CN1639112A - Substituted amides with cannabinoid-1 receptor activity - Google Patents

Abstract

Novel compounds of structural formula (I) are antagonists and/or inverse agonists of the cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the invention are useful as centrally acting drugs in the treatment of the following diseases: psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuroinflammatory disorders including multiple sclerosis and guillain-barre syndrome, and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents and head trauma, anxiety, emergency responses, epilepsy, parkinson's disease, movement disorders, and schizophrenia. These compounds may also be useful in the treatment of substance abuse disorders, obesity or eating disorders, as well as asthma, constipation, chronic intestinal pseudo-obstruction, and cirrhosis of the liver.

Description

Substituted amides having cannabinoid-1 receptor activity

Related applications: None

Background of the invention

Indian cannabis (Cannabis sativa L.) and its derivatives have been used for centuries for medicinal and recreational purposes. The main active ingredient in cannabis and cannabis powder has been identified as Δ ⁹ -tetrahydrocannabinol (Δ ⁹ -THC). Detailed studies have shown that the biological actions of Δ ⁹ -THC and other members of the cannabinoid family occur through two G-protein coupled receptors called CB1 and CB2. CB1 receptors are found primarily in the central and peripheral nervous systems, but also in small amounts in some peripheral organs. CB2 receptors are mainly found in lymphoid tissues and cells. Three endogenous ligands for the cannabinoid receptor derived from arachidonic acid have been identified (anandamide, 2-arachidonoylglycerol and 2-arachidonoylglycerol ether). They are all agonists with activities similar to Δ ⁹ -THC, including sedation, hypothermia, intestinal immobility, antinociception, analgesia, catalepsy, antiemetic, and appetite stimulation.

Studies have been conducted to disrupt each of the mouse cannabinoid receptor genes. Mice dosed with CB1-/-receptors appeared normal and fertile. They resisted the effects of Δ ⁹ -THC and exhibited a marked reduction in the compulsive effects of morphine and the severity of post-drug withdrawal syndrome. They also showed locomotor-reducing activity and hypoalgesic activity. Overexposure to Δ ⁹ -THC can cause binge eating, psychosis, hypothermia, memory loss and sedation. At least one CB1 modulator currently characterized as an inverse agonist or antagonist, N-(1-piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl )-4-methylpyrazole-3-carboxamide (SR141716A) is used in clinical trials for the treatment of eating disorders. However, there remains a need for highly effective low molecular weight CB1 modulators with pharmacokinetic and pharmacodynamic properties suitable for use as human medicines.

The finding that the presynaptic cannabinoid CB1 receptor-mediated inhibition of norepinephrine release in the guinea pig lungs provides evidence that CB1 receptor modulators, such as CB1 inverse agonists, can treat asthma (Europ. J. of Pharmacology, 2001, 431(2), 237-244).

It has been found that CB1 receptor modulators can reverse carbon tetrachloride-induced hypotension in rats with cirrhosis, and reduce increased mesenteric blood flow and portal pressure, thus providing evidence for CB1 receptor modulators in the treatment of cirrhosis (Nature Medicine, 2001, 7(7), 827-832).

US Patents US 5,624,941 and US 6,028,084, PCT applications WO98/43636 and WO98/43635 and EPO application EP-658546 disclose substituted pyrazoles having anticannabinoid receptor activity.

PCT applications WO98/31227 and WO98/41519 also disclose substituted pyrazoles having anticannabinoid receptor activity.

PCT applications WO98/37601, WO00/10967, and WO00/10968 disclose diaryl ether sulfonamides having anticannabinoid receptor activity.

PCT applications WO97/29079 and WO99/02499 disclose alkoxy-isoindolinones and alkoxy-quinolones having anticannabinoid receptor activity.

US Patent No. 5,532,237 discloses N-benzoyl-indole derivatives having anticannabinoid receptor activity.

US Patents US4,973,587, US5,013,837, US5,081,122 and US5,112,820, US5,292,736 disclose aminoalkylindole derivatives having anticannabinoid receptor activity.

PCT application WO 01/58869 discloses pyrazole, pyrrole and imidazole cannabinoid receptor modulators useful in the treatment of respiratory and non-respiratory diseases associated with leukocyte activation.

PCT applications WO 01/64632, 01/64633 and 01/64634 assigned to Aventis describe azetidine derivatives useful as cannabinoid antagonists.

Schultz, E.M, etc. in J.Med.Chem.1967,10,717 and Pines, S.H., etc. disclose maleamic acid compounds affecting plasma cholesterol and penicillin excretion in J.Med.Chem.1967,10,725 .

The compounds of the present invention are modulators of cannabinoid-1 (CB1) receptors and are therefore useful in the treatment, prevention and inhibition of diseases mediated by cannabinoid-1 (CB1) receptors. In particular, the compounds of the invention are antagonists or inverse agonists of the CB1 receptor. The present invention relates to the use of these compounds to modulate cannabinoid-1 (CB1) receptors. Accordingly, the compounds of the present invention are useful as centrally acting agents for the treatment of psychosis, memory loss, cognitive impairment, migraine, neuropathy, neuro-inflammatory diseases including multiple sclerosis and Guerra-Barr syndrome and viral Inflammatory sequelae of acute encephalitis, cerebrovascular accidents and head trauma, anxiety disorders, stress response, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds of the present invention are also useful in the treatment of substance abuse disorders, especially opiate, alcohol, cannabis and nicotine abuse disorders. The compounds of the present invention are also useful in the treatment of eating disorders and the resulting obesity and various complications associated therewith by inhibiting excessive food intake. The compounds of the invention are also useful in the treatment of constipation and chronic pseudo-ileus, and in the treatment of asthma and cirrhosis.

Summary of the invention

The present invention relates to novel substituted amide compounds of general formula I:

and pharmaceutically acceptable salts thereof, which are antagonists and/or inverse agonists of cannabinoid-1 (CB1) receptors, useful for the treatment, prevention and inhibition of diseases mediated by cannabinoid-1 (CB1) receptors . The present invention relates to the use of these novel compounds to selectively antagonize the cannabinoid-1 (CB1) receptor. Accordingly, the compounds of the present invention are useful as centrally acting agents for the treatment of psychosis, memory loss, cognitive impairment, migraine, neuropathy, neuro-inflammatory diseases including multiple sclerosis and Guerra-Barr syndrome and viral Inflammatory sequelae of acute encephalitis, cerebrovascular accident and head trauma, anxiety disorders, stress response, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds of the present invention are also useful in the treatment of substance abuse disorders, especially opiate, alcohol, cannabis and nicotine abuse disorders. The compounds of the present invention are also useful in the treatment of obesity or eating disorders associated with excessive food intake and various complications associated therewith. The compounds of the present invention are also useful in the treatment of constipation and chronic pseudo-bowel obstruction. The compounds of the present invention are also useful in the treatment of liver cirrhosis. These compounds are also useful in the treatment of asthma.

The invention also relates to the treatment of these diseases and the use of the compounds of the invention in the preparation of medicaments for the treatment of these diseases. The present invention also relates to the treatment of these diseases by administering the compound of formula I in combination with other existing drugs.

The present invention also relates to novel compounds of formula I.

The invention also relates to pharmaceutical preparations comprising a compound according to the invention as active ingredient.

The invention further relates to processes for the preparation of the compounds of the invention.

Detailed description of the invention

The compound used in the method of the present invention is represented by a compound of structural formula I or a pharmaceutically acceptable salt thereof:

in:

^R1 is selected from:

(1) heterocycloalkyl,

(2) aryl,

(3) heteroaryl, and

(4)-NR ^a R ^c ;

Wherein aryl and heteroaryl are optionally substituted by 1-3 substituents independently selected from R ^b ;

^R2 is selected from:

(1) C _1-10 alkyl,

(2) C _3-10 cycloalkyl-C _1-4 alkyl,

(3) aryl-C _1-4 alkyl, and

(4) Heteroaryl-C _1-4 alkyl;

wherein cycloalkyl, aryl and heteroaryl are each optionally substituted by 1-3 substituents independently selected from ^R ;

Each R ^a is independently selected from:

(1) hydrogen,

(2) methyl, and

(3) _-CF3 ;

Each R ^b is independently selected from:

(1) Halogen,

(2) cyano,

(3) Trifluoromethyl,

(4) Trifluoromethoxy,

(5) C _1-3 alkoxy, and

(6) C _1-3 alkyl;

^{Rc is} independently selected from:

(1) hydrogen,

(2) C _1-6 alkyl,

(3) aryl,

(4) heteroaryl,

(5) aryl-methyl, and

(6) Heteroaryl-methyl,

Each ^Rc may be unsubstituted or substituted with 1-3 substituents selected from ^Rh ;

R ^is independently selected from:

(1) Cycloalkyl,

(2) aryl, and

(3) heteroaryl,

Each ^R can be unsubstituted or substituted with 1-3 substituents selected from ^Rh ;

Each ^Rh is independently selected from:

(1) Halogen,

(2) C _1-3 alkyl,

(3)-CN, and

(4)-CF ₃ ,

Where the nitrogen of the pyridyl group is unsubstituted, they may optionally be in the form of N-oxides.

In one embodiment of the invention, R ^is selected from:

(1) phenyl,

(2) pyridyl,

(3) indolyl,

(4) 7-aza-indolyl,

(5) Thienyl, and

(6)

wherein each aryl and heteroaryl is optionally substituted with 1 or 2 substituents independently selected from ^Rb , and each pyridyl is optionally in the form of an N-oxide.

In a class of this embodiment of the invention, R ^is selected from:

(1) phenyl,

(2) 3-cyanophenyl,

(3) 3-methylphenyl,

(4) 3,5-difluorophenyl,

(5) 3-pyridyl,

(6) 5-chloro-3-pyridyl,

(7) 5-methyl-3-pyridyl,

(8) 5-cyano-3-pyridyl,

(9) 1-oxygen-5-cyano-3-pyridyl,

(10) 1-indolyl,

(11) 7-aza-indol-N-yl,

(12) 2-thienyl, and

(13)

In this subclass of the invention, R ¹ is 5-cyano-3-pyridyl.

In another embodiment of the present invention, R ^is selected from:

(1) C _1-6 alkyl,

(2) C _3-6 cycloalkylmethyl,

(3) Benzyl,

(4) Heteroarylmethyl,

wherein each of cycloalkyl, phenyl and heteroaryl is optionally substituted with 1-3 substituents independently selected from ^Rb .

In a class of such embodiments of the invention, R ^is selected from:

(1) C _1-6 alkyl,

(2) C _4-6 cycloalkylmethyl,

(3) Benzyl,

(4) pyridyl,

wherein each of cycloalkyl, phenyl and heteroaryl is optionally substituted by 1 or 2 substituents independently selected from ^Rb .

In this subclass of the invention, R ^is selected from:

(1) 2-methylpropyl,

(2) n-pentyl,

(3) Cyclobutylmethyl,

(4) Cyclopentylmethyl,

(5) Cyclohexylmethyl,

(6) Benzyl,

(7) 4-chlorobenzyl,

(8) 4-methylbenzyl,

(9) 4-fluorobenzyl,

(10) 4-methoxybenzyl, and

(11) (5-chloro-2-pyridyl)methyl.

In one embodiment of the invention, each ^Ra is independently selected from:

(1) hydrogen,

(2) methyl, and

(3)—CF ₃ .

In a class of such embodiments of the invention, each ^{Ra is} independently selected from:

(1) Hydrogen, and

(2) Methyl.

In one embodiment of the invention, each R ^b is independently selected from:

(1) Halogen,

(2) cyano,

(3) C _1-3 alkoxy, and

(4) C _1-3 alkyl.

In a class of such embodiments of the invention, each R ^b is independently selected from:

(1) fluorine,

(2) Chlorine,

(3) Bromine,

(4) iodine,

(5) cyano,

(6) methoxy, and

(7) Methyl.

In a subclass of this class of schemes, each R ^b is independently selected from:

(1) fluorine,

(2) Chlorine,

(3) cyano,

(4) methoxy, and

(5) Methyl.

In one embodiment of the invention, each ^Rc is independently selected from:

(1) hydrogen,

(2) C _1-6 alkyl,

(3) phenyl,

(4) pyridyl,

(5) benzyl, and

(6) pyridyl-methyl;

Each ^Rc may be unsubstituted or substituted with a substituent selected from ^Rh .

In one class of embodiments, R ^c is phenyl.

In one embodiment of the invention, ^Rd is selected from:

(1) C _4-6 cycloalkyl,

(2) aryl, and

(3) heteroaryl,

wherein R ^d may be unsubstituted or substituted with 1 or 2 substituents selected from ^Rh .

In one class of the invention, ^Rd is selected from:

(1) phenyl,

(2) pyridyl, and

(3) pyrimidinyl,

wherein R ^d can be unsubstituted or substituted by 1 or 2 substituents selected from ^Rh .

In a subclass of the invention, R ^is selected from:

(1) phenyl,

(2) 4-chlorophenyl,

(3) 3-chlorophenyl,

(4) 3,5-difluorophenyl,

(5) 3,5-dichlorophenyl,

(6) 2-pyridyl,

(7) 5-chloro-2-pyridyl,

(8) 6-methyl-2-pyridyl,

(9) 5-trifluoromethyl-2-pyridyl,

(10) 4-trifluoromethyl-2-pyridyl,

(11) 4-trifluoromethyl-2-pyrimidinyl, and

(12) 6-trifluoromethyl-4-pyrimidinyl.

In another subclass of this invention ^Rd is 5-trifluoromethyl-2-pyridyl.

In one embodiment of the invention, each ^Rh is independently selected from:

(1) Halogen,

(2) C _1-3 alkyl,

(3)-CN, and

(4) _-CF3 .

In a class of such embodiments, each ^Rh is independently selected from:

(1) fluorine,

(2) Chlorine,

(3) methyl,

(4)-CN, and

(5) _-CF3 .

Specific novel compounds that can be used in the methods, uses and compositions of the invention include:

(1) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(4-chlorophenoxy)-2-methylpropionamide;

(2) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylpropionamide;

(3) N-[3-(4-chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(4-chlorophenoxy)-2-methylpropionamide ;

(4) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3,5-difluorophenoxy)-2-methylpropionamide;

(5) N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(3,5-dichlorophenoxy)-2-methylpropanamide;

(6) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-chlorophenoxy)-2-methylpropionamide;

(7) N-[3-(4-chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methyl propionamide;

(8) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropionamide;

(9) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(6-methyl-pyridyloxy)-2-methylpropionamide;

(10) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(phenoxy)-2-methylpropionamide;

(11) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(5-trifluoromethylpyridyloxy)-2-methylpropionamide;

(12) N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)- 2-Methylpropionamide;

(13) N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy )-2-methylpropanamide;

(14) N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridine Oxy)-2-methylpropanamide;

(15) N-[3-(4-chlorophenyl)-2-(5-methyl-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2- Pyridyloxy)-2-methylpropanamide;

(16) N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2- Pyridyloxy)-2-methylpropanamide;

(17) N-[3-(4-chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy )-2-methylpropanamide;

(18) N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methyl Propionamide;

(19) N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidinyloxy)-2-methyl Propionamide;

(20) N-[3-(4-chlorophenyl)-1-methyl-2-(thiophen-3-yl)propyl]-2-(5-chloro-2-pyridyloxy)-2- Methacrylamide;

(2 1) N-[3-(5-chloro-2-pyridyl)-2-phenyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)- 2-Methylpropionamide;

(22) N-[3-(4-methylphenyl)-1-methyl-2-phenylpropyl]-2-(4-trifluoromethylphenoxy)-2-methylpropionamide ;

(23) N-[3-(4-fluorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy )-2-methylpropanamide;

(24) N-[3-(4-chlorophenyl)-2-(1-indolyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-oxypyridine- 2-yl)-2-methylpropanamide;

(25) N-[3-(4-chlorophenyl)-2-(7-azaindole-N-yl)-1-methylpropyl]-2-(5-trifluoromethyl-2 -pyridyloxy)-2-methylpropanamide;

(26) N-[3-(4-chlorophenyl)-2-(1-dihydroindolyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridineoxy Base)-2-methylpropanamide;

(27) N-[3-(4-chlorophenyl)-2-(N-methylanilino)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy )-2-methylpropanamide;

(28) N-[3-(4-methoxyphenyl)-2-(3-cyano-phenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2- Pyridyloxy)-2-methylpropanamide;

(29) N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidinyloxy )-2-methylpropanamide;

(30) N-[2-(3-cyanophenyl)-1,4-dimethylpentyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropane amides;

(31) N-[3-(4-chlorophenyl)-2-(1-oxidation-5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethane -2-pyridyloxy)-2-methylpropanamide;

(32) N-[2-(3-cyanophenyl)-3-cyclobutyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2- Methacrylamide;

(33) N-[2-(3-cyanophenyl)-1-methylheptyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropionamide;

(34) N-[2-(3-cyanophenyl)-3-cyclopentyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2- Methacrylamide;

(35) N-[2-(3-cyanophenyl)-3-cyclohexyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propionamide;

and their pharmaceutically acceptable salts.

"Alkyl", as well as other groups having the prefix "alk" (eg, alkoxy, alkanoyl), refers to carbon chains which may be straight or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.

"Cycloalkyl" means a saturated monocyclic or bicyclic or bridged carbocyclic ring, each having 3-10 carbon atoms. For example, cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

"Aryl" means a monocyclic or bicyclic aromatic ring containing only carbon atoms. Examples of aryl groups include phenyl, naphthyl and the like.

"Heteroaryl" means a monocyclic or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, wherein each ring contains 5-6 atoms. Examples of heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, Azolyl, furyl, triazinyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuryl, benzothienyl, Furo(2,3-b)pyridyl, quinolinyl, indolyl, isoquinolyl, imidazothiazolyl and the like. "Heteroaryl" specifically includes pyridyl, pyrimidinyl and thienyl, the heteroaryl ring may be substituted on one or more carbon or nitrogen atoms.

