HK1251831B - Cyclopropylmethanamines as selective 5-ht(2c) receptor agonists - Google Patents

Description

Cyclopropylmethylamine as a selective 5-HT(2C) receptor agonist

Government Interest Statement

This invention was made with government support under Grant No. R01 MH99993 awarded by NIH/NIDA. The government has certain rights in this invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Patent Application No. 62/109,104, filed January 29, 2015, which is incorporated herein by reference in its entirety.

Technical Field

The present invention relates to compounds that modulate 5-HT(2) receptors. More specifically, the present invention relates to highly selective 5-HT(2C) agonists. The compounds are useful in methods of treating diseases and conditions in which modulation of 5-HT(2) receptors provides a benefit, such as obesity and psychiatric disorders.

Background Art

Serotonin, or 5-hydroxytryptamine (5-HT), is the primary neurotransmitter found primarily in the gastrointestinal tract, platelets, and central nervous system (CNS). 5-HT is involved in regulating various physiological functions, such as intestinal motility, mood, cognition, and appetite (1). These functions are mediated through serotonin receptors, which belong to the G protein-coupled receptor (GPCR) superfamily and consist of seven subfamilies (5-HT _1-7 ) and 14 isoforms (2).

Recently, serotonin 2C (5-HT _2C ) receptors have been shown to be promising drug targets for the treatment of various CNS disorders, including obesity and psychiatric disorders such as schizophrenia, depression, and anxiety (3). In addition, based on studies of their distribution and biological functions, 5-HT(2C) receptors in the basal ganglia may be important for the regulation of repetitive movements, and in the cingulate gyrus they mediate many of the effects of neurotransmitters on obsessive-compulsive/compulsive behaviors. Therefore, 5-HT(2C) receptor agonists may be useful in the treatment of certain neurological disorders, such as Rett syndrome.

One of the many advantages of the 5- _HT2C receptor as a CNS drug target stems from the fact that it is present almost exclusively in the CNS (4). Therefore, compounds that selectively activate this receptor should have limited effects on peripheral tissues. However, activation of two other closely related 5- _HT2 subtypes, the 5- _HT2A and 5- _HT2B receptors, has been reported to be associated with hallucinations and valvular heart disease, respectively (5). Therefore, the identification of ligands with high selectivity for the 5- _HT2A and 5- _HT2B receptors is a key criterion for the advancement of 5- _HT2C agonist therapy. This goal has been challenging due to the high degree of conservation of the molecular determinants involved in ligand recognition within this receptor subfamily (6).

Currently, many 5-HT _2C agonists are being evaluated for potential therapeutic use or as chemical tools for studying the biological effects of the 5-HT _2C receptor (Table 1). Among them, lorcaserin (Belviq) is approved for the treatment of obesity. Although it is reported to have a 100-fold selectivity for 5-HT _2C relative to the 5-HT _2B subtype, lorcaserin has full agonist activity for 5-HT _2B (EC ₅₀ = 943 ± 90 nM, E _max = 100%) (7). Therefore, it is not surprising that lorcaserin was found to result in a higher incidence of valvular heart disease compared to the placebo group in clinical trials (8). Vabicaserin (SCA-136) targets the 5-HT _2C receptor (EC ₅₀ = 8 nM, E _max = 100%) and is being tested in clinical trials for the treatment of schizophrenia (9). However, it shows moderate efficacy ( _Emax = 50%) and good potency ( _EC50 = 12 or 102 nM, depending on receptor density) at the 5- _HT2B receptor (10). The pentacetin analog WAY-163909 shows selectivity for 5- _HT2C ( _EC50 = 8 nM; _Emax = 90%), but has no agonist activity at 5- _HT2A and weak potency at the 5- _HT2B receptor (Emax = 40%). WAY-163909 has good preclinical antipsychotic-like activity in several animal models (11). Compound CP-809,101 is one of the most selective and potent 5- _HT2C ( _EC50 = 0.11 nM, _Emax = 93%) ligands developed, with approximately 600-fold selectivity for 5- _HT2C relative to 5- _HT2B . However, it remains relatively potent against 5- _HT2B ( _EC50 = 65.3 nM, _Emax = 57%) (12). Due to the genotoxicity of this compound, it could not be advanced to clinical evaluation (13). Nevertheless, CP-809,101 has structural similarities to mCPP and MK-212, two compounds discovered decades ago and used as tools for pharmacological studies of the 5- _HT2C receptor (14).

Table 1. Representative 5-HT _2C agonists.

Compounds with a 2-phenylcyclopropylmethylamine backbone were developed as selective 5-HT _2C agonists. This particular backbone was derived from a preliminary high throughput screening (HTS) screening campaign in which tranylcypromine was identified as a hit (15). Studies led to the identification of compounds with a 2-cyclopropylmethoxy group at the 2-position, as shown in the compounds in Table 2. Compounds with fluorine substitution at the 5-position of the phenyl ring showed good potency at the 5-HT _2C receptor (EC ₅₀ = 21 nM) and only moderate selectivity for 5-HT _2B (EC ₅₀ = 289 nM) (16). Substitution of the fluorine atom with a hydroxyl group resulted in improved potency and selectivity, but the bioavailability was found to be too low (F = 3.2% in mice, unpublished data). Compounds lacking substitution at the same position showed good potency as partial agonists (EC ₅₀ = 55 nM, E _max = 61%) with excellent selectivity for 5-HT _2A and 5-HT _2B (17).

Table 2. Selective 5-HT _2C agonists based on the 2-phenylcyclopropylmethanamine framework.

These findings indicate a need in the art for drugs that selectively interact with 5-HT(2) receptor subtypes, particularly selective 5-HT(2C) receptor agonists that exhibit minimal effects on 5-HT(2A) and 5-HT(2B) receptors. Selective 5-HT(2C) receptor agonists may be used to treat obesity and related or associated conditions, including hypertension, hyperlipidemia, diabetes, and cardiovascular disease, while avoiding several related and unrelated receptor interactions that are associated with significant morbidity and mortality, such as valvular heart disease associated with activation of the 5-HT(2B) receptor subtype and hallucinations associated with activation of the 5-HT(2A) receptor subtype.

Selective 5-HT(2C) receptor agonists can be used to treat depression, anxiety, panic disorder, schizophrenia, OCD, epilepsy, migraine and Rett syndrome. In addition, WO 2006/065600 and WO 2007/025144 further disclose 5-HT(2C) receptor agonists for the treatment of Alzheimer's disease, for the prevention or treatment of senile plaques, and for the treatment of sexual dysfunction in men and women, including the treatment of erectile dysfunction.

Many synthetic compounds that exhibit 5-HT(2C) receptor agonist activity have been reported, including, for example, U.S. Patent Nos. 6,962,939, 6,777,407, 7,012,089, 6,953,787, and 7,071,185; U.S. Patent Publication Nos. 2005/197380, 2005/020573, 2006/154290, 2005/026925, 2005/0143452, 2002/032199; and 2005/0261347; and published PCT applications WO 2000/035922, WO 2006/065600, WO 2006/077025, and WO 2005/007614.

An important advance in the art would be the discovery that selective 5-HT(2C) receptor agonists can be used to treat diseases and conditions in which 5-HT(2C) receptor agonism provides a benefit, such as psychiatric disorders, addictive behaviors, cognitive disorders, obesity, movement disorders, and compound addiction. There is a significant need in the art for effective compounds, compositions, and methods for treating these diseases and conditions, either alone or in combination with other therapies for treating these diseases and conditions. The present invention is directed to meeting this need.

Summary of the Invention

The present invention relates to: 5-HT(2C) receptor agonists; pharmaceutical compositions comprising 5-HT(2C) receptor agonists; and methods for treating diseases and conditions in which 5-HT(2C) receptor agonism provides a benefit, such as psychiatric disorders and obesity, comprising administering a therapeutically effective amount of a 5-HT(2C) receptor agonist to a subject in need thereof. The 5-HT(2C) receptor agonists of the present invention exhibit selectivity relative to other members of the 5-HT(2) receptor family.

More specifically, the present invention relates to 5-HT(2C) agonists having structural formula (I):

,

wherein R ¹ is halogen;

R ² is C _1-5 alkyl, fluorinated C _1-3 alkyl, phenyl, benzyl, or –(CH ₂ ) _{1- 3} XCH ₃ ;

X is O or S;

R ^a is hydrogen, fluoro or C _1-3 alkyl; and

n is an integer 1, 2, or 3;

or a pharmaceutically acceptable salt or hydrate thereof.

The compounds of the present invention modulate 5-HT(2) family receptors, particularly 5-HT(2C) receptors. In some embodiments, the compounds of the present invention selectively modulate 5-HT(2C) receptors while exhibiting significantly less or no activity at 5-HT(2B) receptors. In some embodiments, the compounds of the present invention selectively modulate 5-HT(2C) receptors while exhibiting significantly less or no activity at 5-HT(2A) receptors. In preferred embodiments, the compounds of the present invention are selective agonists of 5-HT(2C) receptors while exhibiting significantly less or no activity at 5-HT(2A) receptors and/or 5-HT(2B) receptors.

In another embodiment, the present invention provides a method for treating a condition or disease by administering to a subject in need thereof a therapeutically effective amount of a 5-HT(2C) receptor agonist of structural formula (I). The target disease or condition can be treated by modulating the activity of the 5-HT(2C) receptor, for example, psychiatric disorders, addictive behaviors, cognitive disorders, obesity, movement disorders, and compound addiction.

Another embodiment of the present invention provides a method for treating a disease or condition by modulating 5-HT(2C) receptor activity, comprising administering to a subject in need thereof, such as a human, a therapeutically effective amount of a compound of formula (I). The compound of formula (I) can be administered as the sole therapy or in combination with a therapeutically effective amount of a second therapeutic agent for treating the disease or condition.

In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of structural formula (I) and a pharmaceutically acceptable excipient.

Another embodiment of the present invention is the use of a compound of structural formula (I) and optionally a second therapeutically active agent in a method of treating a disease or condition in a subject in which modulation of 5-HT(2C) receptor activity provides a benefit.

In another embodiment, the present invention provides the use of a composition comprising a compound of structural formula (I) and optionally a second therapeutic agent for the preparation of a medicament for treating a disease or condition of interest, such as a psychiatric disorder.

Another embodiment of the present invention is to provide a kit for human pharmaceutical use comprising: (a) a container, (b1) a packaging composition comprising a compound of structural formula (I), and optionally (b2) a packaging composition comprising a second therapeutic agent useful for treating a disease or condition of interest, and (c) a package insert comprising instructions for use of the composition or the combination for simultaneous or sequential administration for treating the disease or condition of interest.

The compound of structural formula (I) and the second therapeutic agent can be administered together as a single unit dose or separately as multiple unit doses, wherein the compound of structural formula (I) is administered before the second therapeutic agent, or vice versa. It is contemplated that one or more doses of the compound of structural formula (I) and/or one or more doses of the second therapeutic agent can be administered.

In one embodiment, the compound of formula (I) and the second therapeutic agent are administered simultaneously. In a related embodiment, the compound of formula (I) and the second therapeutic agent are administered as a single composition or separate compositions. In another embodiment, the compound of formula (I) and the second therapeutic agent are administered sequentially. The compound of formula (I) can be administered in an amount of about 0.005 to about 500 mg per dose, about 0.05 to about 250 mg per dose, or about 0.5 to about 100 mg per dose.

Another embodiment of the present invention is a method for modulating a 5-HT(2C) receptor in vivo or in vitro comprising contacting the receptor with one or more compounds of formula (I). In a specific embodiment, the method stimulates or activates a 5-HT(2C) receptor. In a specific embodiment, the compound of formula (I) is a 5-HT(2C) receptor agonist or selective agonist.

These and other novel aspects of the invention will become apparent from the following detailed description of the preferred embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 contains a graph of the cumulative distance traveled in an amphetamine stimulatory activity assay using compounds (+)-Example 25, (+)-Example 19, (+)-Example 8, and (+)-Example 10.

DETAILED DESCRIPTION

The present invention relates to novel modulators of 5-HT(2C) activity and their use in therapeutic treatment of conditions such as psychiatric disorders, obesity, cognitive disorders, addiction, movement disorders, and compound addiction. In some embodiments, the compounds of the invention selectively modulate 5-HT(2C) receptors relative to other 5-HT(2) receptors.

The present invention is described in conjunction with preferred embodiments. However, it should be understood that the present invention is not limited to the disclosed embodiments. It should be understood that, given the description of the embodiments of the present invention, those skilled in the art may make various modifications.

The term "disease or condition in which modulation of the 5-HT(2C) receptor provides a benefit" relates to conditions in which the 5-HT(2C) receptor and/or the effects of the 5-HT(2C) receptor are important or necessary, e.g., for the onset, progression, manifestation of the disease or condition, or diseases or conditions known to be treated by modulation of the 5-HT(2C) receptor. Examples of such conditions include, but are not limited to, schizoaffective disorder, anxiety disorders, panic disorder, adjustment disorders, schizophrenia, clinical depression, bipolar disorder, addictive behaviors, compound addictions (e.g., cocaine, methamphetamine, and amphetamines), adjustment disorders, obsessive-compulsive disorder, movement disorders (e.g., Huntington's disease, Parkinson's disease, and movement disorders), cognitive disorders (e.g., Alzheimer's disease and mild cognitive impairment), metabolic disorders (e.g., dyslipidemia, type 2 diabetes, metabolic syndrome, and obesity), chronic pain, dystonia, and eating disorders. One of ordinary skill in the art can readily determine, for any particular cell type, whether a compound treats a disease or condition mediated by the 5-HT(2C) receptor, for example, by assays readily available to assess the activity of a particular compound.

The term "second therapeutic agent" refers to a known therapeutic agent for treating a disease or condition of interest that is different from the compound of formula (I). For example, when obesity is the disease or condition of interest, the second therapeutic agent may be a known anti-obesity drug.

The terms "treatment" and "treatment" used herein refer to eliminating, alleviating, relieving, reversing and/or improving a disease or condition and/or symptoms associated therewith. Although not excluded, treating a disease or condition does not require complete elimination of the disease, condition or symptoms associated therewith, including treatment of acute or chronic signs, symptoms and/or dysfunction. The terms "treatment" and "treatment" used herein may include "preventive treatment," which refers to reducing the likelihood of redeveloping a disease or condition without a disease or condition, or reducing the likelihood of recurrence of a disease or condition that was previously controlled, so "treatment" also includes relapse prevention or stage prevention. The terms "treatment" and synonyms contemplate administering a therapeutically effective amount of a compound of the present invention to an individual in need of such treatment. Treatment can be performed for symptoms, such as suppressing symptoms. It can be performed in a short period of time, dominated in the medium term, or can be a long-term treatment, such as in the context of maintenance therapy.

As used herein, the term "therapeutically effective amount" or "effective dose" refers to an amount of an active ingredient which, when administered, is sufficient to effectively deliver the active ingredient for treating the condition or disease of interest in an individual in need thereof.

The term "container" refers to any receptacle and closure suitable for storing, transporting, dispensing, and/or handling a pharmaceutical product.

The term "package insert" refers to the information that accompanies a drug product and provides a description of how to administer the product, as well as the safety and efficacy data needed to allow physicians, pharmacists, and patients to make an informed decision about the use of the product. The package insert is often considered the "label" for a drug product.

"Concurrent administration," "combination administration," "simultaneous administration," and similar terms mean that two or more agents are administered to the subject being treated simultaneously. "Concurrent" means that each agent is administered simultaneously or sequentially in any order at different time points. However, if they are not administered simultaneously, it means that they are administered to the individual in sequence and close enough in time to provide the desired therapeutic effect and can work in unison. For example, a compound of structural formula (I) can be administered as a second therapeutic agent simultaneously or sequentially at different time points in any order. The compounds of the present invention and the second therapeutic agent can be administered separately in any appropriate form and by any suitable route. When the compounds of the present invention and the second therapeutic agent are not administered concurrently, it should be understood that they can be administered to the subject in need in any order. For example, a compound of the invention can be administered to a subject in need thereof prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or following (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administration of a second therapeutic agent. In various embodiments, the compound of structural formula (I) and the second therapeutic agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 to 2 hours apart, 2 to 3 hours apart, 3 to 4 hours apart, 4 to 5 hours apart, 5 to 6 hours apart, 6 to 7 hours apart, 7 to 8 hours apart, 8 to 9 hours apart, 9 to 10 hours apart, 10 to 11 hours apart, 11 to 12 hours apart, no more than 24 hours apart, or no more than 48 hours apart. In one embodiment, the components of the combination therapy are administered 1 minute to 24 hours apart.

The term "agonist" generally refers to a compound that interacts with and activates a receptor, such as one or more receptors in the 5-HT2 receptor family, and elicits a physiological or pharmacological response characteristic of that receptor.

The term "antagonist" generally refers to a compound that binds to a receptor at the same site as an agonist but does not activate the intracellular response elicited by the active form of the receptor, thus an antagonist can inhibit the intracellular response elicited by an agonist.

As used herein, the term "selective 5-HT(2C) receptor agonist" refers to an agonist compound that selectively binds to and activates the 5-HT(2C) receptor relative to other receptors in the 5-HT2 receptor family. The agonists of the present invention may be selective for the 5-HT(2C) receptor relative to the 5-HT(2B) receptor, selective for the 5-HT(2C) receptor relative to the 5-HT(2A) receptor, or selective for the 5-HT(2C) receptor relative to both the 5-HT(2B) and 5-HT(2A) receptors. In some embodiments, the 5-HT(2C) receptor agonists of the present invention may exhibit agonist activity relative to the 5-HT(2A) receptor. A selective 5-HT(2C) receptor agonist can exhibit 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, or 200-fold or more activity at the 5-HT(2C) receptor compared to either or both of the 5-HT(2B) or 5-HT(2A) receptors.

Selectivity can be assessed, for example, by determining the EC ₅₀ ratio for different receptors. Any reliable and accurate method known in the art for measuring receptor agonist activity can be used to assess the selectivity of a given agonist. As will be appreciated by those skilled in the art, selectivity can be determined, for example, using receptor binding assays or functional assays. In specific embodiments, the methods described in the Examples herein or the methods detailed in the references cited herein can be used. In specific embodiments herein, the 5-HT(2C) receptor agonists of the present invention can also exhibit selectivity for 5-HT receptor families other than the 5-HT2 family. In specific embodiments herein, the 5-HT(2C) receptor agonists of the present invention can exhibit antagonist activity against 5-HT(2B) receptors.

In some embodiments, the 5-HT(2C) receptor agonists of the present invention exhibit an EC ₅₀ value of 100 nM or less for activation of the human 5-HT(2C) receptor. In preferred embodiments, the 5-HT(2C) receptor agonists exhibit an EC ₅₀ value of 25 nM or less for activation of the human 5-HT(2C) receptor. In more preferred embodiments, the 5-HT(2C) receptor agonists exhibit an EC ₅₀ value of 10 nM or less for activation of the human 5-HT(2C) receptor. In some embodiments, the compounds of the present invention exhibit 5-fold or greater selectivity for 5-HT(2C) receptor agonists as compared to the 5-HT(2B) receptor or the 5-HT(2A) receptor, as assessed by determining the EC ₅₀ ratio. In some embodiments, the compounds of the present invention exhibit 10-fold or greater selectivity for 5-HT(2C) receptor agonists as compared to the 5-HT(2B) receptor or the 5-HT(2A) receptor, as assessed by determining the EC 50 ratio. In preferred embodiments, the compounds of the invention exhibit 100-fold or greater selectivity as agonists of the 5-HT(2C) receptor compared to the 5-HT(2B) receptor or the 5-HT(2A) receptor, as assessed by determining the EC50 ratio.

The use of the terms "a", "an", "the" and similar indicators in the context of describing the present invention (particularly in the context of the claims) should be interpreted as covering both the singular and the plural, unless otherwise indicated. Unless otherwise indicated herein, the description of a range of values herein is used only as a shorthand method of individually referring to each individual value falling within the range, and each individual value and sub-range is incorporated into this specification as if individually listed herein. The use of any and all examples or exemplary language (e.g., "such as" and "like") provided herein is intended to better illustrate the present invention, rather than to limit the scope of the present invention, unless otherwise indicated. Any language in the specification should not be construed as indicating that any non-claim element is necessary for implementing the present invention.

Selective 5-HT(2C) receptor agonists are known. For example, the following compounds are potent, moderately selective 5-HT(2C) agonists with 120- and 14-fold selectivity over 5-HT(2A) and 5-HT(2B), respectively ( _EC50 = 585, 65, and 4.8 nM for the 2A, 2B, and 2C subtypes, respectively). These compounds (10-60 mg/kg) also exhibit moderate antidepressant-like effects in commonly used behavioral assays.

However, this compound does not exhibit sufficient selectivity for the 5-HT(2B) receptor to be suitable as a potential clinical candidate. In particular, the degree of selectivity is considered too low to avoid side effects attributed to 5-HT(2B) activity. Therefore, new drug candidates with increased subtype selectivity are sought.

The present invention relates to a 5-HT(2C) receptor agonist of structural formula (I), a composition comprising a compound of structural formula (I), and a therapeutic use of a compound of structural formula (I):

wherein R ¹ is halogen;

R ² is C _1-5 alkyl, fluorinated C _1-3 alkyl, phenyl, benzyl, or –(CH ₂ ) _{1- 3} XCH ₃ ;

X is O or S;

R ^a is hydrogen, fluoro or C _1-3 alkyl; and

n is an integer 1, 2, or 3;

Or a pharmaceutically acceptable salt or hydrate thereof.

In some preferred embodiments, R ¹ is fluorine or chlorine. In other embodiments, n is 1 and R ¹ is fluorine or chlorine. In other embodiments, n is 2 and R ¹ is fluorine and fluorine, chlorine and chlorine, or fluorine and chlorine.

In other preferred embodiments, R ² is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, or isopentyl. In other preferred embodiments, R ² is phenyl or benzyl. In other embodiments, R ² is -CH ₂ CH ₂ F, -CH ₂ CH ₂ CH ₂ F, -CH ₂ CHF ₂ , or -CH ₂ CF ₃ .

In another embodiment, ^R2 is

,,or.

In yet another embodiment, ^R2 is

or.

Compounds of structural formula (I) modulate 5-HT(2C) receptors and are useful in treating a variety of diseases and conditions. In particular, compounds of structural formula (I) are useful in methods of treating diseases or conditions in which the activity of 5-HT(2C) receptors provides a benefit, such as psychiatric conditions and obesity. The methods comprise administering a therapeutically effective amount of a compound of structural formula (I) to a subject in need thereof.

The method further comprises administering to the subject a second therapeutic agent in addition to the compound of formula (I). The second therapeutic agent is selected from agents known to be useful for treating the disease or condition afflicting the subject, such as drugs and adjuvants, for example, therapeutic agents known to be useful for treating specific psychiatric disorders.

As used herein, the term "alkyl" refers to straight and branched chain saturated hydrocarbon groups, non-limiting examples of which include methyl, ethyl, and straight and branched chain propyl, butyl, and pentyl groups containing the specified number of carbon atoms. The term _Cn indicates that the alkyl group has "n" carbon atoms.

The term "halogen" is defined as fluorine, chlorine, bromine and iodine.

In addition, the present invention also includes salts of the 5-HT(2C) receptor agonists of the present invention, which can be used in the methods disclosed herein. The present invention also includes all possible stereoisomers and geometric isomers of the compounds of structural formula (I). The present invention includes racemic compounds and optical isomers. When the compound of structural formula (I) is required as a single enantiomer, it can be obtained by resolving the final product or by stereospecific synthesis from isomerically pure starting materials or using chiral auxiliary reagents, for example, see Z.Ma et al., Tetrahedron: Asymmetry, 8(6) , pages 883-888 (1997). The resolution of the final product, intermediate or starting material can be achieved by any suitable method known in the art. In addition, where tautomers of the compound of structural formula (I) are possible, the present invention is intended to include all tautomeric forms of the compound.

The compounds of the present invention may exist in salt form. In the methods of the present invention, pharmaceutically acceptable salts of the 5 HT(2C) receptor agonists of the present invention are generally preferred. As used herein, the term "pharmaceutically acceptable salt" refers to a salt or zwitterionic form of a compound of formula (I). The salt of the compound of formula (I) can be prepared during the final isolation and purification of the compound, or separately by reacting the compound with an acid having a suitable cation. The pharmaceutically acceptable salt of the compound of formula (I) can be an acid addition salt formed with a pharmaceutically acceptable acid. Examples of acids that can be used to form pharmaceutically acceptable salts include: inorganic acids such as nitric acid, boric acid, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; and organic acids such as oxalic acid, maleic acid, succinic acid, tartaric acid and citric acid. Non-limiting examples of salts of the compounds of the present invention include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogenphosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthenate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzenesulfonate, and p-toluenesulfonate. In addition, available amino groups present in the compounds of the present invention may be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. In view of the foregoing, any reference to the compounds of the present invention appearing herein is intended to include compounds of formula (I) and pharmaceutically acceptable salts, hydrates, or prodrugs thereof.

