as mixtures of diastereomers. Subsequent hydrolysis (e.g., 6M HCl in acetone) can be used to remove both, the sulfinamine auxiliary and ketal side chain. Intramolecular reductive amination (e.g., using polymer bound sodium cyanoborohydride) affords the racemic pyrollidine DDD.
D. Pharmaceutical Compositions
In a second aspect, the invention provides a pharmaceutical composition including a compound of the invention (e.g., a compound of Formulae (I) to (IV)) or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier.
As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for oral administration, e.g., tablets, drenches (aqueous or non-aqueous solutions or suspensions), parenteral administration (including intravenous and intramuscular), or epidural injection as, for example, a sterile solution or suspension, or sustained release formulation. The pharmaceutical compositions of the present invention may also be specifically formulated for administration transdermally.
The pharmaceutical compositions of the invention may be administered orally, parenterally, subcutaneously, transdermally, nasally, or by anal suppository. The pharmaceutical compositions of the invention may also be administered using controlled delivery devices.
Formulations of the present invention include those suitable for oral and parenteral administration, particularly intramuscular, intravenous and subcutaneous administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect, without being toxic to the patient. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient.
In certain embodiments, a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention.
Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, caplets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.
In solid dosage forms of the invention for oral administration (capsules, tablets, caplets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue. Pharmaceutical compositions or unit dosage forms of the present invention in the form of prolonged-action tablets may comprise compressed tablets formulated to release the drug substance in a manner to provide medication over a period of time. There are a number of tablet types that include delayed-action tablets in which the release of the drug substance is prevented for an interval of time after administration or until certain physiological conditions exist. Repeat action tablets may be formed that periodically release a complete dose of the drug substance to the gastrointestinal fluids. Also, extended release tablets that continuously release increments of the contained drug substance to the gastrointestinal fluids may be formed.
Compounds of the invention can be also administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the compounds of this invention. The invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.
All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
Compounds of the present invention may also be formulated as transdermal, topical, and mucosal dosage forms, which forms include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa. (1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Transdermal dosage forms include “reservoir type” or “matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.
Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied.
Depending on the specific tissue to be treated, additional components may be used prior to, in conjunction with, or subsequent to treatment with active ingredients of the invention. For example, penetration enhancers can be used to assist in delivering the active ingredients to the tissue.
The pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied, may also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.
When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% of active ingredient in combination with a pharmaceutically acceptable carrier.
The preparations of the present invention may be given orally and parenterally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, and by intravenous administration. In one embodiment, oral administrations are preferred.
The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient will range from about 0.005 mg per kilogram to about 5 mg per kilogram of body weight per day.
The terms “treatment” or “treating” is intended to encompass therapy, preventing (prophylaxis), preventing relapse, and amelioration of acute symptoms. Note that “treating” refers to either or both of the amelioration of symptoms and the resolution of the underlying condition. In many of the conditions of the invention, the administration of a compound or composition of the invention may act not directly on the disease state, but rather on some pernicious symptom, and the improvement of that symptom leads to a general and desirable amelioration of the disease state
The patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep, as well as poultry and pets in general.
The compounds and pharmaceutical compositions of the invention can be administered in conjunction with other pharmaceutical agents, for instance antimicrobial agents, such as penicillins, cephalosporins, aminoglycosides and glycopeptides. Conjunctive therapy thus includes sequential, simultaneous and separate administration of the active compound in a way that the therapeutic effects of the first administered agent have not entirely disappeared when the subsequent agent is administered.
IV. Methods
A. Binding To Monoamine Transporter
In another aspect the invention provides a method of binding a compound of the invention to a monoamine transporter. The method includes contacting the monoamine transporter and a compound of the invention.
In yet another aspect, the invention provides a method of inhibiting binding of a monoamine transporter ligand to a monoamine transporter (such as serotonin transporter, dopamine transporter and norepinephrine transporter). The method includes contacting the monoamine transporter and a compound of the invention. In an exemplary embodiment the monoamine transporter ligand is an endogenous monoamine, such as serotonin, dopamine or norepinephrine. In another exemplary embodiment, the ligand is a drug molecule or another small molecule known to have binding affinity to a monoamine transporter. In another exemplary embodiment, the monoamine transporter ligand is a radioactively labeled compound, known to bind to the monoamine transporter.
In an exemplary embodiment, inhibition of ligand binding is shown using an ex vivo binding assay, such as those described herein, below in Example 7. In an exemplary embodiment, the compound of the invention inhibits mean binding by between about 1% and about 100%, preferably by between about 10% and about 100%, more preferably by between about 20% and about 90% when compared to vehicle. Inhibition of mean binding is preferably dose dependent.
B. Inhibition of Monoamine Transporter Activity
In yet another aspect, the invention provides a method of modulating (e.g., inhibiting, augmenting) the activity of at least one monoamine transporter, such as serotonin transporter, dopamine transporter and norepinephrine transporter. The method includes contacting the monoamine transporter and a compound of the invention. In an exemplary embodiment, the monoamine transporter is contacted with a compound of the invention by administering to a subject a therapeutically effective amount of the compound of the invention, e.g., a compound according to Formulae (I) to (V), or a pharmaceutically acceptable salt or solvate thereof. In a preferred embodiment, the subject is a human. In another exemplary embodiment, the monoamine transporter is dopamine transporter (DAT), serotonin transporter (SERT) or norepinephrine transporter (NET). In another exemplary embodiment, the compound of the invention inhibits the activity of at least two different monoamine transporters. Inhibition of monoamine transporter activity may be measured using assays known in the art. Exemplary assay formats include in vitro functional uptake assays (Example 6). In an exemplary embodiment, the functional uptake assay utilizes an appropriate cell-line expressing a desired monoamine transporter. In another exemplary embodiment, the functional uptake assay utilizes synaptosomes isolated from brain tissue of an appropriate organism. Alternatively, inhibition of monoamine transporter activity may be assessed using receptor binding experiments known in the art, e.g., utilizing appropriate membrane preparations. Another assay involves treatment of a test subject (e.g., a rat) with a compound of the invention as well as a reference compound, followed by isolation of brain tissue and ex vivo analysis of receptor occupancy, as described herein.
C. Inhibition of Monoamine Uptake
In yet another aspect, the invention provides a method of inhibiting uptake of at least one monoamine (e.g., dopamine, serotonin, norepinephrine) by a cell. The method includes contacting the cell with a compound of the invention. In an exemplary embodiment, the cell is a brain cell, such as a neuron or a glial cell. In one example, inhibition of monoamine uptake occurs in vivo. In an organism, neuronal uptake (also termed reuptake) of a monoamine such as dopamine or serotonin occurs, for example, from the synaptic cleft. Thus, in one embodiment, the neuronal cell is in contact with a synaptic cleft of a mammal. In another exemplary embodiment, inhibition of monoamine uptake occurs in vitro. In those methods the cell, may be a brain cell, such as a neuronal cell or a cell-type, which expresses a recombinant monoamine transporter.
In one embodiment, the compound inhibits uptake of at least two different monoamines. This can, for example, be shown by performing various in vitro functional uptake assays utilizing a cell-type, which simultaneously expresses multiple different monoamine transporters (such as isolated synaptosomes), or may be shown by using two different cell types, each expressing a different monoamine transporter, such as a recombinant dopamine transporter, together with an appropriate, labelled monoamine (Example 6). Inhibition of monoamine uptake is demonstrated when the inhibitor (e.g., a compound of the invention) has an IC₅₀of between about 0.1 nM and about 10 μM, preferably between about 1 nM and about 1 μM, more preferably between about 1 nM and about 500 nM, and even more preferably between about 1 nM and about 100 mM in a functional monoamine uptake assay, such as those described herein below.
D. Treatment of CNS Disorders
In another aspect, the invention provides a method of treating depression by inhibiting the activity at least one monoamine transporter. The method includes administering to a mammalian subject a compound of the invention. In an exemplary embodiment, the mammalian subject is a human. In another exemplary embodiment, the compound of the invention inhibits the activity of at least two different monoamine transporters. For example, the compound of the invention inhibits the activity of at least two of serotonin transporter, dopamine transporter and norepinephrine transporter. Inhibition of monoamine transporter activity may be shown by functional monoamine uptake assays as described herein below (Example 6). Demonstration of anti-depressant activity of a compound of the invention may be shown by utilizing an appropriate animal model of depression, such as the Rat Forced Swim Test, the Mouse Tail Suspension Test and Rat Locomotor Activity Analyses (Example 8). The Rat Forced Swim Test is also suitable for the analysis of compounds having activities against more than one monoamine transporter (mixed monoamine transporter activity). For example, an increase in swimming activity is indicative of serotonin reuptake inhibition, while an increase in climbing activity is indicative of norepinephrine reuptake inhibition. In a preferred embodiment, the compounds of the invention are active in at least one animal model, which can be used to measure anti-depressant-like activities, for instance those assessing immobility. In an exemplary embodiment, the compounds of the invention are active when they inhibit mean immobility by between about 5% and about 90%, preferably between about 10% and about 70% and more preferably between about 10% and about 50% in at least one animal model, when compared to vehicle.
In yet another aspect, the invention provides a method of effecting an anti-depressant-like effect. The method includes administering to a mammalian subject in need thereof a therapeutically effective amount of a compound or composition of the invention, e.g., a compound according to Formulae (I) to (IV), or a pharmaceutically acceptable salt or solvate thereof. Anti-depressant-like effects may be measured using an animal model of disease, such as those described herein.
In a further aspect, the invention provides a method of treating a central nervous system disorder. The method includes administering to a subject in need thereof a therapeutically effective amount of a composition or compound of the invention, e.g., a compound according to Formulae (I) to (IV), or a pharmaceutically acceptable salt or solvate thereof. In a preferred embodiment, the subject is a human.
In another exemplary embodiment, the central nervous system disorder is a member selected from the group consisting of depression (e.g., major depressive disorder, bipolar disorder, unipolar disorder, dysthymia and seasonal affective disorder), cognitive deficits, fibromyalgia, pain (e.g., neuropathic pain), sleep related disorders (e.g., sleep apnea, insomnia, narcolepsy, cataplexy) including those sleep disorders, which are produced by psychiatric conditions, chronic fatigue syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), restless leg syndrome, schizophrenia, anxieties (e.g. general anxiety disorder, social anxiety disorder, panic disorder), obsessive compulsive disorder, posttraumatic stress disorder, seasonal affective disorder (SAD), premenstrual dysphoria, post-menopausal vasomotor symptoms (e.g., hot flashes, night sweats), and neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis), manic conditions, dysthymic disorder, and cyclothymic disorder. In a preferred embodiment, the CNS disorder is depression, such as major depressive disorder. In an exemplary embodiment, the compounds of the invention are useful to treat two conditions/disorders, which are comorbid, such as cognitive deficit and depression.
Central nervous system disorder includes cerebral function disorders, including without limitation, senile dementia, Alzheimer's type dementia, cognition, memory loss, amnesia/amnestic syndrome, epilepsy, disturbances of consciousness, coma, lowering of attention, speech disorders, Lennox syndrome, autism, and hyperkinetic syndrome.
Neuropathic pain includes without limitation post herpetic (or post-shingles) neuralgia, reflex sympathetic dystrophy/causalgia or nerve trauma, phantom limb pain, carpal tunnel syndrome, and peripheral neuropathy (such as diabetic neuropathy or neuropathy arising from chronic alcohol use).
Other exemplary diseases and conditions that may be treated using the methods of the invention include obesity; migraine or migraine headache; urinary incontinence, including without limitation involuntary voiding of urine, dribbling or leakage of urine, stress urinary incontinence (SUI), urge incontinence, urinary exertional incontinence, reflex incontinence, passive incontinence, and overflow incontinence; as well as sexual dysfunction, in men or women, including without limitation sexual dysfunction caused by psychological and/or physiological factors, erectile dysfunction, premature ejaculation, vaginal dryness, lack of sexual excitement, inability to obtain orgasm, and psycho-sexual dysfunction, including without limitation, inhibited sexual desire, inhibited sexual excitement, inhibited female orgasm, inhibited male orgasm, functional dyspareunia, functional vaginismus, and atypical psychosexual dysfunction.

EXAMPLES

1. General Procedures

In the examples, below, the following general experimental procedures were used unless otherwise noted: All commercial reagents were used without further purification. Anhydrous reactions were performed in flame-dried glassware under N₂. NMR spectra were recorded on a Varian 400 MHz spectrometer in deuterochloroform or methanol-d⁴with trimethylsilane (TMS) as an internal reference. Silica gel column chromatography was performed using an ISCO Combiflash system with detection at 254 nm or using ISCO normal phase silica gel cartridges.
Analytical HPLC
Analytical HPLC was performed on a Hewlett Packard Series 1100 pump connected to an Agilent Zorbax RX-C18 5 μm, 4.6×250 mm column, with detection on a Hewlett Packard Series 1100 UV/Vis detector monitoring at 214 and 254 nm. Typical flow rate=1 ml/min. Three different HPLC columns and various elution protocols were used. For example, (1) Agilent Zorbax RX-C18 5 μm, 4.6×250 mm column running a linear gradient. Solvent A=H₂O w/0.05% TFA, Solvent B=MeCN w/0.05% TFA. Time 0 min=5% Solvent B, time 4 min=40% Solvent B, time 8 min=100% Solvent B, 12 min=5% Solvent B, 20 min=5% Solvent B; (2) Phenomenex 3μ C18 column running a 3 minute gradient of 5→100% B (acetonitrile/0.1% formic acid) and solvent A (water/0.1% formic acid); (3) Phenomenex 5μ C18 column running a 5 minute gradient of 5→100% B where solvent B (acetonitrile/0.1% formic acid) and solvent A (water/0.1% formic acid).
Reverse Phase HPLC Purification
Reverse phase HPLC purification was performed on a Gilson system using a Phenomenex 5μ C18 (50×21.2 mm) column. The standard separation method was: 10 minute gradient of 10→100% B (acetonitrile/0.1% formic acid) in solvent A (water/0.1% formic acid). Crude samples were typically dissolved in MeOH. Fractions were concentrated by Genovac (centrifugation at low pressure).
GC-MS
Gas chromatography was performed on a Hewlett Packard 6890 Series GC System with an HP1 column (30 meters, 0.15μ film thickness) coupled to a Hewlett Packard 5973 Series Mass Selective Detector. The following linear temperature gradient was used: 100° c. for 5 minutes, then 20° C./min to 320° C. Hold @320° C. for 10 minutes.
LCMS
LCMS was performed on an Agilent 1100 Series system connected to a Micromass Platform LC. The following column and gradient was used: Column: Luna C18(2), 3 um particle size 30×2.0 mm column dimension. Flow rate=0.5 mL/min, Solvent A=0.1 M N₄Ac in 95% H₂O, 5% MeOH, pH 6.0, Solvent B=Solvent B: 0.1 M N₄Ac in MeOH. Linear gradient with 6 entries: Time 0 min=100% Solvent A, time 10 min=100% Solvent B, time 12 min=100% Solvent B, time 12 min 10 sec=100% Solvent A, time 14 min=100% Solvent A, time 14 min 20 sec=100% Solvent A.
Microwave (μW) Recrystallization
The crude salt (e.g., HCl salt) was loaded into a microwave vessel with a stir bar. The recrystallization solvent was added and the vessel was heated at the target temperature for a given time. The vessel was cooled to 50° C. in the reactor, was then removed and allowed to slowly cool to RT. N,N-dimethyl amines were typically recrystallized in EtOAc or EtOAc:CH₃CN (2:1). N-Me or primary amines were typically recrystallized in CH₃CN.
Formylation-Reduction 1 (General Procedure A)
The amine free base was dissolved in CH₂Cl₂at approximately 0.4 M and concentrated formic acid (1.0 eq relative to the amine), 1-chloro-3,5-dimethoxytriazine (1.1 eq), DMAP (0.03 eq) and N-methylmorpholine (1.1 eq) were added in this order. The solution was heated in the μW (60° C., 10 min.) and cooled to RT. The reaction was monitored by HPLC. When the starting material was consumed, the crude reaction mixture was diluted with CH₂Cl₂(15 mL) and washed with aqueous HCl (twice), saturated aqueous K₂CO₃and brine. The crude product was dried (Na₂SO₄), filtered and concentrated. The crude N-formyl amide was dissolved in anhydrous THF at approximately 0.2 M and borane-THF (e.g., 1.0 M in THF, 3 eq) was added dropwise. The clear solution was heated via μW (150° c., 30 min, FHT), cooled to RT and quenched with 6M HCl (e.g., 10 mL). The solution washed twice with Et₂O (e.g., 20 mL). The aqueous phase was adjusted to pH 12 with 3M NaOH and was then washed three times with EtOAc (e.g., 20 mL). The combined organic layers were dried (Na₂SO₄), filtered and concentrated.
Formylation-Reduction 2 (General Procedure B)
To acetic anhydride (1 eq relative to the amine) under nitrogen at 0° C. was added formic acid (3 eq) dropwise over 3 min. After stirring the reaction mixture for 1 h, a 0.1 M solution of the amine (1 eq) in THF was added dropwise over 5 min. The mixture was allowed to slowly warm, stirring at room temperature for 3 d. The volatiles were removed in vacuo and the residue was purified over silica gel. To a solution of the formamide (1 eq) in THF (10 mL) under nitrogen was added BH₃.S(CH₃)₂(2 M in THF, 2 eq) dropwise over 5 min. The mixture was stirred at room temperature for 20 hours. MeOH, and 2 N aqueous HCl were added and the mixture washed with diethyl ether (50 mL). The pH was adjusted to 14 by addition of 2 N NaOH and the mixture was extracted with diethyl ether (50 mL). The combined organic phases were dried (sodium sulfate), filtered, and concentrated. The crude N-methyl amine was purified by either Gilson RP-HPLC or by transformation to the HCl salt and recrystallization in the indicated solvent.
HCl Salt Formation
The crude amine was dissolved in Et₂O (e.g., 3 mL) and HCl (e.g., 3-5 mL, 2.0 M in Et₂O). The solution was stirred for 1 h and evaporated twice from CH₂Cl₂(e.g., 20 mL). The crude HCl salt was recrystallized in the indicated solvent, filtered and dried in vacuo.
Eschweiler-Clarke N,N-Dimethylation (General Procedure C)
The amine free base (up to 100 mg) was suspended in 37% aqueous formaldehyde (3 mL) and concentrated formic acid (3 mL) was added. The yellowish solution was heated at 100° c. for 1 h and cooled to RT. The clear solution was poured into saturated aqueous K₂CO₃(20 mL) and washed with EtOAc (3×20 mL). The organic washes were combined, washed with brine (1×10 mL), dried (Na₂SO₄), filtered and concentrated. The crude amine was dissolved in Et₂O (3 mL) and HCl (3-5 mL, 2.0 M in Et₂O) was added. The solution was stirred for 1 h and concentrated with CH₂Cl₂(2×20 mL). The crude HCl salt was recrystallized in the indicated solvent, filtered and dried in vacuo. Alternatively, the dimethylamine could be purified on the reverse-phase HPLC system if recrystallization was not unsuccessful.
Methylation Via Reductive Amination with Formaldehyde and NaB(CN)H₃(General Procedure D)
To a stirred solution of the amine (approximately 0.05 M, 1 eq), 37% formaldehyde (10 eq), and acetic acid (1 drop) in CH₂Cl₂at room temperature was added NaBH(OAc)₃(4 eq). The reaction mixture was stirred for 3 days. Saturated NaHCO₃solution was then added and the mixture was extracted with EtOAc. The combined organic layers were dried (sodium sulfate), filtered, and concentrated. The crude amine was purified by either Gilson RP-HPLC or by transformation to the HCl salt and recrystallization.
Borane Reduction of Amide or Nitrile (General Procedure E)
To a solution of the nitrile in anhydrous THF (final concentration: about 0.1M to about 0.2 M) was added dropwise borane-THF (e.g., 1.0M in THF, 3 eq). The reaction mixture was heated in the microwave (maximum temperature: 150° C., about 1 min to about 40 min), cooled to room temperature and then quenched with 6N HCl. The solution washed with EtOAc. The aqueous phase was adjusted to pH 12 with 3N NaOH and extracted three times with EtOAc. The combined organic layers were dried (Na₂SO₄), filtered and concentrated.
The crude amine was purified by column chromatography and/or isolated as the HCl salt after precipitation from ether (e.g., Et₂O) and HCl (e.g., 2.0 M in Et₂O). The crude HCl salt was optionally recrystallized from the indicated solvent.
Reduction of Nitrile with LiAlH₄(General Procedure E1)
To a 0.05 M solution of the nitrile (1 eq) in diethyl ether was added LiAlH₄(5 eq). The reaction mixture was heated at reflux for 30 min before NaOH solution was slowly added to quench the reaction. The product was extracted with diethyl ether. The combined extracts were dried (Na₂SO₄), filtered and concentrated. The residue was dissolved in MeOH and purified by reverse phase HPLC.
JianguoMa Alkylation (General Procedure F)
The primary amine free base or HCl salt was dissolved/suspended in anhydrous CH₂Cl₂(volume to make amine concentration=0.1 M) and neat anhydrous diisopropylethylamine (3 eq) and methyl iodide (1-5 equiv. depending on desired outcome) was added. The clear solution was stirred at RT for 1-5 h and monitored by HPLC. Longer reaction times favor the formation of the N,N-dimethyl amines; shorter reaction times favor formation of the N-methyl amines. The reaction was checked by HPLC and quenched with MeOH (5 mL) when the desired ratio of N-methyl:N,N-dimethyl amines was reached. The reaction was concentrated under reduced pressure and loaded directly onto a Biotage samplet. Purification by silica gel column chromatography used hexane/0.1% DEA as the non-polar phase and ethyl acetate as the polar phase. The following gradient was employed: equilibration with hexane/0.1% DEA, 3 column volumes (CV), linear 0-50% ethyl acetate over 7 CV, hold at 50% ethyl acetate for 5.5 CV. Fractions were checked by HPLC and LCMS. Product fractions eluted around fractions 7-15. Positive fractions were concentrated and converted into HCl salts.
Amide Coupling (General Procedure G)
A solution of the respective carboxylic acid (approximately 0.1M, 1 eq), the respective amine (1-2 eq), N-methylmorpholine (1-2 eq) and PyBOP (1-2 eq) in anhydrous DMF was stirred at RT overnight (The reaction mixture may optionally include DMAP). The reaction mixture was poured into H₂O (e.g., 20 mL) and washed three times with Et₂O (e.g., 3×20 mL). The combined organic layers were dried (Na₂SO₄), filtered and concentrated. The crude product was purified by either silica gel column chromatography, reverse phase HPLC or by transformation to the HCl salt and recrystallization.
Alkyl Lithium Addition to Nitrile (General Procedure I)
To a solution of arylcyclohexanecarbonitrile (approximately 0.16 M, e.g., 12.8 g, 49.0 mmol) in anhydrous toluene at 0° C. was added dropwise a solution of methyllithium (1.6 M, 1.5 eq) over 10 min. The ice bath was removed and the reaction mixture stirred for 30 min. Methanol (65 eq) and sodium borohydride (6 eq) were added portionwise. The mixture was stirred for 45 min and was then carefully quenched with 6 N HCl. The mixture washed with ethyl acetate. The pH of the aqueous layer was adjusted to 14 by addition of 6 N NaOH and was then extracted with ethyl acetate. The combined organic layers were dried (Na₂SO₄), filtered and concentrated to give the crude racemic primary amine. The crude amine was purified by either Gilson RP-HPLC or by transformation to the HCl salt and recrystallization.
Cycloalkyl Nitrile Synthesis (General Procedure J)
To a 0.1 M suspension of sodium hydride (2.5 eq) in anhydrous DMSO was added a 0.4 M solution of aryl acetonitrile (1 eq) in anhydrous DMSO dropwise over 35 min. The mixture was stirred for 30 min and was then added to a 0.24 M solution of 1,5-dibromopentane (1.5 eq) in anhydrous DMSO dropwise over 20 min. The mixture was stirred overnight at room temperature, poured into water and extracted with chloroform or CH₂Cl₂. The organic layers were combined, washed with water, dried (Na₂SO₄), filtered and concentrated. The resulting residue was chromatographed on silica gel to give the arylcyclohexanecarbonitrile.
Alkylation of Alcohol (General Procedure Y)
To a 0.2 M solution of the alcohol (1 eq) in THF was added NaH (60% in mineral oil, 1.5 eq). The reaction mixture was stirred for 20 min before alkyl halide (2 eq) was added. The reaction mixture was stirred for 4 h and was then quenched with saturated NH₄Cl solution. The product was extracted with diethyl ether. The combined organic layers were dried (Na₂SO₄), filtered and concentrated. The residue was purified by silica gel column chromatography (e.g., ethyl acetate/hexane) to give O-alkylated product.
Lithio-amine Addition to Lactone (General Procedure AA)
To a cold solution of alkylamine (5 eq) at −78° C. was added n-Buli (3 eq) and the reaction mixture was stirred for five minutes. A 0.3 M solution of the aryl lactone (1 eq) in anhydrous THF was then added. The mixture was stirred at the low temperature for one hour and at ambient temperature for an additional hour. The reaction was then quenched with saturated ammonium chloride and extracted with MTBE. The combined organic layers were evaporated and the crude oil purified on silica gel to give the amide.

Example 1

Synthesis of Cycloalkyl Amines

1.1. Synthesis of Cycloalkyl Nitriles

The following exemplary cycloalkylcarbonitriles were prepared from the respective aryl nitriles according to General Procedure J:

1-(biphenyl-4-yl)cyclohexanecarbonitrile

HPLC R_t=11.29 min; GC-MS, SCOUT program 13.85 min, M⁺261.

1-(thiophen-2-yl)cyclohexanecarbonitrile

HPLC R_t=10.24 min; GC-MS, SCOUT program 8.42 min, M⁺191.

1-(naphthalen-1-yl)cyclohexanecarbonitrile

HPLC R_t=10.82 min; GC-MS 12.6 min, M⁺235.

1-(4-(trifluoromethoxy)phenyl)cyclohexanecarbonitrile

HPLC R_t=10.76 min; GC-MS 8.59 min, M⁺269.

1.2. Synthesis of Primary Amines from Cycloalkyl Nitriles

The primary amines summarized in Table 1, below, were prepared from the corresponding nitriles according to the indicated General Procedures. Enantiomeric mixtures of selected primary amines were separated by chiral chromatography using the indicated chromatographic methods to give the fast moving enantiomer (E1) and the slow moving enantiomer (E2), respectively.

TABLE 1




Summary of Exemplary Primary Amines

			General
Ar	n	R¹	Procedure

(1-(3,4-dichlorophenyl)cyclobutyl)methanamine (1)


1	H	E

HPLC R_t= 8.16 min; ¹H NMR(400 mHz, MeOH-d⁴) 7.48(d, J=8.31Hz,

1H), 7.37(m, 1H), 7.14-7.10(m, 1H), 3.23(m, 2H), 2.44-2.34(m, 2H),

2.29-2.20(m,2H), 2.14-2.05(m, 1H), 1.93-1.86(m, 1H); LC-MS 6.91

min, (M + 1)⁺230 @ 7.27 min.

(±) 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanamine (2)


3	CH₃	I

Chiral HPLC (AD column; 98:2:0.1 hexanes:isopropanol:diethylamine,

280 nm) to give 2 E1 (R_t= 8 min) and 2 E2 (R_t= 10 min).

HPLC R_t= 8.77 min; ¹H NMR(400 mHz, CD₃OD) 7.52(d, J=8.8Hz, 1H),

7.48(d, J=2.2Hz, 1H), 7.26(dd, J=2.2, 8.8Hz, 1H), 3.21(1H, under

solvent peak), 2.35(broad d, 13.2Hz, 1H), 2.24(broad d, 13.9Hz, 1H),

1.57-1.46(m, 5H), 1.24-1.11(m, 3H), 1.04(d, J=6.6Hz, 3H); LC-MS

8.13 min, (M + 1)⁺272 @ 8.37 min

(±) 1-(1-(3,4-dichlorophenyl)cyclohexyl)-3-methylbutan-1-amine (3)


3	iso-butyl	I

HPLC R_t= 9.49 min; ¹H NMR(400 MHz, MeOH-d⁴) 7.4-7.38(m, 2H),

7.17-7.15(m, 1H), 2.58-2.55(m, 1H), 2.27-2.18(m, 2H), 1.64-1.44(m, 5H),

1.27-1.11(m, 7H), 0.83(d, J=6.96, 3H), 0.78(d, J=6.96Hz, 3H),

0.69-0.62(m, 1H); LC-MS 9.81 min, (M + 1)⁺314 @ 9.95 min.

(1-(3,4-dichlorophenyl)cycloheptyl)methanamine (4)


4	4	H	E

HPLC R_t= 8.96 min; ¹H NMR(400 MHz, CDCl₃) 7.51-7.48(m, 2H),

7.29(dd, J=2.2, 8.4Hz, 1H), 3.0(s, 2H), 2.12-2.07(m, 2H), 1.79-1.73(m,

2H), 1.66-1.38(m, 7H); LC-MS 8.61 min, (M + 1)⁺272 @ 8.81 min

(±) 1-(1-(4-methoxyphenyl)cyclohexyl)ethanamine (5)


3	CH₃	I

HPLC R_t= 8.07 min; LC-MS 5.57 min, (M + 1)⁺234 @ 5.98 min.

(±) 1-(1-(thiophen-2-yl)cyclohexyl)ethanamine (6)


3	CH₃	I

HPLC R_t= 7.81 min; LC-MS 4.90 min, (M + 1)⁺210 @ 5.78 min.

(±) 1-(1-(biphenyl-4-yl)cyclohexyl)ethanamine (7)


3	CH₃	I

HPLC R_t= 9.07 min; LC-MS 7.47 min, (M + 1)⁺280 @ 7.94 min.

(1-(biphenyl-4-yl)cyclohexyl)methanamine (8)


3	H	E

HPLC R_t= 8.96 min; ¹H NMR(400 MHz, CD₃OD) 7.64(d, J=8.43Hz,

2H), 7.57(d, J=7.70Hz, 2H), 7.47(d, J=8.06Hz, 2H), 7.39-7.36(m, 2H),

7.27(t, J=7.33Hz, 1H), 3.01(s, 2H), 2.26-2.24(m, 2H), 1.64-1.52(m, 5H),

1.39-1.38(m, 3H); LC-MS 7.48 min, (M + 1)⁺266 @ 7.86 min.

(1-(thiophen-2-yl)cyclohexyl)methanamine (9)


3	H	E

HPLC R_t= 7.62 min; ¹H NMR(400 MHz, CD₃OD) 7.36(dd, J=1.1,

4.76Hz, 1H), 7.02-6.98(m, 2H), 2.98(s, 2H), 2.13-2.01(m, 2H),

1.98-1.35(m, 8H); LC-MS 4.55 min, (M + 1)⁺196 @ 5.12 min.

(1-(4-(methylthio)phenyl)cyclohexyl)methanamine (10)


3	H	E

HPLC R_t= 8.30 min; ¹H NMR(400 MHz, CD₃OD) 7.33-7.26(m, 4H),

2.96(s, 2H), 2.42(d, J=1.47Hz, 3H), 2.19-2.16(m, 2H), 1.60-1.49(m, 5H),

1.39-1.31(m, 3H); LC-MS 6.07 min, (M + 1)⁺236 @ 6.45 min.

(±) 1-(1-(4-chlorophenyl)cyclohexyl)ethanamine (11)


3	CH₃	I

HPLC R_t= 8.38 min; LC-MS 6.13 min, (M + 1)⁺238 @ 5.84 min.

(1-(naphthalen-1-yl)cyclohexyl)methanamine (12)


3	H	E

HPLC R_t= 8.49 min. ¹H NMR(400 MHz, CD₃OD) 8.39(d, J=8.43Hz,

1H), 7.90(d, J=7.70Hz, 1H), 7.82(d, J=8.06Hz, 1H), 7.58(d, J=7.33Hz,

1H), 7.51-7.42(m, 3H), 3.64(bs, 2H), 2.56-2.51(m, 2H), 1.98-1.94(m,

2H), 1.62-1.50(m, 6H); LC-MS 7.40 min, (M + 1)⁺240 @ 7.62 min.

(±) 1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (13)


3	CH₃	I

SFC w/AD column and 33% MeOH/0.1% DEA, 25° C. column temp., 10

ml/min total flow, 280 nm to give the fast moving enantiomer 13 E1 (R_t=

3.8 min) and the slow moving enantiomer 13 E2 (R_t= 5 min).

13 E1

LC-MS (M + 1)⁺254 @ 8.31 min

13 E2

LC-MS (M + 1)⁺254 @ 8.33 min

(±) 1-(1-(4-chlorophenyl)cyclohexyl)-2-methylpropan-1-amine (14)


3	iso-propyl	I

HPLC R_t= 8.89 min; LC-MS 8.67 min, (M + 1)⁺266 @ 8.85 min.

(1-(4-(trifluoromethoxy)phenyl)cyclohexyl)methanamine (15)


3	H	E

HPLC R_t= 8.63 min; ¹H NMR(400 MHz, CD₃OD) 7.50(d, J=9.16Hz,

2H), 7.28(d, J=8.80Hz, 2H), 3.02(s, 2H), 2.19(d, J=12.8Hz, 2H),

1.67-1.31(m, 8H); LC-MS 7.93 min, (M + 1)⁺274 @ 8.18 min.

1-(1-(naphthalen-1-yl)cyclohexyl)ethanamine (16)


3	CH₃	I

SFC w/AS column and 30% MeOH/0.1% DEA, 280 nm.

16 E1: HPLC R_t= 2.23 min; LC-MS 7.56 min, (M + 1)⁺254 @ 7.78 min

16 E2: LC-MS 7.59 min, (M + 1)⁺254 @ 7.9 min.

1-(1-(3,4-dichlorophenyl)cyclohexyl)propan-1-amine (17)


3	CH₂CH₃	I

SFC w/AS column and 20% MeOH/0.1% DEA, 280 nm.

17 E1: HPLC R_t= 1.58 min; ¹H NMR(400 MHz, CDCl₃) 7.50(d,

J=1.47Hz, 1H), 7.44(d, J=8.43Hz, 1H), 7.29-7.27(m, 1H), 3.01-2.97(m,

1H), 2.44(d, J=13.2Hz, 1H), 2.21(d, J=13.2Hz, 1H), 1.98-1.92(m, 1H),

1.79-1.25(m, 8H), 1.09-1.03(m, 4H); LC-MS 8.89 min, (M + 1)⁺286 @

9.01 min.

17 E2: LC-MS 8.89 min, (M + 1)⁺288 @ 8.91 min.

(±) 1-(1-(4-chlorophenyl)cyclohexyl)propan-1-amine (18)


3	CH₂CH₃	I

HPLC R_t= 8.68 min; LC-MS 7.91 min, (M + 1)⁺252 @ 8.04 min.

1-(1-(4-(trifluoromethoxy)phenyl)cyclohexyl)ethanamine (19)


3	CH₃	I

Chiral HPLC with AD column and 100% MeOH/0.1% DEA, 280 nm

19 E1: HPLC R_t= 1.52 min; LC-MS (15 minute method) 8.18 min,

(M + 1)⁺288 @ 8.35 min.

19 E2: LC-MS (15 minute method) 8.24 min, (M + 1)⁺288 @ 8.27 min.

1-(1-(4-(furan-3-yl)phenyl)cyclohexyl)ethanamine (20)


3	CH₃	I

SFC w/AD column and 35% MeOH/10% IPA/0.1% DEA, 25° C. column

temp., 10 ml/min total flow, 280 nm to give the fast moving enantiomer

E1 and the slow moving enantiomer E2.

20 E1: ¹H NMR(400 MHz, CDCl₃) 7.73(s, 1H), 7.48-7.46(m, 3H), 7.32(d,

J=8.43Hz, 2H), 6.70(d, J=0.7Hz, 1H), 2.77-2.72(m, 1H), 2.37(d,

J=13.2Hz, 1H), 2.30(d, J=13.2Hz, 1H), 1.58-1.42(m, 5H), 1.32-1.22(m,

3H), 0.87(d, J=6.60Hz, 3H); LC-MS 7.94 min, (M + 1)⁺270 @ 8.06 min

20 E2: LC-MS 7.97 min, (M + 1)⁺270 @ 8.12 min

1-(1-(4-chlorophenyl)cyclohexyl)-3-methylbutan-1-amine (21)


3	iso-butyl	I

SFC w/AS column and 15% IPA/0.1% DEA, 25° C. column temp., 10

ml/min total flow, 280 nm to give the fast moving enantiomer E1 and the

slow moving enantiomer E2.

21 E1: HPLC R_t= 9.26 min; ¹H NMR(400 MHz, CDCl₃); 7.31-7.23(m,

4H), 2.57-2.54(m, 1H), 2.32-2.23(m, 2H), 1.65-1.43(m, 6H),

1.24-1.13(m, 4H), 0.93-0.78(m, 7H), 0.70-0.63(m, 1H); LC-MS 9.01 min,

(M + 1)⁺280 @ 9.19 min

21 E2: LC-MS 9.01 min, (M + 1)⁺280 @ 9.19 min

1-(1-(4-(furan-2-yl)phenyl)cyclohexyl)ethanamine (22)


3	CH₃	I

SFC w/OD column and 12% MeOH/0.1% DEA, 40° C. column temp., 10

ml/min total flow, 280 nm to give the fast moving enantiomer E1 and the

slow moving enantiomer E2.

22 E1: HPLC R_t= 8.76 min; ¹H NMR(400 MHz, CDCl₃) 7.66(d,

J=8.54Hz, 2H), 7.45(d, J=1.71Hz, 1H), 7.34(d, J=8.54Hz, 2H), 6.63(d,

J=3.42Hz, 1H), 6.45(dd, J=1.71, 3.42Hz, 1H), 2.83(bs, 1H), 2.39(d,

J=12.7Hz, 1H), 2.30(d, J=11.7Hz, 1H), 1.56-1.45(m, 5H), 1.26(bs, 3H),

0.90(d, J=6.35Hz, 3H); LC-MS 8.09 min, (M + 1)⁺270 @ 8.24 min.

22 E2: LC-MS 8.09 min, (M + 1)⁺280 @ 8.24 min.

(1-(3′,5′-difluorobiphenyl-4-yl)cyclohexyl)methanamine (23)


3	H	E

HPLC R_t= 9.24 min; ¹H NMR(400 mHz, CD₃OD) 7.68-7.64(m, 2H),

7.51(dd, J=1.95, 8.96, 2H), 7.26-7.19(m, 2H), 6.90-6.84(m, 1H),

3.03(s, 2H), 2.28-2.24(m, 2H), 1.67-1.36(m, 8H).

(±) 1-(1-(4-(thiazol-2-yl)phenyl)cyclohexyl)ethanamine (24)


3	CH₃	I

HPLC R_t= 1.50 min; LC-MS (15 minute method) 7.51 min, (M + 1)⁺287

@ 7.72 min; ¹H NMR(400 MHz, CDCl₃) 7.95(d, J=8.43Hz, 2H), 7.85(d,

J=3.30Hz, 1H), 7.44(d, J=8.43Hz, 2H), 7.32(d, J=3.30Hz, 1H), 3.13(d,

J=6.23Hz, 1H), 2.50(d, J=11.36Hz, 1H), 2.33(d, J=12.10Hz, 1H),

1.60-1.57(m, 2H), 1.33-1.20(m, 6H), 0.97-0.83(m, 3H).

(±) 1-(1-(3,4-dichlorophenyl)cyclohexyl)pentan-1-amine (25)


3	n-butyl	I

HPLC R_t= 1.68 min; LC-MS (15 minute method) 9.92 min, (M + 1)⁺316

@ 10.04 min; ¹H NMR(400 MHz, CDCl₃) 7.47-7.42(m, 2H),

7.26-7.23(m, 1H), 2.95(d, J=9.16Hz, 1H), 2.38(d, J=12.10Hz, 1H),

2.23(d, J=12.83Hz, 1H), 1.77-1.56(m, 5H), 1.45(s, 3H), 1.28-1.14(m,

6H), 0.78(t, J₁=13.56Hz, J₂=6.60Hz, 3H).

(±) 1-(1-(3,4-dichlorophenyl)cyclohexyl)heptan-1-amine (26)


3	n-hexyl	I

HPLC R_t= 1.78 min; LC-MS(15 minute method) 10.73 min, (M + 1)⁺344

@ 10.8 min; ¹H NMR(400 MHz, CDCl₃) 7.46-7.41(m, 2H),

7.26-7.21(m, 1H), 2.91(d, J=9.17Hz, 1H), 2.36(d, J=12.46Hz, 1H),

2.23(d, J=13.20Hz, 1H), 1.73-1.44(m, 7H), 1.28-1.14(m, 11H), 0.82(t,

J₁=14.30Hz, J₂=6.96Hz, 3H).

The following compounds were synthesized from the respective cyclohexyl nitrile according to General Procedure E, and were optionally converted to the respective HCl salt form:

(1-(3,4-dichlorophenyl)cyclohexyl)-methanamine hydrochloride (27)

The title compound was synthesized from 1-(3,4-dichlorophenyl)-cyclohexanecarbonitrile (920 mg, 3.62 mmol). The crude HCl salt was recrystallized from 1:5 CH₃CN/IPA (10 mL) to give pure [1-(3,4-Dichloro-phenyl)-cyclohexyl]-methylamine hydrochloride as an off-white solid. HPLC R_t=8.66 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.55-7.51 (m, 2H), 7.35-7.31 (dd, J=2.44, 8.55 Hz, 1H), 3.01 (s, 2H), 2.17-2.12 (m, 2H), 1.65-1.28 (m, 8H); LCMS 8.52 min, (M+1)⁺258 @ 8.78 min.

(1-(3-chlorophenyl)cyclohexyl)methanamine hydrochloride (28)

The title compound was synthesized from 1-(3-chlorophenyl)-cyclohexanecarbonitrile (320 mg, 1.46 mmol). The crude HCl salt was recrystallized from CH₃CN (7.5 mL) to give pure (1-(3-chlorophenyl)cyclohexyl)-methanamine hydrochloride as off-white needles/hay. HPLC R_t=8.18 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.41-7.26 (m, 4H), 3.0 (s, 2H), 2.18-2.15 (m, 2H), 1.64-1.30 (m, 8H); LC-MS 7.72 min, (M+1)⁺224 @ 8.0 min.

(1-(4-chlorophenyl)cyclohexyl)methanamine hydrochloride (29)

The title compound was synthesized from 1-(4-chlorophenyl)-cyclohexanecarbonitrile. The crude HCl salt was recrystallized from CH₃CN (3 mL) to give pure (1-(4-chlorophenyl)cyclohexyl)methanamine hydrochloride as off-white needles/hay. HPLC R_t=8.22 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.38 (s, 4H), 2.97 (s, 2H), 2.19-2.14 (m, 2H), 1.63-1.30 (m, 8H); LC-MS 7.83 min, (M+1)⁺224 at 8.1 min.

(1-(3,4-difluorophenyl)cyclohexyl)methanamine hydrochloride (30)

The title compound was synthesized from 1-(3,4-difluorophenyl)-cyclohexanecarbonitrile. The crude HCl salt was recrystallized from CH₃CN (6 mL) to give pure (1-(3,4-difluorophenyl)cyclohexyl)methanamine hydrochloride (38 mg, 17%) as off-white needles/hay HPLC R_t=8.06 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.34-7.20 (m, 3H), 2.99 (m, 2H), 2.15-2.12 (m, 2H), 1.64-1.31 (m, 8H); LC-MS 7.01 min, (M+1)⁺226 (7.16 min.

(1-phenylcyclohexyl)methaneamine hydrochloride (31)

The title compound was synthesized from 1-phenylcyclohexane-carbonitrile. The crude HCl salt was recrystallized from CH₃CN to give pure (1-phenylcyclohexyl)methaneamine hydrochloride as off-white needles. HPLC R_t=7.59 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.40-7.36 (m, 4H), 7.27-7.25 (m, 1H), 2.98 (s, 2H), 2.22-2.20 (m, 2H), 1.62-1.32 (m, 8H); LC-MS 6.16 min, (M+1)⁺190 @ 6.36 min.

(1-(3-chloro-4-fluorophenyl)cyclohexyl)-methanamine (32)

The title compound was prepared from 1-(3-chloro-4-fluorophenyl)cyclohexanecarbonitrile. A solution of the crude product in MTBE was basicified at 0° C. with KOH, extracted with MTBE and evaporated. The residue was diluted in DCM, filtered through an aminopropyl column and evaporated to give the primary amine (64.1 mg, 25%) as an oil. LCMS R_t=7.62 min, m/z=242 (M+1). ¹H NMR (CDCl₃, δ) 7.34 (dd, J=2.4, 7.1 Hz, 1H), 7.19 (ddd, J=2.4, 4.6, 8.7 Hz, 1H), 7.11 (t, J=8.7 Hz, 1H), 2.68 (s, 2H), 2.1 (m, 2H), 1.6-1.2 (m, 8H), 0.79 (bs, 2H). ¹³C NMR (CDCl₃, δ, mult): 157.4(0), 154.9(0), 142.2(0), 129.5(0), 127.0(0), 126.9(1), 120.8(1), 120.6(1), 116.3(1), 116.1(1), 54.5(2), 43.3(0), 33.7(2), 26.5(2), 22.0(2).

(1-(naphthalen-2-yl)cyclohexyl)methanamine (33)

The title compound was synthesized in 37% yield from 1-(naphthalen-2-yl)cyclohexane-carbonitrile. HPLC R_t(5-100-8)=8.44 min. LCMS R_t=8.22 min, m/z=240 (M+1). ¹H NMR (CDCl₃, δ): 7.9-7.2 (m, 7H), 2.78 (s, 2H), 2.3 (m, 2H), 1.7-1.3 (m, 8H), 0.9 (bs, 2H). ¹³C NMR (CDCl₃, δ, mult): 133.4(0), 131.7(0), 128.0(1), 127.8(1), 127.3(1), 126.4(1), 125.8(1), 125.4(1), 125.2(1), 54.6(2), 43.7(0), 33.8(2), 26.7(2), 22.2(2).

(1-(4-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (34)

The title compound was prepared from 1-(4-(trifluoromethyl)phenyl)-cyclohexanecarbonitrile (127 mg, 0.50 mmol). The crude product was purified by silica gel column chromatography (MeOH/CH₂Cl₂, MeOH from 0% to 10%) to give (1-(4-(trifluoromethyl)phenyl)cyclohexyl)methanamine (62 mg, 48%) as a clear oil. ¹H NMR (CDCl₃): δ 1.26-1.52 (m 4H), 1.54-1.61 (m, 2H), 1.66-1.73 (m, 2H), 2.13-2.18 (m, 2H), 2.28 (s, 3H), 2.63 (s, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H). ¹³C NMR (CDCl₃) δ 22.3, 26.7, 34.8, 42.9, 54.4, 125.5, 125.6, 127.9, 129.9, 149.1. ESI MS m/z 258.

(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)methanamine (35)

The title compound was prepared from 1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbonitrile (115 mg, 0.50 mmol). The crude product was purified by chromatography (SiO₂, MeOH/CH₂Cl₂, MeOH from 0% to 10%) to give (±) (1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)methanamine (58 mg, 50%) as a clear oil. ¹H NMR (CDCl₃) 1.34-1.39 (m, 3H), 1.46-1.54 (m, 7H), 2.01-2.06 (m, 2H), 2.64 (s, 2H), 5.93 (s, 2H), 6.78 (s, 2H), 6.84 (s, 1H). ¹³C NMR (CDCl₃) 22.3, 26.9, 34.3, 43.5, 54.9, 101.1, 107.9, 108.2, 120.6, 138.7, 145.6, 148.2. ESI MS m/z 234.

(1-(3-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (36)

The title compound was prepared from 1-(3-(trifluoromethyl)phenyl)-cyclohexanecarbonitrile (127 mg, 0.50 mmol). The crude product was purified by chromatography (SiO₂, MeOH/CH₂Cl₂, MeOH from 0% to 10%) to give (±) (1-(3-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (26 mg, 20%) as a clear oil. ¹H NMR (CDCl₃): 1.26-1.41 (m, 5H), 1.50-1.63 (m, 5H), 2.12-2.16 (m, 2H), 2.73 (s, 2H), 7.47-7.49 (m, 2H), 7.52-7.55 (m, 1H), 7.58 (s, 1H). ¹³C NMR (CDCl₃) 22.3, 26.7, 33.8, 43.9, 54.6, 122.9, 124.1, 124.2, 129.1, 130.8, 130.9, 146.3. ESI MS m/z 257.

(1-(3-fluorophenyl)cyclohexyl)methanamine (37)

The title compound was prepared from 1-(3-fluorophenyl)cyclohexanecarbonitrile (102 mg, 0.50 mmol). The crude product was purified by chromatography (SiO₂, MeOH/CH₂Cl₂, MeOH from 0% to 10%) to give (±) (1-(3-fluorophenyl)cyclohexyl)methanamine (32 mg, 31%) as a clear oil. ¹H NMR (CDCl₃): 1.26-1.39 (m, 5H), 1.51-1.58 (m, 5H), 2.07-2.10 (m, 2H), 2.69 (s, 2H), 6.88-6.93 (m, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 7.27-7.34 (m, 1H). ¹³C NMR (CDCl₃) 22.3, 26.8, 33.8, 43.9, 54.8, 112.7, 113.0, 114.5, 114.7, 123.0, 123.1, 129.9, 130.0, 162.3, 164.7. ESI MS m/z 208.

(1-(2,4-dichlorophenyl)cyclohexyl)methanamine (38)

¹H NMR (400 MHz, CD₃Cl) δ 7.35 (d, J=2.4 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.19 (dd, J=2.4, 8.4 Hz, 1H), 3.08 (s, 2H), 2.25 (m, 2H), 1.45 (m, 2H), 1.31 (m, 2H), 1.28-1.18 (m, 4H); ¹³C NMR (100 MHz, CD₃Cl) δ 139.91, 134.39, 133.70, 132.89, 132.23 48.61, 45.83, 33.70, 26.77, 26.66, 22.56; ESI MS m/z 258.1.

(1-(6-fluoronaphthalen-2-yl)cyclohexyl)methanamine (39)

The title compound was synthesized according to Scheme 25, below.
To a solution of 6-fluoro-naphthalene-2-carboxylic acid (3.0 g, 15.8 mmol) was added BH₃.THF (31.6 mL, 31.6 mmol). The reaction mixture was stirred overnight before being concentrated. To the residue was added diethyl ether (100 mL) and NaOH solution (10 mL). The organic layer was separated, dried and concentrated. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane 1:7) to afford (6-fluoro-naphthalen-2-yl)-methanol (2.28 g, 82%).
To a solution of (6-fluoro-naphthalen-2-yl)-methanol (2.0 g, 11.3 mmol) in CH₂Cl₂(30 mL) was added PBr₃(1.0 M in CH₂Cl₂, 22.6 mmol). The reaction mixture was stirred for 3 h at room temperature before being quenched by NH₄Cl (30 mL). The organic layer was separated, dried and concentrated. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:10) to afford 2-bromomethyl-6-fluoro-naphthalene (2.23 g, 74%).
To a mixture of 2-bromomethyl-6-fluoro-naphthalene (1.5 g, 5.9 mmoL) in CH₃CN (30 mL) was added KCN (1.16 g, 17.8 mmoL). The reaction mixture was heated at reflux for 6 h before being concentrated. To the residue was added diethyl ether (100 mL) and H₂O (15 mL). The organic layer was separated, dried and concentrated. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:10) to afford the (6-fluoro-naphthalen-2-yl)-acetonitrile (0.88 g, 70%).
The title compound was synthesized from (6-fluoro-naphthalen-2-yl)-acetonitrile (1.0 g, 5.48 mmoL) according to General Procedure J to form the intermediate nitrile (0.98 g, 71%), which was purified by silica gel column chromatography (ethyl acetate/hexane 1:7), followed by General Procedure E.
The crude product was dissolved in MeOH (4 mL) and subjected to reverse phase column chromatography (CH₃CN/H₂O/0.1% formic acid=5% to 100%) to give the title compound (0.53 g, 75%). ¹H NMR (400 MHz, CD₃Cl) δ 8.29 (m, 1H), 8.18 (m, 1H), 7.83 (m, 1H), 7.50 (dd, J=3.6, 6.8 Hz, 1H), 7.41 (dd, J=6.0 Hz, 8.8 Hz, 1H0, 7.06 (dd, J=8.8, 8.8 Hz, 1H), 3.37 (s, 2H), 2.34 (m, 2H), 1.89 (m, 2H), 1.58 (m, 2H), 1.45 (m, 2H); ¹³C NMR (100 MHz, CD₃Cl) δ 168.08, 159.85, 157.34, 132.96, 132.93, 128.58, 128.50, 126.04, 125.69, 125.67, 125.63, 125.47, 125.35, 125.32, 122.44, 122.37, 108.63, 108.44, 47.62, 43.53, 35.59, 26.43, 22.47, 22.31; ESI MS m/z 258.1.

(1-(4-fluoronaphthalen-1-yl)cyclohexyl)methanamine (40)

The title compound was synthesized from 4-fluoro-naphthalene-1-carboxylic acid (2.0 g, 10.3 mmol) according to the synthetic procedures described above for the synthesis of 39 (Scheme 25). The crude product was dissolved in MeOH (4 mL) and subjected to reverse phase column chromatography (CH₃CN/H₂O/0.1% formic acid=5% to 100%) to give 40 (0.51 g). ¹H NMR (400 MHz, CD₃OD) δ 8.48(d, J=8.4 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 7.6 (m, 3H), 7.21 (dd, J=8.4, 8.4 Hz, 1H), 3.67 (s, 2H), 2.52 (m, 2H), 2.04 (m, 2H), 1.68 (m, 2H), 1.50 (m, 4H); ¹³C NMR (100 MHz, CD₃OD), δ 160.04, 157.54, 133.03, 132.99, 131.91, 160.04, 157.54, 133.03, 132.99, 131.01, 128.74, 128.64, 126.64, 125.67, 125.65, 125.51, 125.24, 125.22, 121.80, 121.73, 108.33, 108.14, 47.00, 42.50, 35.12, 26.03, 21.89; ESI MS m/z 258.2.

1.3. Synthesis of Secondary and Tertiary Amines

Compounds in Table 2, below, were synthesized from the indicated primary amine according to the indicated General Procedure and were optionally converted to the corresponding HCl salt form.

