BACKGROUND OF THE INVENTION Marijuana (Cannabis sativa L. ) and its derivatives have been used for centuries for medicinal and recreational purposes. A major active ingredient in marijuana and hashish has been determined to be A9-tetrahydrocannabinol (A9-THC).

Detailed research has revealed that the biological action of A9-THC and other members of the cannabinoid family occurs through two G-protein coupled receptors termed CB1 and CB2. The CB1 receptor is primarily found in the central and peripheral nervous systems and to a lesser extent in several peripheral organs. The CB2 receptor is found primarily in lymphoid tissues and cells. Three endogenous ligands for the cannabinoid receptors derived from arachidonic acid have been identified (anandamide, 2-arachidonoyl glycerol, and 2-arachidonyl glycerol ether).

Each is an agonist with activities similar to A9-THC, including sedation, hypothermia, intestinal immobility, antinociception, analgesia, catalepsy, anti-emesis, and appetite stimulation.

The genes for the respective cannabinoid receptors have each been disrupted in mice. The CB1-/-receptor knockout mice appeared normal and fertile.

They were resistant to the effects of A9-THC and demonstrated a strong reduction in the reinforcing properties of morphine and the severity of withdrawal syndrome.

They also demonstrated reduced motor activity and hypoalgesia. The CB2-/-receptor knockout mice were also healthy and fertile. They were not resistant to the central nervous system mediated effects of administered A9-THC. There were some effects on immune cell activation, reinforcing the role for the CB2 receptor in immune system functions.

Excessive exposure to A9-THC can lead to overeating, psychosis, hypothermia, memory loss, and sedation. Specific synthetic ligands for the cannabinoid receptors have been developed and have aided in the characterization of the cannabinoid receptors: CP55, 940 (J. Pharmacol. Exp. Ther. 1988, 247,1046- 1051); WIN55212-2 (J. Pharmacol. Exp. Ther. 1993,264, 1352-1363) ; SR141716A

(FEBS Lett. 1994,350, 240-244 ; Life Sci. 1995,56, 1941-1947); and SR144528 (J.

Pharmacol. Exp. Ther. 1999,288, 582-589). The pharmacology and therapeutic potential for cannabinoid receptor ligands has been reviewed (Exp. Opin. Ther.

Patents 1998,8, 301-313; Ann. Rep. Med. Chem. , A. Doherty, Ed.; Academic Press, NY 1999, Vol. 34,199-208 ; Exp. Opin. Ther. Patents 2000,10, 1529-1538 ; Trends in Pharma. Sci. 2000,21, 218-224). There is at least one CB1 modulator characterized as an inverse agonist or an antagonist, N- (1-piperidinyl)-5- (4-chlorophenyl)-1- (2, 4- dichlorophenyl) -4-methylpyrazole-3-carboxamide (SR141716A), in clinical trials for treatment of eating disorders at this time. There still remains a need for potent low molecular weight CB 1 modulators that have pharmacokinetic and pharmacodynamic properties suitable for use as human pharmaceuticals.

Treatment of asthma with CB 1 receptor modulators (such as CB 1 inverse agonists) is supported by the finding that presynaptic cannabinoid CB 1 receptors mediate the inhibition of noradrenaline release (in the guinea pig lung) (Europ. J. of Pharmacology, 2001,431 (2), 237-244).

Treatment of cirrhosis of the liver with CB 1 receptor modulators is supported by the finding that a CB 1 receptor modulator will reverse the low blood pressure observed in rats with carbon tetrachloride-induced liver cirrhosis and will lower the elevated mesenteric blood flow and portal vein pressure (Nature Medicine, 2001,7 (7), 827-832).

US Patents US 5,624, 941 and US 6,028, 084, PCT Publications W098/43636, W098/43635, and WO 02/076945 and EP-658546 disclose substituted pyrazoles having activity against the cannabinoid receptors.

PCT Publications W098/31227 and W098/41519 also disclose substituted pyrazoles having activity against the cannabinoid receptors.

PCT Publications W098/37061, WO00/10967, and WO00/10968 disclose diaryl ether sulfonamides having activity against the cannabinoid receptors.

PCT Publications W097/29079 and W099/02499 disclose alkoxy- isoindolones and alkoxy-quinolones as having activity against the cannabinoid receptors.

US Patent US 5,532, 237 discloses N-benzoyl-indole derivatives having activity against the cannabinoid receptors.

US Patents US 4,973, 587, US 5,013, 837, US 5,081, 122, and US 5,112, 820, US 5,292, 736 disclose aminoalkylindole derivatives as having activity against the cannabinoid receptors.

PCT publication WO 01/58869 discloses pyrazoles, pyrroles and imidazole cannabinoid receptor modulators useful for treating respiratory and non- respiratory leukocyte activation-associated disorders.

PCT publications WO 01/64632, 01/64633, and 01/64634 assigned to Aventis are directed to azetidine derivatives as cannabinoid antagonists.

The compounds of the present invention are modulators of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the Cannabinoid-1 (CB 1) receptor. In particular, compounds of the present invention are antagonists or inverse agonists of the CB 1 receptor. The invention is concerned with the use of these compounds to modulate the Cannabinoid-1 (CB1) receptor. As such, compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine. The compounds are also useful for the treatment of eating disorders by inhibiting excessive food intake and the resulting obesity and complications associated therewith, including left ventricular hypertrophy.

The compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction, as well as for the treatment of asthma, and cirrhosis of the liver.

SUMMARY OF THE INVENTION The present invention is concerned with novel substituted amides of the general Formula I:

and pharmaceutically acceptable salts thereof which are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention or suppression of diseases mediated by the Cannabinoid-1 (CB1) receptor.

The invention is concerned with the use of these novel compounds to selectively antagonize the Cannabinoid-1 (CB1) receptor. As such, compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine, including smoking cessation. The compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith, including left ventricular hypertrophy. The compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction. The compounds are also useful for the treatment of cirrhosis of the liver. The compounds are also useful for the treatment of asthma.

The present invention is also concerned with treatment of these conditions, and the use of compounds of the present invention for manufacture of a medicament useful in treating these conditions. The present invention is also concerned with treatment of these conditions through a combination of compounds of formula I and other currently available pharmaceuticals.

The invention is also concerned with pharmaceutical formulations comprising one of the compounds as an active ingredient.

The invention is further concerned with processes for preparing the compounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION The compounds used in the methods of the present invention are represented by structural formula I :

or a pharmaceutically acceptable salt thereof, wherein; RI is selected from: (1) C1-C10alkyl, (2) C3-locycloalkyl, (3) cycloheteroalkyl, (4) aryl, and (5) heteroaryl, wherein alky is optionally substituted with one, two, three or four substituents independently selected from Ra, and each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are optionally substituted with one, two, three or four substituents independently selected from Rb; R2 is selected from: (1) C3-lOcycloalkyl, (2) cycloheteroalkyl, (3) aryl, (4) heteroaryl, (5)-ORd, (6)-NRCRd, and (7) -CO2Rd, wherein each alkyl is optionally substituted with one, two, three or four substituents independently selected from Ra, and each cycloalkyl, and cycloheteroalkyl aryl and heteroaryl are optionally substituted with one, two, three or four substituents independently selected from Rb; R3 is selected from: (1) C 1-4alkYl, (2) C2-4alkenyl, (3) C2-4alkynyl, (4) C3-7cycloalkyl,

wherein alkyl, alkenyl, allcynyl, and cycloalkyl are optionally substituted with one, two, three or four substituents independently selected from Ra; R4 is selected from: (1) hydrogen, (2) C1-4alkyl, (3) C2-4alkenyl, (4) C2 4alkynyl, (5) -ORc, <BR> <BR> <BR> (6)-CO2Rc<BR> <BR> <BR> <BR> <BR> <BR> <BR> (7)-OCORC<BR> <BR> <BR> <BR> <BR> <BR> (8)-OCOORc<BR> <BR> <BR> <BR> <BR> <BR> (9)-OCONRdRe<BR> <BR> <BR> <BR> <BR> <BR> (10)-NRdRe, (11) -NH (CO) ORc, (12) -NRcSO2Rc (13) -S (O) mRc (14) aryl, (15) heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl are optionally substituted with one, two, three or four substituents independently selected from Ra, and aryl and heteroaryl are optionally substituted with one, two, three or four substituents independently selected from Rb; R6 is selected from: (1) hydrogen, (2) C1-4 alkyl, (3) C2 4alkenyl, (4) C2 4alkynyl, (5)-ORd, (6) halogen, (7)-CN, (8)-NRRd wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from Ra; A is a 3-to 8-membered monocyclic saturated ring incorporating the same carbon atom to which R4 is attached and optionally containing one to two heteroatoms

chosen from oxygen, nitrogen, and sulfur, and to which an aryl or heteroaryl ring is fused, wherein said bicyclic ring is optionally fused to another aryl or heteroaryl ring to form a tricyclic ring wherein the A ring system is optionally substituted with one, two, three or four substituents selected from a group independently selected from oxo and Rb ; each Ra is independently selected from: (1)-ORd, (2) -NRcS(O) mRd, (3) -NO2, (4) halogen, (5)-S (O) mRc, (6) -SRc, (7) -S (O) 2ORc, (8) -S(O)mNRcRd, (9) -NRcRd, (10)-O (CReRf) nNRcRd, (11)-C (O) Rc, (12) -CO2Rc, (13) -CO2 (CReRf) nCONRCRd, (14) -OC (O) Rc, (15)-CN, (16)-C (O) NRCRd, (17) -NRcC(O)Rd, (18) -OC (O) NRcRd, (19)-NRcC (O) ORd, (20) -NRcC(O)NRcRd, (21) -CRc (N-ORd), (22) CF3, (23)-OCF3, (24) C3-gcycloalkyl, and (25) cycloheteroalkyl ; each Rb is independently selected from: (1) Ra, C1-10alkyl,

(3) aryl, (4) arylC1-4alkyl, (5) heteroaryl, and (6) heteroarylC1-4alkyl ; Rc and Rd are independently selected from: (1) hydrogen, (2) Cl-loalkyl, (3) C2-10 alkenyl, (4) C2-10alkynyl, (5) cycloalkyl, (6) cycloalkyl-Cl-loalkyl ; (7) cycloheteroalkyl, (8) cycloheteroalkyl-C1-10alkyl ; (9) aryl, (10) heteroaryl, (11) aryl-Cl-loalkyl, and (12) heteroaryl-Cl-loalkyl, or Rc and Rd together with the atom (s) to which they are attached form a heterocyclic ring of 4 to 7 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur and N-Rg, each Rc and Rd may be unsubstituted or substituted on a carbon or nitrogen atom with one, two or three substituents selected from Rh; Re and Rf are independently selected from hydrogen, cl-loalkyl C2-10 alkenyl, C2- loalkynyl, cycloalkyl, cycloalkyl-Cl-lo alkyl, cycloheteroalkyl, cycloheteroalkyl-Cl- 10 alkyl, aryl, heteroaryl, aryl-C1-10alkyl, and heteroaryl-C1-C10 alkyl ; or Re and Rf together with the carbon to which they are attached form a ring of 5 to 7 members containing 0,1, or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen; each Rg is independently selected from (1) hydrogen, (2) Cl-loalkyl, (3) C3-8cycloalkyl, (4) heterocycloalkyl, (5) aryl, (6) arylCl 4alkyl,

(7) heteroaryl, (8) heteroarylC1-4alkyl, (9)-S (O) mRc, (10) -C (O) Rc, (11) -CO2Rc, (12)-C02 (CReRf) nCONRCRd, and (13)-C (O) NRcRd ; each Rh is independently selected from: (1) halogen, (2) C1-10alkyl, (3) C3-gcycloalkyl, (4) heterocycloalkyl, (5) aryl, (6) arylC1-4alkyl, (7) heteroaryl, (8) heteroarylCl 4alkyl, (9) -ORc, (10) -NRcS (O) mRd, (11)-S (0) mRc, (12)-SRc, (13) -S (O) 2ORc, (14) -S(O)mNRcRd, (15) -NRcRd, (16)-O (CReRf) nNRcRd, (17) -C(O)Rc, (18) -CO2Rc, (19) -CO2 (CReRf) nCONRcRd, (20) -OC (O) Rc, (21)-CN, (22) -C(O)NRcRd, (23) -NRcC(O)Rd, (24) -OC (O) NRcRd, (25)-NRCC (O) ORd, (26) -NRcC(O)NRcRd, (27) CF3, and

(28)-OCF3, m is selected from 1 and 2; and n is selected from 1,2, and 3; or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, Rl is selected from: (1) Cl-loalkyl, (2) C3-lOcYcloalkyl-, (3) cycloheteroalkyl, (4) aryl, and (5) heteroaryl, wherein each alkyl is optionally substituted with one to three substituents independently selected from Ra, and each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is optionally substituted with one to three substituents independently selected from Rb.

In one class of this embodiment, Rl is selected from: (1) Cl-4alkyl, (2) C3-locycloallcyl-, (3) cycloheteroalkyl, (4) phenyl, and (5) pyridyl, wherein each alkyl is optionally substituted with one Ra substituent, and each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is optionally substituted with one to three substituents independently selected from Rb.

In one subclass of this embodiment, Rl is selected from: (1) isopropyl, (2) isobutyl, (3) n-propyl, (4) cyclopropyl, (5) cyclobutyl, (6) cyclopentyl, (7) cyclohexyl, (8) piperidinyl, (9) phenyl, and (10) pyridyl,

wherein each alkyl is optionally substituted with one Ra substituent, and each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is optionally substituted with one to three substituents independently selected from Rb.