"Heterocycloalkyl" means a saturated monocyclic or bicyclic or bridged ring containing at least one heteroatom selected from N, S and O, said rings each containing from 3 to 10 atoms, where the attachment position can be carbon or nitrogen . The term also includes single heterocycles fused to aryl or heteroaryl groups where the point of attachment is on a non-aromatic moiety. Examples of "heterocycloalkyl" include indolyl, azaindolyl, and the like. Heterocycloalkyl rings may be substituted on ring carbons and/or ring nitrogen atoms.

"Halogen" includes fluorine, chlorine, bromine and iodine.

When any variable (eg ^R1 , ^Rd , etc.) occurs more than one time in any moiety or in Formula I, its definition on each occurrence is independent of its definition on other occurrences. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

In standard nomenclature used throughout this specification, the terminal portion of the side chain shown is described first, followed by the adjacent functionality towards the site of attachment. For example, a C _1-5 alkylcarbonylamino C _1-6 alkyl substituent is equivalent to:

In selecting compounds of the present invention, one of ordinary skill in the art will recognize that the selection of the various substituents (ie, ^R1 , R2 ^, etc.) should follow well-known principles of attachment and stability of chemical structures.

The term "substituted" should be taken to include multiple substitutions by the stated substituents. When multiple substituent moieties are disclosed or claimed, the substituted compounds may independently be mono- or polysubstituted with one or more of the disclosed or claimed substituent moieties. Independently substituted means that the substituent(s) may be the same or different.

Compounds of formula I may contain one or more asymmetric centers and thus may exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention includes all isomeric forms of the compounds of formula I.

Certain of the compounds described herein contain olefinic double bonds and, therefore, unless otherwise specified, the invention also includes both E and Z geometric isomers.

Tautomers are compounds in which a proton can move rapidly from one atom of the compound to another atom of the compound. Certain of the compounds described herein may exist as tautomers having different points of attachment of hydrogen atoms. Examples of such tautomers may be ketones and their enols known as keto-enol tautomers. Both single tautomers and mixtures thereof are included in compounds of formula I.

Compounds of formula I can be separated into diastereomeric enantiomeric pairs, for example, by fractional crystallization from a suitable solvent such as MeOH or EtOAc or mixtures thereof. The enantiomers thus obtained can then be separated into individual stereoisomers by conventional methods such as using optically active amines as resolving agents or using chiral HPLC columns.

Alternatively, any enantiomer of a compound of general formula I may also be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

It is generally preferred to administer the compounds of the invention as enantiomerically pure preparations. Racemic mixtures can be resolved into the individual enantiomers by a variety of conventional methods. These methods include chiral chromatography, derivatization using chiral auxiliaries followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.

Furthermore, some of the crystalline forms of the compounds of the present invention may exist in polymorphic forms, and thus these polymorphic forms are also included in the present invention. In addition, some of the compounds of the present invention may form solvates with water or common organic solvents. These solvates are also included within the scope of the present invention.

The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc salt etc. Particular preference is given to ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include primary, secondary or tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and salts of basic ion exchange resins, such as the salts of the following amines: Amino acid, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- Ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, halamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, poly Amine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. The term "pharmaceutically acceptable salt" may further include all acceptable salts such as acetate, lactobionate, besylate, laurate, benzoate, malate, bicarbonate, maleate, Salt, Bisulfate, Mandelate, Bitartrate, Methanesulfonate, Borate, Methyl Bromide, Bromide, Methyl Nitrate, Calcium EDTA, Methyl Sulfate, Camphor Sulfonate, mucate, carbonate, naphthalenesulfonate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate , edetate, oxalate, edisulphonate, pamerate, lauryl sulfate, palmitate, ethanesulfonate, pantothenate, fumarate, phosphoric acid Salts/Bisphosphonates, Glucoheptonate, Polygalacturonate, Gluconate, Salicylate, Glutamate, Stearate, Glycoloyl-p-aminophenyl Sulfate, Sulfuric Acid salt, hexylresorcinol salt, basic acetate, halamine, succinate, hydrobromide, tannin, hydrochloride, tartrate, hydroxynaphthoate, 8-chlorophylline , iodide, tosylate, isothiocarbonate, triethiodide, lactate, panoate, valerate, etc., which can be used as dosage forms for improving dissolution or hydrolysis properties, or can be used In sustained release or prodrug formulations.

It should be understood that references herein to compounds of formula I also include their pharmaceutically acceptable salts.

The compounds of the present invention are modulators of the CB1 receptor. In particular, compounds of formula I are antagonists or inverse agonists of the CB1 receptor.

"Agonist" means a compound (hormone, neurotransmitter, or synthetic compound) that binds to a receptor, induces a conformational change in the receptor, and subsequently produces a physiologically relevant agonist ligand for the receptor. Responses that are similar to those of the same, such as contraction, relaxation, secretion, changes in enzyme activity, etc. "Antagonist" refers to a compound that reduces the effect of an agonist. "Inverse agonist"refers to a compound that acts on a receptor but produces the opposite effect to that produced by an agonist for that particular receptor.

The compounds of the present invention are modulators of CB1 receptors and are therefore useful as centrally acting drugs for the treatment of psychosis, amnesia, cognitive impairment, migraine, neuropathy, neuroinflammatory diseases including multiple sclerosis and G-B Two's syndrome and inflammatory sequelae of viral encephalitis, cerebrovascular accident and head trauma, anxiety disorders, stress response, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds of the present invention are also useful in the treatment of substance abuse disorders, especially opiate, alcohol, cannabis and nicotine abuse disorders. The compounds of the present invention are also useful in the treatment of obesity or eating disorders associated with excessive food intake and various complications associated therewith. The compounds of the present invention are also useful in the treatment of constipation and chronic pseudo-bowel obstruction. The compounds of the present invention are also useful in the treatment of liver cirrhosis. These compounds are also useful in the treatment of asthma.

The terms "administering" and/or "administering" a compound are understood to mean providing a compound of the invention or a prodrug of a compound of the invention to an individual in need of treatment.

To practice the methods of treatment of this invention, administering a compound of formula I can be accomplished by administering an effective amount of a compound of formula I to a patient in need of such treatment or prophylaxis. According to the method of the present invention, the need for prophylactic administration is determined by using known risk factors. In the final analysis, the effective amount of an individual compound will be determined by the attending physician and will depend on a variety of factors such as the exact disease being treated, the severity of said disease and other diseases or diseases the patient suffers from, other concomitant conditions required by the patient The route of administration of drugs and therapeutics and other factors in the physician's judgment.

The utility of the compounds of the invention in these diseases or conditions can be demonstrated using animal disease models reported in the literature. The following are examples of such animal disease models: a) Inhibition of food intake. and resulting weight loss in rats (Life Sciences 1998, 63, 113-117); b) reduced sweet food intake in marmosets (Behavioral Pharm.1998, 9, 179-181); c) reduced sucrose and ethanol intake in mice ( Psychopharm.1997,132,104-106); d) enhance the motor activity of rats and improve the sense of position (Psychopharm.1998,135,324-332; Psychopharmacol 2000,151:25-30); e) the spontaneous locomotor activity (J.Pharm.Exp.Ther.1996, 277, 586-594); f) reduce self-administration of opiates in mice (Sci.1999, 283, 401-404); g) sheep as a model of asthma in different stages and bronchial hyperresponsiveness in guinea pigs (for example, see WMAbraham et al., "α ₄ -Integrin mediates delayed bronchial response and prolongation of airway hyperresponsiveness in sheep" J.Clin.Invest.93, 776 (1993) and AAYMiline and PPPiper, "The role of VLA-4 integrin in leukocyte recruitment and bronchial hyperreactivity in guinea pigs", Eur.J.Pharmacol., 282, 243 (1995)); h) in severe Mediation of vasodilation state in liver cirrhosis (Nature Medicine, 2001, 7(7), 827-832); i) amitriptyline-induced constipation in monkeys for evaluation of laxatives (Biol.Pharm.Bulletin(Japan ), 2000, 23(5), 657-9); j) neuropathology of pediatric chronic pseudo-intestinal obstruction and animal models related to the neuropathology of pediatric chronic pseudo-intestinal obstruction (Journal of Pathology (England), 2001, 194(3 ), 277-88).

The size of the prophylactic or therapeutic dose of a compound of formula I will of course vary with the severity of the disease being treated, the particular compound of formula I and its route of administration. It will also vary with the age, weight and response of the individual patient. In general, the daily dosage will range from about 0.001 mg to about 100 mg per kilogram of mammalian body weight, preferably from 0.01 mg to about 50 mg/kg, and most preferably from 0.1 to 10 mg/kg, administered in single or divided doses. On the other hand, it may be desirable to administer dosages outside these ranges in some cases.

Suitable dosage ranges are about 0.001 mg to about 25 mg (preferably 0.01 mg to about 1 mg) of the compound of formula I per kg body weight per day for applications using intravenous compositions, and about 1 mg per kg body weight per day for prophylactic applications. 0.1 mg to about 100 mg (preferably about 1 mg to about 100 mg, more preferably about 1 mg to about 10 mg) of the compound of formula I.

In the case of oral compositions, suitable dosage ranges are, for example, about 0.01 mg to about 1000 mg of the compound of formula I per day, preferably about 0.1 mg to about 10 mg per day. For oral administration, the composition is preferably in the form of a tablet comprising 0.01-1000 mg, preferably 0.01, 0.05, 0.1, 0.5, 1, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 100, 250, 500, 750 or 1000 mg of active ingredient, adjusted according to the symptoms of the dose administered to the treated patient.

Another aspect of the present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier. The term "composition", as in pharmaceutical compositions, is intended to cover the product comprising the active ingredient and one or more inert ingredients (pharmaceutically acceptable excipients) constituting the carrier, as well as the product obtained by combining, complexing or aggregating any two or Components, or any product formed, directly or indirectly, by dissociation of one or more components, or by other type of reaction or interaction of one or more components. Accordingly, the pharmaceutical compositions of the present invention include any composition obtained by admixing a compound of formula I, one or more other active ingredients, and a pharmaceutically acceptable excipient.

An effective dose of a compound of the invention may be provided to a mammal, especially a human, using any suitable route of administration. For example, oral, rectal, topical, parenteral, ophthalmic, pulmonary, nasal, etc. routes may be employed. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, ointments, aerosols, and the like.

The pharmaceutical composition of the present invention includes the compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic components. The term "pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient. Specifically, "pharmaceutically acceptable salt" refers to a salt prepared from pharmaceutically acceptable non-toxic bases or acids (including inorganic bases or inorganic acids or organic bases or organic acids).

The compositions include those suitable for administration by the following routes: oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ophthalmic (ophthalmic), pulmonary (aerosol inhalation), or nasal administration, but the most suitable route in any given case will depend on the nature and severity of the condition being treated and the nature of the active ingredient. They may conveniently be presented in unit dosage form, prepared according to methods well known in the art of pharmacy.

For administration by inhalation, the compounds of the invention are conveniently administered in the form of an aerosol spray provided from a pressurized pack or nebulizer. The compounds of the present invention may also be administered in the form of formulated powders, such powder compositions being inhaled by means of an insufflator powder inhaler. Preferred delivery systems for inhalation are metered dose inhalation (MDI) aerosol (which may be formulated as a suspension or solution of a compound of formula I in a suitable propellant such as a hydrofluorocarbon or hydrocarbon) and powder inhalation (DPI). Aerosol, the latter can be formulated as a dry powder of the compound of formula I with or without other excipients.

Formulations of compounds of formula I suitable for topical use include transdermal formulations, aerosols, creams, solutions, ointments, gels, lotions, powders and the like. Topical pharmaceutical compositions containing the compounds of this invention generally contain from about 0.005% to 5% by weight of active compound in admixture with pharmaceutically acceptable excipients. Transdermal patches suitable for administering the compounds of this invention include those well known to those of ordinary skill in the art. When administered in the form of a transdermal delivery system, the administration should be continuous rather than intermittent throughout the dosage regimen.

In practical application, the active ingredient compound of formula I can be densely mixed with the pharmaceutical carrier according to conventional pharmaceutical mixing techniques. The carrier may take various forms depending on the form of preparation desired for administration, eg, oral or parenteral (including intravenous) administration. In preparing compositions for oral dosage form, any of the usual pharmaceutical media may be used, for example, in preparing oral liquid preparations such as suspensions, elixirs and solutions, water, glycols, oils, alcohols, flavoring agents , preservatives, coloring agents, etc.; while for the preparation of oral solid preparations such as powders, capsules and tablets, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders can be used , disintegrants, etc., with respect to liquid preparations, solid oral preparations are more preferred. Because of their ease of administration, tablets and capsules form the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. Tablets may be coated, if desired, using standard aqueous or non-aqueous techniques.

Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules (including time-release and sustained-release formulations), pills, cachets, powders, granules or tablets, each containing a predetermined Quantities of the active ingredient, either in the form of powders or granules or solutions or suspensions in aqueous liquids, non-aqueous liquids, oil-in-water emulsions or water-in-oil emulsions, including elixirs, tinctures, solutions, mixtures Suspensions, syrups and emulsions. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired form. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Ideally, each tablet contains 0.01-1000 mg, especially 0.01, 0.05, 0.1, 0.5, 1, 2.5, 3, 5, 6, 10, 15, 25, 50, 75, 100, 125, 150, 175 , 180, 200, 225, 500, 750 and 1000 mg of the active ingredient, and adjust the dosage given to the patient to be treated according to the symptoms, while each cachet or capsule contains about 0.01-1,000 mg, especially 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 3, 5, 6, 10, 15, 25, 50, 75, 100, 125, 150, 175, 180, 200, 225, 500, 750, and 1,000 mg active ingredient, of which The dose administered to the treated patient is adjusted according to the symptoms.

Other suitable means of administering the compounds of the invention include injection, intravenous bolus or infusion, intraperitoneal, subcutaneous, intramuscular and topical administration, which may be embedded or not.

An example of the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Another example of the present invention is a pharmaceutical composition prepared by mixing any of the above compounds and a pharmaceutically acceptable carrier. An illustration of the invention is a method of preparing a pharmaceutical composition comprising admixing any of the compounds described above and a pharmaceutically acceptable carrier.

The dose may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times per day. In addition, depending on the nature of the particular compound chosen to be administered, the dosage may not need to be administered frequently, for example weekly, twice or monthly, etc. For infrequent dosing, the unit dose should be increased accordingly.

When administered by the intranasal route, transdermal route, by rectal or vaginal suppository, or by continuous intravenous solution, the administration should be continuous rather than intermittent throughout the dosing regimen.

The following are examples of typical pharmaceutical dosage forms for compounds of formula I:

Injectable Suspension (I.M.) mg/mL

Compound of formula I 10

Methylcellulose 5.0

Tween 80 0.5

Benzyl alcohol 9.0

Benzalkonium Chloride 1.0

Add water for injection to a total volume of 1 mL.

Tablets mg/tablet

Compound of formula I 25

Microcrystalline Cellulose 415

Polyvinylpyrrolidone 14.0

Pregelatinized starch 43.5

Magnesium stearate 2.5

500

Capsule mg/capsule

Compound of formula I 25

Lactose powder 573.5

Magnesium stearate 1.5

600

Aerosol per can

Formula I compound 24mg

Lecithin, NF Liquid Concentrate 1.2mg

Trichlorofluoromethane, NF 4.025g

Dichlorodifluoromethane, NF 12.15g

The compound of formula I may be used in combination with other drugs for the treatment/prevention/suppression or alleviation of the diseases or conditions for which the compound of formula I is suitable for treatment. These other drugs can be administered simultaneously or sequentially with the compound of formula I by usual routes and dosages. When the compound of formula I is used concomitantly with one or more other drugs, it is preferred to use a pharmaceutical composition comprising the compound of formula I and these other drugs. Accordingly, the pharmaceutical compositions of the present invention include those containing, in addition to a compound of formula I, one or more other active ingredients. Examples of other active ingredients that may be used in combination with compounds of formula I include, but are not limited to: antipsychotics, cognition enhancers, antimigraine agents, antiasthmatics, antiinflammatory agents, anxiolytics, antiparkinsonians, antiepileptics , appetite suppressants, and serotonin reuptake inhibitors, and other anti-obesity agents, which may be administered alone or in the same pharmaceutical composition.

It will be appreciated that the compounds of the present invention may be used in combination with other appetite suppressants when used in the treatment or prevention of eating disorders including obesity, bulimia nervosa and compulsive eating disorders.

The present invention also provides a method of treating or preventing eating disorders which comprises administering to a patient in need of such treatment an amount of a compound of the invention and an appetite suppressant in an amount so that together they produce effective relief.

"Obesity" is a symptom of excess body fat. The current definition of obesity is based on the body mass index (MBI), which is calculated as weight/height squared (kg/ ^m2 ). "Obesity" refers to the state of an otherwise healthy individual with a body mass index (BMI) greater than or equal to 30 kg/ ^m2 , or the state of an individual with at least one comorbidity and a BMI of greater than or equal to 27 kg/ ^m2 . "Obese" refers to an otherwise healthy individual with a body mass index (BMI) greater than or equal to 30 kg/ ^m2 , or an individual with at least one comorbidity and a BMI greater than or equal to 27 kg/ ^m2 . An "obesity risk individual" refers to an otherwise healthy individual with 25kg/ ^m2≤BMI <30kg/ ^m2 or an individual with at least one comorbidity and 25kg/ ^m2≤BMI <27kg/ ^m2 .

Asian populations have higher obesity-related risks at low body mass index (BMI). In Asian countries including Japan, "obesity" refers to the state of individuals with a BMI of 25 kg/m ² or more who have at least one complication caused by or associated with obesity that requires weight loss Or improve by losing weight. In Asian countries including Japan, "obese" refers to individuals with a BMI of 25 kg/m ² or more who have at least one obesity-induced or obesity-related complication that requires Improve by losing weight. In Asian countries, "obesity-risk individuals" refers to individuals with a BMI greater than 23 kg/m ² but less than 25 kg/m ² .