TABLE 2




Summary of Exemplary Secondary and Tertiary Amines

Ar	n	R¹	R³	R⁴	General Procedure	Prepared From

1-(1-(3,4-dichlorophenyl)cyclobutyl)-N,N-dimethylmethanamine (41)


1	H	CH₃	CH₃	C	1

HPLC R_t= 8.42 min; ¹H NMR(400 mHz, MeOH-d⁴) 7.58-7.53(m, 2H), 7.34-7.31(m,

1H), 3.63(s, 2H), 2.65(s, 6H), 2.49-2.29(m, 4H), 2.07-1.87(m, 2H);

LC-MS 8.12 min, (M + 1)⁺258 @ 8.1 min

1-(1-(3,4-dichlorophenyl)cyclobutyl)-N-methylmethanamine (42)


1	H	H	CH₃	A	1

HPLC R_t= 8.37 min; ¹H NMR(400 mHz, MeOH-d⁴) 7.57(d, J=8.43Hz, 1H),

7.44(d, J=1.83Hz, 1H), 7.20(dd, J=2.2, 8.43Hz, 1H), 3.45(s, 2H), 2.65(s,

3H), 2.47-2.43(m, 2H), 2.37-2.31(m, 2H), 2.22-2.15(1H), 1.98-1.92(m, 1H);

LC-MS 7.1 min, (M + 1)⁺244 @ 7.28 min.

(±) 1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N-dimethylethanamine (43)


3	CH₃	CH₃	CH₃	C	2

HPLC R_t= 8.93 min; ¹H NMR(400 mHz, CDCl₃) 7.43(d, J=1.83Hz, 1H),

7.35(d, J=8.8Hz, 1H), 7.22-7.19(m, 1H), 2.54(d, J=12.8Hz, 1H), 2.44-2.40(m,

1H), 2.09-2.05(d, J=13.9Hz, 1H), 1.95(s, 6H), 1.56-1.48(m, 5H), 1.25-1.11(m,

3H), 0.76(d, J=6.97Hz, 3H); LC-MS 10.2 min, (M + 1)⁺300 @ 10.26

min.

1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (44 E1)


3	CH₃	CH₃	CH₃	D	2 E1

HPLC R_t= 9.02 min; ¹H NMR (400 MHz, CD₃OD) 7.68(d, J=2.2Hz, 1H),

7.64-7.62(m, 1H), 7.45(dd, J=2.2, 8.43Hz, 1H), 3.56-3.52(m, 1H), 2.88(s,

3H), 2.71(d, J=12.8Hz, 1H), 2.36(d, J=13.2Hz, 1H), 2.19(s, 3H), 1.70-1.60(m,

5H), 1.38-1.25(m, 5H), 1.18-1.12(m, 1H); LC-MS 9.55 min, (M + 1)⁺300 @

9.84 min.

1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (44 E2)


3	CH₃	CH₃	CH₃	D	2 E2

LC-MS 9.47 min, (M + 1)⁺300 @ 9.64 min.

(±) 1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,3-dimethylbutan-1-amine (45)


3	iso-butyl	H	CH₃	A	3

HPLC R_t= 9.57 min; ¹H NMR (400 MHz, CD₃OD) 7.59(d, J=2.20Hz, 1H),

7.54(d, J=8.80Hz, 1H), 7.35(dd, J=2.20, 8.43Hz, 1H), 3.01-2.98(m, 1H),

2.66(s, 3H), 2.39(m, 1H), 2.30(m, 1H), 1.97-1.46(m, 7H), 1.31-1.22(m, 3H),

1.12-1.06(m, 2H), 0.84(d, J=6.60Hz, 3H), 0.70(d, J=6.60Hz, 3H); LC-MS

8.93 min, (M + 1)⁺328 @ 9.18 min.

(±) 1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N,3-trimethylbutan-1-amine (46)


3	iso-butyl	CH₃	CH₃	C	3

R_t= 9.72 min; ¹H NMR(400 MHz, CD₃OD) 8.05(bs, 1H), 7.48-7.46(m, 1H),

7.40(d, J=8.43Hz, 1H), 7.23(dd, J=1.83-8.43Hz, 1H), 2.62(dd, J=3.67,

9.16Hz, 1H), 2.59-2.56(m, 1H), 2.30(s, 6H), 2.19-2.16(m, 1H), 1.61-1.11(m,

12H), 0.88-0.85(m, 6H); LC-MS 11.32 min, (M + 1)⁺342 @ 11.7 min.

(±) 1-(1-(4-methoxyphenyl)cyclohexyl)-N-methylethanamine (47)


3	CH₃	H	CH₃	A	5

HPLC R_t= 8.22 min; ¹H NMR(400 MHz, CD₃OD) 7.30-7.26(m, 2H), 6.97-6.94(m,

2H), 3.76(s, 3H), 3.09-3.04(m, 1H), 2.57(s, 3H), 2.50-2.47(m, 2H),

2.31-2.28(m, 2H), 1.59-1.45(m, 5H), 1.29-1.22(m, 3H), 1.09(d, J=6.60Hz,

3H); LC-MS 5.57 min, (M + 1)⁺248 @ 6.07 min

1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (48 E1)


3	CH₃	H	CH₃	A	2 E1

HPLC R_t= 8.94 min; ¹H NMR(400 MHz, CD₃OD) 7.61-7.58(m, 2H), 7.36(dd,

J=2.2, 8.43Hz, 1H), 3.20-3.16(m, 1H), 2.65(s, 3H), 2.51(d, J=12.5Hz, 1H),

2.34(d, J=10.6Hz, 1H), 1.69-1.55(m, 5H), 1.35-1.12(m, 6H); LC-MS 7.08

min, (M + 1)⁺286 @ 7.46 min. [α]_D= −2.68(c = 0.41, MeOH).

1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (48 E2)


3	CH₃	H	CH₃	A	2 E2

LC-MS 7.03 min, (M + 1)⁺286 @ 7.58 min.

1-(1-(biphenyl-4-yl)cyclohexyl)-N-methylmethanamine (49)


3	H	H	CH₃	A	8

HPLC R_t= 9.06 min; ¹H NMR(400 MHz, CD₃OD) 7.66(d, J=8.06Hz, 2H),

7.59(d, J=8.43Hz, 2H), 7.50(d, J=8.06Hz, 2H), 7.40(d, J=7.70Hz, 2H),

7.31-7.29(m, 1H), 3.14(s, 2H), 2.54(s, 3H), 2.29-2.27(m, 2H), 1.69-1.52(m,

5H), 1.43-1.37(m, 3H); LC-MS 7.05 min, (M + 1)⁺280 @ 7.52 min.

(±) 1-(1-(4-chlorophenyl)cyclohexyl)-N-methylethanamine (50)


3	CH₃	H	CH₃	A	11

HPLC R_t= 8.59 min; ¹H NMR(400 MHz, CD₃OD) 7.43-7.34(m, 4H), 3.14-3.08(m,

1H), 2.59(d, J=0.73Hz, 3H), 2.52-2.48(d, J=12.2Hz, 1H), 2.33-2.29(d,

J=13.4Hz, 1H), 1.59-1.47(m, 5H), 1.31-1.13(m, 3H), 1.09(d, J=6.84Hz,

3H); LC-MS 7.10 min, (M + 1)⁺252 @ 7.32 min.

(±) N-methyl-1-(1-(thiophen-2-yl)cyclohexyl)ethanamine (51)


3	CH₃	H	CH₃	A	6

HPLC R_t= 7.92 min; ¹H NMR(400 MHz, CD₃OD) 7.42-7.40(m, 1H), 7.07-7.04(m,

1H), 7.01-6.99(m, 1H), 3.17-3.10(m, 1H), 2.61(s, 3H), 2.42-2.38(m,

1H); 2.14-2.10(m, 1H), 1.64-1.26(m, 8H), 1.19(d, J=6.59Hz, 3H); LC-MS

5.80 min, (M + 1)⁺224 @ 6.19 min.

N,N-dimethyl-1-(1-(4-(methylthio)phenyl)cyclohexyl)methanamine (52)


3	H	CH₃	CH₃	C	10

HPLC R_t= 8.54 min; ¹H NMR(400 MHz, CD₃OD) 7.39(d, J=8.07Hz, 2H),

7.30-7.28(m, 2H), 3.34(s, 2H), 2.52(s, 6H), 2.43(s, 3H), 2.26-2.23(d, J=11.7Hz,

2H), 1.66-1.52(m, 5H), 1.38-1.37(m, 3H); LC-MS 6.97 min, (M + 1)⁺264 @

7.16 min.

N,N-dimethyl-1-(1-(naphthalen-1-yl)cyclohexyl)methanamine (53)


3	H	CH₃	CH₃	F	12

HPLC R_t= 8.96 min; ¹H NMR(400 MHz, CD₃OD) 8.00-7.86(m, 4H), 7.65(dd,

J=2.2, 8.8Hz, 1H), 7.54-7.51(m, 2H), 3.52(s, 2H), 2.54(s, 6H), 2.46-2.44(d, J=8.43Hz,

2H), 1.84-1.50(m, 9H); LC-MS 8.28 min, (M + 1)⁺268 @ 8.39 min.

(±) 1-(1-(4-chlorophenyl)cyclohexyl)-N,2-dimethylpropan-1-amine (54)


3	iso-propyl	H	CH₃	F	14

HPLC R_t= 9.09 min; ¹H NMR(400 MHz, CD₃OD) 7.40(s, 4H), 2.99(s, 1H),

2.67(s, 3H), 2.45-2.38(m, 2H), 2.17-2.14(m, 1H), 1.61-1.53(m, 5H), 1.31-1.16(m,

3H), 0.98(d, J=7.33Hz, 3H), 0.65(d, J=6.97Hz, 3H); LC-MS 9.26 min,

(M + 1)⁺280 @ 9.29 min.

(±) N,N-dimethyl-1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (55)


3	CH₃	CH₃	CH₃	F	13

HPLC R_t= 9.04 min; ¹H NMR(400 MHz, CDCl₃) 7.82-7.76(m, 4H), 7.58-7.56(m,

1H), 7.45-7.39(m, 2H), 2.78(d, J=12.5Hz, 1H), 2.53-2.48(m, 1H), 2.30(d,

J=13.6Hz, 1H), 1.94-1.18(m, 8H), 0.76(d, J=6.96Hz, 3H); LC-MS 8.04

min, (M + 1)⁺282 @ 8.16 min.

N,N-dimethyl-1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (56 E1)


3	CH₃	CH₃	CH₃	F	13 E1

HPLC R_t= 9.12 min; ¹H NMR(400 MHz, CD₃OD) 8.03(d, J=1.1Hz, 1H),

7.99(d, J=8.80Hz, 1H), 7.96-7.93(m, 1H), 7.90-7.88(m, 1H), 7.65(dd, J=1.83,

8.80Hz, 1H), 7.56-7.51(m, 2H), 3.59(q, J=6.97, 13.9Hz, 1H), 2.95-2.92(m,

1H), 2.87(s, 3H), 2.59-2.56(m, 1H), 2.0(s, 3H), 1.76-1.19(m, 11H); LC-MS

7.37 min, (M + 1)⁺282 @ 7.60 min.

N,N-dimethyl-1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (56 E2)


3	CH₃	CH₃	CH₃	F	13 E2

LC-MS 8.42 min, (M + 1)⁺282 @ 8.57 min.

N-methyl-1-(1-(naphthalen-1-yl)cyclohexyl)methanamine (57)


3	H	H	CH₃	A	12

HPLC R_t= 8.65 min; ¹H NMR(400 MHz, CD₃OD) 8.67(d, J=8.8Hz, 1H),

7.98(d, J=1.47Hz, 1H), 7.96(d, J=1.83Hz, 1H), 7.89(d, J=8.43Hz, 1H),

7.67-7.50(m, 3H), 3.80(bs, 2H), 2.63-2.58(s, 2H), 2.55(s, 3H), 2.05-2.01(bs,

2H), 1.69(bs, 2H), 1.55(bs, 3H); LC-MS 7.36 min, (M + 1)⁺254 @ 7.50 min.

N-methyl-1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (58 E1)


3	CH₃	H	CH₃	A	13 E1

HPLC R_t= 8.93 min; ¹H NMR(400 MHz, CD₃OD) 7.98-7.87(m, 4H), 7.60-7.57(m,

1H), 7.55-7.50(m, 2H), 3.30(1H, hidden), 2.76-2.72(m, 1H), 2.64(s,

3H), 2.59-2.55(m, 1H), 1.69-1.60(m, 6H), 1.41-1.30(m, 3H), 1.21(d, J=6.96Hz,

3H); LC-MS 7.92 min, (M + 1)⁺268 @ 8.06 min.

N-methyl-1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (58 E2)


3	CH₃	H	CH₃	A	13 E2

LC-MS 7.88 min, (M + 1)⁺268 @ 8.00 min.

N-methyl-1-(1-(naphthalen-1-yl)cyclohexyl)ethanamine (59 E1)


3	CH₃	H	CH₃	A	16 E1

HPLC R_t= 1.56 min; LC-MS (5 minute method) 2.75 min, (M + 1)⁺268 @ 2.84

min.; ¹H NMR(300 MHz, CD₃OD) 8.43(s, 1H), 8.33(d, J=8.80Hz, 1H), 7.85(t,

1H), 7.78(d, J=8.07Hz, 1H), 7.56(d, J=7.70Hz, 1H), 7.45-7.38(m, 2H), 4.05(m,

1H), 2.52(bs, 5H), 1.82-1.78(m, 2H), 1.75-1.48(m, 4H), 1.32-1.06(m, 5H).

N-methyl-1-(1-(naphthalen-1-yl)cyclohexyl)ethanamine (59 E2)


3	CH₃	H	CH₃	A	16 E2

LC-MS (15 minute method) 7.19 min, (M + 1)⁺268 @ 7.52 min.

N,N-dimethyl-1-(1-(naphthalen-1-yl)cylcohexyl)ethanamine (60 E1)


3	CH₃	CH₃	CH₃	F	16 E1

HPLC R_t= 1.85 min; LC-MS (5 minute method) 2.63 min, (M + 1)⁺282 @ 2.74

min.

N,N-dimethyl-1-(1-(naphthalen-1-yl)cyclohexyl)ethanamine (60 E2)


3	CH₃	CH₃	CH₃	F	16 E2

LC-MS (15 minute method) 8.08 min, (M + 1)⁺282 @ 8.14 min.

1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N-dimethylpropan-1-amine (61 E1)


3	ethyl	CH₃	CH₃	F	17

HPLC R_t= 1.61 min; LC-MS (15 minute method) 11.91 min, (M + 1)⁺316 @ 12.08

min; ¹H NMR(300 mHz, CD₃OD) 8.40(s, 1H), 7.43-7.37(m, 2H), 7.26-7.22(m,

1H), 2.62(d, J=12.46, 1H), 2.46-2.42(m, 1H), 2.33(s, 6H), 2.17(d, J=2.57, 1H),

1.63-1.46(m, 6H), 1.31-1.18(m, 3H), 1.13-1.04(m, 1H), 0.89(t, 3H).

1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N-dimethylpropan-1-amine (61 E2)


3	ethyl	CH₃	CH₃	F	17 E2

LC-MS (15 minute method) 11.90 min, (M + 1)⁺316 @ 12.04 min.

1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylpropan-1-amine (62 E1)


3	ethyl	H	CH₃	A	17 E1

HPLC R_t= 1.61 min; LC-MS (15 minute method) 9.09 min, (M + 1)⁺302 @ 9.21

min; ¹H NMR(400 mHz, CDCl₃) 7.47-7.42(m, 2H), 7.25(d, J=7.70Hz, 1H),

2.54(s, 3H), 2.42-2.40(m, 1H), 2.33(d, J=13.20, 1H), 2.20(d, J=12.83, 1H),

1.76(t, J=11.73, 1H), 1.68-1.57(m, 5H), 1.36-1.14(m, 4H), 0.89(t, J=7.33Hz,

4H).

1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylpropan-1-amine (62 E2)


3	ethyl	H	CH₃	A	17 E2

LC-MS (15 minute method) 9.31 min, (M + 1)⁺302 @ 9.36 min.

N,N-dimethyl-1-(1-(4-(trifluoromethoxy)phenyl)cyclohexyl)ethanamine (63 E1)


3	CH₃	CH₃	CH₃	F	19 E1

HPLC R_t= 1.58 min; LC-MS (15 minute method) 9.68 min, (M + 1)⁺316 @ 9.90

min. ¹H NMR(400 MHz, CDCl₃) 7.64(d, J=8.80Hz, 2H), 7.39(d, J=8.43Hz,

2H), 4.85(s, 3H), 3.59-3.53(m, 1H), 3.34-3.30(m, 3H), 2.78(d, J=12.5Hz,

1H), 2.40(d, J=13.2Hz, 1H), 1.73-1.59(m, 5H), 1.40-1.34(m, 2H), 1.27-1.25(m,

3H), 1.16-1.15(m, 1H).

N,N-dimethyl-1-(1-(4-(trifluoromethoxy)phenyl)cyclohexyl)ethanamine (63 E2)


3	CH₃	CH₃	CH₃	F	19 E2

LC-MS (15 minute method) 9.69 min, (M + 1)⁺316 @ 9.88 min.

N-methyl-1-(1-(4-(trifluoromethoxy)phenyl)cyclohexyl)ethanamine (64 E1)


3	CH₃	H	CH₃	A	19 E1

HPLC R_t= 1.52 min; LC-MS (15 minute method) 7.82 min, (M + 1)⁺302 @ 7.94

min.; ¹H NMR(400 MHz, CD₃OD) 7.54(d, J=8.80Hz, 2H), 7.37(d, J=8.43Hz,

2H), 3.19-3.14(m, 1H), 2.64(s, 3H), 2.57(d, J=11.73Hz, 1H), 2.39(d,

J=12.83Hz, 1H), 1.69-1.57(m, 5H), 1.37-1.22(m, 3H), 1.14-1.13(d, J=6.6Hz,

3H).

N-methyl-1-(1-(4-(trifluoromethoxy)phenyl)cyclohexyl)ethanamine (64 E2)


3	CH₃	H	CH₃	A	19 E2

LC-MS (15 minute method) 7.91 min, (M + 1)⁺302 @ 8.20 min.

The following compounds were synthesized from the corresponding primary amine according to General Procedure F. The crude product was purified by silica gel column chromatography to give the respective mono- and di-methylated products.

1-(1-(2,4-dichlorophenyl)cyclohexyl)-N-methylmethanamine (65)

The title compound was synthesized from 38. ¹H NMR (400 MHz, CD₃Cl) δ 7.35 (d, J=8.4 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.19 (dd, J=8.4, 2.4 Hz, 1H), 3.00 (s, 2H), 2.31 (s, 3H), 2.31-2.28 (m, 2H), 1.83 (m, 2H), 1.56 (m, 2H), 1.48-1.29 (m, 4H); ¹³C NMR (400 MHz, CD₃Cl) δ 140.61, 134.31, 132.63, 132.53, 132.08, 126.99, 58.24, 44.40, 37.68, 34.44, 26.67, 22.58; ESI MS m/z 272.07.

1-(1-(2,4-dichlorophenyl)cyclohexyl)-N,N-dimethylmethanamine (66)

The title compound was synthesized from 38. ¹H NMR (400 MHz, CD₃Cl) δ 7.42 (d, J=8.8 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.20 (dd, J=8.8, 2.0 Hz, 1H), 3.04 (s, 2H), 2.40 (m, 2H), 2.18 (s, 6H), 1.80 (m, 2H), 1.54 (m, 2H), 1.48-1.32 (m, 4H); ¹³C NMR (100 MHz, CD₃Cl) δ 139.8, 134.27, 133.03, 132.99, 132.07, 127.29, 65.40, 47.26, 44.12, 34.37, 26.37, 22.34; ESI MS m/z 286.1.

1-(1-(6-fluoronaphthalen-2-yl)cyclohexyl)-N-methylmethanamine (67)

The title compound was synthesized from 39. ¹H NMR (400 MHz, CD₃Cl) δ 8.55 (m, 1H), 8.19 (m, 1H), 7.56-7.40 (m, 2H), 7.30 (m, 1H), 3.22 (s, 2H), 2.32 (m, 1H), 2.25 (s, 3H), 2.26 (m, 1H), 1.62 (m, 1H), 1.54-1.35 (m, 5H); ¹³C NMR (400 MHz, CD₃Cl) 167.08, 159.65, 156.34, 132.86, 132.83, 127.56, 127.49, 126.06, 125.92, 125.85, 125.83, 125.72, 125.32, 125.29, 122.11, 122.03, 108.64, 108.45, 60.17, 44.42, 37.61, 36.73, 35.90, 26.89, 26.82, 22.68, 22.73; ESI MS m/z 272.1.

1-(1-(6-fluoronaphthalen-2-yl)cyclohexyl)-N,N-dimethylmethanamine (68)

The title compound was synthesized from 39. ¹H NMR (400 MHz, CD₃Cl) δ 8.47 (m, 1H), 8.17 (m, 1H), 7.50-7.44 (m, 2H), 7.08 (dd, J=10.0, 8.4 Hz, 1H), 2.95 (m, 2H), 2.39 (m, 2H), 2.14 (m, 2H), 1.97 (s, 6H), 1.59 (m, 2H), 1.44(m, 2H); ¹³CNMR (100 MHz, CD₃Cl) 167.07, 158.95, 158.31, 133.87, 132.73, 127.32, 127.23, 126.74, 126.72, 125.32, 125.00, 124.99, 121.96, 121.90, 108.61, 108.41, 68.39, 48.40, 45.03, 37.61, 36.62, 26.91, 22.74; ESI MS m/z 286.3.

1-(1-(4-fluoronaphthalen-1-yl)cyclohexyl)-N-methylmethanamine (69)

The title compound was synthesized from 40. ¹H NMR (400 MHz, CD₃OD) δ 8.5 (m, 1H) 8.19 (m, 1H), 7.5 (m, 3H), 7.10 (dd, J=8.4, 9.0 Hz, 1H), 3.22 (s, 2H), 2.31 (m, 2H), 2.25 (s, 3H), 2.04 (m, 2H), 1.61 (m, 2H), 1.44 (m, 4H); ¹³C NMR (100 MHz, CD₃OD) δ 159.26, 156.78, 136.59, 133.32, 133.29, 159.26, 156.78, 136.59, 133.32, 133.29, 127.56, 127.48, 125.85, 125.85, 125.31, 125.29, 122.11, 122.03, 108.64, 108.46, 60.13, 44.41, 37.59, 36.72, 29.94, 26.89, 26.82, 22.72; ESI MS m/z 272.2.

1-(1-(4-fluoronaphthalen-1-yl)cyclohexyl)-N,N-dimethylmethanamine (70)

The title compound was synthesized from 40. ¹H NMR (400 MHz, CD₃OD) δ 8.44 (m, 1H), 8.18 (m, 1H), 7.50 (m, 3H), 7.09 (dd, J=8.8, 8.8 Hz, 1H), 2.95 (s, 2H), 2.38 (m, 2H), 2.20 (m, 2H), 1.96 (s, 6H), 1.60 (m, 4H), 1.44 (m, 2H); ¹³C NMR (100 MHz, CD₃OD), δ 159.06, 156.57, 133.53, 127.22, 126.76, 126.73, 125.32, 125.00, 124.99, 121.96, 121.89, 108.00, 108.43, 68.40, 48.42, 45.03, 36.63, 29.94, 26.92, 22.74; ESI MS m/z 286.2.

1-(1-(3,4-dichlorophenyl)cyclohex-3-enyl)-N,N-dimethylmethanamine (72)

The title compound was synthesized according to Scheme 26, below.
(a) The primary amine 71 was synthesized from 1-(3,4-dichlorophenyl)-4-oxocyclohexanecarbonitrile according to General Procedures Q, U, and E1. ¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, J=8.4 Hz, 1H), 7.39(s, 1H), 7.17 (d, J=8.4 Hz, 1H), 5.75 (m, 1H), 5.64 (m, 1H), 3.16 (d, J=12.8 Hz, 1H), 3.03 (d, J=12.8 Hz, 1H), 2.5 (d, J=16.8 Hz, 1H), 2.23 (d, J=16.8 Hz, 1H), 2.06 (m, 1H), 1.95 (m, 1H), 1.84 (m, 1H), 1.74 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 140.55, 133.33, 131.96, 131.33, 129.30, 127.53, 126.59, 123.44, 50.25, 39.35, 32.24, 30.58, 22.03; ESI MS m/z 256.1.
The title compound was synthesized from 71 according to General Procedure D. ¹H NMR (400 MHz, CDCl₃) δ 8.35 (broad, 1H), 7.41(s, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 5.75 (m, 1H), 5.62 (m, 1H), 3.02 (s, 2H), 2.64 (d, J=15.6 Hz, 1H), 2.45 (d, J=18.8 Hz, 1H), 2.36 (s, 6H), 1.98 (m, 1H), 1.88 (m, 2H), 1.58 (m, 1H); ¹³C NMR (100 MHz, CDCl₃), δ 144.16, 138.66, 132.99, 131.14, 130.70, 129.04, 127.36, 126.53, 124.13, 69.27, 47.54, 46.45, 40.38, 33.04, 32.93, 21.99; ESI MS m/z 284.0.

N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-N-ethylethanamine (hydrochloride) (73)

(a) Synthesis of 1-(3,4-dichlorophenyl)-N,N-diethylcyclohexane-carboxamide

The amide was synthesized from 1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (232 mg, 0.85 mmol) and diethyl amine using General Procedure G and was isolated in 13% yield as a white solid. HPLC R_t=12.0 min; ¹H NMR (400 mHz, CDCl₃) 7.38-7.26 (m, 2H), 7.08 (dd, J=2.2, 8.4 Hz, 1H), 3.29 (bs, 2H), 2.84 (bs, 2H), 2.26 (d, J=12.1 Hz, 2H), 1.73-1.54 (m, 7H), 1.29-1.24 (m, 2H), 1.08 (bs, 3H), 0.82 (bs, 3H); ¹³C NMR (100 mHz, CDCl₃) 172.9, 147.2, 133.0, 130.8, 130.4, 127.5, 125.2, 51.2, 42.0, 40.9, 37.3, 26.0, 23.7, 13.4, 12.4; GC-MS (SCOUT) 13.2 min, M⁺327.

(b) Synthesis of N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-N-ethylethanamine (hydrochloride)

The title compound was synthesized from 1-(3,4-dichlorophenyl)-N,N-diethylcyclohexanecarboxamide (19 mg, 0.058 mmol) using General Procedure E followed by HCL salt formation. The crude HCl salt was recrystallized from EtOAc (1.5 mL) to give pure [1-(3,4-Dichloro-phenyl)-cyclohexylmethyl]-diethyl-amine hydrochloride as an off-white solid. HPLC R_t=9.07 min; ¹H NMR (MeOH-d⁴) 7.65 (d, J=2.20 Hz, 1H), 7.55 (d, J=8.55 Hz, 1H), 7.43 (dd, J=2.2, 8.55 Hz, 1H), 3.24 (s, 2H), 2.90-2.83 (m, 4H), 2.30-2.25 (m, 2H), 1.68-1.53 (m, 5H), 1.35-1.24 (m, 3H), 1.10 (at, 6H); LCMS 10.8 min, (M+1)⁺314 (11.0 min.

1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N-dimethylmethanamine (hydrochloride) (74)

(a) Synthesis of 1-(3,4-dichlorophenyl)-N,N-dimethylcyclohexane carboxamide

The amide was synthesized from 1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (182 mg, 0.67 mmol) and dimethyl amine using General Procedure G and isolated in 36% yield as a white solid. HPLC R_t=11.27 min; ¹H NMR (400 mHz, CDCl₃) 7.36-7.34 (m, 2H), 7.06 (dd, J=2.2, 8.4 Hz, 1H), 2.71 (bs, 6H), 2.29 (d, J=12.1 Hz, 2H), 1.68-1.53 (m, 7H), 1.25-1.21 (m, 2H); ¹³C NMR (100 mHz, CDCl₃) 173.9, 146.9, 133.0, 130.9, 130.4, 127.4, 125.2, 51.0, 38.1, 36.7, 25.9, 23.6; GC-MS (SCOUT) 12.8 min, M⁺299.

(b) Synthesis of 1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N-dimethylmethanamine (hydrochloride)

The title compound was synthesized from 1-(3,4-dichlorophenyl)-N,N-dimethylcyclohexanecarboxamide (71 mg, 0.24 mmol) using General Procedure E followed by HCl salt formation. The crude HCl salt was recrystallized from CH₃CN (3 mL) to afford the product as an off-white solid. HPLC R_t=8.70 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.72 (d, J=2.44 Hz, 1H), 7.63 (d, J=8.55 Hz, 1H), 7.49 (dd, J=2.44, 8.55 Hz, 1H), 3.47 (bs, 2H), 3.32 (s, 6H), 2.28-2.24 (bs, 2H), 1.81-1.39 (m, 8H); LCMS 9.79 min, (M+1)⁺286 @ 10.0 min.

Synthesis of 1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylmethanamine (hydrochloride) (75)

(a) Synthesis of 1-(3,4-dichlorophenyl)-N-methylcyclohexane-carboxamide

The amide was synthesized from 1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (218 mg, 0.80 mmol) and methyl amine using General Procedure G and was isolated in 35% yield as a white solid. HPLC R_t=10.3 min; ¹H NMR (400 mHz, CDCl₃) 7.47 (d, J=2.20 Hz, 1H), 7.41 (d, J=8.55 Hz, 1H), 7.24 (dd, J=2.44, 8.55 Hz, 1H), 2.71 (d, J=4.88 Hz, 3H), 2.29-2.21 (m, 2H), 1.93-1.85 (m, 2H), 1.61-1.38 (m, 6H); GC-MS (SCOUT) 12.87 min, M⁺285.

(b) Synthesis of 1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylmethanamine (hydrochloride)

The title compound was synthesized from 1-(3,4-dichlorophenyl)-N-methylcyclohexanecarboxamide (80 mg, 0.28 mmol) using General Procedure E followed by HCL salt formation. The crude HCl salt was recrystallized from CH₃CN (3 mL) to give pure 1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylmethanamine hydrochloride as an off-white solid. HPLC R_t=8.67 min; ¹H NMR (400 mHz, CDCl₃) 7.57-7.54 (m, 2H), 7.34 (dd, J=2.2, 8.43 Hz, 1H), 3.12 (s, 2H), 2.54 (s, 3H), 2.16-2.13 (m, 2H), 1.68-1.50 (m, 5H), 1.41-1.30 (m, 3H); LCMS 8.26 min, (M+1)⁺272 @ 8.50 min.

N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-N-methylethanamine (hydrochloride) (76)

(a) 1-(3,4-dichlorophenyl)-N-ethyl-N-methyl-cyclohexane-carboxamide

The amide was synthesized from 1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (390 mg, 1.43 mmol) and ethylmethylamine using General Procedure G and was isolated in 30% yield as a white solid. HPLC R_t=11.66 min; ¹H NMR (400 mHz, CDCl₃) 7.40-7.30 (m, 2H), 7.10 (dd, J=2.2, 8.4 Hz, 1H), 3.31 (bs, 2H), 2.59 (bs, 3H), 2.30 (d, J=12.5 Hz, 2H), 1.76-1.55 (m, 7H), 1.32-1.25 (m, 2H), 1.00 (bs, 3H); ¹³C NMR (100 mHz, CDCl₃) 147.0, 132.9, 130.8, 130.3, 127.5, 125.2, 51.0, 44.5, 36.8, 25.9, 23.5; GC-MS (SCOUT) 13.01 min, M⁺313.

(b) N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-N-methylethanamine

The title compound was synthesized from 1-(3,4-dichlorophenyl)-N-ethyl-N-methylcyclohexanecarboxamide (130 mg, 0.414 mmol) using General Procedure E followed by HCl salt formation. The crude HCl salt was recrystallized from CH₃CN (3 mL) to give pure N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-N-methylethanamine as white crystals. HPLC R_t=9.00 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.65 (d, J=2.2 Hz, 1H), 7.56 (d, J=8.43 Hz, 1H), 7.42 (dd, J=2.2, 8.43 Hz, 1H), 3.43-3.40 (m, 1H), 2.96-2.94 (m, 2H), 2.48 (s, 3H), 2.24 (m, 2H), 1.66-1.53 (m, 5H), 1.41-1.31 (m, 3H), 1.14 (t, 3H); LC-MS 10.07 min, (M+1)⁺300 @ 10.3 min.

N-((1-(3,4-dichlorophenyl)cyclohexyl)-methyl)ethanamine hydrochloride (77)

(a) 1-(3,4-dichlorophenyl)-N-ethylcyclohexane-carboxamide

The amide was synthesized from 1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (280 mg, 1.03 mmol) and ethylamine using General Procedure G and was isolated in 28% yield as a white solid. HPLC R_t=10.61 min; ¹H NMR (400 mHz, CDCl₃) 7.44 (d, J=2.2 Hz, 1H), 7.37 (d, J=8.43 Hz, 1H), 7.21 (dd, J=2.2, 8.4 Hz, 1H), 5.4 (bs, 1H), 3.21-3.14 (m, 2H), 2.25-2.20 (m, 2H), 1.86-1.79 (m, 2H), 1.58-1.52 (m, 5H), 1.35-1.32 (m, 1H), 1.00 (at, 3H); ¹³C NMR (100 mHz, CDCl₃) 174.3, 144.8, 132.8, 130.9, 130.7, 128.7, 126.2, 50.5, 34.8, 34.7, 25.7, 23.0, 14.8; GC-MS (SCOUT) 12.9 min, M⁺299.

(b) N-((1-(3,4-dichlorophenyl)cyclohexyl)-methyl)ethanamine (hydrochloride)

The title compound was synthesized from 1-(3,4-dichlorophenyl)-N-ethylcyclohexanecarboxamide (86 mg, 0.286 mmol) using General Procedure E followed by HCl salt formation. The crude HCl salt was recrystallized from CH₃CN (4.5 mL) to give pure (±) N-((1-(3,4-dichlorophenyl)cyclohexyl)-methyl)ethanamine hydrochloride as colorless crystals. HPLC R_t=8.90 min; ¹H NMR (400 mHz, McOH-d⁴) 7.57 (d, J=2.2 Hz, 1H), 7.54 (d, J=8.43 Hz, 1H), 7.34 (dd, J=2.2, 8.43 Hz, 1H), 3.11 (s, 3H), 2.94-2.88 (q, 2H), 2.18-2.15 (m, 2H), 1.68-1.58 (m, 5H), 1.51-1.30 (m, 3H), 1.17 (t, 3H); LC-MS 8.45 min, (M+1)⁺286 @ 8.7 min.

N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-cyclopropanamine hydrochloride (78)

(a) Synthesis of 1-(3,4-dichlorophenyl)-N-cyclopropylcyclo-hexanecarboxamide

The tile compound was synthesized from 1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (372 mg, 1.37 mmol) and cyclopropylamine using General Procedure G and was isolated in 25% yield as a white solid. HPLC R_t=10.6 min; ¹H NMR (400 mHz, CDCl₃) 7.45 (d, J=2.2 Hz, 1H), 7.39 (d, J=8.43 Hz, 1H), 7.23-7.21 (m, 1H), 5.49 (bs, 1H), 2.62-2.59 (m, 1H), 2.25-2.20 (m, 2H), 1.84-1.78 (m, 2H), 1.59-1.55 (m, 5H), 1.38-1.33 (m, 1H), 0.73-0.68 (m, 2H), 0.37-0.33 (m, 2H); ¹³C NMR (100 mHz, CDCl₃) 176.0, 144.8, 133.0, 131.0, 130.8, 128.6, 126.2, 50.4, 34.9, 25.7, 23.1, 6.91; GC-MS (SCOUT) 13.5 min, M⁺311.

(b) Synthesis of N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-cyclopropanamine hydrochloride

The title compound was synthesized from 1-(3,4-dichlorophenyl)-N-cyclopropylcyclohexane carboxamide (108 mg, 0.35 mmol) using General Procedure E followed by HCl formation. The crude HCl salt was recrystallized from 3:1 EtOAc:CH₃CN (4 mL) and 1:1 EtOAc:CH₃CN (3 mL) to give pure N-((1-(3,4-dichlorophenyl)cyclohexyl)-methyl)cyclopropanamine hydrochloride as white crystals. HPLC R_t=9.02 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.57-7.52 (m, 2H), 7.35 (dd, J=1.83, 8.43 Hz, 1H), 3.29 (s, 2H), 2.56-2.54 (m, 1H), 2.16-2.13 (m, 2H), 1.67-1.30 (m, 8H), 0.78-0.74 (m, 4H); LC-MS 10.6 min, (M+1)⁺298 @ 10.8 min.

Synthesis of (1-(3-chlorophenyl)cyclohexyl)-N-methylmethanamine hydrochloride (79)

General Procedure H: A solution of 1-(3-chlorophenyl)cyclohexane-carbaldehyde (119 mg, 0.53 mmol), methyl amine (291 μL, 0.58 mmol, 2.0 M in THF) and sodium cyanoborohydride (100 mg, 1.59 mmol) in 1:1 MeOH:Triethylorthoformate (4 mL) was shaken at RT overnight. The solution was poured into saturated aqueous K₂CO₃and washed with EtOAc (2×20 mL). The combined organic washes were dried (Na₂SO₄), filtered and concentrated. The crude material was dissolved in Et₂O and HCl (1.5 mL, 2.0 M in Et₂O) was added. The reaction was concentrated and the HCl salt was recrystallized from CH₃CN (4.5 mL) to give pure (1-(3-chlorophenyl)cyclohexyl)-N-methylmethanamine hydrochloride as colorless crystals HPLC R_t=8.25 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.43-7.28 (m, 4H), 3.12 (s, 2H), 2.54 (s, 3H), 2.19-2.16 (m, 2H), 1.67-1.30 (m, 8H); LC-MS 7.29 min, (M+1)⁺238 @ 7.50 min.

N-methyl(1-phenylcyclohexyl)methanamine (hydrochloride) (80)

The title compound was synthesized from 1-phenylcyclohexane-carbaldehyde (126 mg, 0.67 mmol) and methyl amine (370 μL, 0.73 mmol, 2.0 M in THF) according to General Procedure H, followed by HCl salt formation. The HCl salt was recrystallized from CH₃CN to give pure N-methyl(1-phenylcyclohexyl)methanamine hydrochloride (8 mg, 6%) as colorless crystals. HPLC R_t=7.76 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.43-7.38 (m, 4H), 7.28-7.25 (m, 1H), 3.11 (s, 2H), 2.50 (s, 3H), 2.25-2.22 (m, 2H), 1.67-1.23 (m, 8H); LC-MS 6.37 min, (M+1)⁺204 @ 6.62 min.

(1-(3,4-difluorophenyl)cyclohexyl)-N-methylmethanamine hydrochloride (81)

The title compound was synthesized from 1-(3,4-difluorophenyl)-cyclohexanecarbaldehyde (131 mg, 0.58 mmol) and methyl amine (320 μL, 0.64 mmol, 2.0 M in THF) according to General Procedure H, followed by HCl salt formation. The HCl salt was recrystallized from CH₃CN to give pure (1-(3,4-difluorophenyl)cyclohexyl)-N-methylmethanamine hydrochloride as colorless crystals. HPLC R_t=8.15 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.36-7.21 (m, 3H), 3.11 (s, 2H), 2.55 (d, J=3.67 Hz, 3H), 2.15-2.12 (m, 2H), 1.67-1.31 (m, 8H); LC-MS 7.04 min, (M+1)⁺240 @ 7.19 min.

(1-(3-chlorophenyl)cyclohexyl)-N,N-dimethylmethanamine hydrochloride (82)

The title compound was synthesized from 1-(3-chlorophenyl)-N,N-dimethylcyclohexanecarboxamide (191 mg, 0.72 mmol) using General Procedure E, followed by HCl salt formation. The crude HCl salt was recrystallized from 2:1 CH₃CN:EtOAc (4.5 mL) to give pure (1-(3-chlorophenyl)cyclohexyl)-N,N-dimethylmethanamine hydrochloride as an off-white solid (21 mg, 12%). HPLC R_t=8.41 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.51-7.30 (m, 4H), 3.26-3.24 (m, 2H), 2.54 (s, 6H), 2.24-2.20 (m, 2H), 1.72-1.33 (m, 8H); LC-MS 8.16 min, (M+1)⁺252 @ 8.27 min.

(1-(3,4-difluorophenyl)cyclohexyl)-N,N-dimethylmethanamine hydrochloride (83)

The title compound was synthesized from 1-(3,4-difluorophenyl)-N,N-dimethylcyclohexanecarboxamide (195 mg, 0.73 mmol) using General Procedure E (the amide was prepared from the corresponding carboxylic acid according to General Procedure G), followed by HCl salt formation. The crude HCl salt was recrystallized from 1:1 CH₃CN:EtOAc (3.0 mL) to give pure (1-(3,4-difluorophenyl)cyclohexyl)-N,N-dimethylmethanamine hydrochloride as an off-white solid (16 mg, 8%). HPLC R_t=8.24 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.51-7.46 (m, 1H), 7.37-7.34 (m, 2H), 3.31-3.30 (m, 2H), 2.62 (s, 6H), 2.26-2.23 (m, 2H), 1.78-1.38 (m, 8H); LC-MS 7.69 min, (M+1)⁺254 @ 7.91 min.

(1-(4-chlorophenyl)cyclohexyl)-N-methylmethanamine hydrochloride (84)

The title compound was synthesized from 1-(4-chlorophenyl)-N-methylcyclohexanecarboxamide (278 mg, 1.11 mmol) using General Procedure E, followed by HCl salt formation to give pure (1-(4-chlorophenyl)cyclohexyl)-N-methylmethanamine hydrochloride as an off-white solid (185 mg, 70%). HPLC R_t=8.38 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.39 (s, 4H), 3.10 (s, 2H), 2.52 (s, 3H), 2.19-2.16 (m, 2H), 1.65-1.49 (m, 6H), 1.37-1.30 (m, 4H); LC-MS 7.49 min, (M+1)⁺238 (7.63 min.

(1-(4-chlorophenyl)cyclohexyl)-N,N-dimethylmethanamine (85)

The title compound was prepared from 1-(4-chlorophenyl)-N,N-dimethylcyclohexanecarboxamide (241 mg, 0.91 mmol) according to General Procedure E. The crude product was purified by preparative TLC with 10% MeOH/CH₂Cl₂(R_t=0.74) to give (1-(4-chlorophenyl)cyclohexyl)-N,N-dimethylmethanamine free base (11 mg, 5%) as a clear oil. HPLC R_t=8.55 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.30 (q, 4H), 2.30 (s, 2H), 2.09-2.06 (m, 2H), 1.97 (s, 6H), 1.60-1.25 (m, 10H); LC-MS 8.09 min, (M+1)⁺252 @ 8.15 min.

N,N-dimethyl(1-phenylcyclohexyl)methanamine hydrochloride (86)

The title compound was synthesized from N,N-dimethyl-1-phenylcyclohexanecarboxamide (200 mg, 0.87 mmol) using General Procedure E, followed by HCl salt formation. The crude HCl salt was recrystallized from 2:1 EtOAc:CH₃CN to give N,N-dimethyl(1-phenylcyclohexyl)methanamine hydrochloride as an analytically pure off-white solid (8 mg, 4%). HPLC R_t=8.55 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.30 (q, 4H), 2.30 (s, 2H), 2.09-2.06 (m, 2H), 1.97 (s, 6H), 1.60-1.25 (m, 10H); LC-MS 8.09 min, (M+1)⁺252 @ 8.15 min. HPLC R_t=8.03 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.48-7.39 (m, 4H), 7.29-7.28 (m, 1H), 3.34 (d, J=2.57 Hz, 2H), 2.46 (d, J=3.30 Hz, 6H), 2.29-2.26 (m, 2H), 1.67-1.39 (m, 8H); LC-MS 6.62 min, (M+1)⁺218 (6.80 min.

(1-(3,4-dichlorophenyl)cyclopentyl)methanamine (87)

General Procedure G1—Amidation with Oxalyl Chloride: To a solution of 1-(3,4-dichlorophenyl)cyclopentanecarboxylic acid (200 mg, 0.7718 mmol) in DCM (1 mL) and DMF (1 mL) was added oxalyl chloride (1.54 mL, IM in DCM) dropwise. After five minutes, the volatiles were removed in vacuo and the residual oil was dissolved in 2M ammonia (in ethanol). After five minutes, the solvent was again removed, and the residual oil was partitioned between MTBE and aqueous potassium bicarbonate. After drying (sodium sulfate), the solvent was removed to give the crude amide.
The title compound was synthesized from the above amide using General Procedure E. The crude product was purified by reverse-phase preparative HPLC to give the primary amine (20 mg, 11% yield) as a pale-yellow oil. LCMS R_t=7.92 min, m/z=244 (M+1). ¹H NMR (CDCl₃, δ): 7.35 (m, 2H), 7.11 (dd, J=2.2, 8.4 Hz, 1H), 2.72 (s, 2H), 2.0-1.6 (m, 8H), 1.1 (s, 2H). ¹³C NMR (CDCl₃, δ, mult): 147.9(0), 132.1(0), 129.9(0), 129.7(1), 129.3(1), 126.7(1), 51.7(2), 35.2(2), 23.4(2).

(1-(3,4-dichlorophenyl)cyclopentyl)-N-methylmethanamine (88)

The title compound was synthesized from 1-(3,4-dichlorophenyl)-cyclopentanecarboxylic acid and methyl amine using General Procedure G1, followed by General Procedure E in 49% yield. LCMS R_t=11.16 min, m/z=258 (M+1). ¹H NMR (CDCl₃, δ): 7.4 (m, 2H), 7.17 (dd, J=2.2, 8.4 Hz, 1H), 2.65 (s, 2H), 2.34 (s, 3H), 2.1-1.6 (m, 8H). ¹³C NMR (CDCl₃, δ, mult): 148.3(0), 132.1(0), 129.9(1), 129.7(0), 129.1(1), 126.5(1), 62.1(2), 51.6(0), 37.3(3), 36.2(2), 23.5(2).

(1-(3,4-dichlorophenyl)cyclopentyl)-N,N-dimethylmethanamine (89)

The title compound was synthesized from 1-(3,4-dichlorophenyl)-cyclopentanecarboxylic acid and dimethyl amine using General Procedure G1, followed by General Procedure E in 87% yield. LCMS R_t=8.69 min, m/z=272 (M+1). ¹H NMR (CDCl₃, δ): 7.40 (d, J=2.2 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.10 (dd, J=2.1, 8.4 Hz, 1H), 2.43 (s, 2H), 20.1 (s, 6H), 2.0-1.6 (m, 8H). ¹³C NMR (CDCl₃, δ, mult): 149.2(0), 129.5(0), 129.2(1), 126.7(1), 131.6(1), 69.3(2), 52.1(0), 48.0(3), 36.0(2), 23.2(2).

1-(1-(4-fluorophenyl)cyclohexyl)-N-methylmethanamine (90)

(a) Synthesis of 1-(4-fluorophenyl)-N-methylcyclohexanecarboxamide

The title compound was synthesized from 1-(4-fluorophenyl)cyclohexane-carboxylic acid (222 mg, 1 mmol) and methylamine (1 mL, 1M in THF, 1 eq) according to General Procedure G. The crude product was purified by silica gel column chromatography to give the amide (202.6 mg, 86%) as a white solid.

(b) Synthesis of 1-(1-(4-fluorophenyl)cyclohexyl)-N-methylmethanamine

The title compound was synthesized from the above amide (100 mg, 0.43 mmol) according to General Procedure E to give 1-(1-(4-fluorophenyl)cyclohexyl)-N-methylmethanamine (61.6 mg, 66%) as a clear oil. LCMS R_t=6.62 min, m/z=222 (M+1). ¹H NMR (CDCl₃, δ): 7.30 (dd, J=5.4, 8.9 Hz, 2H), 6.97 (t, J=8.8 Hz, 2H), 2.58 (s, 2H), 2.57 (s, 3H), 2.1 (m, 2H), 1.7-1.3 (m, 8H). ¹³CNMR(CDCl₃, δ, mult): 162.1(0), 159.7(0), 141.0(0), 128.5(1), 128.4(1), 115.1(1), 114.9(1), 64.6(2), 41.8(0), 37.3(3), 34.7(2), 26.6(2), 22.1(2).

(1-(4-fluorophenyl)cyclohexyl)methaneamine (91)

The title compound was synthesized from 1-(4-fluorophenyl)-cyclohexane-carboxylic acid and ammonia using General Procedure G, followed by General Procedure E in 99% yield as a clear oil. LCMS R_t=6.76 min, m/z=208 (M+1). ¹H NMR (CDCl₃, δ): 7.24 (ddd, J=3.2, 5.4, 12.2 Hz, 2H), 7.00 (t, J=8.8 Hz, 2H), 2.67 (s, 2H), 2.1 (m, 2H), 1.6-1.2 (m, 8H), 0.79(bs, 2H). ¹³C NMR (CDCl₃, δ, mult): 162.1(0), 159.7(0), 140.3(0), 128.7(1), 128.6(1), 115.1(1), 114.9(1), 54.8(2), 43.2(0), 33.8(2), 26.6(2), 22.1(2).

(1-(4-fluorophenyl)cyclohexyl)-N,N-dimethylmethanamine (92)

The title compound was synthesized from 1-(4-fluorophenyl)cyclohexane-carboxylic acid and dimethyl amine using General Procedure G, followed by General Procedure E in 9% yield as a solid. LCMS R_t=7.22 min, m/z=236 (M+1). ¹H NMR (CDCl₃, δ): 7.32 (dd, J=5.5, 8.9 Hz, 2H), 6.99 (t, J=8.8 Hz, 2H), 2.30 (s, 2H), 2.1 (m, 2H), 1.97, (s, 6H), 1.7-1.3 (m, 8H. ¹³C NMR (CDCl₃, δ, mult): 162.0(0), 159.6(0), 141.7(0), 128.8(1), 128.7(1), 114.7(1), 114.5(1), 72.9(2), 56.5(0), 48.4(3), 34.3(2), 26.6(2), 22.1(2).

N-methyl(1-(naphthalen-2-yl)cyclohexyl)-methanamine (93)

The title compound was synthesized from 1-(naphthalen-2-yl)cyclohexane-carboxylic acid and methyl amine using General Procedure G, followed by General Procedure E in 74% yield as a clear oil. LCMS R_t=7.66 min, m/z=254 (M+1). ¹H NMR (CDCl₃, δ): 7.82 (m, 4H), 7.54 (dd, J=1.8, 8.7 Hz, 1H), 7.45 (m, 2H), 2.69 (s, 2H), 2.3 (m, 2H), 2.25 (m, 3H), 1.8-1.3 (m, 8H). ¹³CNMR(CDCl₃, δ, mult): 142.7(0), 133.4(0), 131.7(0), 128.0(1), 127.9(1), 127.2(1), 126.1(1), 125.7(1), 125.4(1), 125.0(1), 64.4(2), 42.4(0), 37.3(3), 34.7(2), 26.7(2), 22.3(2).

N,N-dimethyl(1-(naphthalen-2-yl)-cyclohexyl)methanamine (94)

The title compound was synthesized from 1-(naphthalen-2-yl)cyclohexane-carboxylic acid and dimethyl amine using General Procedure G, followed by General Procedure E and was obtained in 11% yield as a clear oil. LCMS R_t=6.47 min, m/z=268 (M+1). ¹H NMR (CDCl₃, δ): 7.80 (m, 4H), 7.55 (dd, J=1.7, 8.6 Hz, 1H), 7.45 (m, 2H), 2.2 (m, 2H), 1.97 (s, 6H), 1.8-1.3 (m, 8H). ¹³C NMR(CDCl₃, δ, mult): 133.4, 131.6, 127.9, 127.4, 127.2, 126.2, 126.1, 125.8, 125.5, 125.1, 72.6, 56.6, 48.4, 34.3, 26.6, 22.3.

(1-(4-chloro-3-fluorophenyl)cyclohexyl)-N-methylmethanamine (95)

General Procedure H1—Reductive Amination: To a solution of 1-(4-chloro-3-fluorophenyl)cyclohexanecarbaldehyde (100 mg, 0.4154 mmol) in methylamine (2.1 mL, 2M in THF, 10 eq) was added acetic acid (104 ul, 5% of volume), and methanol was added until the solution became clear. The solution was stirred for two hours. To the solution was added sodium borohydride (40 mg, 3 eq) and stirring was continued for 30 minutes. The reaction was quenched with aqueous potassium carbonate and extracted with MTBE. The organic phase was separated and the solvent removed in vacuo. The residue was redissolved in MTBE and extracted with 3M HCl. The aqueous phase was separated, chilled in ice, and basicified with KOH. The aqueous phase was then extracted with MTBE and the solvent removed in vacuo. The residue was diluted in DCM, filtered through aminopropyl cartridge. The solvent was again removed to give the secondary amine (75.1 mg, 71%) as a clear oil. LCMS R_t=7.39 min, m/z=256 (M+1). ¹H NMR (CDCl₃, δ): 7.34 (t, J=8.2 Hz, 1H), 7.15 (dd, J=2.2, 11.4 Hz, 1H), 7.09 (dd, J=1.9, 8.4 Hz, 1H), 2.58 (s, 2H), 2.28 (s, 3H), 2.0 (m, 2H), 1.7-1.3 (m, 8H). ¹³C NMR (CDCl₃, δ, mult): 159.4(0), 156.9(0), 147.2(0), 147.1(0), 130.2(1), 123.5(1), 123.5(1), 118.0(0), 117.8(0), 115.6(1), 115.4(1), 64.2(2), 42.3(0), 37.3(3), 34.5(2), 26.4(2), 22.1(2).

(1-(3-chloro-4-fluorophenyl)cyclohexyl)-N-methylmethanamine (96)

The title compound was synthesized from 1-(3-chloro-4-fluorophenyl)-cyclohexanecarbaldehyde and methyl amine using General Procedure H1 and was obtained in 55% yield. LCMS R_t=7.73 min, m/z=256 (M+1). ¹H NMR (CDCl₃, δ): 7.37 (dd, J=2.4, 7.1 Hz, 1H), 7.22 (ddd, J=2.4, 4.6, 8.7 Hz, 1H), 7.09 (t, J=8.7 Hz, 1H), 2.58 (s, 2H), 2.29 (s, 3H), 2.0 (m, 2H), 1.7-1.2 (m, 8H). ¹³C NMR (CDCl₃, δ, mult): 157.4(0), 154.9(0), 142.9(0), 129.2(1), 126.8(1), 126.7(1), 120.8(0), 120.6(0), 116.3(1), 116.1(1), 64.2(2), 42.1(0), 37.3(3), 34.6(2), 26.4(2), 22.1(2).