In another embodiment of the present invention, Rl is selected from: (1) aryl, (2) heteroaryl, wherein aryl and heteroaryl are optionally substituted with one, two, three or four substituents independently selected from Rb.

In one class of this embodiment, Rl is selected from: (1) phenyl, and (2) pyridyl; wherein phenyl and pyridyl are optionally substituted with one or two Rb substituents.

In one subclass of this embodiment of the present invention, Rl is selected from: (1) phenyl, (2) 4-fluorophenyl, (3) 2-chlorophenyl, (4) 3-chlorophenyl, (5) 4-chlorophenyl, (6) 3-cyanophenyl, (7) 4-cyanophenyl, (8) 4-methylphenyl, (9) 4-isopropylphenyl, (10) 4-biphenyl, (11) 4-bromophenyl, (12) 4-iodophenyl, (13) 2,4-dichlorophenyl, and (14) 2-chloro-4-fluorophenyl.

In another subclass, Rl is selected from: (1) phenyl, and (2) pyridyl; wherein phenyl and pyridyl are optionally substituted with one or two halogen substituents.

In yet another subclass, RI is phenyl or 4-chlorophenyl.

In still another subclass of this class, Rl is 4-chlorophenyl.

In another embodiment of the present invention, R2 is selected from: (1) Cl-loalkyl, (2) C3-10cycloalkyl, (3) cycloheteroalkyl, (4) aryl, (5) heteroaryl, (6)-ORd, (7)-NRCRd, and (8)-C02Rd, and wherein each alkyl is optionally substituted with one, two or three substituents independently selected from Ra, and each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is optionally substituted with one, two or three substitutents independently selected from Rb.

In a class of this embodiment, R2 is selected from: (1) cyclobutyl, (2) cyclopentyl, (3) cyclohexyl, (4) pyrrolidinyl, (5) pyrimidinyl, (6) benzoxazolyl, (7) dihydroindolyl, (8) dihydroquinolinyl, (9) benzotriazolyl, (10) thiophenyl, (11) indolyl, (12) indazolyl, (13) pyrrolidinyl, (14) pyridazinyl (15) triazolyl, (16) azaindolyl, (17) cyclobutylmethoxy, (18) phenyl, (19) pyridyl,

(20)-NRCRd, and (21)-C02Rd, wherein each alkyl is optionally substituted with one or two Ra substituents and each phenyl or pyridyl is independently with one to three Rb substituents.

In another class of this embodiment, R2 is selected from: (1) aryl, (2) heteroaryl, wherein aryl and heteroaryl are optionally substituted with one, two, three or four substituents independently selected from Rb; In a subclass, R2 is selected from: (1) aryl, and (2) heteroaryl; wherein aryl and heteroaryl are optionally substituted with one or two Rb substituents.

In another subclass, R2 is selected from: (1) phenyl, (2) 4-fluorophenyl, (3) 2-chlorophenyl, (4) 3-chlorophenyl, (5) 4-chlorophenyl, (6) 3-cyanophenyl, (7) 4-cyanophenyl, (8) 4-methylphenyl, (9) 4-isopropylphenyl, (10) 4-biphenyl, (11) 4-bromophenyl, (12) 4-iodophenyl, (13) 2,4-dichlorophenyl, (14) 2-chloro-4-fluorophenyl, and (15) 3-pyridyl.

In still another subclass, R2 is selected from: (1) phenyl, and (2) pyridyl; wherein phenyl and pyridyl are optionally substituted with one or two Rb substituents.

In yet another subclass, R2 is selected from: (1) phenyl, and (2) pyridyl, wherein phenyl and pyridyl are optionally substituted with one or two halogen substituents.

In another subclass, R2 is selected from: (1) phenyl, (2) 4-chlorophenyl, and (3) 3-pyridyl.

In still another subclass, R2 is 4-chlorophenyl.

In one embodiment of the present invention, R3 is selected from: (1) Cl 4alkyl, and (2) cyclopropyl, wherein alkyl and cyclopropyl are optionally substituted with one, two or three Ra substituents.

In one class of this embodiment, R3 is selected from (1) methyl, (2) trifluoromethyl, and (3) cyclopropyl.

In one subclass of this class, R3 is methyl.

In one embodiment of the present invention, R4 is selected from: (1) hydrogen, (2) Cl 4alkyl, and (3) cyclopropyl, wherein alkyl and cyclopropyl are optionally substituted with one, two or three Ra substituents.

In one class of this embodiment, R4 is selected from: (1) hydrogen, (2) methyl, (3) trifluoromethyl, and (4) cyclopropyl.

In one subclass of this class, R4 is selected from hydrogen and methyl.

In one embodiment of the present invention, R6 is hydrogen. When R6 is hydrogen, the structural formula I may be represented as structural formula IA:

In another embodiment of the present invention, R6 is selected from: (1) Cl 4alkyl, (2) C2 4alkenyl, (3) C2-4alkynyl, (4)-ORd, (5) halogen, and (6)-CN, wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from Ra.

In a class of this embodiment, R6 is selected from: (1) methyl, (2) hydroxyl, (3) halogen, and (4)-CN, wherein methyl is optionally substituted with one to three Ra substituents.

In one subclass of this class, R6 is selected from: (1) methyl, (2) hydroxyl, (3) halogen, and (4)-CN.

In one embodiment of the present invenion, A is a 5 to 7 membered monocyclic saturated ring incorporating the same carbon atom to which R4 is attached and optionally containing one or two oxygen heteroatoms and to which an aryl or heteroaryl ring is fused, wherein said bicyclic ring is optionally fused at the aryl/heteroaryl ring to another aryl or heteroaryl ring to form a tricyclic ring and wherein the A ring is optionally substituted with one or two Rb substituents.

In one class of this embodiment, A is a cyclopentyl, cyclohexyl, cycloheptyl, dioxanyl, tetrahydrofuranyl, or oxanyl, ring fused to a phenyl, or pyrrolyl

ring, optionally fused to a phenyl ring to form a tricyclic ring wherein the A ring system is optionally substituted with one, two or three Rb substituents.

In another class of the present invention, ring A is selected from benzodioxanyl, indanyl, 1,2, 3,4-tetrahydronaphthyl, 6,7, 8,9- tetrahydro [a] [7] annulenyl, chromanyl, 2, 3-dihydrobenzyl furanyl, 1,2, 3,4- tetrahydroquinolinyl, 1,2, 3, 4-tetrahydroisoquinolinyl, 1,2, 3,4-tetrahydro-1, 4- quinazolinyl, and 1,2, 3,4-tetrahydrocarbolinyl, each optionally substituted with one or two groups independently selected from Rb.

In one subclass of this class of the present invention, ring A is selected from benzodioxanyl, indanyl, 1,2, 3,4-tetrahydronaphthyl, 6,7, 8,9- tetrahydro [a] [7] annulenyl, chromanyl, 2,3-dihydroenzofuranyl, and 1,2, 3,4- tetrahydrocarbolinyl, each optionally substituted with one or two groups independently selected from Rb.

In one embodiment of the present invention, each Ra is independently selected from: <BR> <BR> <BR> (1)-ORd,<BR> <BR> <BR> <BR> (2) -NHS (O) mRd, (3) halogen, (4) S02RC, (5) SRc, (6) S(O2)ORc, <BR> <BR> <BR> (7) SO2NHRd,<BR> (8) -NRcRd,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> (9)-0 (CH2) nNRCRd (10) -C (O) Rc, (11)-C02RC, (12)-C02 (CH2) nCONHRd, (13) -OC (O) Rc, (14)-CN, (15) -C (O) NHRd, (16) -NHC (O) Rd, (17)-OC OC (O)NHRd, (18) -NHC(O)ORd, (19) -NHC(O)NHRd,

(20) -CH (N-ORd), (21)-CF3, (22)-OCF3, (23) C3-8 cycloalkyl, and (24) cycloheteroalkyl.

In one class of this embodiment of the present invention, each Ra is independently selected from: (1) -ORd, (2) halogen, (3) S02RC, (4) SRc, (5) S (02) ORc, (6) S02NHRd, (7) -NRcRd, (8)-C (O) Rc, (9)-C02RC, (10)-CN, (11)-CH (N-ORd), (12) -CF3, (13)-OCF3, (14) C3-8 cycloalkyl, and (15) cycloheteroalkyl.

In a subclass of this class, each Ra is independently selected from: (1)-ORd, (2) halogen, (3) SO2Rc, (4) SH, (5) SCH3, (6)-NRCRd, (7)-C (O) Rc, (8)-C02RC, (9) -CF3, and (10)-OCF3.

In one embodiment of the present invention, each Rb is independently selected from: (1)-ORd, (2)-NHS (O) mRd, (3)-NO2, (4) halogen, (5) -S (O) 2Rc, (6) -SRc, (7) -S (O) 2ORc, (8)-S (O) 2NHRd, (9) -NRcRd, (10)-O (CH2) nNRcRd, (11) -C(O)Rc, (12) -CO2Rc, (13)-C02 (CReRf) nCONRcRd, (14) -OC (O) Rc, (15)-CN, (16) -C (O) NHRd, (17) -NHC (O) Rd, (18)-OC (O) NHRd, (19) -NHC (O) ORd, (20) -NHC (O) NRCRd, (21) -CH (N-ORd), (22)-CF3, (23)-OCF3, (24) C3-8cycloalkyl, (25) cycloheteroalkyl ; (26) C1-10alkyl, (27) aryl, (28) arylC1-4alkyl, (29) heteroaryl, and (30) heteroarylCl 4alkyl.

In one class of this embodiment of the present invention, each Rb is independently selected from:

(1)-ORd, (2) halogen, (3) SO2Rc, (4) SRc, (5) S (02) ORc, (6) S02NHRd, (7) -NRcRd, (8) -C (O) Rc, (9)-C02RC, (10)-CN, (11)-CH (N-ORd), (12)-CF3, (13)-OCF3, (14) C3-8 cycloalkyl, (15) cycloheteroalkyl, (16) C1-4alkyl, (17) aryl, (18) arylC1-4alkyl, (19) heteroaryl, and (20) heteroarylC1-4alkyl.

In a subclass of this class, each Rb is independently selected from: (1)-ORd, (2) halogen, (3) SO2Rc, (4) SH, (5) SCH3, (6) -NRcRd, (7) -C (O) Rc, (8) -CO2Rc, (9)-CF3, (10)-OCF3, (11) C3-8 cycloalkyl, (12) cycloheteroalkyl, (13) Cl 4alkyl,

(14) phenyl, (15) benzyl, (16) heteroaryl, and (17) heteroaryl-methyl-.

In another subclass of this class, each Rb is independently selected from: (1) methoxy, (2) halogen, (3)-SH, (4)-SCH3, (5)-NH2, (6) -C (O) CH3, <BR> <BR> <BR> (7)-C02H,<BR> <BR> <BR> <BR> (8)-C02CH3, (9)-CF3, (10)-OCF3, (11) C3 6 cycloalkyl, (12) Cl 4alkyl, (13) phenyl, (14) benzyl, (15) heteroaryl.

In still another subclass of this class, each Rb is independently selected from halogen.

In one embodiment of the present invention, each RC is independently selected from: (1) hydrogen, and (2) Cl 4alkyl, either wherein alkyl may be unsubstituted or substituted with one, two or three substituents selected from Rh.

In one class of this embodiment of the present invention, each Rc is independently selected from: (1) hydrogen, and (2) methyl, wherein methyl may be unsubstituted or substituted with one, two or three substituents selected from Rh.

In one subclass of this class, each Rc is independently selected from: (1) hydrogen, and (2) methyl.

In one embodiment of the present invention, each Rd is independently selected from: (1) hydrogen, (2) Cl-loalkyl, (3) cycloalkyl, (4) cycloheteroalkyl, (5) aryl, (6) heteroaryl, and (7) benzyl, either unsubstituted or substituted on a carbon or nitrogen atom with one, two or three substituents selected from Rh.

In one class of this embodiment of the present invention, each Rd is independently selected from: (1) hydrogen, (2) Cl 4alkyl, (3) cycloalkyl, (4) cycloheteroalkyl, (5) phenyl, (6) heteroaryl, and (7) benzyl, either unsubstituted or substituted on a carbon or nitrogen atom with one or two substituents selected from Rh.

In one embodiment of the present invention, Rc and Rd together with the atom (s) to which they are attached form a heterocyclic ring of 5 to 6 members optionally containing one additional heteroatom independently selected from oxygen, sulfur and N-Rg, which may be unsubstituted or substituted with one or two substituents selected from Rh.

In one embodiment of the present invention, each Re is independently selected from hydrogen, Cl 4alkyl, cycloalkyl, cycloheteroalkyl ; phenyl, heteroaryl, and benzyl.

In one class of this embodiment of the present invention, each Re is independently selected from hydrogen, and Cl 4alkyl.

In one subclass of this class, each Re is hydrogen.

In one embodiment of the present invention, each Rf is independently selected from hydrogen, Cl 4alkyl, cycloalkyl, cycloheteroalkyl ; phenyl, heteroaryl, and benzyl.

In one class of this embodiment of the present invention, each Rf is independently selected from hydrogen, and Cl-4alkyl.

In one subclass of this class, each Rf is hydrogen.

In one embodiment of the present invention, Re and Rf together with the carbon to which they are attached form a ring of 5 to 6 members optionally containing a heteroatom selected from oxygen, sulfur and nitrogen.

In one embodiment of the present invention, each Rg is independently selected from (1) hydrogen, (2) Cl 4alkyl, (3) C3-6cycloalkyl, (4) heterocycloalkyl, (5) phenyl, (6) benzyl, (7) heteroaryl, (8) -S(O)2Rc, (9) -C(O)Rc, (10) -CO2Rc, (11)-C02 (CH2) nCONRCRd, and (12)-C (O) NRCRd.