The compound of structural formula (I) may contain one or more asymmetric carbon atoms, so that the compound can exist in different stereoisomeric forms. The compound can be, for example, a racemate or an optically active form. Therefore, the present invention encompasses the racemic form of the compound of structural formula (I), as well as its respective enantiomers and non-racemic mixtures. The optically active form can be obtained by resolving the racemate or by asymmetric synthesis. In some preferred embodiments of the present invention, the enantiomer of the present invention exhibits a specific rotation [α] of + (positive). Preferably, the (+) enantiomer is substantially free of the corresponding (-) enantiomer. Therefore, an enantiomer that is substantially free of the corresponding enantiomer refers to a compound that is separated or separated by a separation technique or is prepared without the corresponding enantiomer. "Substantially free" means that the compound is composed of a significantly larger proportion of one enantiomer. In preferred embodiments, the compound is composed of at least about 90% by weight of the preferred enantiomer. In other embodiments of the present invention, the compound is composed of at least about 99% by weight of the preferred enantiomer. Preferred enantiomers can be separated from the racemic mixture by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and formation and crystallization of chiral salts or prepared by methods described herein. See, for example, Jacques, et al., "Enantiomers, Racemates and Resolutions" (Wiley Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL "Stereochemistry of Carbon Compounds" (McGraw-Hill, NY, 1962); Wilen, SH "Tables of Resolving Agents and Optical Resolutions" p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

It is hypothesized, but not relied upon, that the alkoxy substituent at the 2-position of the phenyl ring can be accommodated within a hydrophobic cavity, the size of which can vary between 5- _HT2C , 5- _HT2A , and 5- _HT2B receptors. This cavity may be slightly larger for the 5- _HT2C receptor compared to the 5- _HT2A and 5- _HT2B receptors because (a) a small group attached to the 2-position exhibits good activity (less selectivity) against all three subtypes and (b) increasing the size of the substituent results in decreased activity against 5- _HT2A and 5- _HT2B while retaining good activity against 5- _HT2C . Thus, by achieving an appropriate balance of size and lipophilicity, more potent 5- _HT2C agonists with improved selectivity relative to the 5- _HT2A and 5- _HT2B subtypes have been discovered.

Synthesis method

The compounds of the invention are prepared using the methods described herein or by routine modification or adaptation of the methods herein, for example, by selection of starting materials, or alteration of reagents, solvents and/or purification methods according to knowledge in the art.

All compounds can be prepared from the reported intermediates or by the following general scheme, starting from 2-methoxybenzaldehydes appropriately substituted on the phenyl ring. Aldehyde (A) is treated with N-methoxy-N-methyl-2-(triphenylphosphoranylidene)acetamide to give (E)-N-methoxy-3-(2-methoxyphenyl)-N-methylacrylamide (B), which, under Corey-Chaykovsky cyclopropanation conditions, affords the trans-conformation of the cyclopropane (C). Weinreb amide (C) is then reduced with DIBAl-H to afford the corresponding aldehyde (D), which is then reduced with _NaBH4 to afford the alcohol (E). Alcohol (E) is then converted to Gabriel imide (F) under Mitsunobu conditions, which can be deprotected with hydrazine to afford the primary amine (G). The methoxy ether (G) is converted to the phenol (H) using boron tribromide (BBr3), with the amino group protected as a Boc intermediate. Williamson ether synthesis or Mitsunobu conditions with phenols provide Boc intermediates (J), which are then deprotected to give compounds (I).

Separation of the N-Boc-amine by chiral HPLC followed by Boc deprotection afforded the (-) and (+) enantiomers in optically pure form.

Synthesis methods and compound characterization data

All chemicals and solvents were purchased from Sigma-Aldrich or Fisher Scientific and used without further purification. Microwave reactions were performed in a Biotage Initiator microwave synthesizer. Synthetic intermediates were purified by CombiFlash flash chromatography on 230-400 mesh silica gel. ¹ H and ¹³ C NMR spectra were recorded on a Bruker DPX-400 or AVANCE-400 spectrometer at 400 MHz and 100 MHz, respectively. NMR chemical shifts are reported in δ (ppm) using the residual solvent peak as a standard (CDCl ₃ : 7.26 ppm ( ¹ H), 77.23 ppm ( ¹³ C); CD ₃ OD: 3.31 ppm ( ¹ H), 49.15 ppm ( ¹³ C); DMSO-d ₆ : 2.50 ppm ( ¹ H), 39.52 ppm ( ¹³ C)). Mass spectra were measured using LC-MS MSD (Hewlett-Packard) in ESI mode with an ionization potential of 70 eV. The purity (greater than 95%) of all final compounds was determined by analytical HPLC (ACE 3AQC ₁₈ column (150×4.6 mm, particle size 3 μM), 0.05% TFA/H ₂ O/0.05% TFA in MeOH gradient elution system).

Example 1

(-)-(2-(5-chloro-4-fluoro-2-methoxyphenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-chloro-4-fluoro-2-methoxyphenyl)cyclopropyl)methanamine (HCl salt)

Route 1:

Step A: 5-Chloro-4-fluoro-2-hydroxybenzaldehyde

3-Fluoro-4-chlorophenol (14.8 g, 100 mmol) was dissolved in TFA (100 mL), and hexamethylenetetramine (16.8 g, 120 mmol) was added portionwise. The mixture was then refluxed overnight. After cooling to room temperature, concentrated H ₂ SO ₄ (4 mL) and H ₂ O (100 mL) were added and stirred for 10 minutes. The mixture was then extracted with CH ₂ Cl ₂ (3×100 mL) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by flash chromatography (0-30% EA in hexanes) to give the sub-title compound as a light yellow solid (5.8 g, 33%). ¹ H NMR (CDCl ₃ , 400 MHz) 11.22 (s, 1H), 9.80 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H).

Step B: 5-Chloro-4-fluoro-2-methoxybenzaldehyde

To a solution of 5-chloro-4-fluoro-2-hydroxybenzaldehyde (5.7 g, 33 mmol) in DMF ( _{50 mL} ) were added _K₂CO₃ (9.1 g, 66 mmol) and MeI (9.4 g, 66 mmol), and the mixture was stirred at room temperature for 3 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over _Na₂SO₄ , concentrated, and purified by flash chromatography to give a white solid (5.2 g, 84%). ^1H NMR ( _CDCl₃ , 400 MHz) 10.33 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 12.0 Hz, 1H), 3.94 (s, 3H).

Step C: (E)-3-(5-chloro-4-fluoro-2-methoxyphenyl)-N-methoxy-N-methylacrylamide

To a solution of 5-chloro-4-fluoro-2-methoxybenzaldehyde (4.1 g, 22 mmol) in CH ₂ Cl ₂ (100 mL) was added N-methoxy-N-methyl(triphenyl-phosphoranylidene)acetamide (9.5 g, 26 mmol), and the solution was stirred at room temperature overnight. The solvent was removed and the solid was purified by flash chromatography to give a white solid (6.2 g, 84%). ¹ H NMR (CDCl ₃ , 400MHz) 7.90 (d, J = 16.0 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 16.0Hz, 1H), 6.72 (d, J = 10.8 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.32 (s, 3H).

Step D: 2-(5-chloro-4-fluoro-2-methoxyphenyl)-N-methoxy-N-methylcyclopropanecarboxamide

To a suspension of trimethylsulfoxide iodide (8.8 g, 40 mmol) in anhydrous DMSO (50 mL) was added portionwise NaH (60% in mineral oil, 1.6 g, 40 mmol) under argon. The mixture was stirred at room temperature for 1 hour, then a solution of (E)-3-(5-chloro-4-fluoro-2-methoxyphenyl)-N-methoxy-N-methylacrylamide (5.5 g, 20 mmol) in anhydrous DMSO (50 mL) was slowly added. The resulting clear solution was stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried _{over Na₂SO₄} , concentrated, and purified by flash chromatography to give a white solid (4.9 g, 85%). ¹ HNMR (CDCl ₃ , 400 MHz) 6.92 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 10.8 Hz, 1H), 3.80 (s, 3H), 3.71 (s, 3H), 3.24 (s, 3H), 2.63 – 2.58 (m, 1H), 2.29 – 2.24(m, 1H), 1.59 – 1.54 (m, 1H), 1.27 – 1.21 (m, 1H).

Step E: (2-(5-chloro-4-fluoro-2-methoxyphenyl)cyclopropyl)methanol

A solution of 2-(5-chloro-4-fluoro-2-methoxyphenyl)-N-methoxy-N-methylcyclopropanecarboxamide (5.0 g, 17.4 mmol) in anhydrous THF (80 mL) was cooled to -78°C under argon. DIBAL-H (1.0 M in cyclohexane, 26.1 mL, 26.1 mmol) was added to the solution, and the solution was stirred at the same temperature for 2 hours. A saturated aqueous Rochelle salt solution (100 mL) was added, the mixture was warmed to room temperature, and extracted with ethyl acetate. The combined extracts were dried _{over Na₂SO₄} , filtered, and concentrated to yield a colorless oil. The oil was then dissolved in MeOH (100 mL), and _NaBH₄ (1.2 g, 31.6 mmol) was added portionwise. After stirring at room temperature for 30 minutes, 1N HCl (30 mL) was added, the mixture was concentrated, _and extracted with _CH₂Cl₂ . The combined extracts were washed with brine, dried over Na ₂ SO ₄ , concentrated, and purified by flash chromatography to give a colorless oil (3.7 g, 92%). ¹ H NMR (CDCl ₃ , 400 MHz) 6.93 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 10.8 Hz,1H), 3.86 – 3.82 (m, 4H), 3.31 (dd, J = 11.2, 8.4 Hz, 1H), 1.88 (br, 1H), 1.84 - 1.79 (m, 1H), 1.20 – 1.16 (m, 1H), 1.03 – 0.98 (m, 1H), 0.90 – 0.85 (m, 1H).

Step F: 2-((2-(5-chloro-4-fluoro-2-methoxyphenyl)cyclopropyl)methyl)isoindoline-1,3-dione

A solution of (2-(5-chloro-4-fluoro-2-methoxyphenyl)cyclopropyl)methanol (3.40 g, 14.7 mmol), triphenylphosphine (5.03 g, 19.2 mmol) and phthalimide (3.25 g, 22.1 mmol) in anhydrous THF (100 mL) was cooled with an ice bath and DEAD (3.34 g, 19.2 mmol) was slowly added. The solution was then allowed to warm to room temperature and stirred overnight. The solution was concentrated to give the crude product, which was purified by flash chromatography (0-20% ethyl acetate/hexanes) to give a white solid (5.0 g, 94%). ¹ H NMR (CDCl ₃ , 400 MHz) 7.89 – 7.86 (m, 2H), 7.75 – 7.72 (m, 2H), 6.84 (d, J =8.4 Hz, 1H), 6.52 (d, J = 11.2 Hz, 1H), 3.79 (dd, J = 14.0, 6.8 Hz, 1H), 3.63(dd, J = 14.0, 8.0 Hz, 1H), 3.49 (s, 3H), 2.08 – 2.03 (m, 1H), 1.40 – 1.35(m, 1H), 1.02 – 0.93 (m, 2H).

Step G: tert-Butyl ((2-(5-chloro-4-fluoro-2-methoxyphenyl)cyclopropyl)methyl)carbamate

To a solution of 2-((2-(5-chloro-4-fluoro-2-methoxyphenyl)cyclopropyl)methyl)isoindoline-1,3-dione (5.0 g, 13.9 mmol) in EtOH (80 mL) was added hydrazine hydrate ( _{N₂H₄ - 1.5H₂O} , 2.5 g, 41.7 mmol), and the mixture was refluxed for 3 hours. After cooling to room temperature, the solvent was removed under vacuum to give a white solid, which was dissolved in 1N NaOH (100 mL) _and extracted with _CH₂Cl₂ . The combined extracts were washed with brine, dried _{over Na₂SO₄} , and filtered. _Et₃N (3.9 mL, 27.8 mmol) and _Boc₂O (4.6 g, 20.8 mmol) were then added, and the solution was stirred at room temperature for 30 minutes. Concentration and purification by flash chromatography afforded the title compound as a white solid (3.9 g, 85%). ¹ H NMR (CDCl ₃ , 400 MHz) 6.91(d, J = 8.4 Hz, 1H), 6.64 (d, J = 10.8 Hz, 1H), 5.19 (br, 1H), 3.87 (s, 3H),3.54 – 3.50 (m, 1H), 2.74 – 2.69 (m, 1H), 1.74 – 1.69 (m, 1H), 1.45 (s, 9H), 1.01 – 0.95 (m, 2H), 0.83 – 0.80 (m, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 158.0 (d, J _CF = 8.2 Hz), 157.0 (d, J _CF = 244.7 Hz), 155.9, 128.2, 127.3 (d, J _CF = 3.4Hz), 111.3 (d, J _CF = 17.6 Hz), 99.8 (d, J _CF = 25.0 Hz), 79.1, 55.9, 45.1, 28.6, 21.1, 16.4, 11.1.

Step H: Racemic tert-butyl ((2-(5-chloro-4-fluoro-2-methoxyphenyl)cyclopropyl)methyl)carbamate (500 mg) was then separated using chiral HPLC (RegisPack chiral column (25 cm×21.1 mm, 10 μM), elution system: 4.75% EtOH/n-hexane (isotonic), flow rate: 18 mL/min). (+)-tert-butyl ((2-(5-chloro-4-(2-(5-chloro-4-fluoro-2-methoxyphenyl)cyclopropyl)methyl)carbamate (170 mg, 100% ee) was separated as the first peak and (−)-tert-butyl ((2-(5-chloro-4-(2-(5-chloro-4-fluoro-2-methoxyphenyl)cyclopropyl)methyl)carbamate was separated as the second peak (165 mg, 98% ee).

Step I: (-)-(2-(5-chloro-4-fluoro-2-methoxyphenyl)cyclopropyl)methanamine (HCl salt)

tert-Butyl (+)-((2-(5-chloro-4-fluoro-2-methoxyphenyl)cyclopropyl)methyl)carbamate (140 mg, 0.42 mmol) was dissolved in 2M HCl(g)/ _Et2O (10 mL) and stirred at room temperature for 48 hours. The white solid was collected by filtration and dried in vacuo to give the sub-title compound (85 mg, 75%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.06 (d, J =8.4 Hz, 1H), 6.91 (d, J = 11.2 Hz, 1H), 3.89 (s, 3H), 3.08 (dd, J = 13.2, 7.2Hz, 1H), 2.93 (dd, J = 13.2, 8.0 Hz, 1H), 2.06 - 2.00 (m, 1H), 1.29 - 1.21(m, 1H), 1.13 - 1.08 (m, 1H), 1.04 - 0.98 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ159.8, 158.6 (d, J _CF = 235.0 Hz), 129.2, 128.0, 112.0 (d, J _CF = 17.9 Hz), 101.2 (d, J _CF = 25.4 Hz), 56.8, 45.1, 19.3, 17.7, 12.9; [α] _D ²⁰ -37.4 ( c 0.5, MeOH).

Step J: (+)-(2-(5-chloro-4-fluoro-2-methoxyphenyl)cyclopropyl)methanamine (HCl salt)

tert-Butyl (-)-((2-(5-chloro-4-fluoro-2-methoxyphenyl)cyclopropyl)methyl)carbamate (135 mg, 0.41 mmol) was dissolved in 2M HCl(g)/ _Et2O (10 mL) and stirred at room temperature for 48 hours. The white solid was collected by filtration and dried in vacuo to give the sub-title compound (70 mg, 64%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.06 (d, J =8.4 Hz, 1H), 6.91 (d, J = 11.2 Hz, 1H), 3.89 (s, 3H), 3.08 (dd, J = 13.2, 7.2Hz, 1H), 2.92 (dd, J = 13.2, 8.0 Hz, 1H), 2.06 - 2.00 (m, 1H), 1.28 - 1.21(m, 1H), 1.14 - 1.08 (m, 1H), 1.04 - 0.98 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ159.8, 158.6 (d, J _CF = 234.8 Hz), 129.2, 128.0, 112.1 (d, J _CF = 17.8 Hz), 101.2 (d, J _CF = 25.7 Hz), 56.8, 45.1, 19.3, 17.7, 12.9; [α] _D ²⁰ +35.6 ( c 0.5, MeOH)

Example 2

(-)-(2-(5-Chloro-2-ethoxy-4-fluorophenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-Chloro-2-ethoxy-4-fluorophenyl)cyclopropyl)methanamine (HCl salt)

Route 2:

Step A: tert-Butyl ((2-(5-chloro-4-fluoro-2-hydroxyphenyl)cyclopropyl)methyl)carbamate

A solution of tert-butyl ((2-(5-chloro-4-fluoro-2-methoxyphenyl)cyclopropyl)methyl)carbamate (4.6 g, 13.9 mmol) in anhydrous DCM (50 mL) was cooled to -78°C under argon. Boron tribromide (1.0 M in DCM, 50 mL) was added via syringe, and the solution was stirred at the same temperature for 2 hours. MeOH (20 mL) was slowly added, the mixture was warmed to room temperature, and concentrated. The residue was suspended in DCM, _Et₃N (8.4 mL, 60 mmol) was slowly added, followed by _Boc₂O (4.37 g, 20 mmol). The mixture was stirred at room temperature for 30 minutes, then 1N HCl was added and stirred for an additional 5 minutes. The organic layer was then separated, washed with saturated _NaHCO₃ and brine, dried _{over Na₂SO₄} , concentrated, and purified by flash chromatography to give the sub-title compound as a white solid (3.2 g, 73%). ¹ H NMR (CDCl ₃ , 400 MHz) 7.84 (br, 1H), 6.89 (d, J =8.0 Hz, 1H), 6.68 (d, J = 10.4 Hz, 1H), 5.10 (br, 1H), 3.49 – 3.45 (m, 1H),2.89 – 2.86 (m, 1H), 1.85 – 1.82 (m, 1H), 1.47 (s, 9H), 1.07 – 1.02 (m, 1H), 0.86 – 0.82 (m, 1H), 0.74 – 0.70 (m, 1H).

Step B: tert-Butyl ((2-(5-chloro-2-ethoxy-4-fluorophenyl)cyclopropyl)methyl)carbamate

To a solution of tert-butyl ((2-(5-chloro-4-fluoro-2-hydroxyphenyl)cyclopropyl)methyl)carbamate (170 mg, 0.53 mmol) in anhydrous DMF (2 mL) was added _K2CO3 (148 _mg , 1.07 mmol) and EtI (168 mg, 1.07 mmol), and the mixture was heated in a microwave reactor at 80°C for 1 hour. Water was added, the mixture was extracted with ethyl acetate, and the combined extracts were dried over _{Na2SO4 ,} concentrated, and purified by flash chromatography to give the sub-title compound as a colorless oil (150 mg, 82%). ¹ H NMR (CDCl ₃ , 400 MHz) 6.91 (d, J = 8.0 Hz, 1H), 6.64 (d, J = 10.8 Hz, 1H), 5.09 (br, 1H), 4.06 (q, J = 7.2 Hz, 2H), 3.59 – 3.56 (m, 1H), 2.73 – 2.68 (m,1H), 1.75 – 1.72 (m, 1H), 1.52 (t, J = 6.4 Hz, 3H), 1.45 (s, 9H), 1.01 – 0.97(m, 2H), 0.81 – 0.77 (m, 1H).

Step C: The racemic form of tert-butyl ((2-(5-chloro-2-ethoxy-4-fluorophenyl)cyclopropyl)methyl)carbamate (150 mg) was then separated by chiral HPLC using a RegisPack chiral column (25 cm × 21.1 mm, 10 µM), elution system: 4.75% EtOH/n-hexane (isotonic), flow rate: 18 mL/min.). (+)-tert-butyl ((2-(5-chloro-2-ethoxy-4-fluorophenyl)cyclopropyl)methyl)carbamate (50 mg, 100% ee ) was separated as the first peak, and (-)-tert-butyl ((2-(5-chloro-2-ethoxy-4-fluorophenyl)cyclopropyl)methyl)carbamate (50 mg, 90% ee ) was separated as the second peak.

Step D: (-)-(2-(5-chloro-2-ethoxy-4-fluorophenyl)cyclopropyl)methanamine (HCl salt)

The sub-title compound was prepared as described in Example 1 from tert-butyl (+)-((2-(5-chloro-2-ethoxy-4-fluorophenyl)-cyclopropyl)methyl)carbamate using 2M HCl(g)/diethyl ether. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.05 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 11.2 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.06(dd, J = 13.2, 7.2 Hz, 1H), 2.97 (dd, J = 13.2, 8.0 Hz, 1H), 2.07 - 2.04 (m,1H), 1.46 (t, J = 7.2 Hz, 3H), 1.31 - 1.27 (m, 1H), 1.11 - 1.07 (m, 1H), 1.04– 1.00 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 159.0, 158.5 (d, J _CF = 243.8 Hz),129.1, 128.1, 112.0 (d, J _CF = 17.9 Hz), 101.9 (d, J _CF = 25.6 Hz), 65.9, 45.1,19.2, 17.9, 15.1, 13.3; [α] _D ²⁰ -30.6 ( c 0.5, MeOH).

Step E: (+)-(2-(5-chloro-2-ethoxy-4-fluorophenyl)cyclopropyl)methanamine (HCl salt)

The sub-title compound was prepared as described in Example 1 from tert-butyl (-)-((2-(5-chloro-2-ethoxy-4-fluorophenyl)cyclopropyl)methyl)carbamate using 2M HCl (g) in diethyl ether. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.05 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 11.2 Hz, 1H), 4.09 (q, J = 6.8 Hz, 2H), 3.06 (dd, J = 12.8, 7.2 Hz, 1H), 2.97 (dd, J = 13.2, 8.0 Hz, 1H), 2.07 - 2.03 (m, 1H), 1.46 (t, J = 7.2 Hz, 3H), 1.32 - 1.27 (m, 1H), 1.11 - 1.07 (m, 1H), 1.04 –1.00 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 159.0, 158.5 (d, J _CF = 243.6 Hz),129.1, 128.0, 112.0 (d, J _CF = 17.6 Hz), 101.9 (d, J _CF = 25.0 Hz), 65.9, 45.1,19.2, 17.8, 15.1, 13.3; [α] _D ²⁰ +28.8 ( c 0.5, MeOH).

Example 3

(-)-(2-(5-chloro-4-fluoro-2-isopropoxyphenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-chloro-4-fluoro-2-isopropoxyphenyl)cyclopropyl)methanamine (HCl salt)

Route 3:

Step A: tert-Butyl ((2-(5-chloro-4-fluoro-2-isopropoxyphenyl)cyclopropyl)methyl)carbamate

To a solution of tert-butyl ((2-(5-chloro-4-fluoro-2-hydroxyphenyl)cyclopropyl)methyl)carbamate (315 mg, 1.0 mmol) in anhydrous DMF (2 mL) were added _{K2CO3 (} 276 mg, 2.0 mmol) and 2-iodopropane (340 mg, 2.0 mmol), and the mixture was heated in a microwave reactor at 90°C for 2 hours. Water was added, the mixture was extracted with ethyl acetate, and the combined extracts were dried _{over Na2SO4} , concentrated, and purified by flash chromatography to give the sub-title compound as a colorless oil (160 mg, 45%). ¹ H NMR (CDCl ₃ , 400 MHz) 6.90 (d, J = 7.6 Hz, 1H), 6.65 (d, J =10.8 Hz, 1H), 5.09 (br, 1H), 4.57 – 4.51 (m, 2H), 3.60 – 3.58 (m, 1H), 2.70 – 2.64 (m, 1H), 1.74 – 1.70 (m, 1H), 1.46 – 1.40 (m, 15H), 1.03 – 0.99 (m, 1H), 0.96 – 0.92 (m, 2H), 0.81 – 0.78 (m, 1H).

Step B: The racemic form of this compound (150 mg) was then separated using chiral HPLC using the same procedure as described in Example 1 and Example 2 to give tert-butyl (+)-((2-(5-chloro-4-fluoro-2-isopropoxyphenyl)cyclopropyl)methyl)carbamate (70 mg, 100% ee ) and (-)-tert-butyl ((2-(5-chloro-4-fluoro-2-isopropoxyphenyl)cyclopropyl)methyl)carbamate (50 mg, 95% ee ) as the second peak.

Step C: (-)-(2-(5-chloro-4-fluoro-2-isopropoxyphenyl)cyclopropyl)methanamine (HCl salt) and (+)-(2-(5-chloro-4-fluoro-2-isopropoxyphenyl)cyclopropyl)methanamine (HCl salt)

(-)-(2-(5-Chloro-4-fluoro-2-isopropoxyphenyl)cyclopropyl)methanamine (HCl salt) and (+)-(2-(5-chloro-4-fluoro-2-isopropoxyphenyl)cyclopropyl)methanamine (HCl salt) were prepared from tert-butyl (+)-((2-(5-chloro-4-fluoro-2-isopropoxyphenyl)cyclopropyl)methyl)carbamate and tert-butyl (-)-((2-(5-chloro-4-fluoro-2-isopropoxyphenyl)cyclopropyl)methyl)carbamate, respectively, using 2M HCl (g) in diethyl ether.

(-)-(2-(5-Chloro-4-fluoro-2-isopropoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.04 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 11.6 Hz, 1H), 4.66 – 4.60 (m, 1H), 3.15 (dd, J = 12.8, 6.8 Hz, 1H), 2.89 (dd, J = 12.8, 8.4 Hz, 1H), 2.06 -2.01 (m, 1H), 1.45 - 1.30 (m, 7H), 1.08 – 0.99 (m, 2H); [α] _D ²⁰ -33.4 ( c 0.5, MeOH).

(+)-(2-(5-Chloro-4-fluoro-2-isopropoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.04 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 11.6 Hz, 1H), 4.66 – 4.60 (m, 1H), 3.15 (dd, J = 12.8, 6.8 Hz, 1H), 2.89 (dd, J = 12.8, 8.4 Hz, 1H), 2.06 -2.01 (m, 1H), 1.45 - 1.30 (m, 7H), 1.08 – 0.99 (m, 2H); [α] _D ²⁰ +32.8 ( c 0.5, MeOH).