(1-(3-chloro-4-fluorophenyl)cyclohexyl)-N,N-dimethylmethanamine (97)

The title compound was synthesized from 1-(3-chloro-4-fluorophenyl)cyclohexanecarbaldehyde and dimethyl amine using General Procedure H1 and was obtained in 88% yield as an oily solid. The title compound was also synthesized from 1-(1-(3-chloro-4-fluorophenyl)-cyclohexyl)-N-methylmethanamine according to General Procedure C.
LCMS R_t=8.81 min, m/z=270 (M+1). ¹H NMR (CDCl₃, δ): 7.38 (dd, J=2.4, 7.2 Hz, 1H), 7.22 (ddd, J=2.4, 4.6, 8.7 Hz, 1H), 7.07 (t, J=8.8 Hz, 1H), 2.29 (s, 2H), 2.0 (m, 2H), 1.99 (s, 6H), 1.7-1.2 (m, 8H). ¹³C NMR (CDCl₃, 6, mult): 157.2(0), 154.7(0), 143.4(0), 129.6(1), 127.1(1), 127.1(1), 120.3(0), 120.1(0), 115.9(1), 115.7(1), 72.5(2), 48.4(3), 43.0(0), 34.1(2), 26.4(2), 22.0(2).

(1-(4-chloro-3-fluorophenyl)cyclohexyl)-methanamine (98)

The title compound was synthesized from 1-(4-chloro-3-fluorophenyl)-cyclohexanecarbonitrile using General Procedure E and was obtained in 19% yield as a clear oil. HPLC R_t=8.28 min. LCMS R_t=8.13 min, m/z=242 (M+1). HCl salt-¹H NMR (DMSO-d6, δ): 7.35 (t, J=8.1 Hz, 1H), 7.17 (d, J=11.3 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 2.82 (s, 2H), 2.1 (m, 2H), 1.7-1.1 (m, 8H). ¹³C NMR (DMSO-d6, δ, mult): 159.2(0), 156.7(0), 143.1(0), 143.0(0), 130.6(1), 124.1(1), 124.1(1), 118.5(0), 118.3(0), 116.2(1), 116.0(1), 50.2(2), 40.6(0), 33.3(2), 25.5(2), 21.4(2).

(1-(4-chloro-3-fluorophenyl)cyclohexyl)-N,N-dimethylmethanamine (99)

The title compound was synthesized from 1-(4-chloro-3-fluorophenyl)cyclohexanecarbaldehyde and dimethyl amine using General Procedure H1 and was obtained in 97% yield. LCMS R_t=9.07 min, m/z=270 (M+1). ¹H NMR (CDCl₃, δ): 7.31 (t, J=8.2 Hz, 1H), 7.17 (dd, J=2.1, 11.7 Hz, 1H), 7.09 (dd, J=1.8, 8.5 Hz, 1H), 2.30 (s, 2H), 2.0 (m, 2H), 1.99 (s, 3H), 1.7-1.3 (m, 8H). ¹³C NMR (CDCl₃, δ, mult): 159.2(0), 156.7(0), 147.8(0), 129.7(1), 123.9(1), 123.8(1), 117.5(0), 117.3(0), 115.9(1), 115.7(1), 72.5(2), 48.4(3), 43.3(0), 34.1(2), 26.4(2), 22.1(2).

N-methyl-1-(1-(4-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (100)

(a) Preparation of 1-(4-(trifluoromethyl)phenyl)cyclohexanecarbonitrile

The title compound was synthesized from 2-(4-(trifluoromethyl)phenyl)-acetonitrile (4.11 g, 22.2 mmol) and 1,5-dibromopentane (3.324 ml, 24.4 mmol) according to General Procedure J and was obtained as a clear oil (4.98 g, 89%).
¹H NMR (CDCl₃) δ 1.23-1.39 (m, 1H), 1.76-1.92 (m, 7H), 2.17 (d, J=11.2 Hz, 2H), 7.63 (s, 4H). ¹³C NMR (CDCl₃) δ 23.7, 25.0, 37.4, 44.7, 122.2, 126.0, 126.7, 130.2, 145.6, GC-MS m/z 253.

(b) Preparation of 1-(4-(trifluoromethyl)phenyl)cyclohexanecarbaldehyde

General Procedure M: To a solution of 1-(4-(trifluoromethyl)phenyl)-cyclohexanecarbonitrile (4.80 g, 18.95 mmol) in toluene (60 ml) at −70° C. was dropwise added 1 M DIBAL in hexane (38 ml, 38 mmol) over 30 min. The mixture was stirred at −70° C. for 30 min and for another 4 h at room temperature, whereupon ethyl formate (3 ml) was added. The mixture was stirred at room temperature for 1 hour and was then poured into saturated NH₄Cl solution (70 ml). After 30 min, 2 M aqueous H₂SO₄(100 ml) was added and the product was extracted with hexanes (3×100 ml). The combined organic phases were dried over MgSO₄and evaporated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes, EtOAc from 0% to 25%) to give 1-(4-(trifluoromethyl)phenyl)-cyclohexanecarbaldehyde (3.0 g, 65%) as clear oil. ¹H NMR (CDCl₃): δ 1.29-1.37 (m, 1H), 1.46-1.55 (m, 2H), 1.59-1.69 (m, 3H), 1.83-1.90 (m, 2H), 2.29-2.34 (m, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 9.40 (s, 1H). ¹³C NMR (CDCl₃) δ 22.9, 25.6, 31.5, 54.7, 125.9, 126.0, 127.8, 129.5, 144.2, 202.0.

(c) Preparation of N-methyl(1-(4-(trifluoromethyl)phenyl)cyclohexyl)-methanamine

General Procedure H2—Reductive Amination: A mixture of 1-(4-(trifluoromethyl)phenyl)cyclohexanecarbaldehyde (256 mg, 1.0 mmol) and methylamine (2.0 M in THF, 3 ml, 6.0 mmol) in 1,2-dichloroethane was stirred at room temperature for 30 min and was then treated with sodium triacetoxyborohydride (297 mg, 1.4 mmol). The reaction mixture was stirred at room temperature overnight and was then quenched with aqueous saturated NaHCO₃solution (10 ml). The product was extracted with EtOAc (3×10 ml). The combined organic layers were dried over MgSO₄and evaporated in vacuo. The residue was purified by silica gel column chromatography (MeOH/CH₂Cl₂, MeOH from 0% to 20%) to give N-methyl-1-(1-(4-(trifluoromethyl)phenyl)cyclohexyl)methanamine (178 mg, 66%). ¹H NMR (CDCl₃): δ 1.26-1.52 (m 4H), 1.54-1.61 (m, 2H), 1.66-1.73 (m, 2H), 2.13-2.18 (m, 2H), 2.28 (s, 3H), 2.63 (s, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H). ¹³C NMR (CDCl₃) δ 22.3, 26.7, 34.7, 37.5, 42.9, 64.5, 125.4, 125.9, 127.6, 128.3, 150.2. ESI MS m/z 271.

N,N-dimethyl-1-(1-(4-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (101)

The title compound was prepared from 1-(4-(trifluoromethyl)phenyl)cyclohexane-carbaldehyde (128 mg, 0.50 mmol) and dimethylamine (2.0 M in THF, 0.5 ml, 1.0 mmol) according to General Procedure H2. The crude product was purified by silica gel column chromatography (MeOH/CH₂Cl₂, MeOH from 0% to 15%) to give N,N-dimethyl-1-(1-(4-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (47 mg, 33%). ¹H NMR (CDCl₃): δ 1.29-1.38 (m 3H), 1.48-1.57 (m, 3H), 1.62-1.68 (m, 2H), 1.97 (s, 6H), 2.13-2.18 (m, 2H), 2.35 (s, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H). ¹³C NMR (CDCl₃) δ 22.4, 26.7, 34.4, 37.5, 43.9, 48.6, 72.8, 123.3, 125.0, 125.1, 126.0, 127.6, 127.9, 128.3, 150.8. ESI MS m/z 286.

1-(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)-N,N-dimethylmethanamine (102)

(a) Synthesis of 1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbonitrile

The title compound was prepared according to General Procedure J to give 1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbonitrile (2.90 g, 57%) as a white solid. ¹H NMR (CDCl₃): δ 1.24-1.35 (m, 1H), 1.74-1.88 (m, 7H), 2.16 (d, J=11.2 Hz, 2H), 5.97 (s, 2H), 6.79 (d, J=8.0 Hz, 1H), 6.95-6.99 (m, 2H). ¹³C NMR (CDCl₃) δ 23.7, 25.0, 37.5, 44.6, 122.5, 122.6, 124.9, 125.0, 129.5, 129.7, 142.8.

(b) Preparation of 1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbaldehyde

The title compound was prepared from the above nitrile according to General Procedure M. The crude product was purified by silica gel column chromatography (EtOAc/hexanes, EtOAc from 0% to 25%) to give 1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbaldehyde (1.65 g, 56%) as a white solid. ¹H NMR (CDCl₃): δ 1.25-1.34 (m, 1H), 1.41-1.50 (m, 2H), 1.57-1.70 (m, 3H), 1.73-1.80 (m, 2H), 2.23-2.30 (m, 2H), 5.94 (s, 2H), 6.75-6.82 (m, 3H), 9.30 (s, 1H). ¹³C NMR (CDCl₃) δ 23.0, 25.8, 31.7, 54.1, 101.4, 107.8, 108.7, 120.8, 133.7, 146.9, 148.5, 202.1.

(c)]-(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)-N,N-dimethylmethanamine

The title compound was prepared from the above 1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbaldehyde (232 mg, 1.0 mmol) and dimethylamine (2.0 M in THF, 1.0 ml, 2.0 mmol) according to General Procedure H2. The crude product was purified by silica gel column chromatography (MeOH/CH₂Cl₂, MeOH from 0% to 15%) to give 1-(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)-N,N-dimethylmethanamine (47 mg, 33%) as clear oil. ¹H NMR (CDCl₃): δ 1.31-1.41 (m 3H), 1.42-1.53 (m, 3H), 1.56-1.63 (m, 2H), 2.01 (s, 6H), 2.03-2.08 (m, 2H), 2.30 (s, 2H), 5.91 (s, 2H), 6.75 (d, J=8.0 Hz, 1H), 6.82 (dd, J=8.0 Hz, 1.6 Hz, 1H), 6.87 (d, J=1.6 Hz, 1H). ¹³C NMR (CDCl₃) δ 22.4, 26.8, 34.7, 37.5, 43.2, 48.2, 73.0, 100.9, 108.0, 108.2, 120.5, 140.3, 145.3, 147.8. ESI MS m/z 262.

1-(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)-N-methylmethanamine (103)

The title compound was prepared from 1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbaldehyde (232 mg, 1.0 mmol) and methylamine (2.0 M in THF, 3 ml, 6.0 mmol) according to General Procedure H2. The crude product was purified by silica gel column chromatography (SiO₂, MeOH/CH₂Cl₂, MeOH from 0% to 20%) to give 1-(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)-N-methylmethanamine (218 mg, 88%). ¹H NMR (CDCl₃): δ 1.26-1.52 (m 4H), 1.54-1.61 (m, 2H), 1.66-1.73 (m, 2H), 2.03-2.12 (m, 2H), 2.28 (s, 3H), 2.60 (s, 2H), 5.90 (s, 2H), 6.75-6.86 (m, 2H), 6.90 (s, 1H). ¹³C NMR (CDCl₃) δ 22.3, 26.7, 35.2, 37.4, 42.3, 64.8, 101.0, 107.6, 108.2, 120.3, 139.4, 145.6, 148.1. ESI MS m/z 248.

N-methyl-1-(1-(3-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (104)

(a) Preparation of 1-(3-(trifluoromethyl)phenyl)cyclohexanecarbonitrile

The title compound was prepared from 2-(3-(trifluoromethyl)phenyl)acetonitrile (3.463 ml, 22.2 mmol) and 1,5-dibromopentane (3.324 ml, 24.4 mmol) according to General Procedure J to yield 1-(3-(trifluoromethyl)phenyl)cyclohexane-carbonitrile (5.40 g, 90%) as a clear oil. ¹H NMR (CDCl₃) δ 1.26-1.39 (m, 1H), 1.76-1.88 (m, 7H), 2.17 (d, J=11.2 Hz, 2H), 7.51-7.60 (m, 3H), 7.73 (s, 1H). ¹³C NMR (CDCl₃) δ 23.7, 25.0, 37.5, 44.6, 122.5, 125.0, 125.1, 126.0, 129.5, 130.0, 142.8, GC-MS m/z 253.

(b) Preparation of 1-(3-(trifluoromethyl)phenyl)cyclohexanecarbaldehyde

The title compound was prepared from the above 1-(3-(trifluoromethyl)phenyl)cyclohexane-carbonitrile (5.60 g, 22.1 mmol) according to General Procedure M. The crude product was purified by silica gel column chromatography (EtOAc/hexanes, EtOAc from 0% to 25%) to give 1-(3-(trifluoromethyl)phenyl)-cyclohexanecarbaldehyde (3.85 g, 68%) as a clear oil. ¹H NMR (CDCl₃): δ 1.25-1.34 (m, 1H), 1.45-1.53 (m, 2H), 1.59-1.67 (m, 3H), 1.80-1.87 (m, 2H), 2.31-2.35 (m, 2H), 7.45-7.53 (m, 3H), 7.58 (s, 1H), 9.38 (s, 1H). ¹³C NMR (CDCl₃) δ 22.8, 25.6, 31.5, 54.6, 123.9, 124.0, 124.3, 129.5, 130.9, 141.3, 148.5, 202.0.

(c) Synthesis of N-methyl-1-(1-(3-(trifluoromethyl)phenyl)-cyclohexyl)methanamine

The title compound was prepared from 1-(3-(trifluoromethyl)phenyl)cyclohexane-carbaldehyde (116 mg, 0.5 mmol) and methylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according to General Procedure H2. The crude product was purified by silica gel column chromatography (MeOH/CH₂Cl₂, MeOH from 0% to 15%) to give N-methyl-1-(1-(3-(trifluoromethyl)phenyl)cyclohexyl)methanamine (50 mg, 45%). ¹H NMR (CDCl₃): δ 1.28-1.52 (m 4H), 1.54-1.60 (m, 2H), 1.69-1.76 (m, 2H), 2.12-2.18 (m, 2H), 2.29 (s, 3H), 2.66 (s, 2H), 7.45-7.48 (m, 2H), 7.56-7.59 (m, 1H), 7.61 (s, 1H). ¹³C NMR (CDCl₃) δ 22.3, 26.7, 34.6, 37.4, 42.6, 64.2, 123.0, 123.9, 127.9, 129.1, 130.8, 131.1, 146.7. ESI MS m/z 271.

N,N-dimethyl-1-(1-(3-(trifluoromethyl)-phenyl)cyclohexyl)-methanamine (105)

The title compound was prepared from 1-(3-(trifluoromethyl)phenyl)cyclohexane-carbaldehyde (128 mg, 0.50 mmol) and dimethylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according to General Procedure H2. The crude product was purified by silica gel column chromatography (MeOH/CH₂Cl₂, MeOH from 0% to 15%) to give N,N-dimethyl-1-(1-(3-(trifluoromethyl)phenyl)cyclohexyl)methanamine (74 mg, 52%) as a clear oil. ¹H NMR (CDCl₃): δ 1.29-1.38 (m 3H), 1.48-1.57 (m, 3H), 1.63-1.70 (m, 2H), 1.97 (s, 6H), 2.11-2.15 (m, 2H), 2.34 (s, 2H), 7.41-7.43 (m, 2H), 7.56-7.59 (m, 1H), 7.63 (s, 1H). ¹³C NMR (CDCl₃) δ 22.4, 26.7, 34.3, 43.9, 48.6, 72.7, 122.4, 124.3, 128.6, 126.0, 131.1, 147.6, 150.8. ESI MS m/z 286.

1-(1-(3-fluorophenyl)cyclohexyl)-N-methylmethanamine (106)

(a) Preparation of 1-(3-fluorophenyl)cyclohexanecarbonitrile

The title compound was prepared from 2-(3-fluorophenyl)acetonitrile (2.58 ml, 22.2 mmol) and 1,5-dibromopentane (3.324 ml, 24.4 mmol) according to General Procedure J to yield 1-(3-fluorophenyl)cyclohexanecarbonitrile (4.43 g, 97%) as a clear oil. ¹H NMR (CDCl₃) δ 1.26-1.39 (m, 1H), 1.76-1.88 (m, 7H), 2.17 (d, J=11.2 Hz, 2H), 6.93-6.98 (m, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.30-7.35 (m, 1H). ¹³C NMR (CDCl3) δ 23.7, 25.0, 37.5, 44.6, 122.5, 125.0, 125.1, 126.0, 129.5, 130.0, 142.8.

(b) Preparation of 1-(3-fluorophenyl)cyclohexanecarbaldehyde

The title compound was prepared from 1-(3-fluorophenyl)cyclohexanecarbonitrile (3.52 g, 17.32 mmol) according to General Procedure M. The crude product was purified by silica gel column chromatography (EtOAc/hexanes, EtOAc from 0% to 25%) to give 1-(3-fluorophenyl)cyclohexanecarbaldehyde (2.01 g, 56%) as a clear oil. ¹H NMR (CDCl₃): δ 1.29-1.37 (m, 1H), 1.44-1.53 (m, 2H), 1.58-1.67 (m, 3H), 1.79-1.85 (m, 2H), 2.26-2.31 (m, 2H), 6.93-6.98 (m, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.30-7.35 (m, 1H), 9.36 (s, 1H). ¹³C NMR (CDCl₃) δ 22.9, 25.7, 31.5, 54.5, 114.4, 123.0, 130.5, 142.8, 162.2, 164.7, 202.0.

(c) Synthesis of 1-(1-(3-fluorophenyl)cyclohexyl)-N-methylmethanamine

The title compound was prepared from the above 1-(3-fluorophenyl)cyclohexane-carbaldehyde (103 mg, 0.5 mmol) and methylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according to General Procedure H2. The crude product was purified by silica gel column chromatography (MeOH/CH₂Cl₂, MeOH from 0% to 15%) to give 1-(1-(3-fluorophenyl)cyclohexyl)-N-methylmethanamine (50 mg, 45%). ¹H NMR (CDCl₃): 1.28-1.52 (m 4H), 1.54-1.60 (m, 2H), 1.69-1.76 (m, 2H), 2.12-2.18 (m, 2H), 2.28 (s, 3H), 2.61 (s, 2H), 7.45-7.48 (m, 2H), 6.87-6.92 (m, 1H), 7.08 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.27-7.32 (m, 1H). ¹³C NMR (CDCl₃) □ 22.4, 26.8, 34.9, 37.5, 42.6, 64.6, 112.7, 112.9, 114.2, 114.4, 122.8, 129.9, 130.0, 162.2, 164.7. ESI MS m/z 222.

1-(1-(3-fluorophenyl)cyclohexyl)-N,N-dimethylmethanamine (107)

The title compound was prepared from 1-(3-fluorophenyl)cyclohexane-carbaldehyde (103 mg, 0.50 mmol) and dimethylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according to General Procedure H2. The crude product was purified by column chromatography (SiO₂, MeOH/CH₂Cl₂, MeOH from 0% to 15%) to give 1-(1-(3-fluorophenyl)cyclohexyl)-N,N-dimethylmethanamine (46 mg, 39%) as a clear oil. ¹H NMR (CDCl₃): δ 1.32-1.38 (m 3H), 1.49-1.56 (m, 3H), 1.59-1.66 (m, 2H), 1.99 (s, 6H), 2.05-2.09 (m, 2H), 2.33 (s, 2H), 6.83-6.88 (m, 1H), 7.08 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.23-7.29 (m, 1H). ¹³C NMR (CDCl₃) δ 22.4, 26.8, 34.4, 43.6, 48.6, 72.9, 112.2, 112.4, 114.6, 114.8, 123.2, 129.4, 129.5, 162.0, 164.5. ESI MS m/z 236.

(±) 1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (108)

(a) Synthesis of 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanol

To a solution of 1-(3,4-dichlorophenyl)cyclohexanecarbaldehyde (440 mg, 1.71 mmol) in anhydrous THF (17 mL) at 0° C. was added slowly methyl lithium (1.6 M in Et₂O, 3.21 mL, 5.14 mmol). The solution was allowed to warm to RT and was stirred for 16 h. It was then quenched with MeOH (5 mL). The crude reaction mixture was poured into 2M HCl (15 mL) and washed with EtOAc (3×20 mL). The combined organic layers were dried (Na₂SO₄), filtered and concentrated to give 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanol. HPLC R_t=11.28 min; ¹H NMR (400 mHz, CDCl₃) 7.44-7.41 (m, 2H), 7.20 (dd, J=2.2, 8.4 Hz, 1H), 3.63-3.58 (m, 1H), 2.39-2.35 (m, 1H), 2.14-2.10 (m, 1H), 1.67-1.48 (m, 5H), 1.31-1.16 (m, 3H), 0.92 (d, J=6.6 Hz, 3H).

(b) Synthesis of 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanone

To a solution of crude 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanol (494 mg, 1.81 mmol) in CH₂Cl₂(18 mL) was added Dess-Martin periodinane (997 mg, 2.35 mmol). The resulting suspension was stirred at RT for 2 h and was then concentrated. The crude ketone was purified by silica gel column chromatography with an EtOAc/hexane gradient (product R_f=0.6 in 10% EtOAc/hexanes) to give 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanone (312 mg, 67%) as an orange oil. HPLC R_t=11.61 min; ¹H NMR (400 mHz, CDCl₃) 7.42-7.40 (m, 2H), 7.15 (dd, J=2.2, 8.4 Hz, 1H), 2.32-2.29 (m, 2H), 1.92 (s, 3H), 1.80-1.74 (m, 2H), 1.65-1.43 (m, 5H), 1.35-1.30 (m, 1H); ¹³C NMR (100 mHz, CDCl₃) 209.5, 143.3, 133.2, 131.3, 130.9, 128.9, 126.3, 56.2, 33.7, 25.8 (2 overlapping peaks), 23.2.

(c) Synthesis of (±)1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine hydrochloride

A mixture of 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanone (247 mg, 0.91 mmol) and methyl amine (455 μL, 2.0 M in THF, 0.91 mmol) was stirred at RT for 2 min. Titanium (IV) isoproxide (336 μL, 1.14 mmol) was then added. The viscous green/yellow solution was stirred at RT for 3 h. NaBH₃CN solution (640 μL, 1.0 M in MeOH, 0.64 mmol) was added and the cloudy solution was stirred at RT for 16 h. The solution was quenched with saturated NaCl solution (3 mL), filtered, and washed with MeOH (50 mL). 6M HCl (20 mL) was added and the aqueous phase washed with Et₂O (2×20 mL). The pH of the aqueous phase was adjusted to pH=12 with 3M NaOH and washed with EtOAc (3×30 mL). The combined organic phases were dried (Na₂SO₄), filtered and concentrated. To a solution of the crude amine in Et₂O (3 mL) was added HCl (3 mL, 2.0 M in Et₂O). The crude HCl salt was recrystallized from CH₃CN (6 mL) at 110° c. to give 1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (8 mg) as white crystals. HPLC R_t=8.90 min; ¹H NMR (400 mHz, CD₃OD) 7.57-7.53 (m, 2H), 7.33-7.31 (m, 1H), 3.15-3.13 (m, 2H), 2.61 (s, 3H), 2.45 (broad d, J=11.73 Hz, 1H), 2.30 (broad d, J=12.46, 1H), 1.59-1.51 (m, 5H), 1.31-1.08 (m, 6H); LC-MS 7.87 min, (M+1)⁺286 (8.10 min.

Synthesis of 1-(1-(3,4-dichlorophenyl)cyclohexyl)propan-1-one

(a) 1-(1-(3,4-dichlorophenyl)cyclohexyl)propan-1-ol

1-(3,4-dichlorophenyl)cyclohexanecarbaldehyde (519 mg, 2.01 mmol) was dissolved in anhydrous THF (17 mL) and cooled to 0° C. Ethyl magnesium chloride (2.0 M in THF, 3.03 mL, 6.06 mmol) was added slowly. The solution was allowed to warm to RT and stir for 16 h, then quenched with MeOH (5 mL). The crude reaction mixture was poured into 2M HCl (15 mL) and washed with EtOAc (3×20 mL). The combined organic washes were dried (Na₂SO₄), filtered and concentrated to give the secondary alcohol (443 mg, 77% for 2 steps) as a white solid. HPLC R_t=11.65 min; ¹H NMR (400 mHz, CDCl₃) 7.43-7.41 (m, 2H), 7.19 (dd, J=2.2, 8.4 Hz, 1H), 3.27-3.23 (m, 1H), 2.37-2.33 (m, 1H), 2.17-2.14 (m, 1H), 1.57-1.46 (m, 6H), 1.29-1.17 (m, 4H), 0.90-0.77 (m, 4H); ¹³C NMR (125 mHz, CDCl₃) 143.0, 132.4, 130.9, 130.1, 130.0, 128.3, 81.7, 47.1, 32.6 (doublet), 26.7, 24.4, 22.2, 11.4.

(b) 1-(1-(3,4-dichlorophenyl)cyclohexyl)propan-1-one

The crude ethyl alcohol product (577 mg, 2.01 mmol) was dissolved in CH₂Cl₂(20 mL) and Dess-Martin Periodinane (1.1 g, 2.61 mmol) was added. The white opaque suspension was stirred at RT for 2 h, then concentrated. The crude ketone was purified by silica gel column chromatography with an EtOAc/hexane gradient (R_f=0.6 in 10% EtOAc/hexanes) to give the desired ethyl ketone (443 mg, 77%) as a white solid. HPLC R_t=12.0 min; ¹H NMR (400 mHz, CDCl₃) 7.44-7.38 (m, 2H), 7.11 (dd, J=2.6, 8.4 Hz, 1H), 2.32-2.20 (m, 4H), 1.80-1.74 (m, 2H), 1.68-1.42 (m, 5H), 1.34-1.26 (m, 2H), 0.90 (t, 3H); ¹³C NMR (125 mHz, CDCl₃) 212.1, 143.6, 133.1, 130.9, 130.8, 128.8, 126.3, 56.0, 33.7, 30.7, 25.8, 23.3, 8.49. This compound can be used to synthesize compounds of the invention with R¹=ethyl, e.g., through reductive amination. Exemplary compounds include:

1.4. Synthesis of 3,4-dichlorophenyl cyclohexylamines with Cyclic Amine Substituents from Corresponding Carboxylic Acids

Compounds in Table 3, below, were synthesized from the corresponding carboxylic acids via the amide intermediate according to General Procedure G and General Procedure E.

TABLE 3


Summary of Exemplary Cyclic Amines

1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)piperidine (109)

HPLC R_t= 9.20 min; ¹H NMR(400 MHz, MeOH-d⁴) 7.65(s, 1H),

7.50(d, J=8.8Hz, 1H), 7.43-7.41(m, 1H), 3.22(t, J=1.47Hz, 1H),

3.05-2.99(m, 2H), 2.73-2.67(m, 2H), 2.22-2.18(m, 2H), 1.71-1.26(m,

14H); LC-MS 11.79 min, (M + 1)⁺326 @ 11.91 min.

4-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)morpholine (110)

HPLC R_t= 8.82 min; ¹H NMR(400 MHz, MeOH-d⁴) 7.66(d, J=1.83Hz,

1H), 7.54(d, J=8.43Hz, 1H), 7.43(dd, J=2.2, 8.43Hz, 1H), 3.81-3.70(m,

4H), 3.46(s, 2H), 3.25-3.24(m, 2H), 3.07-3.04(m, 2H), 2.93-2.88(m,

2H), 2.24-2.20(m, 2H), 1.78-1.70(m, 2H), 1.61-1.31(m, 6H); LC-MS

11.09 min, (M + 1)⁺328 @ 11.28 min.

1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)pyrrolidine (111)

HPLC R_t= 9.12 min; ¹H NMR(400 MHz, CDCl₃) 7.43(d, J=2.20Hz, 1H),

7.35(d, J=8.43Hz, 1H), 7.22-7.20(m, 1H), 2.52(s, 2H), 2.23(s, 3H),

2.05-2.02(m, 2H), 1.65-1.48(m, 10H), 1.38-1.25(m, 3H); LC-MS 9.31

min, (M + 1)⁺312 @ 9.39 min.

1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-4-methylpiperazine (112)

Prepared from Amide Intermediate 298

HPLC R_t= 9.47 min; ¹H NMR(400 MHz, MeOH-d⁴) 7.64(s, 1H), 7.49(d,

J=8.43Hz, 1H), 7.42(d, J=8.79Hz, 1H), 3.46(bs, 4H), 3.10(bs, 3H),

2.83(s, 3H), 2.26-2.22(m, 2H), 1.73-1.67(m, 2H), 1.57-1.28(m, 7H);

LC-MS 10.36 min, (M + 1)⁺341 @ 10.51 min.

(±) 1-((1-(3,4-dichlorophenyl)cyclohexyl)methylamino)-2,3-di-

hydro-1H-inden-2-ol (113)

HPLC R_t= 9.44 min; ¹H NMR(400 MHz, CDCl₃) 7.49(d, J=2.2Hz, 1H),

7.42(d, J=8.43Hz, 1H), 7.26-7.13(m, 4H), 6.91(d, J=6.97Hz, 1H),

4.35-4.32(m, 1H), 3.90(d, J=5.13Hz, 1H), 3.02-2.88(m, 3H), 2.79(d,

J=11.7Hz, 1H), 2.19-2.16(m, 1H), 2.07-2.04(m, 1H), 1.74-1.26(m, 9H);

LC-MS 10.84 min, (M + 1)⁺390 @ 10.99 min.

(±) 1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-3-methylpiperidine

(114)

HPLC R_t= 9.46 min; ¹H NMR(400 MHz, CD₃OD) 7.69(dd, J=1.83,

14.66Hz, 1H), 7.54(d, J=8.43Hz, 1H), 7.49-7.44(m, 1H), 3.51-3.41(m,

1H), 3.26-3.25(d, J=1.47Hz, 1H), 3.06-2.90(m, 3H), 2.73-2.58(m,

1H), 2.43-2.37(m, 1H), 2.25(bs, 2H), 1.96-1.29(m, 11H), 1.08-0.96(m,

1H), 0.78(m, 3H); LC-MS 11.95 min, (M + 1)⁺340 @ 12.18 min.

(±) 1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-2-methylpyrrolidine

(115)

HPLC R_t= 9.25 min; ¹H NMR(400 MHz, CD₃OD) 7.64(s, 1H), 7.55(dd,

J=3.67, 8.43Hz, 1H), 7.42(d, J=7.33Hz, 1H), 3.52(d, J=13.6Hz, 1H),

3.25(s, 2H), 3.00-2.98(m, 1H), 2.69-2.65(m, 1H), 2.37-2.34(m, 1H),

2.11(bs, 2H), 1.91-1.23(m, 14H); LC-MS 10.1 min,

(M + 1)⁺326 @ 10.1 min.

(±) 2-((1-(3,4-dichlorophenyl)cyclohexyl)methylamino)cyclopentanol

(116)

HPLC R_t= 8.86 min; ¹H NMR(400 MHz, CD₃OD) 7.58(d, J=2.57Hz,

1H), 7.53(d, J=8.43Hz, 1H), 7.39-7.36(m, 1H), 4.03-3.98(m, 1H), 3.40(d,

J=13.2Hz, 1H), 3.17-3.10(m, 2H), 2.17-2.04(m, 3H), 1.95-1.89(m, 1H),

1.71-1.32(m, 12H); LC-MS 9.31 min, (M + 1)⁺342 @ 9.42 min.

(±) 2-((1-(3,4-dichlorophenyl)cyclohexyl)methylamino)cyclohexanol (117)

HPLC R_t= 9.1 min; ¹H NMR(400 MHz, CD₃OD) 7.60(d,

J=2.20Hz, 1H), 7.60-7.52(m, 1H), 7.41-7.37(m, 1H), 3.48-3.43(m, 1H),

3.15-3.11(m, 1H), 2.75-2.69(m, 1H), 2.21-2.11(m, 2H), 1.98-1.15(m,

16H); LC-MS 9.50 min, (M + 1)⁺356 @ 9.6 min.

Example 2

Synthesis of 2-Substituted Cycloalkylamines

2.1. Synthesis of 2-Hydroxy-Substituted Cycloalkylamines

The below described compound of the invention were synthesized from the corresponding bromomethyl analogs according to General Procedures O and P (outlined below).

cis-2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclohexanol (cis 121)

cis 121 E1
cis 121 E2

(a) Preparation of racemic (cis)-2-(azidomethyl)-2-(3,4-dichlorophenyl)-cyclohexanol

General Procedure O: A mixture of (cis)-2-(bromomethyl)-2-(3,4-dichlorophenyl)cyclohexanol (148 mg, 0.438 mmol) and sodium azide (85 mg, 1.314 mmol), in DMF (2 ml) was stirred at 70° C. for 48 hours. The reaction mixture was filtered and evaporated in vacuo. The residue was partitioned between water (5 ml) and EtOAc (10 ml). The organic layer was separated, washed with water (2×5 ml), dried over Na₂SO₄, and evaporated to give (cis)-2-(azidomethyl)-2-(3,4-dichlorophenyl)cyclohexanol (110 mg, 84%) as a clear oil.
The enantiomers of (cis)-2-(azidomethyl)-2-(3,4-dichlorophenyl)cyclohexanol were separated using preparative HPLC (ChiralPak OJ column; hexanes:IPA=90:10; 8 ml/min; λ=280 nm) to give cis 120 E1 (retention time=10.5 min) and cis 120 E2 (retention time=13.7 min). The absolute configurations of the chiral centers were not determined. ¹H NMR (CDCl₃) δ 0.96-1.03 (m, 1H), 1.43-1.54 (m, 3H), 1.67-1.75 (m, 4H), 2.00 (brs, 1H), 2.08-2.14 (m, 1H), 3.43 (d, J=12.0 Hz, 1H), 3.65 (d, J=12.0 Hz, 1H), 4.04 (t, J=6.0 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.47 (dd, J=8.4, 2.4 Hz, 1H), 7.75 (s, 1H). ¹³C NMR (CDCl₃) δ 21.4, 22.8, 30.2, 30.4, 47.4, 59.8, 74.0, 127.9, 130.6, 130.8, 131.2, 132.9, 142.7.

(b) Synthesis of cis-2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclohexanols

General Procedure P: To a solution of cis 120 E1 (37 mg, 0.124 mmol) in EtOAc (2 ml) was added Pd/C (10%, 20 mg). A hydrogen balloon was attached and the reaction mixture was stirred at room temperature for 30 min. The mixture was filtered and evaporated. The residue was purified by silica gel column chromatography (MeOH/CH₂Cl₂, MeOH from 0% to 15%) to give the primary amine cis 121 E1 (24 mg, 69%) as clear oil.
Cis 121 E2 was synthesized from cis 120 E2 (31 mg, 0.124 mmol) according to General Procedure P to give the primary amine (21 mg, 72%) as a clear oil.
¹H NMR (CDCl₃) δ0.96-1.03 (m, 1H), 1.23-1.44 (m, 3H), 1.65-1.69 (m, 1H), 1.78-1.83 (m, 2H), 1.98-2.02 (m, 1H), 2.91 (d, J=13.6 Hz, 1H), 3.07 (d, J=13.6 Hz, 1H), 4.03 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.71 (dd, J=12.0, 2.4 Hz, 1H), 7.96 (s, 1H). ¹³C NMR (CD₃Cl): δ 21.4, 24.6, 30.2, 35.2, 46.9, 56.3, 81.1, 129.3, 130.3, 130.4, 131.7, 132.6, 142.7. ESI MS m/z 274.

trans-2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclohexanol (trans 121)

trans 121 E1
trans 121 E2

(a) Preparation of racemic (trans)-2-(Azidomethyl)-2-(3,4-dichlorophenyl)cyclohexanol

The title compound was prepared from trans-2-(bromomethyl)-2-(3,4-dichlorophenyl)cyclohexanol (103 mg, 0.305 mmol) and sodium azide (59 mg, 1.314 mmol) according to General Procedure O to give the azide (70 mg, 76%) as a clear oil. The enantiomers were separated as described to give trans 120 E1 (retention time=11.7 min) and trans 120 E2 (retention time=14.2 min). ¹H NMR (CDCl₃) δ 1.38-1.46 (m, 2H), 1.51-1.56 (m, 1H), 1.62-1.66 (m, 2H), 1.71-1.76 (m, 1H), 1.80-1.93 (m, 3H), 3.43 (d, J=12.4 Hz, 1H), 3.81 (d, J=12.4 Hz, 1H), 4.24 (t, J=4.0 Hz, 1H), 7.25-7.28 (m, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.51 (d, J=1.6 Hz, 1H). ¹³C NMR (CDCl₃) δ 21.3, 21.6, 29.7, 29.8, 46.8, 57.6, 71.3, 126.7, 129.4, 130.4, 130.6, 132.9, 146.5.

(b) Synthesis of trans-2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclohexanol

Trans 121 E1 and trans 121 E2 were prepared from trans 120 E1 and trans 120 E2, respectively, according to General Procedure P. The crude products were purified by chromatography (SiO₂, MeOH/CH₂Cl₂, MeOH from 0% to 15%) to give the primary amines (about 15 mg each, 65%) as clear oils.
¹H NMR (CDCl₃) δ 1.28-1.50 (m, 4H), 1.64-1.86 (m, 3H), 1.98-2.02 (m, 1H), 3.02 (d, J=12.4 Hz, 1H), 3.38 (d, J=12.4 Hz, 1H), 4.20 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.40-7.47 (m, 2H), 7.69 (d, J=1.6 Hz, 1H). ¹³C NMR (CDCl₃) δ 21.5, 22.3, 29.9, 30.4, 44.8, 57.1, 71.5, 126.9, 129.6, 131.1, 131.4, 133.3, 142.9. ESI MS m/z 274.

2.2. Synthesis of 2-Methoxy-Cycloalkylamines

The following compounds were synthesized according to the Scheme, below.

1-(1-(3,4-dichlorophenyl)-2-methoxycyclohexyl)-N-methylmethanamine (124)

A. Synthesis of cis-1-(1-(3,4-dichlorophenyl)-2-methoxycyclohexyl)-N-methylmethanamine (cis 124)

A solution of (±) cis 122 [Boc-protected (±) cis-2-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclohexanol] (0.88 g, 2.27 mmol) and NaH (100 mg, 2.50 mmol) in THF (30 ml) was stirred at room temperature for 30 min. To the mixture was added CH₃I (1.41 ml, 22.7 mmol) and the reaction mixture was stirred at room temperature for 24 hours. It was diluted with water (20 ml) and extracted with CH₂Cl₂(3×30 ml). The organic layer washed with water (2×30 ml) and brine (30 ml), dried over Na₂SO₄, and evaporated in vacuo. The residue was purified by silica gel column chromatography (MeOH/CH₂Cl₂, MeOH from 0% to 5%) to give (±) cis 123.
To a solution of (±) cis 123 in CH₂Cl₂(5 ml) was added dropwise TFA (5 ml) at 0° C. The mixture was stirred at 0° C. for 2 hours and the solvent was removed in vacuo. The residue was dissolved in CH₂Cl₂(10 ml), washed with saturated K₂CO₃solution (5 ml), dried over Na₂SO₄, and evaporated in vacuo. The residue was purified by silica gel column chromatography (MeOH/CH₂Cl₂, MeOH from 0% to 15%) to give (±) cis 124 (0.225 g, 33%) as clear oil. ¹H NMR (CDCl₃) δ 1.38-1.43 (m, 1H), 1.47-1.54 (m, 2H), 1.62-1.66 (m, 1H), 1.74-1.87 (m, 3H), 2.01-2.04 (m, 1H), 2.29 (s, 3H), 2.71 (d, J=14 Hz, 1H), 2.76 (d, J=14 Hz, 1H), 3.25 (s, 3H), 3.52 (dd, J=8.8, 3.2 HZ, 1H), 7.29-7.38 (m, 2H), 7.59 (s, 1H). ¹³C NMR (CDCl₃) δ 21.9, 23.7, 25.0, 31.6, 48.7, 49.1, 56.7, 68.1, 83.3, 128.4, 129.5, 129.7, 131.1, 131.8, 145.8. ESI MS m/z 302.

B. Synthesis of trans-1-(1-(3,4-dichlorophenyl)-2-methoxycyclohexyl)-N-methylmethanamine (trans 124)

The title compound was prepared from (±) trans 122 (0.91 g, 2.34 mmol) according to the procedure described above for the corresponding cis-isomer to give (±) trans 124 (0.219 g, 30%) as clear oil.
The enantiomers of (±) trans 124 were separated using preparative HPLC (ChiralPak OD column; hexanes:IPA:DEA=95:5:0.1; 8 ml/min; λ=280 nm) to give trans 124 E1 (retention time=10 min) and trans 124 E2 (retention time=18 min). The absolute configurations of the chiral centers were not determined. ¹H NMR (CDCl₃) δ 1.24-1.42 (m, 2H), 1.60-1.77 (m, 2H), 1.85-1.92 (m, 2H), 2.33 (s, 3H), 2.70 (d, J=13.6 Hz, 1H), 2.93 (d, J=13.6 Hz, 1H), 3.33 (s, 3H), 3.64 (dd, J=7.6, 2.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.47 (s, 1H). ¹³C NMR (CDCl₃) δ 21.6, 21.8, 24.9, 30.6, 37.4, 46.8, 57.2, 58.5, 81.5, 127.2, 129.7, 130.2, 130.4, 132.7, 145.1. ESI MS m/z 302.

1-(1-(3,4-dichlorophenyl)-2-methoxycyclohexyl)-N,N-dimethylmethanamine (125)

The following compounds were prepared from the respective monomethyl amine according to General Procedure F. The crude products were purified by silica gel column chromatography (dichloromethane/methanol, 0-5% MeOH) to give the desired dimethyl amine.
(±) cis 125 was prepared from (±) cis 124 (54 mg, 83%, clear oil). ¹H NMR (CDCl₃) δ 1.35-1.42 (m, 2H), 1.47-1.54 (m, 2H), 1.62-1.66 (m, 1H), 1.74-1.87 (m, 2H), 2.01-2.04 (m, 1H), 2.12 (s, 6H), 2.31 (d, J=14 Hz, 1H), 2.65 (d, J=14 Hz, 1H), 3.31 (s, 3H), 3.52 (dd, J=8.8, 3.2 HZ, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.42 (dd, J=8.8, 2.4 Hz, 1H), 7.70 (s, 1H). ¹³C NMR (CDCl₃) δ 21.9, 23.7, 25.0, 31.6, 48.7, 49.1, 56.7, 68.1, 83.3, 128.4, 129.5, 129.7, 131.1, 131.8, 145.8. ESI MS m/z 316.
Trans 125 E1 and trans 125 E2 were prepared from trans 124 E1 and trans 124 E2, respectively. 1H NMR (CDCl3) δ 1.24-1.39 (m, 3H), 1.42-1.60 (m, 2H), 1.77-1.88 (m, 2H), 1.91 (s, 6H), 2.25 (d, J=13.6 Hz, 1H), 2.71 (d, J=13.6 Hz, 1H), 3.36 (s, 3H), 3.76 (s, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.49 (s, 1H). 13C NMR (CDCl3) δ 20.9, 21.5, 23.7, 28.8, 48.3, 56.5, 67.6, 79.4, 127.6, 129.8, 130.2, 130.4, 132.2, 145.6. ESI MS m/z 316.

2.3. Synthesis of 2-Aminomethyl-2-aryl-cyclohexanol Analogs via Carboxylic Acids

2.3.1. Preparation of Arylhydroxyacids (130a-130i)

The preparation of Arylhydroxyacids is outlined in Scheme 27, below. Commercial arylboronic acids 126 were converted to the aryllead intermediates 127 using lead acetate and mercuric acetate. Compounds 127 were used in situ to α-arylate 2-ethylcyclohexanonecarboxylate to provide ketoesters 128 as racemic mixtures in 32-71% overall yield. Reduction of racemic ketones 128 with sodium borohydride produced four isomeric hydroxyester products, 129 (±) cis and 129 (±) trans in 29% to quantitative yields. The pair of cis isomers were separated from the pair of trans isomers to give the enantiomeric mixtures 129 (±) cis and 129 (±) trans using a Biotage chromatography system (Sorbent Technologies, 800 g, 40-75 μm SiO₂, heptane/ether). Each of 129 (±) cis and 129 (±) trans were saponified with sodium hydroxide in methanol/water to provide the hydroxyacids 130 (±) cis and 130 (±) trans, respectively, in 55% to quantitative yield after extraction.

2.3.2. General Procedure N: Synthesis of Aryl-Plumbanetriyl Triacetate

A mixture of chloroform (e.g., 200 mL), lead (IV) acetate (e.g., 58.1 g, 131 mmol, 1 eq), and mercuric acetate (2.09 g, 6.55 mmol, 0.05 eq) was warmed to 40° C. The respective arylboronic acid (e.g., 131 mmol) was added in portions over 15 minutes. The mixture was stirred at 40° C. for one hour, then cooled to room temperature and stirred overnight. This crude mixture was used immediately in the next reaction step.
The following compounds were prepared from the corresponding boronic acids 126 following the procedure outlined in General Procedure N, above:

(127a) (3,4-Dichlorophenyl)plumbanetriyl triacetate
(127b) (3,4-Methylenedioxy)plumbanetriyl triacetate
(127c) (4-Chlorophenyl)plumbanetriyl triacetate
(127d) (3-Chlorophenyl)plumbanetriyl triacetate
(127e) (4-Methoxyphenyl)plumbanetriyl triacetate
(127f) (4-Chloro-3-fluorophenyl)plumbanetriyl triacetate
(127 g) (4-Trifluoromethylphenyl)plumbanetriyl triacetate
(127h) (4-Trifluoromethoxyphenyl)plumbanetriyl triacetate
(127i) Naphthalen-2-ylplumbanetriyl triacetate

2.3.3 General Procedure Q: Synthesis of Esters (128a-128i)

To the crude reaction mixture of the respective lead intermediate arylplumbanetriyl triacetate 2 was slowly added pyridine (e.g., 31.8 mL, 393 mmol) and ethyl-2-oxocyclohexanecarboxylate (e.g., 22.3 g, 131 mmol). The reaction mixture was heated to 40° C. and stirred for 72 hours and was then diluted with chloroform (e.g., 200 mL) and poured into water (e.g., 300 mL). The phases were separated and the organic layer washed with 2 N H₂SO₄(2×200 mL), dried over MgSO₄, filtered, and concentrated. The residue was purified by silica gel flash chromatography using the indicated solvent systems to give the alph-keto esters 3.
The following compounds were prepared from the corresponding intermediate 127 following the procedure outlined in General Procedure Q, above:

(128a) (±) Ethyl-1-(3,4-Dichlorophenyl)-2-oxocyclohexane-carboxylate (hexane/ethyl acetate, 100:0 to 90:10, 46%, white solid)
(128b) (±) Ethyl-1-(3,4-methylenedioxy)-2-oxocyclohexane-carboxylate (hexane/ethyl acetate, 9:1, 45%, white solid)
(128c) (±) Ethyl-1-(4-Chlorophenyl)-2-oxocyclohexanecarboxylate (hexane/diethyl ether, 96.6 g, 68%, light yellow oil)
(128d) (±) Ethyl-1-(3-chlorophenyl)-2-oxocyclohexane-carboxylate (hexane/diethyl ether, 130 g, 71%, white solid)
(128e) (±) Ethyl-1-(4-methoxyphenyl)-2-oxocyclohexane-carboxylate (hexane/ethyl acetate, 100:0 to 90:10, 87.0 g, 63%, yellow semi-solid)
(128f) (±) Ethyl-1-(4-Chloro-3-fluorophenyl)-2-oxocyclohexane-carboxylate (hexane/ethyl acetate, 100:0 to 95:5, 67.4 g, 52%, white solid).
(128 g) (±) Ethyl-1-(4-Trifluoromethylphenyl)-2-oxocyclohexanecarboxylate (hexane/ethyl acetate, 100:0 to 90:10, 43.0 g, 34%, white solid).
(128h) Ethyl-1-(4-trifluoromethoxy)-2-oxocyclohexanecarboxylate (hexane/diethyl ether, 49.5 g, 61%, colorless oil)
(128i) (±) Ethyl-1-(naphthalen-2-yl)-2-oxocyclohexanecarboxylate (hexane/ethyl acetate, 100:0 to 90:10, 79.8 g, 60%, yellow semi-solid)

2.3.4. NaBH₄Reduction and Separation of Diastereomers (Synthesis of 129a-129i)

General Procedure R: To a solution of the respective ketoester 3 (e.g., 17.8 g, 56.5 mmol) in ethanol (e.g., 280 mL) at 0° C. was added sodium borohydride (e.g., 2.56 g, 67.8 mmol) portionwise. The mixture was stirred for 3 hours and was then concentrated. The residue was dissolved in diethyl ether (e.g., 200 mL) and 2 N HCl (e.g., 125 mL) was then slowly added. The phases were separated and the aqueous layer was extracted with diethyl ether (e.g., 3×100 mL). The organic layers were combined and washed with brine (e.g., 125 mL), dried over MgSO₄, filtered, and concentrated. The crude product was purified by silica gel flash chromatography using hexane/ethyl acetate or hexane/ethyl ether gradients to give a mixture of cis/trans diastereomers (13-100 g, 59-96% yield).
Separation of the diastereomers was accomplished using a Biotage chromatography system (Sorbent Technologies, 800 g, 40-75 μm SiO₂, heptane/ether, 80:20 isocratic), unless otherwise indicated. Up to 20 g of crude product were separated per injection to obtain the final products with 63-85% overall recovery. Generally, the mixture of trans-enantiomers, (±) trans 129, eluted from the column first, followed by the mixture of cis-enantiomers, (±) cis 129.
The following compounds (cis- and trans-diastereomers each) were prepared from the corresponding intermediate 128 following the procedure outlined in General Procedure R, above.

(cis 129a) (±) cis ethyl-1-(3,4-dichlorophenyl)-2-hydroxycyclohexane-carboxylate
(trans 129a) (±) trans ethyl-1-(3,4-dichlorophenyl)-2-hydroxycyclohexane-carboxylate
(cis 129b) (±) cis ethyl-1-(3,4-methylenedioxy)-2-hydroxycyclohexanecarboxylate
(trans 129b) (±) trans ethyl-1-(3,4-methylenedioxy)-2-hydroxycyclohexanecarboxylate
(cis 129c) (±) cis ethyl-1-(4-chlorophenyl)-2-hydroxycyclohexane-carboxylate
(trans 129c) (±) trans ethyl-1-(4-chlorophenyl)-2-hydroxycyclohexanecarboxylate
(cis 129d) (±) cis ethyl-1-(3-chlorophenyl)-2-hydroxycyclohexane-carboxylate
(trans 4d) (±) trans ethyl-1-(3-chlorophenyl)-2-hydroxycyclohexane-carboxylate
- Separation of the diastereomers was accomplished on a Symmetry C18 Column (50×250, 7μ; MeCN/water 55:45)
(cis 129e) (±) cis ethyl-2-hydroxy-1-(4-methoxyphenyl)cyclohexane-carboxylate
(trans 129e) (±) trans ethyl-2-hydroxy-1-(4-methoxyphenyl)cyclohexane-carboxylate
- The mixture of cis/trans isomers was separated by reverse-phase chromatography.
(cis 129f) (±) cis ethyl-1-(4-Chloro-3-fluorophenyl)-2-hydroxycyclohexane-carboxylate
(trans 129f) (±) trans ethyl-1-(4-Chloro-3-fluorophenyl)-2-hydroxycyclohexane-carboxylate
(cis 129g) (±) cis ethyl-1-(4-trifluoromethylphenyl)-2-hydroxycyclohexanecarboxylate
(trans 129g) (±) trans ethyl-1-(4-trifluoromethylphenyl)-2-hydroxycyclohexanecarboxylate
(cis 129h) (±) cis ethyl-1-(4-trifluoromethoxyphenyl)-2-hydroxycyclohexanecarboxylate
(trans 129h) (±) trans ethyl-1-(4-trifluoromethoxyphenyl)-2-hydroxycyclohexanecarboxylate
(cis 129i) (±) cis ethyl-2-hydroxy-1-(naphthalen-2-yl)cyclohexane-carboxylate
(trans 129i) (±) trans ethyl-2-hydroxy-1-(naphthalen-2-yl)cyclohexane-carboxylate

2.3.5. Saponification (Synthesis of 130a-130i)

General Procedure S: To a solution of the respective (±) cis- or trans-hydroxy ester 129 (e.g., 3.90 g, 12.3 mmol) in water (e.g., 12.0 mL) and methanol (e.g., 22.0 mL) at 0° C. was slowly added sodium hydroxide (e.g., 1.18 g, 29.5 mmol). The mixture was stirred overnight and was then carefully acidified with 2 N HCl and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine (e.g., 40 mL), dried over MgSO₄, and filtered. The solvent was removed in vacuo to give the respective carboxylic acid, either (±) trans 130 or (±) cis 130. Yields for this conversion were found to be between 55% and quantitative.
The following compounds were prepared from the corresponding intermediate 129 following the procedure outlined in General Procedure S, above.

(cis 130a) (±) cis-1-(3,4-Dichlorophenyl)-2-hydroxycyclohexane-carboxylic acid
(trans 130a) (±) trans-1-(3,4-Dichlorophenyl)-2-hydroxycyclohexanecarboxylic acid
(cis 130b) (±) cis-1-(3,4-Methylenedioxy)-2-hydroxycyclohexane-carboxylic acid
(trans 130b) (±) trans-1-(3,4-Methylenedioxy)-2-hydroxycyclohexane-carboxylic acid
(cis 130c) (±) cis-1-(4-Chlorophenyl)-2-hydroxycyclohexane-carboxylic acid
(trans 130c) (±) trans-1-(4-Chlorophenyl)-2-hydroxycyclohexanecarboxylic acid
(cis 130d) (±) cis-1-(3-Chlorophenyl)-2-hydroxycyclohexane-carboxylic acid
(trans 130d) (±) trans-1-(3-Chlorophenyl)-2-hydroxycyclohexane-carboxylic acid
(cis 130e) (±) cis-2-hydroxy-1-(4-methoxyphenyl)cyclohexane-carboxylic acid
(trans 130e) (±) trans-2-Hydroxy-1-(4-methoxyphenyl)cyclohexane-carboxylic acid
(cis 130f) (±) cis-1-(4-Chloro-3-fluorophenyl)-2-hydroxycyclohexanecarboxylic acid
(trans 130f) (±) trans-1-(4-chloro-3-fluorophenyl)-2-hydroxycyclohexanecarboxylic acid
(cis 130g) (±) cis-1-(4-Trifluoromethylphenyl)-2-hydroxycyclohexanecarboxylic acid
(trans 130g) (±) trans-1-(4-Trifluoromethylphenyl)-2-hydroxycyclohexane-carboxylic Acid
(cis 130h) (±) cis-1-(4-Trifluoromethoxyphenyl)-2-hydroxycyclohexanecarboxylic acid
(trans 130h) (±) trans-1-(4-Trifluoromethoxyphenyl)-2-hydroxycyclohexane-carboxylic acid
(cis 130i) (±) cis-2-Hydroxy-1-(naphthalen-2-yl)cyclohexanecarboxylic acid
(trans 130i) (±) trans-2-Hydroxy-1-(naphthalen-2-yl)cyclohexanecarboxylic acid
Preparation of 2-Phenylaminoalcohols (132a-132i)

PyBOP-mediated coupling of hydroxyacids (±) cis 130 and (±) trans 130 with methylamine (e.g., General Procedure G) gave hydroxyamides (±) cis 131 and (±) trans 131, respectively, in 39% to quantitative yield. Reduction of (±) cis 131 and (±) trans 131 with borane.dimethylsulfide complex gave aminoalcohols (±) cis 132 and (±) trans 132, respectively, in 39-95% yield. The enantiomers of (±) cis 132 and (±) trans 132 were separated using preparative chiral HPLC to give the fast moving enantiomer E1 and the slow moving enantiomer E2 (Scheme 28). The absolute configuration of the chiral centers was not determined.