The term "obesity" as used herein is intended to include obesity as defined above.

Obesity-induced or obesity-related complications include, but are not limited to, diabetes mellitus, type II non-insulin-dependent diabetes mellitus, impaired glucose tolerance, impaired fasting glucose, insulin resistance syndrome, dyslipidemia, hypertension, blood Hyperuricemia, gout, coronary artery disease, myocardial infarction, thoracic angina, sleep apnea syndrome, Pickwick syndrome, fatty liver; cerebral infarction, cerebral thrombosis, transient ischemic attack, orthopedic disease, deformity Arthritis, low back pain, menstrual disorders, and infertility. Complications include, inter alia: hypertension, hyperlipidemia, dyslipidemia, glucose intolerance, cardiovascular disease, sleep apnea, diabetes, and other obesity-related conditions.

"Treating" (obesity and obesity-related disorders) means administering a compound or composition of the invention to reduce or maintain body weight in an obese subject. One outcome of treatment is the ability to reduce the body weight of an obese individual relative to the patient's weight immediately prior to administration of a compound or composition of the invention. Another outcome of treatment is the prevention of regaining of weight previously lost due to diet, exercise, or drug therapy. Another outcome of treatment may be a reduction in the incidence and/or severity of obesity-related disorders. Treatment may, as appropriate, reduce the patient's food or caloric intake, including total food intake, or specific components of the diet such as carbohydrates or fat; and/or inhibit the absorption of nutrients; and/or inhibit metabolism rate; and reduce body weight in patients requiring treatment. Treatment may also result in altered metabolic rate, e.g. increased metabolic rate, rather than inhibited or increased metabolic rate in addition to inhibited decreased metabolic rate; and/or minimized metabolic impairment normally associated with weight loss .

"Prevention" (obesity and obesity-related disorders) refers to the administration of a compound or composition of the invention to reduce or maintain body weight in individuals at risk of obesity. One outcome of prophylaxis is the ability to reduce the body weight of an individual at risk of obesity relative to the individual's body weight immediately prior to administration of a compound or composition of the invention. Another consequence of prevention is the prevention of regaining of weight previously lost due to diet, exercise, or drug therapy. Another consequence of prevention is that obesity can be prevented if individuals at risk of obesity are treated with medication before they become obese. Another consequence of prevention is the reduction in the incidence and/or severity of obesity-related disorders if individuals at risk of obesity are treated with medication before they become obese. In addition, if treatment is initiated in an already obese individual, such treatment may prevent the development, retard the progression, or lessen the severity of obesity-related diseases such as, but not limited to, arteriosclerosis, II type diabetes, polycystic ovary disease, cardiovascular disease, osteoarthritis, skin disease, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia and gallstone disease.

Obesity-related disorders are associated with, caused by, or caused by obesity. Examples of obesity-related conditions include binge eating and bulimia, hypertension, diabetes, high plasma insulin concentration and insulin resistance, dyslipidemia, hypercholesterolemia, endometrial cancer, breast cancer, prostate cancer and colon cancer, Osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythm and arrhythmia, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic disease and ovarian disease, cranial Pharyngiomas, Puer-William syndrome, Frölich syndrome, GH-deficient patients, normal variant short stature, Turner's syndrome and those showing low metabolic activity or resting energy expenditure (as total lean mass Percentage of ) decreased in other conditions, such as acute lymphoblastic leukemia. Other examples of obesity-related conditions are metabolic syndrome, also known as Syndrome X, insulin resistance syndrome, sexual dysfunction and fertility disorders such as infertility, hypogonadism in males and hirsutism in females, gastrointestinal motility disorders , such as obesity-related gastroesophageal reflux, respiratory disorders, such as obesity hypoventilation syndrome (Pickwick syndrome), cardiovascular disease, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterollipidemia , hyperuricemia, low back pain, gallbladder disease, gout, and kidney cancer. The compositions of the present invention are also suitable for reducing the risk of secondary morbidities of obesity, such as reducing the risk of left ventricular hypertrophy.

The term "diabetes mellitus" as used herein includes both insulin-dependent diabetes mellitus (ie, IDDM, also called type I diabetes) and non-insulin-dependent diabetes mellitus (ie, NIDDM, also called type II diabetes mellitus). Type I diabetes, or insulin-dependent diabetes, results from an absolute deficiency of insulin, the hormone that regulates glucose utilization. Type II diabetes, or insulin-independent diabetes (ie, non-insulin-dependent diabetes), often occurs in the presence of normal or even elevated insulin levels and may be the result of tissues not responding appropriately to insulin. Most type 2 diabetics also exhibit obesity. The compounds and compositions of the present invention are useful in the treatment of both Type I and Type II diabetes. The compounds and compositions of the present invention are particularly effective for the treatment of type II diabetes. The compounds and compositions of the invention are also useful in the treatment and/or prevention of gestational diabetes.

As used herein, the term "substance use disorder" includes substance dependence or substance abuse with or without physical dependence. Substances associated with these conditions are: alcohol, amphetamines (or amphetamine-like substances), caffeine, marijuana products, cocaine, hallucinogens, inhalants, cannabinoids (marijuana), nicotine, opioids, benzene Ridine (or phencyclidine-like compounds), sedative-hypnotic substances, interbenzodiazepines, and other (or unknown) substances and combinations of all the above substances.

The term "substance abuse disorder" specifically includes drug withdrawal disorders such as alcohol withdrawal with or without perceptual disturbance; alcohol withdrawal delirium; amphetamine withdrawal brain syndrome; nicotine withdrawal brain syndrome; opioid withdrawal Sedative, hypnotic, or anxiolytic withdrawal encephalic syndrome with or without perceptual disturbances; sedative, hypnotic, or anxiolytic withdrawal delirium; and other substance-induced withdrawal reaction syndrome. It should be understood that reference to treatment of nicotine withdrawal syndrome includes treatment of symptoms associated with smoking cessation.

Other "substance use disorders" include substance-induced anxiety disorders with onset during withdrawal; substance-induced mood disorders with onset during withdrawal; and substance-induced sleep disturbances with onset during withdrawal.

It will be appreciated that the combination of conventional antipsychotic drugs and CB1 receptor modulators can enhance the efficacy of mania treatment. Such combination drugs are expected to provide rapid onset of action in the treatment of manic episodes and thus be prescribed on an "as needed" basis. In addition, this combination can also reduce the dosage of antipsychotics without weakening the efficacy of antipsychotics, thereby reducing the risk of adverse reactions to a minimum. A further advantage of this combination is the reduction or prevention of adverse side effects such as acute dystonia, dyskinesia, akathisia and tremor caused by antipsychotic agents due to the action of the CB1 receptor modulator.

The present invention also provides a method for treating or preventing mania, the method comprising administering an appropriate amount of a CB1 receptor modulator and an appropriate amount of an antipsychotic to a patient in need of such treatment or at risk of developing mania, so that Together, they produce effective relief.

It should be understood that the CB1 receptor modulator and the antipsychotic agent may be in the form of a combined preparation that can be used simultaneously, separately or sequentially for the treatment or prevention of mania.

It should be understood that when using the combination drug of the present invention, the CB1 receptor modulator and the antipsychotic agent can be in the same pharmaceutically acceptable carrier and thus can be administered simultaneously. They can be in separate pharmaceutical carriers, such as conventional oral dosage forms for co-administration. The term "combination drug" also refers to a drug in which the compounds are presented in separate dosage forms and administered sequentially. Thus, as an example, the antipsychotic agent may be administered in tablet form, and then within an appropriate time frame, the CB1 receptor modulator may be administered in an oral dosage form such as a tablet or a fast dissolving oral dosage form. "Fast dissolving oral formulation" refers to an orally administered formulation that dissolves in about 10 seconds when placed on the patient's tongue.

It will be appreciated that the combination of conventional antipsychotics and CB1 receptor modulators can enhance the therapeutic effect of schizophrenia. Such combination drugs are expected to provide rapid onset of action in the treatment of schizophrenia, making it possible to be prescribed on an "need basis". In addition, this combination can also reduce the dosage of antipsychotics without weakening the efficacy of antipsychotics, thereby reducing the risk of adverse reactions to a minimum. A further advantage of this combination is the reduction or prevention of adverse side effects such as acute dystonia, dyskinesia, akathisia and tremor caused by antipsychotic agents due to the action of the CB1 receptor modulator.

It should be understood that the combination of conventional antiasthmatic drugs and CB1 receptor modulators can improve the therapeutic effect on asthma.

Therefore, another aspect of the present invention provides the use of the CB1 receptor modulator and anti-asthmatic agent in the preparation of a medicament for treating or preventing asthma.

The present invention also provides a method for treating or preventing asthma, which comprises administering an appropriate amount of CB1 receptor modulator and an appropriate amount of antipsychotic agent to a patient in need of such treatment, so that they together produce an effective relief effect.

The therapeutic methods of the present invention include methods of modulating CB1 receptors and treating diseases mediated by CB1 receptors, in combination with other CB or G-proteins, by administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of the present invention. Compounds of the present invention preferentially and selectively antagonize CB1 receptors compared to coupled receptors.

The term "therapeutically effective amount" is that amount of the compound of structural formula I that a researcher, veterinarian, doctor or other clinical worker seeks to cause a food or medical response in a tissue, system, animal or human body, including alleviating the symptoms of the disease being treated. quantity. These new methods of treatment of the present invention are applicable to conditions known to those skilled in the art. The term "mammal" includes humans.

The following abbreviations are used in the following reaction schemes and examples: aq.: aqueous; API-ES: atmospheric ionization-electrospray (mass spectrometry term); DMF: dimethylformamide; DMSO: dimethyl sulfoxide; EDC: 1 - Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride; EPA: ethylene polyacrylamide (a type of plastic); EtOAc: ethyl acetate; h: hours; HOBt: 1-hydroxybenzotriazole; HPLC: high pressure liquid chromatography; HPLC/MS: high pressure liquid chromatography/mass spectrometry; in vacuo: rotary evaporation; IPAC: isopropyl acetate; KHMDS: hexamethyldisilane LC: liquid chromatography; LC/MS, LC-MS: liquid chromatography-mass spectrometry; M: mole; Me: methyl; MeOH: methanol; mmol: millimole; MS or ms: mass spectrometry; N : equivalent; NaHMDS: sodium hexamethyldisilazide; NMR: nuclear magnetic resonance; PyBOP: (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; R _t : retention Time; rt or RT: room temperature; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TLC: thin layer chromatography.

Compounds of the present invention can be prepared as described in the following reaction schemes and examples.

Reaction scheme 1.

In Reaction Scheme 1, an appropriately substituted amine A is reacted with a carboxylic acid B under standard amide bond-forming conditions to provide the arylamide C. To illustrate the invention, the invention includes the following examples. However, these examples do not constitute limitations to the present invention. They are used only to disclose the method of practicing the invention. Other methods of practicing the invention will be readily apparent to those skilled in the art. Also such methods are considered to be within the scope of the present invention.

General Methods. LC/MS analysis was performed using a MICROMASS ZMD mass spectrometer-AGILENT1100 series HPLC with a YMC ODS-A 4.6×50 mm column, eluted with a solvent gradient of 10-95% B in 4.5 minutes, followed by 95% B Elution was performed for 0.5 minutes, the flow rate was 2.5 mL/min, solvent A=0.06% TFA/water; solvent B=0.05% TFA/acetonitrile. ¹ H-NMR spectra were acquired on a 500 MHz VARIAN spectrometer in CDCl ₃ or CD ₃ OD as indicated, chemical shifts are reported in δ values using solvent peaks as references, and coupling constants are reported in Hertz (Hz).

Reference Example 1

N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-amine hydrochloride

The preparation of two diastereomers (α and β) of N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-amine hydrochloride has been published (Schultz, EM et al. , J. Med. Chem. 1967, 10, 717). Diastereomer α: LC-MS: Calculated for (C ₁₆ H ₁₇ Cl ₂ N): 293, found m/e 294 (M+H) ⁺ (retention time 2.5 min). Diastereomer β: LC-MS: Calculated for (C ₁₆ H ₁₇ Cl ₂ N): 293, found m/e 294 (M+H) ⁺ (retention time 2.2 min).

Reference Example 2

2-Amino-4-(4-chlorophenyl)-3-phenylbutane hydrochloride

The title compound was prepared according to the method described in Reference Example 1.

Diastereomer α:

LC-MS: Calculated for (C ₁₆ H ₁₈ ClN): 259, found m/e 260 (M+H) ⁺ (2.3min).

Diastereomer beta

LC-MS: Calculated for (C ₁₆ H ₁₈ ClN): 259, found m/e 260 (M+H) ⁺ (2.2min).

Reference Example 3

N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-amine hydrochloride

(diastereomer α)

Step A Methyl 3-(4-chlorophenyl)-2-phenylpropanoate

To a solution of methyl phenylacetate (12 g, 80 mmol) and 4-chlorobenzyl bromide (16 g, 80 mmol) in 250 mL of anhydrous THF was added sodium hexamethyldisilazide (1M THF solution, 80 mL, 80 mmol) (potassium hexamethyldisilazide can also be used with similar results). The reaction was warmed to room temperature overnight. The volatiles were removed using a rotary evaporator and the resulting mixture was partitioned between saturated ammonium chloride (200 mL) and EtOAc (200 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to dryness to afford the title compound.

¹ H NMR (500MHz, CD ₃ OD): δ7.36-7.10(m, 9H), 3.81(dd, 1H), 3.52(s, 3H), 3.36(dd, 1H), 3.02(dd, 1H).

Step B 3-(4-Chlorophenyl)-2-phenylpropanoic acid

To a mixture of methyl 3-(4-chlorophenyl)-2-phenylpropanoate (Step A, 20 g, 74 mmol) in acetonitrile (100 mL) and water (100 mL) was added lithium hydroxide monohydrate (8.8 g, 0.21mol). After stirring at room temperature for 3 days, the volatiles were removed by concentration by rotary evaporator, and the residue was partitioned between water (300 mL) and hexane/ether (1:1, 200 mL). The aqueous layer was separated, acidified to pH = 2-3, extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to afford the title compound. ¹ H NMR (500MHz, CD ₃ OD): δ7.34-7.10(m, 9H), 3.82(dd, 1H), 3.36(dd, 1H), 2.98(dd, 1H).

Step C N-methoxy-N-methyl-3-(4-chlorophenyl)-2-phenylpropanamide

To a solution of 3-(4-chlorophenyl)-2-phenylpropanoic acid (Step B, 14 g, 55 mmol) in _CH2Cl2 (125 mL) was added _{dimethylformamide} (50 μL) dropwise at 0 °C and oxalyl chloride (14 g, 0.11 mol). The reaction was warmed to room temperature overnight, concentrated to dryness to obtain the crude acid chloride, which was used directly without further purification. Thus, to a solution of the acid chloride in _CH2Cl2 (250 _mL ) was added N-methoxy-N-methylamine hydrochloride (11 g, 0.11 mol) and triethylamine (dried over activated molecular sieves, 30 mL) at 0 °C , 0.22mol). After stirring at room temperature for 4 hours, the reaction mixture was diluted with diethyl ether (500 ml), washed successively with water, dilute aqueous sodium bisulfate and brine, dried over anhydrous MgSO ₄ , filtered and concentrated to dryness to give the crude product, which was recovered without further purification. Use directly. ¹ H NMR (500MHz, CD ₃ OD): δ7.4-7.1 (m, 9H), 4.38 (s, 3H), 3.35 (dd, 1H), 3.10 (s, 3H), 2.92 (dd, 1H); LC-MS: m/e 304 (3.6 min).

Step D 4-(4-Chlorophenyl)-3-phenyl-2-butanone

To N-methoxy-N-methyl-3-(4-chlorophenyl)-2-phenylpropanamide (step C, 16 g, 53 mmol, dried azeotropically with toluene) at 0°C To THF (200 mL) solution was added methylmagnesium bromide (3M ether solution, 35 mL, 0.11 mol). After stirring at 0 °C for 2 h, the reaction was quenched with MeOH (5 mL) and 2M hydrochloric acid (50 mL). Concentrate on a rotary evaporator to remove volatiles and partition the residue between saturated ammonium chloride (200 mL) and diethyl ether (200 mL). The organic layer was separated and the aqueous layer was extracted with ether (2 x 200 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to give the title compound which was used without further purification. ¹ H NMR (500MHz, CD ₃ OD): δ7.45-7.02(m, 9H), 4.08(dd, 1H), 3.34(dd, 1H), 2.90(dd, 1H), 2.03(s, 3H).

Step E 4-(4-chlorophenyl)-3-phenyl-2-butanol

To a solution of 4-(4-chlorophenyl)-3-phenyl-2-butanone (Step D, 13 g, 50 mmol) in MeOH (100 mL) was added sodium borohydride (3.8 g, 100 mmol) at 0°C. After stirring at 0°C for 30 minutes, the reaction was quenched by adding 2M hydrochloric acid (50 mL). Concentrate on a rotary evaporator to remove volatiles and partition the residue between water (100 mL) and EtOAc (200 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic layer extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give the crude product, which was further purified by flash column chromatography on silica gel (10% EtOAc/hexane as eluent), Pure faster eluting isomers and mixtures containing faster eluting isomers and slower eluting isomers were obtained.

Faster eluting isomer: ¹ H NMR (500 MHz, CD ₃ OD): δ7.25-7.00 (m, 9H), 4.00 (m, 1H), 3.15 (m, 1H), 2.97 (m, 1H ), 2.85(m, 1H), 1.10(d, 3H).