Example 4

(-)-(2-(5-chloro-4-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-chloro-4-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

Route 4:

Step A: tert-Butyl ((2-(5-chloro-4-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methyl)carbamate

A solution of tert-butyl ((2-(5-chloro-4-fluoro-2-hydroxyphenyl)cyclopropyl)methyl)carbamate (316 mg, 1.0 mmol), 2-fluoroethanol (192 mg, 3 mmol), and triphenylphosphine (787 mg, 3 mmol) in anhydrous THF (3 mL) was cooled at 0°C. To this solution was added diethyl azodicarboxylate (522 mg, 3 mmol) dropwise. The mixture was then heated in a microwave at 60°C for 1 hour, then concentrated and purified by flash chromatography (0-30% ethyl acetate in hexanes) to afford the sub-title compound as a colorless oil (280 mg, 78%). ¹ H NMR (CDCl ₃ , 400 MHz) 6.93 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 10.8 Hz, 1H), 4.98 (br, 1H), 4.93 – 4.88 (m, 2H), 4.28 – 4.19(m, 2H), 3.52 – 3.48 (m, 1H), 2.82 – 2.79 (m, 1H), 1.82 – 1.79 (m, 1H), 1.45 (s, 9H), 1.05 – 0.95 (m, 2H), 0.85 – 0.80 (m, 1H).

Step B: (+) - tert-Butyl((2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methyl)carbamate (90 mg, >99% ee ) and (-)-tert-Butyl((2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methyl)carbamate (90 mg, >99% ee ) were prepared using chiral HPLC as described above.

Step C: (-)-(2-(5-chloro-4-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt) and (+)-(2-(5-chloro-4-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

Using the same method as above with HCl/ _Et2O , (-)-(2-(5-chloro-4-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt) and (+)-(2-(5-chloro-4-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt) were prepared from tert-butyl (+) - ((2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methyl)carbamate and tert-butyl (-)-((2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methyl)carbamate, respectively.

(-)-(2-(5-chloro-4-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt) ¹ H NMR (400 MHz, CD ₃ OD) δ 7.10 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 11.2 Hz, 1H), 4.86 -4.76 (m, 2H), 4.35 - 4.24 (m, 2H), 3.05 - 2.97 (m, 2H), 2.10 - 2.04 (m, 1H),1.26 - 1.15 (m, 2H), 1.05 - 1.00 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 158.6,158.5 (d, J _CF = 244.2 Hz), 129.5, 128.3, 112.7 (d, J _CF = 17.8 Hz), 102.3 (d, J _CF = 25.4 Hz), 83.3 (d, J _CF = 167.0 Hz), 69.7 (d, J _CF = 18.8 Hz), 45.0, 19.5,17.8, 12.6; [α] _D ²⁰ -26.4 ( c 0.5, MeOH).

(+)-(2-(5-chloro-4-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.10 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 10.8 Hz, 1H), 4.86 -4.75 (m, 2H), 4.34 - 4.24 (m, 2H), 3.04 - 2.98 (m, 2H), 2.09 - 2.04 (m, 1H),1.25 - 1.15 (m, 2H), 1.05 - 1.00 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 158.6,158.5 (d, J _CF = 243.9Hz), 129.5, 128.3, 112.7 (d, J _CF = 17.5 Hz), 102.3 (d, J _CF = 25.5 Hz), 83.3 (d, J _CF = 167.1 Hz), 69.7 (d, J _CF = 19.0 Hz), 45.0, 19.5,17.8, 12.6; [α] _D ²⁰ +28.4 ( c 0.5, MeOH).

Example 5

(-)-(2-(2-(Allyloxy)-5-chloro-4-fluorophenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(2-(Allyloxy)-5-chloro-4-fluorophenyl)cyclopropyl)methanamine (HCl salt)

Route 5:

The title compound was prepared using a similar method as described above via Scheme 5. The first step used allyl bromide and an alkylating agent in the presence _{of K2CO3} as a base and DMF as a solvent.

(-)-(2-(2-(Allyloxy)-5-chloro-4-fluorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.07 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 11.2 Hz, 1H), 6.18 -6.08 (m, 1H), 5.47 (dd, J = 13.6, 1.6 Hz, 1H), 5.34 (dd, J = 10.4, 1.6Hz,1H), 4.62 (d, J = 5.2 Hz, 2H), 3.06 (dd, J = 12.8, 7.2 Hz, 1H), 2.98 (dd, J =12.8, 8.0 Hz, 1H), 2.11 - 2.05 (m, 1H), 1.32 - 1.28 (m, 1H), 1.13 - 1.01 (m,2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 158.5, 158.4 (d, J _CF = 243.8 Hz), 134.3, 129.2,128.3, 118.8, 112.3 (d, J _CF = 17.6 Hz), 102.4 (d, J _CF = 25.4 Hz), 70.9, 45.0,19.2, 17.9, 13.2; [α] _D ²⁰ -36.2 ( c 0.5, MeOH).

(+)-(2-(2-(Allyloxy)-5-chloro-4-fluorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.07 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 11.2 Hz, 1H), 6.17 -6.08 (m, 1H), 5.47 (dd, J = 13.6, 1.6 Hz, 1H), 5.34 (dd, J = 11.2, 1.2 Hz,1H), 4.62 (d, J = 5.2 Hz, 2H), 3.06 (dd, J = 11.2, 7.2 Hz, 1H), 2.99 (dd, J =12.8, 5.6 Hz, 1H), 2.11 - 2.05 (m, 1H), 1.32 - 1.28 (m, 1H), 1.13 - 1.01 (m,2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 158.5, 158.4 (d, J _CF = 243.7 Hz), 134.3, 129.2,128.3, 118.8, 112.3 (d, J _CF = 17.6 Hz), 102.4 (d, J _CF = 25.4 Hz), 70.9, 45.0,19.2, 17.9, 13.2; [α] _D ²⁰ +34.6 ( c 0.5, MeOH).

Example 6

(-)-(2-(5-chloro-4-fluoro-2-(prop-2-yn-1-yloxy)phenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-chloro-4-fluoro-2-(prop-2-yn-1-yloxy)phenyl)cyclopropyl)methanamine (HCl salt)

Route 6:

The title compound was prepared using a method similar to that described above via Scheme 6. In the first step propargyl bromide was used as the alkylating agent.

(-)-(2-(5-chloro-4-fluoro-2-(prop-2-yn-1-yloxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.11 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 10.8 Hz, 1H), 4.85(d, J = 2.4 Hz, 2H), 3.12 (t, J = 1.6 Hz, 1H), 3.07 (dd, J = 13.2, 7.2 Hz,1H), 2.95 (dd, J = 12.8, 8.0 Hz, 1H), 2.06 - 2.02 (m, 1H), 1.27 - 1.23 (m,1H), 1.16 - 1.12 (m, 1H), 1.05 – 1.00 (m, 1H);[α] _D ²⁰ -31.4 ( c 0.5, MeOH).

(+)-(2-(5-chloro-4-fluoro-2-(prop-2-yn-1-yloxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.11 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 11.2 Hz, 1H), 4.85(d, J = 2.4 Hz, 2H), 3.12 (t, J = 1.6 Hz, 1H), 3.07 (dd, J = 13.2, 7.2 Hz,1H), 2.95 (dd, J = 12.8, 8.0 Hz, 1H), 2.06 - 2.02 (m, 1H), 1.27 - 1.23 (m,1H), 1.16 - 1.11 (m, 1H), 1.05 – 1.00 (m, 1H); [α] _D ²⁰ +31.2 ( c 0.5, MeOH).

Example 7

(-)-(2-(5-Fluoro-2-propoxyphenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-Fluoro-2-propoxyphenyl)cyclopropyl)methanamine (HCl salt)

Route 7:

The title compound was prepared using tert-butyl ((2-(5-fluoro-2-hydroxyphenyl)cyclopropyl)methyl)carbamate (prepared according to US20130281539) as the starting material using Scheme 7. 1-Iodopropane was used as the alkylating agent in the first step.

(-)-(2-(5-Fluoro-2-propoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD)δ 6.93 – 6.86 (m, 2H), 6.73 (dd, J = 9.4, 3.2 Hz, 1H), 6.17 – 6.10 (m, 1H),5.45 (dd, J = 17.2, 1.6 Hz, 1H), 5.30 (dd, J = 10.4, 1.6 Hz, 1H), 4.60 (d, J = 5.6 Hz, 2H), 3.06 (dd, J = 13.2, 7.6 Hz, 1H), 2.98 (dd, J = 13.2, 4.2 Hz,1H), 2.21 – 3H), 2.15 (m, 1H), 1.34 – 1.30 (m, 1H), 1.14 – 1.02 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 158.8 (d, J _CF = 225.7 Hz), 154.9, 135.0, 133.0 (d, J _CF = 7.4 Hz), 118.2, 114.3 (d, J _CF = 17.8 Hz), 114.1, 114.0 (d, J _CF = 37.3 Hz), 71.0,45.1, 19.7, 18.3, 13.7; HRMS (ESI) calcd for [M+H]: 224.1451, Found: 224.1428; [α] _D ²⁰ -16.2 ( c 0.4, MeOH).

(+)-(2-(5-Fluoro-2-propoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD)δ 6.92 – 6.84 (m, 2H), 6.72 (dd, J = 9.6, 2.8 Hz, 1H), 4.02 – 3.93 (m, 2H),3.14 (dd, J = 13.2, 6.8 Hz, 1H), 2.91 (dd, J = 13.2, 8.0 Hz, 1H), 2.21 – 2.15(m, 1H), 1.91 – 1.81 (m, 2H), 1.38 – 1.33 (m, 1H), 1.12 – 1.02 (m, 5H); ¹³ CNMR (100 MHz, CD ₃ OD) δ 158.6 (d, J _CF = 235.2 Hz), 155.4, 132.8 (d, J _CF = 6.8 Hz), 114.0 (d, J _CF = 24.0 Hz), 113.9 (d, J _CF = 23.2 Hz), 113.8 (d, J _CF = 8.3 Hz), 71.7, 45.1, 23.9, 19.6, 18.4, 13.9, 11.1; HRMS (ESI) calcd for [M+H]: 224.1451, found: 224.1428; [α] _D ²⁰ +22.5 ( c 0.5, MeOH).

Example 8

(-)-(2-(2-(Allyloxy)-5-fluorophenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(2-(Allyloxy)-5-fluorophenyl)cyclopropyl)methanamine (HCl salt)

Route 8:

The title compound was prepared via Scheme 8 using a method similar to that described above.

(-)-(2-(2-(Allyloxy)-5-fluorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz,CD ₃ OD) δ 6.93 – 6.86 (m, 2H), 6.73 (dd, J = 9.4, 3.2 Hz, 1H), 6.17 – 6.10 (m,1H), 5.45 (dd, J = 17.2, 1.6 Hz, 1H), 5.30 (dd, J = 10.4, 1.6 Hz, 1H), 4.60(d, J = 5.6 Hz, 2H), 3.06 (dd, J = 13.2, 7.6 Hz, 1H), 2.98 (dd, J = 13.2, 4.2Hz, 1H), 2.21 - 2.15 (m, 1H), 1.34 - 1.30 (m, 1H), 1.14 - 1.02 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 158.8 (d, J _CF = 225.7 Hz), 154.9, 135.0, 133.0 (d, J _CF = 7.4 Hz), 118.2, 114.3 (d, J _CF = 17.8 Hz), 114.1, 114.0 (d, J _CF = 37.3 Hz), 71.0,45.1, 19.7, 18.3, 13.7; HRMS (ESI) calcd for [M+H]: 222.1294, Found: 222.1273; [α] _D ²⁰ -16.2 ( c 0.4, MeOH).

(+)-(2-(2-(Allyloxy)-5-fluorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz,CD ₃ OD) δ 6.93 – 6.86 (m, 2H), 6.73 (dd, J = 9.6, 3.2 Hz, 1H), 6.17 – 6.10 (m,1H), 5.45 (dd, J = 17.2, 1.6 Hz, 1H), 5.30 (dd, J = 10.4, 1.6 Hz, 1H), 4.60(d, J = 4.2 Hz, 2H), 3.07 (dd, J = 12.8, 7.2 Hz, 1H), 2.98 (dd, J = 13.2, 5.6Hz, 1H), 2.21 - 2.17 (m, 1H), 1.35 - 1.31 (m, 1H), 1.14 - 1.04 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 158.8 (d, J _CF = 235.7 Hz), 155.0, 135.0, 133.0 (d, J _CF = 7.4 Hz), 118.2, 114.3 (d, J _CF = 17.0 Hz), 114.1, 114.0 (d, J _CF = 36.1 Hz), 71.0,45.1, 19.7, 18.3, 13.7; HRMS (ESI) calcd for [M+H]: 222.1294, Found: 222.1273; [α] _D ²⁰ +17.5 ( c 0.2, MeOH).

Example 9

(-)-(2-(5-Fluoro-2-((2-fluoroallyl)oxy)phenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-Fluoro-2-((2-fluoroallyl)oxy)phenyl)cyclopropyl)methanamine (HCl salt)

Route 9:

The title compound was prepared via Scheme 9 using a method similar to that described above.

(-)-(2-(5-Fluoro-2-((2-fluoroallyl)oxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 6.98 (dd, J = 8.8, 4.4 Hz, 1H), 6.90 (dt, J = 8.0, 2.8 Hz, 1H), 6.76 (dd, J = 9.2, 2.8 Hz, 1H), 4.88 (dd, J = 14.0, 3.2 Hz, 1H), 4.80 (dd, J = 41.6, 2.8 Hz, 1H), 4.66 (d, J = 14.0 Hz, 2H), 3.11 (dd, J = 13.2, 7.2 Hz,1H), 2.95 (dd, J = 13.2, 8.0 Hz, 1H), 2.21 – 2.15 (m, 1H), 1.37 – 1.32 (m,1H), 1.15 – 1.05 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 163.0 (d, J _CF = 256.2 Hz), 159.2 (d, J _CF = 236.7 Hz), 154.5, 133.5 (d, J _CF = 7.4 Hz), 114.8 (d, J _CF = 8.4Hz), 114.3, 114.2 (d, J _CF = 48.3 Hz), 94.8 (d, J _CF = 16.7 Hz), 67.8 (d, J _CF =32.4 Hz), 45.0, 19.8, 18.2, 13.7; HRMS (ESI) calculated for [M+H]: 240.1200, found: 240.1178; [α] _D ²⁰ -14.3 ( c 0.75, MeOH).

(+)-(2-(5-Fluoro-2-((2-fluoroallyl)oxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 6.98 (dd, J = 8.8, 4.4 Hz, 1H), 6.90 (dt, J = 8.0, 2.8 Hz, 1H), 6.76 (dd, J = 9.2, 2.8 Hz, 1H), 4.88 (dd, J = 14.0, 3.2 Hz, 1H), 4.80 (dd, J = 41.6, 2.8 Hz, 1H), 4.66 (d, J = 14.0 Hz, 2H), 3.11 (dd, J = 13.2, 6.8 Hz,1H), 2.95 (dd, J = 13.2, 8.0 Hz, 1H), 2.21 – 2.16 (m, 1H), 1.37 – 1.33 (m,1H), 1.16 – 1.05 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 163.0 (d, J _CF = 256.2 Hz), 159.2 (d, J _CF = 236.6 Hz), 154.5, 133.5 (d, J _CF = 7.5 Hz), 114.9 (d, J _CF = 8.6Hz), 114.3, 114.2 (d, J _CF = 45.5 Hz), 94.8 (d, J _CF = 16.7 Hz), 67.8 (d, J _CF =32.3 Hz), 45.0, 19.8, 18.3, 13.7; HRMS (ESI) calcd for [M+H]: 240.1200, found: 240.1176; [α] _D ²⁰ +16.0 (c 0.3, MeOH).

Example 10

(-)-(2-(5-Fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-Fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

Route 10:

The title compound was prepared via Scheme 10 using a method similar to that described above.

(-)-(2-(5-Fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 6.97 – 6.86 (m, 2H), 6.76 (dd, J = 9.2, 2.8 Hz, 1H), 4.87 – 4.75 (m,2H), 4.32 – 4.20 (m, 2H), 3.04 – 3.00 (m, 2H), 2.19 - 2.15 (m, 1H), 1.28 -1.17 (m, 2H), 1.06 - 1.02 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 159.0 (d, J _CF =236.0 Hz), δ 1.17 (d, JCF = 1.17), 1.2 (d, _JCF = 2.17), 1.14 (d, JCF = 2.17), 1.2 (d, JCF = 2.17), 1.2 (d, _JCF = 2.17), _1.2 (d, JCF = 2.17), 1.2 (d, _JCF = 2.17), 1.2 (d, JCF = 2.17), 1.2 (d, JCF = 2.17), 1.2 (d, JCF ₌ 2.17), 1.2 (d, JCF = 2.17), 1.2 (d, JCF = 2.17), 1.2 (d, JCF = 2.17) _, 1.2 (d, JCF = 2.17 ₎ , ^1.2 (d, JCF = 2.17), 1.2

(+)-(2-(5-Fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz,CD ₃ OD) δ 6.97 – 6.88 (m, 2H), 6.76 (dd, J = 9.6, 3.2 Hz, 1H), 4.87 – 4.74 (m,2H), 4.32 – 4.22 (m, 2H), 3.03 (d, J = 7.6 Hz, 2H), 2.20 – 2.15 (m, 1H), 1.28– 1.25 (m, 1H), 1.22 – 1.17 (m, 1H), 1.07 – 1.02 (m, 1H); ¹³ C NMR (100 MHz,CD ₃ OD) δ δ 1.57 (d, J _CF ) = 1.44 (d, J CF ) = 1.37 (d, J _{CF ) = 1.69 (d, J CF} ) = 2.17 (d, J _CF ) = 2.17 (d, J CF ) = 1.93 (d, J _CF ) = 2.17 (d, J CF ) = 2.17 (d, J CF ) = 2.16 (d, J _CF ) = 2.17 (d, J _CF ) = 2.16 (d, J CF ) = 2.17 (d, J CF ) = 2.16 (d, J _CF ) = 2.17 (d, J CF ) = 2.16 (d, J CF ) = 2.17 (d, J CF ) = 2.16 (d, J CF ) = 2.17 (d, _J CF ) = 2.16 (d, MeOH ) = 2.15 (d, MeOH ) = 2.15 (d, MeOH ) = 2.15 (d, MeOH ) ⁼ 2.15 ( d , MeOH ) = 2.15

Example 11

(-)-(2-(5-chloro-2-ethoxyphenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-chloro-2-ethoxyphenyl)cyclopropyl)methanamine (HCl salt)

Route 11:

The title compound was prepared via Scheme 11 using tert-butyl ((2-(5-chloro-2-hydroxyphenyl)cyclopropyl)methyl)carbamate (prepared using a similar method as described for tert-butyl ((2-(5-fluoro-2-hydroxyphenyl)cyclopropyl)methyl)carbamate in US20130281539) as the starting material.

(-)-(2-(5-chloro-2-ethoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.13 (dd, J = 8.8, 2.8 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 8.8Hz, 1H), 4.13-4.06 (m, 2H), 3.06 (dd, J = 13.2, 7.2 Hz, 1H), 2.99 (dd, J =13.2, 5.6 Hz, 1H), 2.15 – 2.11 (m, 1H), 1.45 (t, J = 7.2 Hz, 3H), 1.35 – 1.32 (m, 1H), 1.13 – 1.08 (m, 1H), 1.06 – 1.02 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 157.9, 132.7, 128.1, 127.5, 126.5, 113.8, 65.4, 45.1, 19.4, 18.2, 15.3, 13.6; HRMS calcd for [M+H]: 226.0993, found: 227.1001; [α] _D ²⁰ -47.2 ( c 0.5, MeOH).

(+)-(2-(5-chloro-2-ethoxyphenyl)cyclopropyl)methanamine HCl salt. ¹ H NMR (400 MHz, CD ₃ OD) δ7.14 (dd, J = 8.8, 2.8 Hz, 1H), 6.95 (d, J = 2.8 Hz, 1H), 6.90 (d, J = 8.8Hz, 1H), 4.13 – 4.06 (m, 2H), 3.06 (dd, J = 12.8, 7.2 Hz, 1H), 2.98 (dd, J =12.8, 8.0 Hz, 1H), 2.15 – 2.11 (m, 1H), 1.45 (t, J = 6.8 Hz, 3H), 1.35 – 1.31(m, 1H), 1.13 – 1.08 (m, 1H), 1.06 – 1.02 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 157.9, 132.7, 128.1, 127.5, 126.5, 113.8, 65.4, 45.1, 19.4, 18.2, 15.3, 13.6; HRMS calcd for [M+H]: 226.0993, found: 227.1003. [α] _D ²⁰ +39.4 ( c 0.5, MeOH).

Example 12

(-)-(2-(5-chloro-2-propoxyphenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-chloro-2-propoxyphenyl)cyclopropyl)methanamine (HCl salt)

Route 12:

The title compound was prepared via Scheme 12 using a method similar to that described above.

(-)-(2-(5-chloro-2-propoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 360 MHz) δ 7.11 (dd, J = 8.7, 2.6 Hz, 1H), 6.94 (d, J = 2.6 Hz, 1H), 6.87 (d, J = 8.7Hz, 1H), 3.96 (m, 1H), 3.12 (dd, J = 13.1, 6.8 Hz, 1H), 2.89 (dd, J = 13.1,8.2 Hz, 1H), 2.14 – 2.09 (m, 1H), 1.89 – 1.82 (m, 2H), 1.37 – 1.32 (m, 1H),1.10 – 1.01 (m, 5H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ 156.7, 131.5, 126.8, 126.1,125.2, 112.5, 70.1, 43.8, 22.5, 18.0, 17.0, 12.5, 9.8; HRMS (ESI): m/z [M+H] ⁺ calcd: 240.1155, found: 240.1163; [α] _D ²⁰ -46.9 ( c 0.3, CD ₃ OD).

(+)-(2-(5-chloro-2-propoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.13 (dd, J = 8.7, 2.6 Hz, 1H), 6.95 (d, J = 2.6 Hz, 1H), 6.89 (d, J = 8.7Hz, 1H), 3.98 (m, 1H), 3.14 (dd, J = 13.1, 6.8 Hz, 1H), 2.91 (dd, J = 13.1,8.2 Hz, 1H), 2.15 – 2.11 (m, 1H), 1.87 – 1.83 (m, 2H), 1.38 – 1.34 (m, 1H),1.11 – 1.02 (m, 5H); HRMS (ESI): m/z [M+H] ⁺ calcd. for C ₁₃ H ₁₉ ClNO: 240.1155, found: 240.1220; [α] _D ²⁰ +43.4 ( c 0.2, CD ₃ OD).

Example 13

(-)-(2-(2-Butoxy-5-chlorophenyl)cyclopropyl)methanamine (TFA salt)

(+)-(2-(2-Butoxy-5-chlorophenyl)cyclopropyl)methanamine (TFA salt)

Route 13:

The title compound was prepared via Scheme 13 using a method similar to that described above.

(-)-(2-(2-Butoxy-5-chlorophenyl)cyclopropyl)methanamine (TFA salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.14 (dd, J = 2.4, 8.8 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.91 (d, J = 8.8Hz, 1H), 4.01 (m, 2H), 3.13 (dd, J = 13.2, 7.2 Hz, 1H), 2.90 (dd, J = 13.2,7.2 Hz, 1H), 2.12 (m, 1H), 1.81 (m, 2H), 1.56 (m, 2H), 1.35 (m, 1H), 1.09 –0.99 (m, 5H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ 158.0, 132.7, 128.1, 127.4, 126.5,113.8, 69.5, 45.1, 32.6, 20.5, 19.3, 18.3, 14.3, 13.7; HRMS (ESI) calcd for C ₁₄ H ₂₀ NOCl([M+H] ⁺ ) 254.1306; found: 254.1306; [α] _D ²⁰ -30.4 ( c 0.12, CH ₃ OH).

(+)-(2-(2-Butoxy-5-chlorophenyl)cyclopropyl)methanamine (TFA salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.91 (d, J = 8.8Hz, 1H), 4.01 (m, 2H), 3.13 (dd, J = 12.8, 6.8 Hz, 1H), 2.90 (dd, J = 12.8,8.4 Hz, 1H), 2.12 (m, 1H), 1.81 (m, 2H), 1.54 (m, 2H), 1.33 (m, 1H), 1.08 –0.99 (m, 5H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ 158.0, 132.7, 128.1, 127.4, 126.5,113.8, 69.5, 45.1, 32.6, 20.5, 19.3, 18.3, 14.3, 13.7; HRMS (ESI) calcd for C ₁₄ H ₂₀ NOCl([M+H] ⁺ ) 254.1306; found: 254.1317; [α] _D ²⁰ +32.0 ( c 0.14, CH ₃ OH).

Example 14

(-)-(2-(5-chloro-2-isopropoxyphenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-chloro-2-isopropoxyphenyl)cyclopropyl)methanamine (HCl salt)

Route 14:

Example 14

The title compound was prepared via Scheme 14 using a method similar to that described above.

(-)-(2-(5-chloro-2-isopropoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.13 (dd, J = 8.8, 2.4 Hz, 1H), 6.93 (m, 2H), 4.63 (m, 1H), 3.14 (dd, J = 13.2, 6.8 Hz, 1H), 2.89 (dd, J = 12.8, 8.4 Hz, 1H), 2.10 (m, 1H), 1.38 –1.33 (m, 7H), 1.08 – 1.01 (m, 2H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ 156.7, 133.7,128.0, 127.5, 126.5, 115.8, 72.1, 45.1, 22.6, 22.4, 19.5, 18.4, 13.8; HRMS(ESI) calcd for C ₁₃ H ₁₈ NOCl ([M+H] ⁺ ) 240.1150; found: 240.1155; [α] _D ²⁰ -45.9 ( c 0.17, CH ₃ OH).