In one class of this embodiment of the present invention, each Rg is independently selected from: (1) hydrogen, (2) C1-4alkyl, and (3) -C (O) C1 4alkyl.

In one class of this embodiment, each Rg is hydrogen, methyl or methylcarbonyl.

In one subclass of this class, each Rg is hydrogen or methyl.

In one embodiment of the present invention, each Rh is independently selected from: (1) halogen, (2) C1 4alkyl, <BR> <BR> <BR> (3)-O-Cl 4alkyl,<BR> <BR> <BR> <BR> <BR> (4)-S-Cl 4alkyl, (5)-CN, (6) -CF3, and (7)-OCF3.

In one class of this embodiment, each Rh is independently selected from: (1) halogen, (2) methyl, (3) methoxy, (4) methylthio-, (5)-CN, (6)-CF3, and (7)-OCF3.

In one embodiment of the present invention, m is two.

Particular novel compounds which may be employed in the methods, uses and compositions of the present invention, include: (1) N- (2, 3-bis (4-chlorophenyl)-1-methylpropyl)-1, 4-benzodioxane-2-carboxamide, (2) N- (2, 3-bis (4-chlorophenyl)-1-methylpropyl)-indane-1-carboxamide, (3) N- (2, 3-bis (4-chlorophenyl)-1-methylpropyl)-2, 3-dihydrobenzofuran-2- carboxamide, (4) N- (2, 3-bis (4-chlorophenyl)-1-methylpropyl)-1, 2,3, 4-tetrahydrocarbazole-1- carboxamide, (5) N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl]-1, 2,3, 4-tetrahydro-2-naphthamide, (6) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2, 3-dihydrobenzofuran-2- carboxamide, (7) N- [2, 3-bis (4-chlorophenyl)-1-methypropyl]-2-methyl-2, 3-dihydrobenzofuran-2- carboxamide, (8) N- [3- (4-chlorophenyl)-l-methy-2-phenylpropyl]-2-methyl-2, 3- dihydrobenzofuran-2-carboxamide,

(9) N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl]-2-methyl-1, 2,3, 4-tetrahydro-2- naphthamide, (10) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-1, 2,3, 4-tetrahydro-2- naphthamide, (11) N-[3-(4-chlorophenyl)-1-methyl-2-phenylpropyl]-1, 2,3, 4-tetrahydro-2- naphthamide, (12) N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl] chromane-2-carboxamide, (13) N- [3- (4-chlorophenyl)-l-methy-2-phenylpropyl] chromane-2-carboxamide, (14) N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl]-2-methylchromane-2-carboxam ide, (15) N- [3- (4-chlorophenyl)-l-methy-2-phenylpropyl]-2-methylchromane-2- carboxamide, (16) N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl] chromane-3-carboxamide, (17) N- [3- (4-chlorophenyl)-l-methy-2-phenylpropyl] chromane-3-carboxamide, (18) N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl]-3-methylchromane-3-carboxam ide, (19) N- [3- (4-chlorophenyl)-l-methy-2-phenylpropyl]-3-methylchromane-3- carboxamide, (20) N-[2, 3-bis (4-chlorophenyl)-1-methylpropyl]-2-methyl-2, 3-dihydro-1, 4- benzodioxane-2-carboxamide, (21) N-[3- (4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-2, 3-dihydro-1, 4- benzodioxane-2-carboxamide, (22) N-[2, 3-bis (4-chlorophenyl)-1-methylpropyl]-2, 3-dihydro-1, 4-benzodioxane-2- carboxamide, (23) N- [3- (4-chlorophenyl)-l-methy-2-phenylpropyl]-2, 3-dihydro-1, 4-benzodioxane- 2-carboxamide, (24) N- [3- (4-chlorophenyl)-1-methy-3-pyridylpropyl]-2-methyl-2, 3-dihydro-1, 4- benzodioxane-2-carboxamide, (25) N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl]-6, 7,8, 9-tetrahydro-5H- benzo [a] [7] annulene-6-carboxamide, (26) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-6, 7, 8, 9-tetrahydro-5H- benzo [a] [7] annulene-6-carboxamide, (27) N- [2, 3-bis (4-chlorophenyl)-1-methypropyl]-6, 7,8, 9-tetrahydro-5H- benzo [a] [7] annulene-7-carboxamide, (28) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-6, 7,8, 9-tetrahydro-5H- benzo [a] [7] annulene-7-carboxamide,

(29) N- [3- (4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-2, 3-dihydro-1,4- benzodioxane-2-carboxamide, (30) N- [3- (4-chlorophenyl)-1-methy-3-pyridylpropyl]-2-methyl-2, 3-dihydro-1, 4- benzodioxane-2-carboxamide, (31) N- [3- (4-chlorophenyl)-2 (S)-phenyl-l (S) -methylpropyl]-3-methylchromane-3- carboxamide, (32) N- [3- (4-chlorophenyl)-2 (S)-phenyl-1 (S) -methylpropyl] -2-methyl-2, 3-dihydro- 1, 4-benzodioxane-2-carboxamide, (33) N- [3- (4-chlorophenyl)-2 (S)-phenyl-1 (S) -methylpropyl] -6-chloro-2-methyl-2, 3- dihydro-1, 4-benzodioxane-2-carboxamide, (34) N- [3- (4-chlorophenyl)-2 (S)-phenyl-l (S) -methylpropyl] -7-chloro-2-methyl-2, 3- dihydro-1, 4-benzodioxane-2-carboxamide; and pharmaceutically acceptable salts thereof.

In more particular, compounds of the present invention include: (1) N- (2, 3-bis (4-chlorophenyl)-1-methylpropyl)-1, 4-benzodioxane-2-carboxamide, (2) N-(2, 3-bis (4-chlorophenyl)-l-methylpropyl)-indane-l-carboxamide, (3) N- (2, 3-bis (4-chlorophenyl)-1-methylpropyl)-2, 3-dihydrobenzofuran-2- carboxamide, (4) N- (2, 3-bis (4-chlorophenyl)-1-methylpropyl)-1, 2,3, 4-tetrahydrocarbazole-1- carboxamide, (5) N- [2, 3-bis(4-chlorophenyl)-1-methylpropyl]-1, 2,3, 4-tetrahydro-2-naphthamide, diastereomer I, (6) N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl]-1, 2,3, 4-tetrahydro-2-naphthamide, diastereomer II, (7) N-[2, 3-bis (4-chlorophenyl)-1-methylpropyl]-1, 2,3, 4-tetrahydro-2-naphthamide, diastereomer III, (8) N-[2, 3-bis (4-chlorophenyl)-1-methylpropyl]-1, 2,3, 4-tetrahydro-2-naphthamide, diastereomer IV, (9) N [3- (4-chlorophenyl)-1-methy-2-phenylpropyl]-2, 3-dihydrobenzofuran-2- carboxamide diastereomer I, (10) N- [3- (4-chlorophenyl)-l-methy-2-phenylpropyl]-2, 3-dihydrobenzofuran-2- carboxamide diastereomer II, (11) N- [3- (4-chlorophenyl)-l-methy-2-phenylpropyl]-2, 3-dihydrobenzofuran-2- carboxamide, diastereomers I and II (1: 1),

(12) N- [2, 3-bis (4-chlorophenyl)-1-methypropyl]-2-methyl-2, 3-dihydrobenzofuran-2- carboxamide diastereomer I, (13) N- [2, 3-bis (4-chlorophenyl)-1-methypropyl]-2-methyl-2, 3-dihydrobenzofuran-2- carboxamide diastereomer II, (14) N- [2, 3-bis (4-chlorophenyl)-1-methypropyl]-2-methyl-2, 3-dihydrobenzofuran-2- carboxamide, diastereomers I and R (1: 1), (15) N- [3- (4-chlorophenyl)-l-methy-2-phenylpropyl]-2-methyl-2, 3- dihydrobenzofuran-2-carboxamide diastereomer I, (16) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-2, 3- dihydrobenzofuran-2-carboxamide diastereomer II, (17) N- [3- (4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-2, 3- dihydrobenzofuran-2-carboxamide, diastereomers I and II (1: 1), (18) N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl]-2-methyl-1, 2,3, 4-tetrahydro-2- naphthamide diastereomer I, (19) N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl]-2-methyl-1, 2,3, 4-tetrahydro-2- naphthamide, diastereomer II, (20) N- [3- (4-chlorophenyl)-l-methy-2-phenylpropyl]-2-methyl-1, 2,3, 4-tetrahydro-2- naphthamide diastereomers I and II (1: 1), (21) N- [3- (4-chlorophenyl)-1-methy-2-phenylpropyl]-1, 2,3, 4-tetrahydro-2- naphthamide diastereomer I, (22) N [3- (4-chlorophenyl)-1-methy-2-phenylpropyl]-1, 2,3, 4-tetrahydro-2- naphthamide diastereomer II, (23) N- [3- (4-chlorophenyl)-1-methy-2-phenylpropyl]-1, 2,3, 4-tetrahydro-2- naphthamide diastereomers I and II (1: 1), (24) N-[2, 3-bis (4-chlorophenyl)-1-methylpropyl] chromane-2-carboxamide diastereomers I and II (1: 1), (25) N- [3- (4-chlorophenyl)-l-methy-2-phenylpropyl] chromane-2-carboxamide diastereomers I and II (1: 1), (26) N-[2, 3-bis (4-chlorophenyl)-1-methylpropyl]-2-methylchromane-2-carboxam ide diastereomer I, (27) N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl]-2-methylchromane-2-carboxam ide diastereomer II, (28) N-[2, 3-bis (4-chlorophenyl)-1-methylpropyl]-2-methylchromane-2-carboxam ide diastereomers I and II (1 : 1),

(29) N- [3- (4-chlorophenyl)-l-methy-2-phenylpropyl]-2-methylchromane-2- carboxamide diastereomer I, (30) N- [3- (4-chlorophenyl)-l-methy-2-phenylpropyl]-2-methylchromane-2- carboxamide diastereomer II, (31) N- [3- (4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methylchromane-2- carboxamide diastereomers I and II (1: 1), (32) N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl] chromane-3-carboxamide diastereomers I and II (1: 1), (33) N- [3- (4-chlorophenyl)-l-methy-2-phenylpropyl] chromane-3-carboxamide diastereomers I and II (1: 1), (34) N- [2, 3-bis(4-chlorophenyl)-1-methylpropyl]-3-methylchromane-3-car boxamide diastereomers I and II (1: 1), (35) N- [3- (4-chlorophenyl)-l-methy-2-phenylpropyl]-3-methylchromane-3- carboxamide diastereomers I and II (1: 1), (36) N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl]-2-methyl-2, 3-dihydro-1, 4- benzodioxane-2-carboxamide diastereomer I, (37) N-[2, 3-bis (4-chlorophenyl)-1-methylpropyl]-2-methyl-2, 3-dihydro-1,4- benzodioxane-2-carboxamide diastereomer II, (38) N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl]-2-methyl-2, 3-dihydro-1, 4- benzodioxane-2-carboxamide diastereomers I and H (1: 1), (39) N- [3- (4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-2, 3-dihydro-1, 4- benzodioxane-2-carboxamide diastereomer I, (40) N- [3- (4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-2, 3-dihydro-1, 4- benzodioxane-2-carboxamide diastereomer II, (41) N [3- (4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-2, 3-dihydro-1, 4- benzodioxane-2-carboxamide diastereomers I and II (1 : 1), (42) N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl]-2, 3-dihydro-1, 4-benzodioxane-2- carboxamide, diastereomer DI, (43) N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl]-2, 3-dihydro-1, 4-benzodioxane-2- carboxamide diastereomer IV, (44) N- [3- (4-chlorophenyl)-1-methy-2-phenylpropyl]-2, 3-dihydro-1, 4-benzodioxane- 2-carboxamide diastereomer I, (45) N- [3- (4-chlorophenyl)-l-methy-2-phenylpropyl]-2, 3-dihydro-1, 4-benzodioxane- 2-carboxamide diastereomer lI,