Step F 4-(4-Chlorophenyl)-2-methanesulfonyloxy-3-phenylbutane

To a solution of 4-(4-chlorophenyl)-3-phenyl-2-butanol (Step E, faster eluting isomer, 9.0 g, 34 mmol) in EtOAc (100 mL) at 0 °C was added tris Ethylamine (dried over activated molecular sieves, 5.8 mL, 42 mmol) and methanesulfonyl chloride (3.0 mL, 38 mmol). After stirring at 0°C for 30 minutes, saturated aqueous sodium bicarbonate (100 mL) was added to terminate the reaction. After stirring at room temperature for 1 hour, the organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give the title compound which was used without further purification. ¹ H NMR (500MHz, CD ₃ OD): δ7.3-7.0(m, 9H), 5.05(m, 1H), 3.2-3.0(m, 3H), 2.80(s, 3H), 1.40(d, 3H ).

Step G 2-Azido-4-(4-chlorophenyl)-3-phenylbutane

To a solution of 4-(4-chlorophenyl)-2-methanesulfonyloxy-3-phenylbutane (Step F, 12 g, 34 mmol) in DMF (50 mL) was added sodium azide (11 g, 0.17 mol ). After stirring at 120° C. for 1 hour, the reaction mixture was poured into water (200 mL), and the product was extracted with ether (2×100 mL). The combined organic extracts were washed with water, dried over magnesium sulfate, filtered, concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: hexane) to give the title compound.

Step H 2-(N-tert-butoxycarbonyl)amino-4-(4-chlorophenyl)-3-phenylbutane

To a solution of 2-azido-4-(4-chlorophenyl)-3-phenylbutane (Step G, 7.0 g, 24 mmol) in EtOAc (150 mL) was added di-tert-butyl dicarbonate (8.0 g, 37mmol) and platinum dioxide (0.50g, 2.2mmol). The mixture was degassed and then injected with hydrogen using a balloon. After stirring for 1 day, the reaction mixture was filtered through Celite and the filtrate was concentrated to give the crude product, which contained some unreacted di-tert-butyl dicarbonate impurity. ¹ H NMR (500MHz, CD ₃ OD): δ7.25-6.88(m, 9H), 3.89(m, 1H), 3.20(m, 1H), 2.86-2.77(m, 2H), 1.54(s, 9H ), 0.92(d, 3H).

Step I N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-amine hydrochloride (diastereomer α)

2-(N-tert-Butoxycarbonyl)amino-4-(4-chlorophenyl)-3-phenylbutane (Step H, 7.0 g, 24 mmol) was washed with a saturated solution of hydrogen chloride in EtOAc at room temperature (100 mL) for 30 minutes (4M hydrogen chloride in dioxane could also be used with similar results). The mixture was concentrated to dryness to afford the title compound. ¹ H NMR (500MHz, CD ₃ OD): δ7.35-6.98(m, 9H), 3.62(m, 1H), 3.20(dd, 1H), 3.05(m, 1H), 2.98(dd, 1H), 1.19 (d, 3H). LC-MS: m/e 260 (M+H) ⁺ (2.3min).

Reference Example 4

N-[3-(4-Chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-amine hydrochloride

Step A 4-(4-Chlorophenyl)-3(S)-phenyl-2(R)-butanol

A sample of magnesium (20 g, 0.82 mol) was activated by stirring under nitrogen for 12 hours, then anhydrous diethyl ether (100 mL) was added to cover the solid material. The mixture was cooled to 0°C and 4-chlorobenzyl chloride (40 g, 0.25 mmol) in 400 mL of anhydrous ether was added dropwise. After stirring at room temperature for 1 hour, a 32 mL sample of the above solution was added to (1R,2R)-1-phenylpropylene oxide (1.0 g, 7.5 mmol)/100 mL diethyl ether (0° C.) via a syringe. After stirring at 0°C for 2 hours, saturated aqueous ammonium chloride solution (100 mL) was added to terminate the reaction. The organic layer was separated and the aqueous layer was extracted with ether (2 x 100 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel (hexane-15% EtOAc/hexane as eluent) to give title compound. ¹ H NMR (500MHz, CD ₃ OD): δ7.28-7.02(m, 9H), 4.01(m, 1H), 3.14(dd, 1H), 2.97(dd, 1H), 2.85(m, 1H), 1.12(d, 3H).

Step B N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-amine hydrochloride

According to the steps described in Reference Example 3, step FI, using hydrogen chloride in dioxane (4M) instead of hydrogen chloride in EtOAc, the product of step A (4-(4-chlorophenyl)-3(S)-phenyl -2(R)-butanol, 1.8 g, 7.0 mmol) was converted into the title compound. ¹ H NMR (500MHz, CD ₃ OD): δ7.35-6.98(m, 9H), 3.62(m, 1H), 3.20(dd, 1H), 3.05(m, 1H), 2.98(dd, 1H), 1.19 (d, 3H). LC-MS: m/e 260 (M+H) ⁺ (2.3min).

Reference Example 5

N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-amine, hydrochloride (diastereomer α/β10:1 mixture)

Step A 4-(4-Chlorophenyl)-3-pyridyl-2-butanone

At -78°C, 3-pyridylacetone hydrochloride (Wibaud, van der V. Recl. Trav. Chim. Pays-Bas. 1952, 71, 798) (10 g, 58 mmol) and 4-chlorobenzyl chloride ( To a solution of 9.1 g, 58 mmol) in 100 _{mL CH2Cl2} was added cesium hydroxide monohydrate (39 g, 0.23 mol) and tetrabutylammonium iodide (1 g). The reaction was warmed to room temperature overnight and the resulting mixture was partitioned between brine (100 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous _MgSO4 , filtered and concentrated to dryness to afford the title compound. ¹ H NMR (500MHz, CD ₃ OD): δ8.42(d, 1H), 8.34(d, 1H), 7.72(d, 1H), 7.40(dd, 1H), 7.18(d, 2H), 7.06( d, 1H), 4.23(dd, 1H), 3.38(dd, 1H), 2.95(dd, 1H), 2.10(s, 3H). LC-MS: m/e 260(M+H) ⁺ (1.9min ).

Step B N-[3-(4-Chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-amine, hydrochloride (diastereomeric α/β 10:1 mixture)

Following the procedure described in Reference Example 3, Step EI, the product of Step A (4-(4-chlorophenyl)-3-pyridyl-2-butanone) (14 g, 57 mmol) was converted to the title compound. LC-MS: m/e 261 (M+H) ⁺ (1.2min).

Reference Example 6

2-(2-Fluorophenoxy)-2-methylpropionic acid

Step A 2-(2-fluorophenoxy)-2-methylpropionic acid

Sodium hydroxide (7.1 g , 0.18mol), ice bath was applied periodically to maintain slight reflux. After the reflux had subsided, the reaction was stirred for an additional 1 hour. The volatiles were removed using a rotary evaporator and the residue was partitioned between diethyl ether (100 mL), hexane (100 mL) and water (200 mL). The aqueous layer was separated, acidified (pH = 2) with concentrated hydrochloric acid, and extracted with ether (3 x 100 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give the title compound which was used without further purification. ¹ H NMR (500MHz, CD ₃ OD): δ7.15-7.05 (m, 4H), 1.56 (s, 6H). LC-MS: m/e 199 (M+1) ⁺ (2.3min).

The acids of Reference Examples 7 and 8 were prepared following the procedure of Reference Example 6, substituting appropriately substituted phenol for 2-fluorophenol.

Reference Example 7

2-(3-Chlorophenoxy)-2-methylpropionic acid

¹ H NMR (500MHz, CD ₃ OD): δ7.23(t, 1H), 7.00(dd, 1H), 6.93(t, 1H), 6.84(dd, 1H), 1.59(s, 6H).

LC-MS: m/e 215(M+1) ⁺ , (2.7min).

Reference Example 8

2-(3,5-Dichlorophenoxy)-2-methylpropionic acid

¹ H NMR (500MHz, CD ₃ OD): δ7.05(t, 1H), 6.84(d, 2H), 1.60(s, 6H).

Reference Example 9

2-(2-Pyridyloxy)-2-methylbutanoic acid

Step A Benzyl 2-(2-pyridyloxy)propionate

To _a mixture of 2-hydroxypyridine (2.9 g, 30 mmol), benzyl lactate (5.0 g, 21 mmol) and triphenylphosphine (12 g, 47 mmol) in 100 mL _CH2Cl2 was added azodicarboxylate at 0 °C diethyl ester (7.8 mL, 45 mmol). The reaction was warmed to room temperature for 4 hours. The resulting mixture was diluted with hexane (100 mL), then concentrated with 20 g of silica gel. The resulting material was applied to a silica gel column eluting with 10% EtOAc/hexanes to afford the title compound. ¹ H NMR (500MHz, CD ₃ OD): δ8.00(dd, 1H), 7.68(ddd, 1H), 7.36-7.28(m, 5H), 6.94(dd, 1H), 6.84(dd, 1H), 5.30(q, 1H), 5.18(s, 2H), 1.59(d, 3H). LC-MS: m/e 258(M+H) ⁺ (3.3min).

Step B Benzyl 2-(2-pyridyloxy)-2-methylbutyrate

To a solution of benzyl 2-(2-pyridyloxy)propionate (1.6 g, 6.2 mmol) and ethyl iodide (1.5 mL, 25 mmol) in 10 mL of anhydrous THF at -78°C was added hexamethyldi Sodium silylamide (1M in THF, 9.3 mL, 9.3 mmol) (Potassium hexamethyldisilazide in toluene could also be used with similar results). The reaction was warmed to room temperature over 2 hours and partitioned between saturated ammonium chloride (100 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was purified by flash column chromatography on silica gel (10% EtOAc/hexanes) to afford the title compound. ¹ H NMR (500MHz, CD ₃ OD): δ7.87(dd, 1H), 7.63(ddd, 1H), 7.27(m, 3H), 7.18(m, 2H), 6.85(dd, 1H), 6.74( dd, 1H), 5.08(Abq, 2H), 2.13(m, 1H), 1.94(m, 1H), 1.65(s, 3H), 0.95(t, 3H).LC-MS: m/e 286(M +H) ⁺ (3.8min).

Step C 2-(2-pyridyloxy)-2-methylbutanoic acid

A mixture of benzyl 2-(2-pyridyloxy)-2-methylbutanoate (1.6 g, 5.5 mmol) and 10% palladium on charcoal (50 mg) in 50 mL of MeOH was degassed and supplied using a balloon hydrogen. After stirring at room temperature overnight, the reaction mixture was filtered through Celite, washed with MeOH (20 mL), and the filtrate was concentrated to dryness to afford the title compound. ¹ H NMR (500MHz, CD ₃ OD): δ8.03(dd, 1H), 7.64(ddd, 1H), 6.89(dd, 1H), 6.76(dd, 1H), 2.14(m, 1H), 1.94( m, 1H), 1.64(s, 3H), 0.99(t, 3H). LC-MS: m/e 196(M+H) ⁺ (1.8min).

Reference Example 10

2-(2-Pyridyloxy)-2-methylpropionic acid

The title compound was prepared according to the method described in Reference Example 9, wherein methyl iodide and potassium hexamethyldisilazide were used in Step B instead of ethyl iodide and sodium hexamethyldisilazide, respectively. ¹ H NMR (500MHz, CD ₃ OD): δ8.04(dd, 1H), 7.6 4(ddd, 1H), 6.89(dd, 1H), 6.76(dd, 1H), 1.66(s, 6H).LC -MS: m/e 182(M+H) ⁺ (1.5min).

Reference Example 11

N-[3-(4-chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]amine hydrochloride (diastereo Body α)

The title compound was prepared according to the method described in Reference Example 3, wherein in step A, methyl 3,5-difluorophenylacetate (prepared from 3,5-difluorophenylacetic acid and trimethylsilyldiazomethane ) in place of methyl phenylacetate, and lithium tris(sec-butyl)borohydride in THF was used in Step E instead of sodium borohydride in MeOH. LC-MS: m/e 296(M+H) ⁺ (2.39min).

Reference Example 12

N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]amine hydrochloride (diastereomeric a)

Step A 2-(N-tert-butoxycarbonyl)amino-4-(4-chlorophenyl)-3-(3-cyanophenyl) butane

To 5mL of 2-(N-tert-butoxycarbonyl)amino-3-bromophenyl-4-(4-chlorophenyl)butane (prepared according to the method of Reference Example 3 Step H, 1.0g, 2.3mmol) Add zinc cyanide (0.16g, 1.4mmol), tris(dibenzylidene-acetone)dipalladium chloroform complex (3.0mg, 2.8μmol), 1,1'-bis(diphenylphosphino) to the DMF solution Ferrocene (5.0 mg, 9.0 μmol) and water (0.1 mL). After heating at 120° C. for 6 hours in a nitrogen atmosphere, another batch of zinc cyanide (0.16 g, 1.4 mmol), tris(dibenzylidene-acetone) dipalladium chloroform complex (5.0 mg, 4.8 μmol), 1 , 1'-bis(diphenylphosphino)ferrocene (5.0 mg, 9.0 μmol) and water (0.05 mL), and heating was continued for 18 hours. After cooling to room temperature, the resulting mixture was partitioned between water (50 mL) and ether (50 mL). The organic layer was separated and the aqueous layer was extracted with ether (2 x 50 mL). The combined extracts were dried over anhydrous _MgSO4 , filtered, concentrated, and the residue was purified by flash column chromatography on silica gel (20% EtOAc/hexanes as eluent) to afford the title compound. ¹ H NMR (400MHz, CD ₃ OD): δ7.6-7.3(m, 4H), 7.10(d, 2H), 6.92(d, 2H), 3.88(m, 1H), 3.20(m, 1H), 2.97(m, 1H), 1.82(m, 1H), 1.45(s, 9H), 0.94(d, 3H). LC-MS: m/e 385(M+H) ⁺ (3.9min).

Step B N-[3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]amine hydrochloride (diastereomer α)

The title compound was prepared according to the method described in Reference Example 3, step I. LC-MS: m/e 285 (M+H) ⁺ (2.2min).

Reference Example 13

2-Methyl-2-(5-chloro-2-pyridyloxy)propionic acid

Step A Ethyl 2-methyl-2-(5-chloro-2-pyridyloxy)propionate

A mixture of 5-chloro-2-hydroxypyridine (5.0 g, 39 mmol), ethyl 2-bromoisobutyrate (5.7 mL, 39 mmol) and cesium carbonate (25 g, 77 mmol) in 50 mL of acetonitrile was heated at 50 °C overnight. Volatiles were removed by concentration on a rotary evaporator and the residue was partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was purified by flash column chromatography on silica gel (5% EtOAc/hexanes as eluent) to afford the title compound. ¹ H NMR (500MHz, CD ₃ OD): δ7.99(d, 1H), 7.67(dd, 1H), 6.68(d, 1H), 4.13(q, 2H), 1.64(s, 6H), 1.14( t, 3H). LC-MS: m/e 244 (M+H) ⁺ (3.41min).

Step B 2-Methyl-2-(5-chloro-2-pyridyloxy)propanoic acid

A mixture of ethyl 2-methyl-2-(5-chloro-2-pyridyloxy)propionate and sodium hydroxide (0.85 g, 21 mmol) in 15 mL of acetonitrile and 15 mL of water was heated at 50 °C overnight. Concentrate by rotary evaporator to remove volatiles, then partition the residue between 2M hydrochloric acid (100 mL) and diethyl ether (100 mL). The organic layer was separated, washed with water (2×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness to give the title compound. ¹ H NMR (500MHz, CD ₃ OD): δ8.02 (d, 1H), 7.65 (ddd, 1H), 6.77 (d, 1H), 1.66 (s, 6H). LC-MS: m/e 216 ( M+H) ⁺ (2.33min).

Reference Example 14

2-Methyl-2-(5-trifluoromethyl-2-pyridyloxy)propanoic acid

The title compound was prepared as described in Reference Example 13, wherein in Step A, 5-trifluoromethyl-2-hydroxypyridine was used instead of 5-chloro-2-hydroxypyridine. ¹ H NMR (500MHz, CD ₃ OD): δ8.38(br s, 1H), 7.93(dd, 1H), 7.13(d, 1H), 1.70(s, 6H).LC-MS: m/e 250 (M+H) ⁺ (2.6min).

Reference Example 15

2-Methyl-2-(6-methyl-2-pyridyloxy)propanoic acid

The title compound was prepared as described in Reference Example 13, wherein in Step A, 6-methyl-2-hydroxypyridine was used instead of 5-chloro-2-hydroxypyridine. ¹ H NMR (500MHz, CD ₃ OD): δ6.74(d, 1H), 6.53(d, 1H), 2.34(s, 3H), 1.64(s, 6H). LC-MS: m/e 196( M+H) ⁺ (1.3min).

Reference Example 16

2-Amino-3-(1-(1,2,3-triazolyl))-4-(4-chlorophenyl)butane

Step A Benzyl 2-(1-(1,2,3-triazolyl))acetate

Composition of 1,2,3-triazole (2.07 g, 30 mmol), phenyl bromoacetate (6.9 g, 30 mmol) and diisopropylethylamine (5.1 mL, 30 mmol) in 40 _{mL CH2Cl2} was stirred at room temperature mixture overnight. The mixture was then diluted with ether until no precipitate formed. The solid was filtered and washed with ether. The filtrate was concentrated and _the residue was purified by silica gel (using 10% hexane/ _CH2Cl2 as eluent) to afford the isomer of the title compound, 2-(2-(1,2,3-triazolyl)) Benzyl acetate, an amorphous solid. Further elution with _a solvent mixture containing equal amounts of diethyl ether and _CH2Cl2 afforded the title compound as an amorphous solid. ¹ H NMR (400MHz, CDCl ₃ ): δ2.251(s, 2H), 7.26-7.390(m, 5H), 7.723(s, 1H), 7.785(s, 1H).