(+)-(2-(5-chloro-2-isopropoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.12 (dd, J = 8.8, 2.4 Hz, 1H), 6.93 (m, 2H), 4.62 (m, 1H), 3.15 (dd, J = 13.2, 6.4 Hz, 1H), 2.89 (dd, J = 13.2, 8.0 Hz, 1H), 2.11 (m, 1H), 1.37 –1.33 (m, 7H), 1.09 – 1.00 (m, 2H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ 156.7, 133.7,128.0, 127.5, 126.5, 115.8, 72.1, 45.1, 22.6, 22.4, 19.5, 18.4, 13.8; HRMS(ESI) calcd for C ₁₃ H ₁₈ NOCl ([M+H] ⁺ ) 240.1150; found: 240.1156; [α] _D ²⁰ +44.7 ( c 0.17, CH ₃ OH).

Example 15

(-)-(2-(5-chloro-2-isobutoxyphenyl)cyclopropyl)methanamine (TFA salt)

(+)-(2-(5-chloro-2-isobutoxyphenyl)cyclopropyl)methanamine (TFA salt)

Route 15:

The title compound was prepared via Scheme 15 using a method similar to that described above.

(-)-(2-(5-chloro-2-isobutoxyphenyl)cyclopropyl)methanamine (TFA salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.13 (dd, J = 2.4, 8.8 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.89 (d, J =8.8 Hz, 1H), 3.81-3.74 (m, 2H), 3.21 (dd, J = 6.4, 13.2 Hz, 1H), 2.85 (dd, J = 8.4, 13.2 Hz, 1H), 2.14 (m, 2H), 1.39 (m, 1H), 1.09-1.03 (m, 8H). ¹³ C NMR (CD ₃ OD, 100 MHz) δ 158.0, 132.7, 128.1, 127.3, 126.4, 113.8, 76.2, 45.1,29.8, 19.8, 19.7, 19.1, 18.4, 13.8. HRMS (ESI) calcd for C ₁₄ H ₂₀ NOCl ([M+H] ⁺ ) 254.1306; found: 254.1316; [α] _D ²⁰ -50.0 ( c 0.15, CH ₃ OH).

(+)-(2-(5-chloro-2-isobutoxyphenyl)cyclopropyl)methanamine (TFA salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.13 (dd, J = 2.4, 8.8 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.89 (d, J =8.8 Hz, 1H), 3.83-3.74 (m, 2H), 3.21 (dd, J = 6.4, 12.8 Hz, 1H), 2.85 (dd, J = 8.8, 12.8 Hz, 1H), 2.14 (m, 2H), 1.39 (m, 1H), 1.09-1.01 (m, 8H). ¹³ C NMR (CD ₃ OD, 100 MHz) δ 158.0, 132.7, 128.1, 127.3, 126.4, 113.8, 76.2, 45.1,29.8, 19.8, 19.7, 19.1, 18.4, 13.8. HRMS (ESI) calcd for C ₁₄ H ₂₀ NOCl ([M+H] ⁺ ) 254.1306; found: 254.1311; [α] _D ²⁰ +55.4 ( c 0.13, CH ₃ OH).

Example 16

(-)-(2-(5-chloro-2-(isopentyloxy)phenyl)cyclopropyl)methanamine (TFA salt)

(+)-(2-(5-chloro-2-(isopentyloxy)phenyl)cyclopropyl)methanamine (TFA salt)

Route 16:

The title compound was prepared via Scheme 16 using a method similar to that described above.

(-)-(2-(5-chloro-2-(isopentyloxy)phenyl)cyclopropyl)methanamine (TFA salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.14 (dd, J = 2.4, 8.8 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.91 (d, J =8.8 Hz, 1H), 4.04 (m, 2H), 3.15 (dd, J = 6.4, 13.2 Hz, 1H), 2.90 (dd, J =8.4, 12.8 Hz, 1H), 2.12 (m, 1H), 1.87 (m, 1H), 1.73 (m, 2H), 1.35 (m, 1H),1.09-0.99 (m, 8H). ¹³ C NMR (CD ₃ OD, 100 MHz) δ 158.0, 132.7, 128.1, 127.3,126.4, 113.8, 68.3, 45.1, 39.3, 26.5, 23.2, 23.1, 19.3, 18.3, 13.7. HRMS (ESI) calcd for C ₁₅ H ₂₂ NOCl ([M+H] ⁺ ) 268.1463; found: 268.1473; [α] _D ²⁰ -34.9 ( c 0.3, CH ₃ OH).

(+)-(2-(5-chloro-2-(isopentyloxy)phenyl)cyclopropyl)methanamine (TFA salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.14 (dd, J = 2.4, 8.8 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.91 (d, J =8.8 Hz, 1H), 4.04 (m, 2H), 3.15 (dd, J = 6.4, 13.2 Hz, 1H), 2.90 (dd, J =8.4, 12.8 Hz, 1H), 2.12 (m, 1H), 1.87 (m, 1H), 1.73 (m, 2H), 1.36 (m, 1H),1.08-0.99 (m, 8H). ¹³ C NMR (CD ₃ OD, 100 MHz) δ 158.0, 132.7, 128.1, 127.4,126.4, 113.8, 68.3, 45.1, 39.3, 26.5, 23.2, 23.1, 19.3, 18.3, 13.7. HRMS (ESI) calcd for C ₁₅ H ₂₂ NOCl ([M+H] ⁺ ) 268.1463; found: 268.1473; [α] _D ²⁰ +45.5 ( c 0.15, CH ₃ OH).

Example 17

(-)-(2-(5-chloro-2-(2-methoxyethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-chloro-2-(2-methoxyethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

Route 17:

The title compound was prepared via Scheme 17 using a method similar to that described above.

(-)-(2-(5-chloro-2-(2-methoxyethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.26 (dd, J = 2.6, 8.8 Hz, 1H), 7.06 (d, J = 2.5 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 4.27 – 4.22 (m, 2H), 3.91 – 3.85 (m, 2H), 3.46 (s, 3H), 3.23 (dd, J = 6.8, 13.1 Hz, 1H), 2.98 (dd, J = 8.2, 13.0 Hz, 1H), 2.13 (m, 1H),1.30 (m, 1H), 1.20 (m, 1H), 1.06 (m, 1H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ 156.0,132.1, 127.3, 126.6, 126.0, 114.1, 70.9, 68.1, 58.4, 44.0, 18.7, 16.6, 12.2; HRMS (ESI) calcd for C ₁₃ H ₁₈ NO ₂ Cl ([M+H] ⁺ ) 256.1099; found: 256.1095; [α] _D ²⁰ -18.2 ( c 0.23, CD ₃ OD).

(+)-(2-(5-chloro-2-(2-methoxyethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.25 (dd, J = 2.6, 8.7 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.24 – 4.20 (m, 2H), 3.90 – 3.84 (m, 2H), 3.46 (s, 3H), 3.21 (dd, J = 13.1, 6.8 Hz, 1H), 2.98 (dd, J = 13.0, 8.1 Hz, 1H), 2.12 (m, 1H),1.28 (m, 1H), 1.18 (m, 1H), 1.06 (m, 1H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ 156.0,132.1, 127.3, 126.6, 126.0, 114.1, 70.9, 68.1, 58.4, 44.0, 18.7, 16.6, 12.2; HRMS (ESI) calcd for C ₁₃ H ₁₈ NO ₂ Cl ([M+H] ⁺ ) 256.1099; found: 256.1101; [α] _D ²⁰ +11.7 ( c 0.35, CD ₃ OD).

Example 18

(-)-(2-(5-chloro-2-(2-(methylthio)ethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-chloro-2-(2-(methylthio)ethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

Route 18:

Example 18

The title compound was prepared via Scheme 18 using a method similar to that described above.

(-)-(2-(5-chloro-2-(2-(methylthio)ethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.16 (dd, J = 8.8, 2.4 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 6.94(d, J = 8.8 Hz, 1H), 4.25 – 4.20 (m, 2H), 3.14 (dd, J = 12.8, 7.2 Hz, 2H),2.98 – 2.92 (m, 3H), 2.20 (s, 3H), 2.17 – 2.11 (m, 1H), 1.33 –1.28 (m, 1H),1.18 –1.12 (m, 1H), 1.07–1.02 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 157.6, 132.9, 128.2, 127.6, 127.0, 114.2, 68.9, 45.2, 34.4, 19.7, 18.3, 16.0, 13.3; HRMS calcd for [M+H]: 272.0870, found: 272.0874; [α] _D ²⁰ -41.6 ( c 0.4, MeOH).

(+)-(2-(5-chloro-2-(2-(methylthio)ethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.16 (dd, J = 8.8, 2.8 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 6.94(d, J = 8.8 Hz, 1H), 4.25 – 4.20 (m, 2H), 3.14 (dd, J = 12.8, 7.2 Hz, 2H),2.98 – 2.92 (m, 3H), 2.20 (s, 3H), 2.17 – 2.11 (m, 1H), 1.33 –1.27 (m, 1H),1.18 – 1.12 (m, 1H), 1.07 – 1.03 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 157.6, 132.9, 128.2, 127.6, 127.0, 114.2, 68.9, 45.2, 34.4, 19.7, 18.3, 16.0, 13.3; HRMS calcd for [M+H]: 272.0870, found: 272.0870; [α] _D ²⁰ +44.9 ( c 0.4, MeOH).

Example 19

(-)-(2-(5-chloro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-chloro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

Route 19:

The title compound was prepared using a method similar to that described above via Scheme 19. A Mitsunobu reaction was applied in the first step using 2-fluoroethanol in the presence of triphenylphosphine and diethyl azodicarboxylate (DEAD).

(-)-(2-(5-chloro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, D ₂ O) δ 7.10 (dd, J = 9.7, 2.6 Hz, 1H), 6.91 ( d , J = 2.4 Hz, 1H), 6.84 (d, J =9.7 Hz), 4.84 - 4.81 (m, 1H), 4.68 – 4.66 (m, 1H), 4.26 – 4.15 (m, 2H), 3.04 (dd, J = 14.5, 7.8 Hz, 1H), 2.92 (dd, J = 14.4, 5.3 Hz, 1H), 2.01 – 1.98 (m,1H), 1.18 – 1.15 (m, 1H), 1.09 – 1.04 (m, 1H), 0.96 – 0.91 (m, 1H); ¹³ C NMR (100 MHz, D ₂ O) δ 155.8, 132.0, 127.3, 126.8, 126.2, 114.1, 83.3 (d, J _CF =180.8 Hz), 68.6 (d, J _CF =19.8 Hz), 43.9, 18.7, 16.6, 12.2; HRMS calcd for [M+H]: 244.0899, found: 244.0907; [α] _D ²⁰ -32.5 ( c 0.1, MeOH).

(+)-(2-(5-chloro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.18 (dd, J = 8.8, 2.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.95 (d, J = 8.8 Hz), 4.80 – 4.74 (m, 2H), 4.34 – 4.27 (m, 2H), 3.05 – 3.00 (m, 2H),2.15 – 2.11 (m, 1H), 1.27 – 1.17 (m, 2H), 1.06 – 1.02 (m, 1H); ¹³ C NMR (100 MHz, D ₂ O) δ _{δ 155.8, 132.0, 127.3, 126.8, 126.2, 114.1, 83.2 (d, JCF = 180.8 Hz), 68.6 (d, JCF} = 19.7 Hz), 43.9, 18.7, 16.5, 12.1 _; HRMS calcd for [M+H]: 244.0899, found: 244.0908; [α] _D20 ^+37.8 ( c 0.5, MeOH).

Example 20

(-)-(2-(5-chloro-2-(3-fluoropropoxy)phenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-chloro-2-(3-fluoropropoxy)phenyl)cyclopropyl)methanamine (HCl salt)

Route 20:

The title compound was prepared via Scheme 20 using a procedure analogous to that described for Example 19. 3-Fluoropropan-1-ol was used in place of 2-fluoroethanol.

(-)-(2-(5-chloro-2-(3-fluoropropoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, D ₂ O) δ 7.25 (dd, J = 8.8, 2.4 Hz, 1H), 7.04 – 7.01 (m, 2H), 4.78 – 4.76 (m,1H), 4.69 (t, J = 5.6 Hz, 1H), 4.27 – 4.21 (m, 2H), 3.17 (dd, J = 13.2, 7.2Hz, 1H), 3.03 (dd, J = 13.2, 8.0 Hz, 1H), 2.30 – 2.15 (m, 3H), 1.42 – 1.38 (m, 1H), 1.14 – 1.05 (m, 2H); ¹³ C NMR (100 MHz, D ₂ O) δ 155.5, 131.8, 126.9,125.9, 125.6, 114.0, 82.3 ( J _CF = 157.8 Hz), 65.6 ( J _CF = 4.6 Hz), 43.6, 29.5 (d, J _CF = 19.2 Hz), 18.1, 16.2, 12.5; HRMS calcd for [M+H]: 258.1055, found: 258.1056; [α] _D ²⁰ -51.4 ( c 0.15, MeOH).

(+)-(2-(5-chloro-2-(3-fluoropropoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz,CD ₃ OD) δ 7.15 (dd, J = 9.7, 2.9 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 6.90 (d, J = 9.8 Hz), 4.78 – 4.76 (m, 1H), 4.64 (t, J = 6.4 Hz, 1H), 4.18 – 4.11 (m,2H), 3.15 (dd, J = 13.2, 7.2 Hz, 1H), 2.98 (dd, J = 13.2, 8.0 Hz, 1H), 2.26 –2.04 (m, 3H), 1.36 – 1.31 (m, 1H), 1.08 – 1.01 (m, 2H); ¹³ C NMR (D ₂ O, 100 MHz) δ 155.9, 132.0, 127.2, 126.2, 125.9, 114.2, 82.7 ( J _CF = 175.4 Hz), 65.8 (d, J _CF = 5.5 Hz), 43.9, 29.9 (d, J _CF = 21.7 Hz), 18.4, 16.6, 12.8; HRMS calcd for [M+H]: 258.1055, found: 258.1064; [α] _D ²⁰ +44.2 ( c 0.15, MeOH).

Example 21

(-)-(2-(5-chloro-2-(2,2-difluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-chloro-2-(2,2-difluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

Route 21:

The title compound was prepared via Scheme 21 using a method similar to that described above.

(-)-(2-(5-chloro-2-(2,2-difluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD,360 MHz) δ 7.15 (dd, J = 8.7, 2.6 Hz, 1H), 6.98 (d, J = 2.6 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 6.24 (tt, J = 54.8, 3.6 Hz, 1H), 4.27 (dt, J = 14.2, 3.6 Hz,2H), 3.09 (dd, J = 13.1, 6.9 Hz, 1H), 2.90 (dd, J = 13.1, 6.9 Hz, 1H), 2.12 –2.09 (m, 1H), 1.32 – 1.28 (m, 1H), 1.13 – 1.09 (m, 1H), 1.05 – 1.01 (m, 1H); ¹³ C NMR (CD ₃ OD, 90 MHz) δ 155.8, 131.9, 127.1, 126.7, 126.6, 114.3 (t, J _CF =238.0 Hz), 113.2, 67.7(t, J _CF = 27.3 Hz), 43.7, 18.3, 16.9, 12.1; HRMS (ESI): m/z [M+H] ⁺ calcd for C ₁₂ H ₁₅ ClF ₂ NO: 262.0810, found: 262.0830; [α] _D ²⁰ -34.2 ( c 0.2,CD ₃ OD).

(+)-(2-(5-chloro-2-(2,2-difluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.18 (dd, J = 2.6, 8.7 Hz, 1H), 7.02 (d, J = 2.6 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 6.27 (tt, J = 54.8, 3.6 Hz, 1H), 4.30 (dt, J = 14.2, 3.6 Hz,2H), 3.12 (dd, J = 13.1, 6.9 Hz, 1H), 2.93 (dd, J = 13.1, 6.9 Hz, 1H), 2.17 –2.11 (m, 1H), 1.34 – 1.32 (m, 1H), 1.18 – 1.13 (m, 1H), 1.08 – 1.03 (m, 1H); HRMS (ESI): m/z [M+H] ⁺ calcd. for C ₁₂ H ₁₅ ClF ₂ NO: 262.0810, found: 262.0816; [α] _D ²⁰ +32.0 ( c 0.25, CD ₃ OD).

Example 22

(-)-(2-(5-chloro-2-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-chloro-2-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

Route 22:

The title compound was prepared via Scheme 22 using a method similar to that described above.

(-)-(2-(5-chloro-2-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.21 (dd, J = 8.8, 2.4 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 7.01(d, J = 8.8 Hz, 1H), 4.61 (q, J = 8.4 Hz, 2H), 3.21 (dd, J = 13.2, 6.4 Hz,1H), 2.86 (dd, J = 12.6, 8.4 Hz, 1H), 2.15 – 2.10 (m, 1H), 1.41 – 1.35 (m,1H), 1.15 – 1.05 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 156.5, 133.5, 128.6,128.4, 128.1, 125.4 (q, J _CF = 275.4 Hz), 115.0, 67.3 (q, J _CF = 34.5 Hz), 44.9,19.4, 18.2, 13.6; HRMS calcd for [M+H]: 280.0711, found: 280.0719; [α] _D ²⁰ -52.0 (c 0.5, MeOH).

(+)-(2-(5-chloro-2-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.21 (dd, J = 8.8, 2.8 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 7.01(d, J = 8.8 Hz, 1H), 4.61 (q, J = 8.4 Hz, 2H), 3.21 (dd, J = 13.2, 6.4 Hz,1H), 2.86 (dd, J = 13.2, 8.6 Hz, 1H), 2.15 – 2.10 (m, 1H), 1.38 – 1.35 (m,1H), 1.15 – 1.05 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 156.5, 133.5, 128.6,128.4, 128.1, 125.4 (q, J _CF = 275.4 Hz), 115.0, 67.3 (q, J _CF = 35.4 Hz), 44.9,19.4, 18.2, 13.6; HRMS calcd for [M+H]: 280.0711, found: 280.0712; [α] _D ²⁰ +46.3 (c 0.5, MeOH).

Example 23

(-)-(2-(2-(allyloxy)-5-chlorophenyl)cyclopropyl)methanamine (TFA salt)

(+)-(2-(2-(Allyloxy)-5-chlorophenyl)cyclopropyl)methanamine (TFA salt)

Route 23:

The title compound was prepared via Scheme 23 using a method similar to that described above.

(-)-(2-(2-(allyloxy)-5-chlorophenyl)cyclopropyl)methanamine (TFA salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.16 (dd, J = 2.0, 8.8 Hz, 1H), 6.97 (s, 1H), 6.94 (d, J = 8.8 Hz,1H), 6.12 (m, 1H), 5.47 (d, J = 17.2 Hz, 1H), 5.33 (d, J = 10.8 Hz, 1H), 4.62(d, J = 5.2 Hz, 2H), 3.03 (m, 2H), 2.15 (m, 1H), 1.32 (m, 1H), 1.12 – 1.02(m, 2H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ 157.5, 134.8, 132.8, 128.1, 127.6, 126.8,118.4, 114.3, 70.6, 45.1, 19.4, 18.3, 13.5; HRMS (ESI) calcd for C ₁₃ H ₁₆ NOCl ([M+H] ⁺ ) 238.0993; found: 238.0994; [α] _D ²⁰ -54.2 ( c 0.27, CH ₃ OH).

(+)-(2-(2-(Allyloxy)-5-chlorophenyl)cyclopropyl)methanamine (TFA salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.15 (dd, J = 2.0, 8.8 Hz, 1H), 6.97 (s, 1H), 6.93 (d, J = 8.8 Hz,1H), 6.12 (m, 1H), 5.47 (d, J = 17.2 Hz, 1H), 5.33 (d, J = 10.4 Hz, 1H), 4.62(d, J = 4.8 Hz, 2H), 3.03 (m, 2H), 2.15 (m, 1H), 1.33 (m, 1H), 1.14 – 1.01(m, 2H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ 157.5, 134.8, 132.8, 128.1, 127.6, 126.8,118.4, 114.3, 70.6, 45.1, 19.4, 18.3, 13.5; HRMS (ESI) calcd for C ₁₃ H ₁₆ NOCl ([M+H] ⁺ ) 238.0993; found: 238.0999; [α] _D ²⁰ -54.2 ( c 0.27, CH ₃ OH).

Example 24

(-)-(2-(5-chloro-2-((2-methylallyl)oxy)phenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-chloro-2-((2-methylallyl)oxy)phenyl)cyclopropyl)methanamine (HCl salt)

Route 24:

The title compound was prepared via Scheme 24 using a method similar to that described above.

(-)-(2-(5-chloro-2-((2-methylallyl)oxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 360 MHz) δ: 7.11 (dd, J = 2.6, 8.7 Hz, 1H), 6.94 (d, J = 2.6 Hz, 1H),6.88 (d, J = 8.7 Hz, 1H), 5.08 (s, 1H), 4.98 (s, 1H), 4.49 (s, 2H), 3.08 (dd, J = 13.0, 8.2 Hz, 1H), 2.28 (dd, J = 13.0, 6.8 Hz, 1H), 2.16 – 2.12 (m, 1H),1.83 (s, 3H), 1.70 (d, J = 3.4 Hz, 1H), 1.36 – 1.33 (m, 1H), 1.09 – 1.02 (m,1H); HRMS (ESI): m/z [M+H] ⁺ calcd. for C ₁₄ H ₁₉ ClNO: 252.1155, found: 252.1162; [α] _D ²⁰ -45.2 (c 0.21, CD ₃ OD).

(+)-(2-(5-chloro-2-((2-methylallyl)oxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 360 MHz) δ 7.09 (dd, J = 8.7, 2.6 Hz, 1H), 6.96 (d, J = 2.6 Hz, 1H),6.85 (d, J = 8.7 Hz, 1H), 5.07 (s, 1H), 4.97 (s, 1H), 4.48 (s, 2H), 3.07 (dd, J = 13.0, 8.2 Hz, 1H), 2.87 (dd, J = 13.0, 6.8 Hz, 1H), 2.16 – 2.11 (m, 1H),1.82 (s, 3H), 1.68 (d, J = 3.4 Hz, 1H), 1.36 – 1.32 (m, 1H), 1.08 – 1.00 (m,1H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ 156.3, 141.3, 131.6, 127.0, 126.8, HRMS (ESI): m/z [M+H] ⁺ C ₁₄ H ₁₈ Calcd. for ClNO: 252.1155, found: 252.1167; [α] _D ²⁰ +43.6 ( c 0.3, CD ₃ OD).

Example 25

(-)-(2-(5-chloro-2-((2-fluoroallyl)oxy)phenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-chloro-2-((2-fluoroallyl)oxy)phenyl)cyclopropyl)methanamine (HCl salt)

Route 25:

The title compound was prepared via Scheme 25 using a method similar to that described above.

(-)-(2-(5-chloro-2-((2-fluoroallyl)oxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.06 (br, 3H), 7.20 (dd, J = 8.8, 2.4 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 2.8 Hz, 1H), 4.96 (dd, J = 10.4, 3.2 Hz, 1H),4.88 (dd, J = 23.2, 3.2 Hz, 1H), 4.72 (d, J = 14.0 Hz, 2H), 2.92 – 2.81 (m,2H), 2.08 – 2.04 (m, 1H), 1.43 – 1.38 (m, 1H), 1.02 – 0.93 (m, 2H); HRMS(ESI): m/z calcd for C ₁₃ H ₁₆ ClFNO [M+H]: 256.0904, found: 256.0914; [α] _D ²⁰ -40.7 ( c 0.15, CD ₃ OD).

(+)-(2-(5-chloro-2-((2-fluoroallyl)oxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.06 (br, 3H), 7.20 (dd, J = 8.8, 2.4 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 2.8 Hz, 1H), 4.96 (dd, J = 10.4, 3.2 Hz, 1H),4.88 (dd, J = 23.2, 3.2 Hz, 1H), 4.72 (d, J = 14.0 Hz, 2H), 2.92 – 2.81 (m,2H), 2.08 – 2.04 (m, 1H), 1.43 – 1.38 (m, 1H), 1.02 – 0.93 (m, 2H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 160.7 (d, J _CF = 255.7 Hz), 155.1, 132.4, 126.5, 126.2,125.1, 114.1, 94.8 (d, J _CF = 15.4 Hz), 65.7 (d, J _CF = 32.3 Hz), 42.6, 17.8,16.6, 13.4; HRMS (ESI): m/z calcd for C ₁₃ H ₁₆ ClFNO [M+H]: 256.0904, found: 256.0906; [α] _D ²⁰ +43.0 ( c 0.2, CD ₃ OD).

Example 26

(-)-(2-(5-chloro-2-(prop-2-yn-1-yloxy)phenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-chloro-2-(prop-2-yn-1-yloxy)phenyl)cyclopropyl)methanamine (HCl salt)

Route 26:

The title compound was prepared via Scheme 26 using a method similar to that described above.

(-)-(2-(5-chloro-2-(prop-2-yn-1-yloxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.16 (dd, J = 8.8, 2.4 Hz, 1H), 7.03 – 6.99 (m, 2H), 4.82(s, 2H), 3.09 – 3.05 (m, 2H), 2. 99 (dd, J = 12.8, 8.0 Hz, 1H), 2.13 – 2.08(m, 1H), 1.30 – 1.27 (m, 1H), 1.15 – 1.13 (m, 1H), 1.05 – 1.02 (m, 1H); ¹³ CNMR (CD ₃ OD, 100 MHz) δ 156.7, 133.1, 128.2, 128.0, 127.5, 114.6, 79.6, 77.6,57.5, 45.1, 19.6, 18.1, 13.3; HRMS (ESI) calcd for C ₁₃ H ₁₄ NOCl ([M+H] ⁺ ) 236.0837; found: 236.0842; [α] _D ²⁰ -32.7 ( c 0.16, CH ₃ OH).