(46) N- [3- (4-chlorophenyl)-1-methy-2-phenylpropyl]-2, 3-dihydro-1, 4-benzodioxane- 2-carboxamide diastereomers I and II (1: 1), (47) N-[3- (4-chlorophenyl)-1-methy-3-pyridylpropyl]-2-methyl-2, 3-dihydro-1, 4- benzodioxane-2-carboxamide diastereomers I and II (3: 1), (48) N- [3- (4-chlorophenyl)-l-methy-3-pyridylpropyl]-2-methyl-2, 3-dihydro-l, 4- benzodioxane-2-carboxamide diastereomers I and II (1: 1), (49) N- [3- (4-chlorophenyl)-l-methy-3-pyridylpropyl]-2-methyl-2, 3-dihydro-l, 4- benzodioxane-2-carboxamide diastereomer II, (50) N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl]-6, 7,8, 9-tetrahydro-5H- benzo [a] [7] annulene-6-carboxamide diastereomerI, (51) N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl]-6, 7,8, 9-tetrahydro-5H- benzo [a] [7] annulene-6-carboxamide diastereomer II, (52) N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl]-6, 7,8, 9-tetrahydro-5H- benzo [a] [7] annulene-6-carboxamide diastereomers I and II (1: 1), (53) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-6, 7, 8, 9-tetrahydro-5H- benzo [a] [7] annulene-6-carboxamide diastereomer 1, (54) N- [3- (4-chlorophenyl)-1-methy-2-phenylpropyl]-6, 7, 8, 9-tetrahydro-5H- benzo [a] [7] annulene-6-carboxamide diastereomer II, (55) N-[3-(4-chlorophenyl)-1-methy-2-phenylpropyl]-6, 7,8, 9-tetrahydro-5H- benzo [a] [7] annulene-6-carboxamide diastereomers I and Il (1: 1), (56) N-[2, 3-bis (4-chlorophenyl)-1-methypropyl]-6, 7, 8, 9-tetrahydro-5H- benzo [a] [7] annulene-7-carboxamide diastereomers I and II (1: 1), (57) N- [3- (4-chlorophenyl)-l-methy-2-phenylpropyl]-6, 7,8, 9-tetrahydro-5H- benzo [a] [7] annulene-7-carboxamide diastereomers I and II (1 : 1), (58) N- [3- (4-chlorophenyl)-l-methy-2-phenylpropyl]-2-methyl-2, 3-dihydro-1, 4- benzodioxane-2-carboxamide diastereomer I enantiomer A, (59) N [3- (4-chlorophenyl)-1-methy-2-phenylpropyl]-2-methyl-2, 3-dihydro-1, 4- benzodioxane-2-carboxamide diastereomer I enantiomer B, (60) N- [3- (4-chlorophenyl)-l-methy-3-pyridylpropyl]-2-methyl-2, 3-dihydro-1, 4- benzodioxane-2-carboxamide diastereomer I, enantiomer A, (61) N- [3- (4-chlorophenyl)-1-methy-3-pyridylpropyl]-2-methyl-2, 3-dihydro-1, 4- benzodioxane-2-carboxamide diastereomer I, enantiomer B, (62) N- [3- (4-chlorophenyl)-2 (S)-phenyl-l (S)-methylpropyl]-3-methylchromane-3- carboxamide diastereomer I,

(63) N- [3- (4-chlorophenyl)-2 (S)-phenyl-l (S)-methylpropyl]-3-methylchromane-3- carboxamide diastereomer II, (64) N- [3- (4-chlorophenyl)-2 (S)-phenyl-1 (S) -methylpropyl] -2-methyl-2, 3-dihydro- 1, 4-benzodioxane-2-carboxamide diastereomer I, (65) N- [3- (4-chlorophenyl)-2 (S)-phenyl-l (S)-methylpropyl]-2-methyl-2, 3-dihydro- 1, 4-benzodioxane-2-carboxamide diastereomer II, (66) N- [3- (4-chlorophenyl)-2 (S)-phenyl-1 (S)-methylpropyl]-6-chloro-2-methyl-2, 3- dihydro-1, 4-benzodioxane-2-carboxamide diastereomer I, (67) N- [3- (4-chlorophenyl)-2 (S)-phenyl-l (S) -methylpropyl] -7-chloro-2-methyl-2, 3- dihydro-1, 4-benzodioxane-2-carboxamide diastereomer I, (68) N- [3- (4-chlorophenyl)-2 (S)-phenyl-1 (S)-methylpropyl]-6-chloro-2-methyl-2, 3- dihydro-1, 4-benzodioxane-2-carboxamide diastereomer 1I, (69) N- [3- (4-chlorophenyl)-2 (S)-phenyl-1 (S)-methylpropyl]-7-chloro-2-methyl-2, 3- dihydro-1, 4-benzodioxane-2-carboxamide diastereomer II, and pharmaceutically acceptable salts thereof.

"Alkyl", as well as. other groups having the prefix"alk", such as alkoxy, alkanoyl, means carbon chains which may be linear 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.

"Alkenyl"means carbon chains which contain at least one carbon- carbon double bond, and which may be linear or branched or combinations thereof.

Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1- propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.

"Alkynyl"means carbon chains which contain at least one carbon- carbon triple bond, and which may be linear or branched or combinations thereof.

Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.

"Cycloalkyl"means mono-or bicyclic or bridged saturated carbocyclic rings, each having from 3 to 10 carbon atoms. The term also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like.

"Aryl"means mono-or bicyclic aromatic rings containing only carbon atoms. The term also includes aryl group fused to a monocyclic cycloalkyl or monocyclic cycloheteroalkyl group in which the point of attachment is on the

aromatic portion. Examples of aryl include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1,4- benzodioxanyl, and the like. A preferred aryl substituent is phenyl.

"Heteroaryl"means a mono-or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 6 atoms. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, furo (2,3-b) pyridyl, quinolyl, indolyl, isoquinolyl, oxazolidinyl, and the like. The heteroaryl ring may be substituted on one or more carbon atoms. In one embodiment of the present invention, heteroaryl is pyridinyl, benzimidazolyl, imidazolyl, oxazolidinyl, triazolyl, and benzotriazolyl.

"Cycloheteroalkyl"means mono-or bicyclic or bridged saturated rings containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to i0 atoms in which the point of attachment may be carbon or nitrogen. The term also includes monocyclic heterocycle fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. Examples of "cycloheteroalkyl"include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyranyl, tetrahydrofuranyl, 2,3-dihydrofuro (2,3-b) pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, morpholinyl, dioxanyl, oxanyl, tetrahydroisoquinolinyl, dihydroindolyl, dihydroisoindolyl, and the like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2-or 4-pyridones attached through the nitrogen or N-substituted-(lH, 3H) -pyrimidine-2,4-diones (N-substituted uracils). The cycloheteroalkyl ring may be substituted on the ring carbons and/or the ring nitrogens. In one embodiment of the present invention, cycloheteroalkyl is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, dihydroisoindolyl, pyranyl, perhydroazepinyl, and tetrahydrofuranyl.

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

When any variable (e. g., R1, Rd, etc. ) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a Cl-5 alkylcarbonylamino C1-6 alkyl substituent is equivalent to

0 I I C1 5alW1-C-NH-C 6alWl- In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i. e. Rl, R2, etc. , are to be chosen in conformity with well-known principles of chemical structure connectivity and stability.

The term"substituted"shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.

Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

Tautomers are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.

Compounds of the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example MeOH or ethyl acetate or a mixture thereof. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means,

for example by the use of an optically active amine as a resolving agent or on a chiral HPLC column.

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

Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.

It is generally preferable to administer compounds of the present invention as enantiomerically pure formulations. Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.

The term"pharmaceutically acceptable salts"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 salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.

Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. The term"pharmaceutically acceptable salt"further includes all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate,

calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or pro-drug formulations.

It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.

Compounds of the present invention are modulators of the CB 1 receptor. In particular, the compounds of structural formula I are antagonists or inverse agonists of the CB1 receptor.

An"agonist"is a compound (hormone, neurotransmitter or synthetic compound) which binds to a receptor and mimics the effects of the endogenous regulatory compound, such as contraction, relaxation, secretion, change in enzyme activity, etc. An"antagonist"is a compound, devoid of intrinsic regulatory activity, which produces effects by interfering with the binding of the endogenous agonist or inhibiting the action of an agonist. An"inverse agonist"is a compound which acts on a receptor but produces the opposite effect produced by the agonist of the particular receptor.

Compounds of this invention are modulators of the CB 1 receptor and as such are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine. The compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith, including left ventricular hypertrophy. The compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction. The compounds are also

useful for the treatment of cirrhosis of the liver. The compounds are also useful for the treatment of asthma.

The terms"administration of"and or"administering a"compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.

The administration of the compound of structural formula I in order to practice the present methods of therapy is carried out by administering an effective amount of the compound of structural formula I to the patient in need of such treatment or prophylaxis. The need for a prophylactic administration according to the methods of the present invention is determined via the use of well known risk factors.

The effective amount of an individual compound is determined, in the final analysis, by the physician in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration other drugs and treatments which the patient may concomitantly require, and other factors in the physician's judgment.

The utilities of the present compounds in these diseases or disorders may be demonstrated in animal disease models that have been reported in the literature. The following are examples of such animal disease models: a) suppression of food intake and resultant weight loss in rats (Life Sciences 1998,63, 113-117); b) reduction of sweet food intake in marmosets (Behavioural Pharm. 1998,9, 179-181); c) reduction of sucrose and ethanol intake in mice (Psychopharm. 1997,132, 104- 106); d) increased motor activity and place conditioning in rats (Psychopharm. 1998, 135,324-332 ; Psychopharmacol 2000,151 : 25-30); e) spontaneous locomotor activity in mice (J. Pharm. Exp. Ther. 1996,277, 586-594); f) reduction in opiate self- administration in mice (Sci. 1999,283, 401-404); g) bronchial hyperresponsiveness in sheep and guinea pigs as models for the various phases of asthma (for example, see W. M. Abraham et al.,"ot4-Integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep. "J. Clin. Invest. 93,776 (1993) and A. A. Y. Milne and P. P. Piper, "Role of VLA-4 integrin in leucocyte recruitment and bronchial hyperresponsiveness in the gunea-pig."Eur. J. Pharmacol. , 282,243 (1995) ); h) mediation of the vasodilated state in advanced liver cirrhosis induced by carbon tetrachloride (Nature Medicine, 2001,7 (7), 827-832); i) amitriptyline-induced constipation in cynomolgus monkeys is beneficial for the evaluation of laxatives

(Biol. Pharm. Bulletin (Japan), 2000,23 (5), 657-9); j) neuropathology of paediatric chronic intestinal pseudo-obstruction and animal models related to the neuropathology of paediatric chronic intestinal pseudo-obstruction (Journal of Pathology (England), 2001,194 (3), 277-88).

The magnitude of prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula I and its route of administration.

It will also vary according to the age, weight and response of the individual patient.

In general, the daily dose range lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.

For use where a composition for intravenous administration is employed, a suitable dosage range is from about 0.001 mg to about 100 mg (preferably from 0. 01 mg to about 50 mg, more preferably 0.1 mg to 10 mg) of a compound of Formula I per kg of body weight per day.

In the case where an oral composition is employed, a suitable dosage range is, e. g. from about 0.01 mg to about 1000 mg of a compound of Formula I per day, preferably from about 0.1 mg to about 10 mg per day. For oral administration, the compositions are preferably provided in the form of tablets containing from 0.01 to 1,000 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 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.

For the treatment of diseases of the eye, ophthalmic preparations for ocular administration comprising 0.001-1% by weight solutions or suspensions of the compounds of Formula I in an acceptable ophthalmic formulation may be used.

Another aspect of the present invention provides pharmaceutical compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier. The term"composition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient (s), and the inert ingredient (s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical

compositions of the present invention encompass any composition made by admixing a compound of Formula I, additional active ingredient (s), and pharmaceutically acceptable excipients.

Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.

The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. By"pharmaceutically acceptable"it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In particular, the term "pharmaceutically acceptable salts"refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.

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

For administration by inhalation, the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulizers. The compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device. The 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 suitable propellants, such as fluorocarbons or hydrocarbons and dry powder inhalation (DPI) aerosol, which may be formulated as a dry powder of a compound of Formula I with or without additional excipients.

Suitable topical formulations of a compound of formula I include transdermal devices, aerosols, creams, solutions, ointments, gels, lotions, dusting powders, and the like. The topical pharmaceutical compositions containing the compounds of the present invention ordinarily include about 0.005% to 5% by weight of the active compound in admixture with a pharmaceutically acceptable vehicle.

Transdermal skin patches useful for administering the compounds of the present invention include those well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course be continuous rather than intermittent throughout the dosage regimen.

In practical use, the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e. g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compounds of Formula I may also be administered by controlled release means and/or delivery devices such as those described in U. S. Patent Nos. 3,845, 770; 3,916, 899; 3,536, 809; 3,598, 123; 3,630, 200 and 4,008, 719.

Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules (including timed release and sustained release formulations), pills, cachets, powders, granules or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid,

an oil-in-water emulsion or a water-in-oil liquid emulsion, including elixirs, tinctures, solutions, 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 admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. 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 such as powder or granules, 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. Desirably, each tablet contains from 0.01 to 1,000 mg, particularly 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 1,000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. and each cachet or capsule contains from about 0.01 to 1,000 mg, particularly 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 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.

Additional suitable means of administration of the compounds of the present invention include injection, intravenous bolus or infusion, intraperitoneal, subcutaneous, intramuscular and topical, with or without occlusion.

Exemplifying the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Also exemplifying the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. An illustration of the invention is a process for making a pharmaceutical composition comprising combining 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 dosage may be administered in divided doses of two, three or four times daily.

Furthermore, based on the properties of the individual compound selected for

administration, the dose may be administered less frequently, e. g., weeldy, twice weekly, monthly, etc. The unit dosage will, of course, be correspondingly larger for the less frequent administration.

When administered via intranasal routes, transdermal routes, by rectal or vaginal suppositories, or through a continual intravenous solution, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

The following are examples of representative pharmaceutical dosage forms for the 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 Water for injection to a total volume of 1 mL Tablet mg/tablet Compound of Formula I 25 Microcrystalline Cellulose 415 Povidone 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 canister Compound of Formula I 24 mg Lecithin, NF Liq. Cone. 1.2 mg Trichlorofluoromethane, NF 4.025 g Dichlorodifluoromethane, NF 12.15 g

Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of Formula I is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula I. Examples of other active ingredients that may be combined with a compound of Formula I include, but are not limited to: antipsychotic agents, cognition enhancing agents, anti-migraine agents, anti-asthmatic agents, antiinflammatory agents, anxiolytics, anti-Parkinson's agents, anti-epileptics, anorectic agents, serotonin reuptake inhibitors, and other anti-obesity agents, which may be administered separately or in the same pharmaceutical compositions.

The present invention also provides a method for the treatment or prevention of a CB1 receptor modulator mediated disease, which method comprises administration to a patient in need of such treatment or at risk of developing a CB 1 receptor modulator mediated disease of an amount of a CB 1 receptor modulator and an amount of one or more active ingredients, such that together they give effective relief.