Step B 2-(1-(1,2,3-triazolyl))acetic acid :

To a solution of benzyl 2-(1-(1,2,3-triazolyl))acetate (Step A, 8.68 g, 39.9 mmol) in 150 mL of MeOH was added palladium hydroxide (20% on charcoal, 800 mg) , the mixture was hydrogenated overnight with atmospheric hydrogen in a Parr shaker at room temperature and 45 psi. The catalyst was filtered through a bed of Celite, washing with MeOH. The filtrate was concentrated to give a solid, which was dried under vacuum at 50°C for 36 hours to give the title compound. ¹ H NMR (400MHz, CD ₃ OD): δ5.3(s, 2H), 7.75(s, 1H), 8.016(s, 1H).

Step C N-methoxy-N-methyl-2-(1-(1,2,3-triazolyl))acetamide:

_Oxalyl chloride ( _0.95 mL, 11 mmol). Vigorous effervescence was observed. The mixture was stirred at room temperature for 4 hours, then cooled to -78°C. A solution of N,O-dimethylhydroxylamine hydrochloride (1.2 g, 13 mmol) and diisopropylethylamine (6.0 mL, 35 mmol) in 10 _mL of _CH2Cl2 was added slowly over 3 minutes. The mixture was then warmed to room temperature and stirred overnight. The reaction mixture was then diluted with ether until no more precipitate appeared. The solid was filtered and washed with ether. The filtrate was concentrated and the residue was purified on silica gel using EtOAc as eluent to afford the title compound as an amorphous solid. ¹ H NMR (400MHz, CDCl ₃ ): δ3.252(s, 3H), 3.812(s, 3H), 5.379(s, 2H), 7.753 &7.761(s's, 2H).

Step D N-methoxy-N-methyl-3-(4-chlorophenyl)-2-(1-(1,2,3-triazolyl)) propionamide

To a solution of N-methoxy-N-methyl-2-(1-(1,2,3-triazolyl))acetamide (Step C, 1.19 g, 7 mmol) in 15 mL THF at -78 °C Lithium hexamethyldisilazide (1M in THF, 8.4 mL, 8.4 mmol) was added dropwise. After stirring for an additional 30 minutes, a solution of 4-chlorobenzyl bromide (1.65 g, 8 mmol) in 5 mL of THF was added dropwise. The mixture was warmed to room temperature and stirred for 5.5 h. This mixture was then purified by silica gel using 40% EtOAc/hexanes as eluent to afford the title compound. ¹ H NMR (400MHz, CDCl ₃ ): δ3.186(s, 3H), 3.234-3.267(m, 1H), 3.453-3.506(m, 1H), 3.582(s, 3H), 6.145-6.188(m, 1H), 7.048-7.279(m, 4H), 7.726(s, 1H), 7.954(s, 1H).

Step E 2-Azido-3-(1-(1,2,3-triazolyl))-4-(4-chlorophenyl)butane:

According to the method described in Reference Example 3, Step DG, the product of Step D, N-methoxy-N-methyl-3-(4-chlorophenyl)-2-(1-(1,2, 3-Triazolyl))propanamide was converted to the title compound. ¹ H NMR (400MHz, CDCl ₃ ): δ1.219-1.246 (d's, 3H), 3.253-4.754 (m, 4H), 6.866-7.299 (d's, 4H), 7.313, 7.618, 7.63 & 7.706 (s's, 2H) ).

Step F 2-Amino-3-(1-(1,2,3-triazolyl))-4-(4-chlorophenyl)butane:

To a solution of 2-azido-3-(1-(1,2,3-triazolyl))-4-(4-chlorophenyl)butane (Step E, 138 mg, 0.5 mmol) in 4 mL of MeOH Platinum oxide (14 mg) was added. Using a balloon filled with hydrogen, the mixture was hydrogenated under an atmosphere of hydrogen at room temperature for 3 hours. The catalyst was filtered through a bed of Celite, washing with MeOH. The filtrate was concentrated to give the title compound as an oil. ¹ H NMR (400MHz, CDCl ₃ ): δ1.085-1.174 (d's, 3H), 3.220-3.361 (m, 2H), 3.517-3.563 (m, 3H), 4.379-4.431 (m, 1H), 6.679- 7.719(d's, 4H), 7.297, 7.40, 7.592 &7.607(s's, 2H).

Reference Example 17

N-[3-(4-chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]amine hydrochloride (diastereomeric a)

Step A 2-(N-tert-butoxycarbonyl)amino-4-(4-chlorophenyl)-3-(3-methylphenyl)butane

2-(N-tert-butoxycarbonyl)amino-3-(3-bromophenyl)-4-(4-chlorophenyl)butane (reference example 3, step H, 0.50g, 1.1mmol), Tetramethyltin (0.41g, 2.3mmol), triphenylphosphine (0.12g, 0.46mmol), lithium chloride (0.38g, 9.1mmol) and bis(triphenylphosphine)palladium dichloride (0.12g, 0.17 mmol) in 20 mL of anhydrous DMF was heated at 100° C. for 18 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature and partitioned between water (100 mL) and ether (100 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel (10% EtOAc/hexanes as eluent) to give the title compound. ¹ H NMR (400MHz, CD ₃ OD): δ7.2-6.8(m, 8H), 3.84(m, 1H), 3.16(m, 1H), 2.80-2.68(m, 2H), 2.24(s, 3H ), 1.45(s, 9H), 0.86(d, 3H). LC-MS: m/e 396(M+Na) ⁺ (4.4min).

Step B N-[3-(4-Chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]amine hydrochloride (diastereomer α)

The title compound was prepared by the method described in Step I of Reference Example 3. LC-MS: m/e 274 (M+H) ⁺ (2.5min).

Reference Example 18

N-[3-(5-chloro-2-pyridyl)-2(S)-phenyl-1(S)-methylpropyl]amine hydrochloride (non-para Enantiomer α)

Step A 5-Chloro-2-methylpyridine

In a nitrogen atmosphere, 2,5-dichloropyridine (15g, 0.10mol), tetramethyltin (15mL, 0.11mol) and bis(triphenylphosphine)palladium dichloride (2.0g, 2.8 mmol) in 200 mL of anhydrous DMF for 72 hours. The reaction mixture was cooled to room temperature and poured into a saturated solution of potassium fluoride (200 mL). The resulting mixture was partitioned between water (500 mL) and ether (500 mL). The organic layer was separated and the aqueous layer was extracted with ether (200 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (eluent: 2-10% ether/hexane) to obtain the title compound. ¹ H NMR (500MHz, CD ₃ OD): δ8.41(d, 1H), 7.75(dd, 1H), 7.30(d, 1H), 2.53(s, 3H).

Step B 4-(5-Chloro-2-pyridyl)-3(S)-phenyl-2(R)-butanol

To a solution of 5-chloro-2-picoline (Step A; 1.1 g, 8.7 mmol) in 15 mL of anhydrous diethyl ether at 0 °C was added phenyllithium (1.8 M cyclohexane/diethyl ether solution, 7.2 mL, 13 mmol), the reaction was stirred at room temperature for 30 minutes. The resulting mixture was cooled to 0 °C again, (1R,2R)-1-phenylpropylene oxide (2.3 g, 17 mmol) was added, and the reaction was warmed to room temperature overnight. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel (eluent: 10-40% EtOAc/hexanes) to give the title compound. ¹ H NMR (500MHz, CD ₃ OD): δ8.28(d, 1H), 7.59(dd, 1H), 7.25-7.12(m, 5H), 7.05(d, 1H), 4.03(m, 1H), 3.29(dd, 1H), 3.19(dd, 1H), 3.12(m, 1H), 1.12(d, 3H).

Step C 2(S)-Azido-4-(5-chloro-2-pyridyl)-3(S)-phenylbutane

To 4-(5-chloro-2-pyridyl)-3-phenyl-2-butanol (Step B, 0.24g, 0.92mmol), triphenylphosphine (1.5g, 1.4mmol) and diphenylphosphine To a mixture of acyl azide (0.30 mL, 1.4 mmol) in 5 mL of anhydrous THF was added diethyl azodicarboxylate (0.24 mL, 1.4 mmol). After stirring overnight at room temperature, the resulting mixture was concentrated with silica gel (10 g), and the residue was applied to a silica gel column. Elution with 5-15% EtOAc/hexanes gave the title compound. ¹ H NMR (500MHz, CD ₃ OD): δ8.35(d, 1H), 7.52(dd, 1H), 7.25-7.05(m, 5H), 6.95(d, 1H), 3.81(m, 1H), 3.48(m, 1H), 3.15-3.05(m, 2H), 1.14(d, 3H).

Step D N-[3-(5-chloro-2-pyridyl)-2(S)-phenyl-1(S)-methylpropyl]amine hydrochloride

The product from Step C (0.20 g, 0.70 mmol) was converted to the title compound following the procedure of Reference Example 3, Step HI, substituting HCl/Dioxane solution (4M) for HCl/EtOAc. ¹ H NMR (500MHz, CD ₃ OD): δ8.75(d, 1H), 8.19(dd, 1H), 7.55(d, 1H), 7.4-7.2(m, 5H), 3.78(m, 1H), 3.62(dd, 1H), 3.48(m, 1H), 3.43(dd, 1H), 1.22(d, 3H). LC-MS: m/e 261(M+H) ⁺ (2.2min).

Reference Example 19

N-[2-(3-bromophenyl)-3-(5-chloro-2-pyridyl)-1-methylpropyl]amine hydrochloride (non-para Enantiomer α)

Step A 3-Bromophenylacetone

To a solution of N-methoxy-N-methylacetamide (10 g, 100 mmol) in 100 mL of anhydrous ether was added 3-bromobenzylmagnesium bromide (0.25M in ether, 200 mL, 50 mmol) at 0°C. The reaction was warmed to room temperature overnight and quenched by the addition of saturated ammonium chloride (100 mL). The organic layer was separated and the aqueous layer was extracted with hexane (100 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to give the title compound. ¹ H NMR (500MHz, CD ₃ OD): δ7.45-7.40(m, 2H), 7.26(t, 1H), 7.19(d, 1H), 2.20(s, 3H).

Step B 3-(3-bromophenyl)-4-(5-chloro-2-pyridyl)-2-butanone

A suspension of 5-chloro-2-picoline (Reference Example 18, Step A, 6.4 g, 50 mmol) and N-bromosuccinimide (12.5 g, 70 mmol) in 100 mL of carbon tetrachloride was heated to Under slight reflux (bath temperature 90°C), 2,2'-azobisisobutyronitrile (0.74 g) was added in portions within 30 minutes. After stirring at this temperature for 5 hours, the reaction mixture was concentrated. The resulting slurry was diluted with EtOAc (100 mL), then washed with water (100 mL), saturated aqueous sodium bicarbonate/saturated aqueous sodium thiosulfate, and brine. The organic solution was dried over anhydrous sodium sulfate, filtered, concentrated to dryness, _and the residue was purified by flash column chromatography on silica gel (eluent: 2-15% ether/ _CH2Cl2 (1:1) in hexanes) , to obtain 2-bromomethyl-5-chloropyridine (6.0 g, 60%), which was then used in subsequent reactions. Thus, 2-bromomethyl-5-chloropyridine (6.0 g, 29 mmol) and 3-bromophenylacetone (step A, 6.0 g, 28 mmol) and tetrabutyl iodide were added under vigorous stirring at -78 °C. To a solution of ammonium (20 mg) in 30 mL _CH2Cl2 was added cesium hydroxide monohydrate (10 g, 60 mmol), then the reaction was slowly warmed to _room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel (eluent: 5-40% EtOAc/hexane) to give the title compound. ¹ H NMR (500MHz, CD ₃ OD): δ8.44(d, 1H), 7.66(dd, 1H), 7.46-7.41(m, 2H), 7.24(t, 1H), 7.22(d, 1H), 7.15(d, 1H), 4.42(dd, 1H), 3.54(dd, 1H), 3.07(dd, 1H), 2.12(s, 3H). LC-MS: m/e 338(M+H) ⁺ ( 3.0min).

Step C 3-(3-bromophenyl)-4-(5-chloro-2-pyridyl)-2-butanol

To a solution of 3-(3-bromophenyl)-4-(5-chloro-2-pyridyl)-2-butanone (Step B, 6.7 g, 20 mmol) in 50 mL of anhydrous THF at -78 °C was added Lithium tri(sec-butyl)borohydride (1.0M solution in THF, 30 mL, 30 mmol), warmed the reaction to room temperature overnight. The reaction was cooled to 0°C, 2M hydrochloric acid (50 mL) was carefully added, and the resulting mixture was partitioned between hexane (200 mL) and water (200 mL). The aqueous layer was separated and the organic layer was extracted with 2M hydrochloric acid (2 x 100 mL). The aqueous layer extracts were combined, neutralized (pH > 12) with 5N aqueous sodium hydroxide solution, and extracted with EtOAc (2 x 200 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound.

Step D: N-[2-(3-bromophenyl)-3-(5-chloro-2-pyridyl)-1-methylpropyl]amine hydrochloride

The product from Step C (5.9 g, 17 mmol) was converted to the title compound following the procedure described in Reference Example 18, Step CD. LC-MS: m/e 338 (M+H) ⁺ (2.3min).

Reference Example 20

N-[2-(5-bromo-2-pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]amine hydrochloride (non-para Enantiomer α)

Step A 5-Bromo-3-pyridylacetone

3,5 dibromopyridine (50 g, 0.21 mol), isopropenyl acetate (26 mL, 0.23 mmol), tris(dibenzylideneacetone) dipalladium (1.0 g, 1.1 mmol) and 2-(diphenyl A mixture of phosphino)-2'-(N,N-dimethylamino)biphenyl (1.6 g, 4.2 mmol) in 400 mL of toluene was heated at 100° C. for 2 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated to approximately 100 mL. The resulting mixture was applied to a silica gel column eluting with 0-60% EtOAc/hexanes to afford the title compound. ¹ H NMR (500MHz, CD ₃ OD): δ8.54(br s, 1H), 8.33(br s, 1H), 7.88(br s, 1H), 3.90(s, 2H), 2.25(s, 3H) .

Step B 3-(5-bromo-3-pyridyl)-4-(4-chlorophenyl)-2-butanol

The title compound was prepared as described in Reference Example 19, Step BC, substituting 4-chlorobenzyl chloride for 2-bromomethyl-5-pyridine and 5-bromo-3-pyridylacetone for 3-bromophenyl Acetone (Step A), . ¹ H NMR (500MHz, CD ₃ OD): δ8.43(d, 1H), 8.24(d, 1H), 7.98(dd, 1H), 7.17(d, 2H), 7.07(d, 2H), 4.04( m, 1H), 3.16(dd, 1H), 3.0-2.9(m, 2H), 1.04(d, 3H).

Step C N-[2-(5-Bromo-3-pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]amine hydrochloride (diastereomer α)

The title compound was prepared according to the method described in Reference Example 4, step B. LC-MS: m/e339(M+H) ⁺ (2.5min).

Reference Example 21

N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]amine hydrochloride (not Enantiomer α)

Step A 5-cyano-3-pyridylacetone

The title compound was prepared according to the method described in Reference Example 20, wherein in Step A, 5-bromonicotinonitrile (5-bromo-3-cyanopyridine) was used instead of 3,5-dibromopyridine. ¹ H NMR (400MHz, CD ₃ OD): δ8.89(d, 1H), 8.60(d, 1H), 8.02(t, 1H), 3.98(s, 2H), 2.24(s, 3H).

Step B N-[3-(4-Chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]amine hydrochloride (diastereomer α/β 5: 1)

The title compound was prepared as described in Reference Example 5, wherein in Step A, 5-cyano-3-pyridylacetone was used instead of 3-pyridylacetone. LC-MS: m/e 286(M+H) ⁺ (1.9min).

Reference Example 22

N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]amine hydrochloride (not Enantiomer α)

Step A 5-Chloro-3-pyridylacetone

The title compound was prepared according to the method described in Reference Example 20, wherein in step A, 3,5-dichloropyridine was used instead of 2,5-dibromopyridine and 2-(di-tert-butylphosphino)biphenyl was used instead of 2 -(diphenylphosphino)-2'-(N,N-dimethylamino)biphenyl. ¹ H NMR (500MHz, CD ₃ OD): δ8.42(d, 1H), 8.27(d, 1H), 7.73(dd, 1H), 3.90(s, 2H), 2.25(s, 3H).

Step B N-[3-(4-Chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]amine hydrochloride (diastereomer α)

The title compound was prepared as described in Reference Example 20, Step BC, wherein in Step B, 5-chloro-3-pyridylacetone was used instead of 5-bromo-3-pyridylacetone. LC-MS: m/e 295(M+H) ⁺ (1.9min).

Reference Example 23

N-[3-(4-chlorophenyl)-2-(5-methyl-3-pyridyl)-1-methylpropyl]amine hydrochloride (non Enantiomer α)

The title compound was prepared according to the method described in Reference Example 17, wherein 2-(N-tert-butoxycarbonyl)amino-3-(5-bromo-3-pyridyl)-4-(4-chlorobenzene was used in Step A base)butane (reference example 20, intermediate of Step B) instead of 2-(N-tert-butoxycarbonyl)amino-3-(3-bromophenyl)-4-(4-chlorophenyl)butane . LC-MS: m/e 275(M+H) ⁺ (1.3min).

Reference Example 24

2-Methyl-2-(2-pyrimidinyloxy)propanoic acid

The title compound was prepared as described in Reference Example 13, wherein in Step A, 2-hydroxypyrimidine was used instead of 5-chloro-2-hydroxypyridine. ¹ H NMR (500MHz, CD ₃ OD): δ8.53(d, 2H), 7.09(t, 1H), 1.74(s, 6H).

Reference Example 25

2-Methyl-2-(4-trifluoromethyl-2-pyridyloxy)propanoic acid

The title compound was prepared as described in Reference Example 13, wherein in Step A, 4-trifluoromethyl-2-hydroxypyridine was used instead of 5-chloro-2-hydroxypyridine. ¹ H NMR (500MHz, CD ₃ OD): δ8.30(d, 1H), 7.18(d, 1H), 7.05(s, 1H), 1.71(s, 6H).