(+)-(2-(5-chloro-2-(prop-2-yn-1-yloxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.16 (dd, J = 8.8, 2.4 Hz, 1H), 7.03 – 6.99 (m, 2H), 4.81(s, 2H), 3.09 – 3.04 (m, 2H), 2.99 (dd, J = 13.2, 7.6 Hz, 1H), 2.13 – 2.08(m, 1H), 1.31 – 1.27 (m, 1H), 1.16 – 1.12 (m, 1H), 1.06 – 1.02 (m, 1H); ¹³ CNMR (CD ₃ OD, 100 MHz) δ 156.7, 133.1, 128.2, 128.0, 127.5, 114.6, 79.6, 77.6,57.5, 45.1, 19.6, 18.1, 13.3; HRMS (ESI) calcd for C ₁₃ H ₁₄ NOCl ([M+H] ⁺ ) 236.0837; found: 236.0840; [α] _D ²⁰ +47.3 ( c 0.22, CH ₃ OH).

Example 27

(-)-(2-(5-chloro-2-phenoxyphenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(5-Chloro-2-phenoxyphenyl)cyclopropyl)methanamine (HCl salt)

Route 27:

The title compound was prepared using a similar method as described above via Scheme 27. The first step was carried out with diphenyliodonium p-toluenesulfonate (1.2 eq) in the presence of t -BuOK (1.1 eq) using THF as solvent (for reference, see Jalalian, N. et al. Org Lett 2011, 13, 1552-1555.).

(-)-(2-(5-chloro-2-phenoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 360 MHz) δ: 7.34 (m, 1H), 7.19 (dd, J = 2.6, 7.8 Hz, 1H), 7.08 (m, 2H), 6.90 (d, J =7.8 Hz, 2H), 6.84 (d, J = 8.4 Hz, 1H), 2.84 (m, 1H), 2.68 (m, 1H), 2.08 (m, 1H), 1.31 (m, 1H), 1.15 (m, 1H), 0.96 (m, 1H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ: 157.9, 154.2, 134.8, 129.9, 129.3, 127.4, 126.6, 123.2, 120.9, 117.6, 43.4,18.8, 17.0, 12.5; HRMS (ESI): m/z [M+H] ⁺ calcd for C ₁₆ H ₁₇ ClNO: 274.0999, found: 274.1025; [α] _D ²⁰ -33.1 (c 0.13, CD ₃ OD).

(+)-(2-(5-Chloro-2-phenoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ: 7.37 (m, 1H), 7.20 (dd, J = 2.6, 7.8 Hz, 1H), 7.11 (m, 2H), 6.94 (d, J =7.8 Hz, 2H), 6.87 (d, J = 8.4 Hz, 1H), 2.87 (m, 1H), 2.72 (m, 1H), 2.11 (m, 1H), 1.36 (m, 1H), 1.17 (m, 1H), 1.01 (m, 1H); HRMS (ESI): m/z [M+H] ⁺ calcd for C ₁₆ H ₁₇ ClNO: 274.0999, found: 274.0999; [α] _D ²⁰ +30.5 (c 0.21, CD ₃ OD).

Example 28

(-)-(2-(2-(Benzyloxy)-5-chlorophenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(2-(Benzyloxy)-5-chlorophenyl)cyclopropyl)methanamine (HCl salt)

Route 28:

The title compound was prepared via Scheme 28 using a method similar to that described above.

(-)-(2-(2-(Benzyloxy)-5-chlorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.49 (m, 2H), 7.38 (m, 3H), 7.15 (dd, J = 2.5, 8.7 Hz, 1H), 6.98 (m,2H), 5.12 (s, 2H), 3.00 (dd, J = 7.2, 13.0 Hz, 1H), 2.90 (dd, J = 7.9, 13.0Hz, 1H), 2.12 (m, 1H), 1.31 (m, 1H), 1.12-1.00 (m, 2H). ¹³ C NMR (CD ₃ OD, 100 MHz) δ 158.1, 138.8, 133.3, 130.2, 129.7, 129.4, 128.5, 128.1, 127.2, 114.8,72.2, 45.4, 19.7, 18.7, 13.8. HRMS (ESI) calcd for C ₁₇ H ₁₈ NOCl ([M+H] ⁺ ) 288.1150; found: 288.1162; [α] _D ²⁰ -18.1 ( c 0.66, CH ₃ OH).

(+)-(2-(2-(Benzyloxy)-5-chlorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.49 (m, 2H), 7.38 (m, 3H), 7.15 (dd, J = 2.5, 8.7 Hz, 1H), 6.98 (m,2H), 5.12 (s, 2H), 3.00 (dd, J = 7.2, 13.0 Hz, 1H), 2.90 (dd, J = 7.9, 12.9 Hz, 1H), 2.13 (m, 1H), 1.32 (m, 1H), 1.12-1.01 (m, 2H). ¹³ C NMR (CD ₃ OD, 100 MHz) δ 158.1, 138.8, 133.3, 130.2, 129.7, 129.4, 128.5, 128.1, 127.2, 114.8,72.2, 45.4, 19.7, 18.7, 13.8. HRMS (ESI) calcd for C ₁₇ H ₁₈ NOCl ([M+H] ⁺ ) 288.1150; found: 288.1158; [α] _D ²⁰ +17.5 ( c 0.94, CH ₃ OH).

Example 29

(-)-(2-(3-chloro-2-fluoro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(3-chloro-2-fluoro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt)

Route 29:

Step A: 3-Chloro-2-fluoro-6-methoxybenzaldehyde

Under argon, diisopropylamine (1.71 mL, 12 mmol) was dissolved in anhydrous THF (20 mL) and the solution was cooled to -78 ^° C. A solution of n -BuLi (2.5 M, 6.0 mL, 12 mmol) was slowly added and the solution was stirred for 0.5 h. To this solution was added a solution of 1-chloro-2-fluoro-4-methoxybenzene (1.60 g, 10 mmol) in anhydrous THF (20 mL), and the mixture was stirred for an additional 20 min. Anhydrous DMF (2.0 mL) was then slowly added, and the mixture was warmed to room temperature. Water was added, and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated to give the sub-title intermediate (1.9 g, 100%) as a yellow solid.

Step B: tert-Butyl ((2-(3-chloro-2-fluoro-6-methoxyphenyl)cyclopropyl)methyl)carbamate

This intermediate was prepared from 3-chloro-2-fluoro-6-methoxybenzaldehyde using the same method as described in Example 1. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.18 (t, J = 8.8 Hz, 1H), 6.58 (dd, J = 8.8, 1.6 Hz, 1H), 5.30 (br, 1H), 3.87 (s, 3H), 3.58 – 3.54 (m, 1H), 2.76 – 2.68 (m, 1H), 1.53 – 1.44 (m, 10H), 1.24 – 1.17 (m, 2H), 0.92 – 0.87 (m, 1H).

Step C: tert-Butyl ((2-(3-chloro-2-fluoro-6-methoxyphenyl)cyclopropyl)methyl)carbamate was separated by chiral preparative HPLC to give tert-butyl (+)-((2-(3-chloro-2-fluoro-6-methoxyphenyl)cyclopropyl)methyl)carbamate and (-)-tert-butyl ((2-(3-chloro-2-fluoro-6-methoxyphenyl)cyclopropyl)methyl)carbamate.

Step D: (-)-(2-(3 _- Chloro-2-fluoro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt) and (+)-(2-(3-chloro-2-fluoro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt) were prepared from tert-butyl (+)-((2-(3-chloro-2-fluoro-6-methoxyphenyl)cyclopropyl)methyl)carbamate and tert-butyl (-)-((2-(3-chloro-2-fluoro-6-methoxyphenyl)cyclopropyl)methyl)carbamate, respectively, using HCl/Et2O as described above.

(-)-(2-(3-chloro-2-fluoro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz,CD ₃ OD) δ 7.28 (t, J = 8.8 Hz, 1H), 6.79 (dd, J = 9.2, 1.6 Hz, 1H), 3.87 (s,3H), 3.11 (dd, J = 13.2, 6.8 Hz, 1H), 2.90 (dd, J = 13.2, 8.0 Hz, 1H), 1.82 –1.76 (m, 1H), 1.48 – 1.43 (m, 1H), 1.23 – 1.18 (m, 1H), 1.09 – 1.03 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 160.1 (d, J _CF = 6.6 Hz), 158.7 (d, J _CF = 243.8 Hz), 129.6, 118.9 (d, J _CF = 20.1 Hz), 113.9 (d, J _CF = 19.3 Hz), 108.5, 56.8, 45.4,18.4, 13.7, 13.1; [α] _D ²⁰ -54.0 ( c 0.15, MeOH).

(+)-(2-(3-chloro-2-fluoro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz,CD ₃ OD) δ 7.29 (t, J = 8.8 Hz, 1H), 6.79 (dd, J = 8.8, 1.6 Hz, 1H), 3.88 (s,3H), 3.11 (dd, J = 12.8, 6.4 Hz, 1H), 2.90 (dd, J = 12.8, 8.4 Hz, 1H), 1.82 –1.77 (m, 1H), 1.48 – 1.44 (m, 1H), 1.24 – 1.18 (m, 1H), 1.09 – 1.04 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 160.1 (d, J _CF = 6.6 Hz), 158.7 (d, J _CF = 243.8 Hz), 129.6, 118.9 (d, J _CF = 20.1 Hz), 113.8 (d, J _CF = 19.3 Hz), 108.4, 56.8, 45.4,18.4, 13.7, 13.0; [α] _D ²⁰ +50.0 ( c 0.1, MeOH).

Example 30

(-)-(2-(3-Chloro-6-ethoxy-2-fluorophenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(3-Chloro-6-ethoxy-2-fluorophenyl)cyclopropyl)methanamine (HCl salt)

Route 30:

The title compound was prepared via Scheme 30 using a method similar to that described above.

(-)-(2-(3-Chloro-6-ethoxy-2-fluorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz,CD ₃ OD) δ 7.26 (t, J = 8.8 Hz, 1H), 6.77 (d, J = 9.2 Hz, 1H), 4.12 – 4.06 (m,2H), 3.08 (dd, J = 12.8, 7.2 Hz, 1H), 2.97 (dd, J = 13.2, 7.6 Hz, 1H), 1.86 –1.81 (m, 1H), 1.58 – 1.53 (m, 1H), 1.45 (t, J = 7.6 Hz, 3H), 1.27 – 1.24 (m,1H), 1.09 – 1.05 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 159.4 (d, J _CF = 6.4 Hz), 158.7 (d, J _CF = 244.0 Hz), 129.4, 119.0 (d, J _CF = 14.0 Hz), 113.6 (d, J _CF =19.3 Hz), 109.3, 65.8, 45.4, 18.3, 15.1, 14.0, 13.1; [α] _D ²⁰ -52.7 (c 0.15, MeOH).

(+)-(2-(3-Chloro-6-ethoxy-2-fluorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz,CD ₃ OD) δ 7.26 (t, J = 8.8 Hz, 1H), 6.77 (dd, J = 8.8, 1.6 Hz, 1H), 4.13–4.06 (m, 2H), 3.09 (dd, J = 13.2, 7.2 Hz, 1H), 2.97 (dd, J = 13.2, 7.6 Hz,1H), 1.85 – 1.81 (m, 1H), 1.58 – 1.55 (m, 1H), 1.46 (t, J = 6.8 Hz, 3H), 1.28– 1.23 (m, 1H), 1.10 – 1.06 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 159.4 (d, J _CF =6.4 Hz), 158.7 (d, J _CF = 243.7 Hz), 129.4, 119.0 (d, J _CF = 14.4 Hz), 113.6 (d, J _CF = 19.3 Hz), 109.3, 65.9, 45.4, 18.3, 15.1, 14.0, 13.1; [α] _D ²⁰ +58.2 (c0.15, MeOH).

Example 31

(-)-(2-(3-chloro-2-fluoro-6-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(3-chloro-2-fluoro-6-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

Route 31:

The title compound was prepared via Scheme 31 using a method similar to that described above.

(-)-(2-(3-chloro-2-fluoro-6-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400MHz, CD ₃ OD) δ 7.29 (t, J = 8.8 Hz, 1H), 6.81 (d, J = 9.2 Hz, 1H), 4.88 – 4.83(m, 1H), 4.77 – 4.75 (m, 1H), 4.35 - 4.21 (m, 2H), 3.09 (dd, J = 13.2, 7.2Hz, 1H), 2.98 (dd, J = 13.2, 7.6 Hz, 1H), 1.88 – 1.83 (m, 1H), 1.55 – 1.51(m, 1H), 1.32 – 1.28 (m, 1H), 1.12 – 1.06 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ159.0 (d, J _CF = 6.4 Hz), 158.7 (d, J _CF = 244.0 Hz), 129.5, 119.4 (d, J _CF = 14.7Hz), 114.4 (d, J _CF = 19.2 Hz), 109.5, 83.3 (d, J _CF = 167.4 Hz), 69.6 (d, J _CF =19.0 Hz), 45.3, 18.5, 13.9, 13.1; [α] _D ²⁰ -53.0 (c 0.3, MeOH).

(+)-(2-(3-chloro-2-fluoro-6-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.29 (t, J = 8.8 Hz, 1H), 6.81 (dd, J = 8.8, 1.4 Hz, 1H), 4.88– 4.83 (m, 1H), 4.77 – 4.74 (m, 1H), 4.33 - 4.23 (m, 2H), 3.10 (dd, J = 12.8,7.2 Hz, 1H), 2.98 (dd, J = 13.2, 7.6 Hz, 1H), 1.88 – 1.83 (m, 1H), 1.55 –1.51 (m, 1H), 1.32 – 1.28 (m, 1H), 1.12 – 1.06 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 159.0 (d, J _CF = 6.5 Hz), 158.7 (d, J _CF = 244.4 Hz), 129.5, 119.4 _{[ α} ] D ​ _​ ​ _{​ ​} ²⁰ +53.5 (c 0.4, MeOH).

Example 32

(-)-(2-(6-(Allyloxy)-3-chloro-2-fluorophenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(6-(Allyloxy)-3-chloro-2-fluorophenyl)cyclopropyl)methanamine (HCl salt)

Route 32:

The title compound was prepared via Scheme 32 using a method similar to that described above.

(-)-(2-(6-(Allyloxy)-3-chloro-2-fluorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.26 (t, J = 8.4 Hz, 1H), 6.79 (d, J = 9.2 Hz, 1H), 6.17 – 6.07 (m, 1H), 5.46 (d, J = 17.2 Hz, 1H), 5.33 (d, J = 10.4 Hz, 1H), 4.61 (d, J =5.2 Hz, 2H), 3.08 – 2.97 (m, 2H), 1.88 – 1.83 (m, 1H), 1.59 – 1.52 (m, 1H),1.28 – 1.22 (m, 1H), 1.11 – 1.06 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 159.0 (d, J _CF = 6.4 Hz), 158.7 (d, J _CF = 243.9 Hz), 134.4, 129.4, 119.2 (d, J _CF = 14.6Hz), 118.7, 113.9 (d, J _CF = 19.3 Hz), 109.7, 70.9, 45.3, 18.4, 13.9, 13.1; [α] _D ²⁰ -54.0 (c 0.3, MeOH).

(+)-(2-(6-(Allyloxy)-3-chloro-2-fluorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.26 (t, J = 8.6 Hz, 1H), 6.79 (dd, J = 9.2, 1.6 Hz, 1H), 6.17– 6.07 (m, 1H), 5.46 (dd, J = 17.2, 1.4 Hz, 1H), 5.33 (dd, J = 10.4, 1.2 Hz,1H), 4.61 (d, J = 5.6 Hz, 2H), 3.08 – 2.97 (m, 2H), 1.88 – 1.83 (m, 1H), 1.57– 1.52 (m, 1H), 1.28 – 1.22 (m, 1H), 1.11 – 1.06 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 159.0 (d, J _CF = 6.6 Hz), 158.7 (d, J _CF = 243.8 Hz), 134.4, 129.4,119.2 (d, J _CF = 14.5 Hz), 118.7, 113.9 (d, J _CF = 19.2 Hz), 109.7, 70.9, 45.3,18.4, 13.9, 13.1; [α] _D ²⁰ +55.0 (c 0.2, MeOH).

Example 33

(-)-(2-(4,5-Dichloro-2-methoxyphenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(4,5-Dichloro-2-methoxyphenyl)cyclopropyl)methanamine (HCl salt)

Route 33:

Step A: 4,5-Dichloro-2-hydroxybenzaldehyde

3,4-Dichlorophenol (20.0 g, 0.123 mol) was added to methanesulfonic acid (120 mL) and stirred for 15 minutes to give a clear solution. Hexamethylenetetramine (18.8 g, 0.134 mol) was slowly added to the solution in small portions. The mixture was then heated to 105 ° C and stirred for 15 minutes, then cooled to room temperature and poured into a mixture of ice and water (1.2 L). The mixture was extracted with DCM (200 mL * 3), and the combined extracts were dried over sodium sulfate and concentrated to give the sub-title intermediate as a crude yellow solid (18.2 g, 77%).

Step B: 4,5-Dichloro-2-methoxybenzaldehyde

The crude product from Step A (18.2 g, 95 mmol) was dissolved in DMF (100 mL), and _{K₂CO₃ (} 26.2 g, 0.19 mol) and iodomethane (27.0 g, 0.19 mol) were added. The mixture was stirred at room temperature overnight. Water (500 mL) was then added, and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, concentrated, and purified by flash chromatography to afford the sub-title intermediate as a white solid (5.6 g, 22%). ^1H NMR ( _CDCl₃ , 400 MHz) 10.34 (s, 1H), 7.87 (s, 1H), 7.10 (s, 1H), 3.94 (s, 3H).

Step C: tert-Butyl ((2-(4,5-dichloro-2-methoxyphenyl)cyclopropyl)methyl)carbamate

The sub-title compound was prepared from 4,5-dichloro-2-methoxybenzaldehyde using a procedure analogous to that described in Example 1. ¹ H NMR (CDCl ₃ , 400 MHz) 6.95 (s, 1H), 6.88 (s, 1H), 5.16 (br, 1H), 3.86 (s, 3H), 3.54 – 3.49 (m, 1H), 2.77 – 2.71 (m, 1H), 1.78 – 1.73 (m, 1H), 1.46 (s, 9H), 1.02 – 0.97 (m, 2H), 0.87 – 0.84 (m, 1H).

Step D: (-)-(2-(4,5-dichloro-2-methoxyphenyl)cyclopropyl)methanamine (HCl salt) and (+)-(2-(4,5-dichloro-2-methoxyphenyl)cyclopropyl)methanamine (HCl salt).

tert-Butyl ((2-(4,5-dichloro-2-methoxyphenyl)cyclopropyl)methyl)carbamate was separated using chiral HPLC to give (+)-((2-(4,5-dichloro-2-methoxyphenyl)cyclopropyl)methyl)carbamate and (-)-((2-(4,5-dichloro-2-methoxyphenyl)cyclopropyl)methyl)carbamate, which were treated with 2M HCl/diethyl ether as described above to give (-)-(2-(4,5-dichloro-2-methoxyphenyl)cyclopropyl)methanamine (HCl salt) and (+)-(2-(4,5-dichloro-2-methoxyphenyl)cyclopropyl)methanamine (HCl salt), respectively.

(-)-(2-(4,5-Dichloro-2-methoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.11 (s, 2H), 3.88 (s, 3H), 3.08 (dd, J = 13.2, 7.2 Hz, 1H), 2.92(dd, J = 13.2, 8.0 Hz, 1H), 2.09 – 2.04 (m, 1H), 1.28 – 1.26 (m, 1H), 1.16 –1.10 (m, 1H), 1.06 – 1.00 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 159.1, 131.6,131.5 129.2, 124.5, 113.7, 56.8, 45.0, 19.5, 17.8, 13.2; [α] _D ²⁰ -37.4 ( c 0.3 ,MeOH).

(+)-(2-(4,5-Dichloro-2-methoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.11 (s, 2H), 3.89 (s, 3H), 3.08 (dd, J = 13.2, 7.6 Hz, 1H), 2.93(dd, J = 12.8, 8.0 Hz, 1H), 2.09 – 2.04 (m, 1H), 1.29 – 1.26 (m, 1H), 1.15 –1.10 (m, 1H), 1.06 – 1.02 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 159.1, 131.6,131.5, 129.2, 124.5, 113.7, 56.8, 45.0, 19.5, 17.8, 13.2; [α] _D ²⁰ +37.7 ( c 0.4, MeOH).

Example 34

(-)-(2-(4,5-Dichloro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(4,5-Dichloro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

Route 34:

The title compound was prepared via Scheme 34 using a method similar to that described above.

(-)-(2-(4,5-Dichloro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.16 (s, 1H), 7.15 (s, 1H), 4.88 – 4.75 (m, 2H), 4.36 – 4.24(m, 2H), 3.04 – 3.01 (m, 2H), 2.13 – 2.08 (m, 1H), 1.29 – 1.26 (m, 1H), 1.23– 1.19 (m, 1H), 1.08 – 1.03 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 158.1, 131.9,131.6, 129.5, 125.1, 114.8, 83.3 (d, J _CF = 167.1 Hz), 69.7 (d, J _CF = 18.9 Hz), 44.9, 19.7, 17.9, 12.9; [α] _D ²⁰ -32.4 ( c 0.5 , MeOH).

(+)-(2-(4,5-Dichloro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.16 (s, 1H), 7.15 (s, 1H), 4.88 – 4.75 (m, 2H), 4.36 – 4.24(m, 2H), 3.04 – 3.01 (m, 2H), 2.13 – 2.08 (m, 1H), 1.29 – 1.26 (m, 1H), 1.23– 1.19 (m, 1H), 1.08 – 1.03 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 158.1, 131.9,131.6, 129.5, 125.1, 114.8, 83.3 (d, J _CF = 167.1 Hz), 69.7 (d, J _CF = 18.9 Hz), 44.9, 19.7, 17.9, 12.9; [α] _D ²⁰ +30.2 ( c 0.5 , MeOH).

Example 35

(-)-(2-(2-(allyloxy)-4,5-dichlorophenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(2-(allyloxy)-4,5-dichlorophenyl)cyclopropyl)methanamine (HCl salt)

Route 35:

The title compound was prepared via Scheme 35 using a method similar to that described above.

(-)-(2-(2-(Allyloxy)-4,5-dichlorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400MHz, CD ₃ OD) δ 7.12 (s, 1H), 7.10 (s, 1H), 6.17 – 6.07 (m, 1H), 5.47 (dd, J =17.6, 1.6 Hz, 1H), 5.34 (dd, J = 10.4, 1.6 Hz, 1H), 4.63 (d, J = 5.2 Hz, 2H),3.08 – 2.97 (m, 2H), 2.14 – 2.09 (m, 1H), 1.37 – 1.32 (m, 1H), 1.15 – 1.03(m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 157.9, 134.3, 131.9, 131.4, 129.2, 124.7,118.7, 115.0, 70.9, 44.9, 19.4, 17.9, 13.5; [α] _D ²⁰ -35.0 ( c 0.4, MeOH).

(+)-(2-(2-(allyloxy)-4,5-dichlorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400MHz, CD ₃ OD) δ 7.12 (s, 1H), 7.10 (s, 1H), 6.17 – 6.07 (m, 1H), 5.47 (dd, J =17.2, 1.2 Hz, 1H), 5.34 (d, J = 10.4 Hz, 1H), 4.63 (d, J = 5.2 Hz, 2H), 3.08– 2.96 (m, 2H), 2.14 – 2.09 (m, 1H), 1.39 – 1.32 (m, 1H), 1.15 – 1.03 (m,2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 157.9, 134.3, 131.9, 131.4, 129.2, 124.7,118.7, 115.0, 70.9, 44.9, 19.4, 17.9, 13.5; [α] _D ²⁰ +37.6 ( c 0.3 , MeOH).

Example 36

(-)-(2-(2,3-Dichloro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(2,3-Dichloro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt)

Route 36:

Step A: 2,3-Dichloro-6-methoxybenzaldehyde

A solution of 1,2-dichloro-4-methoxybenzene (12.5 g, 70.6 mmol) in anhydrous THF (100 mL) was cooled to -78 ° C under argon. n-BuLi (2.5 M in hexane, 31 mL, 77.7 mmol) was slowly added to the solution, and the mixture was stirred at the same temperature for 0.5 hours, and then DMF (6.0 mL, 77.7 mmol) was added via a syringe. The mixture was stirred at the same temperature for 15 minutes, and then slowly warmed to room temperature. Water was added and the mixture was extracted with ethyl acetate. The combined extracts were concentrated and recrystallized from ethyl acetate/hexane to give the sub-title compound (7.5 g, 52%) as a light yellow solid. ¹ H NMR (CDCl ₃ , 400 MHz) 10.46 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 12.0Hz, 1H), 3.92 (s, 3H).

Step B: tert-Butyl ((2-(2,3-dichloro-6-methoxyphenyl)cyclopropyl)methyl)carbamate

The sub-title compound was prepared from 2,3-dichloro-6-methoxybenzaldehyde using a method analogous to that described in Example 1. ¹ H NMR (CDCl ₃ , 400 MHz) 7.28 (d, J = 9.2 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 5.20 (br, 1H), 3.85 (s, 3H), 3.52 – 3.47 (dd, J = 12.0, 8.8 Hz, 1H), 2.90 (dd, J = 12.0, 9.2 Hz, 1H), 1.55 – 1.45 (m, 10H), 1.27 – 1.21 (m, 1H), 1.02 – 0.95 (m, 2H).