In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a CB 1 receptor modulator and one or more active ingredients, together with at least one pharmaceutically acceptable carrier or excipient.

Thus, according to a further aspect of the present invention there is provided the use of a CB1 receptor modulator and one or more active ingredients for the manufacture of a medicament for the treatment or prevention of a CB 1 receptor modulator mediated disease. In a further or alternative aspect of the present invention, there is therefore provided a product comprising a CB1 receptor modulator and one or more active ingredients as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of CB 1 receptor modulator mediated disease. Such a combined preparation may be, for example, in the form of a twin pack.

It will be appreciated that for the treatment or prevention of eating disorders, including obesity, bulimia nervosa and compulsive eating disorders, a compound of the present invention may be used in conjunction with other anorectic agents.

The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anorectic agent, such that together they give effective relief.

Suitable anoretic agents of use in combination with a compound of the present invention include, but are not limited to, aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof.

A particularly suitable class of anorectic agent are the halogenated amphetamine derivatives, including chlorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof Particularly preferred halogenated amphetamine derivatives of use in combination with a compound of the present invention include: fenfluramine and dexfenfluramine, and pharmaceutically acceptable salts thereof.

It will be appreciated that for the treatment or prevention of obesity, the compounds of the present invention may also be used in combination with a selective serotonin reuptake inhibitor (SSRI).

The present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an SSRI, such that together they give effective relief.

Suitable selective serotonin reuptake inhibitors of use in combination with a compound of the present invention include: fluoxetine, fluvoxamine, paroxetine, imipramine and sertraline, and pharmaceutically acceptable salts thereof.

It will be appreciated that for the treatment or prevention of obesity, the compounds of the present invention may also be used in combination with an opioid antagonist.

The present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an opioid antagonist, such that together they give effective relief.

Suitable opioid antagonists of use in combination with a compound of the present invention include: naltrexone, 3-methoxynaltrexone, naloxone and nalmefene, and pharmaceutically acceptable salts thereof.

It will be appreciated that for the treatment or prevention of obesity, the compounds of the present invention may also be used in combination with another anti-obesity agent.

The present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of another anti-obesity agent, such that together they give effective relief.

Suitable anti-obesity agents of use in combination with a compound of the present invention, include, but are not limited to: 1) growth hormone secretagogues, such as those disclosed and specifically described in U. S. Patent 5,536, 716; 2) growth hormone secretagogue receptor agonists/antagonists, such as NN703, hexarelin, MK-0677, SM-130686, CP-424, 391, L-692, 429 and L-163, 255, and such as those disclosed in U. S. Patent No. 6,358, 951, U. S. Patent Application Nos. 2002/049196 and 2002/022637, and PCT Application Nos. WO 01/56592 and WO 02/32888 ; 3) melanocortin agonists, such as Melanotan II or those described in WO 99/64002 and WO 00/74679; 4) Mc4r (melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron), ME-10142, and ME-10145 (Melacure), and those disclosed in PCT Application Nos. WO 01/991752, WO 01/74844, WO 02/12166, WO 02/11715, and WO 02/12178 ; 5) ß-3 agonists, such as AD9677/TAK677 (Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A, and such as those

disclosed in U. S. Patent Application Nos. 5,705, 515, and US 5,451, 677 and PCT Patent Publications W094/18161, W095/29159, W097/46556, W098/04526 and W098/32753, WO 01/74782, and WO 02/32897; 6) 5HT-2 agonists; 7) 5HT2C (serotonin receptor 2C) agonists, such as BVT933, DPCA37215, WAY161503, R- 1065, and those disclosed in U. S. Patent No. 3,914, 250, and PCT Application Nos.

WO 02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO 02/51844, WO 02/40456, and WO 02/40457; 8) orexin antagonists, such as SB- 334867-A, and those disclosed in PCT Patent Application Nos. WO 01/96302, WO 01/68609, WO 02/51232, WO 02/51838 and WO 02/090355; 9) melanin concentrating hormone antagonists; 10) melanin-concentrating hormone 1 receptor (MCH1R) antagonists, such as T-226296 (Takeda), and those disclosed in PCT Patent Application Nos. WO 01/82925, WO 01/87834, WO 02/06245, WO 02/04433, WO 02/51809 and WO 02/083134, and Japanese Patent Application No. JP 13226269; 11) melanin-concentrating hormone 2 receptor (MCH2R) agonist/antagonists; 12) galanin antagonists; 13) CCK agonists; 14) CCK-A (cholecystokinin-A) agonists, such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623 and SR146131, and those discribed in U. S. Patent No. 5,739, 106; 15) GLP-1 agonists; 16) corticotropin- releasing hormone agonists; 17) NPY 5 antagonists, such as GW-569180A, GW- 594884A, GW-587081X, GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR- 120819A and JCF-104, and those disclosed in U. S. Patent Nos. 6,140, 354,6, 191,160, 6,313, 298,6, 337,332, 6,329, 395,6, 326,375, 6,335, 345, and 6,340, 683, European Patent Nos. EP-01010691, and EP-01044970, and PCT Patent Publication Nos. WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/27063, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648; 18) NPY 1 antagonists, such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI- 264879A, and those disclosed in U. S. Patent No. 6,001, 836, and PCT Patent Publication Nos. WO 96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528 ; 19) histamine receptor-3 (H3) modulators; 20) histamine receptor-3 (H3) antagonists/inverse agonists, such as hioperamide, 3- (lH-imidazol-4-yl) propyl N- (4-pentenyl) carbamate, clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), and those described and disclosed

in PCT Application No. WO 02/15905, and 0- [3- (lH-imidazol-4-yl) propanol]- carbamates (Kiec-Kononowicz, K. et al., Pharmazie, 55: 349-55 (2000) ), piperidine- containing histamine H3-receptor antagonists (Lazewska, D. et al., Pharmazie, 56: 927-32 (2001), benzophenone derivatives and related compounds (Sasse, A. et al., Arch. Pharm. (Weinheim) 334: 45-52 (2001) ), substituted N-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55: 83-6 (2000) ), and proxifan derivatives (Sasse, A. et al. , J. Med. Chem.. 43: 3335-43 (2000) ) ; 21) (3-hydroxy steroid dehydrogenase-1 inhibitors (ß-HSD-l) ; 22) PDE (phosphodiesterase) inhibitors, such as theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram, and cilomilast ; 23) phosphodiesterase-3B (PDE3B) inhibitors; 24) NE (norepinephrine) transport inhibitors, such as GW 320659, despiramine, talsupram, and nomifensine; 25) non-selective serotonin/norepinephrine transport inhibitors, such as sibutramine or fenfluramine ; 26) ghrelin antagonists, such as those disclosed in PCT Application Nos. WO 01/87335, and WO 02/08250 ; 27) leptin, including recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen); 28) leptin derivatives, such as those disclosed in U. S. Patent Nos.

5,552, 524,5, 552,523, 5,552, 522,5, 521,283, and PCT International Publication Nos.

WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, WO 96/23517, WO 96/23518, WO 96/23519, and WO 96/23520; 29) BRS3 (bombesin receptor subtype 3) agonists; 30) CNTF (Ciliary neurotrophic factors), such as GI-181771 (Glaxo- SmithKline), SR146131 (Sanofi Synthelabo), butabindide, PD170, 292, and PD 149164 (Pfizer); 31) CNTF derivatives, such as axokine (Regeneron), and those disclosed in PCT Application Nos. WO 94/09134, WO 98/22128, and WO 99/43813; 32) monoamine reuptake inhibitors, such as those disclosed in PCT Application Nos.

WO 01/27068, and WO 01/62341 ; 33) UCP-1 (uncoupling protein-1), 2, or 3 activators, such as phytanic acid, 4- [ (E)-2- (5, 6,7, 8-tetrahydro-5,5, 8,8-tetramethyl-2- napthalenyl)-l-propenyl] benzoic acid (TTNPB), retinoic acid, and those disclosed in PCT Patent Application No. WO 99/00123 ; 34) thyroid hormone (3 agonists, such as KB-2611 (KaroBioBMS), and those disclosed in PCT Application No. WO 02/15845, and Japanese Patent Application No. JP 2000256190; 35) FAS (fatty acid synthase) inhibitors, such as Cerulenin and C75; 36) DGAT1 (diacylglycerol acyltransferase 1) inhibitors; 37) DGAT2 (diacylglycerol acyltransferase 2) inhibitors; 38) ACC2 (acetyl-CoA carboxylase-2) inhibitors; 39) glucocorticoid antagonists; 40) acyl- estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa, M. et al. , Obesity Research, 9: 202-9 (2001); 41) lipase inhibitors, such as orlistat (Xenical0), Triton

WR1339, RHC80267, lipstatin, tetrahydrolipstatin, teasaponin, diethylumbelliferyl phosphate, and those disclosed in PCT Application No. WO 01/77094; 42) fatty acid transporter inhibitors; 43) dicarboxylate transporter inhibitors; 44) glucose transporter inhibitors; 45) phosphate transporter inhibitors; 46) serotonin reuptake inhibitors, such as those disclosed in U. S. Patent Application No. 6,365, 633, and PCT Patent Application Nos. WO 01/27060, and WO 01/162341 ; 47) Metformin (Glucophage (X3) ; and/or 48) Topiramate (Topimax (E)).

Specific NPY5 antagonists of use in combination with a compound of the present invention are selected from the group consisting of: (1) 3-oxo-N- (5-phenyl-2-pyrazinyl)-spiro [isobenzofuran-1 (3H), 4'-piperidine]-l'- carboxamide, (2) 3-oxo-N- (7-trifluoromethylpyrido [3,2-b] pyridin-2-yl) spiro-[isobenzofuran- 1 (3H), 4'-piperidine]-1'-carboxamide, (3) N- [5- (3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro- [isobenzofuran-1 (3H), 4'- piperidine]-1'-carboxamide, (4) trans-3'-oxo-N- (5-phenyl-2-pyrimidinyl) spiro [cyclohexane-1, 1' (3'H) - isobenzofuran]-4-carboxamide, (5) trans-3'-oxo-N-[1-(3-quinolyl)-4-imidazolyl] spiro [cyclohexane-1, 1' (3'H) - isobenzofuran]-4-carboxamide, (6) trans-3-oxo-N- (5-phenyl-2-pyrazinyl) spiro [4-azaiso-benzofuran- 1 (3H), 1'- cyclohexane]-4'-carboxamide, (7) trans-N- [5- (3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro [5-azaisobenzofuran- 1 (3H), 1'-cyclohexane]-4'-carboxamide, (8) trans-N- [5- (2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro [5-azaisobenzofuran- 1 (3H), 1'-cyclohexane]-4'-carboxamide, (9) trans-N- [1- (3, 5-difluorophenyl) -4-imidazolyl] -3-oxospiro [7-azaisobenzofuran- 1 (3H), 1'-cyclohexane]-4'-carboxamide, (10) trans-3-oxo-N- (l-phenyl-4-pyrazolyl) spiro [4-azaisobenzofuran-1 (3H), 1'- cyclohexane]-4'-carboxamide, (11) trans-N- [1- (2-fluorophenyl)-3-pyrazolyl]-3-oxospiro [6-azaisobenzofuran- 1 (3H), 1'-cyclohexane]-4'-carboxamide, (12) trans-3-oxo-N-(l-phenyl-3-pyrazolyl) spiro [6-azaisobenzofuran-1 (3H), l'- cyclohexane]-4'-carboxamide, (13) trans-3-oxo-N- (2-phenyl-1, 2,3-triazol-4-yl) spiro [6-azaisobenzofuran- 1 (3H), 1'-cyclohexane]-4'-carboxamide,

and pharmaceutically acceptable salts and esters thereof.

It will be appreciated that for the treatment or prevention of obesity, the compounds of the present invention may also be used in combination with are inhibitors of the enzyme 11 ß-HSDl. Generally, glucocorticoid concentrations are modulated by tissue-specific 1113-hydroxysteroid dehydrogenase enzymes. The 1113-hydroxysteroid dehydrogenase type 1 enzyme (11 ß-HSDl) is a low affinity enzyme that generally uses NADP+ as a cofactor rather than NAD+ (Agarwal et al., 1989). In vitro studies have shown that 11 [3-HSD1 is capable of acting as both a reductase and a dehydrogenase. However, llß-HSDl in vivo generally acts as a reductase, converting 11-ketoglucocorticoids, such as cortisone, to 11 ß-hydroxyglucocorticoids such as cortisol.

Excessive levels of cortisol have been associated with obesity, perhaps due to increased hepatic gluconeogenesis. Thus, the administration of an effective amount of an llß-HSDl inhibitor in combination with a CB1 antagonist of the present invention may be useful in the treatment or control of obesity. Particular inhibitors of 11 ß-HSDl useful in combination with the compounds of the present invention include: 3-(1-adamantyl)-4-ethyl-5-(ethylthio)-4H-1, 2,4-triazole, 3- (1- adamantyl)-5- (3, 4, 5-trimethoxyphenyl)-4-methyl-4H-1, 2,4-triazole, and 3- adamantanyl-4,5, 6,7, 8,9, 10, 11, 12, 3a-decahydro-1, 2,4-triazolo [4, 3-a] [I 1] annulene.

"Obesity"is a condition in which there is an excess of body fat. The operational definition of obesity is based on the Body Mass Index (BMI), which is calculated as body weight per height in meters squared (kg/m2)."Obesity"refers to a condition whereby an otherwise healthy subject has a Body Mass Index (BMI) greater than or equal to 30 kg/m2, or a condition whereby a subject with at least one co- morbidity has a BMI greater than or equal to 27 kg/m2. An"obese subject"is an otherwise healthy subject with a Body Mass Index (BMI) greater than or equal to 30 kg/m2 or a subject with at least one co-morbidity with a BMI greater than or equal to 27 kg/m2. A"subject at risk for obesity"is an otherwise healthy subject with a BMI of 25 kg/m2 to less than 30 kg/m2 or a subject with at least one co-morbidity with a BMI of 25 kg/m2 to less than 27 kg/m2.