Reference Example 26

2-Methyl-2-(6-trifluoromethyl-4-pyrimidinyloxy)propanoic acid

The title compound was prepared as described in Reference Example 13, wherein in Step A, 6-trifluoromethyl-4-hydroxypyrimidine was used instead of 5-chloro-2-hydroxypyridine. ¹ H NMR (500MHz, CD ₃ OD): δ8.81(s, 1H), 7.28(s, 1H), 1.75(s, 6H). LC-MS: m/e251(M+H) ⁺ (2.1min ).

Reference Example 27

2-Methyl-2-(5-trifluoromethyl-2-pyridyloxy)propanoic acid

In two nitrogen-flushed 12L three-necked round bottom flasks (each equipped with a thermometer and reflux condenser), a THF solution of KHMDS (0.91M, 3.52L each, 3.205mol, 1.5eq) was added. Cool the solution to -70°C and stir mechanically. Ethyl 2-hydroxyisobutyrate (98%) (463 mL, 447 g, 3.38 mol) was added to each vial over 30 minutes, keeping the reaction temperature below -62°C. After 10 minutes, 338 g (2.14 mol) of 2-chloro-5-trifluoromethylpyridine was added to each vial in one portion. The cooling bath was removed and the reaction was allowed to warm to 20°C overnight (approximately 16 hours). The reaction was monitored by TLC (silica gel, 90/10 Hex/EtOAc) and HPLC:

Sodium hydroxide (1.36 L, 5N) was added to each reaction flask and the reaction was refluxed overnight (approximately 22 hours). The reactions were pooled and concentrated on a rotary evaporator to remove THF. Water (4 L) was added to the concentrate, and the resulting solution was extracted with n-heptane (2 x 4 L). The aqueous layer was added to 2N HCl (9 L, 18 mol) over 10 minutes with stirring. The resulting suspension was aged for 30 minutes (temperature 30° C.) and then filtered. The filter cake was washed with water (3 x 2 L) and air dried to give a moist tan solid.

The resulting material was dissolved in n-heptane (4 L) at 65°C. Add IPAc (1 L) and DARCO KB (40 g, 100 mesh). The mixture was stirred for 15 minutes, filtered through Celite, and the filter cake was washed with 4:1 heptane/IP Ac (3 x 500 mL). Concentrate the filtrate to about 2 L to obtain a white suspension. The slurry was rinsed with heptane (2 x 3 L) and concentrated to approximately 3 L. The resulting white slurry was cooled to 0°C and aged for 1 hour. The product was filtered and the filter cake was washed with cold heptane (1 L) to give the title compound as white crystals. HPLC column: YMC Combiscreen Pro C18, 50×4.6 mm; mobile phase: A 0.1% THF/H ₂ O; B CH ₃ CN. Gradient: 90/10 A/B-10/90 A/B, 4 minutes. Flow rate: 4mL/min. Detection: 254nm. Room temperature 2-chloro-5-trifluoromethylpyridine 2.1min. Room temperature 2-ethoxy-5-trifluoromethylpyridine 2.9min. Room temperature product ester 3.1min. Room temperature final product acid 2.05min.

Reference Example 28

2-Amino-3-dihydroindol-N-yl-4(4-chloro)phenylbutane

Step A Ethyl 3-(4-chlorophenyl)-2-indolin-N-ylpropanoate . To a stirred suspension of 4 Angstrom molecular sieves was added 1.1 g LiOH- _H2O (26.25 mmol) in DMF (20 mL) in an oven-dried flask under nitrogen atmosphere. After stirring at room temperature for 30 minutes, 2.8 mL (25 mmol) of indoline was added dropwise. After reacting at room temperature for 1 hour, 2.9 mL (26.25 mmol) of ethyl bromoacetate was added dropwise. After 1.5 hours the solids were filtered off and the residue was washed with copious amounts of EtOAc. The organic phase was washed 3 times with water, then the organics were dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The crude material was then dissolved in 75 mL of anhydrous THF, added to a dry round bottom flask under nitrogen, cooled to -78°C, and then treated with 26.25 mL of 1M NaHMDS solution. The resulting solution was stirred at -78°C for 30 min, then the enolate was alkylated with 5.4 g (26.25 mmol) p-chlorobenzyl bromide (solution in 25 mL dry THF). The reaction was warmed to room temperature overnight. Water was added the next day to terminate the reaction. The aqueous layer was extracted with 3 large portions of EtOAc. The combined organic phases were dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give the title compound as a yellow oil. LC/MS m/e = 331 (M+1). TLCR _f = 0.22 (20:1 hexane:EtOAc). ¹ H NMR (500 MHz, CDCl ₃ ): δ 1.11 (t, J = 3.55 Hz, 3H ), 2.96(m, 2H), 3.06(m, 1H), 3.25(m, 1H), 3.60(t, 2H), 4.07(m, 2H), 4.36(t, J=3.75Hz, 1H).

Step B. N,O-Dimethyl-3-(4-chlorophenyl)-2-indolin-N-ylpropanamide . Under a nitrogen atmosphere, add 11.75 mL of 1M (CH ₃ ) ₂ AlCl in _{CH2Cl2 solution} . After warming to room temperature, a solution of 970 mg (2.94 mmol) ethyl 3-(4-chlorophenyl)-2-indolylpropanoate (obtained from Step A) in 10 mL was added via addition funnel. After stirring at room temperature for 5 hours, 35 mL of pH 8 phosphate buffer was added, and the resulting mixture was vigorously stirred for 30 minutes. The phases were separated and the aqueous layer was extracted twice with chloroform. The combined organics were washed with water and dried over _MgSO4 . A brown oil was collected. This crude material was used in the next step. TLC R _f = 0.12 (10:1 hexane:EtOAc). ¹ H NMR (500 MHz, CDCl ₃ ): δ 2.83 (m, 1H), 2.97 (m, 2H), 3.13 (s, 3H), 3.34 ( m, 1H), 3.45(s, 3H), 3.61(m, 2H), 4.87(b, 1H), 6.54(d, 1H), 6.66(t, J=7.1Hz, 1H), 7.07(t, J =7.1Hz, 2H), 7.18(d, J=8.5Hz, 2H), 7.24(d, J=8.5Hz, 2H).

Step C. 4-(4-Chlorophenyl)-3-dihydroindol-N-ylbutan-2-one

In an oven-dried flask under nitrogen atmosphere, add N,O-dimethyl-3-(4-chlorophenyl)-2-dihydroindolylpropanamide (from Step B, 965 mg) in 25 mL To a stirred solution in anhydrous THF was added dropwise 2.8 mL of 1M _CH3MgBr in THF. The resulting solution was stirred for 4 hours while the solution was allowed to warm to room temperature. Then add approximately 20 mL of water. The mixture was extracted three times with 50 mL of ether. The combined extracts were dried over magnesium sulfate. The solvent was removed under reduced pressure to give a brown oil which was used in the next step without further purification. LC/MS m/e = 301 (M+1). TLC R _f = 0.5 (4:1 hexane:EtOAc). ¹ H NMR (500 MHz, CDCl ₃ ): δ 2.14 (s, 3H), 2.81 ( dd, J=14.6, 6.6Hz, 1H), 2.97(t, J=8.5Hz, 2H), 3.26(m, 2H), 3.5(m, 1H), 4.21(dd, J=6.6, 6.6Hz), 6.39(d, J=8Hz, 1H), 6.66(dd, J=7.7Hz, 1H), 7.07(m, 2H), 7.13(d, J=8.5Hz), 7.22(d, J=8.3Hz).

Step D. 4-(4-Chlorophenyl)-3-dihydroindol-N-ylbutan-2-onemethyloxime

A solution of 472 mg (1.573 mmol) of the product from Step C and 263 mg (3.147 mmol) of methoxylamine hydrochloride in absolute ethanol was treated with 255 μL (3.147 mmol) of pyridine. The solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and ether. The aqueous phase was extracted with ether. The extracts were then combined, dried over magnesium sulfate, filtered, and concentrated to obtain crude material. Both E and Z isomers were used in the next step. LC/MS m/e = 330 (M+1). TLC R _f = 0.77 and 0.65 (4:1 hexane:EtOAc). ¹ H NMR (500 MHz, CDCl ₃ ): δ 1.78 (2s, 1H), 2.88(dd, J=6.2, 13.8Hz, 1H), 2.95(m, 2H), 3.30(m, 2H), 3.45(m, 1H), 3.75 and 3.89(2s, 3H), 4.21(dd, J= 6.9, 7.8Hz, 1H), 6.28 and 6.47(2d, J=8.1, 1H), 6.61(m, 1H), 7.02(m, 2H), 7.22(m, 4H).

Step E. 2-Amino-3-indolin-N-yl-4(4-chloro)phenylbutane

At room temperature under a nitrogen atmosphere, in an oven-dried flask equipped with a water condenser, 301 mg (0.914 mmol) of 4-(4-chlorophenyl)-3-dihydroindolylbutan-2-one methyl A solution of the genoxime (from Step D) in 1.5 mL of anhydrous THF was treated with 3.7 mL (3.7 mmol) of 1M _BH3 -THF. The solution was then heated to 75°C for 2 days. The solution was then cooled to 0°C and treated with crushed ice until effervescence ceased. Then 500 μL of 20% KOH was added and the solution was heated at 45° C. for 2 hours. The solution was then cooled to room temperature and extracted 3x with diethyl ether. The combined extracts were dried over magnesium sulfate, filtered and concentrated to give the crude amine which was used in the next experiment without further purification. LC/MSm/e=302 (M+1). ¹ H NMR (500MHz, CDCl ₃ ): δ1.13, 1.14 (2d, J=6.5Hz, 1H), 1.55-1.60 (m, 2H), 2.80- 3.10(m, 4H), 3.30-3.60(m, 2H), 6.348 and 6.38(2d, J=7.9Hz, 1H), 6.50-6.78(m, 2H), 6.95-7.24(m, 5H).

Reference Example 29

2-Amino-3-indol-N-yl-4(4-chloro)phenylbutane

This compound was prepared in a similar manner to Reference Example 28, wherein in Step A, sodium hydride was used as the base instead of the lithium hydroxide monohydrate/molecular sieve combination. LC-MS: Calculated (C ₁₈ H _19C lN ₂ ): 299, found m/e 300 (M+H) ⁺ (2.4min).

Reference Example 30

2-Amino-3-(N-methyl, N-phenyl)amino-4(4-chloro)phenylbutane

The compound was prepared according to a method similar to that of Reference Example 28, LC-MS: calculated value (C ₁₇ H ₂₁ ClN ₂ ): 289, measured value m/e 290 (M+H) ⁺ (2.4min).

Reference Example 31

2-Amino-3-(7-azaindol-N-yl)-4(4-chloro)phenylbutane

This compound was prepared in a similar manner to Reference Example 28. LC-MS: Calculated (C ₁₇ H ₁₈ ClN ₃ ): 300, found m/e 301 (M+H) ⁺ (2.7min).

Reference Example 32

4-(4-Methylphenyl)-3-phenylbutan-2-amine (mixture of 4 isomers)

Step A 1-Phenylacetone

To a solution of N-methyl-N-methoxyacetamide (9.9 mL, 97 mmol) in ether (300 mL) was added benzylmagnesium chloride (97 mL, 1M in ether) at 0°C. The resulting white cloudy reaction mixture was warmed to room temperature for 2 hours, then quenched by careful addition of 1N hydrochloric acid (100 mL). The organic phase was separated, washed with brine, dried over magnesium sulfate, concentrated. The crude product was purified by silica gel column chromatography (eluent: 0-10% EtOAc/hexanes) to afford the title compound. ¹ H NMR (500MHz, CDCl ₃ ): δ7.36(t, J=7.1Hz, 2H), 7.30(t, J=7.3Hz, 1H), 7.24(d, J=7.3Hz, 2H), 3.72( s, 2H), 2.18(s, 3H). LC-MS m/e135(M+H) ⁺ (1.95min).

Step B 4-(4-methylphenyl)-3-phenylbutan-2-one

In a solvent-free flask, 1-phenylacetone (200 mg, 1.49 mmol) was mixed with potassium hydroxide powder (167 mg, 2.98 mmol) and tetrabutylammonium bromide (1 mol%, 5 mg). The mixture was stirred at room temperature for 90 minutes, then 1-(chloromethyl)-4-methylbenzene (198 μl, 1.49 mmol) was added. The reaction mixture was then stirred overnight before dilution with the addition of water and dichloromethane. The aqueous layer was separated, neutralized to pH 7 with 2N hydrochloric acid, and then extracted with dichloromethane. The combined organic washings were dried over magnesium sulfate and concentrated. The crude product was purified by silica gel column chromatography (eluent: 0-10% EtOAc/hexanes) to afford the title compound. ¹ H NMR (500MHz, CDCl ₃ ): δ7.35(t, J=7.0Hz, 2H), 7.29(t, J=7.4Hz, 1H), 7.23(d, J=7.1Hz, 2H), 7.05( d, 7.8Hz, 2H), 6.98(d, J=7.8Hz, 2H), 3.94(t, J=7.3Hz, 1H), 3.43(dd, J=13.9, 7.5Hz, 1H), 2.91(dd, J=14, 7.1Hz, 1H), 2.32(s, 3H), 2.08(s, 3H). LC-MS m/e 239(M+H) ⁺ (3.61min).

Step C 4-(4-methylphenyl)-3-phenylbutan-2-amine

To a solution of 4-(4-methylphenyl)-3-phenylbutan-2-one (308 mg, 1.29 mmol) in 7M ammonia/MeOH (5 mL) and acetic acid (3 mL) was added sodium cyanoborohydride (130mg, 2.06mmol), the reaction was stirred overnight at room temperature. The reaction was quenched by pouring into 2M sodium carbonate, followed by extraction with EtOAc. The aqueous layer is salinized and extracted again. The combined organic extracts were dried over magnesium sulfate and concentrated to give the title compound as a mixture of 4 isomers which was used without further purification. LC-MS: m/e 240(M+H) ⁺ (2.22min).

Reference Example 33

3-[2-Amino-1-(4-fluorobenzyl)propyl]benzonitrile

Preparation using the method described in Example 5, Steps B and C, using 3-(2-oxopropyl)benzonitrile and 1-(chloromethyl)-4-fluorobenzene as reactants in Step B . LC-MS: m/e 269(M+H) ⁺ (2.87min).

Reference Example 34

2-(1H-1,2,3-Benzotriazol-1-yl)-3-(4-chlorophenyl)-1-methylpropylamine

Step A 2-(1H-1,2,3-Benzotriazol-1-yl)-N-methoxy-N-methylacetamide

1.77g (10mmol) 2-(1H-1,2,3-benzotriazol-1-yl) acetic acid, 1.07g (11mmol) N, O-dimethylhydroxylamine hydrochloride, 5.8g (11mmol) A mixture of PyBOP and 3.4 mL (24.2 mmol) of diisopropylethylamine in 50 mL of dichloromethane was stirred overnight at room temperature. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, followed by drying over anhydrous magnesium sulfate. Removal of the solvent gave a crude product which was further purified by silica gel using 60% EtOAc/hexanes as solvent to afford 2.01 g of the desired amide as a solid. ¹ H NMR (CDCl ₃ ): δ3.26(s, 3H), 3.84(s, 3H), 5.63(s, 2H), 7.35-8.2(m, 4H).

Step B 2-(1H-1,2,3-Benzotriazol-1-yl)-3-(4-chlorophenyl)-N-methoxy-N- methyl-propionamide

At -78°C, a solution of 2.0 g (9 mmol) 2-(1H-1,2,3-benzotriazol-1-yl)-N-methoxy-N-methylacetamide in 15 mL of anhydrous THF 10 mL (10 mmol) of 1M lithium bis(trimethylsilyl)amide was added dropwise. After stirring for 25 minutes, a solution of 2.06 g (10 mmol) 4-chlorobenzyl bromide in 2 mL of dry THF was added. The resulting reaction mixture was warmed to room temperature and stirred for 6 hours. The reaction was quenched, diluted with 75 mL of EtOAc, and washed three times with 10 mL of brine. After drying, the organic phase solvent was removed to give the crude product, which was further purified by silica gel using 40% EtOAc/hexanes as solvent to give the desired product as a solid. ¹ H NMR (CDCl ₃ ): δ3.2(s, 3H), 3.834(s, 3H), 3.52(m, 1H), 3.7(m, 1H), 6.32(t, 1H), 6.9-8.2(m , 8H).

Step C 2-(1H-1,2,3-Benzotriazol-1-yl)-3-(4-chlorophenyl)-butan-2-one

At 0°C, to 1.73g (5mmol) 2-(1H-1,2,3-benzotriazol-1-yl)-3-(4-chlorophenyl)-N-methoxy-N-methyl Add 4 mL (10 mmol) of 2.5 M methylmagnesium bromide ether solution to 10 mL of anhydrous THF solution of yl-propionamide. The reaction mixture was stirred for 4 hours while warming to room temperature. The reaction was quenched by adding 10 mL of 1N HCl, and the resulting mixture was partitioned between EtOAc and water. The organic phase was washed with brine, then dried over anhydrous magnesium sulfate. Removal of the solvent gave the crude ketone, which was further purified on silica gel using 40% EtOAc/hexanes to give the desired ketone.

Step D 2-(1H-1,2,3-Benzotriazol-1-yl)-3-(4-chlorophenyl)-1-methylpropylamine

At 0°C, add 1.18g (4mmol) of 2-(1H-1,2,3-benzotriazol-1-yl)-3-(4-chlorophenyl)-butan-2-one in 8.5mL ( To a solution of 60 mmol) 7N ammonia/methanol was added 4 mL (964 mmol) of glacial acetic acid, followed by 410 mg (6.5 mmol) of sodium cyanoborohydride. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was partitioned between EtOAc and saturated sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel using a mixture of 5% 2N methanolic ammonium solution and 95% _CH2Cl2 to afford the desired amine as _a mixture of diastereomers. LC-MS, room temperature = 2.0 min, m/e = 301.