Step C: The racemic form of tert-butyl ((2-(2,3-dichloro-6-methoxyphenyl)cyclopropyl)methyl)carbamate was separated by chiral HPLC to give tert-butyl (-)-((2-(2,3-dichloro-6-methoxyphenyl)cyclopropyl)methyl)carbamate and (+)-tert-butyl ((2-(2,3-dichloro-6-methoxyphenyl)cyclopropyl)methyl)carbamate, which was subsequently treated with 2M HCl/diethyl ether to give (-)-(2-(2,3-dichloro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt) and (+)-(2-(2,3-dichloro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt).

(-)-(2-(2,3-Dichloro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (d, J = 8.8 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H),3.06 (d, J = 7.2 Hz, 2H), 1.78 – 1.73 (m, 1H), 1.44 – 1.40 (m, 1H), 1.21 –1.15 (m, 1H), 1.11 – 1.06 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 159.9, 135.9,130.2, 129.6, 125.7, 111.7, 56.7, 45.4, 20.1, 18.3, 15.2; [α] _D ²⁰ -62.0 ( c 0.1, MeOH).

(+)-(2-(2,3-Dichloro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (d, J = 9.2 Hz, 1H), 6.96 (d, J = 9.2 Hz, 1H), 3.88 (s, 3H),3.06 (d, J = 7.2 Hz, 2H), 1.77 – 1.74 (m, 1H), 1.44 – 1.42 (m, 1H), 1.21 –1.15 (m, 1H), 1.09 – 1.05 (m, 1H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 159.9, 135.9,130.2, 129.6, 125.7, 111.7, 56.7, 45.4, 20.1, 18.3, 15.2; [α] _D ²⁰ +69.0 ( c 0.2, MeOH).

Example 37

(-)-(2-(2,3-Dichloro-6-ethoxyphenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(2,3-Dichloro-6-ethoxyphenyl)cyclopropyl)methanamine (HCl salt)

Route 37:

The title compound was prepared via Scheme 37 using a method similar to that described above.

(-)-(2-(2,3-Dichloro-6-ethoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz,CD ₃ OD) δ 7.36 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 9.2 Hz, 1H), 4.14 – 4.03 (m,2H), 3.35 (dd, J = 13.2, 6.0 Hz, 1H), 2.82 (dd, J = 13.2, 8.8 Hz, 1H), 1.79 –1.75 (m, 1H), 1.50 – 1.45 (m, 4H), 1.20 – 1.13 (m, 2H); ¹³ C NMR (100 MHz,CD ₃ OD) δ 159.2, 135.8, 130.0, 129.6, 125.4, 112.7, 65.7, 45.4, 20.2, 18.6,15.3, 15.2; [α] _D ²⁰ -62.0 ( c 0.2, MeOH).

(+)-(2-(2,3-Dichloro-6-ethoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz,CD ₃ OD) δ 7.36 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 4.14 – 4.06 (m,2H), 3.36 (dd, J = 13.2, 6.0 Hz, 1H), 2.83 (dd, J = 13.2, 8.8 Hz, 1H), 1.80 –1.76 (m, 1H), 1.52 – 1.46 (m, 4H), 1.22 – 1.14 (m, 2H); ¹³ C NMR (100 MHz,CD ₃ OD) δ 159.2, 135.8, 130.0, 129.7, 125.5, 112.7, 65.8, 45.4, 20.2, 18.6,15.3, 15.2; [α] _D ²⁰ +48.8 ( c 0.4, MeOH).

Example 38

(-)-(2-(2,3-Dichloro-6-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(2,3-Dichloro-6-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

Route 38:

The title compound was prepared via Scheme 38 using a method similar to that described above.

(-)-(2-(2,3-Dichloro-6-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.09 (br, 3H), 7.48 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.8 Hz,1H), 4.90 – 4.73 (m, 2H), 4.32 – 4.22 (m, 2H), 3.26 – 3.22 (m, 1H), 2.64 –2.59 (m, 1H), 1.78 – 1.73 (m, 1H), 1.45 – 1.41 (m, 1H), 1.18 – 1.12 (m, 1H),1.04 – 1.00 (m, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 157.1, 133.8, 128.8, 128.6,123.5, 112.4, 82.2 (d, J _CF = 165.6 Hz), 68.1 (d, J _CF = 18.6 Hz), 42.7, 18.7,16.9, 14.0; [α] _D ²⁰ -96.0 ( c 0.1, MeOH).

(+)-(2-(2,3-Dichloro-6-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.11 (br, 3H), 7.47 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.8 Hz,1H), 4.89 – 4.73 (m, 2H), 4.32 – 4.22 (m, 2H), 3.24 (dd, J = 12.4, 5.2 Hz,1H), 2.64 – 2.59 (m, 1H), 1.78 – 1.73 (m, 1H), 1.45 – 1.41 (m, 1H), 1.18 –1.13 (m, 1H), 1.04 – 1.00 (m, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 157.0, 133.7,128.8, 128.6, 123.5, 112.4, 82.2 (d, J _CF = 165.6 Hz), 68.1 (d, J _CF = 18.6 Hz), 42.7, 18.6, 16.9, 13.9; [α] _D ²⁰ +70.0 ( c 0.1, MeOH).

Example 39

(-)-6-(Allyloxy)-2,3-dichlorophenyl)cyclopropyl)methylamine (HCl salt)

(+)-6-(Allyloxy)-2,3-dichlorophenyl)cyclopropyl)methylamine (HCl salt)

Route 39:

The title compound was prepared via Scheme 39 using a method similar to that described above.

(-)-6-(Allyloxy)-2,3-dichlorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz,CD ₃ OD) δ 7.37 (d, J = 9.2 Hz, 1H), 6.94 (d, J = 9.2 Hz, 1H), 6.18 – 6.08 (m,1H), 5.46 (dd, J = 17.2, 1.6 Hz, 1H), 5.34 (dd, J = 10.8, 1.2 Hz, 1H), 4.62(d, J = 5.2 Hz, 2H), 3.30 (dd, J = 13.2, 8.8 Hz, 1H), 2.86 (dd, J = 13.2, 8.8Hz, 1H), 1.83 – 1.77 (m, 1H), 1.48 – 1.45 (m, 1H), 1.23 – 1.12 (m, 2H); ¹³ CNMR (100 MHz, CD ₃ OD) δ 158.8, 135.9, 134.4, 130.0, 129.9, 125.8, 118.9,113.3, 70.9, 45.3, 20.2, 18.5, 15.3; [α] _D ²⁰ -68.0 ( c 0.1, MeOH).

(+)-6-(Allyloxy)-2,3-dichlorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz,CD ₃ OD) δ 7.37 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.18 – 6.08 (m,1H), 5.47 (dd, J = 17.2, 1.6 Hz, 1H), 5.34 (dd, J = 10.4, 1.2 Hz, 1H), 4.63(d, J = 5.2 Hz, 2H), 3.30 (dd, J = 12.8, 8.8 Hz, 1H), 2.86 (dd, J = 12.8, 8.8Hz, 1H), 1.83 – 1.79 (m, 1H), 1.48 – 1.46 (m, 1H), 1.23 – 1.15 (m, 2H); ¹³ CNMR (100 MHz, CD ₃ OD) δ 158.8, 135.9, 134.5, 130.0, 129.9, 125.8, 118.8,113.3, 71.0, 45.4, 20.2, 18.6, 15.3; [α] _D ²⁰ +64.0 ( c 0.1, MeOH).

Example 40

(-)-(2-(4,5-Difluoro-2-methoxyphenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(4,5-Difluoro-2-methoxyphenyl)cyclopropyl)methanamine (HCl salt)

Route 40:

Step A: tert-Butyl ((2-(4,5-difluoro-2-methoxyphenyl)cyclopropyl)methyl)carbamate

The subtitle intermediate was prepared from 4,5-difluoro-2-methoxybenzaldehyde using a method analogous to that described in Example 1. ¹ H NMR (CDCl ₃ , 400 MHz) 6.74 (dd, J = 11.2, 9.2 Hz, 1H), 6.65 (dd, J = 12.0,6.8 Hz, 1H), 5.23 (br, 1H), 3.86 (s, 3H), 3.56 – 3.52 (m, 1H), 2.73 – 2.68 (m, 1H), 1.75 – 1.72 (m, 1H), 1.46 (s, 9H), 1.01 – 0.95 (m, 2H), 0.85 – 0.82 (m, 2H).

Step B: Racemic tert-butyl ((2-(4,5-difluoro-2-methoxyphenyl)cyclopropyl)methyl)carbamate was separated using chiral HPLC to give tert-butyl (+)-((2-(4,5-difluoro-2-methoxyphenyl)cyclopropyl)methyl)carbamate and (-)-((2-(4,5-difluoro-2-methoxyphenyl)cyclopropyl)methyl)carbamate, both of which were treated with 2M HCl/ _Et2O to give (-)-(2-(4,5-difluoro-2-methoxyphenyl)cyclopropyl)methanamine (HCl salt) and (+)-(2-(4,5-difluoro-2-methoxyphenyl)cyclopropyl)methanamine (HCl salt), respectively.

(-)-(2-(4,5-difluoro-2-methoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 6.94 - 6.88 (m, 2H), 3.87 (s, 3H), 3.08 (dd, J = 13.2, 7.2 Hz, 1H),2.93 (dd, J = 13.2, 8.0 Hz, 1H), 2.09 - 2.03 (m, 1H), 1.27 - 1.23 (m, 1H),1.13 - 1.08 (m, 1H), 1.04 - 1.00 (m, 1H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ 156.2 (d, J _CF = 7.4 Hz), 150.2 (dd, J _CF = 242.7, 13.5 Hz), 145.5 (dd, J _CF = 236.5, 12.6Hz), 127.1, 116.4 (d, J _CF = 19.2 Hz), 101.6 (d, J _CF = 21.4 Hz), 56.9, 45.1,19.5, 17.8, 13.1; [α] _D ²⁰ -7.9 ( c 0.7, MeOH).

(+)-(2-(4,5-Difluoro-2-methoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 6.94 - 6.88 (m, 2H), 3.87 (s, 3H), 3.08 (dd, J = 13.2, 7.2 Hz, 1H),2.93 (dd, J = 13.2, 8.0 Hz, 1H), 2.08-2.03 (m, 1H), 1.26 - 1.22 (m, 1H), 1.14- 1.08 (m, 1H), 1.04 - 0.98 (m, 1H); [α] _D ²⁰ +6.0 ( c 0.2, MeOH).

Example 41

(-)-(2-(2-Ethoxy-4,5-difluorophenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(2-Ethoxy-4,5-difluorophenyl)cyclopropyl)methanamine (HCl salt)

Route 41:

The title compound was prepared via Scheme 41 using a method similar to that described above.

(-)-(2-(2-Ethoxy-4,5-difluorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 6.93 - 6.86 (m, 2H), 4.10 – 4.03 (m, 2H), 3.07 (dd, J = 13.2, 7.2 Hz,1H), 2.97 (dd, J = 13.2, 8.0 Hz, 1H), 2.11 – 2.06 (m, 1H), 1.45 (t, J = 7.2Hz, 3H), 1.31 - 1.28 (m, 1H), 1.10-1.01 (m, 2H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ 155.4 (dd, J _CF = 7.6, 1.9 Hz), 150.0 (dd, J _CF = 242.5, 13.4 Hz), 145.4 (dd, J _CF = 236.3, 12.7 Hz), 127.3, 116.2 (d, J _CF = 18.7 Hz), 102.5 (d, J _CF = 21.2 Hz), 66.0, 45.0, 19.4, 17.9, 15.1, 13.5; [α] _D ²⁰ -13.2 ( c 0.35, MeOH).

(+)-(2-(2-Ethoxy-4,5-difluorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 6.93 - 6.86 (m, 2H), 4.10 – 4.03 (m, 2H), 3.07 (dd, J = 13.2, 7.2 Hz,1H), 2.97 (dd, J = 13.2, 8.0 Hz, 1H), 2.11 – 2.06 (m, 1H), 1.45 (t, J = 7.2 Hz, 3H), 1.31-1.27 (m, 1H), 1.10-1.01 (m, 2H); [α] _D ²⁰ +13.5 ( c 0.2, MeOH).

Example 42

(-)-(2-(4,5-difluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(4,5-difluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

Route 42:

The title compound was prepared via Scheme 42 using a method similar to that described above.

(-)-(2-(4,5-difluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD,400 MHz) δ 6.99 – 6.93 (m, 2H), 4.88 – 4.74 (m, 2H), 4.32 – 4.22 (m, 2H),3.03 – 3.00 (m, 2H), 2.11 – 2.08 (m, 1H), 1.25 – 1.15 (m, 2H), 1.05 – 1.01(m, 1H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ 155.0 (dd, J _CF = 7.4, 2.0 Hz), 150.1 (dd, J _CF = 243.0, 13.5 Hz), 145.8 (dd, J _CF = 237.3, 12.6 Hz), 127.6, 116.6 (d, J _CF =19.5 Hz), 102.9 (d, J _CF = 21.4 Hz), 83.4 (d, J _CF = 166.9 Hz), 69.9 (d, J _CF =18.8 Hz), 44.9, 19.7, 17.8, 12.8; [α] _D ²⁰ -1.5 ( c 0.4, MeOH).

(+)-(2-(4,5-Difluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 6.99 – 6.93 (m, 2H), 4.88 – 4.74 (m, 2H), 4.32 – 4.22 (m, 2H), 3.03 – 3.00 (m, 2H), 2.11 – 2.07 (m, 1H), 1.24 – 1.15 (m, 2H), 1.05 – 1.00 (m, 1H); [α] _D ²⁰ +1.4 ( c 0.1, MeOH).

Example 43

(-)-(2-(4,5-Difluoro-2-propoxyphenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(4,5-Difluoro-2-propoxyphenyl)cyclopropyl)methanamine (HCl salt)

Route 43:

The title compound was prepared via Scheme 43 using a method similar to that described above.

(-)-(2-(4,5-difluoro-2-propoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 6.93 - 6.86 (m, 2H), 4.00 – 3.93 (m, 2H), 3.16 (dd, J = 12.8, 6.8 Hz,1H), 2.90 (dd, J = 13.2, 8.4 Hz, 1H), 2.13 – 2.09 (m, 1H), 1.89 – 1.83 (m,2H), 1.36 – 1.32 (m, 1H), 1.11-1.02 (m, 5H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ 155.5 (dd, J _CF = 7.5, 2.0 Hz), 150.0 (dd, J _CF = 229.0, 13.4 Hz), 145.5 (dd, J _CF =236.3, 12.6 Hz), 127.3, 116.1 (d, J _CF = 19.2 Hz), 102.5 (d, J _CF = 21.2 Hz),71.9, 45.0, 23.7, 19.3, 18.0, 13.6, 11.0; [α] _D ²⁰ -17.7 ( c 0.3, MeOH).

(+)-(2-(4,5-Difluoro-2-propoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 6.92 - 6.86 (m, 2H), 3.99 – 3.93 (m, 2H), 3.16 (dd, J = 12.8, 6.8 Hz,1H), 2.90 (dd, J = 13.2, 8.0 Hz, 1H), 2.12 – 2.07 (m, 1H), 1.87 – 1.81 (m,2H), 1.35 – 1.30 (m, 1H), 1.11-1.00 (m, 5H); [α] _D ²⁰ +18.0 ( c 0.05, MeOH).

Example 44

(-)-(2-(2-(allyloxy)-4,5-difluorophenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(2-(Allyloxy)-4,5-difluorophenyl)cyclopropyl)methanamine (HCl salt)

Route 44:

The title compound was prepared via Scheme 44 using a method similar to that described above.

(-)-(2-(2-(Allyloxy)-4,5-difluorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 6.95-6.88 (m, 2H), 6.18 – 6.08 (m, 1H), 5.47 (dd, J = 17.2, 1.6 Hz, 1H), 5.33 (dd, J = 10.4, 1.6 Hz, 1H), 4.60 (d, J = 5.2 Hz, 2H), 3.07 (dd, J = 12.8, 7.2 Hz, 1H), 2.98 (dd, J = 13.2, 8.0 Hz, 1H), 2.17 – 2.09 (m, 1H),1.33 – 1.29 (m, 1H), 1.13-1.02 (m, 2H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ 155.0 (dd, J _CF = 7.6, 2.0 Hz), 150.0 (dd, J _CF = 242.8, 13.5 Hz), 145.7 (dd, J _CF = [ _α ] _{D 20} ^​ -14.0 ( c 0.4, MeOH).

(+)-(2-(2-(Allyloxy)-4,5-difluorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 6.94 - 6.89 (m, 2H), 6.18 – 6.08 (m, 1H), 5.47 (dd, J = 17.2, 1.6 Hz, 1H), 5.33 (dd, J = 10.8, 1.6 Hz, 1H), 4.60 (d, J = 5.2 Hz, 2H), 3.06 (dd, J = 13.2, 7.2 Hz, 1H), 2.97 (dd, J = 13.2, 7.6 Hz, 1H), 2.17 – 2.08 (m, 1H),1.33 – 1.28 (m, 1H), 1.13 – 1.02 (m, 2H); [α] _D ²⁰ + 12.0 ( c 0.1, MeOH).

Example 45

(-)-(2-(2,3-Difluoro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(2,3-Difluoro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt)

Route 45:

Step A: tert-Butyl ((2-(2,3-difluoro-6-methoxyphenyl)cyclopropyl)methyl)carbamate

The sub-title intermediate was prepared from 2,3-difluoro-6-methoxybenzaldehyde using a method analogous to that described in Example 1. ¹ H NMR (CDCl ₃ , 400 MHz) 6.93 (q, J = 9.2 Hz, 1H), 6.52 – 6.48 (m, 1H), 5.28 (br, 1H), 3.85 (s, 3H), 3.59 – 3.54 (m, 1H), 2.74 – 2.68 (m, 1H), 1.53 – 1.50 (m, 1H), 1.45 (s, 9H), 1.23 – 1.18 (m, 2H), 0.91 -0.86 (m, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 156.0, 155.2 (d, J _CF = 5.8 Hz), 150.2 (dd, J _CF = 244.9, 13.8Hz), 145.8 (dd, J _CF = 224.7, 14.0 Hz), 119.2 (d, J _CF = 11.4 Hz), 113.9 (d, J _CF = 18.2 Hz), 104.9 (dd, J _CF = 6.5, 3.5 Hz), 79.1, 56.0, 45.5, 28.6, 19.7, 12.4,11.6.

Step B: Racemic tert-butyl ((2-(2,3-difluoro-6-methoxyphenyl)cyclopropyl)methyl)carbamate was separated using chiral HPLC to give tert-butyl (+)-((2-(2,3-difluoro-6-methoxyphenyl)cyclopropyl)methyl)carbamate and (-)-((2-(2,3-difluoro-6-methoxyphenyl)cyclopropyl)methyl)carbamate, which were treated with 2M HCl/ _Et2O to give (-)-(2-(2,3-difluoro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt) and (+)-(2-(2,3-difluoro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt), respectively.

(-)-(2-(2,3-Difluoro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.08 (q, J = 9.6 Hz, 1H), 6.74 – 6.71 (m, 1H), 3.86 (s, 3H), 3.13 (dd, J = 13.2, 6.8 Hz, 1H), 2.92 (dd, J = 13.2, 8.4 Hz, 1H), 1.85 – 1.79 (m, 1H),1.54 – 1.47 (m, 1H), 1.27 – 1.21 (m, 1H), 1.11 – 1.05 (m, 1H); [α] _D ²⁰ -36.9 ( c 0.7, MeOH).

(+)-(2-(2,3-Difluoro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.08 (q, J = 9.6 Hz, 1H), 6.75 – 6.71 (m, 1H), 3.86 (s, 3H), 3.13 (dd, J = 12.8, 6.8 Hz, 1H), 2.91 (dd, J = 12.8, 8.4 Hz, 1H), 1.85 – 1.79 (m, 1H),1.51 – 1.46 (m, 1H), 1.27 – 1.22 (m, 1H), 1.10 – 1.05 (m, 1H); [α] _D ²⁰ +38.0 ( c 0.2, MeOH).

Example 46

(-)-(2-(6-Ethoxy-2,3-difluorophenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(6-Ethoxy-2,3-difluorophenyl)cyclopropyl)methanamine (HCl salt)

Route 46:

The title compound was prepared via Scheme 46 using a method similar to that described above.

(-)-(2-(6-Ethoxy-2,3-difluorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.05 (q, J = 9.6 Hz, 1H), 6.72 – 6.68 (m, 1H), 4.11 – 4.04 (m, 2H),3.09 (dd, J = 13.2, 7.6 Hz, 1H), 2.98 (dd, J = 13.2, 7.6 Hz, 1H), 1.89 – 1.85(m, 1H), 1.62 – 1.58 (m, 1H), 1.45 (t, J = 7.2 Hz, 3H), 1.32 – 1.28 (m, 1H),1.10 – 1.06 (m, 1H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ 156.0 (dd, J _CF = 5.5, 2.1 Hz), 151.3 (dd, J _CF = 243.0, 14.0 Hz), 146.7 (dd, J _CF = 237.1, 13.8 Hz), 119.5 (d, J _CF = 11.1 Hz), 115.4 (d, J _CF = 18.2 Hz), 107.9 (dd, J _CF = 6.4, 3.5 Hz), 65.9,45.4, 18.2, 15.2, 13.9, 13.0; [α] _D ²⁰ -45.2 ( c 0.5, MeOH).

(+)-(2-(6-Ethoxy-2,3-difluorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.05 (q, J = 9.6 Hz, 1H), 6.72 – 6.68 (m, 1H), 4.11 – 4.04 (m, 2H),3.10 (dd, J = 12.8, 7.2 Hz, 1H), 2.98 (dd, J = 13.2, 8.0 Hz, 1H), 1.89 – 1.85(m, 1H), 1.62 – 1.59 (m, 1H), 1.45 (t, J = 7.2 Hz, 3H), 1.32 – 1.28 (m, 1H),1.10 – 1.07 (m, 1H); [α] _D ²⁰ +37.5( c 0.2, MeOH).

Example 47

(-)-(2-(2,3-Difluoro-6-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(2,3-Difluoro-6-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

Route 47:

The title compound was prepared via Scheme 47 using a method similar to that described above.

(-)-(2-(2,3-Difluoro-6-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.09 (q, J = 9.6 Hz, 1H), 6.77 – 6.73 (m, 1H), 4.88 – 4.86 (m,1H), 4.77 – 4.74 (m, 1H), 4.31 – 4.20 (m, 2H), 3.10 (dd, J = 13.2, 7.6 Hz,1H), 2.99 (dd, J = 13.2, 7.6 Hz, 1H), 1.89 – 1.84 (m, 1H), 1.56 – 1.53 (m,1H), 1.35 – 1.31 (m, 1H), 1.12 – 1.07 (m, 1H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ 155.6 (dd, J _CF = 5.6, 2.1 Hz), 151.4 (dd, J _CF = 243.7, 13.9 Hz), 147.0 (dd, J _CF = 238.0, 13.8 Hz), 119.9 (d, J _CF = 11.5 Hz), 115.6 (d, J _CF = 18.3 Hz), 108.2 (dd, J _CF = 3.6 Hz), 83.4 (d, J _CF = 167.1 Hz), 69.7 (d, J _CF = 18.9 Hz), 45.2,18.4, 13.8, 12.9; [α] _D ²⁰ -36.0 ( c 0.5, MeOH).

(+)-(2-(2,3-Difluoro-6-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD,400 MHz) δ 7.09 (q, J = 9.6 Hz, 1H), 6.77 – 6.73 (m, 1H), 4.88 – 4.85 (m,1H), 4.76 – 4.74 (m, 1H), 4.31 – 4.20 (m, 2H), 3.09 (dd, J = 13.2, 7.6 Hz,1H), 2.99 (dd, J = 12.8, 7.6 Hz, 1H), 1.89 – 1.84 (m, 1H), 1.56 – 1.53 (m,1H), 1.35 – 1.31 (m, 1H), 1.12 – 1.07 (m, 1H); [α] _D ²⁰ +30.2 ( c 0.2, MeOH).

Example 48

(-)-(2-(2,3-Difluoro-6-propoxyphenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(2,3-Difluoro-6-propoxyphenyl)cyclopropyl)methanamine (HCl salt)

Route 48:

The title compound was prepared via Scheme 48 using a method similar to that described above.

(-)-(2-(2,3-Difluoro-6-propoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400MHz) δ 7.05 (q, J = 9.6 Hz, 1H), 6.71 – 6.68 (m, 1H), 4.01 – 3.90 (m, 2H),3.14 (dd, J = 13.2, 7.6 Hz, 1H), 2.93 (dd, J = 12.8, 8.0 Hz, 1H), 1.90 – 1.81(m, 3H), 1.66 – 1.58 (m, 1H), 1.30 – 1.25 (m, 1H), 1.11 – 1.05 (m, 4H); ¹³ CNMR (CD ₃ OD, 100 MHz) δ 156.1, 151.3 (dd, J _CF = 242.9, 14.3 Hz), 146.6 (dd, J _CF = 237.0, 13.7 Hz), 119.4 (d, J _CF = 11.2 Hz), 115.4 (d, J _CF = 18.2 Hz), 107.7(dd, J _CF = 6.2, 3.5 Hz), 71.8, 45.3, 23.8, 18.2, 14.0, 13.1, 11.1; [α] _D ²⁰ -50.3( c 0.4, MeOH).