2.3.6. General Procedure G2 (Amide Bond Formation)

A mixture of the respective carboxylic acid 130 (e.g., 3.56 g, 12.3 mmol), PyBOP (e.g., 7.04 g, 13.5 mmol), methylamine (e.g., 2 M in THF, 37.0 mL, 74.0 mmol), and triethylamine (e.g., 1.24 g, 12.3 mmol) was stirred at room temperature overnight. The mixture was acidified with 2 N HCl and was then extracted with ethyl acetate (e.g., 3×60 mL). The organic layers were combined, optionally washed with NaHCO₃solution, washed with brine (e.g., 50 mL), dried over MgSO₄, filtered, and concentrated. The residue was purified by silica gel flash chromatography using hexane/ethyl acetate or CH₂Cl₂/MeOH gradients and/or optionally triturated with e.g., diethyl ether to give the respective N-methyl amine 131.

2.3.7. General Procedure G3 (Amide Bond Formation)

A mixture of respective carboxylic acid 130 (e.g., 9.50 g, 37.3 mmol), PyBOP (e.g., 19.4 g, 37.3 mmol), methylamine (e.g., 2 M in THF, 20.5 mL, 41.0 mmol), N-methylmorpholine (e.g., 4.50 mL, 41.0 mmol) and DMAP (e.g., 5.00 g, 41.0 mmol) was stirred in DMF (e.g., 373 mL) at room temperature overnight. The mixture was diluted with EtOAc (e.g., 3 L). The layers were separated and the organic layer washed with 0.5 M HCl (e.g., 3×1 L), saturated aqueous NaHCO₃(3×600 mL), saturated aqueous LiCl (600 mL), brine (600 mL), dried, filtered and concentrated. The residue was purified by silica gel chromatography using hexane/ethyl acetate or CH₂Cl₂/MeOH gradients to give the respective N-methyl amine 131.
The following compounds were prepared from the corresponding intermediate 130 using the procedures outlined in General Procedure G2 or General Procedure G3, above, or slightly modified versions thereof.

(cis 131a) (±) cis-1-(3,4-Dichlorophenyl)-2-hydroxy-N-methylcyclohexane-carboxamide
(trans 131a) (±) trans-1-(3,4-Dichlorophenyl)-2-hydroxy-N-methylcyclohexanecarboxamide
(cis 131b) (±) cis-1-(3,4-Methylenedioxy)-2-hydroxy-N-methylcyclohexanecarboxamide
(trans 131b) (±) trans-1-(3,4-Methylenedioxy)-2-hydroxy-N-methylcyclohexanecarboxamide
(cis 131c) (±) cis-1-(4-Chlorophenyl)-2-hydroxy-N-methylcyclohexanecarboxamide
(trans 131c) (±) trans-1-(4-Chlorophenyl)-2-hydroxy-N-methylcyclohexanecarboxamide
(cis 131d) (±) cis-1-(3-Chlorophenyl)-2-hydroxy-N-methylcyclohexanecarboxamide
(trans 131d) (±) trans-1-(3-Chlorophenyl)-2-hydroxy-N-methylcyclohexanecarboxamide
(cis 131e) (±) cis 2-Hydroxy-1-(4-methoxyphenyl)-N-methylcyclohexanecarboxamide
(trans 131e) (±) trans 2-Hydroxy-1-(4-methoxyphenyl)-N-methylcyclohexanecarboxamide
(cis 131f) (±) cis-1-(4-Chloro-3-fluorophenyl)-2-hydroxy-N-methylcyclohexane carboxamide
(trans 131f) (±) trans-1-(4-Chloro-3-fluorophenyl)-2-hydroxy-N-methylcyclohexane Carboxamide
(cis 131g) (±) cis-1-(4-Trifluoromethylphenyl)-2-hydroxy-N-methylcyclohexane Carboxamide
(trans 131g) (±) trans-1-(4-Trifluoromethylphenyl)-2-hydroxy-N-methylcyclohexane Carboxamide
(cis 131h) (±) cis-1-(4-Trifluoromethoxyphenyl)-2-hydroxy-N-methylcyclohexane Carboxamide
(trans 131h) (±) trans-1-(4-Trifluoromethoxyphenyl)-2-hydroxy-N-methylcyclohexane Carboxamide

2.3.8. General Procedure T (Reduction of Amide 131 to Amine 132)

To a solution of the respective N-methylcarboxamide 131 (e.g., 2.70 g, 8.93 mmol) in tetrahydrofuran (90.0 mL) was slowly added borane.dimethylsulfide (2 M in THF, 13.4 mL, 26.8 mmol). The mixture was stirred 48 hours at reflux. After cooling, the mixture was acidified by careful addition of 2 N HCl. The mixture was concentrated in vacuo and the residue was washed with diethyl ether (e.g., 60 mL). The phases were separated and the aqueous layer was made basic through addition of 2 N NaOH and was then extracted with ethyl acetate (e.g., 3×150 mL). The ethyl acetate layers were combined, washed with brine (100 mL), dried over MgSO₄, filtered, and concentrated. The residue was purified by silica gel flash chromatography using e.g., dichloromethane/methanol gradients to give the respective amines (±) cis 132 and (±) trans 132.
The enantiomers for each of the amines (±) cis 132 and (±) trans 132 were separated using preparative chiral HPLC. Typical conditions are listed below:
1. ChiralPak AD; heptane:EtOH:DEA=95:5:0.1; μ=25 ml/min; λ=275 nm.
2. Regis O1; hexanes:IPA:DEA=90:10:0.1; μ=25 ml/min; and λ=280 nm.
Absolute configurations of the chiral centers were not determined. Compounds are identified by E1 for the fast moving enantiomer and E2 for the slow moving enantiomer.
The following compounds were prepared from the corresponding intermediate 131 using the procedures outlined in General Procedure T or a slightly modified version thereof.

cis-2-(3,4-Dichlorophenyl)-2-((methylamino)methyl)cyclohexanol (133)

The enantiomeric mixture of (±) cis 132a was separated (ChiralPak AD column; heptane:EtOH:DEA=95:5:0.1; μ=25 ml/min; λ=275 nm) to give 133 E1 (retention time=15.5 min) and 133 E2 (retention time=20.7 min). ¹H NMR (CDCl₃) δ 0.96-1.03 (m, 1H), 1.23-1.44 (m, 3H), 1.65-1.69 (m, 1H), 1.78-1.84 (m, 2H), 2.01-2.06 (m, 1H), 2.29 (s, 3H), 2.66 (d, J=13.6 Hz, 1H), 2.91 (d, J=13.6 Hz, 1H), 3.97 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.71 (dd, J=12.0, 2.4 Hz, 1H), 7.96 (s, 1H). ¹³C NMR (CDCl₃) δ 21.3, 24.9, 29.9, 35.9, 36.7, 46.2, 66.9, 81.4, 118.0, 129.2, 130.4, 131.6, 132.6, 142.7. ESI MS m/z 289.

trans-2-(3,4-Dichlorophenyl)-2-((dimethylamino)methyl)cyclohexanol (134)

The enantiomeric mixture of (±) trans 132a was separated (ChiralPak AD column; heptane:EtOH:DEA=95:5:0.1; μ=25 ml/min; and λ=275 nm) to give 134 E1 (retention time=13.4 min) and 134 E2 (retention time=18.9 min). ¹H NMR (CDCl₃) δ 1.28-1.50 (m, 4H), 1.64-1.86 (m, 3H), 1.98-2.02 (m, 1H), 2.32 (s, 3H), 2.97 (d, J=12.4 Hz, 1H), 3.30 (d, J=12.4 Hz, 1H), 4.20 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.40-7.47 (m, 2H), 7.69 (d, J=1.6 Hz, 1H). ¹³C NMR (CDCl₃) δ 21.9, 24.3, 32.4, 36.7, 37.5, 45.7, 57.1, 74.1, 126.7, 129.4, 130.4, 130.6, 132.9, 146.5. ESI MS m/z 289.

cis-2-(4-chlorophenyl)-2-((methylamino)methyl)cyclohexanol (135)

The enantiomeric mixture (±) cis 132c can be separated (e.g., Regis O1 column; hexanes:IPA:DEA=90:10:0.1; μ=25 ml/min; and λ=280 nm) to give 135 E1 and 135 E2.

trans-2-(4-chlorophenyl)-2-((methylamino)methyl)-cyclohexanol (136)

The enantiomeric mixture (±) trans 132c was separated (Regis O1 column; hexanes:IPA:DEA=90:10:0.1; μ=25 ml/min; and λ=280 nm) to give 136 E1 (retention time=6.8 min) and 136 E2 (retention time=8.9 min). ¹H NMR (CDCl₃) δ 1.28-1.47 (m, 4H), 1.64-1.87 (m, 3H), 1.96-2.02 (m, 1H), 2.31 (s, 3H), 2.98 (d, J=12.4 Hz, 1H), 3.29 (d, J=12.4 Hz, 1H), 4.24 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.30 (d, J=10.8 Hz, 2H), 7.58 (d, J=10.8 Hz, 2H). ¹³C NMR (CDCl₃) δ 21.9, 24.4, 32.4, 36.7, 37.5, 45.7, 57.1, 74.3, 128.6, 128.9, 132.1, 144.6. ESI MS m/z 254.

cis-2-(3-chlorophenyl)-2-((methylamino)methyl)cyclohexanol (137)

The enantiomeric mixture of (±) cis 132d can be separated (e.g., Regis O1 column; hexanes:IPA:DEA=90:10:0.1; μ=25 ml/min; and λ=280 nm) to give 137 E1 and 137 E2.

trans-2-(3-chlorophenyl)-2-((methylamino)methyl)cyclohexanol (138)

The enantiomeric mixture (±) trans 132d was separated (Regis O1 column; hexanes:IPA:DEA=90:10:0.1; μ=25 m/min; and λ=280 nm) to give 138 E1 (retention time=5.9 min) and 138 E2 (retention time=7.6 min). ¹H NMR (CDCl₃) δ 1.28-1.47 (m, 4H), 1.64-1.87 (m, 3H), 1.96-2.02 (m, 1H), 2.31 (s, 3H), 2.98 (d, J=12.4 Hz, 1H), 3.29 (d, J=12.4 Hz, 1H), 4.25 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.18-7.22 (m, 1H), 7.29-7.32 (m, 1H), 7.48-7.52 (m, 1H), 7.60 (s, 1H). ¹³C NMR (CDCl₃) δ 22.1, 24.4, 32.5, 36.7, 37.5, 45.9, 57.2, 74.1, 125.3, 126.7, 127.4, 134.8, 148.3. ESI MS m/z 254.

cis-2-((methylamino)methyl)-2-(4-methoxyphenyl)cyclohexanol (139)

The enantiomeric mixture (±) cis 132e was separated (Regis O1 column; hexanes:IPA:DEA=90:10:0.1; μ=25 ml/min; and λ=275 nm) to give 139 E1 (retention time=5.7 min) and 139 E2 (retention time=7.1 min). ¹H NMR (CDCl₃) δ 1.02-1.10 (m, 1H), 1.21-1.39 (m, 3H), 1.62-1.66 (m, 1H), 1.76-1.94 (m, 2H), 2.04-2.08 (m, 1H), 2.26 (s, 3H), 2.62 (d, J=12.4 Hz, 1H), 2.88 (d, J=12.4 Hz, 1H), 3.77 (s, 3H), 3.96 (dd, J=11.2 Hz, 4.0 Hz, 1H), 6.86 (d, J=8.8 Hz, 2H), 7.73 (d, J=8.8 Hz, 1H). ¹³C NMR (CDCl₃) δ 21.4, 25.0, 30.0, 35.8, 36.7, 46.2, 55.3, 67.1, 81.9, 113.8, 130.4, 133.7, 157.8. ESI MS m/z 250.

(±) trans-2-(4-Methoxyphenyl)-2-((methylamino)methyl)cyclohexanol (140)

The enantiomeric mixture (±) trans 132e was separated (ChiralPak AD column; hexanes:IPA:DEA=90:10:0.1; μ=25 ml/min; and λ=275 nm) to give 140 E1 (retention time=5.3 min) and 140 E2 (retention time=7.1 min). ¹H NMR (CDCl₃) δ 1.23-1.46 (m, 4H), 1.62-1.87 (m, 3H), 1.92-2.00 (m, 1H), 2.28 (s, 3H), 2.95 (d, J=12.4 Hz, 1H), 3.24 (d, J=12.4 Hz, 1H), 3.78 (s, 3H), 4.25 (dd, J=10.4 Hz, 3.2 Hz, 1H), 6.87 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H). ¹³C NMR (CDCl₃) δ 22.1, 24.4, 32.5, 36.7, 37.7, 45.1, 55.4, 57.6, 74.4, 114.1, 128.0, 137.9, 157.9. ESI MS m/z 250.

cis-2-(4-Chloro-3-fluorophenyl)-2-((methylamino)methyl)cyclohexanol (141)

The enantiomeric mixture (±) cis 132f was separated (Regis O1 column; hexanes:IPA:DEA=95:5:0.1; μ=25 ml/min; λ=275 nm) to give 141 E1 (retention time=7.2 min) and 141 E2 (retention time=10.8 min). ¹H NMR (CDCl₃) δ 1.28-1.50 (m, 4H), 1.64-1.86 (m, 3H), 1.98-2.02 (m, 1H), 2.32 (s, 3H), 2.97 (d, J=12.4 Hz, 1H), 3.30 (d, J=12.4 Hz, 1H), 4.19 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.32-7.38 (m, 2H), 7.42-7.52 (m, 1H). ¹³C NMR (CDCl₃) δ 22.0, 24.4, 32.5, 36.8, 37.7, 45.7, 57.1, 74.3, 115.7, 115.9, 118.6, 118.7, 123.6, 130.7, 147.5, 157.2, 159.7. ESI MS m/z 272.

trans-2-(4-chloro-3-fluorophenyl)-2-((methylamino)methyl)cyclohexanol (142)

The enantiomeric mixture (±) trans 132f was separated (Regis O1 column; hexanes:IPA:DEA=95:5:0.1; μ=25 ml/min; λ=275 nm) to give 142 E1 (retention time=6.7 min) and 142 E2 (retention time=8.6 min). ¹H NMR (CDCl₃) δ 0.96-1.03 (m, 1H), 1.23-1.44 (m, 3H), 1.65-1.69 (m, 1H), 1.78-1.84 (m, 2H), 2.01-2.06 (m, 1H), 2.29 (s, 3H), 2.66 (d, J=13.6 Hz, 1H), 2.91 (d, J=13.6 Hz, 1H), 3.97 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.56 (dd, J=12.0, 2.4 Hz, 1H), 7.74(dd, J=12.0, 2.4 Hz, 1H). ¹³C NMR (CDCl₃) δ 21.3, 24.9, 29.9, 35.9, 36.7, 46.8, 67.0, 81.5, 118.0, 118.3, 125.9, 126.0, 130.4, 143.4, 156.9, 159.3. ESI MS m/z 272.

cis-2-((methylamino)methyl)-2-(4-(trifluoromethyl)phenyl)cyclohexanol (143)

The enantiomeric mixture (±) cis 132g was separated (Regis O1 column; hexanes:IPA:DEA=95:5:0.1; μ=25 ml/min; λ=275 nm) to give 143 E1 (retention time=8.2 min) and 143 E2 (retention time=11.8 min). ¹H NMR (CDCl₃) δ 1.05-1.13 (m, 1H), 1.26-1.36 (m, 2H), 1.45-1.52 (m, 2H), 1.61-1.70 (m, 1H), 1.79-1.85 (m, 1H), 1.93-1.99 (m, 2H), 2.03 (s, 6H), 2.67(d, J=13.6 Hz, 1H), 3.28 (d, J=13.6 Hz, 1H), 3.95 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.4 Hz, 1.2 Hz, 2H). ¹³C NMR (CDCl₃) δ 22.0, 24.4, 32.5, 36.8, 37.7, 46.0, 57.1, 74.2, 123.1, 125.6, 125.7, 125.9, 127.5, 128.5, 128.8, 150.3. ESI MS m/z 288.

trans-2-((Methylamino)methyl)-2-(4-(trifluoromethyl)phenyl)cyclohexanol (144)

The enantiomeric mixture (±) trans 132g was separated (Regis O1 column; hexanes:IPA:DEA=95:5:0.1; μ=25 ml/min; λ=275 nm) to give 144 E1 (retention time=7.9 min) and 144 E2 (retention time=11.2 min). ¹H NMR (CDCl₃) δ 0.91-1.02 (m, 1H), 1.27-1.43 (m, 3H), 1.65-1.69 (m, 1H), 1.83-1.88 (m, 2H), 2.11-2.16 (m, 1H), 2.28 (s, 3H), 2.68 (d, J=13.6 Hz, 1H), 2.97 (d, J=13.6 Hz, 1H), 4.02 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.98 (d, J=8.4 Hz, 2H). ¹³C NMR (CDCl₃) δ 21.4, 24.9, 30.0, 36.0, 36.7, 47.1, 67.1, 81.6, 125.3, 125.4, 125.8, 128.3, 128.6, 129.9, 146.6. ESI MS m/z 288.

cis-2-((Methylamino)methyl)-2-(4-(trifluoromethoxy)phenyl)cyclohexanol (145)

The enantiomeric mixture (±) cis 132h was separated (Regis O1 column; hexanes:IPA:DEA=95:5:0.1; μ=25 ml/min; λ=275 nm) to give 145 E1 (retention time=5.1 min) and 145 E2 (retention time=8.2 min). ¹H NMR (CDCl₃) δ 1.05-1.13 (m, 1H), 1.26-1.36 (m, 2H), 1.45-1.52 (m, 2H), 1.30-1.48 (m, 4H), 1.68-1.88 (m, 3H), 1.99-2.03 (m, 1H), 2.32 (s, 3H), 3.02 (d, J=12.4 Hz, 1H), 3.31 (d, J=12.4 Hz, 1H), 4.27 (dd, J=10.4 Hz, 4.0 Hz, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H). ¹³C NMR (CDCl₃) δ 21.3, 22.0, 24.5, 32.5, 36.7, 37.9, 45.5, 57.1, 74.3, 119.4, 120.8, 121.1, 122.0, 128.5, 131.0, 144.7, 147.6. ESI MS m/z 304.

trans-2-((Methylamino)methyl)-2-(4-(trifluoromethoxy)phenyl)cyclohexanol (146)

The enantiomeric mixture (±) trans 132h was separated (Regis O1 column; hexanes:IPA:DEA=95:5:0.1; μ=25 ml/min; λ=275 nm) to give 146 E1 (retention time=4.4 min) and 146 E2 (retention time=5.8 min). ¹H NMR (CDCl₃) δ 0.96-1.04 (m, 1H), 1.25-1.42 (m, 3H), 1.65-1.69 (m, 1H), 1.81-1.88 (m, 2H), 2.07-2.16 (m, 1H), 2.29 (s, 3H), 2.68 (d, J=11.6 Hz, 1H), 2.95 (d, J=11.6 Hz, 1H), 4.00 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.18 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H). ¹³C NMR (CDCl₃) δ 21.3, 25.0, 30.0, 36.0, 36.7, 46.6, 67.1, 81.6, 119.4, 120.8, 122.0, 131.0, 140.7, 147.5. ESI MS m/z 304.

cis-2-((dimethylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol (147)

The enantiomeric mixture of (±) cis 1321 was separated (ChiralPak AD column; hexanes:IPA:DEA=90:10:0.1; μ=60 ml/min; λ=280 nm) to give 147 E1 (retention time=20.7 min) and 147 E2 (retention time=28.2 min). ¹H NMR (CDCl₃) δ 0.96-1.03 (m, 1H), 1.22-1.41 (m, 3H), 1.60-1.65 (m, 1H), 1.84-1.92 (m, 1H), 2.01-2.12 (m, 1H), 2.22 (s, 3H), 2.66 (d, J=13.6 Hz, 1H), 3.01 (d, J=13.6 Hz, 1H), 4.05 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.19-7.24 (m, 2H), 7.71-7.87 (m, 4H), 8.49 (s, 1H). ¹³C NMR (CDCl₃) δ 21.6, 25.1, 30.1, 35.9, 36.7, 47.1, 66.7, 81.9, 126.0, 126.1, 126.6, 127.5, 128.3, 128.5, 129.5, 132.1, 133.6, 139.3. ESI MS m/z 270.

trans-2-((dimethylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol (148)

The enantiomeric mixture (±) trans 1321 was separated (ChiralPak AD column; hexanes:IPA:DEA=90:10:0.1; μ=60 ml/min; λ=280 nm) to give 148 E1 (retention time=25.7 min) and 148 E2 (retention time=40.8 min). ¹H NMR (CDCl₃) δ 1.28-1.50 (m, 4H), 1.71-1.86 (m, 2H), 1.95-2.06 (m, 2H), 2.25 (s, 3H), 3.06 (d, J=12.4 Hz, 1H), 3.30 (d, J=12.4 Hz, 1H), 4.45 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.39-7.44(m, 2H), 7.60-7.63 (m, 1H), 7.76-7.85 (m, 3H), 8.14 (s, 1H). ¹³C NMR (CDCl₃) δ 22.1, 24.6, 32.7, 36.8, 37.7, 45.9, 57.1, 74.4, 124.8, 125.9, 126.2, 126.3, 127.5, 128.4, 128.5, 132.2, 133.8, 143.2. ESI MS m/z 270.

cis-2-((methylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol (149)

(a) cis-2-hydroxy-N-methyl-1-(naphthalen-2-yl)cyclohexanecarboxamide (300)

A mixture of (±) cis-2-hydroxy-1-(naphthalen-2-yl)cyclohexanecarboxylic acid (9.74 g, 36.1 mmol), PyBOP (18.8 g, 36.1 mmol), methylamine (2 M in THF, 19.8 mL, 39.7 mmol), N-methylmorpholine (4.36 mL, 39.7 mmol) and DMAP (4.84 g, 39.7 mmol) was stirred in DMF (361 mL) at room temperature overnight. The mixture was diluted with EtOAc (1.5 L). The layers were separated and the organic layer washed with 0.5 M HCl (3×600 mL), saturated aqueous NaHCO₃(3×500 mL), brine (300 mL), dried and concentrated. The residue was triturated with diethyl ether to give (±) cis-2-hydroxy-N-methyl-1-(naphthalen-2-yl)cyclohexanecarboxamide (7.36 g, 72%) as a light yellow solid.

(b) cis-2-((methylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol

The title compound can be prepared from the above amide, for example, according to General Procedure E.

(±) trans-2-((methylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol (150)

(a) (±) trans-2-hydroxy-N-methyl-1-(naphthalen-2-yl)cyclohexanecarboxamide (301)

A mixture of (±) trans-2-hydroxy-1-(naphthalen-2-yl)cyclohexanecarboxylic acid (9.72 g, 36.0 mmol), PyBOP (18.7 g, 36.0 mmol), methylamine (2 M in THF, 19.8 mL, 39.6 mmol), N-methylmorpholine (4.35 mL, 39.6 mmol) and DMAP (4.83 g, 39.6 mmol) was stirred in DMF (360 mL) at room temperature overnight. The mixture was diluted with EtOAc (1.5 L). The layers were separated and the organic layer washed with 1 M HCl (3×600 mL), saturated aqueous NaHCO₃(3×500 mL), brine (500 mL), dried and concentrated to give (±)-2-hydroxy-N-methyl-1-(naphthalen-2-yl)cyclohexanecarboxamide (8.66 g, 85%) as a light yellow solid.

(b) trans-2-((methylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol

2.4. Preparation of Tertiary Amines (151a to 151i)

Treatment of the respective methylamines 132 (Scheme 29) with a methylating reagent, e.g., iodomethane and N,N′-diisopropylethylamine (DIEA) in acetone or CH₂Cl₂(modified General Procedure F) gave the dimethylamines cis 151 E1, c is 151 E2, trans 151 E1, and trans 151 E2.
(Modified General Procedure F) To the solution of the respective N-methylamine 132 (e.g., 86 mg. 0.285 mmol) and DIEA (e.g., 0.164 ml, 0.942 mmol) in acetone (0.5 ml) was added CH₃I (e.g., 0.020 ml, 0.314 mmol). The mixture was stirred at room temperature overnight and the solvent was then removed in vacuo. The residue was dissolved in CH₂Cl₂(e.g., 10 ml), washed with saturated K₂CO₃solution (e.g., 5 ml), dried over Na₂SO₄, and evaporated in vacuo. The crude product was purified by silica gel flash chromatography using e.g., dichloromethane/methanol gradients to give the respective dimethylamine 151 in 40 to 70% yield.
The following compounds were prepared from the corresponding methylamine 133-148 using modified General Procedure F outlined above, or slightly modified versions thereof.

cis-2-(3,4-dichlorophenyl)-2-((dimethylamino)methyl)cyclohexanol (152)

152 E1, 152 E2
The title compounds were prepared from 133 E1 and 133 E2, respectively. ¹H NMR (CDCl₃) δ0.82-0.96 (m, 1H), 1.10-1.18 (m, 1H), 1.28-1.39 (m, 2H), 1.64-1.70 (m, 1H), 1.83-1.98 (m, 9H), 2.60 (d, J=13.2 Hz, 1H), 2.70 (d, J=13.2 Hz, 1H), 3.97 (dd, J=11.2, 4.8 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.73 (dd, J=8.4 Hz, 2.0 Hz, 1H). 7.98 (d, J=2 Hz, 1H). ¹³C NMR (CDCl₃) δ 21.0, 25.1, 29.9, 37.2, 46.0, 47.8, 75.9, 80.8, 129.5, 130.0, 130.2, 131.9, 132.4, 143.7. ESI MS m/z 303.

trans-2-(3,4-dichlorophenyl)-2-((dimethylamino)methyl)cyclohexanol (153)

153 E1, 153 E2
The title compounds were prepared from 134 E1 and 134 E, respectively. ¹H NMR (CDCl₃) δ 1.21-1.35 (m, 2H), 1.42-1.48 (m, 2H), 1.56-1.66 (m, 1H), 1.77-1.98 (m, 3H), 2.03 (s, 6H), 2.58 (d, J=14.0 Hz, 1H), 3.25 (d, J=14.0 Hz, 1H), 4.18 (dd, J=9.6 Hz, 2.8 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.46 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H). ¹³C NMR (CDCl₃) δ22.1, 24.1, 32.5, 36.9, 44.6, 44.7, 66.3, 74.8, 127.0, 129.6, 130.0, 130.3, 132.5, 148.2. ESI MS m/z 303.

trans-2-(4-chlorophenyl)-2-((dimethylamino)methyl)cyclohexanol (154)

154 E1, 154 E2
The title compounds were prepared from 136 E1 and 136 E2, respectively. ¹H NMR (CDCl₃) δ 1.21-1.35 (m, 2H), 1.42-1.48 (m, 2H), 1.56-1.66 (m, 1H), 1.77-1.84 (m, 1H), 1.89-1.98 (m, 2H), 2.03 (s, 6H), 2.58 (d, J=14.0 Hz, 1H), 3.20 (d, J=14.0 Hz, 1H), 4.26 (dd, J=9.6 Hz, 2.8 Hz, 1H), 7.30 (d, J=10.8 Hz, 2H), 7.58 (d, J=10.8 Hz, 2H). ¹³C NMR (CDCl₃) δ 22.1, 24.1, 32.5, 36.7, 44.6, 47.7, 66.3, 74.8, 128.6, 128.8, 131.8, 146.0. ESI MS m/z 268.

Cis-2-((dimethylamino)methyl)-2-(4-methoxyphenyl)cyclohexanol (155)

155 E1, 155 E2
The title compounds were prepared from 139 E1 and 139 E2, respectively. ¹H NMR (CDCl₃) δ0.92-1.00 (m, 1H), 1.07-1.12 (m, 1H), 1.25-1.36 (m, 2H), 1.61-1.66 (m, 1H), 1.80-2.03 (m, 9H), 2.59 (q, J=13.2 Hz, 2H), 3.95 (dd, J=11.6 Hz, 4.0 Hz, 1H), 6.82 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.4 Hz, 2H). ¹³C NMR (CDCl₃) δ 21.1, 25.3, 30.0, 37.1, 45.5, 47.7, 55.3, 76.0, 81.5, 113.6, 130.7, 134.6, 157.6. ESI MS m/z 264.

trans-2-((dimethylamino)methyl)-2-(4-methoxyphenyl)cyclohexanol (156)

156 E1, 156 E2
The title compounds were prepared from 140 E1 and 140 E2, respectively. ¹H NMR (CDCl₃) δ 1.26-1.37 (m, 2H), 1.43-1.48 (m, 2H), 1.58-1.66 (m, 1H), 1.76-1.82 (m, 1H), 1.88-2.00 (m, 2H), 2.05 (s, 6H), 2.61 (d, J=14.0 Hz, 1H), 3.14 (d, J=14.0 Hz, 1H), 4.31 (dd, J=10.0 Hz, 3.2 Hz, 1H), 6.86 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H). ¹³C NMR (CDCl₃) δ 22.2, 13.7, 32.4, 36.1, 44.0, 47.7, 55.4, 67.4, 74.9, 113.7, 128.2, 139.1, 157.7. ESI MS m/z 263.

Cis-2-(4-chloro-3-fluorophenyl)-2-((dimethylamino)methyl)cyclohexanol (157)

157 E1, 157 E2
The title compounds were prepared from 141 E1 and 141 E2, respectively. ¹H NMR (CDCl₃) δ 1.21-1.35 (m, 2H), 1.42-1.48 (m, 2H), 1.56-1.66 (m, 1H), 1.77-1.98 (m, 3H), 2.03 (s, 6H), 2.56(d, J=14.0 Hz, 1H), 3.25 (d, J=14.0 Hz, 1H), 4.18 (dd, J=9.6 Hz, 2.8 Hz, 1H), 7.32-7.35 (m, 2H), 7.43 (d, J=8.4 Hz, 1H). ¹³C NMR (CDCl₃) δ 22.1, 24.1, 32.5, 36.9, 44.6, 44.7, 66.4, 74.9, 115.8, 116.1, 118.2, 118.4, 123.8, 130.3, 148.9, 157.0, 159.5. ESI MS m/z 286.

Trans-2-(4-chloro-3-fluorophenyl)-2-((dimethylamino)methyl)cyclohexanol (158)

158 E, 158 E2
The title compounds were synthesized from 142 E1 and 142 E2, respectively. ¹H NMR (CDCl₃) δ 0.82-0.96 (m, 1H), 1.10-1.18 (m, 1H), 1.28-1.39 (m, 2H), 1.64-1.70 (m, 1H), 1.83-1.98 (m, 9H), 2.60 (d, J=13.2 Hz, 1H), 2.70 (d, J=13.2 Hz, 1H), 3.97 (dd, J=11.2, 4.8 Hz, 1H), 7.28 (t, J=8.4 Hz, 1H), 7.55-7.58 (m, 1H). 7.75-7.79 (m, 1H). ¹³C NMR (CDCl₃) δ 21.0, 25.1, 29.9, 37.2, 46.1, 47.7, 75.9, 80.8, 118.3, 118.5, 126.3, 130.2, 144.4, 156.8, 159.3. ESI MS m/z 286.

cis-2-((dimethylamino)methyl)-2-(4-(trifluoromethyl)phenyl)cyclohexanol (159)

159 E1, 159 E2
The title compounds were prepared from 143 E1 and 143 E2, respectively. ¹H NMR (CDCl₃) δ 1.05-1.13 (m, 1H), 1.26-1.36 (m, 2H), 1.45-1.52 (m, 2H), 1.61-1.70 (m, 1H), 1.79-1.85 (m, 1H), 1.93-1.99 (m, 2H), 2.03 (s, 6H), 2.67(d, J=13.6 Hz, 1H), 3.28 (d, J=13.6 Hz, 1H), 3.95 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H). ¹³C NMR (CDCl₃) δ 22.1, 24.0, 32.4, 36.8, 44.9, 66.4, 74.8, 123.2, 125.3, 125.4, 125.9, 127.7, 128.2, 128.5, 151.7. ESI MS m/z 302.

trans-2-((dimethylamino)methyl)-2-(4-(trifluoromethyl)phenyl)cyclohexanol (160)

160 E1, 160 E2
The title compounds were prepared from 144 E1 and 144 E2, respectively. ¹H NMR (CDCl₃) δ 0.82-0.93 (m, 1H), 1.14-1.21 (m, 1H), 1.30-1.40 (m, 2H), 1.67-1.70 (m, 1H), 1.87-2.09 (m, 9H), 2.65-2.75 (m, 2H), 4.00-4.05 (m, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.99 (d, J=8.4 Hz, 2H). ¹³C NMR (CDCl₃) δ 21.1, 25.2, 30.0, 37.4, 46.4, 47.6, 76.0, 81.0, 125.1, 125.2, 125.9, 128.0, 128.4, 130.2, 131.8, 147.6. ESI MS m/z 302.

cis-2-((dimethylamino)methyl)-2-(4-(trifluoromethoxy)phenyl)cyclohexanol (161)

161 E1, 161 E2
The title compounds were prepared from 145 E1 and 145 E2, respectively. ¹H NMR (CDCl₃) δ 1.26-1.37 (m, 2H), 1.43-1.50 (m, 2H), 1.59-1.68 (m, 1H), 1.78-1.84 (m, 1H), 1.92-1.97 (m, 2H), 2.03 (s, 6H), 2.61 (d, J=14.0 Hz, 1H), 3.24 (d, J=14.0 Hz, 1H), 4.28 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.8 Hz, 2H). ¹³C NMR (CDCl₃) δ 22.2, 24.0, 32.4, 36.7, 44.4, 47.7, 66.7, 74.9, 119.5, 120.8, 122.0, 128.7, 131.2, 146.1, 147.4. ESI MS m/z 302.

trans-2-((dimethylamino)methyl)-2-(4-(trifluoromethoxy)phenyl)cyclohexanol (162)

162 E1, 162 E2
The title compounds were prepared from 146 E1 and 146 E2, respectively. ¹H NMR(CDCl₃) δ0.90-0.97 (m, 1H), 1.12-1.19 (m, 1H), 1.29-1.39 (m, 2H), 1.65-1.69 (m, 1H), 1.84-2.04 (m, 9H), 2.60 (d, J=14.0 Hz, 1H), 2.70 (d, J=14.0 Hz, 1H), 4.00 (dd, J=11.6 Hz, 4.0 Hz, 1H), 7.14 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 2H). ¹³C NMR (CDCl₃) δ 21.0, 25.2, 29.9, 37.3, 46.0, 47.7, 76.1, 81.1, 120.6, 122.0, 131.2, 141.7, 147.4. ESI MS m/z 318.

Cis-2-((dimethylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol (163)

163 E1, 163 E2
The title compounds were synthesized from 147 E1 and 147 E2, respectively. ¹H NMR (CDCl₃) δ0.82-0.96 (m, 1H), 1.10-1.18 (m, 1H), 1.28-1.39 (m, 2H), 1.64-1.70 (m, 1H), 1.83-1.98 (m, 9H), 2.60 (d, J=13.2 Hz, 1H), 2.70 (d, J=13.2 Hz, 1H), 4.05 (dd, J=11.2, 4.8 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.73 (dd, J=8.4 Hz, 2.0 Hz, 1H). 7.98 (d, J=2 Hz, 1H). ¹³C NMR (CDCl₃) δ 21.0, 25.1, 29.9, 37.2, 46.0, 47.8, 75.9, 80.8, 126.0, 126.1, 126.6, 127.5, 128.3, 128.5, 129.5, 132.1, 133.6, 139.3. ESI MS m/z 284.

trans-2-((dimethylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol (164)

164 E1, 164 E2
The title compounds were prepared from 148 E1 and 148 E2, respectively. ¹H NMR (CDCl₃) δ 1.29-1.42 (m, 2H), 1.47-1.54 (m, 2H), 1.65-1.74 (m, 1H), 1.80-1.86 (m, 1H), 1.97-2.10 (m, 3H), 2.03 (s, 6H), 2.72 (d, J=14.0 Hz, 1H), 3.26 (d, J=14.0 Hz, 1H), 4.49 (dd, J=9.6 Hz, 2.8 Hz, 1H), 7.41-7.48 (m, 2H), 7.61 d, J=8.8 Hz, 1H), 7.79-7.86 (m, 3H), 8.18 (s, 1H). ¹³C NMR (CDCl₃) δ 22.3, 24.0, 32.5, 36.4, 44.8, 47.8, 66.6, 75.1, 125.5, 125.8, 126.0, 126.2, 127.5, 127.8, 128.5, 132.1, 133.8, 144.6. ESI MS m/z 284.

2.5. Preparation of 4a-(3,4-dichlorophenyl)-3-methyloctahydro-2H-benzo[e][1,3]oxazine

A solution of the respective methylamine 132 (e.g., 26.5 mg, 0.0919 mmol) in formaldehyde (e.g., 37%, 2 ml) and formic acid (e.g., 96%, 2 ml) was heated at 100° C. for 2 hours. After cooling to room temperature, the mixture was washed with hexanes (e.g., 3×4 ml). The aqueous solution was then made basic with 5 N KOH solution to pH 12. The mixture was extracted with t-butyl methylether (e.g., 3×5 ml) and the combined organic layers were dried over Na₂SO₄, and the solvent was evaporated. The residue was purified by reverse phase HPLC (C-18 column, CH₃CN/water, CH₃CN from 5% to 100%) to give the respective oxazine.

Cis-4a-(3,4-dichlorophenyl)-3-methyloctahydro-2H-benzo[e][1,3]oxazine (165)

165 E1 prepared from 133 E1
165 E2 prepared from 133 E2
¹H NMR (CDCl₃) δ 0.97-1.17 (m, 1H), 1.23-1.45 (m, 3H), 1.72-1.90 (m, 3H), 2.03 (s, 3H), 2.15 (d, J=12.8 Hz, 1H), 2.81 (d, J=12.4 Hz, 1H), 3.32-3.43 (m, 1H), 3.72 (d, J=7.8 Hz, 1H), 4.57 (d, J=7.8 Hz, 1H), 4.89-4.97 (m, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.60-7.68 (m, 1H), 7.81 (s, 1H). ¹³C NMR (CDCl₃) δ 21.2, 26.0, 27.8, 35.6, 41.0, 42.8, 69.1, 85.1, 88.7, 129.5, 129.9, 130.4, 131.8, 132.0, 144.6. ESI MS m/z 300.

Trans-4a-(3,4-dichlorophenyl)-3-methyloctahydro-2H-benzo[e][1,3]oxazine (166)

166 E1 prepared from 134 E1
166 E2 prepared from 134 E2
¹H NMR (CDCl₃) δ 1.25-1.41 (m, 2H), 1.48-1.79 (m, 4H), 1.88 (d, J=13.8 Hz, 1H), 1.98 (d, J=11.4 Hz, 1H), 2.13 (s, 3H), 2.58-2.68 (m, 2H), 3.62 (d, J=7.5 Hz, 1H), 4.00 (s, 1H), 4.55 (d, J=7.5 Hz, 1H), 7.20-7.27 (m, 1H), 7.39-7.46 (m, 2H). ¹³C NMR (CDCl3) δ 20.3, 22.1, 27.0, 28.4, 40.4, 41.5, 68.5, 77.4, 87.8, 126.5, 129.3, 130.4, 130.7, 133.0, 144.7. ESI MS m/z 300.

2.6. Synthesis of cis- and trans-3-(aminomethyl)-3-(3,4-dichlorophenyl)cyclopentanol (167)

(a) Synthesis of 1-(3,4-dichlorophenyl)cyclopent-3-enecarbonitrile

To ice-cold DMSO (100 mL) was added 60% NaH (11.0 g, 2.3 eq) in portions. The cooling bath was removed and the solution was stirred at ambient temperature for ten minutes. A solution of 2-(3,4-dichlorophenyl)acetonitrile (2.0 g, 10.75 mmol) in DMSO (50 mL) was added. The brown solution was stirred for 15 minutes before cis-1,4-dichlorobutene (1.0 mL, 0.9 eq) was added. The reaction mixture was stirred overnight and was then poured into water. The product was extracted with DCM. The organic layer washed with brine, evaporated, diluted with 50% ethyl acetate in hexanes, washed with water, and evaporated. The residual oil was separated on silica to give the nitrile (966 mg, 43%) as a pale-brown oil. GCMS R_t=10.8 min m/z=237 (M+). ¹H NMR (CDCl₃, δ): 7.51 (d, J=2.3 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.28 (dd, J=2.3, 8.5 Hz, 1H), 5.79 (s, 2H), 3.27 (d, J=14.7 Hz, 2H), 2.87 (d, J=14.7 Hz, 2H). ¹³C NMR(CDCl₃, δ): 141.9, 133.2, 132.1, 131.0, 128.5, 127.6, 125.0, 124.0, 48.4.

(b) Synthesis of 3-(aminomethyl)-3-(3,4-dichlorophenyl)cyclopentanol

A mixture of 1-(3,4-dichlorophenyl)cyclopent-3-enecarbonitrile (119 mg, 0.500 mmol) and borane-THF (2 mL, 1M in THF, 2 eq) was heated at 65° C. for 2 hours. The reaction was cautiously quenched with ethanol (0.5 mL), sodium hydroxide (1 mL, 5M aqueous) and stirred for two hours. It was then extracted with MTBE and evaporated. The residue was purified by HPLC to give cis 167 and trans 167.
cis 167: LCMS R_t=4.7 min, m/z=260 (M+1). ¹H NMR (CDCl₃, δ): 7.39 (d, J=8.4 Hz, 1H), 7.37 (d, J=2.2 Hz, 1H), 7.13 (dd, J=2.2, 8.4 Hz, 1H), 4.48 (m, 1H), 3.21 (s, 1H), 2.68 (dd, J=13.0, 15.7 Hz, 2H), 2.32 (dd, J=6.4, 13.7 Hz, 1H), 2.2-1.8 (m, 4H), 1.7 (m, 1H), 1.2 (bs, 2H). ¹³C NMR (CDCl₃, δ): 147.9, 132.2, 130.1, 129.2, 126.6, 72.9, 52.6, 51.9, 45.4, 34.3, 33.0.
trans 167: LCMS R_t=5.7 min, m/z=260 (M+1). ¹H NMR (CDCl₃, δ): 7.37 (d, J=8.4 Hz, 1H), 7.35 (d, J=2.3 Hz, 1H), 7.11 (dd, J=2.3, 8.4 Hz, 1H), 4.33 (m, 1H), 2.86 (d, J=13.0 Hz, 1H), 2.74 (d, J=13.0 Hz, 1H), 2.5 (bs, 3H), 2.25 (dd, J=6.0, 14.0 Hz, 1H), 2.2-1.7 (m, 5H). ¹³C NMR (CDCl₃, δ): 149.2, 132.2, 130.1, 129.9, 128.8, 126.1, 72.6, 52.7, 52.1, 46.7, 36.2, 32.8.

1-(1-(3,4-dichlorophenyl)cyclopent-3-enyl)-N-methylmethanamine (168)

(a) Synthesis of 1-(3,4-dichlorophenyl)cyclopent-3-enecarbaldehyde

To a −78° C. solution of the nitrile (238 mg, 1 mmol) in 5 mL toluene was added dibal (2 mL, 2 eq) dropwise. After 45 minutes, the cold solution was quenched with ethyl acetate (2 mL) and stirred at ambient temperature for 30 minutes. The solution was diluted with ethyl acetate and washed with 3M HCl, water, and brine. The organic layer was dried with sodium sulfate, filtered and evaporated. The crude product was purified by silica gel column chromatography to give the aldehyde (161 mg, 67%) as a clear oil. TLC R_f(25% EA/Hex)=0.13. GCMS R_t=7.7 min m/z=165 (M+). ¹H NMR (CDCl₃, δ): 5.89 (t, J=3.1 Hz, 2H), 3.09 (t, J=2.8 Hz, 2H), 2.96 (s, 3H), 2.6 (m, 2H), 2.2 (m, 2H). ¹³C NMR (CDCl₃, δ): 180.2, 127.7, 39.1, 24.9, 23.4.

(b) Synthesis of 1-(1-(3,4-dichlorophenyl)cyclopent-3-enyl)-N-methylmethanamine (168)

To a solution of the aldehyde (100 mg, 0.4154 mmol) in methylamine (2.1 mL, 2M in THF, 10 eq) was added acetic acid (104 ul, 5% of volume), and enough methanol to make a clear solution. The solution was stirred for two hours. To this was added sodium borohydride (40 mg, 3 eq) and stirring was continued for 30 minutes. The reaction was quenched with aqueous potassium carbonate and extracted with MTBE. The organic phase was separated and the solvent removed in vacuo. The residue was redissolved in MTBE and extracted with 3M HCl. The aqueous phase was separated, chilled in ice, and basicified with KOH. The aqueous phase was then extracted with MTBE and the solvent removed in vacuo. The residue was diluted in DCM, filtered through aminopropyl cartridge. The solvent was again removed to give the title compound (75.1 mg, 71%) as a clear oil. LCMS R_t(SCM)=6.28 min; m/z=256 (M+1). ¹H NMR (CDCl₃, δ): 7.36 (d, J=8.4 Hz, 1H), 7.35 (d, J=2.2 Hz, 1H), 7.10 (dd, J=2.2, 8.4 Hz, 1H), 5.73 (s, 2H), 5.67 (m, 6H), 2.31 (s, 3H). ¹³C NMR (CDCl₃, δ, mult): 148.6(0), 132.2(0), 130.1(1), 129.8(0), 129.2(1), 129.1(1), 126.5(1), 63.1(2), 50.6(0), 43.2(2), 37.1(3).

2.7. Synthesis of 2-Hydroxymethyl Analogs

Synthesis of Aryl Lactones
General Procedure K: To a solution of lactone (5 mmol) and Pd(dba)₂(5 mol %) and toluene (6 mL) which was stirring under nitrogen in a sealed vial, was added tri-t-butylphosphine (1 M in toluene, 5 mol %), LiHMDS (1M in hexanes, 1.2 eq), and the aryl bromide (1.5 eq). The solution was heated in the microwave for fifteen minutes (max temp=140° C.). After cooling, the mixture was diluted with hexane, washed with 3M HCl, and evaporated.
Alternatively, To a flame-dried 250 mL round bottom flask was added Pd(dba)₂(1 mol %) and toluene. The vessel was purged with nitrogen and sealed before tri-t-butylphosphine (1M in toluene, 1.1 mol %) was added via syringe followed by the aryl bromide (51.27 mmol) as a solution in toluene (15 mL). LiHMDS (1 M in hexanes, 1.3 eq) was added and the solution was stirred at ambient temperature for 15 min. The lactone (1.3 eq) was added dropwise as a solution in toluene (20 mL). The mixture was allowed to stir at ambient temperature overnight (16 h) and then partitioned between hexane and, in succession, 10% aqueous HCl, 10% aqueous K₂CO₃, and brine. The volatile components were removed in vacuo to give the crude arylated lactone.

(2-(3,4-dichlorophenyl)-2-((ethylamino)methyl)-cyclohexyl)methanol (169)

169 E1, 169 E2

(a) Synthesis of racemic 7a-(3,4-dichlorophenyl)hexahydroisobenzofuran-1(3H)-one

The title compound was prepared in 30% yield according to General Procedure K as a pale-yellow oil. GCMS R_t(SCM)=13.0 min; m/z=284 (M+).
¹H NMR (CDCl₃, δ): 7.50 (d, J=2.3 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 7.25 (dd, J=2.3, 8.5 Hz, 1H), 4.05 (dd, J=4.9, 8.9 Hz, 1H), 3.94 (dd, J=2.4, 8.9 Hz, 1H), 2.8 (m, 1H), 2.2 (m, 1H), 2.0 (m, 1H), 1.8-1.3 (m, 6H). ¹³C NMR (CDCl₃, δ, mult): 177.7(0), 140.7(0), 133.0(0), 131.7(0), 130.7(1), 128.6(1), 125.9(1), 70.1(2), 51.7(1), 40.5(2), 34.0(2), 26.9(2), 23.0(2), 22.9(2).

(b) (2-(3,4-dichlorophenyl)-2-((ethylamino)methyl)-cyclohexyl)methanol

The title compound was prepared from racemic 7a-(3,4-dichlorophenyl)hexahydroisobenzofuran-1(3H)-one and ethylamine according to General Procedures AA, followed by General Procedure E. The racemic aminol was separated using a chiral column (Chiracel OD column; 95:5:0.1 hexanes:IPA:DEA, λ=254 nm, 1 mL/min) to give the fast moving enantiomer 169 E1 (R_t=7.5 min) and the slow moving enantiomer 169 E2 (R_t=9.7 min). LCMS R_t=7.88 min, m/z=316 (M+1). ¹H NMR (CDCl₃, δ): 7.4 (m, 2H), 7.17 (dd, J=2.4, 8.5 Hz, 1H), 3.7 (m, 2H), 3.10 (d, J=12.3 Hz, 1H), 2.71 (d, J=12.3 Hz, 1H), 2.6 (m, 2H), 2.3 (m, 1H), 1.9-1.3 (m, 8H), 1.04 (t, J=7.2 Hz, 3H). ¹³C NMR (CDCl₃, δ, mult): 146.5(0), 133.1(0), 130.8(1), 130.0(0), 128.5(1), 125.7(1), 63.2(2), 53.6(br, 2), 45.4(0), 43.9(2), 41.9(1), 39.8(br, 2), 26.1(2), 24.8(2), 22.0(2), 14.5(3).

cis-(2-(3,4-dichlorophenyl)-2-((methylamino)methyl)-cyclohexyl)methanol (170)

170 E1, 170 E2
The title compound was prepared from racemic 7a-(3,4-dichlorophenyl)-hexahydroisobenzofuran-1(3H)-one and methylamine according to General Procedures AA and E. The racemic aminol was separated using a chiral column (Chiracel OD column; 95:5:0.1 hexanes:IPA:DEA, λ=254 nm, 1 mL/min) to give the fast moving enantiomer 170 E1 (R_t=9.0 min) and the slow moving enantiomer 170 E2 (R_t, =11.5 min). LCMS R_t=6.46 min, m/z=302 (M+1). ¹H NMR (CDCl₃, δ): 7.42-7.40 (m, 2H), 7.18 (dd, J=2.4, 8.5 Hz, 1H), 3.7 (m, 2H), 3.05 (d, J=12.3 Hz, 1H), 2.67 (d, J=12.3 Hz, 1H), 2.35 (s, 3H), 2.0-1.2 (m, 9H). ¹³C NMR (CDCl₃, δ, mult): 146.4(0), 133.0(0), 130.8(1), 130.0(0), 128.5(1), 125.7(1), 63.2(2), 62.5(2), 45.4(2), 42.4 (0), 41.8(1), 36.0(3), 26.1(2), 24.8(2), 22.0(2).

cis-(2-((dimethylamino)methyl)-2-phenylcyclohexyl)methanol (171)

171 E1, 171 E2

(a) Synthesis of 7a-Phenyl-hexahydro-isobenzofuran-1-one

The title compound was prepared from hexahydro-isobenzofuran-1-one (10 g, 1.3 eq) and phenyl bromide (5.4 mL, 51.27 mmol) according to General Procedure K. It was obtained as a clear oil (7.40 g, 67%). HPLC R_t(5-100-8)=9.8 min. ¹H NMR (CDCl₃, δ): 7.4-7.2 (m, 5H), 4.05 (dd, 1H), 3.90 (dd, 1H), 2.8 (m, 1H), 2.3 (m, 1H), 2.0 (m, 1H), 1.8-1.3 (m, 6H). ¹³C NMR (CDCl₃, δ, mult): 178.6 (0), 140.5 (0), 128.8 (1), 127.3 (1), 126.3 (1), 70.3 (2), 52.5 (0), 41.0 (1), 34.2 (2), 27.5 (2), 23.4 (2), 23.2 (2).

(b) Synthesis of 2-Hydroxymethyl-1-phenyl-cyclohexanecarboxylic acid dimethylamide

The amide was synthesized from the above lactone according to General Procedure AA. The crude product was purified by silica gel column chromatography to give a clear oil (239 mg, 100%). ¹H NMR (CDCl₃, δ): 7.4-7.0 (m, 5H), 5.4 (bs, 1H), 3.5-3.2 (m, 4H), 3.0 (m, 1H), 2.6 (m, 1H), 2.4 (m, 1H), 2.2 (m, 1H), 2.1 (m, 1H), 1.9-1.7 (m, 3H), 1.6-1.3 (m, 3H), 1.17 (t, 3H), 0.90 (t, 3H). ¹³C NMR (CDCl₃, δ, mult): 175.5 (0), 142.9 (0), 128.7 (br), 126.8 (1), 63.1 (2), 57.3 (0), 53.3 (1), 43.1 (2), 41.1 (2), 35.2 (2), 26.7 (2), 26.6 (2), 23.4 (2), 13.0 (3), 12.1 (3).