Example 35

3-(4-Chlorophenyl)-2-(thien-3-yl)-1-methylpropylamine

The title amine was prepared as described in Reference Example 34, using thiophene-3-acetic acid in Step A instead of 2-(1H-1,2,3-benzotriazol-1-yl)acetic acid. LC-MS, room temperature = 2.19min, m/e = 266.

Reference Example 36

2-(3-cyanophenyl)-3-cyclobutyl-1-methylpropylamine

Step A 1-(3-cyanophenyl)acetone

Using 3-bromobenzonitrile and isopropenyl acetate as starting materials, the title compound was prepared according to the method of Reference Example 20, Step A.

Step B 3-(3-cyanophenyl)-4-cyclobutyl-butan-2-one

To a solution of 1.45 g (9.07 mmol) of 1-(3-cyanophenyl)acetone in 18 mL of acetonitrile was added 1.1 mL (9.5 mmol) of cyclobutyl bromide and 5.91 g (18.1 mmol) of cesium carbonate. After heating the solution in a 60°C bath overnight, it was cooled and filtered. The filtrate was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash column eluting with a gradient of 5-10% EtOAc/hexanes to isolate the title compound. ¹ H NMR (500MHz, CDCl ₃ ): δ1.5-2.2(m, 9H), 2.13(s, 3H), 3.64(m, 1H), 7.4-7.7(m, 4H).

Step C 2-(3-cyanophenyl)-3-cyclobutyl-1-methylpropylamine

The amine was prepared according to the method of Reference Example 3, step E-I. LC-MS, room temperature = 2.48min, m/e = 229.

The compounds of Reference Examples 37 and 38 were obtained according to the method described in Reference Example 36.

Reference Example 37

2-(3-cyanophenyl)-3-cyclopentyl-1-methylpropylamine

LC-MS, RT=2.7min, m/e=243.

Reference Example 38

2-(3-cyanophenyl)-3-cyclohexyl-1-methylpropylamine LC-MS, RT=2.8min, m/e=257.

Example 1

Automated Synthesis of One-Dimensional Amide Libraries

The following one-dimensional synthesis of a single pure compound library was performed on the MYRIAD CORE system. All reactors were dried at 120° C. for 12 hours in a nitrogen stream before use. Solvents were all dried over molecular sieves for at least 12 hours before use. Prepare a suitable stock solution of N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-amine hydrochloride (alpha isomer) in pyridine with 0.05 Equivalent (relative to N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-amine hydrochloride (alpha isomer)) of dimethylaminopyridine; The resulting various carboxylic acids were dissolved in DMSO immediately before use. The relative amounts of reactants and coupling reagents are shown in Table 1.

Table 1. substance Dosage/reactor MW concentration Mmols equivalent acid, dissolved in DMSO 1mL N/A 0.2M 0.2 1.67 EDC/HOBt mixture in deuterated chloroform 0.8mL EDC: 191.71HOBt: 135.13 0.25M each 0.2 each 1.67 each Amine, dissolved in pyridine, containing catalytic amount of dimethylaminopyridine (~0.05eq.) 0.6mL 294.227 0.2M 0.12 1.0

Method: Add the appropriate different acid subunit (1.0 mL, 0.2 mmol, 0.2 M in DMSO) to one of a total of 192 10 mL MYRIAD ground glass reactors under a nitrogen atmosphere; repeat for the remaining 191 reactors This was done until a different acid was listed for all 192 reactors. EDC/HOBt mixtures (0.8 mL, 0.2 mmol, 0.25 M each in deuterochloroform) were then added to each of the 192 reactors under a nitrogen atmosphere. Finally, N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-amine hydrochloride (α isomer) (0.6 mL , 0.12mmol, 0.2M pyridine solution). Under nitrogen sparge agitation (1 s nitrogen pulse every 30 minutes), the reaction was then aged at room temperature (20-25°C) for 4 hours, followed by aging at 65°C for 16 hours. Reactions were analyzed by HPLC-MS method 1 .

Analytical LC Method 1:

Column: MetaChem Polaris C-18A, 30mm×4.6mm, 5.0μm

Eluent A: 0.1% TFA/water

Eluent B: 0.1% TFA/acetonitrile

Gradient: 5% B to 95% B in 3.3 minutes, gradient in 0.3 minutes

Return to 5%B

Flow rate 2.5mL/min.

Column temperature: 50℃

Injection volume: 5 μL of undiluted crude reaction mixture

Detection: UV, 220 and 254nm.

MS: API-ES ionization method, mass scanning range (100-700)

ELSD: Light Scattering Detector

The crude reaction was purified by preparative HPLC with UV detection (preparative method 2). Then adopt LC-MS to analyze the purity of each fraction collected (analytical method 3); each fraction with purity greater than 90% is pooled in the 40mL EPA vial that has determined tared weight, freeze-dried. Preparative LC Method 2:

Column: MetaChem Polaris C-18A, 100mm×21.2mm, 10μm

Eluent A: 0.1% TFA/water

Eluent B: 0.1% TFA/acetonitrile

Balance before injection: 1.0min

Keep after injection: 0.0min

Gradient: 10% B to 100% B in 6.0 minutes, re-hold at 100% B

Hold for 2.0 minutes, then return from 100% B gradient in 1.5 minutes

to 5%B

Flow rate 25mL/min.

Column temperature: room temperature

Injection volume: 1.5 mL of undiluted crude reaction mixture

Detection: UV, 220 and 254nm.

Analysis method 3:

Column: MetaChem Polaris C-18A, 30mm×2.0mm, 3.0μm

Eluent A: 0.1% TFA/water

Eluent B: 0.1% TFA/acetonitrile

Gradient: 5% B to 95% B in 2.0 minutes, 0.1 minute gradient back to

5%B

Flow rate 1.75mL/min.

Column temperature: 60℃

Injection volume: 5 μL undiluted fraction

Detection: UV, 220 and 254nm.

MS: API-ES ionization mode, mass scanning range (100-700)

ELSD: Light Scattering Detector

Freeze drying parameters:

Initial freezing set point: -70°C, 1h

The setting value of the condenser in the drying stage: -50°C

Drying Stage Table: Storage temperature(℃) Duration (minutes) Vacuum set value (mTorr) -60°C 240 25 -40°C 240 25 5°C 480 25 20°C 1000 25

Examples 2 and 3

N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-chlorophenoxy)-2-methylpropanamide (Diastereomers α and β)

A drop of _DMF and oxalyl _chloride (0.27 mL , 3.0 mmol). After stirring at room temperature for 1 hour, the reaction mixture was concentrated using a rotary evaporator, dried under vacuum, and the resulting crude acid chloride was used directly without further purification. Therefore, the resulting crude acid chloride was dissolved _in 1 mL of _CH2Cl2 and added to 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride (Reference Example 1) (containing some non-para The α isomer of _the enantiomer β impurity, 0.20 g, 0.60 mmol) and N-methylmorpholine (0.27 mL, 2.4 mmol) were suspended in 4 mL _CH2Cl2 . After stirring at room temperature for 6 hours, the reaction mixture was applied to a silica gel column and eluted with 10% EtOAc to obtain the pure product of the faster eluting isomer (diastereomer α) and the slower eluting isomer (diastereomer α). Enantiomer β).

Diastereomer α: ¹ H NMR (500MHz, CD ₃ OD): δ 7.24(d, 2H), 7.20(d, 2H), 7.05(d, 2H), 7.01(d, 2H), 6.94(d , 2H), 6.76(d, 2H), 4.25(m, 1H), 3.03(dd, 1H), 2.88(ddd, 1H), 2.67(dd, 1H), 1.59(s, 3H), 1.53(s, 3H), 0.88 (d, 3H). LC-MS: m/e 490 (M+H) ⁺ (4.7min).

Diastereomer β: ¹ H NMR (500MHz, CD ₃ OD): δ7.16(d, 2H), 7.14(d, 2H), 7.09(d, 2H), 6.99(d, 2H), 6.88(d , 2H), 6.64(d, 2H), 4.33(m, 1H), 3.12(dd, 1H), 3.03(ddd, 1H), 2.74(dd, 1H), 1.36(s, 3H), 1.30(d, 3H), 1.30(s, 3H). LC-MS: m/e 490(M+H) ⁺ (4.7min).

Examples 4-7 (Table 2) were prepared according to the method described in Examples 2 and 3, wherein the appropriate amine prepared in the reference example was used instead of 2-amino-3,4-bis(4-chlorophenyl)butyl alkane hydrochloride and the appropriate acid prepared in the reference example in place of 2-(4-chlorophenoxy)-2-methylpropionic acid. In some cases, similar results were obtained using commercially available acids or acid chlorides and using N-diisopropylethylamine instead of N-methylmorpholine. The designation of the diastereomers (α or β) corresponds to that of the starting amine.

Table 2. Compounds prepared according to the methods described in Examples 2-3.

Example 8 and 9

N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-chlorophenoxy)-2-methylpropanamide (Diastereomer α, Enantiomers A and B)

For separation of enantiomers, preparative HPLC was performed on a Gilson HPLC system. Therefore, N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-chlorophenoxy)-2-methylpropanamide (diastereomer α ) (embodiment 60, 1.0g) Chiralpak AD post (2cm * 25cm) on the solution in hexane (3ml)/ethanol (7mL), with 5% ethanol/hexane elution (flow velocity 9mL/min, every time Injection of 500 μL) yielded two pure enantiomers.

Faster eluting enantiomer (Enantiomer A): Analytical HPLC: retention time = 7.8 min (Chiralpal AD column, flow rate = 0.75 mL/min, 5% ethanol/hexane). LC-MS: m/e 490 (M+H) ⁺ (4.7min).

Slower eluting enantiomer (Enantiomer B): Analytical HPLC: retention time = 9.6 min (Chiralpak AD column, flow rate = 0.75 mL/min, 5% ethanol/hexane). LC-MS: m/e 490 (M+H) ⁺ (4.7min).

According to the method described in Example 8-9, by appropriately changing (1) the composition of eluent (4-15% ethanol/hexane), (2) flow rate (6-9mL/min) and (3) injection volume ( 200-2000 μL), the corresponding racemates (Table 2) were isolated to obtain the compounds of Examples 10-17 as single enantiomers (Table 3).

Table 3. Enantiomeric compounds isolated according to the methods described in Examples 8-9.

According to the method described in Example 2-3, from N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-amine hydrochloride of reference example 4 Example 18 was prepared by coupling the salt with the appropriate carboxylic acid (Table 4).

Table 4. Single enantiomer compounds prepared from N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-amine of Reference Example 4 .

Example 19

N-[2,3-bis(4-chlorophenyl)-1-methylpropyl]-2-(4-chlorophenylamino)-2-methylpropionyl amine

To 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride (diastereomer α, first part, reference example 1, 0.31g, 0.94mmol) and 2-(4-chloro To a mixture of phenylamino)-2-methylpropanoic acid ₍ 0.20 g, 0.94 mmol) in 5 mL of _CH2Cl2 was added N-methylmorpholine (0.41 mL, 3.5 mmol) and tris(pyrrolidinyl)phosphine Onium hexafluorophosphate (0.73 g, 1.4 mmol). After stirring overnight at room temperature, the reaction mixture was applied to a silica gel column eluting with 30% EtOAc/hexanes to afford the title compound. ¹ H NMR (400MHz, CD ₃ OD): δ7.17(d, 2H), 7.04(d, 2H), 7.02(d, 2H), 6.97(d, 2H), 6.70(d, 2H), 6.56( d, 2H), 4.20(m, 1H), 3.02(dd, 1H), 2.78(ddd, 1H), 2.64(dd, 1H), 1.52(s, 3H), 1.45(s, 3H), 0.82(d , 3H).LC-MS: m/e 489 (M+H) ⁺ (4.3min)

Example 20

N-(2,3-diphenyl-1-methylpropyl)-2-(4-chlorophenoxy)-2-methylpropanamide (non-para Enantiomer β)

A solution of 2-(4-chlorophenoxy)-2-methylpropanoic acid (20 mg, 0.095 mmol) in _CH2Cl2 (1 mL) and DMF (10 μL) was treated with _oxalyl chloride (11 μL). After 30 minutes, the reaction _was concentrated and the residue was dissolved in 1 mL _CH2Cl2 . This solution was then added to a mixture of 16 mg of N-(2,3-diphenyl-1-methylpropylamine (β-isomer from Reference Example 2) and 1 mL of saturated NaHCO ₃ . The reaction was stirred overnight and washed with The organic layer was pipetted off. The solution was purified by preparative TLC eluting with 30% EtOAc/hexanes to afford the title compound. ¹ H NMR (500 MHz, CDCl ₃ ): δ 1.17 (d, 3H), 1.36 ( s, 3H), 1.46(s, 3H), 2.85-3.05(m, 3H), 4.44(m, 1H), 6.37(d, 1H), 6.75-7.4(m, 14H). LC-MS: R _t ＝4.4min.m/e 422.2(M+1).

Following the procedure of Example 20, substituting the appropriate amine for N-(2,3-diphenyl-1-methylpropylamine and the appropriate carboxylic acid for 2-(4-chlorophenoxy)-2- Methyl-propionic acid, the compounds in Table 5 below were prepared.

table 5

Following the method of Example 2-3, replace N-(2,3-diphenyl-1-methylpropylamine with the appropriate amine and replace 2-(4-chlorophenoxy)-2 with the appropriate carboxylic acid - Methylpropionic acid, the compounds in Table 6 below were prepared.

Table 6. Compounds prepared according to the method described in Example 2-3

The compounds in Table 7 below were isolated according to the enantiomer separation methods described in Examples 8-9.

Table 7. Enantiomeric compounds isolated according to the methods described in Examples 8-9.

The N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-amine hydrochloride obtained in Reference Example 4 and a suitable acid were used to prepare the following Compounds in Table 8 were obtained as single enantiomers.

Table 8. Individual enantiomeric compounds prepared with N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-amine hydrochloride.

According to the method described in Example 2-3 (via acid chloride intermediate) or Example 19 (using coupling agent), N-[3-(4-chlorophenyl)-2(S)-phenyl-1( S)-methylpropyl]-amine hydrochloride (reference example 4) or N-[3-(5-chloro-2-pyridyl)-2(S)-phenyl-1(S)-methyl Starting from propyl]-amine hydrochloride (Reference Example 18) and the appropriate carboxylic acid, the compounds of Examples 30-33 (Table 9) were prepared.

Table 9.

Examples 34-39 (Table 10) were prepared from the amines and acids of the appropriate reference examples as described in Examples 2-3 (via acid chloride intermediate) or Example 19 (using coupling reagent).

Table 10.

According to the method described in Example 8-9, by appropriately changing (1) eluent composition (4-15% ethanol/hexane), (2) flow rate (6-9mL/min) and (3) injection volume (200 -2000 μL), isolation of the corresponding racemate (Table 10) afforded the compounds of Examples 41-52 as single enantiomers (Table 11).

Table 11. Enantiomeric compounds isolated according to the methods described in Examples 8-9.

Separation on a silica gel column provided Examples 53-56 in the diastereomeric form (isomer A or B) shown (Table 12). Separation on the above chiral AD column afforded the single enantiomers shown.

Table 12.

Example 57

2-Methyl-N-[1-methyl-3-(4-methylphenyl)-2-phenylpropyl]-2-[[5-(trifluoromethyl) Pyridin-2-yl]oxy}propanamide

At room temperature, 2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanoic acid (Reference Example 14, 250mg, 1.04mmol) and 4-(4- To a solution of methylphenyl)-3-phenylbutan-2-amine (Reference Example 102, 260 mg, 1.04 mmol, mixture of 4 isomers) in CH ₂ Cl ₂ (5.5 mL) was sequentially added two Isopropylethylamine (272 μl, 1.56 mmol), PyBOP (649 mg, 1.25 mmol), and the reaction mixture was stirred overnight. The reaction mixture was purified directly on a silica gel column eluting with 0-30% EtOAc/hexanes to afford the title compound as a mixture of 4 isomers. The diastereomers were separated by HPLC on a ZORBAX RxSi column (eluting with 97% hexane:3% ethanol at 20 mL/min) with retention times:

- Less polar diastereomer: 4.73 minutes; more polar diastereomer: 5.87 minutes. Alternatively, the more polar diastereomers were separated on a ChiralPak AD column by eluting with 95 hexane:5% ethanol at 8 mL/min to give the enantiomers with retention times:

- The less polar enantiomer: 6.84 minutes; the more polar enantiomer: 8.36 minutes.

Less polar diastereomer: ¹ H NMR (500 MHz, CDCl ₃ ): δ8.44(s, 1H), 7.86 (dd, J=8.6, 2.5Hz, 1H), 7.19(t, J=3.2Hz , 3H), 7.00(dd, J=21.3, 8.0Hz, 4H), 6.91(m, 2H), 6.83(d, J=8.7Hz, 1H), 5.70(d, J=9.4Hz, 1H), 4.43 (m, 1H), 3.02(dd, J=13.3, 6.7Hz, 1H), 2.84(dt, J=7.3, 4.3Hz, 1H), 2.84(dd, J=13.2, 7.7Hz, 1H), 2.29( s, 3H), 1.69 (s, 3H), 1.66 (s, 3H), 1.03 (d, J = 6.8Hz, 3H). LC-MS: m/e 471 (M+H) ⁺ (4.22min).

More polar diastereomer: ¹ H NMR (500 MHz, CDCl ₃ ): δ8.40 (s, 1H), 7.83 (dd, J=8.7, 2.6 Hz, 1H), 7.21 (m, 3H), 7.00 (dd, J=30.4, 6.2Hz, 4H), 6.82(t, J=9.2Hz, 3H), 5.84(d, J=9.2Hz, 1H), 4.36(ddt, J=9.1, 6.7, 6.6Hz, 1H), 3.06(dd, J=12.8, 4.1Hz, 1H), 2.88(m, 1H), 2.26(s, 3H), 1.78(s, 3H), 1.73(s, 3H), 0.92(d, J = 6.6Hz, 3H). LC-MS: m/e 471 (M+H) ⁺ (4.17min).