The increased risks associated with obesity occur at a lower Body Mass Index (BMI) in Asians. In Asian countries, including Japan, "obesity"refers to a condition whereby a subject with at least one obesity-induced or obesity-related co- morbidity that requires weight reduction or that would be improved by weight reduction, has a BMI greater than or equal to 25 kg/m2. In Asian countries, including

Japan, an"obese subject"refers to a subject with at least one obesity-induced or obesity-related co-morbidity that requires weight reduction or that would be improved by weight reduction, with a BMI greater than or equal to 25 kg/m2. In Asian countries, a"subject at risk of obesity"is a subject with a BMI of greater than 23 kg/m2 to less than 25 kg/m2.

As used herein, the term"obesity"is meant to encompass all of the above definitions of obesity.

Obesity-induced or obesity-related co-morbidities include, but are not limited to, diabetes, non-insulin dependent diabetes mellitus-type 2, impaired glucose tolerance, impaired fasting glucose, insulin resistance syndrome, dyslipidemia, hypertension, hyperuricacidemia, gout, coronary artery disease, myocardial infarction, angina pectoris, sleep apnea syndrome, Pickwickian syndrome, fatty liver; cerebral infarction, cerebral thrombosis, transient ischemic attack, orthopedic disorders, arthritis deformans, lumbodynia, emmeniopathy, and infertility.

In particular, co-morbidities include: hypertension, hyperlipidemia, dyslipidemia, glucose intolerance, cardiovascular disease, sleep apnea, diabetes mellitus, and other obesity-related conditions.

"Treatment" (of obesity and obesity-related disorders) refers to the administration of the compounds of the present invention to reduce or maintain the body weight of an obese subject. One outcome of treatment may be reducing the body weight of an obese subject relative to that subject's body weight immediately before the administration of the compounds of the present invention. Another outcome of treatment may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of treatment may be decreasing the occurrence of and/or the severity of obesity-related diseases. The treatment may suitably result in a reduction in food or calorie intake by the subject, including a reduction in total food intake, or a reduction of intake of specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient absorption; and/or the inhibition of the reduction of metabolic rate; and in weight reduction in patients in need thereof. The treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss.

"Prevention" (of obesity and obesity-related disorders) refers to the administration of the compounds of the present invention to reduce or maintain the

body weight of a subject at risk of obesity. One outcome of prevention may be reducing the body weight of a subject at risk of obesity relative to that subject's body weight immediately before the administration of the compounds of the present invention. Another outcome of prevention may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of prevention may be preventing obesity from occurring if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Another outcome of prevention may be decreasing the occurrence and/or severity of obesity- related disorders if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Moreover, if treatment is commenced in already obese subjects, such treatment may prevent the occurrence, progression or severity of obesity-related disorders, such as, but not limited to, arteriosclerosis, Type II diabetes, polycystic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.

The obesity-related disorders herein are associated with, caused by, or result from obesity. Examples of obesity-related disorders include overeating and bulimia, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e. g, children with acute lymphoblastic leukemia. Further examples of obesity-related disorders are metabolic syndrome, also known as syndrome X, insulin resistance syndrome, sexual and reproductive dysfunction, such as infertility, hypogonadism in males and hirsutism in females, gastrointestinal motility disorders, such as obesity-related gastro-esophageal reflux, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, and kidney cancer. The compounds of the present

invention are also useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy.

The term"diabetes, "as used herein, includes both insulin- dependent diabetes mellitus (i. e., IDDM, also known as type I diabetes) and non- insulin-dependent diabetes mellitus (i. e., NIDDM, also known as Type II diabetes.

Type I diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization. Type II diabetes, or insulin-independent diabetes (i. e. , non-insulin-dependent diabetes mellitus), often occurs in the face of normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most of the Type Il diabetics are also obese. The compounds of the present invention are useful for treating both Type I and Type II diabetes. The compounds are especially effective for treating Type I1 diabetes. The compounds of the present invention are also useful for treating and/or preventing gestational diabetes mellitus.

It will be appreciated that for the treatment or prevention of migraine, a compound of the present invention may be used in conjunction with other anti- migraine agents, such as ergotamines or 5-HT1 agonists, especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.

It will be appreciated that for the treatment of depression or anxiety, a compound of the present invention may be used in conjunction with other anti- depressant or anti-anxiety agents.

Suitable classes of anti-depressant agents include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, oc-adrenoreceptor antagonists, neurokinin-1 receptor antagonists and atypical anti-depressants.

Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Suitable examples of tertiary amine tricyclics include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine, and pharmaceutically acceptable salts thereof. Suitable examples of secondary amine tricyclics include: amoxapine, desipramine, maprotiline, nortriptyline and protriptyline, and pharmaceutically acceptable salts thereof.

Suitable selective serotonin reuptake inhibitors include: fluoxetine, fluvoxamine, paroxetine, imipramine and sertraline, and pharmaceutically acceptable salts thereof.

Suitable monoamine oxidase inhibitors include: isocarboxazid, phenelzine, tranylcypromine and selegiline, and pharmaceutically acceptable salts thereof.

Suitable reversible inhibitors of monoamine oxidase include: moclobemide, and pharmaceutically acceptable salts thereof.

Suitable serotonin and noradrenaline reuptake inhibitors of use in the present invention include: venlafaxine, and pharmaceutically acceptable salts thereof.

Suitable CRF antagonists include those compounds described in International Patent Specification Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677.

Suitable neurokinin-1 receptor antagonists may be peptidal or non- peptidal in nature, however, the use of a non-peptidal neurolcinin-l receptor antagonist is preferred. In a preferred embodiment, the neurokinin-1 receptor antagonist is a CNS-penetrant neurokinin-1 receptor antagonist. In addition, for convenience the use of an orally active neurokinin-1 receptor antagonist is preferred. To facilitate dosing, it is also preferred that the neurokinin-1 receptor antagonist is a long acting neurokinin-1 receptor antagonist. An especially preferred class of neurokinin-1 receptor antagonists of use in the present invention are those compounds which are orally active and long acting.

Neurokinin-1 receptor antagonists of use in the present invention are fully described, for example, in U. S. Patent Nos. 5,162, 339,5, 232,929, 5,242, 930, 5,373, 003,5, 387,595, 5,459, 270,5, 494,926, 5,496, 833,5, 637,699 ; European Patent Publication Nos. EP 0 360 390,0 394 989,0 428 434,0 429 366,0 430 771,0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0 512 902, 0 514 273, 0 514274, 0514275, 0514276, 0515681, 0517589, 0520555, 0522808, 0528 495,0 532 456,0 533 280,0 536 817,0 545 478,0 558 156,0 577 394,0 585 913,0 590 152,0 599 538, 0 610 793,0 634 402,0 686 629,0 693 489,0 694 535,0 699 655,0 699 674,0 707 006,0 708 101,0 709 375,0 709 376,0 714 891,0 723 959,0 733 632 and 0 776 893; PCT International Patent Publication Nos. WO 90/05525, 90/05729,91/09844, 91/18899,92/01688, 92/06079, 92/12151,92/15585, 92/17449, 92/20661,92/20676, 92/21677,92/22569, 93/00330,93/00331, 93/01159,93/01165,

93/01169,93/01170, 93/06099,93/09116, 93/10073, 93/14084,93/14113, 93/18023, 93/19064,93/21155, 93/21181,93/23380, 93/24465,94/00440, 94/01402,94/02461, 94/02595,94/03429, 94/03445,94/04494, 94/04496,94/05625, 94/07843,94/08997, 94/10165,94/10167, 94/10168, 94/10170,94/11368, 94/13639,94/13663, 94/14767, 94/15903,94/19320, 94/19323, 94/20500,94/26735, 94/26740,94/29309, 95/02595, 95/04040,95/04042, 95/06645,95/07886, 95/07908,95/08549, 95/11880, 95/14017, 95/15311,95/16679, 95/17382,95/18124, 95/18129, 95/19344, 95/20575,95/21819, 95/22525,95/23798, 95/26338,95/28418, 95/30674, 95/30687, 95/33744,96/05181, 96/05193,96/05203, 96/06094,96/07649, 96/10562,96/16939, 96/18643,96/20197, 96/21661,96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066,97/08144, 97/14671, 97/17362, 97/18206,97/19084, 97/19942,97/21702, 97/49710, 98/24438-98/24441, 98/24442-98/24445, 02/16343, and 02/16344; and in British Patent Publication Nos. 2 266 529,2 268 931,2 269 170,2 269 590,2 271 774, 2 292 144,2 293 168, 2 293 169, and 2 302 689.

Specific neurokinin-1 receptor antagonists of use in the present invention include: (1) ()- (2R3R, 2S3S)-N-1 [2-cyclopropoxy-5- (trifluoromethoxy)-phenyl] methyll- 2-phenylpiperidin-3-amine; (2) 2- (S)- (3, 5-bis (trifluoromethyl) benzyloxy)-3 (S)- (4-fluorophenyl)-4- (3- (5-oxo- 1H, 4H-1, 2, 4-triazolo) methyl) morpholine; (3) 2- (R)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-4- (3- (5-oxo-lH, 4H- 1, 2,4-triazolo) methyl)-3- (S)-phenyl-morpholine ; (4) 2- (S)- (3, 5-bis (trifluoromethyl) benzyloxy)-4- (3- (5-oxo-lH, 4H-1, 2,4- triazolo) methyl)-3- (S)-phenyl-morpholine ; (5) 2- (R)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-3- (S)- (4-fluorophenyl)- 4- (3- (5-oxo-lH, 4H-1, 2,4-triazolo) methyl) morpholine; (6) 2- (R)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-4- (5- (N, N- dimethylamino) methyl-l, 2,3-triazol-4-yl) methyl-3- (S)-phenylmorpholine ; (7) 2- (R)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-4- (5- (N, N- dimethylamino) methyl-1, 2,3-triazol-4-yl) methyl-3- (S)- (4- fluorophenyl) morpholine; (8) (3S, 5R, 6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy) phenyl]-6-phenyl-1-oxa-7- aza-spiro [4.5] decane; (9) (3R, 5R, 6S)-3- [2-cyclopropoxy-5- (trifluoromethoxy) phenyl]-6-phenyl-l-oxa- 7-aza-spiro [4.5] decane;

(10) 2- (R)- (l- (S)- (3, 5-bis (trifluoromethyl) phenyl)-2-hydroxyethoxy)-3- (S)- (4- fluorophenyl)-4- (1, 2,4-triazol-3-yl) methylmorpholine ; (11) 2- (R)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-3- (S)- (4-fluorophenyl)- 4- (3- (4-monophosphoryl-5-oxo-1H-1, 2,4-triazolo) methyl) morpholine; (12) 2- (R)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-3- (S)- (4-fluorophenyl)- 4-(3-(1-monophosphoryl-5-oxo-lH-1, 2,4-triazolo) methyl) morpholine; (13) 2- (R)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-3- (S)- (4-fluorophenyl)- 4- (3- (2-monophosphoryl-5-oxo-1H-1, 2,4-triazolo) methyl) morpholine; (14) 2- (R)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-3- (S)- (4-fluorophenyl)- 4-(3-(5-oxyphosphoryl-lH-1, 2,4-triazolo) methyl) morpholine; (15) 2- (S)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-3- (S)- (4-fluorophenyl)-4- (3- (1-monophosphoryl-5-oxo-4H-1, 2,4-triazolo) methyl) morpholine; (16) 2- (R)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-4- (4-N, N- dimethylaminobut-2-yn-yl)-3- (S)- (4-fluorophenyl) morpholine; or a pharmaceutically acceptable salt thereof.

Suitable atypical anti-depressants include: bupropion, lithium, nefazodone, trazodone and viloxazine, and pharmaceutically acceptable salts thereof.

Suitable classes of anti-anxiety agents include benzodiazepines and 5-HT1A agonists or antagonists, especially 5-HTlA partial agonists, and corticotropin releasing factor (CRF) antagonists.

Suitable benzodiazepines include: alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam, and pharmaceutically acceptable salts thereof.

Suitable 5-HT1A receptor agonists or antagonists include, in particular, the 5-HT1A receptor partial agonists buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.

Suitable corticotropin releasing factor (CRF) antagonists include those previously discussed herein.

As used herein, the term"substance abuse disorders"includes substance dependence or abuse with or without physiological dependence. The substances associated with these disorders are: alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, marijuana, nicotine, opioids, phencyclidine (or phencyclidine-like compounds),

sedative-hypnotics or benzodiazepines, and other (or unknown) substances and combinations of all of the above.

In particular, the term"substance abuse disorders"includes drug withdrawal disorders such as alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances. It will be appreciated that reference to treatment of nicotine withdrawal includes the treatment of symptoms associated with smoking cessation.

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

It will be appreciated that a combination of a conventional antipsychotic drug with a CB 1 receptor modulator may provide an enhanced effect in the treatment of mania. Such a combination would be expected to provide for a rapid onset of action to treat a manic episode thereby enabling prescription on an"as needed basis". Furthermore, such a combination may enable a lower dose of the antispychotic agent to be used without compromising the efficacy of the antipsychotic agent, thereby minimizing the risk of adverse side-effects. A yet further advantage of such a combination is that, due to the action of the CB 1 receptor modulator, adverse side-effects caused by the antipsychotic agent such as acute dystonias, dyskinesias, akathesia and tremor may be reduced or prevented.