(c) Synthesis of cis-(2-((dimethylamino)methyl)-2-phenylcyclohexyl)methanol

The title compound was synthesized from the above amide according to General Procedure E. The enantiomeric amines were separated on a Chiracel OD semiprep column (95:5:0.05 Hex/IPA/DEA) to give the fast-moving enantiomer 171 E1 (6.6 mg, 5.4%) and the slow-moving enantiomer 171 E2 (6.0 mg, 4.9%). LCMS R_t=5.84 min, m/z=248 (M+1). ¹H NMR (CDCl₃, δ): 7.42 (d, J=7.7 Hz, 2H), 7.31 (t, J=7.8 Hz, 2H), 7.18 (t, J=7.3 Hz, 1H), 3.95 (dd, J=6.6, 11.5 Hz, 1H), 3.83 (d, J=11.5 Hz, 1H), 2.96 (d, J=13.5 Hz, 1H), 2.6 (m, 1H), 2.53 (d, J=13.5 Hz, 1H), 1.99 (s, 6H), 1.9-1.1 (m, 8H). ¹³CNMR (CDCl₃, δ): 128.0, 127.0, 125.6, 64.2, 46.6, 45.3, 41.6, 26.8, 24.2, 22.1.

cis-(2-(3,4-dichlorophenyl)-2-((dimethylamino)methyl)cyclohexyl)methanol (172)

172 E, 172 E2
Powdered LAH (76 mg, 4 eq) was added to a solution of 1-(3,4-dichlorophenyl)-2-(hydroxymethyl)-N,N-dimethylcyclohexanecarboxamide (0.5 mmol) in THF (5 mL). After one hour at ambient temperature, the reaction was quenched with aqueous ammonium chloride, washed with MTBE, basicified with KOH, extracted with MTBE and evaporated to give the crude amine (108 mg) as a yellow-black oil. The crude oil was filtered (aminopropyl) and the enantiomers were separated on a Chiracel OD column (98:2:0.1 Hex/IPA/DEA) to give the fast-moving enantiomer 172 E1 (30.1 mg, 19%) and the slow-moving enantiomer 172 E2 (26.6 mg, 17%). LCMS R_t=8.33 min, m/z=316 (M+1). ¹H NMR (CDCl₃, ): 7.50 (d, J=2.4 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H), 7.26 (dd, J=2.4, 8.6 Hz, 1H), 3.92 (dd, J=6.5, 11.6 Hz, 1H), 3.77 (dd, J=1.2, 11.7 Hz, 1H), 2.95 (d, J=13.7 Hz, 1H), 2.5 (m, 2H), 2.02 (s, 6H), 1.8-1.1 (m, 8H). ¹³C NMR (CDCl₃, δ, mult): 147.6, 132.2, 129.9, 129.6, 129.3, 126.6, 63.9, 46.8, 45.4, 41.8, 38.7, 29.7, 26.5, 23.9, 22.0.

cis-(2-(3,4-dichlorophenyl)-2-((methylamino)methyl)-cyclopentyl)methanol (173)

rac 173, 173 E1, 173 E2

(a) Synthesis of cis-6a-(3,4-dichlorophenyl)hexahydro-1H-cyclopenta[c]furan-1-one

The title compound was prepared from lactone (630 mg, 5 mmol) and dichlorophenylbromide (1.69 g, 1.5 eq) according to General Procedure K. The crude product was separated by silica gel column chromatography to give the lactone (578 mg, 44%) as a pale-brown oil. TLC R_f(25% EA/hex)=0.34. GC-MS R_t=12.48 min, m/z=270 (M+). ¹H NMR (CDCl₃, δ): 7.49 (d, J=2.3 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.24 (dd, J=2.3, 8.4 Hz, 1H), 4.50 (dd, J=7.3, 9.6 Hz, 1H), 4.14 (dd, J=2.2, 9.6 Hz, 1H), 3.1 (m, 1H), 2.60 (ddd, J=3.0, 6.4, 12.5 Hz, 1H), 2.2-1.6 (m, 5H). ¹³C NMR (CDCl₃, δ, mult): 179.7(0), 140.6(0), 132.8(0), 131.5(0), 130.6(1), 128.3(1), 125.8(1), 72.7(2), 59.4(0), 46.2(1), 40.3(2), 34.4(2), 25.8(2).

(b) Synthesis of cis-(2-(3,4-dichlorophenyl)-2-((methylamino)methyl)-cyclopentyl)methanol

The title compound was prepared from the above lactone and methylamine according to General Procedures AA and E to give racemic 173, which was separated by chiral HPLC (AD column; 2:3:95:0.1 MeOH:EtOH:Hex:DEA) to give the fast moving enantiomer 173 E1 (6.5 min) and the slow moving enantiomer 173 E2 (8.5 min). LCMS (14 min) R_t=5.98 min, m/z=288 (M+1). ¹H NMR (CDCl₃, δ): 7.6 (m, 1H), 7.4 (m, 2H), 6.8 (bs, 1H), 3.7 (m, 2H), 2.8 (m, 3H), 2.32 (s, 3H), 2.1-1.2 (m, 6H). ¹³C NMR (CDCl₃, 6, mult): 147.3(0), 132.5(0), 130.2(1), 130.1(1), 129.3(0), 126.9(1), 63.7(2), 58.3(2), 52.9(0), 47.1(1), 41.6(2), 36.0(3), 28.6(2), 22.1(2).

2.8. Synthesis of 2-Methyl-Cycloalkylamines

(±)-cis-(1-(3,4-dichlorophenyl)-2-methylcyclohexyl)methanamine hydrochloride (174)

The title compound was synthesized from 1-(3,4-dichlorophenyl)-2-methylcyclohexanecarbonitrile (159 mg, 0.60 mmol) according to General Procedure E, followed by HCl salt formation. The crude HCl salt was recrystallized from CH₃CN (1.5 mL) to give the title compound as white crystals. HPLC R_t=8.86 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.60-7.59 (m, 1H), 7.58-7.50 (m, 1H), 7.39-7.35 (m, 1H), 3.32-3.13 (m, 2H), 2.13-2.04 (m, 1H), 1.73-1.33 (m, 8H), 0.86 (d, J=6.96 Hz, 3H); LC-MS 8.8 min, (M+1)⁺272 @ 9.0 min.

(±) cis-1-(1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-N,N-dimethylmethanamine hydrochloride (175)

((+/−)-(cis)-1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-methanamine free base (110 mg, 0.41 mmol), paraformaldehyde (ca. 100 mg), polymer bound cyanoborohydride (762 mg, 2.13 mmol/g, 1.62 mmol) and concentrated AcOH (1 mL) were suspended in 10 mL THF. The solution was shaken overnight, then filtered and diluted with EtOAc. The organic phase washed with 3M NaOH (2×20 mL) and brine (20 mL), dried (Na₂SO₄), filtered and concentrated. The crude material was dissolved in Et₂O (3 mL) and HCl (ca. 1.5 mL, 2.0 M in Et₂O) was added. A white ppt. formed immediately. The crude HCl salt was recrystallized from EtOAc (1.5 mL) to give pure ((+/−)-(cis)-1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-N,N-dimethylmethanamine hydrochloride as white crystals. HPLC R_t=9.1 min; ¹H NMR (400 mHz, MeOH-d⁴) 7.73 (d, J=2.2 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.51-7.48 (m, 1H), 3.58-3.54 (m, 1H), 3.42-3.39 (m, 1H), 2.64-2.52 (m, 6H), 2.20-2.18 (m, 2H), 1.83-1.76 (m, 1H), 1.63-1.42 (m, 6H), 1.01 (d, J=7.33 Hz, 3H); LC-MS 10.1 min, (M+1)⁺300 (10.3 min.

(±) cis-1-(1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-N-methylmethanamine (176)

((+/−)-(cis)-1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-methanamine free base (421 mg, 1.55 mmol) was dissolved in 3:1 THF:H₂O (8 mL) and K₂CO₃(322 mg, 2.33 mmol) was added. The solution was stirred for 2 minutes, then BOC₂O (338 mg, 1.55 mmol) was added. After 2 h, the solution was poured into H₂O and the layers were separated. The organic layer washed with H₂O (1×20 mL) and brine (1×20 mL), dried (Na₂SO₄), filtered and concentrated. A portion of the N—BOC amine (113 mg) was used directly in the next reaction. LAH (34 mg, 0.9 mmol) was suspended in anhydrous THF (2 mL) and the amine (113 mg, 0.30 mmol) in anhydrous THF (3 mL) was added dropwise. The solution was heated in the MW (160° C., 5 min, FHT). The crude reaction was quenched with 6M HCl (10 mL). The solution washed with EtOAc (2×20 mL) and the EtOAc washes were discarded. After the pH of the aqueous phase was adjusted to 12 with 3M NaOH, it washed again with EtOAc (3×20 mL). The combined “second” organic washes were dried (Na₂SO₄), filtered and concentrated. The crude amine was purified by PTLC with 10% MeOH/CH₂Cl₂to give ((+/−)-(cis)-1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-N-methylmethanamine as a clear oil. HPLC R_t=8.91 min; ¹H NMR (400 mHz, CDCl₃) 7.48 (d, J=2.57 Hz, 1H), 7.39-7.36 (m, 1H), 7.25-7.23 (m, 1H), 2.71 (s, 2H), 2.38 (s, 3H), 2.11-2.03 (m, 1H), 1.85-1.73 (m, 2H), 1.70-1.60 (m, 1H), 1.53-1.33 (m, 5H), 0.83 (d, J=6.98 Hz, 3H); LC-MS 8.70 min, (M+1)⁺286 @ 8.97 min.

(±) cis-N-((1-(3,4-dichlorophenyl)-2-methylcyclohexyl)methyl)ethanamine (177)

t-Butyl (1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-methylcarbamate (97 mg, 0.261 mmol) was dissolved in anhydrous DMF (3 mL) and NaH (60% dispersion in mineral oil, 21 mg, 0.52 mmol) was added. The solution was heated via MW (75° C., 5 min), and cooled to RT. Ethyl iodide (62 mL, 0.78 mmol) was added and the solution was heated via MW (100° C., 20 min). The yellow mixture was poured into H₂O (20 mL) and washed with Et₂O (3×20 mL). The combined organic washes were dried (Na₂SO₄), filtered and concentrated. Purification by silica gel column chromatography with 0→10% EtOAc/hexanes gave tert-butyl (1-(3,4-dichlorophenyl)-2-methylcyclohexyl)methylethylcarbamate (32 mg, 0.08 mmol) as a clear oil. tert-butyl (1-(3,4-dichlorophenyl)-2-methylcyclohexyl)methylethylcarbamate (32 mg, 0.08 mmol) was dissolved in 1:1 CH₂Cl₂:TFA (3 mL) and stirred for 2 h then concentrated. The crude amine was dissolved in EtOAc (20 mL) and washed with 3M NaOH (2×20 mL) and brine (20 mL), then dried (Na₂SO₄), filtered and concentrated. The crude amine was purified by PTLC with 10% MeOH/CH₂Cl₂to give the title compound as a clear oil. HPLC R_t=9.17 min; ¹H NMR (400 mHz, CDCl₃) 7.51 (d, J=2.2 Hz, 1H), 7.37 (d, J=8.43 Hz, 1H), 7.27-7.25 (m, 1H), 2.76 (d, J=1.47 Hz, 2H), 2.59 (q, 2H), 2.08-2.05 (m, 1H), 1.78-1.77 (m, 1H), 1.67-1.64 (m, 1H), 1.52-1.36 (m, 5H), 1.05 (at, 3H), 0.81 (d, J=6.97 Hz, 3H); LC-MS 8.94 min, (M+1)⁺300 @ 9.17 min.

Example 3

Synthesis of 3-Substituted Cyclohexylamine Analogs

3.1. Synthesis of 3-(aminomethyl)-3-(3,4-dichlorophenyl)-cyclohexanol analogs

The synthesis of 3-(aminomethyl)-3-(3,4-dichlorophenyl)cyclohexanol is outlined in Scheme 30, below. Reaction of 3-ethoxy-2-cyclohexen-1-one 178 with 3,4-dichlorophenylmagnesium bromide in THF followed by quenching the Grignard mixture with diluted H₂SO₄gave 3-(3,4-dichlorophenyl)-2-cyclonexen-1-one 179. Addition of CN⁻ to the α,β-unsaturated ketone by heating 179 with KCN in the presence of NH₄Cl in aqueous DMF afforded the cyano ketone 180 in 30% yield. The ketone was reduced to the alcohol 181 using NaBH₄in ethanol at 0° C. The major product was the cis diastereomer and the minor product was the trans diastereomer. The amine 182 was formed through reduction of the nitrile with BH₃.THF at room temperature overnight in 83% yield. Protection of the amino group with Boc-anhydride afforded 183. The diastereomers were then separated using reverse phase HPLC.

3.1.1. Preparation of Boc Protected Primary Amines 14

The primary amine 182 (mixture of cis and trans diastereomers, 1.8 g, 6.57 mmol) was added to a 10% triethylamine solution in MeOH (40 ml). To this mixture was added di-tert-butyl dicarbonate (1.72 g, 7.88 mmol) with vigorous stirring. The mixture was stirred at room temperature for 3 hours. The solvent was then removed in vacuo. The residue was dissolved in EtOAc (70 ml), washed with saturated K₂CO₃solution (3×40 ml), 5% HCl (2×40 ml), brine (40 ml), dried over Na₂SO₄, and evaporated. The residue was purified by silica gel column chromatography (MeOH/CH₂Cl₂, MeOH from 0 to 5%) to yield 183 (2.45 g, 97%) as a clear oil. The diastereomers of 183 were separated (C-18 column, 50% acetonitrile, 50% water) to give the cis isomer cis 183 (1.83 g) and the trans isomer trans 183 (0.45 g).
cis 183: ¹H NMR (CDCl₃) δ 1.19-1.31 (m, 4H), 1.37 (s, 9H), 1.68-1.72 (m, 1H), 1.87-1.90 (m, 1H), 2.13 (d, J=12.8 Hz, 1H), 2.41 (d, J=12.8 Hz, 1H), 2.58 (brs, 1H), 3.09-3.22 (m, 2H), 3.54-3.66 (m, 1H), 4.72 (t, J=6.0 Hz, 1H), 7.18-7.21 (m, if H), 7.40-7.49 (m, 2H). ¹³C NMR (CDCl₃) δ 20.2, 28.5, 32.7, 35.8, 42.0, 44.8, 53.5, 66.8, 79.7, 126.7, 129.4, 130.6, 130.8, 133.0, 143.9, 156.3. ESI MS m/z 374.
trans 183: ¹H NMR (CDCl₃) δ 1.21-1.38 (m, 4H), 1.39 (s, 9H), 1.60-1.66 (m, 1H), 1.87-1.90 (m, 1H), 1.98 (d, J=10.8 Hz, 1H), 2.26 (d, J=10.8 Hz, 1H), 2.76 (brs, 1H), 3.30-3.45 (m, 2H), 398-4.08 (m, 1H), 7.06-7.18 (m, 1H), 7.39-7.43 (m, 2H). ¹³C NMR (CDCl₃) δ 20.4, 28.5, 33.0, 35.1, 42.1, 43.1, 46.6, 67.1, 79.7, 125.6, 128.4, 130.5, 130.6, 132.8, 147.6, 156.2. ESI MS m/z 374.

3.1.2. Chiral HPLC Separation of Enantiomers

The enantiomers of cis 183 were separated using a preparative HPLC procedure (ChiralPak OD column; hexanes:IPA=90:10; 8 ml/min; λ=280 nm) to give cis 183 E1 (retention time=10 min) and cis 183 E2 (retention time=18 min). The absolute configuration of the chiral centers was not determined.
The enantiomers of trans 183 were separated using a preparative HPLC procedure (ChiralPak OD column; hexanes:IPA=90:10; 8 ml/min; λ=280 nm) to give trans 183 E1 (retention time=15 min) and trans 183 E2 (retention time=21 min). The absolute configuration of the chiral centers was not determined.

3.1.3. Preparation of Primary Amines 182 (Removal of Boc-group)

General Procedure U: To the solution of the respective Boc-protected primary amine 183 (e.g., 38 mg, 0.102 mmol) in CH₂Cl₂(e.g., 2 ml) was added TFA (e.g., 2 ml) at 0° C. The mixture was stirred at 0° C. for one hour and the solvent was removed in vacuo. The residue was dissolved in CH₂Cl₂(10 ml), washed with saturated K₂CO₃solution (2×3 ml), dried over Na₂SO₄, and then filtered through an aminopropyl cartridge. The solvent was removed to give the respective primary amine 182.
The following compounds were prepared following the procedure outlined in General Procedure U, above.

Cis-3-(aminomethyl)-3-(3,4-dichlorophenyl)cyclohexanol (184)

184 E1, 184 E2
¹H NMR (CDCl₃): δ1.21-1.39 (m, 4H), 1.42-1.52 (m, 2H), 1.63-1.70 (m, 1H), 1.80-1.90 (m, 1H), 2.20 (d, J=12.8 Hz, 1H), 2.43 (d, J=12.8 Hz, 1H), 2.62 (s, 2H), 3.51-3.60 (m, 1H), 7.16-7.20 (m, 1H), 7.40-7.49 (m, 2H). ¹³C NMR (CDCl₃) δ 20.5, 32.8, 36.2, 42.5, 45.5, 57.0, 67.0, 126.9, 129.5, 130.7, 130.8, 133.0, 144.3. ESI MS m/z 274.

Trans-3-(aminomethyl)-3-(3,4-dichlorophenyl)cyclohexanol (185)

185 E1, 185 E2
¹H NMR (CDCl₃): δ 1.21-1.30 (m, 4H), 1.42-1.58 (m, 3H), 1.77-1.82 (m, 1H), 2.00-2.05 (m, 2H), 2.34-2.40 (m, 1H), 2.85 (d, J=13.2 Hz, 1H), 2.90 (d, J=13.2 Hz, 1H), 3.85-3.93 (m, 1H), 7.18-7.20 (m, 1H), 7.40-7.43 (m, 2H). ¹³C NMR (CDCl₃) δ 20.3, 32.6, 35.3, 42.2, 48.6, 67.4, 125.8, 128.6, 130.4, 132.7, 133.9, 147.9. ESI MS m/z 274.

3.1.4. Preparation of Secondary Amines 15

General Procedure F1: A solution of acetic anhydride (e.g., 0.118 ml, 1.254 mmol) and formic acid (e.g., 0.058 ml, 1.546 mmol) in THF (e.g., 1.5 ml) was heated in a microwave at 100° C. for 5 min. After cooling to room temperature, a solution of the respective primary amine 182 (e.g., 107 mg, 0.392 mmol) in THF (e.g., 1.5 ml) was added. The mixture was heated in the microwave at 100° C. for 5 min. The solvent was then removed in vacuo. The residue was dissolved in THF (e.g., 1.5 ml), and BH₃.THF (e.g., 1 ml, 1.0 mmol) was added. The mixture was heated in the microwave at 60° C. for 6 min. The reaction was then quenched by the addition of MeOH (e.g., 2 ml) and 6N HCl (e.g., 1 ml). The solvent was removed in vacuo. To the residue was added 1 N NaOH solution to pH 12. The aqueous solution was extracted with CH₂Cl₂(e.g., 3×10 ml). The combined organic phases were dried over Na₂SO₄and evaporated in vacuo. The residue was purified by silica gel column chromatography (MeOH/CH₂Cl₂, 0-10%) to give the respective secondary amine 186.
The following compounds were prepared according to the procedures outlined in General Procedure F1, above.

Cis-3-(3,4-dichlorophenyl)-3-((methylamino)methyl)cyclohexanol (187)

187 E1, 187 E2
¹H NMR (CDCl₃): δ 1.37-1.42 (m, 1H), 1.49-1.58 (m, 1H), 1.63-1.70 (m, 2H), 1.90-2.05 (m, 1H), 2.28 (d, J=12.8 Hz, 1H), 2.46 (s, 3H), 2.85 (d, J=12.4 Hz, 1H), 3.38 (d, J=12.4 Hz, 1H), 3.63-3.78 (m, 2H), 3.88-3.92 (m, 1H), 7.23 (d, J=7.2 Hz, 1H), 7.40-7.49 (m, 2H). ¹³C NMR (CDCl₃) δ 20.3, 30.1, 33.7, 35.1, 45.5, 61.4, 62.9, 65.9, 126.3, 129.0, 131.2, 131.4, 133.3, 144.1. ESI MS m/z 288.

Trans-3-(3,4-dichlorophenyl)-3-((methylamino)methyl)cyclohexanol (188)

¹H NMR (CDCl₃): δ 1.15-1.26 (m, 1H), 1.36-1.44 (m, 2H), 1.52-1.63 (m, 1H), 1.76-1.82 (m, 1H), 2.03 (t, J=13.2 Hz, 1H), 2.29 (s, 3H), 2.41-2.45 (m, 1H), 2.68 (d, J=12.0 Hz, 1H), 2.78 (d, J=12.0 Hz, 1H), 3.84-3.91 (m, 1H), 7.20 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.38-7.44 (m, 2H). ¹³C NMR (CDCl₃) δ 20.7, 33.9, 35.1, 37.4, 42.8, 42.9, 58.4, 67.0, 125.5, 128.3, 130.4, 130.5, 132.7, 148.5. ESI MS m/z 288.
188 E1, 188 E2

3.1.5. Preparation of Tertiary Amines 189

General Procedure D1: A mixture of 37% formaldehyde (e.g., 0.096 ml, 1.183 mmol) and 96% formic acid (e.g., 0.056 ml, 1.183 mmol) in water (e.g., 2 ml) was added to the respective primary amine 182 (e.g., 130 mg, 0.473 mmol) at 0° C. The mixture was heated to 100° C. overnight. The reaction mixture was then washed with hexanes (e.g., 3×10 ml), and evaporated in vacuo. The residue was purified by reverse phase HPLC (C-18 column, CH₃CN/water, CH₃CN from 5% to 100%) to give the respective tertiary amine 189.
The following compounds were prepared according to General Procedure D1, above.

Cis-3-(3,4-dichlorophenyl)-3-((dimethylamino)methyl)cyclohexanol (190)

190 E1, 190 E2
¹H NMR(CDCl₃): δ 1.23-1.36 (m 2H), 1.46-1.53 (m, 1H), 1.59 (dd, J=12.8 Hz, 8 Hz, 1H), 1.68-1.73 (m, 1H), 1.81-1.85 (m, 1H), 2.05 (s, 6H), 2.07-2.10 (m, 1H), 2.27 (d, J=13.6 Hz, 1H), 2.37 (d, J=13.6 Hz, 1H), 2.43 (m, 1H), 2.63 (brs, 1H), 3.59-3.65 (m, 1H), 7.21 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H). ¹³C NMR (CDCl₃) δ 20.2, 33.7, 35.7, 42.2, 45.0, 48.4, 66.9, 73.5, 126.9, 129.4, 129.8, 130.3, 132.5, 146.2. ESI MS m/z 302.

Trans-3-(3,4-dichlorophenyl)-3-((dimethylamino)methyl)cyclohexanol (191)

191 E1, 191 E2
¹H NMR (CDCl₃) δ 1.16-1.26 (m, 1H), 1.34-1.45 (m, 2H), 1.50-1.61 (m, 1H), 1.75-1.81 (m, 1H), 1.95 (s, 6H), 1.99-2.03 (m, 1H), 2.14 (brs, 1H), 2.40-2.47 (m, 2H), 2.55 (d, J=13.6 Hz, 1H), 3.84-3.91 (m, 1H), 7.21 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H). 13C NMR (CDCl₃) δ 20.6, 33.8, 35.1, 42.6, 43.0, 48.2, 66.3, 67.7, 125.8, 128.5, 129.8, 130.0, 132.2, 150.0. ESI MS m/z 302.

3.1.6. Synthesis of cis-1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-methanamine (192)

To a solution of 1-(3,4-dichloro-phenyl)-3-methoxy-cyclohexanecarbonitrile (150 mg, 0.53 mmoL) in THF (5 mL) was added BH₃.THF (1.0 M, 1.59 mL, 1.59 mmoL). The reaction mixture was stirred overnight before being concentrated. The residue was dissolved in MeOH (3 mL) and subjected to reverse phase column chromatography (CH₃CN/H₂O/0.1% Formic acid=5% to 100%) to give the desired product (109 mg, 72%).

3.2. Synthesis of 3-Disubstituted Aryl-Cyclohexylamines

Synthesis of 3-Aminomethyl-3-(3,4-dichloro-phenyl)-1-methyl-cyclohexanol (193)

The title compound was synthesized from 1-(3,4-dichlorophenyl)-3-oxo-cyclohexanecarbonitrile (1.0 g, 3.7 mmol) according to General Procedure Y, followed by General Procedure E (Scheme 31). The crude product was dissolved in MeOH (4 mL) and subjected to reverse phase column chromatography (CH₃CN/H₂O/0.1% formic acid=5% to 100%) to give (±) 3-aminomethyl-3-(3,4-dichloro-phenyl)-1-methyl-cyclohexanol (0.57 g, 81%).

193 E1, 193 E2
To a solution of 3-aminomethyl-3-(3,4-dichloro-phenyl)-1-methyl-cyclohexanol (0.5 g, 1.74 mmoL) in CH₂Cl₂(15 mL) was added Et₃N (528 mg, 727 mL, 5.22 mmol) and (BOC)₂O (567 mg, 2.60 mmol). The reaction mixture was stirred for 2 h at room temperature before being quenched by a saturated NH₄Cl solution (10.0 mL). The product was extracted with CH₂Cl₂(2×15 mL). The combined extracts were washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:5) to afford (±)tert-butyl (1-(3,4-dichlorophenyl)-3-hydroxy-3-methylcyclohexyl)-methylcarbamate (0.61 g, 90%). The enantiomers were separated (chiral AD column with hexane/iso-propanol/DEA=95:5:0.1) to afford the fast moving enantiomer E1 (0.22 g, retention time 4.085 min) and the slow moving enantiomer E2 (0.32 g, retention time 6.051 min). To a solution of the respective enantiomer E1 (200 mg, 0.52 mmol) or E2 (200 mg, 0.52 mmol) in CH₂Cl₂(4 mL) was added TFA (2.0 mL). The reaction mixtures were stirred for 0.5 h before being concentrated. The mixtures were each purified by reverse phase column chromatography (CH₃CN/H₂O) to give the amines 193 E1 and 193 E2 in each 80% yield. ¹HNMR (400 MHz, CDCl₃) δ 8.32 (broad, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.37 (dd, J=2.0, 8.4 Hz, 1H), 3.55 (s, 2H), 2.15 (m, 2H) 1.88 (m, 1H), 1.74-1.58 (m, 4H), 1.40 (m, 1H), 1.21 (m, 3H); ¹³CNMR (100 MHz, CD₃OD) δ 146.42, 132.75, 131.01, 130.83, 128.41, 125.97, 69.31, 46.48, 44.85, 40.15, 37.81, 32.81, 32.54, 30.91, 18.17; ESI MS m/z=288.4.

3.3. Synthesis of Chiral 3-Methoxy-Cyclohexylamines

1-(3,4-dichlorophenyl)-3-methoxycyclohexanecarbonitrile was synthesized from 1-(3,4-dichloro-phenyl)-3-oxo-cyclohexanecarbonitrile (1.5 g, 5.61 mmoL) according to General Procedure W, followed by General Procedure EE (Scheme 32). The crude product was purified by silica gel column chromatography (ethyl acetate/hexane=1:7).
The cis enantiomers (170 mg) were separated (chiral OD column; ethanol/methanol/hexane/DEA=1; 1:98:0.1) to give the fast moving enantiomer E1 (67 mg) and the slow moving enantiomer E2 (81 mg).
E1 was converted to 192 and E2 (120 mg, 0.42 mmoL) was converted to 194 according to General Procedure E. The crude product was dissolved in MeOH (3 mL) and subjected to reverse phase column chromatography (CH₃CN/H₂O/0.1% formic acid=5% to 100%) to give the desired product (90.4 mg, 75%). ¹H NMR (400 MHz, CD₃Cl) δ 7.46 (m, 2H), 7.20 (m, 1H), 3.02 (s, 3H), 3.08 (m, 1H), 2.83 (s, 2H), 2.46 (m, 1H), 2.22 (m, 1H), 1.92 (m, 1H), 1.76 (m, 1H), 1.46 (m, 2H), 1.24 (m, 2H); ¹³C NMR (100 MHz, CD₃Cl) δ 141.71, 133.41, 131.46, 131.27, 129.67, 126.84, 75.30, 55.99, 51.80, 42.43, 39.20, 32.66, 31.31, 19.84; ESI MS m/z 288.1.
Likewise, the methylated trans-enantiomers (100 mg) were separated using a chiral OD column (ethanol/methanol/hexane/DEA=1:1:98:0.1) to give trans E1 (43 mg) and trans E2 (38 mg). Trans E2 (38 mg, 0.13 mmoL) was converted to the respective amine according to General Procedure E. The crude product was dissolved in MeOH (1 mL) and subjected to reverse phase column chromatography (CH₃CN/H₂O/0.1% formic acid=5% to 100%) to give the desired product 195 E2 (31.2 mg, 82%). ¹H NMR (400 MHz, CD₃Cl) δ 7.47 (m, 2H), 7.22 (m, 1H), 3.04 (s, 3H), 3.10 (m, 1H), 2.85 (s, 2H), 2.49 (m, 1H), 2.20 (m, 1H), 1.94 (m, 1H), 1.74 (m, 1H), 1.49 (m, 2H), 1.26 (m, 2H); ¹³C NMR (100 MHz, CD₃C1) δ 141.69, 133.52, 131.64, 131.09, 129.78, 127.01, 76.01, 56.109, 51.68, 42.56, 39.40, 32.77, 31.42, 20.01; ESI MS m/z 288.1.

3.4. Synthesis of Secondary and Tertiary Amines

Compounds in Table 4, below were prepared from the indicated amine according to General Procedure F.

TABLE 4

	R^d	R^e	R³	R⁴

cis-1-(1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-N-meth-

ylmethanamine (196)

H

OCH₃

CH₃

H

The compound was prepared from 194.

The crude product was subjected to silica gel column

chromatography (Ethyl acetate/hexane/DEA = 1/4/0.1%) to give 196

(26.7 mg, 32%) and 197 (37.6 mg, 37%).

¹H NMR(400 MHz, CD₃Cl) δ 7.43(d, J=2.0Hz, 1H), 7.41(d,

J=8.8Hz, 1H), 7.21(dd, J=2.0, 8.8Hz, 1H), 3.12(s, 3H), 3.07(m,

1H), 2.54(m, 1H), 2.55(s, 2H), 2.28(s, 3H), 2.26(m, 1H), 2.19(m,

1H), 1.70(m, 1H), 1.40(m, 2H), 1.22(m, 2H); ¹³C NMR(100

MHz, CD₃Cl) δ 144.77, 132.98, 130.68, 130.30, 129.44, 126.80,

75.83, 66.66, 55.89, 44.22, 40.19, 37.53, 33.81, 33.37, 20.43; ESI

MS m/z 308.1.

cis-1-(1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-N,N-di-

methylmethanamine (197)

H

OCH₃

CH₃

The compound was prepared from 194.

The crude product was subjected to silica gel column

chromatography (Ethyl acetate/hexane/DEA = 1/4/0.1%) to give 196

(26.7 mg, 32%) and 197 (37.6 mg, 37%).

¹H NMR(400 MHz, CD₃Cl) δ 7.45(d, J=2.4Hz, 1H), 7.38(d,

J=8.4Hz, 1H), 7.22(dd, J=2.4, 8.4Hz, 1H), 3.22(s, 3H), 3.06(m,

1H), 2.56(m, 1H), 2.28(s, 2H), 2.19(m, 1H), 2.02(s, 6H), 2.04-1.96(m,

1H), 1.68(m, 1H), 1.40(m, 1H), 1.20(m, 2H); ¹³C NMR

(100 MHz, CD₃Cl) δ 145.41, 132.53, 130.30, 129.84, 129.70,

127.10, 75.99, 74.35, 55.88, 48.76, 45.54, 39.82, 33.19, 32.32,

20.46; ESI MS m/z 316.1.

cis-3-(3,4-dichlorophenyl)-1-methyl-3-((meth-

ylamino)methyl)cyclohexanol (198)

CH₃

OH

CH₃

H

The compound was prepared from 193 E2.

¹HNMR(400 MHz, CD₃OD) δ 7.51(d, J=2.4Hz, 1H), 7.45(d,

J=8.4Hz, 1H), 7.31(dd, J=2.4, 8.4Hz, 1H), 3.31(d, J=13.2Hz, 1H),

3.20(d, J=13.2Hz, 1H), 2.23(s, 3H), 2.00(m, 2H), 1.88(m, 1H),

1.75(m, 1H), 1.68(m, 1H), 1.60(m, 2H), 1.39(m, 1H), 1.05(s,

3H); ¹³CNMR(100 mHz, CD₃OD), δ 146.32, 132.08, 130.19,

127.68, 128.37, 126.07, 69.45, 61.35, 46.74, 41.79, 38.58, 35.86,

32.74, 30.36, 18.97; ESI MS m/z 302.1.

cis-3-(3,4-dichlorophenyl)-3-((dimethylamino)methyl)-1-meth-

ylcyclohexanol (199)

CH₃

OH

CH₃

The compound was prepared from 193 E2.

¹H NMR(400 MHz, CD₃OD) δ 8.44(broad, 1H), 7.64(d, J=2.0Hz,

1H), 7.55(d, J=8.8Hz, 1H), 7.42(dd, J=2.0, 8.8Hz, 1H), 4.05(d,

J=13.2Hz, 1H), 3.53(d, J=13.2Hz, 1H) 2.558(s, 6H), 2.30(m, 1H),

2.15(m, 1H), 1.95(m, 1H), 1.80(d, J=14Hz, 1H), 1.68(m, 2H),

1.41(td, J=4.0, 13.2Hz, 2H), 1.33(s, 3H); ¹³C NMR(100

MHz, CD₃OD) δ 148.30, 132.86, 130.99, 130.88, 128.21, 125.84,

69.03, 65.32, 44.56, 41.65, 39.83, 37.63, 36.48, 30.89, 18.36; ESI

MS m/z 316.2.

cis-1-(1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-N-meth-

ylmethanamine (200)

H

OCH₃

CH₃

H

The compound was prepared from 192.

¹H NMR(400 MHz, CD₃Cl) δ 7.43(d, J=2.0Hz, 1H), 7.41(d,

J=8.8Hz, 1H), 7.21(dd, J=2.0, 8.8Hz, 1H), 3.12(s, 3H), 3.07(m,

1H), 2.54(m, 1H), 2.55(s, 2H), 2.28(s, 3H), 2.26(m, 1H), 2.19(m,

1H), 1.70(m, 1H), 1.40(m, 2H), 1.22(m, 2H); ¹³C NMR(100 MHz,

CD₃Cl) δ 144.77, 132.98, 130.68, 130.30, 129.44, 126.80,

75.83, 66.66, 55.89, 44.22, 40.19, 37.53, 33.81, 33.37, 20.43; ESI

MS m/z 308.1.

cis-1-(1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-N,N-di-

methylmethanamine (201)

H

OCH₃

CH₃

The compound was prepared from 192.

¹H NMR(400 MHz, CD₃Cl) δ 7.45(d, J=2.4Hz, 1H), 7.38(d,

J=8.4Hz, 1H), 7.22(dd, J=2.4, 8.4Hz, 1H), 3.22(s, 3H), 3.06(m,

1H), 2.56(m, 1H), 2.28(s, 2H), 2.19(m, 1H), 2.02(s, 6H), 2.04-1.96(m,

1H), 1.68(m, 1H), 1.40(m, 1H), 1.20(m, 2H); ¹³C NMR(100

MHz, CD₃Cl) δ 145.41, 132.53, 130.30, 129.84, 129.70,

127.10, 75.99, 74.35, 55.88, 48.76, 45.54, 39.82, 33.19, 32.32,

20.46; ESI MS m/z 316.1.

cis-3-(3,4-dichlorophenyl)-3-((methylamino)ethyl)cyclohexanol

(202)

CH₃

OH

CH₃

H

The compound was prepared from 193 E1.

¹HNMR(400 MHz, CD₃OD) δ 7.51(d, J=2.4Hz, 1H), 7.45(d,

J=8.4Hz, 1H), 7.31(dd, J=2.4, 8.4Hz, 1H), 3.31(d, J=13.2Hz, 1H),

3.20(d, J=13.2Hz, 1H), 2.23(s, 3H), 2.00(m, 2H), 1.88(m, 1H),

1.75(m, 1H), 1.68(m, 1H), 1.60(m, 2H), 1.39(m, 1H), 1.05(s,

3H); ¹³CNMR(100 mHz, CD₃OD) δ 146.32, 132.08, 130.19,

127.68, 128.37, 126.07, 69.45, 61.35, 46.74, 41.79, 38.58, 35.86,

32.74, 30.36, 18.97; ESI MS m/z 302.1.

cis-3-(3,4-dichlorophenyl)-3-((di-

methylamino)methyl)cyclohexanol (203)

CH₃

OH

CH₃

The compound was prepared from 193 E1.

¹H NMR(400 MHz, CD₃OD) δ 8.44(broad, 1H), 7.64(d, J=2.0Hz,

1H), 7.55(d, J=8.8Hz, 1H), 7.42(dd, J=2.0, 8.8Hz, 1H), 4.05(d,

J=13.2Hz, 1H), 3.53(d, J=13.2Hz, 1H) 2.558(s, 6H), 2.30(m, 1H),

2.15(m, 1H), 1.95(m, 1H), 1.80(d, J=14Hz, 1H), 1.68(m, 2H),

1.41(td, J=4.0, 13.2Hz, 2H), 1.33(s, 3H); ¹³C NMR(100 MHz,

CD₃OD) δ 148.30, 132.86, 130.99, 130.88, 128.21, 125.84,

69.03, 65.32, 44.56, 41.65, 39.83, 37.63, 36.48, 30.89, 18.36; ESI

MS m/z 316.2.

(1-(3,4-dichlorophenyl)-3,3-difluorocyclohexyl)-methanamine (204)

The title compound was synthesized from 1-(3,4-dichloro-phenyl)-3-oxo-cyclohexanecarbonitrile (0.60 g, 2.2 mmol) according to General Procedure CC, followed by General Procedure E. The crude product was dissolved in MeOH (3 mL) and subjected to reverse phase column chromatography (CH₃CN/H₂O/0.1% Formic acid=5% to 100%) to give (86 mg, 72%). ¹H NMR (400 MHz, CD₃OD) δ 7.64 (d, J=7.4 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.39 (dd, J=2.4, 8.4 Hz, 1H), 3.23 (s, 2H), 2.4 (m, 2H), 2.52 (m, 2H), 1.95 (m, 2H), 1.80 (m, 2H); ¹³C NMR (100 MHz, CD₃OD) δ 142.17, 132.94, 131.58, 130.96, 129.06, 126.54, 123.11, 47.74, 41.65, 40.23, 32.98, 30.69, 18.21, 41.26; ESI MS m/z 294.0.

1-(1-(3,4-dichlorophenyl)-3,3-difluorocyclohexyl)-N-methylmethanamine (205)

205 E1, 205 E2
The title compound was synthesized from 204 according to General Procedure F. The crude product was subjected to silica gel column chromatography (ethyl acetate/hexane/DEA=1:4:0.1) to give the mono-methylated analog (25 mg, 30%) and the N,N-dimethylated analog (36 mg, 41%). The racemic mixture of the monomethylated analog was purified by chiral column chromatography (OJ column; Hexane/ⁱpropanol/DEA=98/2/0.1) to give the fast moving enantiomer 205 E1 (5.2 mg) and the slow moving enantiomer 205 E2 (6.3 mg). ¹H NMR (400 MHz, CD₃Cl) δ 7.42 (d, J=2.4 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.18 (dd, J=2.4, 8.8 Hz, 1H), 2.68 (s, 2H), 2.38-2.19 (m, 2H), 2.29 (s, 3H), 2.00-1.90 (m, 2H), 1.90-1.66 (m, 4H); ¹³C NMR (100 MHz, CD₃Cl) δ 132.78, 130.69, 130.45, 128.68, 126.09, 126.03, 123.69, 61.73, 45.5, 41.26, 37.41, 34.14, 32.05, 18.84; ESI MS m/z 308.1.

1-(1-(3,4-dichlorophenyl)-3,3-difluorocyclohexyl)-N,N-dimethylmethanamine (206)

The racemic mixture of the dimethylated analog (Example above) was purified by chiral column chromatography (OJ column; hexane:ⁱpropanol:DEA=98:2:0.1) to give the fast moving enantiomer 206 E1 (5.2 mg) and the slow moving enantiomer 206 E2 (6.3 mg). ¹H NMR (400 MHz, CD₃OD) δ 7.41 (d, J=2.4 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.18 (dd, J=2.4, 8.8 Hz, 1H), 2.36 (s, 2H), 2.36-2.24 (m, 1H), 2.07 (s, 6H), 1.94-1.80 (m, 4H), 1.74-1.64 (m, 2H); ¹³C NMR (100 MHz, CD₃OD) δ 136.17, 132.27, 130.18, 129.99, 129.03, 126.47, 70.42, 48.52, 44.5, 40.26, 34.12, 31.58, 18.881; ESI MS m/z 332.1.

Example 4

Synthesis of 4-Substituted Cyclohexylamine Analogs

4.1. Synthesis of Aryl Acetonitriles

General Procedure V: To a 1.0 M solution of the carboxylic acid (1 eq) in THF was added BH₃/THF (3 eq). The reaction mixture was stirred overnight before being concentrated. To the residue was added diethyl ether and NaOH solution. The organic layer was separated, dried (Na₂SO₄) and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to afford the aryl alcohol.
To a 0.4 M solution of the aryl alcohol (1 eq) in CH₂Cl₂was added PBr₃(2 eq). The reaction mixture was stirred for 3 h at room temperature before being quenched with saturated aqueous NH₄Cl. The organic layer was separated, dried (Na₂SO₄) and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to afford the aryl alkyl bromide.
To a 0.2M solution of the aryl alkyl bromide (1 eq) in CH₃CN was added KCN (3 eq). The reaction mixture was heated to reflux for 6 h before being concentrated. To the residue was added diethyl ether and H₂O. The organic layer was separated, dried (Na₂SO₄) and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to afford the desired aryl acetonitrile.

4.2. Synthesis of 1-(aryl)-4-oxocyclohexanecarbonitriles

Aryl-4-oxocyclohexanecarbonitriles were prepared according to the Scheme, above, or procedures described in WO 00/25770 and WO 03/063797, the disclosures of which are incorporated herein by reference for all purposes. Minor modifications of the described procedures were used when appropriate. For example, 2.2 equivalents of acrylate may be used in step 1, NaH (60% dispersion in mineral oil) reduction was performed in refluxing toluene, and microwave irradiation was used for reactions up to a multigram scale in the final decarboxylation step. An exemplary synthesis of 1-(naphthalen-2-yl)-4-oxocyclohexanecarbonitrile is outlined below.

4.2.1. Synthesis of dimethyl 3-cyano-3-(naphthalen-2-yl)hexanedioate

2-naphthylacetonitrile (3.45 g, 20.6 mmol) and methyl acrylate (9.7 ml, 107 mmol) were suspended in 2-methyl-2-propanol (10 ml). Heat was applied to the reaction vessel until the solution became clear. The mixture was cooled to room temperature, at which time (Bu)₄NOH (6.9 mmol, 0.33 equiv.) was added as a solution in 2-methyl-2-propanol:methanol (1:2). The combined reaction mixture was heated to reflux for 4 h under vigorous stirring at which time the reaction appeared complete by GC-MS. After allowing the reaction to cool the mixture was partitioned between H₂O (75 ml) and EtOAc (50 ml). The aqueous layer was removed and washed with EtOAc (2×50 ml). The combined organic phases were washed with NaHCO₃(sat. aq.) and brine and dried over MgSO₄. After filtration the solvent was removed in vacuo. The crude product was purified by flash column chromatography (25% EtOAc in hexanes) to isolate the title compound as a light yellow oil (5.75 g, 82%).

4.2.2. Synthesis of methyl 5-cyano-2-hydroxy-5-(naphthalen-2-yl)cyclohex-1-enecarboxylate

To a solution of the diester nitrile (2.3 g, 6.77 mmol) in dry toluene (46 ml) was added NaH (60% suspension in mineral oil, 820 mg, 20.33 mmol). The reaction mixture was heated to reflux for 3 h at which time no starting material remained (GC-MS). The reaction was cooled to room temperature and carefully quenched with NH₄Cl (aq., 100 ml) and extracted with EtOAc (3×50 ml). The combined organics were washed with brine, dried over MgSO₄, filtered, and the solvent removed in vacuo. The resulting oily product, suspended in mineral oil, washed with hexanes to afford the desired product as a light yellow solid (1.4 g, 67% yield). The material was used in the following step without further purification.

4.2.3. Synthesis of 1-(naphthalen-2-yl)-4-oxocyclohexanecarbonitrile

The above ketoester (0.75 g, 2.44 mmol) was dissolved in DMSO (11 ml) and H₂O (0.5 ml) and was sealed in a 20 ml microwave reaction vial equipped with a magnetic stir bar. The reaction mixture was heated to 160° C. for 10 min in a microwave reactor at which time complete conversion was observed by HPLC. The reaction was diluted with EtOAc (50 ml) and washed with 10% LiCl (aq., 2×30 ml) followed by a brine wash. The organic layer was removed, dried over MgSO₄, filtered, and the solvent was removed in vacuo. The product was further purified by flash column chromatography (25% EtOAc in hexanes) to afford the desired ketone (0.55 g, 90% yield) as a colorless oil, which solidified upon standing.

4.3. Synthesis of 4-hydroxy-1-aryl-cyclohexanecarbonitrile (NaBH₄Reduction)

General Procedure W: To a solution of the ketonitrile (1 eq) in dry methanol (about 0.1 M) at 0° C. was added NaBH₄(4 eq) portionwise. The mixture was allowed to warm to 22° C. and was stirred at this temperature for about 2 h, or until complete (e.g., HPLC). It was diluted with H₂O and the aqueous layer was extracted with Et₂O. The combined organic layers were washed with brine, dried over MgSO₄and filtered. The solvent was removed in vacuo to afford the resulting alcohol, typically as one diastereomer.

4.4. Synthesis of 4-hydroxy-1-aryl-cyclohexanecarbonitrile with Inverse Stereochemistry at C-4 (Mitsunobu Reaction)

General Procedure X: To a solution of PPh₃(1.2 eq) in dry toluene (about 0.1 M) was added p-NO₂-benzoic acid (1.2 eq) and the resulting suspension was cooled to −30° C. To the mixture was added a 2 M solution of the respective nitrile alcohol (1 eq) in toluene (about) in one portion and a 1.0 M solution of DEAD (1.2 eq) in toluene dropwise over 15 min. The mixture was allowed to warm to 22° C. and was stirred for 15 h, at which time the reaction was quenched with saturated aqueous NaHCO₃. The aqueous layer was extracted with EtOAc, the combined organic layers were dried over MgSO₄, filtered and the solvent was removed in vacuo to afford the benzoate intermediate, which was used without further purification (0.61 g, 74% yield).
To a solution of the crude benzoate (1 eq) in MeOH (about 0.1 M) was added a 1.0 M solution of NaOMe (95%, 1.11 eq) in THF and the mixture was allowed to stir at 22° C. for 4 h. The solvent was removed in vacuo and the resulting residue was taken up in H₂O and extracted with EtOAc. The combined organics were dried over MgSO₄, filtered and the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography (EtOAc in hexanes) to afford the desired nitrile alcohol.

4.5. Synthesis of Tertiary Alcohols

General Procedure Y: To a solution of the ketonitrile (1 eq) in dry THF (about 0.4 M) at −78° C. was added dropwise MeLi (1.4 M in Et₂O, 2 eq) so as to maintain an internal temperature of <−60° C. The reaction mixture was stirred at −78° C. for 3 h and the reaction was then quenched with H₂O (e.g., 1 ml). The reaction mixture was allowed to warm to 22° C. and was then diluted with CH₂Cl₂. The organic layer washed with aqueous NaHCO₃and brine, dried over MgSO₄and filtered and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (e.g., 0-60% EtOAc in hexanes) to return starting material, fast moving diastereomer as well as the slow moving diastereomer (major product). Solvent removal afforded the desired products as white solids.

4.6.Chlorination

General Procedure Z: To a solution of the amino alcohol (1 eq) in MeOH containing 10% (v/v) NEt₃was added BOC₂O (2 eq) and the resulting mixture was stirred at 22° C. for 3 h, at which time the solvent was removed in vacuo. Silica gel column chromatography (e.g., EtOAc in hexanes) afforded the carbamate as a clear oil.
To a solution of the purified carbamate (1 eq) in DMF (about 0.1 M) and CCl₄(1.5 eq) was added KF (3 eq) and PPh₃(2 eq) and the resulting mixture was stirred at 22° C. for 3 h. Saturated aqueous NaHCO₃was then added to quench the reaction and the aqueous layer was extracted with EtOAc. The combined organic phases were dried over Na₂SO₄, filtered and the solvent was removed in vacuo to afford the halogenated mixture e.g., as a 3:1 ratio of chlorinated to α-eliminated product (66% conversion). Silica gel column chromatography (e.g., EtOAc in hexanes) afforded the chlorinated carbamate.
The BOC group was removed and the HCl salt was prepared by the addition of 4M HCl (Et₂O) to the carbamate. After stirring for 1 h, the HCl salt was filtered off.

4.7. Fluorination

General Procedure BB: A 0.2 M solution of the nitrile alcohol (1 eq) in CHCl₃was added drop-wise to a 0.1 M solution of morpholino sulfurtrifluoride (4 eq) in CHCl₃(about 0.1 M) at −15° C. over 5 min. The resulting mixture was stirred between −30 and −15° C. for 30 min, at which time MeOH (5 eq) and saturated aqueous NaHCO₃were added. The aqueous layer was extracted with EtOAc, dried over Na₂SO₄, filtered and the solvent removed in vacuo. Silica gel column chromatography (e.g., EtOAc in hexanes) afforded fluorinated and α-eliminated products e.g., in a 1:1 ratio.

4.8. Difluorination

General Procedure CC: A 0.5 M solution of the ketonitrile (1 eq) in CHCl₃was added drop-wise to a 2 M solution of morpholino sulfurtrifluoride (4 eq) in CHCl₃at −30° C. over 5 min. The resulting mixture was stirred between −30 and 0° C. for 2 h, at which time MeOH and saturated aqueous NaHCO₃were added. The aqueous layer was extracted with EtOAc, dried over Na₂SO₄, filtered and the solvent was removed in vacuo. Silica gel column chromatography (e.g., EtOAc in hexanes) afforded difluorinated and α-eliminated products.

4.9. Synthesis of Fluoromethyl Analogs

General Procedure DD: To a solution of the ketonitrile (concentration about 0.3 M, 1 eq) and trimethylsulfonium iodide (1.5 eq) in dry DMSO was added a solution of KOtBu (1.5 eq) in dry DMSO (about 0.7 M). The mixture was stirred at 22° C. for 5 h, at which time the reaction appeared complete by GC-MS. The reaction mixture was diluted with brine, and extracted with EtOAc. The combined organic layers were dried over MgSO₄, filtered, and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography (e.g., EtOAc in hexanes) to afford two diastereomeric epoxides, termed the faster moving diastereomer (FMD) and the slower moving diastereomer (SMD).
To a 1M solution of TBAF in THF (4 eq) in a clean glass reaction flask was added HF (48% in H₂O, 4 eq). The solvent was removed in vacuo and the resulting mixture was added to a mixture of the above epoxide (1 eq) and KHF₂(3 eq) in a microwave reaction vial. The reagents were washed down the side of the vial with heptane (minimal volume) and the reaction mixture was heated in the microwave at 120° C., for 15 min (FHT). After the reaction mixture was cooled to 22° C., the mixture was diluted with H₂O and saturated aqueous NaHCO₃and was extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered and the solvent was removed in vacuo to afford crude fluoromethylated nitrile, which was purified by silica gel chromatography (EtOAc in hexanes) to afford the pure product as a white solid (>20:1 regioselectivity).

4.10. Synthesis of Methylamine

General Procedure F2: To a 0.1 M solution of the amine (1 eq) in MeOH containing 10% (v/v) NEt₃was added BOC₂O (1.2 eq) and the resulting mixture was stirred at 22° C. for 3 h, at which time the solvent was removed in vacuo. Silica gel column chromatography (EtOAc in hexanes) afforded the carbamate.
To a 0.1 M solution of the purified carbamate (1 eq) in THF was added LAH (IM THF, 2 eq) and the resulting mixture was heated to 65° C. for 6 h. After the reaction was complete (HPLC), 6M HCl was added followed by saturated aqueous K₂CO₃. The product was extracted with EtOAc. The combined organics were dried over MgSO₄, filtered and the solvent was removed in vacuo. The crude mono-methylamine was purified by either Gilson RP-HPLC or by transformation to the HCl salt and recrystallization.

4.11. Alkylation of Alcohol

General Procedure EE: To a 0.2 M solution of the alcohol (1 eq) in THF was added NaH (60% in mineral oil, 1.5 eq). The reaction mixture was stirred for 20 min before alkyl halide (2 eq) was added. It was stirred for 4 h before being quenched with saturated NH₄Cl solution. The product was then extracted with diethyl ether. The combined organic layers were dried (Na₂SO₄), filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give O-alkylated product.

4.12. Preparation of Ketals

General Procedure FF: To a 0.1 M solution of the ketone (1 eq) in benzene was added ethylene glycol (3 eq) and TsOH—H₂O (0.4 eq). The reaction mixture was heated at reflux for 6 h before being concentrated. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO₃, dried (Na₂SO₄), filtered and concentrated. The residue was purified by silica gel column chromatography (Ethyl acetate/hexane/DEA) to give the ketal.

4.13. Synthesis of 4-Substituted Cycloalkylamines

Compounds in Table 5, below, were synthesized from the respective 1-(aryl)-4-oxocyclohexanecarbonitriles according to the indicated General Procedures.

TABLE 5


Summary of 4-Substituted Cycloalkylamines

			General
Ar	R^b	R^c	Procedure

4-(aminomethyl)-4-(naphthalen-2-yl)cyclohexanol (207)



H	OH	W, E

HPLC R_t= 7.54 min; LC-MS(5 minute method) 2.24 min, (M + 1)⁺ 256.0

@ 2.31 min; ¹H-NMR(400 MHz, CDCl₃) 7.84-7.75(m, 4H), 7.51-7.43(m,

3H), 3.79(m, 1H), 2.88(brs, 2H), 2.10-1.97(m, 4H), 1.75-1.56(m, 4H).

4-(aminomethyl)-4-(naphthalen-2-yl)cyclohexanol (208)



OH	H	W, X, E

HPLC R_t= 6.83 min; LC-MS(15 minute method) 4.71 min, (M + 1)⁺

256.0 @ 4.73 min; ¹H-NMR(400 MHz, CD₃OD) 8.04-7.93(m, 4H),

7.69-7.49(m, 3H), 3.72(m, 1H), 3.13(s, 2H), 2.63(d, J=13.5Hz, 2H),

1.99-1.85(m, 2H), 1.80-1.68(m, 2H), 1.47-1.31(m, 2H).

4-(aminomethyl)-1-methyl-4-(naphthalen-2-yl)cyclohexanol (209)



OH	Me	Y, E

HPLC R_t= 7.06 min; LC-MS(M + 1)⁺ 270.1; ¹H-NMR(400 MHz, CDCl₃)

7.86-7.79(m, 4H), 7.58(brs, 2H), 7.43-7.35(m, 3H), 2.84(brs, 2H), 2.25

(m, 2H), 1.77(m, 2H), 1.58(m, 2H), 1.49(m, 2H), 1.28(s, 3H).