Example 58

N-[2-(3-cyanophenyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-methyl-2-{[5-(three Fluoromethyl)pyridin-2-yl]oxy}propionamide

The preparation was carried out as described in Example 57 except using 3-[2-amino-1-(4-fluorobenzyl)propyl]benzonitrile (Ref. Example 33) as the amine component to give the title compound as 4 A mixture of isomers. The diastereomers were separated by HPLC on a Zorbax RxSi column (eluting with 96% hexane: 4% ethanol at 20 mL/min) with retention times: less polar diastereomer: 11.75 minutes; Highly polar diastereomer: 15.17 minutes. Alternatively, the more polar diastereomers were separated on a ChiralPak AD column by eluting with 92% hexane:8% ethanol at 8 mL/min to give the enantiomers with retention times: less polar The enantiomer: 9.65 minutes; the more polar enantiomer: 11.78 minutes.

Less polar diastereomer: ¹ H NMR (500 MHz, CD ₃ OD): δ8.29 (s, 1H), 7.93 (dd, J=8.7, 2.5 Hz, 1H), 7.50 (m, 1H) , 7.42(m, 1H), 7.27(m, 2H), 6.96-6.78(m, 5H), 5.70(d, J=9.6Hz, 1H), 4.33(m, 1H), 3.18-3.04(m, 2H ), 2.7(dd, J=13.5, 6.6Hz, 1H), 1.52(s, 3H), 1.35(s, 3H), 1.17(d, J=6.6Hz, 3H).LC-MS: m/e 500 (M+H) ⁺ (4.33min).

More polar diastereomer: ¹ H NMR (500 MHz, CD ₃ OD): δ8.28 (s, 1H), 7.95 (dd, J=8.7, 2.5 Hz, 1H), 7.50 (d, J= 7.5Hz, 1H), 7.36(m, 3H), 7.05(d, J=8.9Hz, 3H), 6.78(m, 2H), 6.72(m, 2H), 4.26(dq, J=10, 6.6Hz, 1H), 3.04(dd, J=13.7, 3.4Hz, 1H), 2.85(ddt, J=11.2, 3.7Hz, 1H), 2.63(dd, J=13.7, 11.4Hz, 1H), 1.77(s, 3H ), 1.74 (s, 3H), 0.81 (d, J=6.8Hz, 3H). LC-MS: m/e 500 (M+H) ⁺ (4.25min).

The compounds of Table 13 were prepared from the amines and acids of the appropriate reference examples as described in Examples 2-3 (via acid chloride intermediates) or Example 19 (using coupling reagents).

Table 13.

Following the separation of enantiomers described in Examples 8-9, the compounds in Table 14 were isolated.

Table 14. Enantiomeric compounds isolated according to the methods described in Examples 8-9.

Example 64

N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl-2-(5-trifluoromethyl Pyridine N-oxide of -2-pyridyloxy)-2-methylpropanamide (enantiomer B)

N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy base)-2-methylpropanamide (enantiomer B, Example 50, 0.10 g, 0.19 mmol) and m-chloroperoxybenzoic acid (77%, 0.15 g, 0.67 mmol) in 2 mL of dichloromethane The mixture was stirred at room temperature for 14 hours. The reaction mixture was then concentrated and the residue was purified by reverse phase C18 column HPLC using 30-100% acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title ^compound1H NMR (500MHz, _CD3OD ): δ8 .58(s, 1H), 8.32(br s, 1H), 8.1y(s, 1H), 7.99(br d, 1H), 7.97(dd, 1H), 7.81(s, 1H), 7.16(d, 2H), 7.06(d, 1H), 6.87(d, 2H), 4.28(m, 1H), 3.11(dd, 1H), 3.01(m, 1H), 2.71(dd, 1H), 1.75(s, 3H ), 1.74(s, 3H), 0.94(d, 3H). LC-MS: m/e 533(M+H) ⁺ (4.1min).

Example 65

Cannabinoid Receptor-1 (CB1) Binding Assay

Binding affinity was determined based on recombinant human CB1 receptor expressed in Chinese hamster ovary (CHO) cells (Felder et al., Mol. Pharmacol. 48:443-450, 1995). The total assay volume was 250 μl (240 μl CB1 receptor membrane solution + 5 μl test compound solution + 5 μl [ ³ H]CP-55940 solution). The final concentration of [ ³ H]CP-55940 was 0.6 nM. Binding buffer contained 50 mM Tris-HCl, pH 7.4, 2.5 mM EDTA, 5 mM MgCl ₂ , 0.5 mg/mL fatty acid-free bovine serum albumin and protease inhibitors (Cat# P8340, Sigma). To initiate the binding reaction, 5 μl of the radioligand solution was added and the mixture was incubated for 1.5 hours at 30° C. on a shaker with gentle shaking. Binding was terminated by filtration through GF/C filters pre-soaked in 0.05% polyethyleneimine using a 96-well harvester. The amount of bound radiolabel was determined using a scintillation counter. The apparent binding affinities of different compounds were estimated from IC50 values (DeBlasi et al., Trends Pharmacol Sci 10:227-229, 1989).

Binding assays for CB2 receptors were performed in a similar manner using recombinant human CB2 receptors expressed in CHO cells.

Example 66

Functional Activity Assay of Cannabinoid Receptor-1 (CB1)

Functional activation of the CB1 receptor is based on recombinant human CB1 receptor expressed in CHO cells (Felder et al., Mol. Pharmacol. 48:443-450, 1995). In order to determine the agonist activity or inverse agonist activity of the test compound, 50μl of CB1-CHO cell suspension was mixed with the test compound and 70ul assay buffer (containing 0.34mM 3-isobutyl-1-methylxanthine and 5.1uM Forskolin) were mixed in a 96-well plate. Assay buffer consisted of Earle's balanced salt solution supplemented with 5 mM _MgCl2 , 1 mM glutamine, 10 mM HEPES and 1 mg/mL bovine serum albumin. Incubate the mixture at room temperature for 30 minutes and stop the reaction by adding 30 μL/well of 0.5M HCl. The total level of intracellular cAMP was quantified using New England nuclear scintillation plate and cAMP radioimmunoassay kit.

To determine the antagonist activity of the test compound, the reaction mixture also contained 0.5 M of the agonist CP55940, and the recovery of the effect of CP55940 was quantified. Alternatively, a series of dose-response curves of CP55940 are prepared, with increasing concentrations of the test compound in each dose-response curve.

Functional assays for CB2 receptors were performed in a similar manner using recombinant human CB2 receptors expressed in CHO cells.

Although the present invention has been described and illustrated with reference to some preferred embodiments, those skilled in the art will understand that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the present invention. Accordingly, the invention is to be limited only by the scope of the appended claims, which should be interpreted in the broadest possible light on reasonable grounds.

Claims (17)

1. A compound of structural formula I or a pharmaceutically acceptable salt thereof: in: ^R1 is selected from: (1) heterocycloalkyl, (2) aryl, (3) heteroaryl, and (4)-NR ^a R ^c ; wherein aryl and heteroaryl are optionally substituted by 1-3 substituents independently selected from ^R ; ^R2 is selected from: (1) C _1-10 alkyl, (2) C _3-10 cycloalkyl-C _1-4 alkyl, (3) aryl-C _1-4 alkyl, and (4) Heteroaryl-C _1-4 alkyl; wherein cycloalkyl, aryl and heteroaryl are each optionally substituted by 1-3 substituents independently selected from ^R ; Each R ^a is independently selected from: (1) hydrogen, (2) methyl, and (3) _-CF3 ; Each R ^b is independently selected from: (1) Halogen, (2) cyano, (3) Trifluoromethyl, (4) Trifluoromethoxy, (5) C _1-3 alkoxy, and (6) C _1-3 alkyl; ^{Rc is} independently selected from: (1) hydrogen, (2) C _1-6 alkyl, (3) aryl, (4) heteroaryl, (5) aryl-methyl, and (6) Heteroaryl-methyl, Each ^Rc may be unsubstituted or substituted with 1-3 substituents selected from ^Rh ; R ^is independently selected from: (1) Cycloalkyl, (2) aryl, and (3) heteroaryl, Each ^R can be unsubstituted or substituted with 1-3 substituents selected from ^Rh ; Each ^Rh is independently selected from: (1) Halogen, (2) C _1-3 alkyl, (3)-CN, and (4)-CF ₃ , Where the nitrogen of the pyridyl group is unsubstituted, they may optionally be in the form of N-oxides. 2. Compounds and pharmaceutically acceptable salts thereof according to claim 1, wherein ^R is selected from: (1) phenyl, (2) pyridyl, (3) indolyl, (4) 7-aza-indolyl, (5) Thienyl, and (6)

wherein each aryl and heteroaryl is optionally substituted with 1 or 2 substituents independently selected from ^Rb , and each pyridyl is optionally in the form of an N-oxide. 3. compounds and pharmaceutically acceptable salts thereof according to claim 2, wherein ^R is selected from: (1) phenyl, (2) 3-cyanophenyl, (3) 3-methylphenyl, (4) 3,5-difluorophenyl, (5) 3-pyridyl, (6) 5-chloro-3-pyridyl, (7) 5-methyl-3-pyridyl, (8) 5-cyano-3-pyridyl, (9) 1-oxygen-5-cyano-3-pyridyl, (10) 1-indolyl, (11) 7-aza-indol-N-yl, (12) 2-thienyl, and (13)

4. Compounds and pharmaceutically acceptable salts thereof according to claim 3, wherein R ¹ is 5-cyano-3-pyridyl. 5. Compounds and pharmaceutically acceptable salts ^thereof according to claim 2, wherein R is selected from: (1) C _1-6 alkyl, (2) C _3-6 cycloalkylmethyl, (3) Benzyl, (4) Heteroarylmethyl, wherein each cycloalkyl, aryl and heteroaryl is optionally substituted with 1-3 substituents independently selected from ^Rb . 6. The compound and pharmaceutically acceptable salts thereof according to claim 5, wherein ^R is selected from: (1) 2-methylpropyl, (2) n-pentyl, (3) Cyclobutylmethyl, (4) cyclopentylmethyl, (5) cyclohexylmethyl, (6) benzyl, (7) 4-chlorobenzyl, (8) 4-methylbenzyl, (9) 4-fluorobenzyl, (10) 4-methoxybenzyl, and (11) (5-Chloro-2-pyridyl)methyl. 7. Compounds and pharmaceutically acceptable salts thereof according to claim 2, wherein R ^is selected from: (1) C _4-6 cycloalkyl, (2) aryl, and (3) heteroaryl, wherein R ^d may be unsubstituted or substituted with 1 or 2 substituents selected from ^Rh . 8. Compounds and pharmaceutically acceptable salts thereof according to claim 7, wherein R ^is selected from: (1) phenyl, (2) pyridyl, and (3) pyrimidinyl, wherein R ^d can be unsubstituted or substituted by 1 or 2 substituents selected from ^Rh . 9. Compounds and pharmaceutically acceptable salts thereof according to claim 8, wherein R ^is selected from: (1) phenyl, (2) 4-chlorophenyl, (3) 3-chlorophenyl, (4) 3,5-difluorophenyl, (5) 3,5-dichlorophenyl, (6) 2-pyridyl, (7) 5-chloro-2-pyridyl, (8) 6-methyl-2-pyridyl, (9) 5-trifluoromethyl-2-pyridyl, (10) 4-trifluoromethyl-2-pyridyl, (11) 4-trifluoromethyl-2-pyrimidinyl, and (12) 6-trifluoromethyl-4-pyrimidinyl. 10. Compounds and pharmaceutically acceptable salts thereof according to claim 1, which are selected from the group consisting of: (1) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(4-chlorophenoxy)-2-methylpropionamide; (2) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(2-pyridyloxy)-2-methylpropionamide; (3) N-[3-(4-chlorophenyl)-1-methyl-2-(3-pyridyl)propyl]-2-(4-chlorophenoxy)-2-methylpropionamide ; (4) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3,5-difluorophenoxy)-2-methylpropionamide; (5) N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(3,5-dichlorophenoxy)-2-methylpropanamide; (6) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(3-chlorophenoxy)-2-methylpropionamide; (7) N-[3-(4-chlorophenyl)-2-(3,5-difluorophenyl)-1-methylpropyl]-2-(2-pyridyloxy)-2-methyl propionamide; (8) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropionamide; (9) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(6-methyl-pyridyloxy)-2-methylpropionamide; (10) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(phenoxy)-2-methylpropionamide; (11) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(5-trifluoromethylpyridyloxy)-2-methylpropionamide; (12) N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)- 2-Methylpropionamide; (13) N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy )-2-methylpropanamide; (14) N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridine Oxy)-2-methylpropanamide; (15) N-[3-(4-chlorophenyl)-2-(5-methyl-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2- Pyridyloxy)-2-methylpropanamide; (16) N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2- Pyridyloxy)-2-methylpropanamide; (17) N-[3-(4-chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy )-2-methylpropanamide; (18) N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methyl Propionamide; (19) N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidinyloxy)-2-methyl Propionamide; (20) N-[3-(4-chlorophenyl)-1-methyl-2-(thiophen-3-yl)propyl]-2-(5-chloro-2-pyridyloxy)-2- Methacrylamide; (21) N-[3-(5-chloro-2-pyridyl)-2-phenyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2 - methylpropionamide; (22) N-[3-(4-methylphenyl)-1-methyl-2-phenylpropyl]-2-(4-trifluoromethylphenoxy)-2-methylpropionamide ; (23) N-[3-(4-fluorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy )-2-methylpropanamide; (24) N-[3-(4-chlorophenyl)-2-(1-indolyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-oxopyridine-2 -yl)-2-methylpropanamide; (25) N-[3-(4-chlorophenyl)-2-(7-azaindole-N-yl)-1-methylpropyl]-2-(5-trifluoromethyl-2 -pyridyloxy)-2-methylpropanamide; (26) N-[3-(4-chlorophenyl)-2-(1-dihydroindolyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridineoxy Base)-2-methylpropanamide; (27) N-[3-(4-chlorophenyl)-2-(N-methylanilino)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy )-2-methylpropanamide; (28) N-[3-(4-methoxyphenyl)-2-(3-cyano-phenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2- Pyridyloxy)-2-methylpropanamide; (29) N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidinyloxy )-2-methylpropanamide; (30) N-[2-(3-cyanophenyl)-1,4-dimethylpentyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropane amides; (31) N-[3-(4-chlorophenyl)-2-(1-oxidation-5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethane -2-pyridyloxy)-2-methylpropanamide; (32) N-[2-(3-cyanophenyl)-3-cyclobutyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2- Methacrylamide; (33) N-[2-(3-cyanophenyl)-1-methylheptyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropionamide; (34) N-[2-(3-cyanophenyl)-3-cyclopentyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2- Methacrylamide; (35) N-[2-(3-cyanophenyl)-3-cyclohexyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl propionamide. 11. The compound according to claim 9, and pharmaceutically acceptable salts thereof, wherein ^Rd is 5-trifluoromethyl-2-pyridyl. 12. The compound and pharmaceutically acceptable salts thereof according to claim 11, said compound being selected from the group consisting of: (1) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-2-(5-trifluoromethylpyridyloxy)-2-methylpropionamide; (2) N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)- 2-Methylpropionamide; (3) N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy )-2-methylpropanamide; (4) N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridine Oxy)-2-methylpropanamide; (5) N-[3-(4-chlorophenyl)-2-(5-methyl-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2- Pyridyloxy)-2-methylpropanamide; (6) N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2- Pyridyloxy)-2-methylpropanamide; (7) N-[3-(4-chlorophenyl)-2-(3-methylphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy )-2-methylpropanamide; (8) N-[3-(5-chloro-2-pyridyl)-2-phenyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2 - methylpropionamide; (9) N-[3-(4-fluorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy )-2-methylpropanamide; (10) N-[3-(4-chlorophenyl)-2-(1-indolyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-oxopyridine-2 -yl)-2-methylpropanamide; (11) N-[3-(4-chlorophenyl)-2-(7-azaindole-N-yl)-1-methylpropyl]-2-(5-trifluoromethyl-2 -pyridyloxy)-2-methylpropanamide; (12) N-[3-(4-chlorophenyl)-2-(1-dihydroindolyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy Base)-2-methylpropanamide; (13) N-[3-(4-chlorophenyl)-2-(N-methylanilino)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy )-2-methylpropanamide; (14) N-[3-(4-methoxyphenyl)-2-(3-cyano-phenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2- Pyridyloxy)-2-methylpropanamide; (15) N-[2-(3-cyanophenyl)-1,4-dimethylpentyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropane amides; (16) N-[3-(4-chlorophenyl)-2-(1-oxidation-5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethane -2-pyridyloxy)-2-methylpropanamide; (17) N-[2-(3-cyanophenyl)-3-cyclobutyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2- Methacrylamide; (18) N-[2-(3-cyanophenyl)-1-methylheptyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropionamide; (19) N-[2-(3-cyanophenyl)-3-cyclopentyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2- Methacrylamide; (20) N-[2-(3-cyanophenyl)-3-cyclohexyl-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methyl Propionamide. 13. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 14. Use of a compound of claim 1 for the manufacture of a medicament for the treatment of cannabinoid-1 receptor mediated diseases in a patient in need of such treatment. 15. Use according to claim 14, wherein the cannabinoid-1 receptor mediated disease is an eating disease associated with excessive food intake. 16. Use according to claim 15, wherein the eating disorder associated with excessive food intake is obesity. 17. Use of a compound according to claim 1 for the manufacture of a medicament for preventing obesity in an individual at risk of obesity.