(+)-(2-(2,3-Difluoro-6-propoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400MHz) δ 7.05 (q, J = 9.6 Hz, 1H), 6.71 – 6.68 (m, 1H), 4.01 – 3.90 (m, 2H),3.13 (dd, J = 13.2, 7.6 Hz, 1H), 2.93 (dd, J = 13.2, 8.0 Hz, 1H), 1.90 – 1.81(m, 3H), 1.66 – 1.57 (m, 1H), 1.30 – 1.25 (m, 1H), 1.11 – 1.05 (m, 4H); [α] _D ²⁰ +42.5 ( c 0.2, MeOH).

Example 49

(-)-(2-(6-(allyloxy)-2,3-difluorophenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(6-(allyloxy)-2,3-difluorophenyl)cyclopropyl)methanamine (HCl salt)

Route 49:

The title compound was prepared via Scheme 49 using a method similar to that described above.

(-)-(2-(6-(Allyloxy)-2,3-difluorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.06 (q, J = 9.6 Hz, 1H), 6.75 – 6.71 (m, 1H), 6.16 – 6.09 (m, 1H), 5.46 (dd, J = 17.2, 1.6 Hz, 1H), 5.32 (dd, J = 10.8, 1.6 Hz, 1H), 4.59(d, J = 5.6 Hz, 2H), 3.08 (dd, J = 13.2, 7.6 Hz, 1H), 3.01 (dd, J = 13.2, 7.6Hz, 1H), 1.91 – 1.86 (m, 1H), 1.61 – 1.56 (m, 1H), 1.31 – 1.27 (m, 1H), 1.12– 1.08 (m, 1H); ¹³ C NMR (CD ₃ OD, 100 MHz) δ 155.7 (d, J _CF = 5.6 Hz), 151.3 (dd, J _CF = 243.3, 14.0 Hz), 146.8 (dd, J _CF = 237.6, 13.8 Hz), 134.6, 119.7 (d, J _CF =11.2 Hz), 118.6, 115.5 (d, J _CF = 18.3 Hz), 108.5, 71.1, 45.3, 18.3, 13.9,13.0; [α] _D ²⁰ -46.8 ( c 0.5, MeOH).

(+)-(2-(6-(Allyloxy)-2,3-difluorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.06 (q, J = 9.6 Hz, 1H), 6.75 – 6.71 (m, 1H), 6.16 – 6.08 (m, 1H), 5.46 (dd, J = 17.2, 1.6 Hz, 1H), 5.32 (dd, J = 10.4, 1.6 Hz, 1H), 4.59(d, J = 5.6 Hz, 2H), 3.07 (dd, J = 13.2, 7.6 Hz, 1H), 3.00 (dd, J = 13.2, 7.6Hz, 1H), 1.91 – 1.85 (m, 1H), 1.60 – 1.56 (m, 1H), 1.31 – 1.26 (m, 1H), 1.11– 1.06 (m, 1H); [α] _D ²⁰ +41.6 ( c 0.2, MeOH).

Example 50

(-)-(2-(2-chloro-3-fluoro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(2-chloro-3-fluoro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt)

Route 50:

Step A: 2-Chloro-3-fluoro-6-methoxybenzaldehyde

A solution of 2-chloro-3,6-difluorobenzaldehyde (5.0 g, 29.3 mmol) in anhydrous THF (25 mL) and MeOH (60 mL) was heated to 60°C, a solution of MeONa in MeOH (25% wt%, 1.6 mL) was added, and the mixture was stirred at 60°C overnight. The mixture was concentrated and the residue was taken up in ethyl _acetate , washed with water, dried over _Na₂SO₄ , concentrated, and purified by flash chromatography (0-30% ethyl acetate/hexanes) to give a white solid (3.75 g, 68%). ^1H NMR (400 MHz, _CDCl₃ ) δ 10.48 (s, 1H), 7.31 (t, J = 8.0 Hz, 1H), 6.88 (dd, J = 8.0, 4.0 Hz, 1H), 3.92 (s, 3H).

Step B: tert-Butyl ((2-(2-chloro-3-fluoro-6-methoxyphenyl)cyclopropyl)methyl)carbamate

The subtitle intermediate was prepared from 2-chloro-3-fluoro-6-methoxybenzaldehyde using a method analogous to that described in Example 1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.98 (t, J = 8.8 Hz, 1H), 6.69 (dd, J = 9.0, 4.0 Hz, 1H), 5.22 (br, 1H), 3.85 (s, 3H), 3.53 – 3.48 (m, 1H), 2.91 – 2.85 (m, 1H), 1.53 – 1.49 (m, 1H), 1.47 (s, 3H), 1.27 – 1.24 (m, 1H), 1.06 – 0.97 (m, 2H).

Step C: Racemic tert-butyl ((2-(2-chloro-3-fluoro-6-methoxyphenyl)cyclopropyl)methyl)carbamate was separated by chiral HPLC to give tert-butyl (-)-((2-(2-chloro-3-fluoro-6-methoxyphenyl)cyclopropyl)methyl)carbamate and (+)-((2-(2-chloro-3-fluoro-6-methoxyphenyl)cyclopropyl)methyl)carbamate, which were treated with 2M HCl/ _Et2O to give (-)-(2-(2-chloro-3-fluoro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt) and (+)-(2-(2-chloro-3-fluoro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt), respectively.

(-)-(2-(2-Chloro-3-fluoro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.10 (t, J = 8.8 Hz, 1H), 6.92 (dd, J = 9.2, 4.4 Hz, 1H), 3.86 (s,3H), 3.10 – 3.00 (m, 2H), 1.76 – 1.73 (m, 1H), 1.47 – 1.42 (m, 1H), 1.19 –1.08 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 157.1, 154.2 (d, J _CF = 237.8 Hz),129.1, 124.6 (d, J _CF = 18.2 Hz), 115.5 (d, J _CF = 22.9 Hz), 111.1 (d, J _CF = 8.5 Hz), 56.8, 45.4, 19.6, 17.5, 14.7; [α] _D ²⁰ -66.4 (c 0.3, MeOH).

(+)-(2-(2-Chloro-3-fluoro-6-methoxyphenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.10 (t, J = 8.8 Hz, 1H), 6.92 (dd, J = 9.2, 4.4 Hz, 1H), 3.86 (s,3H), 3.10 – 3.00 (m, 2H), 1.76 – 1.73 (m, 1H), 1.47 – 1.43 (m, 1H), 1.19 –1.07 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 157.1, 154.2 (d, J _CF = 237.9 Hz),129.1, 124.6 (d, [ α ] _D ²⁰ _{+69.4 (} c 0.3 , MeOH) _.

Example 51

(-)-(2-(2-Chloro-6-ethoxy-3-fluorophenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(2-Chloro-6-ethoxy-3-fluorophenyl)cyclopropyl)methanamine (HCl salt)

Route 51:

The title compound was prepared via Scheme 51 using a method similar to that described above.

(-)-(2-(2-Chloro-6-ethoxy-3-fluorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz,CD ₃ OD) δ 7.06 (t, J = 8.8 Hz, 1H), 6.88 (dd, J = 9.2, 4.4 Hz, 1H), 4.10–4.02 (m, 2H), 3.32 (dd, J = 12.8, 6.0 Hz, 1H), 2.83 (dd, J = 13.2, 8.8 Hz,1H), 1.80–1.77 (m, 1H), 1.53–1.48 (m, 1H), 1.44 (t, J = 7.2 Hz, 3H), 1.20–1.15 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 156.4, 154.1 (d, J _CF = 237.8 Hz), 129.2, 124.5 (d, J _CF = 18.2 Hz), 115.4 (d, J _CF = 22.7 Hz), 112.2 (d, J _CF = 7.5Hz), 65.9, 45.4, 19.6, 17.8, 15.3, 14.8; [α] _D ²⁰ -62.0 ( c 0.3, MeOH).

(+)-(2-(2-Chloro-6-ethoxy-3-fluorophenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz,CD ₃ OD) δ 7.08 (t, J = 8.8 Hz, 1H), 6.89 (dd, J = 9.2, 4.4 Hz, 1H), 4.13–4.03 (m, 2H), 3.32 (dd, J = 12.8, 6.0 Hz, 1H), 2.85 (dd, J = 13.2, 8.8 Hz,1H), 1.82–1.78 (m, 1H), 1.54–1.50 (m, 1H), 1.46 (t, J = 7.2 Hz, 3H), 1.21– 1.16 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 156.4, 154.1 (d, J _CF = 237.7 Hz), 129.3, 124.5 (d, J _CF = 18.1 Hz), 115.4 (d, J _CF = 22.7 Hz), 112.2 (d, J _CF = 7.5Hz), 65.9, 45.4, 19.6, 17.8, 15.3, 14.8; [α] _D ²⁰ +70.7 ( c 0.3, MeOH).

Example 52

(-)-(2-(2-chloro-3-fluoro-6-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

(+)-(2-(2-chloro-3-fluoro-6-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt)

Route 52:

The title compound was prepared via Scheme 52 using a method similar to that described above.

(-)-(2-(2-chloro-3-fluoro-6-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.11 (t, J = 8.8 Hz, 1H), 6.94 (dd, J = 9.0, 4.2 Hz, 1H), 4.88– 4.85 (m, 1H), 4.77 – 4.74 (m, 1H), 4.32 – 4.20 (m, 2H), 3.34 (dd, J = 13.2,6.4 Hz, 1H), 2.85 (dd, J = 13.2, 8.8 Hz, 1H), 1.85 – 1.79 (m, 1H), 1.56 –1.50 (m, 1H), 1.23 – 1.18 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 156.0, 154.5 (d, J _CF = 238.6 Hz), 129.7, 124.7 (d, J _CF = 18.2 Hz), 115.5 (d, J _CF = 22.9 Hz), 112.6 (d, J _CF = 7.6 Hz), 83.4 (d, J _CF = 167.3 Hz), 69.8 (d, J _CF = 18.9 Hz), 45.3, 19.7, 17.7, 14.7; [α] _D ²⁰ -54.5 ( c 0.2, MeOH).

(+)-(2-(2-chloro-3-fluoro-6-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine (HCl salt). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.11 (t, J = 8.8 Hz, 1H), 6.94 (dd, J = 9.0, 4.2 Hz, 1H), 4.88– 4.85 (m, 1H), 4.78 – 4.74 (m, 1H), 4.33 – 4.20 (m, 2H), 3.34 (dd, J = 13.2,8.8 Hz, 1H), 2.85 (dd, J = 13.2, 8.8 Hz, 1H), 1.85 – 1.79 (m, 1H), 1.56 –1.52 (m, 1H), 1.24 – 1.17 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 156.0, 154.5 (d, J _CF = 238.6 Hz), 129.7, 124.7 (d, J _CF = 18.2 Hz), 115.5 (d, J _CF = 22.8 Hz), 112.6 (d, J _CF = 7.7 Hz), 83.4 (d, J _CF = 167.3 Hz), 69.8 (d, J _CF = 19.0 Hz), 45.3, 19.7, 17.7, 14.7; [α] _D ²⁰ +61.4 ( c 0.3, MeOH).

Example 53

(-)-(2-(6-(Allyloxy)-2-chloro-3-fluorophenyl)cyclopropyl)methanamine HCl salt

(+)-(2-(6-(Allyloxy)-2-chloro-3-fluorophenyl)cyclopropyl)methanamine HCl salt

Route 53:

The title compound was prepared via Scheme 53 using a method similar to that described above.

(-)-(2-(6-(allyloxy)-2-chloro-3-fluorophenyl)cyclopropyl)methanamine HCl salt. ¹ H NMR (400MHz, CD ₃ OD) δ 7.09 (t, J = 8.8 Hz, 1H), 6.92 (dd, J = 9.2, 4.4 Hz, 1H), 6.16– 6.07 (m, 1H), 5.46 (dd, J = 17.6, 1.6 Hz, 1H), 5.33 (dd, J = 10.6, 1.4 Hz,1H), 4.60 (d, J = 5.6 Hz, 2H), 3.29 (dd, J = 13.2, 6.4 Hz, 1H), 2.87 (dd, J =12.8, 8.6 Hz, 1H), 1.84 – 1.77 (m, 1H), 1.53 – 1.47 (m, 1H), 1.22 – 1.17 (m,2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 156.1, 154.3 (d, J _CF = 238.3 Hz), 134.7, [ _α ] D _{20 ​ ​} ^​ -52.0 ( c 0.2, MeOH).

(+)-(2-(6-(allyloxy)-2-chloro-3-fluorophenyl)cyclopropyl)methanamine HCl salt. ¹ H NMR (400MHz, CD ₃ OD) δ 7.09 (t, J = 8.8 Hz, 1H), 6.92 (dd, J = 9.2, 4.4 Hz, 1H), 6.17– 6.08 (m, 1H), 5.46 (dd, J = 17.6, 1.6 Hz, 1H), 5.33 (dd, J = 10.4, 1.2 Hz,1H), 4.60 (d, J = 4.8 Hz, 2H), 3.29 (dd, J = 13.6, 6.0 Hz, 1H), 2.87 (dd, J =12.8, 8.8 Hz, 1H), 1.84 – 1.78 (m, 1H), 1.53 – 1.47 (m, 1H), 1.21 – 1.17 (m,2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 156.1, 154.3 (d, J _CF = 238.0 Hz), 134.7, [ _α ] D _{20 ​ ​} ^​ +61.8 ( c 0.4, MeOH).

Therefore, the compounds of the present invention include but are not limited to:

In one embodiment, the invention relates to a method of treating a subject suffering from a disease or condition in which agonism of the 5-HT(2C) receptor provides a benefit, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of structural formula (I).

The methods described herein relate to the use of a compound of formula (I) and an optional second therapeutic agent for treating diseases and conditions in which modulation of 5-HT(2C) receptor activity provides a benefit. The methods of the present invention can be achieved by administering a compound of formula (I) as a pure compound or as a pharmaceutical composition. Administration of the pharmaceutical composition or pure compound of formula (I) can be performed during or after the onset of the disease or condition of interest. Typically, the pharmaceutical composition is sterile and does not contain toxic, carcinogenic, or mutagenic compounds that could cause adverse reactions upon administration.

In many embodiments, the compound of structural formula (I) is administered with a second therapeutic agent that is useful for treating a disease or condition in which modulation of the 5-HT(2C) receptor provides a benefit. The second therapeutic agent is different from the compound of structural formula (I). The compound of structural formula (I) and the second therapeutic agent can be administered simultaneously or sequentially. In addition, the compound of structural formula (I) and the second therapeutic agent can be administered as a single composition or as two separate compositions. The compound of structural formula (I) and the second therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect.

The second therapeutic agent is administered in an amount to provide its desired therapeutic effect.The effective dosage range of each second therapeutic agent is known in the art, and the second therapeutic agent is administered to an individual in need thereof within the range so determined.

Thus, the present invention relates to compositions and methods for treating diseases or conditions in which modulation of 5-HT(2C) receptors provides a benefit. The present invention also relates to pharmaceutical compositions comprising a compound of structural formula (I) and an optional second therapeutic agent useful for treating diseases and conditions in which modulation of 5-HT(2C) receptors provides a benefit. Also provided are kits comprising: a compound of structural formula (I) and an optional second therapeutic agent useful for treating diseases and conditions in which modulation of 5-HT(2C) receptors provides a benefit, packaged separately or together; and an insert with instructions for use of these active agents.

The compound of formula (I) and the second therapeutic agent can be administered together as a single unit dose or separately as multiple unit doses, wherein the compound of formula (I) is administered before the second therapeutic agent or vice versa. One or more doses of the compound of formula (I) and/or one or more doses of the second therapeutic agent can be administered. The compound of formula (I) can therefore be used in combination with one or more second therapeutic agents, such as, but not limited to, known drugs for treating mental disorders.

Within the meaning of the present invention, the term "disease" or "condition" or "disorder" refers to a disturbance and/or abnormality that is generally considered a pathological condition or function and that can manifest itself in the form of specific signs, symptoms and/or functional disorders. As demonstrated below, the compounds of structural formula (I) are potent modulators of 5-HT(2C) receptors and are useful in the treatment of diseases and conditions in which 5-HT(2C) receptor modulation provides a benefit.

The compounds of structural formula (I) are therefore generally useful as modulators (agonists, partial agonists, antagonists, partial antagonists, and selective agonists) of the 5-HT(2) receptor family. More specifically, the compounds of the present invention act as 5-HT(2) receptor agonists. Even more specifically, the compounds of the present invention act as agonists or selective agonists of the 5-HT(2C) receptor. Thus, the compounds of structural formula (I) are useful in treating diseases, conditions, and disorders associated with the 5-HT(2C) receptor, or in ameliorating undesirable symptoms associated therewith.

Diseases, conditions, disorders, symptoms associated with 5-HT(2C) receptors include, inter alia, obesity, eating disorders, diabetes, cardiovascular disease, sleep disorders (e.g., sleep apnea), central nervous system disorders, central nervous system injury (e.g., trauma, stroke, or spinal cord injury), gastrointestinal disorders (irritable bowel syndrome), depression, atypical depression, bipolar disorder, anxiety disorders, adjustment disorders, obsessive-compulsive disorder, social phobia or panic disorder, sexual dysfunction, psychosis, schizophrenia, headache-related conditions, chronic pain, dystonia, increased intracranial pressure, epilepsy, personality disorders, Alzheimer's disease, age-related behavioral disorders, behavioral disorders associated with dementia, organic psychiatric disorders, childhood psychiatric disorders, aggression, age-related memory impairment, chronic fatigue syndrome, drug and alcohol addiction, bulimia, anorexia nervosa, and premenstrual tension.

5-HT(2C) receptor-related disorders, conditions, diseases and symptoms treatable by compounds of structural formula (I) include, inter alia:

Obesity, eating disorders (e.g., bulimia, bulimia, or anorexia nervosa), gastrointestinal disorders, gastrointestinal motility disorders, chemotherapy-induced emesis, diabetes, sleep disorders, sleep apnea, hypertension, high blood pressure, hyperlipidemia, cardiovascular disease, central nervous system disorders, central nervous system damage associated with trauma, stroke or spinal cord injury or complications, psychiatric disorders, obsessive-compulsive disorder, anxiety disorders, panic disorder, schizophrenia, schizoaffective disorder, schizotypal disorder, L-DOPA-induced psychosis, psychosis, dementia, memory impairment, intellectual disability associated with Alzheimer's disease, bipolar disorder, adjustment disorders, depression, movement disorders, dystonia, chronic pain, Parkinson's disease, Alzheimer's disease, sexual dysfunction in men or women, erectile dysfunction, epilepsy, headache, and migraine. 5-HT(2C) receptor agonists are particularly useful in treating obesity and its complications, including type II diabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke, osteoarthritis, sleep apnea, gallbladder disease, gout, certain cancers, certain infertility disorders, and premature death.

5-HT(2C) receptor agonists may also be used in methods of reducing food intake in an individual, inducing satiety in an individual, controlling weight gain in an individual, and generally providing a benefit to the individual in the form of weight loss.

Additional diseases and conditions that are associated with the 5-HT(2C) receptor and that can be treated by the compounds of the present invention are disclosed in US Patent Publication Nos. 2008/0119477 and WO 2006/065600, each of which is incorporated herein by reference in its entirety.

The present invention provides methods for treating disorders, diseases, conditions and symptoms of mammals (and particularly humans) by administering a therapeutically effective amount of a compound of the present invention to an individual (mammal in need of treatment or prevention) in need of treatment or prevention. The result of the treatment can partially or completely alleviate, suppress, prevent, improve and/or alleviate the disorder, condition or one or more symptoms thereof. Administration includes any form of administration known in the art that is effective for a given type of disease or disorder, is intended to include administration in any suitable dosage form, and is also intended to include administering a compound, a pharmaceutically acceptable salt, solvate or ester thereof, alone or in a pharmaceutically acceptable carrier thereof, or administering a prodrug derivative or analog of a compound of the present invention, which will form an equivalent amount of active compound or substance in vivo. Individuals in need of treatment or prevention include individuals diagnosed with a given disorder or condition, and individuals suspected of having the disorder or condition, for example, due to displaying certain symptoms.

In a preferred embodiment, the present invention provides a method for treating the above-disclosed diseases and conditions, comprising administering a therapeutically effective amount of a compound of structural formula (I) to a subject in need thereof.

In one embodiment, the present invention provides a method for treating the above-disclosed diseases and conditions, comprising administering to a subject in need thereof a compound of structural formula (I) or a pharmaceutically acceptable salt thereof in an amount sufficient to treat the condition. The composition of structural formula (I) can be used as the sole therapeutic agent or in combination with a second treatment for the condition.

In another embodiment, the present invention provides a method of treating a disease or condition disclosed above, comprising: (a) administering to a subject in need thereof an amount of a compound of formula (I); and (b) administering to the subject an amount of a second therapeutic agent useful for treating the disease or condition. The amounts administered are each effective to treat the disease or condition. In another embodiment, the amounts are together effective to treat the disease or condition.

In another embodiment, the present invention provides a method for treating the above-disclosed diseases or conditions, comprising administering to a subject in need thereof a pharmaceutical composition comprising an amount of a compound of formula (I) effective to treat the disease or condition.

In one embodiment, the compound of structural formula (I) or a pharmaceutically acceptable salt thereof is administered prior to administration of the second therapeutic agent.

In another embodiment, the compound of structural formula (I), or a pharmaceutically acceptable salt thereof, is administered with a second therapeutic agent.

Suitable agents that can be used in combination with the compounds of structural formula (I) include anti-obesity drugs, such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4 agonists, cholecystokinin-A (CCKAA) agonists, serotonin and norepinephrine reuptake inhibitors (e.g., sibutramine), sympathomimetics, beta-blockers, _3- adrenergic receptor agonists, dopamine agonists (e.g., bromocriptine), melanocyte-stimulating hormone receptor analogs, cannabinoid 1 receptor antagonists (e.g., SR141716: N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide), melanin-concentrating hormone antagonists, leptin (OB protein), leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors (e.g., tetrahydrolipidase inhibitor or orlistat), anorexigenic drugs (e.g., bombesin agonists), neuropeptide Y antagonists, thyromimetic drugs, dehydroepiandrosterone or its analogs, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factor (e.g., Axokine ^™ ), human agouti-related protein (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, neuromedin U receptor agonists, noradrenergic anorectics (e.g., phentermine, mazindol, etc.) and appetite suppressants (e.g., bupropion). In some embodiments, the anti-obesity drug is selected from orlistat, sibutramine, bromocriptine, ephedrine, leptin, phentermine, and pseudoephedrine.

Other anti-obesity drugs, including those described above, are known, or will be apparent, to those of ordinary skill in the art in light of this disclosure.

It will be appreciated that the scope of combination therapy of the compounds of the present invention with other anti-obesity, anorectic, appetite suppressant and related agents is not limited to those listed above, but includes in principle any combination with any agent or pharmaceutical composition used to treat overweight and obese individuals.

Other suitable agents besides anti-obesity drugs that can be used in combination with the compounds of structural formula (I) include agents useful for treating concurrent diseases. For example, individuals who are overweight or obese have an increased risk of morbidity and mortality from concurrent diseases such as, but not limited to, congestive heart failure, type II diabetes, atherosclerosis, dyslipidemia, hyperinsulinemia, hypertension, insulin resistance, hyperglycemia, retinopathy, nephropathy, and neuropathy. Treatment of one or more of the diseases cited herein includes the use of one or more drugs known in the art belonging to the indicated drug classes, including but not limited to the following: sulfonylureas, meglitinides, biguanides, α-glucosidase inhibitors, peroxisome proliferator-activated receptor-γ (i.e., PPAR-γ) agonists, insulin, insulin analogs, HMG-CoA reductase inhibitors, cholesterol-lowering drugs (e.g., fibrates, including fenofibrate, bezafibrate, gemfibrozil, clofibrate, etc.; bile acid sequestrants, including cholestyramine, colestipol, etc. and niacin), antiplatelet agents (e.g., aspirin and adenosine diphosphate receptor antagonists, including clopidogrel, ticlopidine, etc.), angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and adiponectin. According to one aspect of the present invention, the compounds of the present invention can be used in combination with agents or drugs belonging to one or more drug classes cited herein.

Some embodiments of the present invention include methods of treating a disease, disorder, or condition described herein, comprising administering to a subject in need of such treatment a therapeutically effective amount or dose of a compound of structural formula (I) in combination with at least one agent selected from the group consisting of sulfonylureas, meglitinides, biguanides, α-glucosidase inhibitors, peroxisome proliferator-activated receptor-γ (i.e., PPAR-γ) agonists, insulin, insulin analogs, HMG-CoA reductase inhibitors, cholesterol-lowering drugs (e.g., fibrates, including fenofibrate, bezafibrate, gemfibrozil, clofibrate, etc.; bile acid sequestrants, including cholestyramine, colestipol, etc., and niacin), antiplatelet agents (e.g., aspirin and adenosine diphosphate receptor antagonists, including clopidogrel, ticlopidine, etc.), angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and adiponectin.

Suitable agents that can be used in combination with compounds of structural formula (I) include α-glucosidase inhibitors. α-glucosidase inhibitors belong to a class of drugs that competitively inhibit digestive enzymes such as α-amylase, maltase, α-dextrinase, sucrase, etc. in the pancreas and/or small intestine. The reversible inhibition of α-glucosidase inhibitors delays, reduces, or otherwise lowers blood glucose levels by delaying the digestion of starch and sugars. Some representative examples of α-glucosidase inhibitors include acarbose, N-(1,3-dihydroxy-2-propyl) vinblastine (commonly known as voglibose), miglitol, and α-glucosidase inhibitors known in the art.