4-(aminomethyl)-1-methyl-4-(naphthalen-2-yl)cyclohexanol (210)



Me	OH	Y, E

HPLC R_t= 1.39; LC-MS(15 minute method) 6.92 min, (M + 1)⁺ 270.0 @

6.88 min.

(4-chloro-1-(naphthalen-2-yl)cyclohexyl)methanamine (211)



Cl	H	W, E, Z

HPLC R_t= 2.38 min; ¹H-NMR(400 MHz, CD₃OD) 8.07-7.95(m, 4H),

7.65(dd, J=9.0, 1.5Hz, 1H), 7.61-7.51(m, 2H), 4.14(m, 1H), 3.18(s,

2H), 2.68(d, J=13.5Hz, 2H), 2.20(d, J=13.5Hz, 2H), 1.89-1.62(m, 4H).

¹³C-NMR(100 MHz, CD₃OD) 134.0, 132.9, 129.5, 128.1, 127.4,

127.2, 126.4, 124.1, 58.6, 50.6, 40.4, 32.4, 32.1.

LC-MS(15 minute method) 8.10 min, (m/z) 274.0 @ 8.18 min.

(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)methanamine (212)



F	H	W, BB, E

HPLC R_t= 2.14 min; ¹H-NMR(400 MHz, CD₃OD) 8.00-7.87(m, 4H),

7.63-7.51(m, 3H), 4.76(m, 0.5H), 4.61(m, 0.5H), 3.19(s, 2H),

2.52(m, 2H), 2.01-1.97(m, 2H), 1.82-1.76(m, 2H), 1.64-1.59(m, 2H).

LC-MS(15 minute method) 7.30 min, (M + 1)⁺

258.1 @ 7.36 min

(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)methanamine (213)



H	F	W, X, BB, E

HPLC R_t= 1.48 min; ¹H-NMR(400 MHz, CDCl₃) 7.87-7.62(m, 4H),

7.52-7.44(m, 3H), 4.75(m, 0.5H), 4.63(m, 0.5H), 2.79(s, 2H), 2.23(d,

J=13.5Hz, 2H), 1.97-1.90(m, 4H), 1.70-1.52(m, 2H). ¹³C-NMR(100 MHz,

CDCl₃) 128.6, 128.1, 127.6, 126.6, 126.3, 126.0, 125.2, 90.6, 55.4,

28.1, 27.8, 27.6. LC-MS(M + 1)+ 258.1.

4-(aminomethyl)-4-(benzo[d][1,3]dioxol-5-yl)cyclohexanol (214)



H	OH	W, E

HPLC R_t= 1.18 min; LC-MS(15 minute method) 4.51 min, (M + 1)⁺

250.0 @ 4.4.51 min; ¹H-NMR(400 MHz, CD₃OD) 8.38(brs, 1H), 6.98(d,

J=2.0Hz, 1H), 6.85(dd, J=8.0, 2.0Hz, 1H), 6.82(d, J=8.0Hz, 1H),

5.95(s, 2H), 3.78(m, 1H), 3.03(s, 2H), 2.04-1.91(m, 4H), 1.71-1.58(m,

4H). ¹³C-NMR(100 MHz, CD₃OD) 120.3, 108.3, 107.1, 101.4,

66.2, 63.5, 40.0, 29.0.

4-(aminomethyl)-4-(benzo[d][1,3]dioxol-5-yl)-1-methylcyclohexanol (215)



Me	OH	Y, E

HPLC R_t= 1.64 min; ¹H-NMR(400 MHz, CD₃OD) 8.37(brs, 1H), 6.97(s,

1H), 6.90(d, J=8.0Hz, 1H), 6.85(d, J=8.0Hz, 1H), 5.97(s, 2H), 2.92(s,

2H), 2.13(d, J=13.5Hz, 2H), 1.89(t, J=13.0Hz, 2H), 1.56(d, J=13.5Hz,

2H), 1.38(t, J=13.0Hz, 2H), 1.05(s, 3H). ¹³C-NMR(100 MHz, CD₃OD)

120.8, 108.4, 107.4, 101.5, 34.1, 29.7, 29.0, 28.8. LC-MS(M + 1)⁺ 264.1.

4-(aminomethyl)-4-(benzo[d][1,3]dioxol-5-yl)-1-methylcyclohexanol (216)



OH	Me	Y, E

HPLC R_t= 2.03 min; LC-MS(15 minute method) 0.60 min, (M + 1)⁺

264.1 @ 0.70 min; ¹H-NMR(400 MHz, CD₃OD) 8.44(brs, 1H), 6.98(d,

J=1.5Hz, 1H), 6.91(dd, J=8.5, 1.5Hz, 1H), 6.86(d, J=8.5Hz, 1H),

5.96(s, 2H), 3.11(s, 2H), 2.20-2.01(m, 2H), 1.77-1.71(m, 2H),

1.60-1.56(m, 4H), 1.27(s, 3H). ¹³C-NMR(100 MHz, CD₃OD) 168.1,

149.0, 147.0, 120.1, 108.3, 106.9, 101.4, 68.7, 39.7, 34.6, 30.0, 27.2.

4-(aminomethyl)-1-(fluoromethyl)-4-(naphthalen-2-yl)cyclohexanol (217)



CH₂F	OH	DD, E

HPLC R_t= 1.84 min; LC-MS(15 minute method) 6.65 min, (M + 1)⁺

288.2 @ 6.75 min; ¹H-NMR(400 MHz, CD₃OD) 7.99-7.87(m, 4H),

7.63(dd, J=9.0, 2H), 7.54-7.50(m, 2H), 4.04(s, 1H), 3.92(s, 1H),

3.09(s, 2H), 2.46(d, J=13.5Hz, 2H), 2.03(t, J=13.5Hz, 2H), 1.63(d,

J=13.5Hz, 2H), 1.45(t, J=13.5Hz, 2H). ¹³C-NMR(100 MHz,

CD₃OD) 136.1, 133.9, 132.8, 129.3, 128.0, 127.4, 127.3, 126.3, 124.3,

90.6, 88.9, 52.1, 41.0, 28.3, 28.2, 27.6.

4-(aminomethyl)-1-(fluoromethyl)-4-(naphthalen-2-yl)cyclohexanol (218)



OH	CH₂F	DD, E

HPLC R_t= 1.19 min; LC-MS(15 minute method) 4.91 min, (M + 1)⁺

288.1 @ 4.89 min; ¹H-NMR(400 MHz, CD₃OD) 7.97-7.86(m, 4H),

7.63(dd, J=9.0, 2.0Hz, 1H), 7.53-7.48(m, 2H), 4.38(s, 1H), 4.26(s,

1H), 3.35(s, 2H), 2.33(dt, J=13.5, 3.5Hz, 2H), 2.00(m, 2H), 1.81(dt,

J=13.5, 3.5Hz, 2H), 1.65(m, 2H). ¹³C-NMR(100 MHz, CD₃OD)

133.9, 132.9, 129.1, 128.1, 127.3, 126.3, 126.2, 125.9, 123.7, 89.4, 87.7,

69.6, 45.9, 39.8, 28.5, 28.4.

4-(aminomethyl)-1-methyl-4-(4-(trifluoromethoxy)phenyl)-cyclohexanol

(219)



Me	OH	Y, E

HPLC R_t= 1.45 min; LC-MS(15 minute method) 7.48 min, (M + 1)⁺

304.1 @ 7.60 min; ¹H-NMR(400 MHz, CD₃OD) 8.40(brs, 2H), 7.58(dd,

J=9.0, 2.5Hz, 2H), 7.34(d, J=9.0Hz, 2H), 3.00(s, 2H), 2.20(d,

J=13.5Hz, 2H), 1.96(t, J=13.5Hz, 2H), 1.59(d, J=14.0Hz, 2H), 1.31(t,

J=13.5Hz, 2H), 1.07(s, 3H). ¹³C-NMR(100 MHz, CD₃OD) 129.4, 121.5,

68.0, 51.9, 40.4, 34.0, 29.6, 28.5.

4-(aminomethyl)-4-(4-(trifluoromethoxy)phenyl)cyclohexanol (220)



H	OH	W, E

HPLC R_t= 1.34 min; ¹H-NMR(400 MHz, CDCl₃) 8.44(brs, 1H),

7.60-7.56(m, 2H), 7.33(d, J=9.0Hz, 2H), 3.76(m, 1H), 3.15(s, 2H),

2.11-1.99(m, 4H), 1.64(m, 4H). ¹³C-NMR(100 MHz, CDCl₃) 168.0,

148.4, 128.9, 121.4, 66.3, 49.0, 40.0, 29.0, 28.8.

LC-MS(M + 1)⁺ 290.2.

(4,4-difluoro-1-(naphthalen-2-yl)cyclohexyl)methanamine (221)



F	F	CC, E

HPLC R_t= 1.18 min; LC-MS(15 minute method) 7.70 min, (M + 1)⁺

276.2 @ 7.76 min; ¹H-NMR(400 MHz, CD₃OD) 8.39(brs, 2H),

8.01-7.88(m, 4H), 7.64(d, J=8.5Hz, 1H), 7.54-7.51(m, 2H), 3.18(s,

2H), 2.60(d, J=13.5Hz, 2H), 2.09-1.90(m, 4H), 1.89-1.71(m, 2H).

¹³C-NMR(100 MHz, CD₃OD) 133.8, 132.9, 129.6, 128.1, 127.4,

127.0, 126.5, 126.4, 123.8, 50.0, 30.2, 30.0, 29.7, 29.6.

Synthesis of Secondary and Tertiary Amines

Compounds in Table 6, below, were synthesized from the respective 1-(aryl)-4-oxocyclohexanecarbonitriles according to the indicated General Procedures.

TABLE 6


Summary of Secondary and Tertiary Amines

						General
Ar	R¹	R³	R⁴	R^b	R^c	Procedure

1-methyl-4-((methylamino)methyl)-4-(naphthalen-2-yl)-

cyclohexanol (222)



H	H	CH₃	OH	CH₃	F2

Prepared from: 209

¹H-NMR(400 MHz, CDCl₃) 8.88(brs, 2H), 7.97-7.79(m, 4H), 7.54-7.46

(m, 3H), 3.12(m, 2H), 2.24(m, 2H), 2.23(t, J=5.0Hz, 3H), 2.04

(m, 2H), 1.71(m, 2H), 1.60(m, 2H), 1.35(s, 3H). ¹³C-NMR(100 MHz,

CDCl₃) 133.7, 132.6, 129.6, 128.6, 127.6, 127.0, 126.8, 126.7, 123.9,

70.1, 35.7, 35.1, 30.6. LC-MS(M + 1)⁺ 284.1.

1-methyl-4-((methylamino)methyl)-4-(naphthalen-2-

yl)cyclohexanol (223)



H	H	CH₃	CH₃	OH	E, F2

¹H-NMR(400 MHz, CDCl₃) 9.24(brs, 2H), 7.94-7.83(m, 4H), 7.57(d,

J=9.0Hz, 1H), 7.53-7.48(m, 2H), 3.03(s, 2H), 2.58(s, 3H), 2.59-2.43

(m, 4H), 1.68(d, J=13.5Hz, 2H), 1.46-1.39(m, 2H), 1.04(s, 3H).

¹³C-NMR(100 MHz, CDCl₃) 137.8, 133.7, 132.5, 129.4, 128.4, 127.7,

127.0, 126.7, 126.6, 124.5, 69.1, 62.4, 41.6, 35.1, 34.9, 30.6, 28.2. LC-

MS(M + 1)⁺ 284.1.

4-((dimethylamino)methyl)-1-methyl-4-(naphthalen-2-

yl)cyclohexanol (224)



H	CH₃	CH₃	OH	CH₃	C

Prepared from: 209

¹H-NMR(400 MHz, CDCl₃) 7.89-7.80(m, 4H), 7.60(dd, J=8.5, 2.0

Hz, 1H), 7.52-7.45(m, 2H), 2.54(s, 2H), 2.35-2.21(m, 2H), 2.00(s,

6H), 1.99-1.85(m, 2H), 1.73-1.53(m, 4H), 1.35(s, 3H). LC-MS

(M + 1)⁺ 298.0.

4-((dimethylamino)methyl)-1-methyl-4-(naphthalen-2-

yl)cyclohexanol (225)



H	CH₃	CH₃	CH₃	OH	C

¹H-NMR(400 MHz, CDCl₃) 7.93(m, 4H), 7.68(dd, J=8.8, 2.0Hz,

1H), 7.52(m, 2H), 3.42(s, 2H), 2.50(s, 6H), 2.44(d, J=13.2Hz, 2H),

2.05(dt, J=13.6, 3.2Hz, 2H), 1.63(d, J=13.2Hz, 2H), 1.41(dt, J=13.6,

3.2Hz, 2H), 1.05(s, 3H). ¹³C-NMR(100 MHz, CDCl₃) 138.1,

135.3, 134.3, 130.9, 129.7, 129.3, 129.0, 128.2, 126.3, 73.4, 69.5, 47.6,

42.8, 35.6, 31.4, 30.9. LC-MS(M + 1)⁺ 298.0.

4-((methylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (226)



H	H	CH₃	H	OH	F2

Prepared from: 207

¹H-NMR(400 MHz, CD₃OD) 7.99-7.87(m, 4H), 7.63(dd, J=8.5, 2.0

Hz, 1H), 7.54-7.52(m, 2H), 3.81(m, 1H), 3.32(s, 2H), 2.57(s, 3H),

2.18(m, 4H), 1.72(m, 4H). ¹³C-NMR(100 MHz, CD₃OD) 135.1,

134.1, 130.5, 129.3, 128.6, 127.8, 127.7, 127.6, 125.2, 67.5, 61.9, 35.4,

30.2, 30.1. LC-MS(M + 1)⁺ 270.0.

4-((methylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (227)



H	H	CH₃	OH	H	F2

Prepared from: 208

¹H-NMR(400 MHz, CDCl₃) 7.92-7.82(m, 4H), 7.59-7.47(m, 3H),

3.77(m, 1H), 2.66(s, 2H), 2.61(d, J=13.5Hz, 2H), 2.29(s, 3H), 1.97-1.88

(m, 2H), 1.65(t, J=13.5Hz, 2H), 1.42-1.20(m, 4H). LC-MS

(M + 1)⁺ 270.1.

4-((dimethylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (228)



H	CH₃	CH₃	OH	H	F

Prepared from: 208

¹H-NMR(400 MHz, CD₃OD) 8.11-7.89(m, 4H), 7.70(d, J=9.0Hz,

1H), 7.60-7.51(m, 2H), 3.72(m, 1H), 3.52(brs, 2H), 2.69(d, J=13.0Hz,

2H), 2.57(s, 6H), 2.00-1.72(m, 4H), 1.50-1.32(m, 2H). LC-MS

(M + 1)⁺ 284.1.

4-((dimethylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (229)



H	CH₃	CH₃	H	OH	C

Prepared from: 207

¹H-NMR(400 MHz, CD₃OD) 7.90-7.77(m, 4H), 7.63(d, J=9.0Hz,

1H), 7.52-7.41(m, 2H), 3.73(m, 1H), 2.72(s, 2H), 2.25-2.12(m, 2H),

2.09-1.91(m, 2H), 1.95(s, 6H), 1.82-1.60(m, 4H). LC-MS(M + 1)⁺

284.1.

1-(4-chloro-1-(naphthalen-2-yl)cyclohexyl)-N,N-

dimethylmethanamine (230)



H	CH₃	CH₃	Cl	H	C

Prepared from: 211

¹H-NMR(400 MHz, CDCl₃) 7.91-7.82(m, 4H), 7.55(dd, J=9.0, 1.5

Hz, 1H), 7.52-7.47(m, 2H), 4.06(m, 1H), 2.42(s, 2H), 2.18-2.01(m,

4H), 2.04(s, 6H), 1.83-1.71(m, 4H). LC-MS(m/z) 302.3.

1-methyl-4-(1-(methylamino)ethyl)-4-(naphthalen-2-

yl)cyclohexanol (231)



CH₃	H	CH₃	CH₃	OH	I, F2

Prepared from the corresponding nitrile.

Enantiomers(E1, E2) separated by SFC w/AD column and 30%

MeOH/0.1% DEA, 280 nm.

¹H-NMR(400 MHz, CD₃OD) 7.93-7.84(m, 4H), 7.63(d, J=8.5Hz,

1H), 7.55-7.45(m, 2H), 2.59(q, J=7.0Hz, 1H), 2.44-2.22(m, 1H),

2.23(s, 3H), 2.18-2.03(m, 2H), 1.66-1.23(m, 5H), 1.04(d, J=7.0Hz,

3H), 1.01(s, 3H). LC-MS(M + 1)⁺ 298.1.

1-(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)-N-methylmethanamine

(232)



H	H	CH₃	F	H	F2

Prepared from: 212

¹H-NMR(400 MHz, CDCl₃) 7.87-7.81(m, 4H), 7.54-7.45(m, 3H),

4.74(m, 0.5H), 4.61(m, 0.5H), 2.70(s, 2H), 2.52(m, 2H), 2.25(s, 3H),

2.01-1.94(m, 2H), 1.76-1.56(m, 4H). ¹³C-NMR(100 MHz,

CDCl₃) 133.7, 132.1, 128.8, 128.3, 127.6, 126.4, 126.3, 126.1, 124.7,

92.8, 91.1, 63.7, 42.0, 37.3, 31.2, 31.1, 28.7, 28.5. LC-MS(M + 1)⁺

272.2.

1-(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)-N,N-

dimethylmethanamine (233)



H	CH₃	CH₃	F	H	C

Prepared from: 212

¹H-NMR(400 MHz, CDCl₃) 7.82(m, 4H), 7.54(dd, J=8.5, 2.0Hz,

1H), 7.45(m, 2H), 4.71(m, 0.5H), 4.58(m, 0.5H), 2.45(m, 2H), 2.42

(s, 2H), 2.00(s, 6H), 1.97(m, 2H), 1.77-1.57(m, 4H). ¹³C-NMR(100

MHz, CDCl₃) 133.7, 132.0, 128.2, 128.1, 127.6, 126.3, 126.0, 125.7,

125.5, 93.4, 91.7, 72.2, 48.7, 30.9, 30.8, 28.8, 28.6. LC-MS(M + 1)⁺

286.4.

4-(1-(dimethylamino)ethyl)-1-methyl-4-(naphthalen-2-

yl)cyclohexanol (234)



CH₃	CH₃	CH₃	CH₃	OH	I, C

Prepared from the corresponding nitrile.

Enantiomers(E1, E2) separated by Chiral HPLC, AD column, 280 nm,

90/10/0.1 hexanes/isopropanol/diethylamine.

¹H-NMR(400 MHz, CDCl₃) 7.83-7.79(m, 4H), 7.61(m, 1H), 7.49-7.43

(m, 2H), 3.01(q, J=7.5Hz, 1H), 2.82(brd, J=13.0Hz, 1H), 2.62

(brs, 1H), 2.23(d, J=13.5Hz, 1H), 2.00(s, 6H), 2.00-1.85(m, 1H),

1.59-1.40(m, 4H), 1.30-1.21(m, 1H), 1.02(s, 3H), 0.84(d, J=7.0Hz,

3H). ¹³C-NMR(100 MHz, CDCl₃) 133.5, 132.0, 128.3, 127.5, 127.3,

125.9, 125.7, 69.6, 44.0, 42.5, 35.5, 35.2, 31.2, 29.7, 28.6, 11.7, 7.6.

LC-MS(M + 1)⁺ 312.3.

1-(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)-N,N-

dimethylmethanamine (235)



H	CH₃	CH₃	H	F	C

Prepared from: 213

¹H-NMR(400 MHz, CDCl₃) 7.81(m, 4H), 7.55(d, J=8.0Hz, 1H),

7.45(m, 2H), 4.72(m, 0.5H), 4.60(m, 0.5H), 2.46(s, 2H), 2.22(d,

J=13.5Hz, 2H), 2.05-1.91(m, 4H), 1.96(s, 6H), 1.69-1.56(m, 2H). ¹³C-

NMR(100 MHz, CDCl₃) 133.6, 132.0, 128.2, 127.9, 127.6, 126.3,

126.0, 125.8, 125.7, 90.8, 89.1, 73.2, 48.7, 28.7, 27.8, 27.6. LC-MS

(M + 1)⁺ 286.2.

1-(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)-N-methylmethanamine

(236)



H	H	CH₃	H	F	A

Prepared from: 213

¹H-NMR(400 MHz, CDCl₃) 8.27(brs, 1H), 7.89-7.83(m, 4H), 7.53-7.49

(m, 3H), 4.73(m, 0.5H), 4.61(m, 0.5H), 2.84(s, 2H), 2.34(d,

J=13.5Hz, 2H), 2.30(s, 3H), 2.08-1.96(m, 4H), 1.54(t, J=13.0Hz, 2H).

LC-MS(M + 1)⁺ 272.2.

4-(benzo[d][1,3]dioxol-5-yl)-4-((methylamino)methyl)cyclohexanol

(237)



H	H	CH₃	H	OH	F2

Prepared from: 214

¹H-NMR(400 MHz, CDCl₃) 6.87(d, J=2.0Hz, 1H), 6.81(dd, J=8.0,

2.0Hz, 1H), 6.76(d, J=8.0Hz, 1H), 5.94(s, 2H), 3.76(m, 1H), 2.65

(s, 2H), 2.29(s, 3H), 2.08-2.02(m, 2H), 1.82-1.70(m, 4H), 1.62-1.56

(m, 2H). ¹³C-NMR(100 MHz, CDCl₃) 145.8, 119.8, 108.2, 107.3,

101.1, 68.7, 62.2, 41.4, 37.5, 30.8, 30.5. LC-MS(M + 1)⁺ 264.1.

4-(benzo[d][1,3]dioxol-5-yl)-4-

((dimethylamino)methyl)cyclohexanol (238)



H	CH₃	CH₃	H	OH	F

Prepared from: 214

¹H-NMR(400 MHz, CD₃OD) 6.88(s, 1H), 6.81(d, J=8.0Hz, 1H),

6.75(dd, J=8.0, 2.0Hz, 1H), 5.92(s, 2H), 3.78(m, 1H), 2.39(s, 2H),

2.04-1.99(m, 2H), 1.99(s, 6H), 1.78-1.67(m, 4H), 1.58(m, 2H). ¹³C-

NMR(100 MHz, CD₃OD) 120.1, 108.0, 107.8, 101.0, 70.7, 68.4, 48.5,

31.7, 30.3, 30.0. LC-MS(M + 1)⁺ 278.2.

4-(benzo[d][1,3]dioxol-5-yl)-1-methyl-4-

((methylamino)methyl)cyclohexanol (239)



H	H	CH₃	CH₃	OH	F2

Prepared from: 215

¹H-NMR(400 MHz, CD₃OD) 8.45(brs, 1H), 6.98(s, 1H), 6.92(d,

J=8.0Hz, 1H), 6.87(d, J=8.0Hz, 1H), 5.97(s, 2H), 3.03(s, 2H), 2.56(s,

3H), 2.14(d, J=13.5Hz, 2H), 1.91(t, J=13.0Hz, 2H), 1.55(d,

J=13.5Hz, 2H), 1.34(t, J=13.0Hz, 2H), 1.07(s, 3H). ¹³C-NMR(100

MHz, CD₃OD) 168.2, 149.2, 147.2, 132.9, 120.9, 108.5, 108.4, 107.5,

101.5, 68.0, 62.4, 40.5, 34.1, 34.0, 29.8, 29.0, 28.8. LC-MS(M + 1)⁺

278.3.

4-(benzo[d][1,3]dioxol-5-yl)-4-((dimethylamino)methyl)-1-

methylcyclohexanol (240)



H	CH₃	CH₃	CH₃	OH	C

Prepared from: 215

¹H-NMR(400 MHz, CD₃OD) 8.54(brs, 1H), 6.99(d, J=1.5Hz, 1H),

6.95(dd, J=8.5, 1.5Hz, 1H), 6.84(d, J=8.5Hz, 1H), 5.96(s, 2H),

2.92(s, 2H), 2.34(s, 6H), 2.12(d, 13.0Hz, 2H), 1.89(t, J=13.5Hz,

2H), 1.53(d, J=13.0Hz, 2H), 1.37(d, J=13.5Hz, 2H), 1.03(s, 3H).

¹³C-NMR(100 MHz, CD₃OD) 120.9, 108.2, 107.8, 101.4, 72.9, 68.2,

46.5, 34.1, 29.8, 29.5. LC-MS(M + 1)⁺ 292.2.

4-(benzo[d][1,3]dioxol-5-yl)-1-methyl-4-

((methylamino)methyl)cyclohexanol (241)



H	H	CH₃	OH	CH₃	F

Prepared from: 216

¹H-NMR(400 MHz, CD₃OD) 8.39(brs, 1H), 7.00-6.86(m, 3H), 5.96

(s, 2H), 3.22(s, 2H), 2.58(s, 3H), 2.17(m, 2H), 1.78-1.74(m, 2H),

1.65-1.59(m, 4H), 1.27(s, 3H). ¹³C-NMR(100 MHz, CD₃OD) 149.0,

147.2, 120.0, 108.4, 106.9, 101.5, 39.7, 34.5, 34.0, 30.3, 27.4. LC-MS

(M + 1)⁺ 278.1.

4-(benzo[d][1,3]dioxol-5-yl)-4-((dimethylamino)methyl)-1-

methylcyclohexanol (242)



H	CH₃	CH₃	OH	CH₃	C

Prepared from: 216

¹H-NMR(400 MHz, CD₃OD) 8.54(brs, 1H), 7.00(d, J=2.0Hz, 1H),

6.93(dd, J=8.5, 2.0Hz, 1H), 6.83(d, J=8.5Hz, 1H), 5.94(s, 2H),

3.03(s, 2H), 2.33(s, 6H), 2.16(m, 2H), 1.73(m, 2H), 1.57(t, J=6.0Hz,

4H), 1.26(s, 3H). ¹³C-NMR(100 MHz, CD₃OD) 120.1, 108.1,

107.3, 101.3, 46.4, 34.8, 30.9. LC-MS(M + 1)⁺ 292.1.

1-(fluoromethyl)-4-((methylamino)methyl)-4-(naphthalen-2-

yl)cyclohexanol (243)



H	H	CH₃	CH₂F	OH	A

Prepared from: 217

¹H-NMR(400 MHz, CD₃OD) 8.50(brs, 1H), 7.99-7.87(m, 4H), 7.63

(d, J=8.0Hz, 1H), 7.54-7.50(m, 2H), 4.03(s, 1H), 3.91(s, 1H), 3.19

(s, 2H), 2.54(s, 3H), 2.46(d, J=13.5Hz, 2H), 2.06(t, J=13.5Hz,

2H), 1.62(d, J=13.5Hz, 2H), 1.41(t, J=13.5Hz, 2H). ¹³C-NMR(100

MHz, CD₃OD) 136.0, 133.9, 132.9, 129.4, 128.0, 127.3, 127.3, 126.4,

124.2, 90.6, 88.9, 69.3, 62.4, 41.1, 34.1, 28.2, 28.1, 27.8. LC-MS

(M + 1)⁺ 302.3.

4-((dimethylamino)methyl)-1-(fluoromethyl)-4-(naphthalen-2-

yl)cyclohexanol (244)



H	CH₃	CH₃	CH₂F	OH	F

Prepared from: 217

¹H-NMR(400 MHz, CDCl₃) 7.81(m, 4H), 7.55(dd, J=8.5, 1.5Hz,

1H), 7.47-7.44(m, 2H), 4.08(s, 1H), 3.96(s, 1H), 2.43(s, 2H), 2.34(d,

J=13.5Hz, 2H), 2.01(dt, J=13.5, 3.0Hz, 2H), 1.98(s, 6H), 1.61(d,

J=14.0Hz, 2H), 1.38(dt, J=13.5, 3.0Hz, 2H). ¹³C-NMR(100 MHz,

CDCl₃) 144.1, 133.7, 132.0, 128.2, 128.0, 127.6, 126.6, 126.0, 126.9,

125.7, 91.7, 90.0, 74.3, 48.8, 44.0, 29.2, 29.1, 28.4. LC-MS(M + 1)⁺

316.2.

1-(fluoromethyl)-4-((methylamino)methyl)-4-(naphthalen-2-

yl)cyclohexanol (245)



H	H	CH₃	OH	CH₂F	A

Prepared from: 218

¹H-NMR(400 MHz, CD₃OD) 7.99-7.87(m, 4H), 7.64(dd, J=8.5, 2.0

Hz, 1H), 7.53-7.51(m, 2H), 4.39(s, 1H), 4.27(s, 1H), 3.46(s, 2H),

2.58(s, 3H), 2.37-2.29(m, 2H), 2.00(m, 2H), 1.86-1.79(m, 2H), 1.65

(m, 2H). ¹³C-NMR(100 MHz, CD₃OD) 129.2, 128.1, 127.3, 126.4,

126.3, 125.8, 123.5, 34.1, 28.9, 28.4, 28.3. LC-MS(M + 1)⁺ 302.3.

4-((dimethylamino)methyl)-1-(fluoromethyl)-4-(naphthalen-2-

yl)cyclohexanol (246)



H	CH₃	CH₃	OH	CH₂F	F

Prepared from: 218

¹H-NMR(400 MHz, CDCl₃) 7.81(m, 4H), 7.54(dd, J=9.0, 1.5Hz,

1H), 7.47-7.42(m, 2H), 4.45(s, 1H), 4.33(s, 1H), 2.54(s, 2H), 2.25-2.20

(m, 2H), 1.96(s, 6H), 1.96-1.91(m, 2H), 1.78-1.63(m, 4H). ¹³C-

NMR(100 MHz, CDCl₃) 133.7, 132.0, 128.3, 127.9, 127.5, 126.0,

125.7, 125.6, 125.3, 89.7, 88.0, 48.5, 29.8, 29.7. LC-MS(M + 1)⁺ 316.4.

1-methyl-4-((methylamino)methyl)-4-(4-

(trifluoromethoxy)phenyl)cyclohexanol (247)



H	H	CH₃	CH₃	OH	F2

Prepared from: 219

¹H-NMR(400 MHz, CD₃OD) 8.34(brs, 2H), 7.58(d, J=8.5Hz, 2H),

7.36(d, J=8.5Hz, 2H), 3.10(s, 2H), 2.58(s, 3H), 2.20(d, J=13.0Hz,

2H), 1.98(dt, J=13.5, 3.0Hz, 2H), 1.58(d, J=13.5Hz, 2H), 1.29(dt,

J=13.5, 3.0Hz, 2H), 1.05(s, 3H). ¹³C-NMR(100 MHz, CD₃OD)

129.4, 127.3, 121.6, 67.8, 62.2, 40.5, 34.1, 33.9, 29.7, 28.7. LC-MS

(M + 1)⁺ 318.2.

4-((dimethylamino)methyl)-1-methyl-4-(4-

(trifluoromethoxy)phenyl)cyclohexanol (248)



H	CH₃	CH₃	CH₃	OH	C

Prepared from: 219

¹H-NMR(400 MHz, CDCl₃) 7.39(d, 8.5Hz, 2H), 7.15(d, J=8.5Hz,

2H), 2.30(s, 2H), 2.09(d, J=13.5Hz, 2H), 1.97(s, 6H), 1.88(dt,

J=13.5, 3.0Hz, 2H), 1.52(d, J=13.0Hz, 2H), 1.34(dt, J=13.5, 3.5Hz,

2H), 1.11(s, 3H). ¹³C-NMR(100 MHz, CDCl₃) 129.0, 120.6, 48.7,

35.2, 29.4. LC-MS(M + 1)⁺ 332.3.

4-((methylamino)methyl)-4-(4-

(trifluoromethoxy)phenyl)cyclohexanol (249)



H	H	CH₃	H	OH	F2

Prepared from: 220

LC-MS(15 minute method) 6.57 min, (M + 1)+ 304.2 @ 6.75 min; 1H-

NMR(400 MHz, CD₃OD) 8.42(brs, 1H), 7.58(d, J=8.5Hz, 2H), 7.34

(d, J=8.5Hz, 2H), 3.78-3.75(m, 1H), 3.24(s, 2H), 2.59(s, 6H),

2.09-2.01(m, 4H), 1.65-1.62(m, 4H). 13C-NMR(100 MHz, CD₃OD),

167.9, 128.9, 121.5, 66.1, 59.5, 40.2, 34.1, 28.9.

4-((dimethylamino)methyl)-4-(4-

(trifluoromethoxy)phenyl)cyclohexanol (250)



H	CH₃	CH₃	H	OH	C

Prepared from: 220

¹H-NMR(400 MHz, CDCl₃) 7.38(d, J=9.0Hz, 2H), 7.14(d, J=9.0Hz,

2H), 3.81-3.78(m, 1H), 2.42(s, 2H), 2.10-2.03(m, 2H), 1.96(s,

6H), 1.86-1.78(m, 2H), 1.70-1.57(m, 4H). ¹³C-NMR(100 MHz,

CDCl₃) 147.4, 128.5, 122.0, 120.6, 94.6, 70.6, 68.2, 48.5, 42.2, 30.3,

30.1, 29.6. LC-MS(M + 1)⁺ 318.3.

1-(4,4-difluoro-1-(naphthalen-2-yl)cyclohexyl)-N-

methylmethanamine (251)



H	H	CH₃	F	F	F2

Prepared from: 221

¹H-NMR(400 MHz, CDCl₃) 7.89-7.79(m, 4H), 7.53-7.48(m, 3H),

2.70(s, 2H), 2.51(d, J=13.0Hz, 2H), 2.26(s, 3H), 2.05-1.91(m, 4H),

1.87-1.77(m, 2H). ¹³C-NMR(100 MHz, CDCl₃) 139.9, 133.6, 132.2,

128.9, 128.2, 127.6, 126.5, 126.3, 126.2, 124.6, 64.1, 42.0, 37.4, 31.0,

30.9, 30.8, 30.7, 30.5. LC-MS(M + 1)⁺ 290.3.

1-(4,4-difluoro-1-(naphthalen-2-yl)cyclohexyl)-N,N-

dimethylmethanamine (252)



H	CH₃	CH₃	F	F	F

Prepared from: 221

¹H-NMR(400 MHz, CDCl₃) 7.82(m, 4H), 7.53(d, J=8.5Hz, 1H),

7.47(m, 2H), 2.45(apd, J=10.0Hz, 2H), 1.97(s, 2H), 2.05-1.89(m,

4H), 1.97(s, 6H), 1.85-1.74(m, 2H). ¹³C-NMR(100 MHz, CDCl₃)

128.3, 128.2, 127.6, 126.3, 126.2, 125.9, 125.3, 72.4, 48.6, 31.0, 30.7,

30.5, 30.4. LC-MS(M + 1)⁺ 304.2.

3,4-Dichlorophenyl-Cyclohexylamine Analogs

TABLE 7


Summary of 3,4-Dichlorophenyl-Cyclohexylamine Analogs

				General
R^b	R^c	R³	R⁴	Procedure

(1-(3,4-dichlorophenyl)-4-fluorocyclohexyl)methanamine (253)

F

H

W, BB, E

¹H NMR(400 MHz, CDCl₃) δ 8.02(broad, 1H), 7.46(d, J=8.0Hz, 1H),

7.43(s, 1H), 7.19(d, J=8.0Hz, 1H), 4.62(m, 1H), 2.83(s, 2H), 2.26(m,

2H), 1.90(m, 2H), 1.58(m, 4H); ¹³C NMR(100 MHz, CDCl₃), δ 141.52,

133.57, 131.80, 131.39, 129.57, 126.66, 91.08, 89.37, 49.49, 40.58,

30.02, 29.94, 27.92, 27.72; ESI MS m/z 276.

1-(1-(3,4-dichlorophenyl)-4-fluorocyclohexyl)-N,N-

dimethylmethanamine (254)

F

H

CH₃

W, BB, E, D

Prepared from 253

¹H NMR(400 MHz, CDCl₃) δ 8.31(broad, 1H), 7.47(d, J=2.4Hz, 1H),

7.44(d, J=8.4Hz, 1H), 7.26(dd, J=8.14, 2.4Hz, 1H), 4.62(m, 1H), 2.68

(s, 2H), 2.26(m, 2H), 2.22(s, 6H), 1.95(m, 2H), 1.70(t, J=13.6Hz,

1H), 1.57(m, 2H); ¹³C NMR(100 MHz, CDCl₃) δ 166.24, 144.8, 133.23,

130.88, 129.44, 126.88, 91.90, 90.19, 70.43, 47.54, 41.98, 30.83, 30.74,

28.22, 28.02; ESI MS m/z 304.

(1-(3,4-dichlorophenyl)-4-methoxycyclohexyl)methanamine (255)

H

OCH₃

H

W, EE, E

¹H NMR(400 MHz, CD₃OD) δ 7.46(m, 2H), 7.22(d, J=7.6Hz, 1H), 6.69

(broad, 2H), 3.31(s, 3H), 2.80(s, 2H), 1.91(m, 4H), 1.72(m, 1H), 1.40

(m, 2H); ¹³C NMR(100 MHz, CDCl₃) δ 142.92, 133.53, 131.78, 131.26,

129.46, 126.87, 75.16, 55.65, 50.76, 40.98, 28.54, 25.77;

ESI MS m/z 288.

1-(1-(3,4-dichlorophenyl)-4-methoxycyclohexyl)-N,N-

dimethylmethanamine (256)

H

OCH₃

CH₃

W, EE, E, D

Prepared from 255

¹H NMR(400 MHz, CD₃OD) 7.46(d, J=2.8Hz, 1H), 7.37(d, J=8.4Hz,

1H), 7.23(dd, J=2.0, 8.4Hz, 1H), 3.32(s, 3H), 3.23(m, 1H), 2.34(s, 2H),

1.87(s, 6H), 1.84(m, 2H), 1.78(m, 2H), 1.56(m, 2H), 1.48(m, 2H); ¹³C

NMR(100 MHz, CD₃OD) 141.57, 133.26, 131.56, 131.34, 130.02,

128.66, 69.25, 50.70, 47.73, 40.57, 30.79, 30.31; ESI MS m/z 316.0.

(1-(3,4-dichlorophenyl)-4-methoxycyclohexyl)methanamine (257)

OCH₃

H

W, X, EE, E

¹H NMR(400 MHz, CD₃OD) δ 7.44(m, 2H), 7.20(d, J=7.6Hz, 1H), 6.68

(broad, 2H), 3.29(s, 3H), 2.82(s, 1H), 1.90(m, 4H), 1.73(m, 1H), 1.43

(m, 2H); ¹³C NMR(100 MHz, CDCl₃), δ 141.92, 133.33, 131.38, 131.14,

129.75, 126.99, 75.06, 55.90, 50.95, 41.23, 28.43, 25.93;

ESI MS m/z 288.

1-(1-(3,4-dichlorophenyl)-4-methoxycyclohexyl)-N,N-

dimethylmethanamine (258)

OCH₃	H	CH₃	CH₃	W, X, EE, E,
				D

Prepared from 257

¹H NMR(400 MHz, CD₃OD) 7.45(d, J=2.4Hz, 1H), 7.36(d, J=8.8Hz,

1H), 7.21(dd, J=2.4, 8.8Hz, 1H), 3.33(s, 3H), 3.25(m, 1H), 2.37(s, 2H),

1.96(s, 6H), 1.91(m, 2H), 1.80(m, 2H), 1.66(m, 2H), 1.54(m, 2H); ¹³C

NMR(100 MHz, CD₃OD) 141.28, 133.16, 131.23, 131.24, 129.94,

127.56, 69.15, 50.80, 47.64, 40.48, 30.89, 30.26; ESI MS m/z 316.0.

1-(1-(3,4-dichlorophenyl)-4-methoxycyclohexyl)-N-methylmethanamine

(259)

OCH₃	H	CH₃	H	W, X, EE, E,
				A

Prepared from 257

¹H NMR(400 MHz, CDCl₃) δ 7.42(d, J=2.4Hz, 1H), 7.40(d, J=8.4Hz,

1H), 7.19(dd, J=2.4, 8.4Hz, 1H), 3.28(s, 3H), 3.25(m, 1H), 2.56(s, 2H),

2.32(m, 1H), 2.29(s, 3H), 1.88(m, 2H), 1.56(m, 1H), 1.24(m, 2H); ¹³C

NMR(100 MHz, CDCl₃) δ 144.76, 132.95, 132.95, 130.64, 130.29,

129.59, 126.92, 78.96, 64.90, 55.79, 42.43, 37.48, 31.88, 29.93, 27.58;

ESI MS m/z 302.1.

(1-(3,4-dichlorophenyl)-4-fluorocyclohexyl)methanamine (260)

H

F

H

W, X, BB, E

¹H NMR(400 MHz, CD₃OD) δ 8.4(broad, 1H), 7.65(d, J=2.0Hz, 1H),

7.59(d, J=8.4Hz, 1H), 7.42(dd, J=2.0, 8.4Hz, 1H), 4.67(d, J=48.4Hz,

1H), 3.05(s, 2H), 2.18(m, 2H), 1.90(m, 4H), 1.51(m, 2H), 1.49(m, 2H);

¹³C NMR(100 MHz, CD₃OD) δ 140.69, 133.19, 131.44, 131.24, 129.78,

127.43, 140.00, 88.69, 87.02, 50.75, 40.48, 27.37, 26.82, 26.61;

ESI MS m/z 276.0.

1-(1-(3,4-dichlorophenyl)-4-fluorocyclohexyl)-N,N-

dimethylmethanamine (261)

H	F	CH₃	CH₃	W, X, BB, E,
				D

Prepared from 260

¹H NMR(400 MHz, CD₃OD) 7.47(d, J=2.4Hz, 1H), 7.44(d, J=8.8Hz,

1H), 7.26(dd, J=2.4, 8.8Hz, 1H), 4.60(m, 1H), 2.69(s, 2H), 2.26(m,

2H), 2.22(s, 6H), 1.95(m, 2H), 1.70(m, 2H), 1.56(m, 2H); ¹³C NMR

(100 MHz, CD₃OD) 141.28, 133.22, 131.24, 130.87, 129.44, 126.88,

91.90, 90.20, 70.43, 47.54, 41.98, 30.83, 30.74, 28.22, 28.03;

ESI MS m/z 274.0.

4-(aminomethyl)-4-(3,4-dichlorophenyl)cyclohexanol (262)

OH

H

W, X, E

¹H NMR(400 MHz, CD₃OD) 7.63(d, J=2.4Hz, 1H), 7.59(d, J=8.8Hz,

1H), 7.40(dd, J=2.4, 8.8Hz, 1H), 3.66(m, 1H), 3.02(s, 2H), 2.40(m,

2H), 1.86(m, 2H), 1.62(m, 2H), 1.24(m, 2H); ¹³C NMR(100 MHz,

CD₃OD) 141.28, 133.16, 131.23, 131.24, 129.94, 127.56, 69.15, 50.80,

47.64, 40.48, 30.89, 30.26; ESI MS m/z 274.0.

4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)cyclohexanol (263)

OH

H

CH₃

W, X, E, D

Prepared from 262

¹H NMR(400 MHz, CD₃OD) 7.64(d, J=2.4Hz, 1H), 7.55(d, J=8.8Hz,

1H), 7.36(dd, J=2.4, 8.8Hz, 1H), 3.55(m, 1H), 3.01(s, 2H), 2.24(m,

2H), 2.23(s, 6H), 1.79(m, 2H), 1.67(m, 2H), 1.33(m, 2H); ¹³C NMR

(100 MHz, CD₃OD) 141.11, 133.06, 131.33, 131.31, 129.88, 127.76,

69.35, 51.82, 47.64, 45.78, 40.32, 30.77, 29.16;

ESI MS m/z 302.0.

1-(1-(3,4-dichlorophenyl)-4-fluorocyclohexyl)-N-methylmethanamine

(264)

F

H

CH₃

H

W, BB, E, A

Prepared from 253

¹H NMR(400 MHz, CDCl₃) δ 7.46(d, J=2.0Hz, 1H), 7.44(d, J=8.4Hz,

1H), 7.23(dd, J=2.0, 8.4Hz, 1H), 4.47(d, J=48.8Hz, 1H), 2.71(s, 2H),

2.34(s, 3H), 2.28(m, 2H), 1.94(m, 2H), 1.59(m, 4H); ¹³C NMR(100

MHz, CDCl₃), δ 144.46, 133.02, 130.69, 130.26, 129.47, 126.83, 90.63,

88.41, 64.91, 48.67, 42.24, 37.56, 29.97, 28.75, 28.92, 28.39, 27.71,

27.41; ESI MS m/z 290.0.

(1-(3,4-dichlorophenyl)-4-phenoxycyclohexyl)methanamine (265)

OPh

H

W, X, E

¹H NMR(400 MHz, CD₃OD) 8.40(broad, 1H), 7.66(d, J=2.0Hz, 1H),

7.60(d, J=8.8Hz, 1H), 7.42(dd, J=2.0, 8.8Hz, 1H), 7.22(m, 2H), 6.84

(m, 3H), 4.43(m, 1H), 3.31(s, 2H), 2.40(m, 2H), 2.01(m, 2H), 1.75(m,

2H), 1.49(m, 2H); ¹³C NMR(100 MHz, CD₃OD) 157.57, 141.57, 133.23,

131.37, 131.27, 129.69, 129.32, 127.32, 120.79, 115.94, 74.26, 49.93,

48.52, 48.44, 40.45, 30.31, 27.01; ESI MS m/z 336.1.

1-(1-(3,4-dichlorophenyl)-4-phenoxycyclohexyl)-N,N-

dimethylmethanamine (266)

Oph

H

CH₃

W, X, E, F

Prepared from 265

¹H NMR(400 MHz, CD₃OD) 7.46(d, J=2.0Hz, 1H), 7.40(d, J=8.4Hz,

1H), 7.24(m, 3H), 6.90(m, 1H), 6.84(m, 2H), 4.25(m, 1H), 2.36(s, 2H),

2.30(m, 2H), 2.08(s, 6H), 2.0(m, 2H), 1.70(m, 2H), 1.48(m, 2H); ¹³C

NMR(100 MHz, CD₃OD) 157.57, 141.527, 133.10, 132.68, 130.45,

129.98, 129.67, 127.16, 120.92, 116.19, 75.87 72.52, 49.93, 48.56,

48.44, 40.45, 31.40, 27.82; ESI MS m/z 378.0.

(1-(3,4-dichlorophenyl)-4,4-difluorocyclohexyl)methanamine (267)

F

H

CC, E

¹H NMR(400 MHz, CD₃OD) δ 8.4(broad, 1H), 7.67(d, J=2.4Hz, 1H),

7.62(d, J=8.4Hz, 1H), 7.43(dd, J=8.4, 2.4Hz, 1H), 3.10(s, 2H), 2.40

(m, 2H), 2.20(m, 2H), 1.90(m, 2H), 1.70(m, 2H); ¹³C NMR(100 MHz,

CD₃OD) δ 133.43, 131.82, 137.41, 129.57, 127.20, 122.35, 49.58, 47.60,

40.18, 30.05, 29.76, 29.51, 29.45; ESI MS m/z 294.0.

1-(1-(3,4-dichlorophenyl)-4,4-difluorocyclohexyl)-N-

methylmethanamine (268)

F

CH₃

H

CC, E, F

Prepared from 267 to give 268 and 269, which were separated by silica

gel column chromatography(ethyl acetate/hexane/DEA = 1:4:0.1).

¹H NMR(400 MHz, CD₃OD) δ 8.5(broad, 1H), 7.68(d, J=2.4Hz, 1H),

7.62(d, J=8.4Hz, 1H), 7.44(dd, J=8.4, 2.4Hz, 1H), 3.20(s, 2H), 2.58(s,

3H), 2.40(m, 2H), 2.05(m, 2H), 1.92(m, 2H), 1.70(m, 2H); ¹³C NMR

(100 MHz, CD₃OD) δ 139.86, 133.53, 131.96, 131.30, 129.54, 127.16,

122.46, 59.57, 48.03, 40.24, 34.09, 29.94, 29.80, 29.70, 29.45;

ESI MS m/z 307.9.

1-(1-(3,4-dichlorophenyl)-4,4-difluorocyclohexyl)-N,N-

dimethylmethanamine (269)

F

CH₃

CC, E, F

Prepared from 267 to give 268 and 269, which were separated by silica gel

column chromatography(ethyl acetate/hexane/DEA = 1:4:0.1)

¹H NMR(400 MHz, CD₃OD) δ 7.58(d, J=2.4Hz, 1H), 7.50(d, J=8.4Hz,

1H), 7.37(dd, J=8.4, 2.4Hz, 1H), 2.43(s, 2H), 2.30(m, 2H), 2.01(s,

6H), 1.98(m, 2H), 1.82(m, 2H), 1.65(m, 2H); ¹³C NMR(100 MHz,

CD₃OD) δ 139.86, 133.53, 131.96, 131.30, 129.54, 127.16, 122.46,

59.57, 48.03, 40.24, 34.09, 30.41, 30.17, 29.90, 29.81;

ESI MS m/z 322.0.

1-(8-(3,4-dichlorophenyl)-1,4-dioxaspiro[4.5]decan-8-yl)-N-

methylmethanamine (270)



CH₃	H	FF, E, F

270 and 271 were separated by silica gel column chromatography(ethyl

acetate/hexane/DEA = 1:4:0.1).

¹H NMR(400 MHz, CD₃Cl) δ 7.42(d, J=2.4Hz, 1H), 7.38(d, J=8.8Hz,

1H), 7.19(dd, J=2.4, 8.8Hz, 1H), 3.90(m, 4H), 2.59(s, 2H), 2.27(s, 6H),

2.18(m, 2H), 1.82(m, 2H), 1.62(m, 2H), 1.46(m, 2H); ¹³C NMR(100

MHz, CD₃Cl) δ 132.84, 130.54, 130.31, 129.39, 126.72, 109.02, 64.48,

64.47, 41.91, 37.57, 31.74, 31.35; ESI MS m/z 330.1.

1-(8-(3,4-dichlorophenyl)-1,4-dioxaspiro[4.5]decan-8-yl)-N,N-

dimethylmethanamine (271)



CH₃	CH₃	FF, E, F

¹H NMR(400 MHz, CD₃Cl) δ 7.44(d, J=2.4Hz, 1H), 7.36(d, J=8.8Hz,

1H), 7.21(dd, J=2.4, 8.8Hz, 1H), 3.91(m, 4H), 2.32(s, 2H), 2.13(m,

2H), 1.98(s, 3H), 1.80(m, 2H), 1.62(m, 2H), 1.42(m, 2H); ¹³C NMR

(100 MHz, CD₃Cl) δ 145.35, 132.38, 130.14, 130.15, 129.62, 129.71,

127.11, 72.01, 64.48, 64.47, 48.58, 42.87, 31.35; ESI MS m/z 344.1.

4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-methylcyclohexanol (272)

OH

CH₃

H

Y, E

Stereoisomers(cis- and trans-) were separated after methylation(General

Procedure S) by silica gel column chromatography(ethyl

acetate/hexane = 1:15 to 1:7) and subsequent transformations were

performed using one stereoisomer, respectively.

¹H NMR(400 MHz, CD₃OD) δ 8.22(broad, 1H), 7.33(d, J=2.0Hz, 1H),

7.32(d, J=8.8Hz, 1H), 7.10(dd, J=8.8, 2.0Hz, 1H), 2.85(s, 2H), 1.92

(m, 2H), 1.51(m, 2H), 1.40(m, 4H), 1.10(s, 3H); ¹³C NMR(100 MHz,

CD₃OD), δ 133.18, 131.29, 130.92, 129.00, 126.27, 68.63, 40.14, 34.52,

29.62, 28.171; ESI MS m/z 288.2.

4-(3,4-dichlorophenyl)-1-methyl-4-((methylamino)methyl)cyclohexanol

(273)

OH

CH₃

H

Y, E, F

Prepared from 272 to give 273 and 274, which were separated by silica

gel column chromatography(ethyl acetate/hexane/DEA = 1:4:0.1).

¹H NMR(400 MHz, CD₃OD) δ 7.44(d, J=2.0Hz, 1H), 7.39(d, J=8.8Hz,

1H), 7.21(dd, J=2.0, 8.8Hz, 1H), 2.65(s, 2H), 2.30(s, 3H), 2.04(m,

2H), 1.74(m, 2H), 1.62(m, 2H), 1.50(m, 2H), 1.28(s, 3H); ¹³C NMR

(100 MHz, CD₃OD) δ 132.79, 130.48, 130.25, 129.01, 126.29,

69.90, 60.98, 41.42, 37.57, 35.66, 30.60, 29.92, 29.17;

ESI MS m/z 302.2.

4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-

methylcyclohexanol (274)

OH

CH₃

Y, E, F

Prepared from 272 to give 273 and 274 which were separated by silica gel

column chromatography(ethyl acetate/hexane/DEA = 1:4:0.1).

¹H NMR(400 MHz, CD₃OD) δ 7.45(d, J=2.4Hz, 1H), 7.36(d, J=8.8Hz,

1H), 7.22(dd, J=2.4, 8.8Hz, 1H), 2.37(m, 2H), 2.20(m, 2H), 198(m,

6H), 1.76(m, 2H), 1.58(m, 2H), 1.48(m, 2H), 1.28(s, 3H); ¹³C NMR

(100 MHz, CD₃OD) δ 132.32, 130.07, 129.75, 129.38, 126.74, 70.25,

48.53, 35.94, 30.546, 28.49; ESI MS m/z 316.2.

4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-methylcyclohexanol (275)

CH₃

OH

H

Y, E

Stereoisomers(cis- and trans-) were separated after methylation(General

Procedure S) by silica gel column chromatography(ethyl

acetate/hexane = 1:15 to 1:7) and subsequent transformations were

performed using one stereoisomer, respectively.

¹H NMR(400 MHz, CD₃OD) δ 8.5(broad, 1H), 7.02(s, 1H), 7.57(d,

J=8.8Hz, 1H), 7.40(d, J=8.8Hz, 1H), 2.98(s, 2H), 2.18(m, 2H), 1.94

(m, 2H), 1.58(m, 2H), 1.28(m, 2H), 1.07(s, 3H); ¹³C NMR(100 MHz,

CD₃OD) δ 140.93, 133.07, 131.19, 131.12, 129.92, 127.61, 67.90, 51.74,

40.64, 34.05, 29.66, 28.60, 28.37; ESI MS m/z 288.2.

4-(3,4-dichlorophenyl)-1-methyl-4-((methylamino)methyl)cyclohexanol

(276)

CH₃

OH

CH₃

H

Y, E, F

Prepared from 275(General Procedure F) to give 276 and 277, which were

separated by silica gel column chromatography(ethyl acetate/hexane/

DEA = 1:4:0.1).