Thus, according to a further aspect of the present invention there is provided the use of a CB 1 receptor modulator and an antipsychotic agent for the manufacture of a medicament for the treatment or prevention of mania.

The present invention also provides a method for the treatment or prevention of mania, which method comprises administration to a patient in need of such treatment or at risk of developing mania of an amount of a CB 1 receptor modulator and an amount of an antipsychotic agent, such that together they give effective relief.

In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a CB1 receptor modulator and an

antipsychotic agent, together with at least one pharmaceutically acceptable carrier or excipient.

It will be appreciated that the CB 1 receptor modulator and the antipsychotic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of mania. Such combined preparations may be, for example, in the form of a twin pack.

In a further or alternative aspect of the present invention, there is therefore provided a product comprising a CB 1 receptor modulator and an antipsychotic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of mania.

It will be appreciated that when using a combination of the present invention, the CB1 receptor modulator and the antipsychotic agent may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously. The term"combination"also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, the antipsychotic agent may be administered as a tablet and then, within a reasonable period of time, the CB 1 receptor modulator may be administered either as an oral dosage form such as a tablet or a fast- dissolving oral dosage form. By a"fast-dissolving oral formulation"is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about 10 seconds.

Included within the scope of the present invention is the use of CB 1 receptor modulators in combination with an antipsychotic agent in the treatment or prevention of hypomania.

It will be appreciated that a combination of a conventional antipsychotic drug with a CB 1 receptor modulator may provide an enhanced effect in the treatment of schizophrenic disorders. Such a combination would be expected to provide for a rapid onset of action to treat schizophrenic symptoms thereby enabling prescription on an"as needed basis". Furthermore, such a combination may enable a lower dose of the CNS agent to be used without compromising the efficacy of the antipsychotic agent, thereby minimizing the risk of adverse side-effects. A yet further advantage of such a combination is that, due to the action of the CB 1 receptor

modulator, adverse side-effects caused by the antipsychotic agent such as acute dystonias, dysldnesias, akathesia and tremor may be reduced or prevented.

As used herein, the term"schizophrenic disorders"includes paranoid, disorganized, catatonic, undifferentiated and residual schizophrenia; schizophreniform disorder; schizoaffective disorder; delusional disorder; brief psychotic disorder; shared psychotic disorder; substance-induced psychotic disorder; and psychotic disorder not otherwise specified.

Other conditions commonly associated with schizophrenic disorders include self-injurious behavior (e. g. Lesch-Nyhan syndrome) and suicidal gestures.

Suitable antipsychotic agents of use in combination with a CB 1 receptor modulator include the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of antipsychotic agent. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. Suitable examples of dibenzazepines include clozapine and olanzapine.

An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone.

Other antipsychotic agents include loxapine, sulpiride and risperidone. It will be appreciated that the antipsychotic agents when used in combination with a CB 1 receptor modulator may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, olanzapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.

Other classes of antipsychotic agent of use in combination with a CB 1 receptor modulator include dopamine receptor antagonists, especially D2, D3 and D4 dopamine receptor antagonists, and muscarinic ml receptor agonists. An example of a D3 dopamine receptor antagonist is the compound PNU-99194A. An example of a D4 dopamine receptor antagonist is PNU-101387. An example of a muscarinic ml receptor agonist is xanomeline.

Another class of antipsychotic agent of use in combination with a CB 1 receptor modulator is the 5-HT2A receptor antagonists, examples of which include MDL100907 and fananserin. Also of use in combination with a CB1 receptor modulator are the serotonin dopamine antagonists (SDAs) which are believed to combine 5-HT2A and dopamine receptor antagonist activity, examples of which include olanzapine and ziperasidone.

Still further, NK-1 receptor antagonists may be favorably employed with the CB 1 receptor modulators of the present invention. Preferred NK-1 receptor antagonists for use in the present invention are selected from the classes of compounds described in European Patent Specification No. 0 577 394, and International Patent Specification Nos. 95/08549,95/18124, 95/23798, 96/05181, and 98/49710 (Application No. PCT/GB97/01630). The preparation of such compounds is fully described in the aforementioned publications.

Particularly preferred NK-1 receptor antagonists of use in the present invention include: (3S, 5R, 6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy) phenyl]-6- phenyl-1-oxa-7-aza-spiro [4.5] decane; (3R, 5R, 6S)-3- [2-cyclopropoxy-5- (trifluoromethoxy) phenyl]-6-phenyl-l-oxa-7-aza- spiro [4.5] decane; (+)-(2R3R, 2S3S)-N-{ [2-cyclopropoxy-5-(trifluoromethoxy) phenyl] methyl}-2-phenylp iperidin-3-amine; 2- (S)- (3, 5-bis (trifluoromethyl) benzyloxy)-3 (S)- (4-fluorophenyl)-4- (3- (5-oxo-lH, 4H- 1,2, 4-triazolo) methyl) morpholine; 2- (R)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-4- (3- (5-oxo-lH, 4H-1, 2,4- triazolo) methyl)-3- (S)-phenyl-morpholine ; 2- (S)- (3, 5-bis (trifluoromethyl) benzyloxy)-4- (3- (5-oxo-lH, 4H-1, 2,4-triazolo) methyl) - 3- (S)-phenyl-morpholine ; 2- (R)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-3- (S)- (4-fluorophenyl)-4- (3- (5- oxo-lH, 4H-1, 2,4-triazolo) methyl) morpholine; 2- (R)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-4- (5- (N, N- dimethylamino) methyl-1, 2,3-triazol-4-yl) methyl-3- (S)-phenylmorpholine ; 2- (R)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-4- (5- (N, N- dimethylamino) methyl-1, 2,3-triazol-4-yl) methyl-3- (S)- (4-fluorophenyl) morpholine; 2- (R)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-3- (S)- (4-fluorophenyl)-4- (3- (4- monophosphoryl-5-oxo-1H-1, 2,4-triazolo) methyl) morpholine;

2- (R)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-3- (S)- (4-fluorophenyl)-4- (3- (1- monophosphoryl-5-oxo-1H-1, 2,4-triazolo) methyl) morpholine; 2- (R)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-3- (S)- (4-fluorophenyl)-4- (3- (2- monophosphoryl-5-oxo-lH-1, 2, 4-triazolo) methyl) morpholine; 2- (R)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-3- (S)- (4-fluorophenyl)-4- (3- (5- oxyphosphoryl-lH-1, 2,4-triazolo) methyl) morpholine; 2- (S)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-3- (S)- (4-fluorophenyl)-4- (3- (l- monophosphoryl-5-oxo-4H-1, 2,4-triazolo) methyl) morpholine; 2- (R)- (l- (R)- (3, 5-bis (trifluoromethyl) phenyl) ethoxy)-4- (4-N, N-dimethylaminobut-2- yn-yl)-3- (S)- (4-fluorophenyl) morpholine; 2- (R)- (l- (S)- (3, 5-bis (trifluoromethyl) phenyl)-2-hydroxyethoxy)-3- (S)- (4- fluorophenyl)-4- (1, 2,4-triazol-3-yl) methylmorpholine; or a pharmaceutically acceptable salt thereof.

It will be appreciated that a combination of a conventional anti- asthmatic drug with a CB 1 receptor modulator may provide an enhanced effect in the treatment of asthma.

Thus, according to a further aspect of the present invention there is provided the use of a CB 1 receptor modulator and an anti-asthmatic agent for the manufacture of a medicament for the treatment or prevention of asthma.

The present invention also provides a method for the treatment or prevention of asthma, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anti-asthmatic agent, such that together they give effective relief.

Suitable anti-asthmatic agents of use in combination with a compound of the present invention include, but are not limited to: (a) VLA-4 antagonists such as natalizumab and the compounds described in US 5,510, 332, W097/03094, W097/02289, W096/40781, W096/22966, W096/20216, W096/01644, W096/06108, W095/15973 and W096/31206 ; (b) steroids and corticosteroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) antihistamines (Hl-histamine antagonists) such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, desloratadine, cetirizine, fexofenadine,

descarboethoxyloratadine, and the like ; (d) non-steroidal anti-asthmatics including P2-agonists (such as terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol, salmeterol, epinephrine, and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (such as zafirlukast, montelukast, pranlukast, iralukast, pobilukast, and SKB-106, 203), and leukotriene biosynthesis inhibitors (such as zileuton and BAY-1005); (e) anti-cholinergic agents including muscarinic antagonists (such as ipratropium bromide and atropine); and (f) antagonists of the chemokine receptors, especially CCR-3; and pharmaceutically acceptable salts thereof.

It will be appreciated that a combination of a conventional anti- constipation drug with a CB 1 receptor modulator may provide an enhanced effect in the treatment of constipation.

Thus, according to a further aspect of the present invention there is provided the use of a CB 1 receptor modulator and an anti-constipation agent for the manufacture of a medicament for the treatment or prevention of constipation.

The present invention also provides a method for the treatment or prevention of constipation, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anti-constipation agent, such that together they give effective relief.

It will be appreciated that a combination of a conventional anti- constipation drug with a CB 1 receptor modulator may provide an enhanced effect in the treatment of chronic intestinal pseudo-obstruction.

Thus, according to a further aspect of the present invention there is provided the use of a CB1 receptor modulator and an anti-constipation agent for the manufacture of a medicament for the treatment or prevention of chronic intestinal pseudo-obstruction.

The present invention also provides a method for the treatment or prevention of chronic intestinal pseudo-obstruction, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anti-constipation agent, such that together they give effective relief.

Suitable anti-constipation agents of use in combination with a compound of the present invention include, but are not limited to, osmotic agents,

laxatives and detergent laxatives (or wetting agents), bulking agents, and stimulants; and pharmaceutically acceptable salts thereof.

A particularly suitable class of osmotic agents include, but are not limited to sorbitol, lactulose, polyethylene glycol, magnesium, phosphate, and sulfate; and pharmaceutically acceptable salts thereof.

A particularly suitable class of laxatives and detergent laxatives, include, but are not limited to, magnesium, and docusate sodium; and pharmaceutically acceptable salts thereof.

A particularly suitable class of bulking agents include, but are not limited to, psyllium, methylcellulose, and calcium polycarbophil ; and pharmaceutically acceptable salts thereof.

A particularly suitable class of stimulants include, but are not limited to, anthroquinones, and phenolphthalein; and pharmaceutically acceptable salts thereof.

It will be appreciated that a combination of a conventional anti- cirrhosis drug with a CB 1 receptor modulator may provide an enhanced effect in the treatment of cirrhosis of the liver.

Thus, according to a further aspect of the present invention there is provided the use of a CB1 receptor modulator and an anti-cirrhosis agent for the manufacture of a medicament for the treatment or prevention of cirrhosis of the liver.

The present invention also provides a method for the treatment or prevention of cirrhosis of the liver, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an anti-cirrhosis agent, such that together they give effective relief.

Suitable anti-cirrhosis agents of use in combination with a compound of the present invention include, but are not limited to, corticosteroids, penicillamine, colchicine, interferon-y, 2-oxoglutarate analogs, prostaglandin analogs, and other anti- inflammatory drugs and antimetabolites such as azathioprine, methotrexate, leflunamide, indomethacin, naproxen, and 6-mercaptopurine ; and pharmaceutically acceptable salts thereof.

The method of treatment of this invention comprises a method of modulating the CB 1 receptor and treating CB 1 receptor mediated diseases by administering to a patient in need of such treatment a non-toxic therapeutically

effective amount of a compound of this invention that selectively antagonizes the CB 1 receptor in preference to the other CB or G-protein coupled receptors.

The term"therapeutically effective amount"means the amount the compound of structural formula I that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disorder being treated. The novel methods of treatment of this invention are for disorders known to those skilled in the art. The term"mammal"includes humans.

The weight ratio of the compound of the Formula I to the second active ingredient may be varied and will depend upon the effective dose of each ingredient.

Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula I is combined with a (3-3 agonist the weight ratio of the compound of the Formula I to the (3-3 agonist will generally range from about 1000: 1 to about 1: 1000, preferably about 200: 1 to about 1: 200. Combinations of a compound of the Formula I and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

Abbreviations used in the following Schemes and Examples: API-ES: brine: saturated sodium chloride solution Celite: CELITE brand diatomaceous earth DMAP: 4-dimethylaminopyridine DMF: dimethylformamide DMSO: dimethylsulfoxide EDC: l-ethyl-3- (3-dimethylaminopropyl)-carbodiimide hydrochloride Et: ethyl g or gm: gram h or hr: hours HOAc : acetic acid HOBt : 1-hydroxybenzotriazole HPLC : high pressure liquid chromatography il vacuo : rotoevaporation LC-MS liquid chromatography-mass spectrum Me: methyl

mg: milligram MHz : megahertz min: minutes mL : milliliter MPLC: medium pressure liquid chromatography MS or ms: mass spectrum N/A: Not applicable Ph: phenyl rt: room temperature Rt: TFA: trifluoroacetic acid THF : tetrahydrofuran TLC: thin layer chromatography uL, ul, pLor, ul : microliter UV : ultra-violet Compounds of the present invention may be prepared by procedures illustrated in the accompanying scheme. Scheme 1. 4 + R4 EDC, HOBT, DMSO ! H7 SNH2 HOw Pyridine, DMAP, CDC13, Ri N HO A 4h at 20-25°C then 16hr at 2 H W R e, 65°C C In Scheme 1, an appropriately substituted amine A is reacted with an aryl carboxylic acid B under standard amide bond forming conditions to afford the arylamide C.