Suitable medicaments that can be used in combination with the compounds of this invention include sulfonylureas.Sulfonylureas (SU) are medicines that promote pancreatic B cells to secrete insulin by transmitting insulin secretion signals through the SU receptors in the cell membrane.Examples of sulfonylureas include glibenclamide, glipizide, glimepiride and other sulfonylureas known in the art.

Suitable agents that can be used in combination with compounds of structural formula (I) include meglitinides. Meglitinides target postprandial hyperglycemia and have demonstrated efficacy comparable to sulfonylureas in lowering _HbA1c . Examples of meglitinides include repaglinide, nateglinide, and other meglitinides known in the art.

Suitable agents that can be used in combination with compounds of formula (I) include biguanides. Biguanides represent a class of drugs that stimulate anaerobic glycolysis, increase peripheral tissue insulin sensitivity, inhibit intestinal glucose absorption, inhibit hepatic gluconeogenesis, and inhibit fatty acid oxidation. Examples of biguanides include phenformin, metformin, buformin, and biguanides known in the art.

Suitable agents that can be used in combination with compounds of structural formula (I) include α-glucosidase inhibitors. α-glucosidase inhibitors competitively inhibit digestive enzymes such as α-amylase, maltase, α-dextrinase, sucrase, etc. in the pancreas and/or small intestine. The reversible inhibition of α-glucosidase inhibitors delays, reduces, or otherwise lowers blood glucose levels by delaying the digestion of starch and sugars. Examples of α-glucosidase inhibitors include acarbose, N-(1,3-dihydroxy-2-propyl) vinblastine (commonly known as voglibose), miglitol, and α-glucosidase inhibitors known in the art.

Suitable agents that can be used in conjunction with compounds of formula (I) include peroxisome proliferator-activated receptor-γ (i.e., PPAR-γ) agonists. Peroxisome proliferator-activated receptor-γ agonists represent a class of compounds that activate the nuclear receptor PPAR-γ and, thereby, regulate the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. Such drugs also help regulate fatty acid metabolism. Examples of PPAR-γ agonists include rosiglitazone, pioglitazone, tesalizumab, nyglitazone, GW-409544, GW-501516, and PPAR-γ agonists known in the art.

Suitable agents that can be used in combination with compounds of structural formula (I) include HMG-CoA reductase inhibitors. HMG-CoA reductase inhibitors are also known as statins, which belong to a class of drugs that lower blood cholesterol levels by inhibiting hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is the rate-limiting enzyme in cholesterol biosynthesis. Statins lower serum LDL concentrations by upregulating the activity of LDL receptors and are responsible for clearing LDL from the blood. Some representative examples of statins include rosuvastatin, pravastatin and its sodium salt, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin, BMS's "super statins" and HMG-CoA reductase inhibitors known in the art.

Suitable agents that can be used in combination with the compounds of the present invention include angiotensin converting enzyme (ACE) inhibitors. ACE inhibitors belong to a class of drugs that partially reduce blood sugar levels and lower blood pressure by inhibiting angiotensin converting enzyme. Examples of ACE inhibitors include captopril, enalapril, alacepril, delapril, ramipril, lisinopril, imidapril, benazepril, cilazapril, cilazapril, enalapril, fosinopril, movipril, perindopril, quinapril, spirapril, temocapril, trandolapril, and ACE inhibitors known in the art.

Suitable agents that can be used in combination with the compounds of the present invention include angiotensin II receptor antagonists. Angiotensin II receptor antagonists target angiotensin II receptor subtype 1 (i.e., AT1) and have shown beneficial effects on hypertension. Examples of angiotensin II receptor antagonists include losartan (and potassium salt form) and angiotensin II receptor antagonists known in the art.

Other treatments for one or more of the diseases cited herein include the use of agents known in the art that are of the types mentioned, but are not limited to, the following: amylin agonists (e.g., pramlintide), insulin secretagogues (e.g., GLP-1 agonists; exendin-4; insulinotropin (NN2211); dipeptidyl peptidase inhibitors (e.g., NVP-DPP-728), acyl-CoA cholesterol acetyltransferase inhibitors (e.g., ezetimibe, ilutimibe, and similar compounds), cholesterol absorption inhibitors (e.g., ezetimibe, pamaqueside, and similar compounds), cholesterol ester transfer protein inhibitors (e.g., CP-529414, JTT-705, CETi-1, and similar compounds), microsomal triglyceride transfer protein inhibitors (e.g., implitapide, and similar compounds), cholesterol regulators (e.g., NO-1886, and similar compounds), bile acid regulators (e.g., GT103-279, and similar compounds), and squalene synthase inhibitors.

Squalene synthesis inhibitors belong to a class of drugs that lower blood cholesterol levels by inhibiting squalene synthesis. Examples of squalene synthesis inhibitors include (S)-α[bis[2,2-dimethyl-1-oxopropoxy)methoxy]phosphino]-3-phenoxybenzenebutanesulfonic acid, monopotassium salt (BMS-188494) and squalene synthesis inhibitors known in the art.

In this method, a therapeutically effective amount of one or more compounds of formula (I), typically formulated in accordance with pharmaceutical practice, is administered to a person in need thereof. Whether such treatment is indicated depends on the individual case and is subject to medical evaluation (diagnosis), which takes into account the presence of signs, symptoms, and/or disorders, the risk of developing specific signs, symptoms, and/or disorders, and other factors.

The compound of structural formula (I) can be administered by any suitable route, for example, orally, buccally, by inhalation, topically, topically through the eye, intranasally, intrabronchially, sublingually, rectally, intravaginally, through a lumbar puncture pool or intrathecally, through the urethra, through the nose, transdermally, i.e., transdermally, or parenterally (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and/or surgical implantation at a specific site). Parenteral administration can be accomplished using a needle and syringe or using high-pressure techniques.

Pharmaceutical compositions include those wherein the compound of formula (I) is present in sufficient amounts and administered in an effective amount to achieve its intended purpose. The exact formulation, route of administration, and dosage are determined by the individual physician in view of the diagnosed condition or disease. The dosage and interval can be individually adjusted to provide a level of the compound of formula (I) sufficient to maintain a therapeutic effect.

Toxicity and therapeutic efficacy of compounds of structural formula (I) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as those used to determine _LD50 (the dose lethal to 50% of the population) and _ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between _LD50 and _ED50 . Compounds that exhibit high therapeutic indices are preferred. Data obtained from these data can be used to formulate a dosage range for use in humans. The dose preferably lies within a range of circulating compound concentrations that includes the _ED50 with little or no toxicity. The dose can vary within this range depending on the dosage form employed and the route of administration utilized. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

The therapeutically effective amount of the compound of formula (I) required for therapy varies according to the nature of the disease or condition being treated, the desired length of active time, and the age and condition of the patient, and is ultimately determined by the attending physician. The dose and interval can be adjusted individually to provide a plasma level of the compound/structural formula (I) sufficient to maintain the desired therapeutic effect. The desired dose can be conveniently administered in a single dose or in multiple doses given at appropriate intervals, such as one, two, three, four or more sub-doses per day. Multiple doses are usually required or needed. For example, the compound of formula (I) can be administered at the following frequencies: 1 dose per day at 4-day intervals, delivering 4 doses (q4d×4); 1 dose per day at 3-day intervals, delivering 4 doses (q3d×4); 1 dose per day at 5-day intervals (qd x 5); 1 dose per week for three weeks (qwk3); 5 daily doses, 2 days of rest, another 5 daily doses (5/2/5); or any dosage regimen determined to be suitable for the situation.

The dosage of a composition containing a compound of structural formula (I) or a composition containing the same can be about 1 ng/kg to about 200 mg/kg, about 1 μg/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg body weight. The dosage of the composition can be any dosage, including but not limited to about 1 μg/kg, 10 μg/kg, 25 μg/kg, 50 μg/kg, 75 μg/kg, 100 μg/kg, 125 μg/kg, 150 μg/kg, 175 μg/kg, 200 μg/kg, 225 μg/kg, 250 μg/kg, 275 μg/kg, 300 μg/kg, 325 μg/kg, 350 μg/kg, 375 μg/kg, 400 μg/kg, 425 μg/kg, 450 μg/kg, 475 μg/kg, 500 μg/kg, 525 μg/kg, 550 μg/kg, 575 μg/kg, 600 μg/kg, 625 μg/kg, 650 μg/kg, 675 μg/kg, 700 The above dosages are examples of average cases, but there may be individual cases where higher or lower dosages are useful, and these are within the scope of the invention. In practice, the physician determines the actual dosing regimen that will be most suitable for an individual patient and it may vary with the age, weight, and response of the particular patient.

The compound of formula (I) used in the methods of the present invention is typically administered in an amount of about 0.005 to about 500 mg per dose, about 0.05 to about 250 mg per dose, or about 0.5 to about 100 mg per dose. For example, the compound of formula (I) can be administered in an amount of about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg per dose, including all doses between 0.005 and 500 mg.

The compounds of the present invention are generally administered in admixture with a pharmaceutical carrier selected with respect to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions used according to the present invention are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate processing of the compounds of formula (I).

The term "carrier" refers to a diluent, adjuvant or excipient that accompanies administration of a compound of formula (I). Such pharmaceutical carriers can be liquids, such as water and oils, including oils of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. The carrier can be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silicon dioxide, urea, etc. In addition, adjuvants, stabilizers, thickeners, lubricants and colorants can be used. Pharmaceutically acceptable carriers are sterile. When a compound of formula (I) is administered intravenously, water is a preferred carrier. Saline solutions and aqueous glucose solutions and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice flour, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dry skim milk, glycerol, propylene glycol, water, ethanol, etc. If desired, the present compositions may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

These pharmaceutical compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee manufacturing, emulsification, encapsulation, embedding or lyophilization methods. Appropriate formulations depend on the selected route of administration. When a therapeutically effective amount of a compound of formula (I) is administered orally, the composition is typically in the form of tablets, capsules, powders, solutions, pills, granules, tinctures, emulsions, syrups or elixirs. When administered in tablet form, the composition can additionally contain a solid carrier, such as gelatin or an adjuvant. Tablets, capsules and powders contain about 0.01% to about 95%, preferably about 1% to about 50% of a compound of formula (I). When administered in liquid form, a liquid carrier, such as water, petroleum or an oil of animal or plant origin, can be added. The liquid form of the composition can further comprise physiological saline solution, glucose or other sugar solutions or glycols. When administered in liquid form, the composition contains about 0.1% to about 90%, preferably about 1% to about 50% by weight of a compound of formula (I).

When administering the compound of formula (I) of therapeutically effective amount by intravenous, skin or subcutaneous injection, said composition is a pyrogen-free, parenteral acceptable aqueous solution form. Suitably considering pH, isotonicity, stability etc., the preparation of such parenteral acceptable solution is within the technical scope of this area. Preferred compositions for intravenous, skin or subcutaneous injection usually contain isotonic solvent. Compound of formula (I) can be infused together with other fluids in 10-30 minute span or in several hours.

The compound of formula (I) can be easily combined with pharmaceutically acceptable carriers well known in the art. This carrier allows the active agent to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral intake by patients to be treated. The pharmaceutical preparations for oral use can be obtained as follows: the compound of formula (I) is added to a solid excipient, optionally grinding the resulting mixture, and if necessary, after adding suitable adjuvants, processing the particle mixture to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If necessary, disintegrants can be added.

The compounds of formula (I) can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection can be in unit dose form, for example, in ampoules or multidose containers, and preservatives can be added. The compositions can be in the form of suspensions, solutions or emulsions in oily or aqueous solvents and can contain preparatants such as suspending agents, stabilizers and/or dispersants.

Pharmaceutical compositions for parenteral administration include aqueous solutions of active agents in water-soluble form. In addition, suspensions of compounds of formula (I) can be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or solvents include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. Optionally, the suspension can also contain suitable stabilizers or reagents that increase the solubility of the compound and allow the preparation of highly concentrated solutions. Alternatively, the compositions of the present invention can be in powder form for use in a suitable solvent such as sterile, pyrogen-free water for example.

The compound of structural formula (I) can also be formulated into rectal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases. In addition to the above-mentioned preparations, the compound of structural formula (I) can also be formulated into depot preparations. Such long-acting preparations can be given by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Therefore, for example, the compound of structural formula (I) can be formulated with suitable polymerization or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins.

In particular, the compounds of formula (I) can be administered orally, buccally or sublingually in the form of tablets containing excipients (e.g., starch or lactose), or in the form of capsules or ovules, alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavorings or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable additives such as suspending agents. The compounds of formula (I) can also be injected parenterally, for example, intravenously, intramuscularly, subcutaneously or intracoronaryally. For parenteral administration, the compounds of formula (I) are preferably used in the form of a sterile aqueous solution, which may contain other substances, such as salts or monosaccharides such as mannitol or glucose, to make the solution isotonic with the blood.

Compounds of structural formula (I) were prepared and tested for their ability to modulate the activity of the 5-HT(2) receptor family. Specifically, compounds were prepared and tested to determine their effects on the 5-HT(2) receptor family. The methods are described below and the results are summarized in Table 3.

Pharmacological testing of selected compounds in a calcium flux assay.

5-HT _2A , 5-HT _2B and 5-HT _{2C -INI} receptors expressed on HEK-293 cells

Before inoculation, Flp-In-293 cells stably expressing human 5-HT _2A , 5-HT _2B or 5-HT _2C-INI were grown in DMEM containing 10% dialyzed FBS for 24-48 hours. Cells were plated in 384-well transparent black bottom cell culture plates coated with Poly- _L -Lys in DMEM containing 1% dialyzed FBS at a density of 12,000 cells per well in 50 μL for 24 hours. Prior to the experiment, the culture medium was removed and 20 μL of assay buffer (20 mM Hepes, pH 7.40, Hanks balanced salt solution, 2.5 mM probenecid, 1X FLIPR calcium dye) were added, and the cells were incubated at 37°C for 1 hour. Serial dilutions of each test drug were prepared at 3 × final concentrations and transferred to 384-well plates. Each drug plate contained serially diluted 5-HT and lorcaserin for internal reference. Cell and drug plate are placed in FLIPR ^TETRA fluorescence imaging plate reader (Molecular Dynamics). FLIPR ^TETRA is programmed to read baseline 10 seconds (1 reading/second), then 10 μ L drug/well is added, and read extra 120 seconds. Fluorescence is normalized to the mean value (first 10 readings) of baseline, and the maximum multiple increase peak value of every kind of drug and control (5-HT and lorcaserin) is measured. Data are plotted as the function of drug concentration, and compared and normalized with the internal 5-HT reference value of each flat plate recorded. Use S-type dose-response function regression normalization data. The data of two independent experiments (n=2) are provided, carried out in quadruplicate. Use GraphPad Prism 6.0 software to analyze. 5-HT _2C EC ₅₀ confidence intervals (5-HT: 0.16 - 0.26 nM; lorcaserin: 3.1 - 3.9 nM), E _max standard deviation (5-HT: 100% ± 1.04; lorcaserin: 99% ± 0.75); 5-HT _2B EC ₅₀ confidence intervals (5-HT: 0.66 - 1.17 nM; lorcaserin: 429- 527 nM), E _max standard deviation (5-HT: 100% ± 1.69; lorcaserin: 92% ± 3.01); 5-HT _2A EC ₅₀ confidence intervals (5-HT: 1.60 - 2.16 nM; lorcaserin: 275 - 329 nM), E _max standard deviation (5-HT: 100% ± 1.03; lorcaserin: 68% ± 0.83).

Rat 5-HT _2C-INI receptor expressed on PO1C cells

The rat PO1C cell line stably expressing rat 5-HT2C _-INI was plated on a 384-well transparent black bottom cell culture plate coated with Poly-L-Lys in DMEM-1% dialyzed FBS (12,000 cells/well). Prior to the experiment, the culture medium was removed, 20 μl of assay buffer (20 mM Hepes, pH 7.40, Hanks balanced salt solution, 2.5 mM probenecid, 1X FLIPR calcium dye) was added, and the cells were incubated at 37°C for 1 hour. Serial dilutions of each test drug were prepared at 3× final concentration and transferred to a 384-well plate. The cells and drug plates were placed in a FLIPR ^TETRA fluorescence imaging plate reader (Molecular Dynamics) and programmed to read the baseline for 10 seconds (1 reading/second), then 10 μL of drug/well was added and read for an additional 120 seconds. Fluorescence was normalized to the mean value of baseline (first 10 readings), and the maximum fold increase peak value for each drug and control (5-HT) was determined. Data were plotted and normalized to 5-HT using a sigmoidal dose-response function regression. Data from two independent experiments (n = 2) performed in quadruplicate are provided. Analyses were performed using GraphPad Prism 6.0 software.

Table 3. Pharmacological profiles of selected compounds using recombinant stably expressed human 5- _HT2A , 5- _HT2B and 5-HT2C _-INI receptors in HEK-293 cell lines using a fluorescence imaging plate reader (FLIPR) ("NA", no activity at 10 μM; "NT", not tested; ^a , data obtained with rat 5-HT2C _-INI receptor expressed on PO1C cells):

In vivo testing in schizophrenia-like animal models. Adult male C57BL/6J mice (Jackson Laboratories, Bar Harbor, ME) were injected (i.p.) with vehicle (Veh) or different doses of the compound and placed outdoors for 15 minutes. The mice were removed and given (i.p.) Veh or 3 mg/kg amphetamine (AMPH; Sigma-Aldrich, St. Louis, MO) and returned to the outdoors for 105 minutes. VersaMax software (AccuScan Instruments, Columbus, OH) was used to monitor locomotor activity as the distance traveled in an automated Omnitech Digiscan device. The results were presented as mean and standard deviation of the mean using SPSS software (IBM, Armonk, NY). Data for the 0-15 minute interval were analyzed by three-way ANOVA for conditions (vehicle and AMPH), treatment, dose (10 or 20 mg/kg), and dose of the embedded treatment (reflecting the different doses tested for each compound). Because activity was significantly different between groups in the 0-15 minute interval, RMAOVA was run with sequential sums of squares (controlling for group differences in 0-15 minutes) for the test intervals (0-15 and 16-120 minutes), condition, treatment, dose, and dose (treatment) to control for these group differences. All post hoc analyses were pairwise comparisons with Bonferroni correction, with p < 0.05 considered significant.

Compounds (+)-Example 25, (+)-Example 19, (+)-Example 8, and (+)-Example 10 were tested in this model. Adult male C57BL/6J mice were given vehicle (Veh) or one of the test compounds and placed in the outdoor area for 15 minutes. They were removed and given Veh or d-amphetamine (AMPH) and immediately returned to the outdoor area for 105 minutes. As shown in the figure below, d-amphetamine significantly increased locomotor activity in the Veh-AMPH group from 16 to 120 minutes compared to the Veh-Veh group. Each of the four compounds administered at a dose of 10 or 20 mg/kg significantly reduced AMPH-stimulated hyperactivity relative to the Veh-AMPH group (p value < 0.035). While responses to 10 and 20 mg/kg of (+)-Example 19 and (+)-Example 10 did not differ by dose, compounds (+)-Example 25 and (+)-Example 8 dose-dependently inhibited hyperactivity, such that locomotion at the 20 mg/kg dose was similar to that of the Veh-Veh group. Importantly, each of the four compounds alone at a 20 mg/kg dose (20-Veh group) had little effect on the spontaneous activity of the injected animals.

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Claims (39)

1. Compounds having the following structural formula: , Where ^R1 is a halogen; ^R2 is a fluorinated _C1-3 alkyl group or –( _CH2 ) _{1-3XCH3 ;} X is O or S; and n is an integer, which is 1, 2, or 3; Or its pharmaceutically acceptable salts or hydrates. 2. Compound 1 of claim 1, wherein R ¹ is fluorine or chlorine. 3. The compound of claim 1, wherein n is 1 and ^R1 is fluorine or chlorine. 4. The compound of claim 1, wherein n is 2 and ^R1 is fluorine and fluorine, chlorine and chlorine, or fluorine and chlorine. _{5. The} compound _of any one of claims 1 to 4, wherein ^R2 is _-CH2CH2F , _{-CH2CH2CH2F , -CH2CHF2} or _{–CH2CF3 .} 6. The compound of any one of claims 1 to 4, wherein ^R2 is _–CH2CH2 - _O - _CH3 or _–CH2CH2 - _S - _CH3 . 7. Compound 1 of claim 1, wherein R ¹ is F, n is 1, and R ² is –CH ₂ CH ₂ F. 8. A racemic mixture of the compounds of any one of claims 1 to 7. 9. The (+)-enantiomer of the compound of any one of claims 1 to 7. 10. The (+)-enantiomer of claim 9, which is substantially free of (-)-enantiomers. 11. The (-)-enantiomer of the compound of any one of claims 1 to 7. 12. The (-)-enantiomer of claim 11, which is substantially free of (+)-enantiomers. 13. Compounds selected from: ,,,,,,,,,,,,,and. 14. Selected from the following compounds: (+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methylamine; and (+) (2-(5-chloro-2-(3-fluoropropoxy)phenyl)cyclopropyl)methylamine; Or its salt. 15. A composition comprising (a) the compound of claim 1, (b) a second therapeutic agent for treating a disease or condition in which regulation of 5-HT(2C) provides benefit, and (c) optionally an excipient and/or a pharmaceutically acceptable carrier. 16. The composition of claim 15, wherein the second therapeutic agent comprises a therapeutic agent that can be used to treat mental disorders, metabolic disorders, neurological disorders, or eating disorders. 17. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or solvent. 18. Use of the compound of claim 1 in a medicament for preparing a disease or condition in which modulation of the 5-HT(2C) receptor provides benefit, said method comprising administering a therapeutically effective amount of the compound of claim 1 to an individual in need. 19. The use of claim 18, wherein the 5-HT(2C) receptor is activated. 20. The use of claim 18, wherein the method further comprises administering a second therapeutic agent in a therapeutically effective amount for treating the disease or condition. 21. The use of claim 18, wherein the disease or condition is selected from: obesity, eating disorders, diabetes, cardiovascular disease, sleep disorders, central nervous system disorders, gastrointestinal disorders, headache-related conditions, chronic pain, increased intracranial pressure, epilepsy, age-related behavioral disorders, chronic fatigue syndrome, drug and alcohol addiction, premenstrual stress, chemotherapy-induced vomiting, trauma-related central nervous system injury, stroke, or spinal cord injury. 22. The use of claim 18, wherein the disease or condition is a central nervous system disorder or central nervous system injury. 23. The use of claim 22, wherein the central nervous system disorder is schizophrenia, psychosis, dystonia, addictive behavior, movement disorder, or cognitive impairment. 24. The use of claim 18, wherein the disease or condition is a metabolic or eating disorder. 25. The use of claim 24, wherein the metabolic or eating disorder is a lipid disorder, type 2 diabetes, diabetes insipidus, metabolic syndrome, or obesity. 26. The use of claim 18, wherein the disease or condition is a gastrointestinal disorder, sleep apnea, cardiovascular disease, dementia, mild cognitive impairment, Parkinson's disease, Alzheimer's disease, intellectual disability associated with Alzheimer's disease, Huntington's disease, movement disorder, chronic pain, migraine, epilepsy, alcohol and drug abuse or addiction, or sexual dysfunction in men or women. 27. The use of claim 18, wherein the disease or condition is a neurological disorder. 28. The use of claim 27, wherein the neurological disorder is Rett syndrome. 29. Use of the compound of claim 1 in the preparation of a medicament for reducing individual food intake. 30. Use of the compound of claim 1 in the preparation of a medicament for inducing a feeling of fullness in an individual. 31. Use of the compound of claim 1 in the preparation of a medicament for controlling weight gain in an individual. 32. Use of the compound of claim 1 in a medicament for preparing a method for modulating a 5-HT(2C) receptor in vivo or in vitro, said method comprising contacting the receptor compound of claim 1. 33. The use of claim 32, wherein the 5-HT(2C) receptor is activated or stimulated. 34. The use of claim 33, wherein the 5-HT(2C) receptor is selectively activated or stimulated relative to the 5-HT(2A) receptor and the 5-HT(2B) receptor. 35. The use of claim 21, wherein the central nervous system disorder is psychosis, dystonia, depression, bipolar disorder, obsessive-compulsive disorder, or movement disorder; wherein the headache-related condition is headache; wherein the age-related behavioral disorder is Alzheimer's disease, Parkinson's disease, dementia-related behavioral disorder, or age-related memory disorder; wherein the male or female sexual dysfunction is erectile dysfunction; wherein the cardiovascular disease is hypertension or hyperlipidemia; wherein the eating disorder is bulimia, bulimia, or anorexia nervosa; wherein the sleep disorder is sleep apnea; wherein the gastrointestinal disorder is irritable bowel syndrome or gastrointestinal motility disorder; and wherein the comorbidities of obesity are type II diabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke, osteoarthritis, sleep apnea, gallbladder disease, gout, cancer, infertility, or premature death. 36. The use of claim 35, wherein the mental illness is schizophrenia, anxiety disorder, adjustment disorder, social phobia, panic disorder, personality disorder, organic mental disorder, childhood mental disorder, aggression, mental disorder, or L-DOPA-induced mental illness; wherein the depression is atypical depression; and wherein the headache is migraine. 37. The use of claim 36, wherein the anxiety disorder is anxiety; wherein the panic disorder is panic; and wherein the schizophrenia is schizophrenic disorder or schizoaffective disorder. 38. The use of claim 23, wherein the addictive behavior is compound addiction; wherein the schizophrenia is schizophrenic disorder; and wherein the psychosis is anxiety, panic disorder, schizoaffective disorder, adjustment disorder, clinical depression, bipolar disorder, or obsessive-compulsive disorder. 39. The use of claim 26, wherein the cardiovascular disease is hypertension or hyperlipidemia; and wherein the dementia is memory impairment.