¹H NMR(400 MHz, CD₃OD) δ 7.43(d, J=2.0Hz, 1H), 7.40(d, J=8.8Hz,

1H), 7.20(dd, J=8.8, 2.0Hz, 1H), 2.54(s, 2H), 2.27(s, 3H), 2.08(m, 2H),

1.90(m, 2H), 1.52(m, 2H), 1.30(m, 2H), 1.11(s, 3H); ¹³C NMR(100

MHz, CD₃OD) δ 132.86, 130.56, 130.23, 129.63, 127.06, 69.68, 69.94,

42.40, 37.56, 35.16, 31.05, 29.82; ESI MS m/z = 302.2.

4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-

methylcyclohexanol (277)

CH₃

OH

CH₃

Y, E, F

Prepared from 275(General Procedure F) to give 276 and 277, which were

separated by silica gel column chromatography(ethyl acetate/hexane/

DEA = 1:4:0.1).

¹H NMR(400 MHz, CD₃OD) δ 7.44(d, J=2.4Hz, 1H), 7.36(d, J=8.8Hz,

1H), 7.21(dd, J=2.4, 8.8Hz, 1H), 7.21(dd, J=2.4, 8.8Hz, 1H), 2.28(s,

2H), 2.04(m, 2H), 1.99(s, 6H), 1.85(m, 2H), 1.51(m, 2H), 1.30(m, 2H),

1.09(s, 3H); ¹³C NMR(100 MHz, CD₃OD) δ 132.37, 130.14, 129.92,

129.73, 127.39, 73.73, 69.65, 48.72, 43.45, 35.15, 31.16, 29.32;

ESI MS m/z = 316.2.

4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-ethylcyclohexanol (278)

OH

ethyl

H

Y, E

Stereoisomers(cis- and trans-) were separated after alkylation(General

Procedure S) by silica gel column chromatography(ethyl

acetate/hexane = 1:15 to 1:7) and subsequent transformations were

performed using one stereoisomer, respectively.

¹H NMR(400 MHz, CD₃Cl) δ 7.40(d, J=2.4Hz, 1H), 7.39(d, J=8.4Hz,

1H), 7.17(dd, J=2.4, 8.4Hz, 1H), 2.77(s, 2H), 2.12-1.94(m, 2H),

1.90-1.74(m, 2H), 1.72-1.64(m, 1H), 1.61-1.50(m, 3H),

1.48-1.38(m, 1H), 0.89(t, J=8.0Hz, 3H); ¹³C NMR(100 MHz, CD₃Cl)

δ 146.40, 132.79, 130.54, 130.35, 129.14, 126.38, 71.21, 49.55, 33.84,

32.94, 29.34, 7.51; ESI MS m/z 302.2.

4-(3,4-dichlorophenyl)-1-ethyl-4-((methylamino)methyl)cyclohexanol

(279)

OH

ethyl

CH₃

H

Y, E, F

Prepared from 278(General Procedure F) to give 279 and 280, which were

separated by silica gel column chromatography(ethyl acetate/hexane/

DEA = 1:4:0.1).

¹H NMR(400 MHz, CD₃Cl) δ 7.64(d, J=2.4Hz, 1H), 7.58(d, J=8.4Hz,

1H), 7.41(dd, J=2.4, 8.4Hz, 1H), 3.30(s, 3H), 2.58(s, 2H), 2.16-2.09(m,

2H), 1.84-1.76(m, 2H), 1.68-1.50(m, 6H), 0.94(t, J=7.6Hz, 3H); ¹³C

NMR(100 MHz, CD₃Cl) δ 133.02, 131.27, 131.08, 130.96, 128.96,

126.49, 69.96, 39.96, 34.20, 31.90, 29.45, 6.33; ESI MS m/z 316.1.

4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-ethylcyclohexanol

(280)

OH

ethyl

CH₃

Y, E, F

Prepared from 278(General Procedure F) to give 279 and 280, which were

separated by silica gel column chromatography(ethyl acetate/hexane/

DEA = 1:4:0.1).

¹H NMR(400 MHz, CD₃OD) δ 7.60(d, J=2.4Hz, 1H), 7.49(d, J=8.8Hz,

1H), 7.40(dd, J=2.4, 8.8Hz, 1H), 2.83(s, 2H), 2.16(s, 6H), 2.12-2.00

(m, 2H), 1.86-1.74(m, 2H), 1.64-1.46(m, 6H), 0.92(t, J=7.2Hz, 3H);

¹³C NMR(100 MHz, CD₃OD) 132.20, 130.26, 130.25, 129.94, 129.17,

126.84, 70.45, 46.79, 41.18, 32.33, 29.86, 6.40; ESI MS m/z 330.0.

4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-ethylcyclohexanol (281)

ethyl

OH

H

Y, E

Stereoisomers(cis- and trans-) were separated after alkylation(General

Procedure S) by silica gel column chromatography(ethyl

acetate/hexane = 1:15 to 1:7) and subsequent transformations were

performed using one stereoisomer, respectively.

¹H NMR(400 MHz, CD₃OD) δ 7.63(d, J=2.0Hz, 1H), 7.58(d, J=8.4Hz,

1H), 7.40(dt, J=2.0, 8.4Hz, 1H), 2.98(s, 2H), 2.18(d, J=13.2Hz, 2H),

1.90(dt, J=2.8, 13.6Hz, 2H), 1.36(d, J=13.2Hz, 2H), 1.32(q, J=7.6Hz,

2H), 1.21(td, J=2.8, 13.6Hz, 2H), 0.81(t, J=7.6Hz, 3H); ¹³C NMR(100

MHz, CD₃OD) δ 140.68, 133.11, 131.27, 131.15, 129.95, 127.63, 69.95,

51.88, 40.89, 35.68, 31.72, 28.18; ESI MS m/z 284.1.

4-(3,4-dichlorophenyl)-1-ethyl-4-((methylamino)methyl)cyclohexanol

(282)

ethyl

OH

CH₃

H

Y, E, F

Prepared from 281(General Procedure F) to give 282 and 283, which were

separated by silica gel column chromatography(ethyl acetate/hexane/

DEA = 1:4:0.1).

¹H NMR(400 MHz, CD₃Cl) δ 7.63(d, J=2.0Hz, 1H), 7.56(d, J=8.4Hz,

1H), 7.43(dd, J=2.0, 8.4Hz, 1H), 3.31(s, 3H), 2.56(s, 2H), 2.14-2.10(m,

2H), 1.82-1.78(m, 2H), 1.66-1.51(m, 6H), 0.93(t, J=7.6Hz, 3H); ¹³C

NMR(100 MHz, CD₃Cl) δ 133.22, 131.37, 131.28, 131.02, 129.10,

126.51, 69.87, 39.93, 34.22, 32.40, 29.25; ESI MS m/z 316.1.

4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-ethylcyclohexanol

(283)

ethyl

OH

CH₃

Y, E, F

Prepared from 281(General Procedure F) to give 282 and 283, which were

separated by silica gel column chromatography(ethyl acetate/hexane/

DEA = 1:4:0.1).

¹H NMR(400 MHz, CD₃OD) δ 7.54(s, 1H), 7.45(d, J=8.4Hz, 1H), 7.35

(d, J=8.4Hz, 1H), 2.37(s, 2H), 2.09(d, J=13.6Hz, 1H), 1.98(s, 6H),

1.86(t, J=14.0Hz, 1H), 1.50(d, J=14.0Hz, 1H), 1.28(q, J=6.8Hz, 2H),

1.20(t, J=14.0Hz, 1H), 0.79(t, J=6.8Hz, 3H); ¹³C NMR(100 MHz,

CD₃OD) δ 145.17, 131.92, 130.03, 129.99, 129.38, 127.79, 73.89, 70.62,

47.57, 43.26, 35.75, 32.09, 28.96; ESI MS m/z 332.1.

4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-propylcyclohexanol (284)

n-	OH	H	H	Y, E
propyl

¹H NMR(400 MHz, CD₃OD) δ 7.63(s, 1H), 7.56(d, J=8.0Hz, 1H), 7.41

(d, J=8.0Hz, 1H), 3.30(s, 2H), 2.15(m, 2H), 1.84(m, 2H), 1.64(m,

2H), 1.54(m, 2H), 1.42(m, 2H), 0.95(t, J=6.8Hz, 3H); ¹³C NMR(100

MHz, CD₃OD) δ 132.89, 131.13, 130.99, 129.09, 126.67, 70.03, 43.61,

39.76, 32.37, 29.48, 29.18, 16.04, 13.94; ESI MS m/z 316.4.

4-(3,4-dichlorophenyl)-4-((methylamino)methyl)-1-propylcyclohexanol

(285)

n-	OH	CH₃	H	Y, E, F
propyl

Prepared from 284(General Procedure F) to give 285 and 286, which were

separated by silica gel column chromatography(ethyl acetate/hexane/

DEA = 1:4:0.1).

¹H NMR(400 MHz, CD₃OD) δ 8.38(broad, 1H), 7.64(d, J=2.0Hz, 1H),

7.62(d, J=8.8Hz, 1H), 7.41(dd, J=2.0, 8.8Hz, 1H), 3.34(s, 2H), 2.60(s,

3H), 2.16(m, 2H), 1.82(m, 2H), 1.64(m, 2H), 1.52(m, 2H), 1.42(m,

2H), 0.95(t, J=6.8Hz, 1H); ¹³C NMR(100 MHz, CD₃OD) δ 133.03,

131.33, 131.11, 130.99, 129.06, 126.57, 69.94, 39.87, 34.01, 32.33,

29.45, 29.14, 16.01, 15.96, 13.88; ESI MS m/z 330.2.

4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-

propylcyclohexanol (286)

n-	OH	CH₃	CH₃	Y, E, F
propyl

Prepared from 284(General Procedure F) to give 285 and 286, which were

separated by silica gel column chromatography(ethyl acetate/hexane/

DEA = 1:4:0.1).

¹H NMR(400 MHz, CD₃OD) δ 7.45(d, J=2.0Hz, 1H), 7.36(d, J=8.8Hz,

1H), 7.21(dd, J=2.0, 8.8Hz, 1H), 2.40(s, 2H), 2.02-1.94(m, 2H), 1.96

(s, 6H), 1.76(m, 2H), 1.60(m, 2H), 1.48(m, 2H), 1.40(m, 2H), 0.95(t,

J=6.8Hz, 1H); ¹³C NMR(100 MHz, CD₃OD) δ 132.25, 130.03, 129.69,

129.21, 126.58, 71.52, 48.46, 43.59, 33.27, 30.08, 16.44, 14.92;

ESI MS m/z 344.2.

cis-4-(3,4-dichlorophenyl)-4-((methylamino)methyl)cyclohexanol (287)

299 to 287
The title compound was prepared from (1s,4s)-4-(aminomethyl)-4-(3,4-dichlorophenyl)cyclohexanol 299 (63 mg, 0.230 mmol) according to General Procedure F2. The crude product was purified by chromatography (SiO₂, MeOH/CH₂Cl₂, 0:100 to 10:90) to give (1s,4s)-4-(3,4-dichlorophenyl)-4-((methylamino)methyl)cyclohexanol (40 mg, 61%) as clear oil. ¹H NMR (400 MHz, CDCl₃): δ 1.57-1.72 (m 4H), 1.78-1.83 (m, 2H), 2.04-2.11 (m, 2H), 2.30 (s, 3H), 2.68 (s, 2H), 3.78-3.82 (m, 1H), 7.20 (dd, J=8.4, 2.4 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.44 (s, 1H). ESI MS m/z 288.

(1s,4s)-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-cyclohexanol (288)

299 to 288
The title compound was prepared from (1s,4s)-4-(aminomethyl)-4-(3,4-dichlorophenyl)cyclohexanol (PharmaCore, 63 mg, 0.230 mmol) according to General Procedure F2. The crude product was purified by reverse phase HPLC (C-18 column, CH₃CN/water, CH₃CN from 5% to 100%) to give (1s,4s)-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)cyclohexanol (50 mg, 75%). ¹H NMR (400 MHz, CDCl₃): δ 1.57-1.68 (m 4H), 1.77-1.86 (m, 3H), 1.99 (s, 6H), 2.00-2.08 (m, 1H), 2.41 (s, 2H), 3.79-3.82 (m, 1H), 7.22 (dd, J=8.4, 2.4 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.45 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 29.5, 30.2, 42.4, 48.6, 68.0, 70.4, 126.8, 129.4, 129.7, 130.1, 132.3, 147.1. ESI MS m/z 302.

4-(3,4-Dichloro-phenyl)-4-methylaminomethyl-cyclohexanone (289)

To a solution of 270 (20 mg, 0.060 mmol) in acetone-H₂O (1:1, 1.5 mL) was added TsOH—H₂O (12 mg, 0.060 mmol). The reaction mixture was stirred overnight before being concentrated. The residue was dissolved in MeOH (1 mL) and subjected to reverse phase column chromatography (CH₃CN:H₂O:0.1% formic acid=5% to 100%) to give 4-(3,4-dichloro-phenyl)-4-methylaminomethyl-cyclohexanone (8.5 mg, 50%). ESI MS m/z 286.1.

trans-4-(aminomethyl)-4-(3,4-dichlorophenyl)-N-ethyl-N-methylcyclo-hexanamine (290)

To a solution of 1-(3,4-dichlorophenyl)-4-oxocyclohexanecarbonitrile (600 mg, 2.22 mmol) in MeOH (10 mL) was added MeNH₂.HCl (1.0 M in THF, 4.44 mL, 4.44 mmol), HCO₂H (0.2 mL) and NaB(CN)H₃(420 mg, 6.66 mmol). The reaction mixture was stirred overnight before being concentrated. The residue was dissolved in MeOH (2 mL) and subjected to reverse phase column chromatography (CH₃CN/H₂O/0.1% formic acid=5% to 100%) to give the mixture of cis- and trans-isomers (446 mg, 71%), which were separated (OD column, ethanol:methanol:hexane:DEA=3:2:95:0.1) to give the cis-analog (88 mg) and the trans-analog (332 mg).
To a solution of the above trans-analog (200 mg, 0.71 mmol) in CH₂Cl₂(5 mL) was added pyridine (0.5 mL) and acetyl chloride (80.3 mg, 72.2 μL, 1.06 mmol). The reaction mixture was stirred for 2 h before being quenched with saturated NH₄Cl. The product was extracted with CH₂Cl₂(20 mL×2), dried and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate/hexane=1:10 to 1:1) to give trans-1-(3,4-dichlorophenyl)-4-(ethyl(methyl)amino)cyclohexanecarbonitrile (202 mg, 88%).
The title compound was synthesized from the above nitrile (150 mg, 0.46 mmol) according to General Procedure E. The crude product was dissolved in MeOH (2 mL) and subjected to reverse phase column chromatography (CH₃CN:H₂O:0.1 formic acid=5% to 100%) (77 mg, 76%). ESI MS m/z 315.2.

(±)(1-(naphthalen-2-yl)cyclohex-3-enyl)methanamine (291)

The unsaturated amine (1-(naphthalen-2-yl)cyclohex-3-enecarbonitrile) was prepared according to General Procedure BB and was formed together with the monofluorinated intermediate in a 1:1 ratio.
To a 1M solution of LAH in THF (0.2 ml, 0.184 mmol), which was diluted up to 1 ml with Et₂O, was added a solution of 1-(naphthalen-2-yl)cyclohex-3-enecarbonitrile (0.043 g, 0.184 mmol) in Et₂O (2 ml) and the resulting mixture was stirred at 35° C. for 16 h. The reaction was then quenched with K₂CO₃(sat. aq., 5 ml). It was extracted with EtOAc (2×25 ml) and the combined organic phases were dried over Na₂SO₄, decanted and the solvent was removed in vacuo to give the product (0.042 g, 96%), which was pure by HPLC.
The corresponding HCl salt was prepared by the addition of 2M HCl (Et₂O) to the free amine. After stirring for 1 h, the white precipitate was filtered off to afford pure (1-(naphthalen-2-yl)cyclohex-3-enyl)methanamine. LC-MS (m/z+) 238.1.

(±) N-methyl-1-(1-(naphthalen-2-yl)cyclohex-3-enyl)methanamine (292)

The title compound was formed as a byproduct in the reduction of the fluorinated carbamate. Preparative HPLC separation (ChiralPak-AD column, 95:2.5:2.5:0.1 Hexanes:EtOH:MeOH:HNEt₂) afforded the crude product, which was converted to the corresponding HCl salt by the addition of 2M HCl (Et₂O) to the free amine. After stirring for 1 h, the white precipitate was filtered off to afford pure N-methyl-1-(1-(naphthalen-2-yl)cyclohex-3-enyl)methanamine hydrochloride salt (0.021 g). ¹H-NMR (400 MHz, CDCl₃) δ 9.04 (brs, 1H), 8.67 (brs, 1H), 7.79-7.67 (m, 4H), 7.45 (m, 3H), 5.80 (d, J=8.0 Hz, 1H), 5.59 (d, J=7.5 Hz, 1H), 3.21 (brs, 1H), 3.12 (brs, 1H), 2.89 (m, 1H), 2.57 (m, 1H), 2.22-1.99 (m, 2H), 2.15 (s, 6H), 1.75 (m, 2H). ¹³C-NMR (100 MHz, CDCl₃) δ 138.6, 133.5, 132.6, 129.1, 128.6, 127.7, 127.2, 126.9, 126.6, 126.5, 124.3, 59.7, 40.0, 35.6, 33.7, 31.4, 22.5. LC-MS (m/z+) 252.1.

N,N-dimethyl(1-(naphthalen-2-yl)cyclohex-3-enyl)methanamine (293)

The title compound was prepared from 292 according to General Procedure C (0.023 g, 49% yield). ¹H-NMR (400 MHz, CDCl₃) δ 7.81-7.74 (m, 4H), 7.54 (dd, J=9.0, 2.0 Hz, 1H), 7.46-7.41 (m, 2H), 5.82 (m, 1H), 5.60 (apd, J=10.0 Hz, 1H), 2.70 (d, J=13.0 Hz, 1H), 2.63 (d, J=17.5 Hz, 1H), 2.53 (d, J=13.5 Hz, 1H), 2.43 (m, 1H), 2.02 (m, 2H), 1.98 (s, 6H), 1.72-1.70 (m, 2H). ¹³C-NMR (100 MHz, CDCl₃) δ 132.0, 128.3, 127.5, 127.2, 125.8, 125.8, 125.6, 125.5, 125.4, 70.8, 48.5, 34.4, 31.9, 22.9. LC-MS (m/z+) 266.1.

4′,8-dimethyl-8,9-dihydro-7H-spiro[[1,3]dioxolo[4,5-h]isoquinoline-6,1′-cyclohexan]-4′-ol (diastereomer 1) (294)

The title compound was isolated as a byproduct in the Eschweiler-Clark alkylation (General Procedure C) of the amine 215. The two products were separated by reverse phase preparative HPLC (CH₃CN: H₂O) to afford the product as the formate salt: ¹H-NMR (400 MHz, CHCl₃) δ 8.42 (brs, 1H), 6.57 (s, 1H), 5.92 (s, 1H), 3.91 (s, 2H), 3.18 (s, 2H), 2.79 (s, 3H), 1.92-1.87 (m, 2H), 1.74-1.60 (m, 6H), 1.39 (s, 3H). LC-MS (m/z+) 290.3.

4′,8-dimethyl-8,9-dihydro-7H-spiro[[1,3]dioxolo[4,5-h]isoquinoline-6,1′-cyclohexan]-4′-ol (diastereomer 2) (295)

The title compound was isolated as a byproduct in the Eschweiler-Clark alkylation (General Procedure C) of the amine 216. The two products were separated by reverse phase preparative HPLC (CH₃CN:H₂O). ¹H-NMR (400 MHz, CD₃OD) δ 8.38 (brs, 1H), 7.02 (s, 1H), 6.59 (s, 1H), 5.93 (s, 2H), 4.07 (s, 2H), 3.34 (s, 2H), 2.91 (s, 3H), 2.23-2.19 (m, 2H), 1.65-1.53 (m, 6H), 1.26 (s, 3H). ¹³C-NMR (100 MHz, CD₃OD) δ 106.2, 101.6, 58.1, 56.5, 43.6, 33.7, 32.4, 30.1. LC-MS (M+1) 290.2.

2-(1-(3,4-dichlorophenyl)cyclohexyl)pyrrolidine (296)

(a) (R)—N-(1-(1-(3,4-dichlorophenyl)cyclohexyl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide

A flame dried flask under N₂was charged with anhydrous Et₂O (5 mL) and (1,3-Dioxan-2-ylethyl)-magnesium bromide (0.5M in THF, 5.6 mL, 2.8 mmol) and cooled to −78° C. (R,E)-N-((1-(3,4-dichlorophenyl)cyclohexyl)methylene)-2-methylpropane-2-sulfinamide (460 mg, 1.28 mmol) in anhydrous Et₂O (3 mL) was added dropwise and the solution was stirred at −78° C. for 1 h, then allowed to warm to RT overnight. After 20 h sat'd aqueous Na₂SO₄solution (4 mL) was added and the suspension was filtered, dried (Na₂SO₄), filtered and concentrated. Purification on the Biotage with a 25M column and an ethyl acetate/hexane (0.1% DEA) gradient (0→100% EtOAc over 3 CV, hold at 100% EtOAc for 5 CV) gave the pure title compound (300 mg, 49%) as a clear oil. HPLC R_t=2.62 min; ¹H NMR (400 MHz, CDCl₃) 7.45-7.43 (m, 2H), 7.24-7.22 (d, J=8.43 Hz, 1H), 4.44-4.42 (m, 1H), 4.11-4.04 (m, 2H), 3.75-3.67 (m, 2H), 3.11-3.01 (m, 2H), 2.64 (d, J=12.8 Hz, 1H), 2.27 (d, J=13.9 Hz, 1H), 2.04-1.99 (m, 1H), 1.88-1.44 (m, 8H), 1.33-1.19 (m, 12H), 0.93-0.80 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) 141.8, 132.7, 130.8, 130.4, 130.2, 128.4, 101.7, 66.8, 66.3, 57.1, 46.2, 34.3, 32.5, 26.1, 25.7 (d), 23.1, 22.2, 21.8; LC-MS 10.5 min, (M+1)⁺476 @ 10.6 min.

(b) 2-(1-(3,4-dichlorophenyl)cyclohexyl)pyrrolidine formate

The above sulfinamide (58 mg, 0.13 mmol) was dissolved in wet acetone (3 mL) and 6 M HCl (1 mL) was added. The clear reaction was stirred for 16 h, poured into 6 M HCl and washed with Et₂O (2×10 mL). The Et₂O washes were discarded. The aqueous phase was made basic (pH=10-11) with sat'd aqueous K₂CO₃, at which point a white precipitate appeared. The basic aqueous phase was washed with EtOAc (4×20 mL) and the EtOAc washes were combined, dried (Na₂SO₄), filtered and concentrated. The crude imine was dissolved in anhydrous THF (4 mL) in a product vial and polymer bound cyanoborohydride (Argonaut, 2.43 mmol/g, 327 mg, 0.796 mmol) and glacial acetic acid (35 mL, 0.597 mmol) were added. The slightly yellow clear solution was shaken at RT for 16 h and filtered. The resin washed with CH₂Cl₂and the combined washes were concentrated. The crude amine was dissolved in MeOH (3 mL) and purified on the Gilson with the standard method. Fractions containing the major peak (Rt ˜3.4 min) were concentrated on the Genevac and combined to give the title compound as a formate salt (37 mg, 31%). HPLC R_t=1.5 min; ¹H NMR (400 MHz, CDCl₃) 8.45 (s, 1H), 7.48 (d, J=1.83 Hz, 1H), 7.45 (d, J=8.43 Hz, 1H), 7.28-7.26 (m, 1H), 3.48-3.43 (m, 1H), 3.17-3.11 (m, 1H), 3.04-2.98 (m, 1H), 2.31 (d, J=12.8 Hz, 2H), 1.84-1.51 (m, 10H), 1.26-1.16 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) 168.1, 141.2, 133.3, 131.2, 131.0, 130.5, 127.8, 69.4, 45.3, 43.7, 33.1, 31.0, 25.9 (d), 23.6, 21.8(d); LC-MS 8.35 min, (M+1)⁺298@ 8.51 min.

2-(1-(naphthalen-2-yl)cyclohexyl)pyrrolidine (297)

(a) Synthesis of (R)—N-(3-(1,3-dioxan-2-yl)-1-(1-(naphthalen-2-yl)cyclohexyl)propyl)-2-methylpropane-2-sulfinamide

A flame dried flask under N₂was charged with anhydrous Et₂O (3 mL) and (1,3-Dioxan-2-ylethyl)-magnesium bromide (0.5M in THF, 6.78 mL, 3.39 mmol) and cooled to −78° C. (R,E)-2-methyl-N-((1-(naphthalen-2-yl)cyclohexyl)methylene)propane-2-sulfinamide (524 mg, 1.54 mmol) in anhydrous Et₂O (3 mL) was added dropwise and the solution was stirred at −78° C. for 1 h, then allowed to warm to RT overnight. After 20 h sat'd aqueous Na₂SO₄solution (4 mL) was added and the suspension was filtered, dried (Na₂SO₄), filtered and concentrated. Purification on the Biotage with a 25M column and an ethyl acetate/hexane (0.1% DEA) gradient (0→100% EtOAc over 3 CV, hold at 100% EtOAc for 5 CV) gave the title compound (581 mg, 83%) as a clear oil. HPLC (JPK method) R_t=2.61 min; ¹H NMR (400 MHz, CDCl₃) 7.85-7.80 (m, 4H), 7.53 (d, J=8.8 Hz, 1H), 7.48-7.45 (m, 2H), 4.38 (t, J=5.13 Hz, 1H), 4.10-3.99 (m, 2H), 3.77-3.62 (m, 2H), 3.25 (d, J=8.8 Hz, 1H), 3.15-3.10 (m, 1H), 2.88 (d, J=12.1 Hz, 1H), 2.51 (d, J=11.7 Hz, 1H), 2.03-1.90 (m, 2H), 1.64-1.59 (m, 4H), 1.49-1.42 (m, 2H), 1.31-1.23 (m, 4H), 1.12 (s, 9H), 0.87-0.83 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) 138.5, 133.6, 132.0, 128.2, 128.1, 127.5, 126.9, 126.2, 126.0, 102.1, 67.0, 66.7, 57.0, 46.4, 35.0, 34.8, 32.8, 26.2 (d), 25.9, 23.3, 22.6, 22.2; LC-MS 10.4 min, (M+1)⁺458 @ 10.6 min.

(b) Synthesis of 2-(1-(naphthalen-2-yl)cyclohexyl)pyrrolidine formate

The above sulfinamide (317 mg, 0.694 mmol) was dissolved in wet acetone (12 mL) and 6 M HCl (4 mL) was added. The clear reaction was stirred for 16 h, poured into 6 M HCl and washed with Et₂O (2×20 mL). The Et₂O washes were discarded. The aqueous phase was made basic (pH=10-11) with sat'd aqueous K₂CO₃, at which point a white precipitate appeared. The basic aqueous phase was washed with EtOAc (4×30 mL) and the EtOAc washes were combined, dried (Na₂SO₄), filtered and concentrated. The crude imine was dissolved in anhydrous THF (7 mL) in a product vial and polymer bound cyanoborohydride (Argonaut, 2.43 mmol/g, 697 mg, 1.69 mmol) and glacial acetic acid (73 mL, 1.27 mmol) were added. The slightly yellow clear solution was shaken at RT for 16 h and filtered. The resin washed with CH₂Cl₂and the combined washes were concentrated. The crude amine was dissolved in MeOH (3 mL) and purified on the Gilson with the standard method. Fractions containing the major peak (Rt˜3.4 min) were concentrated on the Genevac and combined to give the title compound as the formate salt (96 mg, 49%). HPLC R_t=1.58 min; ¹H NMR (400 MHz, CDCl₃) 8.51 (s, 1H), 7.88-7.78 (m, 4H), 7.55-7.52 (dd, J=1.47, 8.80 Hz, 1H), 7.48-7.42 (m, 2H), 3.61-3.57 (m, 1H), 3.04-2.99 (m, 1H), 2.86-2.82 (m, 1H), 2.56-2.53 (m, 2H), 1.84-1.53 (m, 9H), 1.39-1.25 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) 168.3, 137.7, 133.6, 132.2, 128.7, 128.3, 127.8, 127.4, 126.3, 126.2, 125.5, 69.5, 45.2, 43.8, 33.4, 31.1, 26.0 (d), 23.6, 22.0 (d); LC-MS 8.14 min, (M+1)⁺280 @ 8.23 min.

Example 5

Scaled-up Syntheses of 225, 93, 48 E1 and 277

5.1. Scaled-up Synthesis of (1s,4s)-4-((dimethylamino)methyl)-1-methyl-4-(naphthalen-2-yl)cyclohexanol (225)

5.1.1. General

Reagents and solvents were used as received from commercial suppliers. Proton and carbon nuclear magnetic resonance spectra were obtained on a Bruker AC 300 spectrometer at 300 and 75 MHz, respectively. High-pressure liquid chromatography was performed on an Agilent 1100 series instrument. Gas chromatography-mass spectroscopy was performed on a Hewlett-Packard G1800A GCD System.
Compound 225 was prepared following the procedures outlined in Scheme 33, below.

5.1.2. Preparation of dimethyl 4-cyano-4-(naphthalen-2-yl)heptanedioate

A 3-L, three-necked flask equipped with a temperature probe, reflux condenser, addition funnel and overhead stirrer was charged with 2-naphthylacetonitrile (300 g, 1.79 mol), methylacrylate (600 mL, 6.65 mol) and tert-butanol (900 mL). A solution of tetrabutylammonium hydroxide (1 M; 75 mL, 75 mmol) in methanol was added slowly through an addition funnel over a period of 30 min (Note: Highly exothermic). The resulting clear solution was stirred at 70° C. for 2 h and assayed by TLC (3:7 EtOAc/Heptane; stained using Hanessian solution) and GC. The reaction mixture was cooled to room temperature before being concentrated under reduced pressure. The residue was partitioned between 2 M HCl (1 L) and MTBE (4 L). The phases were separated and the aqueous phase was extracted with MTBE (500 mL). The combined organic phases were washed with brine (1 L), dried over MgSO₄, filtered and concentrated under reduced pressure at 40-45° C. to give a residue which was passed through a bed of silica (1:4 EtOAc/Heptane) to yield the title compound [569 g, 93%, 100% (AUC) by GC] as an off-white solid. ¹H NMR (CDCl₃, 300 MHz): δ 7.75 (2 d merged, 2H), 7.45 (dd, 1H), 3.5 (s, 6H), 2.4-2.2 (m, 6H), 2.15-1.98 (m, 2H).

5.1.3. Preparation of methyl 5-cyano-5-(naphthalen-2-yl)-2-oxocyclohexanecarboxylate

A 12-L, three-neck flask equipped with a temperature probe, reflux condenser, addition funnel and overhead stirrer was charged with potassium tert-butoxide (365 g, 3.2 mol) and toluene (2.4 L). A solution of dimethyl 4-cyano-4-(naphthalen-2-yl)heptanedioate (500 g, 1.4 mol) in toluene (4 L) was added through an addition funnel. The reaction mixture was heated to 90° C. and stirred for 1.5 h. The progress of the reaction was monitored by TLC (3:7 EtOAc: Heptane). The reaction mixture was cooled to 20° C. and quenched slowly with 2 M HCl (2 L) and extracted with EtOAc (4 L). The phases were separated and the organic phase washed with brine (2×1 L), dried over MgSO₄, filtered and concentrated under reduced pressure at 40-45° C. to yield compound 9 (546 g, 120%) as a yellow solid. It was taken into the next step without further purification. ¹H NMR (DMSO-d₆, 300 MHz): δ 8.1 (s, 1H), 8.0-7.9 (m, 4H), 7.7 (dd, 1H), 7.5 (m, 2H), 7.3 (dd, 1H), 7.2 (m, 1H), 3.7 (s, 3H), 3.4 (s, 1H), 3 (d, 1H), 2.9-2.6 (m, 2H), 2.5 (d, 1H), 2.8-2.5 (m, 2H), 2.48-2.3 (m, 6H).

5.1.4. Preparation of 1-(naphthalen-2-yl)-4-oxocyclohexanecarbonitrile

A 12-L, four-neck flask equipped with a temperature probe, reflux condenser and overhead stirrer was charged with methyl 5-cyano-5-(naphthalen-2-yl)-2-oxocyclohexanecarboxylate (600 g, 1.9 mol), brine (1 L) and DMSO (6 L). The mixture was heated to 135° C. and stirred for 12 h. The progress of the reaction was monitored by TLC (2:3 EtOAc/Heptane). After 12 h, the reaction mixture was cooled to room temperature, diluted with water (6 L) and extracted twice with MTBE (5 L, 3 L). The combined organic phases were washed with brine (4×3 L), dried over MgSO₄and filtered. The filtrate was concentrated under reduced pressure at 40-45° C. to give a residue which was triturated with heptane/MTBE (1:1, 2 L). The resulting slurry was stirred for 2 h, filtered and dried under high vacuum for 12 h to yield the title compound (301 g, 62%) as an off-white solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 8.1 (s, 1H), 8.0-7.9 (m, 4H), 7.8 (dd, 1H), 7.6 (m, 2H), 7.3 (dd, 1H), 7.2 (m, 1H), 3.1 (s, 1H), 2.8 (m, 2H), 2.2-2.6 (m, 8H), 1.2(s, 2H).

5.1.5. Preparation of cis-4-hydroxy-4-methyl-1-(naphthalen-2-yl)cyclohexanecarbonitrile

A dried 5-L, three-neck flask equipped with a temperature probe, addition funnel, nitrogen line and overhead stirrer was charged with 1 M solution of MeLi in ether (800 mL, 1.23 mol) using canula under anhydrous atmosphere. (Note: MeLi is highly flammable; strictly anhydrous conditions are required.) The solution was cooled to −70° C. and added to a solution of 1-(naphthalen-2-yl)-4-oxocyclohexanecarbonitrile (160 g, 0.642 mol) in anhydrous THF (1,600 mL) slowly over a period of 40 min maintaining the temperature below −50° C. The mixture was stirred at −70° C. for 1 h. Progress of the reaction was monitored by TLC (2:3 EtOAc/Heptane) and GC. The reaction was cautiously quenched with saturated ammonium chloride solution (700 mL) when the startin material was <15% by GC. The typical ratio of starting material: (a): (b) by GC was 1:7:2. The desired cis-nitrile (a) was a major and more polar compound by TLC. The reaction mixture was gradually warmed to room temperature and diluted with EtOAc (500 mL), DI water (200 mL), and the mixture was stirred for 5 min. The phases were separated and the aqueous phase was extracted with EtOAc (500 mL). The combined organic phases were washed with brine (1 L), dried over MgSO₄, filtered and concentrated under reduced pressure at 40-45° C. to afford a residue which was purified by chromatography (10-40% EtOAc in heptane). The pure fractions of most polar compound by TLC were pooled and concentrated to yield the cis-nitrile (a) [88.5 g, 52%, 99% (AUC) by GC] as an off-white solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 8.1 (s, 1H), 8.0-7.8 (m, 3H), 7.75 (dd, 1H), 7.58 (2H, dd), 4.65 (s, 1H), 2.3-2.0 (m, 4H), 1.8 (dt, 2H), 1.68 (dd, 2H), 1.2 (s, 3H).

5.1.6. Preparation of cis-4-(aminomethyl)-1-methyl-4-(naphthalen-2-yl)cyclohexanol

A dried 5-L, three-neck flask equipped with a temperature probe, addition funnel, nitrogen line and overhead stirrer was charged with 1.0 M solution of BH₃.THF (1.29 L, 1.29 mol) using canula under anhydrous atmosphere. (Note: BH₃.THF is highly flammable; strictly anhydrous conditions are required.) The solution was cooled to 10° C. and added to a solution of nitrile (a) (114 g, 0.429 mol) in anhydrous THF (1.2 L) slowly over period of 30 min maintaining the temperature below 25° C. The mixture was stirred at room temperature for 16 h. The reaction was cautiously quenched with 6 M HCl (250 mL) until pH 1-2. (Note: Evolution of hydrogen gas; proper vent was needed). The reaction mixture was concentrated under reduced pressure to give a residue which was diluted with MTBE (600 mL) and water (300 mL). The precipitated boron salts were filtered and the phases of filtrate were separated. The aqueous phase was adjusted to pH 9-10 using 6 M NaOH solution and extracted with dichloromethane (3×400 mL). The combined organic phases were washed with brine (300 mL), dried over MgSO₄, filtered and concentrated under reduced pressure at 40-45° C. to yield the primary amine (92.1 g, 80%) as a foamy solid which was taken into next step without further purification. ¹H NMR (CD₃OD, 300 MHz): δ 7.95-7.8 (m, 4H), 7.6 (d, 1H), 7.5-7.4 (m, 2H), 2.7 (s, 2H), 2.3 (dd, 2H), 1.9 (dt, 2H), 1.6 (dd, 2H), 1.4 (dt, 2H), 1.05 (s, 3H).

5.1.7. Preparation of 225

A 3-L, three-neck flask equipped with a temperature probe, nitrogen line, condenser, heating mantle and overhead stirrer was charged with cis-4-(aminomethyl)-1-methyl-4-(naphthalen-2-yl)cyclohexanol (92 g, 0.341 mol), 37% aqueous formaldehyde (300 mL), formic acid (46 mL) and water (300 mL). The mixture was heated to 85° C. and stirred overnight. (Note: Gas evolution (CO₂) was observed at 60° C.) The reaction was monitored by TLC (9:1 DCM/MeOH). After 16 h, the reaction mixture was cooled to room temperature, diluted with water (400 mL) and washed with heptane (2×300 mL). The aqueous phase was adjusted to pH 2.0 using 6 M HCl and washed with dichloromethane (2×100 mL). The aqueous phase was adjusted to pH 9-10 using 6 M NaOH and extracted with dichloromethane (3×400 mL). The combined organic phases were washed with brine (500 mL), dried over MgSO₄, filtered and concentrated under reduced pressure at 40-45° C. to yield 225 (71.1 g, 70.3%) as a off-white solid, which was taken into salt formation step without further purification. ¹H NMR (CDCl₃, 300 MHz): δ 7.92-7.8 (m, 4H), 7.65 (d, 1H), 7.5-7.4 (m, 2H), 2.45 (s, 2H), 2.3 (dd, 2H), 1.99 (s and dd merged, 8H), 1.6 (dd, 2H), 1.5 (dt, 2H), 1.1 (s, 3H).

5.1.8. Preparation of 225 Hydrochloride

A 2-L, three-neck flask equipped with a temperature probe, heating mantle, nitrogen line and overhead stirrer was charged with 225 (83 g, 0.28 mol), ethanol (300 mL) and heated to 50° C. until a clear solution was obtained. The solution was cooled to room temperature and added to a solution of 2 M HCl in ether (150 mL) slowly over period of 10 min. The precipitated solids were stirred for 1 h at room temperature and filtered. The cake washed with mixture of MTBE/EtOH (2:1, 100 mL), dried overnight under high vacuum to provide 225 hydrochloride [60.4 g, 66%, 97.7% (AUC) by HPLC]. ¹H NMR (CD₃OD, 300 MHz): δ 8.1 (m, 4H), 7.7 (d, 1H), 7.6 (dd, 2H), 3.5 (s, 2H), 2.55 (s, 6H), 2.45 (dd, 2H), 2.1 (dt, 2H), 1.75 (dd, 2H), 1.5 (dt, 2H), 1.1 (s, 3H). ¹³C NMR (CD₃OD, 300 MHz): δ 138.1, 135.3, 134.3, 130.8, 129.7, 129.2, 128.9, 128.1, 126.2, 73.3, 69.5, 47.5, 42.8, 35.6, 31.3, 30.89.
5.2. Scaled-up Synthesis of N-methyl-1-(1-(naphthalen-2-yl)cyclohexyl)methanamine (93)
The title compound was synthesized according to Scheme 34, below.

5.2.1. Synthesis of 2-Naphthylacetonitrile

To a stirred solution of sodium cyanide (10.5 g, 0.214 mol) in H₂O (20 mL) was added a solution of 2-(bromomethyl)naphthalene (40.0 g, 0.181 mol) in EtOH (170 mL). The resulting mixture was heated at reflux for 3 h, then spin-evaporated in vacuo. The residue was partitioned between H₂O (175 mL) and CH₂Cl₂(200 mL). The aqueous layer was further extracted with CH₂Cl₂(3×200 mL). The combined organic layers were dried over MgSO₄(5 g) and spin-evaporated in vacuo to a solid. The solid was dissolved in refluxing EtOH (100 mL). The clarified solution was stored at 3° C. for 16 h. Solids were collected by filtration and dried to constant weight in vacuo to give 24.8 g (81.9%) of product suitable for further transformation. A total of 257.2 g of material was prepared in this fashion.

5.2.2. Synthesis of 1-(2-Naphthyl)cyclohexanecarbonitrile

To a stirred suspension of NaH (12.0 g, 0.3 mol) (60 wt % oil dispersion) in DMSO (480 mL) was added a solution of 1 (20.0 g, 0.120 mol) in DMSO (120 mL) dropwise, in a thin stream. The resulting mixture was stirred at 25° C. for 1 h. The mixture was cooled to 15° C. and 1,5-dibromopentane (41.2 g, 0.179 mol) was added dropwise, while maintaining the temperature at ≦22° C. The resulting mixture was stirred at 25° C. for 18 h. The mixture was cooled to 15° C. and quenched with sat. aq. NH₄Cl (100 mL). The resulting mixture was partitioned between H₂O (1.2 L) and t-butyl methyl ether (MTBE) (300 mL). The aqueous layer was further extracted with MTBE (200 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO₄(5 g) and spin-evaporated in vacuo to an oil. The oil was chromatographed on a silica gel column (1.0 kg) packed in, and eluted with hexanes-EtOAc (4:1) (8.0 L). Appropriate fractions as determined by TLC were combined and spin-evaporated in vacuo to an oil, which solidified when pumped down, giving 27.4 g (97.0%) of purified product. A total of 240.2 g of product suitable for further transformation was prepared in this fashion.

5.2.3. Synthesis of 1-(2-Naphthyl)cyclohexanecarboxaldehyde)

To a cold (−78° C.), stirred mixture of 2 (140.9 g, 0.5988 mol) in toluene (1.85 L) was added diisobutylaluminum hydride (DIBAL-H) (1.0 M in toluene) (1.273 L) dropwise, at such a rate as to maintain the temperature at ≦−65′. The resulting mixture was stirred at −78° C. for 3 h. EtOAc (1.5 L) was added, followed by the dropwise addition of aq. 1 M HCl (1.5 L). The resulting mixture was filtered to remove gelatinous solids. The biphasic filtrate was separated. The filter cake washed with EtOAc (3×500 mL). The combined organic layer washed with brine (500 mL), dried over MgSO₄(20 g) and spin-evaporated in vacuo to give 127.0 g (89.0%) of product suitable for further transformation. A total of 197.7 g of product was prepared in a similar fashion.

5.2.4. Synthesis of N-methyl(1-(naphthalen-2-yl)cyclohexyl)-methanamine

To a stirred solution of 3 (127.0 g, 0.5329 mol) in 2.0 M methylamine (in THF) (1.8 L, 3.6 mol) was added 20 drops of acetic acid. The resulting mixture was stirred at 25° C. for 3 h. Potassium borohydride (64.2 g, 1.19 mol) was added, and stirring at 25° C. was continued for 18 h. The mixture was quenched by the careful addition of aq. 1 M HCl to pH ˜2. The resulting biphasic mixture was separated. The organic layer was extracted with aq. 1 M HCl (2×500 mL). The combined aqueous layers were basified with 6 M NaOH to pH ˜10, and extracted with EtOAc (3×1.0 L). The combined organic layers were washed with brine (750 mL), dried over MgSO₄(20 g) and spin-evaporated in vacuo to give 88.4 g (65.5%) of crude free-base as an oil. This material was combined with 61.3 g of similar material and chromatographed on a silica gel pad (1.5 kg) packed in and eluted with CH₂Cl₂-MeOH (6:1) (12.2 L). Appropriate fractions as determined by TLC were combined and spin-evaporated in vacuo to give 141.0 g (94.2% recovery) of an oil. The oil was dissolved in CH₂Cl₂(500 mL). A solution of 1.0 M HCl (in Et₂O) (600 mL) was slowly added with stirring. The resulting suspension was filtered. The solids were suspended in warm (38° C.) CH₂Cl₂(500 mL), then re-collected by filtration and dried to constant weight in vacuo at 25° C. to give 91.1 g of 93 HCl salt, mp; 228-230° C. (dec., uncorrected).

5.3. Scaled-up Asymmetric Synthesis of 48 E1

The title compound was prepared via asymmetric synthesis according to the synthetic route outlined in Scheme 35, below. The absolute configuration of the chiral center α to the amine was not determined. Rather, the final material was correlated via chiral HPLC to an authentic sample of 48 E1 and 48 E2 and the intermediates were assigned by analogy.

5.3.1. Synthesis of 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanone

A 2 L round bottom flask was charged with a magnetic stir bar and 100.8 g (396.6 mmol) of 1-(3,4-dichloro-phenyl)-cyclohexanecarbonitrile and was flushed with N₂. The solid was then dissolved with 960 mL of dry toluene and the mixture was cooled to −78° C. The chilled homogeneous solution was then treated with 300 mL of a 1.6 M solution of MeLi (in Et₂O). The resulting pale yellow solution was allowed to slowly warm to r.t. and left to stir for 12 h. The mixture was then chilled to −20° C. and quenched with 2 N HCl. The biphasic mixture was extracted with MTBE (2×). The combined organic layers were washed sequentially with a saturated solution of K₂HCO₃and brine before drying over Na₂SO₄. The dried mixture was filtered and all volatiles were removed under reduced pressure to give 107.5 g (396.6 mmol) of the title compound as a pale yellow oil in >90% purity (as determined by reverse phase LCMS). This material was used in subsequent steps without further purification: ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.39 (m, 2H), 7.14 (d, 1H, J=8.4 Hz), 2.31-2.28 (m, 2H), 1.91 (s, 3H), 1.79-1.74 (m, 2H), 1.69-1.54 (m, 3H), 1.51-1.41 (m, 2H), 1.35-1.26 (m, 1H).

5.3.2. Synthesis of N-(1-(1-(3,4-dichlorophenyl)cyclohexyl)ethylidene)-2-methylpropane-2-sulfinamide

A mixture of 10.53 g (38.8 mmol) of 1-(1-(3,4-dichlorophenyl)cyclohexyl)-ethanone (7.02 g, 57.9 mmol) of (R)-TBSA, 16.1 mL of Ti(OEt)₄and 80 mL of anhydrous toluene was heated to 110° C. under an atmosphere of N₂for 2 days. The mixture was cooled to rt and poured into a vigorously stirred solution of brine and the resulting biphasic mixture was extracted with EtOAc. The combined organic layers were dried (Na₂SO₄), filtered and concentrated under reduced pressure. The resulting residue was chromatographed on SiO₂using Hexanes/EtOAc (9:1) to afford 9.5 g (65%) of the title compound: ¹H NMR (300 MHz, CDCl₃) δ 7.43-7.39 (m, 2H), 7.17 (dd, 1H, J=8.7, 2.4 Hz), 2.25-2.15 (m, 2H), 2.06 (s, 3H), 1.95-1.88 (m, 2H), 1.61-1.50 (m, 6H), 1.31 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 187.1, 144.2, 133.1, 131.2, 130.8, 129.3, 126.7, 57.1, 53.9, 34.5, 34.3, 26.0, 22.92, 22.89, 22.7, 19.7.

5.3.3. Synthesis of N-(1-(1-(3,4-dichlorophenyl)cyclohexyl)ethyl)-2-methylpropane-2-sulfinamide

2-Methyl-propane-2-sulfinic acid {1-[1-(3,4-dichloro-phenyl)-cyclohexyl]-ethyl}-amide: 56 g (149.6 mmol) of 2-Methyl-propane-2-sulfinic acid {1-[1-(3,4-dichloro-phenyl)-cyclohexyl]-ethylidene}-amide was dissolved in 1 L of THF. The solution was chilled to −20° C. and treated with 49 g (190 mmol) of Cp₂ZrHCl. The mixture was allowed to warm to rt and left to stir overnight before cooling back to −20° C. and quenching with a saturated solution of NH₄Cl. The mixture was warmed to rt extracted with EtOAc (3×). The combined organic layers were washed with H₂O, brine and then dried over Na₂SO₄. All volatiles were then removed under reduced pressure. The resulting mixture was suspended in MTBE and filtered. All volatiles were again removed under reduced pressure to give 54 g (96%) of the title compound as a white solid in >90% chemical purity and was used without further purification. The diastereomeric ratio was determined to be >98% (reverse phase HPLC: Symmetry C18 column; solvent gradient using H₂O:ACN with 0.05% TFA): ¹H NMR (300 MHz, CDCl₃) δ 7.45-7.41 (m, 2H), 7.20 (dd, 1H, J=8.6, 2.3 Hz), 3.34-3.25 (m, 1H), 3.01 (d, 1H, J=6.9 Hz), 2.50-2.44 (m, 1H), 2.23-2.17 (m, 1H), 1.65-1.48 (m, 5H), 1.34-1.17 (m, 3H), 1.13 (s, 9H), 0.98 (d, 3H, J=6.6 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 141.9, 132.8, 131.1, 130.6, 130.4, 128.5, 60.6, 56.1, 46.5, 33.7, 33.0, 26.6, 22.8, 22.3, 22.1, 16.8.

5.3.4. Synthesis of 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanamine

54 g (143.5 mmol) of 2-Methyl-propane-2-sulfinic acid {1-[1-(3,4-dichloro-phenyl)-cyclohexyl]-ethyl}-amide was dissolved in 300 mL of MeOH, cooled to 0° C. and 300 mL of a 4N HCl solution (in dioxane) was added. After 3 h, the solution was concentrated under reduced pressure. The resulting slurry was suspended in 1.2 L of Et₂O and left to stir over night at rt before collecting the solid by filtration. The resulting pale yellow solid washed with Et₂O and dried. The solid was dissolved in CH₂Cl₂and washed with a 20% K₂HCO₃. The organic layer was isolated, washed with brine and concentrated under reduced pressure to yield 38 g (97%) of 2 E1 in >99% ee (ChiralPak AD, using heptane/EtOH/DEA 95:5:0.1 as the eluent).

5.3.5. Synthesis of N-(1-(1-(3,4-dichlorophenyl)cyclohexyl)-ethyl)formamide

N-{1-[1-(3,4-Dichloro-phenyl)-cyclohexyl]-ethyl}-formamide: 50 g (184.4 mmol) of 1-[1-(3,4-Dichloro-phenyl)-cyclohexyl]-ethylamine was dissolved in 1 L of ethylformate and left to stir under an N₂atmosphere for 24 h before removing all volatiles under reduced pressure. The resulting solid was filtered through a plug of SiO₂(using CH₂Cl₂₁MeOH (20:1) as the eluent) to afford 51.32 g (93%) of the title compound after the removal of all volatiles. This material was used in the subsequent step without further purification.

5.3.6. Synthesis of 1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine hydrochloride (48 E1)

To the refluxing solution of N-{1-[1-(3,4-dichloro-phenyl)-cyclohexyl]-ethyl}-formamide (5.2 g, 17.32 mmol) in anhydrous THF (75 mL) was added slowly BH₃.SMe₂(2N solution in THF, 26 mL, 51.96 mmol). The solution was stirred at 70° C. for 20 mins then a distillation head was installed. The solution was refluxed for 2 h, during which SMe₂was distilled, and the solution was cooled to R.T. and concentrated using a rotary evaporator. The pale yellow residue was cooled to 0° C. and added slowly to methanol (20 mL) to destroy the excess borane. The resulting clear solution was added to 6N aqueous HCl (50 mL) and heated to reflux for 40 minutes, then cooled to room temperature. The solid that formed was filtered and washed with water (2×50 mL), followed by slurrying in ethyl ether (200 mL) and filtration to give 48 E1 as a white solid. (4.04 g, 72.5%). Note: Same reaction was run on a 50 g scale with 70% yield.

5.4. Scaled-up Synthesis of 277

5.4.1. General Experimental Details

Reagents and solvents were used as received from commercial suppliers. Proton and carbon nuclear magnetic resonance spectra were obtained on a Bruker AC 300 spectrometer at 300 and 75 MHz, respectively. High-pressure liquid chromatography was performed on an Agilent 1100 series instrument. Gas chromatography-mass spectroscopy was performed on a Hewlett-Packard G1800A GCD System.

5.4.2. Synthesis of dimethyl 4-cyano-4-(3,4-dichlorophenyl)-heptanedioate

To a 2-L, three-neck flask equipped with a temperature probe, reflux condenser, addition funnel and overhead stirrer was charged with 3,4-dichlorophenylacetonitrile (100 g, 0.54 mol), methylacrylate (139.56 g, 1.62 mol) and tert-butanol (475 mL). To the mixture was added very slowly (highly exothermic) 1.0 M solution of tetrabutylammonium hydroxide (11 mL, 0.011 mol) in methanol. After the addition was complete, the temperature rose from 21.1° C. to 68.4° C. The resulting clear solution was stirred at 70° C. for 2 h and assayed by TLC (3:7 EtOAc/Heptane; stained using Hanessian solution) and GC. The reaction mixture was cooled to room temperature before being concentrated under reduced pressure. The residue was partitioned between 2 M HCl (500 mL), brine (200 mL) and MTBE (1.5 L). The phases were separated and the aqueous phase was extracted with MTBE (250 mL). The combined organic phases were washed with brine (500 mL), dried over MgSO₄and filtered. The filtrate was concentrated under reduced pressure at 40-45° C. to yield the title compound [192.1 g, 99%, 100% (AUC) by GC] as an off-white solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 7.75 (m, 2H), 7.45 (dd, 1H), 3.5 (s, 6H), 2.4-2.2 (m, 6H), 2.15-1.98 (m, 2H).

5.4.3. Synthesis of methyl 5-cyano-5-(3,4-dichlorophenyl)-2-oxocyclohexanecarboxylate

To a 12-L, three-neck flask equipped with a temperature probe, reflux condenser, addition funnel and overhead stirrer was charged with potassium tert-butoxide (266 g, 2.3 mol) and toluene (1 L). A solution of dimethyl 4-cyano-4-(3,4-dichlorophenyl)-heptanedioate (402 g, crude, 386 g theoretical, 1.07 mol) in toluene (3 L) was added through an addition funnel. The reaction mixture was heated to 90° C. and stirred for 1 h. The progress of the reaction was monitored by TLC (4:6 EtOAc/Heptane; stained using Hanessian solution). After 1 h, the reaction mixture was cooled to 15° C. and quenched slowly with 2 M HCl (2.3 L). The phases were separated and the aqueous phase was extracted with MTBE (1 L). The combined organic phases were washed with brine (2×1 L), dried over MgSO₄, filtered and concentrated under reduced pressure at 40-45° C. to yield the title compound (424 g, >100%) as a yellow solid. The crude was taken into next step without further purification. ¹H NMR (CDCl₃, 300 MHz): δ 7.8 (d, 1H), 7.7 (d, 1H), 7.6 (dd, 1H), 3.7 (s, 3H), 2.9 (d, 1H), 2.8-2.5 (m, 3H), 2.4-2.3 (m, 3H).

5.4.4. Synthesis of 1-(3,4-dichlorophenyl)-4-oxocyclohexanecarbonitrile

To 12-L, four-neck flask equipped with a temperature probe, reflux condenser and overhead stirrer was charged with methyl 5-cyano-5-(3,4-dichlorophenyl)-2-oxocyclohexanecarboxylate (424 g, crude, 350 g theoretical, 1.07 mol), brine (500 mL) and DMSO (3.4 L). The mixture was heated to 135° C. and stirred for 12 h. The progress of the reaction was monitored by TLC (4:6 EtOAc/Heptane; stained using Hanessian solution). The reaction mixture was cooled to room temperature and combined with the crude mixture from a previous 145 g batch reaction, diluted with water (6 L), extracted with MTBE (6 L), and then EtOAc/MTBE (3:5, 8 L). The organics were combined and washed with brine (4×2.5 L), dried over MgSO₄, filtered and concentrated under reduced pressure at 40-45° C. to afford a residue which was triturated with heptane/MTBE (1:1, 1.2 L). The resulting slurry was stirred for 0.5 h, filtered and dried under high vacuum for 2 h to afford the title compound [313 g, 77% over 2 steps, 100% (AUC) by GC] as an off-white solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 7.9 (d, 1H), 7.75 (dd, 1H), 7.6 (dd, 1H), 2.8-2.5 (m, 2H), 2.48-2.3 (m, 6H).

5.4.5. Synthesis of 1-(3,4-dichlorophenyl)-4-hydroxy-4-methylcyclohexanecarbonitrile

To a dry 5-L, three-neck flask equipped with a temperature probe, addition funnel, nitrogen line and overhead stirrer was charged with 1.0 M solution of MeLi in ether (680 mL, 1.04 mol) using canula under anhydrous atmosphere (Note: MeLi is highly flammable; strictly anhydrous conditions are required). The solution was cooled to −70° C. and added a solution of 1-(3,4-dichlorophenyl)-4-oxocyclohexanecarbonitrile (198 g, 0.738 mol) in anhydrous THF (1,600 mL) slowly over a period of 45 min while maintaining the temperature below −50° C. The mixture was stirred at −70° C. for 1 h. The progress of the reaction was monitored by TLC (2:3 EtOAc/heptane; stained using Hanessian solution) and GC. The reaction was cautiously quenched with saturated ammonium chloride solution (700 mL) when starting material was <15% by GC. The typical ratio of starting material: (a): (b) by GC was 3.1:70.5:26.4. The desired cis-nitrile (a) was a major and more polar compound by TLC. The reaction mixture was diluted with EtOAc (600 mL), DI water (300 mL), and stirred for 5 min. The phases were separated and the aqueous phase was extracted with EtOAc (600 mL). The combined organic phases were washed with brine (1 L), dried over MgSO₄and filtered. The filtrate was concentrated under reduced pressure at 40-45° C. to yield a residue which was purified by chromatography (10-40% EtOAc in heptane). The pure fractions of most polar compounds by TLC were pooled and concentrated to yield the cis nitrile (a) [114 g, 54.5%, 100% (AUC) by GC] as an off-white solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 7.85 (s, 1H), 7.7 (d, 1H), 7.55 (dd, 1H), 4.6 (s, 1H), 2.15-1.85 (m, 4H), 1.8 (dt, 2H), 1.6 (dd, 2H), 1.15 (s, 3H).

5.4.6. Synthesis of cis-4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-methylcyclohexanol

To a dry 5-L, three-neck flask equipped with a temperature probe, addition funnel, nitrogen line and overhead stirrer was charged with 1.0 M solution of BH₃.THF (980 mL, 0.984 mol) using canula under anhydrous atmosphere (Note: BH₃.THF is highly flammable; strictly anhydrous conditions are required). The solution was cooled to 10-15° C. and added to a solution of the cis-nitrile (a) (114 g, 0.401 mol) in anhydrous THF (1,400 mL) slowly over a period of 30 min while maintaining the temperature below 25° C. The mixture was stirred at room temperature overnight. The reaction was cautiously quenched with 6 M HCl (300 mL) until pH 2-2.0. The reaction mixture was concentrated under reduced pressure and the residue was taken into a 5-L flask equipped with overhead stirrer and addition funnel. DI water (500 mL) was added into the flask and adjusted pH to 9-10 using 6 M NaOH solution. The aqueous phase was extracted with dichloromethane (3×500 mL). The combined organic phases were taken into another 5-L flask and charged slowly with 6 M HCl (400 ml). The precipitated HCl salt was filtered and the filtrate was taken into a separating funnel. The aqueous phase was taken into a 5-L flask and charged with water (2 L) and the HCl salt. The pH of the mixture was adjusted to 9-10 using 6 M NaOH solution and extracted with dichloromethane (2 L). The combined organic phases were washed with brine (1 L), dried over MgSO₄and filtered. The filtrate was concentrated under reduced pressure at 40×5° C. to yield the title compound (104 g, 90%) as a foamy solid which was taken into next step without further purification. ¹H NMR (CD₃OD, 300 MHz): δ 7.45 (d and s merged, 2H), 7.25 (dd, 1H), 2.5 (s, 2H), 1.95 (dt, 2H), 1.7 (ddd, 2H), 1.45 (dt, 2H), 1.15 (ddd, 2H), 0.9 (s, 3H).

5.4.7. Synthesis of 4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-methylcyclohexanol (277)

To a 3-L, three-neck flask equipped with a temperature probe, nitrogen line and overhead stirrer was charged with cis-4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-methylcyclohexanol (99 g, 0.343 mol), 37% aqueous formaldehyde (80 mL), formic acid (80 mL) and cooled to 5-10° C. Sodium cyanoborohydride (72 g, 1.14 mol) was added in portions and stirred for 1 h at room temperature. The progress of the reaction was monitored by TLC (9:1:0.1 DCM/MeOH/TEA). After 2 h, the reaction was not complete. Additional 37% aqueous formaldehyde (3.2 mL), formic acid (3.2 mL), and sodium cyanoborohydride (2.88 g, 4.58 mmol) was added. The reaction was quenched with 6 M NaOH solution (100 mL) and concentrated under reduced pressure to give a residue which was diluted with dichloromethane (2 L), 6 M NaOH solution (500 mL), and brine (500 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (1 L). The combined organic phases were dried over MgSO₄and filtered. The filtrate was concentrated under reduced pressure at 40-45° C. to yield 277 (104 g, 96%) as an off-white solid which was taken into salt formation step without further purification. ¹H NMR (CDCl₃, 300 MHz): δ 7.45 (s, 1H), 7.4 (d, 1H), 7.2 (dd, 1H), 2.3 (s, 2H), 2.05 (dd, 1H), 2.0 (s, 6H), 1.9 (ddd, 2H), 1.55 (dd, 2H), 1.3 (m, 3H), 1.1 (s, 3H).

5.4.8. Preparation of 4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-methylcyclohexanol 277 hydrochloride

To a 3-L, three-neck flask equipped with a temperature probe, nitrogen line and overhead stirrer was charged with free base of 277 (crude from previous reaction, 0.328 mol) and ethanol (500 mL). The mixture was heated to 50° C. until a clear solution was obtained. The solution was cooled to room temperature and added to a solution of 2 M HCl in ether (200 mL) slowly. After 5 min, precipitation of HCl salt was observed. The slurry was stirred for 1 h at room temperature and filtered. The cake washed with a mixture of MTBE/EtOH (2:1, 200 mL) and dried over night under high vacuum to yield 277 hydrochloride [80.8 g, 70%, 98.0% (AUC) by HPLC]. ¹H NMR (D₂O, 300 MHz): δ 7.65 (d, 1H), 7.55 (d, 1H), 7.5 (dd, 1H), 3.5 (s, 2H), 2.5 (s, 6H), 2.15 (dd, 2H), 1.85 (dt, 2H), 1.5 (dd, 2H), 1.3 (dt, 2H), 0.05 (s, 3H).

Example 6

In Vitro Analyses (Monoamine Uptake Assays)

The compounds of the invention were tested for their inhibition of functional uptake of serotonin (5-HT), norepinephrine (NE), and dopamine (DA), in synaptosomes prepared from rat whole brain, hypothalamus, or corpus striatum, respectively, and/or using recombinant human transporters, as described herein, below. Compounds were initially tested at 10 μM in duplicate. Compounds showing ≧50% inhibition of uptake were further tested at 10 different concentrations in duplicate in order to obtain full inhibition curves. IC₅₀values (concentration inhibiting control activity by 50%) were then determined by nonlinear regression analysis of the inhibition curves. Results are summarized in Table 8, below.

6.1. Serotonin Functional Uptake Assay for Rat Reuptake Transporter

Quantification of 5-HT uptake was performed using synaptosomes isolated in a 0.32M sucrose buffer from a male Wistar rat cortex. The uptake of radiolabelled 5-HT by synaptosomes (100 μg of proteins/point) was allowed by incubating them in a well for 15 min at 37° C. in presence of test compounds and [³H]5-hydroxytryptamine (serotonin; 0.1 μCi/point).
Synaptosomes and [³H]serotonin were prepared in a Krebs buffer pH 7.4 containing 25 mM NaHCO₃, 11 mM glucose and 50 μM ascorbic acid. This incubation buffer was oxygenated during 5 minutes before incubation. Basal control was incubated for 15 minutes at 4° C. in order to avoid any uptake. Following this incubation the uptake was stopped by filtration through a unifilter 96-wells GFB Packard plate washed with Krebs buffer containing 25 mM NaHCO₃in order to eliminate the free [³H]serotonin. The radioactivity associated to the synaptosomes retained on the unifilter corresponding to the uptake was then measured with a microplate scintillation counter (Topcount, Packard) using a scintillation fluid. Nonspecific binding was measured in the presence of an excess of cold, unlabeled ligand. Specific binding was obtained by subtracting nonspecific binding from total binding.
The reference compound was imipramine tested at 10 concentrations ranging from 10⁻¹¹M to 10⁻⁵M in order to obtain an IC₅₀value. See, Perovics and Müller, Arzeim. Forsch./Drug Res., 45:1145-1148 (1995).

6.2. Serotonin Functional Uptake Assay for Human Reuptake Transporter

Inhibition of human serotonin reuptake transporter was assayed using the recombinant human serotonin transporter expressed in HEK-293 cells using a published method (Gu H et al., J. Biol. Chem. 1994, 269 (10): 7124-7130). HEK-293 cells expressing human serotonin transporter were plated before the assay. Test compound and/or vehicle was preincubated with cells in modified HEPES buffer pH 7.1 or pH 7.4 for 20 minutes at 18 to 25° C. and 65 nM [³H]serotonin was then added for an additional timed incubation period (ten to thirty minutes). Cells with internalized [³H]serotonin were washed and the amount of tritium taken into cells is counted using a liquid scintillation counter to determine [³H]serotonin uptake. Non-specific binding of tritium was measured in a control reaction containing 10 μM fluoxetine, and was subtracted from the counts for assays to correct for non-specific binding of tritium. Reduction of [³H]serotonin uptake by 50 percent or more (≧50%) relative to an uninhibited control reaction indicates significant inhibitory activity. Compounds were screened at 10, 1, 0.1, 0.01 and 0.001 μM. The reference compound for the assay was fluoxetine, for which the IC₅₀value of 7.1 nM was obtained in a typical experiment.

6.3. Dopamine Functional Uptake Assay for Rat Reuptake Transporter

Quantification of dopamine uptake was performed using synaptosomes isolated in a 0.32 M sucrose buffer from a male Wistar rat striatum. The uptake of radiolabelled dopamine by synaptosomes (20 μg of proteins/point) was allowed by incubating them for 15 minutes at 37° C. in the presence of test compounds and [³H]-dopamine (0.1 μCi/point). The experiment was performed in a deep well.
Synaptosomes and [³H]-dopamine were prepared in a Krebs buffer pH 7.4 containing 25 mM NaHCO₃, 11 mM glucose and 50 μM ascorbic acid. This incubation buffer was oxygenated for 5 minutes before incubation. Basal control was incubated for 15 minutes at 4° C. in order to avoid any uptake. Following this incubation, the uptake was stopped by filtration through a unifilter 96-wells GFB Packard plate washed with Krebs buffer containing 25 mM NaHCO₃in order to eliminate free [³H]-dopamine. The radioactivity associated to the synaptosomes retained onto the unifilter corresponding to the uptake was then measured with a microplate scintillation counter (Topcount, Packard) using a scintillation fluid.
The reference compound was GRB12909 tested at 8 concentrations ranging from 10⁻¹¹M to 10⁻⁶M in order to obtain an IC₅₀value. See, Jankowsky et al., J. Neurochem. 1986, 46:1272-1276).

6.4. Dopamine Functional Uptake Assay for Human Reuptake Transporter

Inhibition of human dopamine reuptake transporter was assayed using the recombinant human dopamine transporter expressed in either CHO-K1 or HEK293 cells using a published method (Pristupa, Z. B. et al., Mol. Pharmacol. 45: 125-135, 1994). Either CHO-K1 or HEK293 cells expressing human recombinant dopamine transporter were plated before the assay. Test compound and/or vehicle was preincubated with cells in modified HEPES buffer pH 7.1 or pH 7.4 for 20 minutes at 18 to 25° C. and 50 nM [³H]dopamine was then added for an additional timed incubation period (10 to 30 minutes). After washing the cells to remove [³H]dopamine not internalized, the cells were lysed, and the amount of tritium in the lysate was measured using a liquid scintillation counter to determine [³H]dopamine uptake. Non-specific binding of tritium was measured in a control reaction containing 10 μM nomifensine, and was subtracted from the counts for assays to correct for non-specific binding of tritium. Reduction of [³H]dopamine uptake by 50 percent or more (≧50%) relative to an uninhibited control reaction indicates significant inhibitory activity. Compounds were screened at 10, 1, 0.1, 0.01 and 0.001 μM. The reference compound for the assay was nomifensine, for which the IC₅₀value of 11 nM was obtained in a typical experiment.

6.5. Norepinephrine Functional Uptake Assay For Rat Reuptake Transporter

Quantification of norepinephrine uptake was performed using synaptosomes isolated in a 0.32 M sucrose buffer from a male Wistar rat hypothalamus. The uptake of radiolabelled norepinephrine by synaptosomes (100 μg of proteins/point) was allowed by incubating them for 20 minutes at 37° C. in presence of test compounds and [³H]-norepinephrine (0.1 μCi/point). The experiment was performed in a deep well.
Synaptosomes and [³H]-norepinephrine were prepared in a Krebs buffer pH 7.4 containing 25 mM NaHCO₃, 11 mM glucose and 50 μM ascorbic acid. This incubation buffer was oxygenated for 5 minutes before incubation. Basal control was incubated for 20 minutes at 4° C. in order to avoid any uptake. Following this incubation, the uptake was stopped by filtration through a unifilter 96-wells GFB Packard plate washed with Krebs buffer containing 25 mM NaHCO₃in order to eliminate the free [³H]-norepinephrine. The radioactivity associated to the synaptosomes retained onto the unifilter corresponding to the uptake was then measured with a microplate scintillation counter (Topcount, Packard) using a scintillation fluid.
The reference compound was protriptyline tested at 13 concentrations ranging from 10⁻¹¹M to 10⁻⁵M in order to obtain an IC₅₀value. See, Perovics and Müller, Arzeim. Forsch./Drug Res., 45:1145-1148 (1995).

6.6. Norepinephrine Functional Uptake Assay for Human Reuptake Transporter

Inhibition of human norepinephrine reuptake transporter was assayed using the recombinant human norepinephrine transporter expressed in either HEK293 or MDCK cells using a published method (Galli A et al., J. Exp. Biol. 198: 2197-2212, 1995). The cells were plated before the assay. Test compound and/or vehicle was preincubated with cells in modified HEPES buffer pH 7.1 or pH 7.4 for 20 minutes at 18 to 25° C. Following the preincubation, 25 nM [³H]norepinephrine was added for an additional timed incubation period (10 to 20 minutes). After the cells were washed to remove [³H]norepinephrine not internalized, the cells were lysed, and the amount of tritium in the cell lysate was measured using a liquid scintillation counter to determine [³H]norepinephrine uptake. Non-specific binding of tritium was measured in a control reaction containing 10 μM imipramine (or 10 μM nisoxetine), and was subtracted from the counts for assays to correct for non-specific binding of tritium. Reduction of [³H]norepinephrine uptake by 50 percent or more (≧50%) relative to an uninhibited control reaction indicates significant inhibitory activity. Compounds were screened at 10, 1, 0.1, 0.01 and 0.001 μM. The reference compounds for the assay were desipramine and nisoxetine, for which IC₅₀values of 1.9 nM and 5.3 nM respectively were obtained in typical experiments.

6.7. Results for Monoamine Uptake Assays

The results of the monoamine uptake assays are provided in Table 8, below.

TABLE 8


Summary of Results - In vitro Monoamine Uptake Assays

					Rat
		Human			IC₅₀
Cmpd.		IC₅₀(nM)			(nM)
No.	hSERT	hNET	hDAT	rSERT	rNET	rDAT

73	2240	6	1	710	15	6
74	19	4	1	30	6	10
27	201	273	150	500	150	95
75	169	85	21	110	20	58
76	156	9	1
77	158	19	4
170 E1	1030	189	1190
170 E2	673	26	427
78	651	36	2
172 E1	51	4	66
172 E2	89	127	762
174	246	2495	2781
175	55	15	125
176	533	612	775
177	3220	84	322
28	4560	1840	707
29	5240	1480	195
30	4520	>10,000	5870
31	>10,000	>10,000	>10,000
80	9170	>10,000	>10,000
79	768	270	884
101	96	529	268
102	195	586	420
100	1500	6630	3410
103	3540	5090	7740
81	2720	2190	3640
88	829	171	93
89	278	63	9
32	949	902	424
87	1470	334	139
82	55	9990	42
83	57	61	57
33	305	232	83
98	>10,000	782	419
105	1530	28	625
107	224	146	546
104	9490	516	5160
106	8330	816	1770
34	>10,000	6690	5320
35	>10,000	2970	4710
36	6550	1630	>10,000
37	>10,000	5760	>10,000
84	1870	326	395
85	102	51	26
96	688	137	170
97	31	10	11
95	480	160	324
91	>10,000	8550	1830
90	839	1850	3360
92	33	206	125
93	34	295	90
94	3	7	3
99	145	26	17
86	249	346	384
133 E1	969	217	355
133 E2	342	374	886
134 E1	260	179	598
134 E2	1260	132	149
173	1550	277	412
1	1290	175	103
41	898	22	82
165 E1	1580	183	66
165 E2	661	620	978
166 E1	176	310	245
166 E2	90	32	99
173 E1	1660	1350	388
173 E2	406	174	280
2	543	316	69
169 E2	332	22	87
169 E1	1100	242	778
152 E1	405	32	18
152 E2	77	157	585
153 E1	17	19	85
153 E2	64	135	25
42	935	280	761
cis 121	>10,000	2060	3390
E1
cis 121	3160	6580	>10,000
E2
trans	247	303	687
121 E1
trans	8150	392	665
121 E2
2 E1	406	167	180
2 E2	821	1040	770
108	65	36	85
43	15	7	64
3	331	888	<1
109	9674	114	12
4	637	2783	75
110	7932	790	2
111	8571	232	1.7
112	299	39	<1
298	>10,000	6730	76
184 E1	>10,000	2977	213
184 E2	>10,000	3385	789
187 E1	1896	1095	209
187 E2	376	928	17
116	2060	633	3
117	7903	405	33
115	>10,000	41	<1
114	>10,000	1813	16
113	2574	2217	285
185 E1	>10,000	>10,000	421
185 E2	>10,000	>10,000	121
190 E1	2962	442	24
190 E2	44	17	3	120	340	45
191 E1	2532	747	42
191 E2	426	74	2
45	5936	964	9
46	>10,000	>10,000	349
188 E1	4479	10000	426
188 E2	>10,000	5287	66
44 E1	12	10	36	14	2.2	150
cis 167	>10,000	>10,000	2217
trans	4912	1092	145
167
168	1465	732	108
253	906	949	37
254	294	19	<1	190	2.4	100
71	1298	1342	123
72	136	63	1.7
299	3873	2377	720
44 E2	239	570	219	210	44	1800
5	7115	5004	1522
287	1037	335	192
255	1421	2472	170
256	69	39	157	280	130	990
288	84	18	22	67	11	370
47	364	2894	5171
48 E2	149	441	297	230	74	550
48 E1	81	57	30	54	5.1	170
257	2075	6546	1999
259	5892	1179	665
6	>10,000	>10,000	1000
7	255	3987	527
260	2146	1772	306
261	30	62	7
262	>10,000	>10,000	4283
263	674	187	498
8	855	8733	996
9	>10,000	9987	>10,000
49	286	9217	739
10	1905	7446	2928
264	1052	194	17
11	7549	2811	532
265	109	3464	1454
266	168	2811	859
12	1517	5761	6043	1100	480	1900
57	1079	3177	1777	2200	740	2300
51	2948	>10,000	>10,000
50	1069	950	499
cis 124	6857	5934	5313
trans	2489	842	1475
124 E1
trans	227	288	187
124 E2
14	2953	257	46
267	1290	3256	147
268	704	241	27
269	787	36	<1
300	>10,000	7625	1733
301	>10,000	>10,000	8785
cis 125	684	399	871
trans	6	158	1408
125 E1
trans	32	783	1113
125 E2
52	44	1063	176
13	377	324	122
194	330	1832	2369
196	1445	732	911
197	227	67	450
192	>10,000	>10,000	1957
200	2051	3742	1100
201	261	518	88
204	2253	3457	296
205 E1	4208	999	800
205 E2	1714	326	12
cis 132i	708	5555	153
trans	28	353	140
132i
15	1398	>10,000	>10,000
206 E1	72	121	59
206 E2	306	7	<1
147 E1	94	5764	1391	18	370	1200
147 E2	2500	9706	1344	1700	1200	1500
148 E1	97	538	464	36	81	250
148 E2	229	1136	289	330	4900	680
53	<1	20	1	6.5	2.9	6.1
54	2387	857	85
55	<1	61	72
163 E1	43	2793	413	260	4200	1100
163 E2	139	2650	309	1900	3200	1500
164 E1	2	152	36	9.6	500	230
164 E2	13	194	40	45	720	140
195 E2	45	>10,000	5320
270	469	515	376
271	79	42	197
289	469	1467	282
290	992	>10,000	1388
17	657	119	29
16	1764	4034	4085
13 E1	187	528	66
18	3892	794	184
19	107	3177	2316
13 E2	60	779	108
56 E1	<1	21	28	2.9	2.3	24
56 E2	63	468	145	120	79	100
272	>10,000	9572	2601
273	830	474	528
274	809	321	251
275	1187	943	518
276	210	55	71	360	17	190
277	34	13	41	42	2.7	43
58 E1	6	23	63	9.5	3.6	22
58 E2	118	341	176	100	33	160
140 E1	2688	>10,000	8819
140 E2	>10,000	>10,000	5667
139 E1	>10,000	>10,000	>10,000
139 E2	>10,000	>10,000	>10,000
20	24	5847	275
20 E1	40	6439	369
20 E2	60	>10,000	437
21	2095	7192	43
207	142	3602	1025
209	1158	>10,000	4758
222	609	5347	2090
225	7	23	167
223	73	145	874
22	296	3727	141
155 E1	2986	>10,000	>10,000
155 E2	6281	>10,000	>10,000
136 E1	>10,000	6497	2871
136 E2	>10,000	>10,000	3375
138 E1	>10,000	1341	918
138 E2	6996	3946	2539
21 E1	9661	7606	234
21 E2	1235	6041	64
193 E2	957	>10,000	3163
193 E1	416	897	266
198	2324	>10,000	1940
202	868	1625	58
199	2188	2585	462
203	56	166	1.4
156 E1	76	>10,000	1310
156 E2	653	>10,000	3996
226	44	737	278
23	62	7678	682
22 E1	63	2624	136
22 E2	101	5566	112
208	1987	>10,000	7667
227	742	4103	5778
228	96	387	1565
229	11	33	40
224	69	665	993
154 E1	2170	3679	795
154 E2	439	981	888
16 E1	1755	1291	1286
16 E2	7296	1910	9248
211	55	1274	195
230	30	104	11
231 E1	1276	136	460
231 E2	63	19	83
291	185	784	72
212	91	948	75
213	283	2031	337
17 E1	355	66	71
17 E2	709	93	5
60 E1	184	86	748
60 E2	4632	3304	6740
61 E1	5947	1504	959
59 E2	4396	2197	3875
59 E1	1589	486	1754
61 E2	9442	1555	116
293	42	33	4
232	744	904	25
233	37	64	3
62 E1	3176	414	39
62 E2	4241	121	4
19 E1	1514	1901	696
19 E2	398	4027	735
234 E1	3382	820	346
234 E2	18	33	21
63 E2	2	1110	1818
64 E1	58	2797	>10,000
64 E2	32	2647	3640
63 E1	194	5946	6537
235	9	256	92
292	360	903	89
236	38	718	444
38	472	>10,000	9647
65	1618	3644	1936
66	221	587	355
278	5143	>10,000	3193
279	383	2477	1449
280	7	371	242
25	78	1029	90
26	740	2102	238
214	>10,000	10000	>10,000
237	7296	>10000	9129
238	1178	3533	5715
215	4192	>10000	6243
239	8661	7372	9451
240	1812	3694	9029
39	295	6644	2237
67	230	3149	1761
68	19	603	343
294	>10,000	>10,000	>10,000
281	256	788	384
282	296	289	186
283	20	41	37
216	>10,000	>10,000	>10,000
241	>10,000	>10,000	>10,000
242	7656	>10,000	>10,000
295	>10,000	>10,000	>10,000
217	47	1838	1975
243	26	293	851
244	14	59	334
24	364	6380	1370
141 E1	3687	2229	1252
141 E2	2771	10000	3665
142 E1	1898	>10,000	5247
142 E2	2315	>10,000	7852
218	480	>10,000	5587
245	538	10000	2274
246	43	984	282
40	753	7668	2324
69	930	2290	605
70	29	261	214
157 E1	1303	3725	575
157 E2	290	3446	849
158 E1	8439	7497	945
158 E2	2991	>10,000	5023
145 E1	75	10000	4726
145 E2	220	>10,000	6520
146 E1	4545	>10,000	>10,000
146 E2	2284	>10,000	>10,000
219	269	>10,000	>10,000
247	707	9690	10000
248	159	5689	7252
220	6150	10000	>10,000
249	405	>10,000	>10,000
250	47	1669	10000
284	7896	6662	2462
285	1139	4038	1897
286	46	182	198
162 E2	247	>10,000	>10,000
162 E1	495	>10,000	>10,000
161 E2	1.1	4395	4609
161 E1	9	8626	9950
221	61	5825	182
251	199	2131	107
252	11	108	6
252	12	134	5
143 E1	8611	>10,000	8787
143 E2	7172	>10,000	8630
144 E1	5626	>10,000	10000
144 E2	8748	>10,000	9858
159 E1	1255	>10,000	3801
159 E2	42	10000	2310
160 E1	7193	>10,000	9725
160 E2	5091	>10,000	>10,000
296	73	87	27
297	40	57	13

In Table 8, compound numbers correspond to those used in the Examples above. In addition, the following abbreviations have been used in Table I:SERT (serotonin transporter), NET (norepinephrine transporter) and DAT (dopamine transporter).
The above results indicate that compounds of the invention exhibit potent inhibition of neuronal uptake of NE, DA, and/or 5-HT, and compare favorably with potencies seen for various existing therapeutic agents. For example, reported potencies (IC₅₀or K_ivalues) of approved and launched drugs include: fluoxetine (PROZAC®), 7 nM for inhibition of human 5-HT reuptake transporter; methylphenidate (RITALIN®), 193 nM and 38 nM for inhibition of human dopamine and norepinephrine reuptake transporters, respectively (Eshleman et al., J. Pharmacol. Exp. Ther. 1999, 289: 877-885); amitriptyline (ELAVIL®), 63 nM and 67 nM for inhibition of the human norepinephrine and serotonin reuptake transporters, respectively and venlafaxine (EFFEXOR®, a so-called serotonin norepinephrine reuptake inhibitor (SNRI) 145 and 1420 nM, for inhibition of the human serotonin, and norepinephrine reuptake transporters respectively (Vaishnavi et al., Biol. Psychiatry. 2004, 55: 320-322). The multiple inhibition of the neuronal uptake of NE, DA and/or 5-HT displayed by the compounds of the invention provides the clinician with the ability to more effectively treat CNS disorders, including without limitation affective disorders, cerebral function disorders, anxiety disorders, neuropathic pain, and migraine or migraine headache, by elevating various monoamine levels in the brain simultaneously and over the same dose-range without the need to titrate separate drugs.

Example 7

Ex Vivo Binding Assays

Receptor occupancy of central noradrenaline (NA), 5-HT and dopamine (DA) transporter sites following peripheral administration of compounds was determined using [³H] nisoxetine, [³H] citalopram and [³H] WIN 35428 binding, respectively. Liquid scintillation counting was used to quantify the radioactivity.

7.1. Methods

C57BL/6 mice (25-30 g) were dosed orally with either vehicle or compound at 4 dose levels. Mice were sacrificed 60 minutes after treatment. Whole brains were removed and cortex and striata dissected out before being frozen on dry ice. The brain tissue was stored at −20° C. until the day of the assay. The cortex from each hemisphere was frozen separately. One was used to determine occupancy of NA transporter sites and the other occupancy of 5-HT transporter sites. Striatum was used to determine occupancy of DA transporter sites.

7.2. Membrane Preparation

Frontal cortex from each hemisphere or striata was homogenised individually in ice-cold assay buffer using a tight fitting glass/Teflon homogeniser and used immediately in the binding assay.
[³H] Citalopram Binding to 5-HT Transporter (SERT) Sites in Mouse Brain
Cortical membranes (400 μl; equivalent to 1.25 mg wet weight of tissue/tube) were incubated with 50 μl of [³H] citalopram at a single concentration of 1.3 nM and either 50 μl of buffer (total binding) or 50 μl of paroxetine (0.5 μM; non-specific binding) for 1 h at 27° C. For each animal, three tubes were used for the determination of total binding and three tubes were used for the determination of non-specific binding.
[³H] Nisoxetine Binding to Norepinephrine Transporter (NET) Sites in Mouse Brain
Cortical membranes (400 μl; equivalent to 6.0 mg wet weight of tissue/tube) were incubated with 50 μl of [³H] nisoxetine at a single concentration of 0.6 nM and either 50 μl of buffer (total binding) or 50 μl of mazindol (1 μM; non-specific binding) for 4 h at 4° C. For each animal, three tubes were used for the determination of total binding and three tubes were used for the determination of non-specific binding.
[³H] WIN 35428 Binding to DA Transporter (DAT) Sites in Mouse Brain
Striatal membranes (200 μl; equivalent to 2 mg wet weight of tissue/tube) were incubated with 25 μl of [³H] WIN 35428 at a single concentration of 24 nM and either 25 μl of buffer (total binding) or 25 μl of GBR12935 (1 μM; non-specific binding) for 2 h at 4° C. For each animal, two tubes were used for the determination of total binding and two tubes for the determination of non-specific binding.
Membrane bound radioactivity was recovered by filtration under vacuum through Skatron 11731 filters, presoaked in 0.5% PEI, using a Skatron cell harvester. Filters were rapidly washed with ice-cold phosphate buffer and radioactivity (dpm) was determined by liquid scintillation counting (1 ml Packard MV Gold scintillator).

7.3. Data Analysis

A value for specific binding (dpm) was generated by the subtraction of mean non-specific binding (dpm) from mean total binding (dpm) for each animal. Data are presented as mean specific binding (dpm) and as a percentage of the vehicle-treated control taken as 100%.

7.4. Results Summary

Ex vivo SERT, NET and DAT binding/receptor occupancy data were generated for selected compounds of the invention. Results are summarized in Table 9, below. Results showed that the compounds exhibited varying SERT, NET and DAT inhibition ratios.

TABLE 9


Ex Vivo Binding Profile in Mice.

Treatment	Mean Specific Binding (dpm) ± S.E.M.
Dose	(Values in Brackets Denote % Transporter Occupancy)

(mg/kg, PO)	NET	SERT	DAT

225	0	1570 ± 31	4639 ± 294	20453 ± 2500
	1	1170 ± 68 (25)*	3842 ± 152 (17)*	19787 ± 3338 (3)
	3	813 ± 64 (48)*	2118 ± 139 (54)*	21666 ± 3698 (−6)
	10	393 ± 21 (75)*	904 ± 35 (81)*	18872 ± 2775 (8)
	30	230 ± 33 (85)*	414 ± 37 (91)*	14618 ± 1209 (29)
48 E1	0	2405 ± 150	4345 ± 123	20378 ± 1315
	1	2111 ± 119 (12)	4398 ± 39 (−1)	20656 ± 1531 (−1)
	3	1911 ± 144 (21)*	3957 ± 224 (9)	18039 ± 1265 (11)
	10	954 ± 115 (60)*	2796 ± 100 (36)*	9792 ± 977 (52)*
	30	346 ± 55 (86)*	1003 ± 104 (77)*	3173 ± 541 (84)*
276	0	1541 ± 87	4269 ± 299	15011 ± 2450
	1	1602 ± 51 (−4)	3743 ± 199 (12)	18155 ± 2275 (−21)
	3	1631 ± 92 (−6)	3685 ± 292 (14)	16312 ± 2396 (−9)
	10	1553 ± 27 (−1)	3092 ± 207 (28)*	15879 ± 2265 (−6)
	30	1138 ± 59 (26)*	1558 ± 169 (64)*	10397 ± 931 (31)
58 E1	0	1763 ± 45	3410 ± 200	16873 ± 1162
	1	1705 ± 71 (3)	3245 ± 107 (5)	15732 ± 1360 (7)
	3	1748 ± 56 (1)	3021 ± 182 (11)	14938 ± 2613 (11)
	10	1262 ± 79 (28)*	1799 ± 115 (47)*	17215 ± 2151 (−2)
	30	502 ± 36 (71)*	469 ± 43 (86)*	12876 ± 2152 (24)
153 E2	0	1915 ± 57	3223 ± 109	20775 ± 1607
	1	1804 ± 79 (6)	3271 ± 199 (−1)	22774 ± 916 (−10)
	3	1726 ± 44 (10)	2968 ± 100 (8)	24159 ± 1313 (−16)
	10	1734 ± 62 (9)	2327 ± 150 (28)*	22015 ± 1912 (−6)
	30	1140 ± 53 (40)*	1359 ± 89 (58)*	16194 ± 1293 (22)
164 E1	0	1040 ± 76	3504 ± 223	21321 ± 1994
	1	1122 ± 58 (−8)	2796 ± 133 (20)*	23574 ± 1313 (−11)
	3	1046 ± 23 (−1)	2273 ± 74 (35)*	18002 ± 1516 (16)
	10	903 ± 48 (13)	783 ± 61 (78)*	17727 ± 2871 (17)
	30	610 ± 59 (41)	271 ± 50 (92)*	15630 ± 1085 (27)
56 E1	0	767 ± 34	3326 ± 78	43705 ± 2192
	1	616 ± 50 (20)*	2625 ± 138 (19)*	41561 ± 1611 (5)
	3	368 ± 17 (52)*	1346 ± 109 (58)*	42127 ± 2130 (4)
	10	106 ± 20 (86)*	278 ± 42 (91)*	33478 ± 1779 (23)*
	30	19 ± 2 (98)*	151 ± 60 (95)*	14637 ± 1567 (67)*
277	0	1007 ± 16	1423 ± 120	43023 ± 2628
	1	950 ± 46 (6)	1508 ± 86 (−6)	35827 ± 2302 (17)
	3	824 ± 30 (18)*	1491 ± 75 (−5)	34136 ± 4104 (21)
	10	533 ± 25 (47)*	1416 ± 43 (0)	33230 ± 2807 (23)
	30	294 ± 42 (71)*	1384 ± 101 (3)	31743 ± 4406 (26)

*p < 0.05, vs. vehicle (0); One Way ANOVA

Example 8

In Vivo Analyses

8.1. Rat Forced Swim Test

The method, which detects antidepressant activity, followed that described by Porsolt et al. (Eur. J. Pharmacol., 47, 379-391, 1978) and modified by Lucki et al. (Psychopharm., 121, 66-72, 1995). Rats forced to swim in a situation from which they cannot escape rapidly become immobile. Antidepressants decrease the duration of immobility. In addition, distinct patterns of active behaviors are produced by antidepressants that selectively inhibit norepinephrine (NE) and serotonin (5-HT) uptake in this test. Selective NE reuptake inhibitors decrease immobility by increasing climbing behaviors whereas selective 5-HT reuptake inhibitors decrease immobility by increasing swimming behaviors.
Rats were individually placed in a cylinder (Height=40 cm; Diameter=20 cm) containing 22 cm water (25° C.) for 15 minutes on the first day of the experiment (Session 1) and were then put back in the water 24 hours later for a 5 minute test (Session 2). The sessions were videotaped and duration of immobility as well as swimming and climbing behaviors during the 5 minute test were measured. Twelve rats were tested in each group. The test was performed blind. Compounds were typically evaluated at 3 doses (1-30 mg/kg), administered orally 2 times: 24 hours and 30-60 minutes before the test (Session 2), and compared with a vehicle control group. Desipramine (20 mg/kg i.p.), administered under the same experimental conditions, was used as the positive reference substance.
Data were analyzed by one way analysis of variance (ANOVA) followed by post-hoc comparisons where appropriate. An effect will be considered significant if p<0.05. Data are represented as the mean and standard error to the mean (s.e.m).

8.2. Mouse Tail Suspension Test

The method, which detects antidepressant activity, follows that described by Stéru et al. (Psychopharmacology, 85, 367-370, 1985). Rodents, suspended by the tail, rapidly become immobile. Antidepressants decrease the duration of immobility.
The behavior of the animal was recorded automatically for 5 minutes using a computerized device (Med-Associates Inc.) similar to that developed by Stéru et al. (Prog. Neuropsychopharmacol. Exp. Psychiatry, 11, 659-671, 1987). Ten to twelve mice were tested in each group. The test was performed blind. Compounds were typically evaluated at 3 doses (1-30 mg/kg), administered orally one time: 30-60 minutes before the test, and compared with a vehicle control group. Desipramine (100 mg/kg), administered under the same experimental conditions, was used as the positive reference substance.
Data were analyzed by one way analysis of variance (ANOVA) followed by post-hoc comparisons where appropriate. An effect was considered significant if p<0.05. Data are represented as the mean and standard error to the mean (s.e.m).

8.3. Locomotor Activity

In order to ensure effects of the compounds on immobility time were not related to a general stimulant effect on baseline motor activity, locomotor activity was assessed using photocell monitored cages (Med-Associates Inc.). Each test chamber was equipped with infrared photocell beams to measure movement of the animals. Horizontal and vertical activity were measured
Rats or mice were pretreated with vehicle or test compounds and placed back in home cage, following which they will be individually placed in locomotor cages and activity was monitored in 5 minute intervals for up to 60 min.
Data were analyzed by one way analysis of variance (ANOVA) followed by post-hoc comparisons where appropriate. An effect was considered significant if p<0.05. Data are represented as the mean and standard error to the mean (s.e.m).

8.4. Result Summary

Selected compounds of the invention were evaluated in the mouse tail suspension and locomotor activity test (Table 10). Results showed that all tested compounds exhibited an antidepressant-like profile (i.e., significantly decreased immobility time) with MED's in the range of 3-30 mg/kg, PO. At doses active in the tail suspension test, no change or a decrease in baseline motor activity was observed indicating that antidepressant-like activity was not due to a general stimulant effect.

Selected compounds of the invention were also evaluated in the rat forced swim and locomotor activity tests (Table 11). All tested compounds exhibited antidepressant-like effects with MED's in the range of 10-30 mg/kg, PO. The decrease in immobility produced by these compounds appeared to be due to increases in swimming and climbing behaviors indicative of mixed transporter activity (i.e., SNRI profiles). In conclusion, the tested compounds of the invention exhibited an anti-depressant profile in at least three animal models, the mouse tail suspension test and rat locomotor activity test as well as the rat forced swim test.

TABLE 10


Mouse Tail Suspension and Locomotor Activity Results

		Mouse Locomotor
	Mouse Tail Suspension	Activity
Treatment	Mean Immobility	Total Distance
Dose (mg/kg, PO)	Time ± S.E.M.	Traveled ± S.E.M.

153 E2	0	200.1 ± 5.8	537.2 ± 67.2
	3	195.4 ± 7.7	625.5 ± 88.8
	10	170.2 ± 6.3*	519.5 ± 88.4
	30	154.5 ± 8.4*	573.7 ± 63.6
44 E1	0	198.3 ± 7.6	660.0 ± 51.6
	3	188.9 ± 7.3	576.5 ± 66.9
	10	174.5 ± 8.1	721.1 ± 36.5
	30	120.4 ± 9.0*	402.3 ± 71.0*
93	0	204.6 ± 5.6	494.0 ± 64.1
	3	203.5 ± 8.0	644.0 ± 55.7
	10	185.4 ± 7.9	606.9 ± 72.4
	30	162.0 ± 8.1*	737.6 ± 89.5
48 E1	0	199.9 ± 6.7	647.7 ± 42.6
	3	189.8 ± 7.2	622.5 ± 101.6
	10	174.1 ± 5.8*	620.0 ± 79.4
	30	134.5 ± 9.6*	468.6 ± 114.2
134 E2	0	200.0 ± 6.7	782.8 ± 94.2
	3	191.4 ± 6.2	862.7 ± 100.4
	10	170.8 ± 6.0*	671.6 ± 63.3
	30	137.2 ± 7.2*	728.2 ± 107.7
75	0	194.2 ± 6.0	659.4 ± 63.1
	3	187.8 ± 9.6	653.5 ± 48.4
	10	177.7 ± 5.8	608.8 ± 83.4
	30	143.5 ± 5.8*	655.3 ± 117.7
148 E1	0	207.6 ± 7.8	445.7 ± 71.5
	3	193.7 ± 6.0	584.8 ± 65.7
	10	189.3 ± 5.9	486.3 ± 74.3
	30	174.5 ± 5.0*	559.6 ± 88.2
225	0	195.1 ± 4.1	735.2 ± 54.5
	0.3	188.1 ± 8.0	519.5 ± 56.4*
	1	186.5 ± 5.2	423.4 ± 62.3*
	3	158.5 ± 4.9*	415.9 ± 61.6*
225	0	192.5 ± 6.3	336.6 ± 77.5
	3	155.2 ± 6.0*	341.8 ± 78.3
	10	137.8 ± 5.2*	234.2 ± 49.4
	30	136.3 ± 2.5*	177.4 ± 47.8
164 E1	0	197.3 ± 7.0	509.4 ± 92.7
	3	183.8 ± 6.5	377.8 ± 67.6
	10	162.1 ± 4.6*	210.3 ± 40.4*
	30	155.3 ± 7.8*	494.0 ± 84.9
56 E1	0	203.6 ± 4.5	439.6 ± 63.5
	3	184.0 ± 4.8	410.2 ± 89.3
	10	174.8 ± 6.1*	440.2 ± 62.6
	30	141.9 ± 7.4*	252.2 ± 55.8
277	0	199.8 ± 6.1	378.9 ± 45.2
	3	182.3 ± 8.1	418.8 ± 80.6
	10	164.4 ± 6.8*	411.8 ± 87.8
	30	147.1 ± 3.1*	327.7 ± 67.1
276	0	202.7 ± 6.3	565.9 ± 104.3
	3	182.0 ± 4.2	625.9 ± 47.5
	10	164.1 ± 5.7*	382.4 ± 63.4
	30	160.2 ± 7.2*	607.8 ± 57.8
164 E2	0	184.6 ± 10.1	520.4 ± 103.8
	3	181.8 ± 6.3	518.2 ± 106.1
	10	179.1 ± 4.5	464.5 ± 86.2
	30	141.8 ± 6.0*	669.9 ± 75.6
17 E1	0	197.3 ± 5.6	463.0 ± 73.4
	3	184.7 ± 9.0	649.3 ± 78.4
	10	182.6 ± 4.1	478.3 ± 88.5
	30	150.9 ± 7.8*	428.3 ± 120.6

*p < 0.05, vs. vehicle (0); One Way ANOVA

TABLE 11


Rat Forced Swim and Locomoter Activity Results

		Rat Locomotor
Treatment		Activity
Dose		Total Distance
(mg/kg,	Rat Forced Swim (Means ± S.E.M.)	Traveled ±

PO)	Immobility	Swimming	Climbing	S.E.M.

48 E1	0	48.0 ± 2.1	4.8 ± 1.2	7.0 ± 1.5	1480.0 ± 67.4
	3	49.6 ± 1.5	3.7 ± 1.0	7.1 ± 0.6	1869.9 ± 188.4
	10	35.6 ± 3.5*	6.5 ± 1.6	17.9 ± 2.5*	1825.3 ± 109.3
	30	26.9 ± 4.4*	9.7 ± 1.7*	20.6 ± 2.9*	1840.6 ± 56.6
153	0	50.8 ± 1.8	1.0 ± 0.3	8.2 ± 1.8	1685.1 ± 106.8
E2	3	49.9 ± 1.7	1.9 ± 0.8	8.8 ± 1.5	1577.8 ± 80.1
	10	44.0 ± 2.1	4.3 ± 1.1*	11.7 ± 1.8	1994.2 ± 263.9
	30	31.3 ± 6.7*	4.6 ± 1.3*	22.2 ± 5.2*	2033.7 ± 215.4
93	0	48.5 ± 1.4	3.7 ± 0.7	7.8 ± 1.1	1682.2 ± 66.8
	3	44.5 ± 2.5	6.5 ± 1.6	9.0 ± 1.3	1802.6 ± 150.6
	10	41.4 ± 2.8	6.9 ± 1.3	12.8 ± 2.2	1641.0 ± 144.5
	30	25.8 ± 5.4*	12.0 ± 2.1*	22.2 ± 3.5*	2095.6 ± 147.2
277	0	46.5 ± 2.9	1.2 ± 0.6	12.1 ± 2.7	1586.0 ± 191.3
	3	50.4 ± 1.1	0.8 ± 0.3	9.0 ± 1.2	1406.2 ± 84.9
	10	42.5 ± 2.6	3.7 ± 0.9*	13.8 ± 2.3	1861.4 ± 187.8
	30	14.6 ± 3.5*	6.1 ± 1.4*	35.6 ± 5.2*	2612.4 ± 210.8*
225	0	52.4 ± 1.8	0.8 ± 0.4	6.8 ± 1.8	1610.3 ± 101.1
	3	50.8 ± 1.8	0.8 ± 0.3	8.4 ± 1.7	1783.4 ± 182.7
	10	47.6 ± 3.0	1.2 ± 0.6	11.1 ± 2.7	1628.5 ± 159.2
	30	33.4 ± 4.8*	1.1 ± 0.5	25.0 ± 4.6*	2182.8 ± 151.2*
56 E1	0	53.8 ± 0.6	0.4 ± 0.2	5.8 ± 0.7	1272.6 ± 113.2
	3	52.2 ± 1.6	0.3 ± 0.2	7.1 ± 1.6	1227.9 ± 84.4
	10	50.7 ± 1.0	0.8 ± 0.3	8.6 ± 0.9	1230.8 ± 64.8
	30	40.4 ± 2.7*	1.0 ± 0.4	17.9 ± 2.4*	1359.8 ± 132.7

*p < 0.05, vs. vehicle (0); One Way ANOVA

The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

Claims

1. A compound having a structure according to Formula (I):

wherein

n is an integer from 0 to 2;

s is an integer from 1 to 3;

m is an integer from 0 to 12, with the proviso that when n is 0, then m is not greater than 8; and when n is 1, then m is not greater than 10;

Ar is a member selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and a fused ring system;

each X is a member independently selected from the group consisting of H, halogen, CN, CF₃, OR⁵, SR⁵, acyl, C(O)OR⁵, C(O)NR⁶R⁷, S(O)₂R⁵, S(O)₂NR⁶R⁷, NR⁶R⁷, NR⁶S(O)₂R⁵, NR⁶C(O)R⁵, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl,

wherein

each R⁵, R⁶and R⁷is a member independently selected from the group consisting of H, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl,

wherein two of R⁵, R⁶and R⁷, together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring;

each R¹and R²is a member independently selected from the group consisting of H, halogen, CN, CF₃, OR⁸, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl,

wherein

R⁸is a member selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl; and

R³and R⁴are members independently selected from the group consisting of H, OR⁹, acyl, C(O)OR⁹, S(O)₂R⁹, N═N, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, with the proviso that when one member of R³and R⁴is N═N, then the other member is not present,

wherein

R⁹is a member selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl;

wherein

at least two of R¹, R², R³, R⁴and X, together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring;

at least one of R¹, R², R³and R⁴is optionally joined with Ar to form a 5- to 7-membered ring;

and any pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemic mixture, enantiomerically enriched mixture, and enantiomerically pure form thereof.

2. The compound according to claim 1, wherein said compound is chiral.

3. The compound according to claim 1 having a Formula, which is a member selected from the group consisting of Formula (II) and Formula (III):

4. The compound according to claim 3, said compound having a Formula, which is a member selected from the group consisting of:

wherein X¹and X²are members independently selected from the group consisting of H, OR⁵, SR⁵, halogen, CN, CF₃, S(O)₂R⁵, NR⁶R⁷, NR⁶S(O)₂R⁵, NR⁶C(O)R⁵, acyl, substituted or unsubstituted C₁-C₄alkyl and substituted or unsubstituted C₁-C₄heteroalkyl,

wherein at least two of R¹, R³, R⁴, X¹and X², together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring.

5. The compound according to claim 4, wherein X¹and X²are members independently selected from the group consisting of H, methyl, ethyl, n-propyl, OH, OMe, Ot, F, Cl, CN, CH₂OH, CH₂OMe, and CF₃.

6. The compound according to claim 4, wherein R¹is H or substituted or unsubstituted C₁-C₄alkyl.

7. The compound according to claim 4, wherein R³and R⁴are members independently selected from the group consisting of substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl.

8. The compound according to claim 3, wherein Ar is a member selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted naphthyl.

9. The compound according to claim 8, wherein Ar has a structure, which is a member selected from the group consisting of:

wherein

Y, Z, Y¹and Z¹are members independently selected from the group consisting of H, halogen, CF₃, CN, OR¹¹, SR¹¹, NR¹²R¹³, NR¹²S(O)₂R¹¹, NR¹²C(O)R¹¹, S(O)₂R¹¹, acyl, C(O)OR¹¹, C(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹²S(O)₂R¹¹, NR¹²C(O)R¹¹, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl,

wherein

two of Y, Z, Y1 and Z1, together with the atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring; and

each R¹¹, R¹²and R¹³is a member independently selected from the group consisting of H, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl,

wherein two of R¹¹, R¹²and R¹³, together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring.

10. The compound of claim 9, wherein Y, Z, Y¹and Z¹are members independently selected from the group consisting of H, CF₃, OR¹¹, SR¹¹, OCF₃, halogen and CN.

11. The compound of claim 9, wherein Ar has the structure:

12. A composition comprising a first stereoisomer and at least one additional stereoisomer of a compound according to claim 1, wherein said first stereoisomer is present in a diastereomeric excess of at least 80% relative to said at least one additional stereoisomer.

13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

14. A method of inhibiting binding of a monoamine transporter ligand to a monoamine transporter, said method comprising contacting said monoamine transporter and a compound of claim 1.

15. A method of inhibiting the activity of at least one monoamine transporter, said method comprising contacting said monoamine transporter and a compound of claim 1.

16. The method of claim 14 or 15, wherein said monoamine transporter is a member selected from the group consisting of serotonin transporter (SERT), dopamine transporter (DAT), norepinephrine transporter (NET) and combinations thereof.

17. The method of claim 15, wherein said compound inhibits the activity of at least two different monoamine transporters.

18. A method of inhibiting uptake of at least one monoamine by a cell, said method comprising contacting said cell and a compound of claim 1.

19. The method of claim 18, wherein said monoamine is a member selected from the group consisting of serotonin, dopamine, norepinephrine and combinations thereof.

20. The method of claim 18, wherein said compound inhibits uptake of at least two different monoamines.

21. The method of claim 18, wherein said cell is a neuronal cell.

22. A method of treating depression by inhibiting the activity of at least one monoamine transporter, said method comprising administering to a mammalian subject a compound of claim 1.

23. The method of claim 22, wherein said mammalian subject is a human.

24. The method of claim 22, wherein said compound inhibits said activity of at least two different monoamine transporters.

25. A method of treating a central nervous system disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1.

26. The method of claim 25, wherein said subject is a human.

27. The method of claim 25, wherein said central nervous system disorder is a member selected from the group consisting of depression, cognitive deficit, fibromyalgia, pain, sleep disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), restless leg syndrome, schizophrenia, anxiety, obsessive compulsive disorder, posttraumatic stress disorder, premenstrual dysphoria, and neurodegenerative disease.

28. The method according to claim 27, wherein said depression is a member selected from the group consisting of major depressive disorder (MDD), unipolar depression, bipolar disorder, seasonal affective disorder (SAD) and dysthymia.

29. The method according to claim 27, wherein said neurodegenerative disease is Parkinson's disease.

30. The method according to claim 27, wherein said sleep disorder is sleep apnea.

31. The method according to claim 27, wherein said pain is neuropathic pain.

32. A compound having a structure, which is a member selected from the group consisting of:

wherein

n is an integer from 0 to 2;

p is an integer from 0 to 2;

wherein

at least two of R¹, R²and X, together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring;

at least one of R¹and R²is optionally joined with Ar to form a 5- to 7-membered ring;

and any salt form, solvate, enantiomer, diastereomer, racemic mixture, enantiomerically enriched mixture, and enantiomerically pure form thereof.

33. The compound of claim 32, wherein p is 0.