In order to illustrate the invention, the following examples are included. These examples do not limit the invention. They are only meant to suggest a method of reducing the invention to practice. Those skilled in the art may find other methods of practicing the invention which are readily apparent to them. However, those methods are also deemed to be within the scope of this invention.

General Procedures.

The LC/MS analyses were preformed using a Micromass ZMD mass spectrometer coupled to an Agilent 1100 Series HPLC utilizing a YMC ODS-A 4.6 x

50 mm column eluting at 2.5 mL/min with a solvent gradient of 10 to 95% B over 4.5 min, followed by 0.5 min at 95% B: solvent A = 0.06% TFA in water; solvent B = 0.05% TFA in acetonitrile. 1H-NMR spectra were obtained on a 500 MHz Varian Spectrometer in CDC13 or CD30D as indicated and chemical shifts are reported as 8 using the solvent peak as reference and coupling constants are reported in hertz (Hz).

REFERENCE EXAMPLE 1

N-f2, 3-bis (4-chlorophenyl)-1-methylpropyll-amine hydrochloride The preparation of the two diastereomers (alpha and beta) of N- [2, 3- bis (4-chlorophenyl)-1-methylpropyl]-amine hydrochloride salt has been disclosed (Schultz, E. M, et al. J. Med Chenu. 1967, 10, 717).

Diastereomer oc : LC-MS: calculated for C16Hl7Cl2N 293, observed m/e 294 (M + H) + (retention time 2.5 min).

Diastereomer (3 : LC-MS: calculated for C16Hl7Cl2N 293, observed m/e 294 (M + H) + (retention time 2.2 min).

REFERENCE EXAMPLE 2

N-r3-(4-chlorophenyl)-2-phenyl-l-methelpropall-amine hydrochloride (Diastereomer a)

Step A 3- (4-Chlorophenyl)-2-phenylpropanoic acid, methyl ester.

To a solution of methyl phenylacetate (12 g, 80 mmol) and 4- chlorobenzyl bromide (16 g, 80 mmol) in 250 mL of anhydrous tetrahydrofuran at- 78 °C was added sodium hexamethyldisilazide (1 M in tetrahydrofuran, 80 mL, 80 mmol) (potassium hexamethyldisilazide in toluene may be used with similar results).

The reaction was allowed to warm to room temperature overnight. The volatile materials were removed on a rotary evaporator, and the resulting mixture was partitioned between saturated ammonium chloride (200 mL) and ethyl acetate (200 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD30D): 6 7.36-7. 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-phenylpropionate (Step A, 20 g, 74 mmol) in acetonitrile (100 mL) and water (100 mL) was added lithium hydroxide monohydrate (8.8 g, 0.21 mol). After stirring at room temperature for 3 days, the volatile materials were removed by concentrating on a rotary evaporator and the residue was partitioned between water (300 mL) and hexane/ether (1 : 1,200 mL).

The water layer was separated, acidified to pH = 2-3, and extracted with ethyl acetate (2 x 200 mL) The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD30D): 8 7.34-7. 10 (m, 9H), 3.82 (dd, 1H), 3.36 (dd, 1H), 2.98 (dd, 1H).

Step N-Methoxy-N-methyl-3- (4-chlorophenyl)-2-phenylpropanamide.

To a solution of 3- (4-chlorophenyl)-2-phenylpropionic acid (Step B, 14 g, 55 mmol) in methylene chloride (125 mL) at 0 °C was added dimethylformamide (50) iL) and oxalyl chloride (14 g, 0.11 mol) dropwise. The reaction was allowed to warm to room temperature overnight and concentrated to dryness to give the crude acyl chloride, which was used without further purification. Thus, to a solution of the acyl chloride in methylene chloride (250 mL) was added N-methoxy-N-methylamine hydrochloride (11 g, 0.11 mol) and triethyl amine (dried over activated molecular sieves, 30 mL, 0.22 mol) at 0 °C. After stirring at room temperature for 4 h, the reaction mixture was diluted with ether (500 mL) and successively washed with water, dilute aqueous sodium hydrogen sulfate and brine, dried over anhydrous

magnesium sulfate, filtered and concentrated to dryness to give the crude product which was used without further purification. 1H NMR (500 MHz, CD30D) : 8 7.4- 7.1 (m, 9H), 4. 38 (br, 1H), 3.48 (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 a solution of N-methoxy-N-methyl-3- (4-chlorophenyl)-2- phenylpropanamide (Step C, 16 g, 53 mmol, dried by azeotroping with toluene) in anhydrous tetrahydrofuran (200 mL) at 0 °C was added methylmagnesium bromide (3 M in ether, 35 mL, 0.11 mol). After stirring at 0 °C for 2 h, the reaction was quenched with methanol (5 mL) and 2 M hydrochloric acid (50 mL). The volatile materials were removed by concentrating on a rotary evaporator and the residue partitioned between saturated ammonium chloride (200 mL) and 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. 1H NMR (500 MHz, CD30D) : 5 7.45-7. 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 methanol (100 mL) at 0 °C was added sodium borohydride (3.8 g, 100 mmol). After stirring at 0 °C for 30 min, the reaction was quenched by addition of 2 M hydrochloric acid (50 mL). The volatile materials were removed by concentrating on a rotary evaporator and the residue partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give the crude product, which was purified by flash column chromatography on silica gel eluted with 10% ethyl acetate in hexane to afford the pure faster eluting isomer and a mixture containing both the faster eluting isomer and the slower eluting isomer.

Faster eluting isomer: 1H NMR (500 MHz, CD30D): b 7.25-7. 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 ethyl acetate (100 mL) at 0 °C was added triethyl amine (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 min, the reaction was quenched by addition of saturated aqueous sodium bicarbonate (100 mL). After stirring at room temperature for 1 h, 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. 1H NMR (500 MHz, CD30D): 6 7.3-7. 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 dimethylformamide (50 mL) was added sodium azide (11 g, 0.17 mol). After stirring at 120 °C for 1 h, the reaction mixture was poured into water (200 mL), and the product was extracted with ether (2 x 100 mL). The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to dryness, and the residue was purified on a silica gel column eluting with hexane to 2% ethyl acetate in hexane 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 ethyl acetate (150 mL) was added di (tert-butyl) dicarbonate (8.0 g, 37 mmol) and platinum dioxide (0.50 g, 2.2 mmol). The mixture was degassed and filled with hydrogen with a balloon. After stirring for 1 day, the reaction mixture was filtered through CELITE diatomaceous earth, and the filtrate was concentrated to give the crude product, which was contaminated with some unreacted di (tert-butyl) dicarbonate. 1H NMR (500 MHz, CD30D) : 8 7.25-6. 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-f3- (4-chlorophenyl)-2-phenyl-l-methylpropyll-amine hydrochloride (Diastereomer oc).

2- (N-tert-butoxycarbonyl) amino-4- (4-chlorophenyl)-3-phenylbutane (Step H, 7.0 g, 24 mmol) was treated with a saturated solution of hydrogen chloride in ethyl acetate (100 mL) at room temperature for 30 min (4 M hydrogen chloride in dioxane may be used with similar results). The mixture was concentrated to dryness to give the tittle compound. 1H NMR (500 MHz, CD30D) : 8 7. 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. 3 min).

REFERENCE EXAMPLE 3

N-r3- (4-chlorophenyl)-2 (S)-phenyl-1 (S)-methylpropyll-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 h, and anhydrous ether (100 mL) was added to cover the solid material. The mixture was cooled to 0 °C, and was added 4-chlorobenzyl chloride (40 g, 0.25 mmol) in 400 mL of anhydrous ether dropwise. After stirring at room temperature for 1 h, a sample of the above solution (32 mL) was added to (lR, 2R)-l- phenylpropylene oxide (1.0 g, 7.5 mmol) in 100 mL of ether at 0 °C via syringe.

After stirring at 0 °C for 2 h, the reaction was quenched by addition of saturated aqueous ammonium chloride (100 mL). The organic layer was separated and the aqueous layer 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 eluted with hexane to 15% ethyl acetate in hexane to afford the title compound. 1H NMR (500 MHz, CD30D) : 8 7.28-7. 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-r3-(4-chlorophenyl)-2 (S)-phenyl-l (S)-methvlpropyll-amine, hydrochloride The product of Step A (4- (4-chlorophenyl)-3 (S) -phenyl-2 (R)-butanol, 1.8 g, 7.0 mmol) was converted to the title compound (1.6 g) following the steps described in Reference Example 2, Steps F-I, except hydrogen chloride in dioxane (4 M) was used in place of hydrogen chloride in ethyl acetate. 1H NMR (500 MHz, CD30D) : 8 7.35-6. 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) + (2.3 min).

REFERENCE EXAMPLE 4

N-f3- (4-chlorophenyl)-2- (3-pvridyl)-l-methylpropyl1-amine, hydrochloride (mixture of diastereomers ot/ß 10: 1) Step A 4- (4-Chlorophenyl)-3-pyridyl-2-butanone.

To a solution of 3-pyridylacetone hydrochloride (Wibaud, van der V.

Recl. Trav. Chiiii. Pays-Bas. 1952, 71, 798) (10 g, 58 mmol) and 4-chlorobenzyl chloride (9.1 g, 58 mmol) in 100 mL of methylene chloride at-78 °C was added cesium hydroxide monohydrate (39 g, 0.23 mol) and tetrabutyl ammonium iodide (1 g). The reaction was allowed to warm to room temperature overnight, and the resulting mixture was partitioned between brine (100 mL) and ethyl acetate (100 mL).

The organic layer was separated and the aqueous layer extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD30D) : 6 8.42 (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. 9 min).

Step B N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-amine, hydrochloride (mixture of diastereomers oc/ (3 10: 1).

The product of Step 1 (4- (4-chlorophenyl)-3-pyridyl-2-butanone) (14 g, 57 mmol) was converted to the title compound (8.0 g) following the procedure described in Reference Example 2, Steps E-1. LC-MS: m/e 261 (M + H) + (1.2 min).

REFERENCE EXAMPLE 5

2-Methyl-2, 3-dihydrobenzofuran-2-carboxylic acid.

StepA Methyl 2. 3-Dihydrobenzofuran-2-carboxylate.

To a solution of 2,3-dihydrobenzofuran-2-carboxylic acid (Chembridge, 0.90 g, 5.5 mmol) in 20 mL of methanol and 20 mL of methylene chloride at 0 °C was added trimethylsilyldiazomethane (2 M in hexane) until a yellow color persisted. After stirring at room temperature for 15 min, the reaction was concentrated to dryness to afford the title compound.

Step B 2-Methyl-2, 3-dihydrobenzofuran-2-carboxylic acid, methyl ester.

To a solution of methyl 2,3-dihydrobenzofuran-2-carboxylate (Step A, 1.0 g, 5.5 mmol) and methyl iodide (1.8 mL, 28 mmol) in 20 mL of anhydrous tetrahydrofuran at-78 °C was added potassium tert-butoxide (1 M in tetrahydrofuran, 8.4 mL, 8.4 mmol). The reaction was allowed to warm to room temperature overnight, and the resulting mixture was diluted with ethyl acetate (100 mL), washed with aqueous saturated ammonium chloride (100 mL) and water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography eluted with 2-5% ethyl acetate in hexane to give the title compound. 1H NMR (500 MHz, CD30D) : 8 7.16 (d, 1H), 7.12 (t, 1H), 6.86 (t, 1H), 6.76 (d, 1H), 3.75 (s, 3H), 3.58 (d, 1H), 3.17 (d, 1H), 1.66 (s, 3H).

Step C 2-Methyl-2, 3-dihydrobenzofuran-2-carboxylic acid.

To a solution of methyl 2-methyl-2,3-dihydrobenzofuran-2-carboxylate (Step B, 0.22 g, 1.1 mmol) in 5 mL of dimethylsulfoxide was added potassium hydroxide (0.64 g, 11 mmol) in 0.5 mL of water. After stirring at room temperature for 1 h, the reaction mixture was partitioned between ether (50 mL) and 1 M hydrochloric acid (50 mL). The organic layer was separated and the aqueous layer extracted with ether (3 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD30D): 8 7.17 (d, 1H), 7.12 (t, 1H), 6.86 (t, 1H), 6.79 (d, 1H), 3.60 (d, 1H), 3.18 (d, 1H), 1.67 (s, 3H).

REFERENCE EXAMPLE 6

2-Methyl-1, 2, 3, 4-tetrahydro-2-naphthoic acid.

The title compound was prepared following the procedures described for Reference Example 5 substituting 2,3-dihydrofuran-2-carboxylic acid with 1,2, 3,4- tetrahydro-2-naphthoic acid at Step A and potassium tert-butoxide in tetrahydrofuran with potassium hexamethyldisilazide (0.5 M in toluene) at Step B. 1H NMR (500 MHz, CD30D) : 6 7.12-7. 0 (m, 4H), 3.71 (d, 1H), 3.22 (d, 1H), 2.84 (t, 1H), 2.65 (d, 1H), 2.17 (m, 1H), 1.77 (m, 1H), 1.28 (s, 3H).

REFERENCE EXAMPLE 7 2-Methylchromane-2-carboxylic acid.

The title compound was prepared following the procedures described for Reference Example 5 substituting 2, 3-dihydrofuran-2-carboxylic acid with chromane-2-carboxylic acid at Step A and potassium tert-butoxide in tetrahydrofuran with potassium hexamethyldisilazide (0.5 M in toluene) at Step B. 1H NMR (500 MHz, CD30D) : b 7.07 (t, 1H), 7.03 (d, 1H), 6.82 (m, 2H), 2.75 (m, 2H), 2.40 (m, 1H), 1.80 (m, 1H), 1.60 (s, 3H).

REFERENCE EXAMPLE 8 Chromane-3-carboxylic Acid Step A 4-Oxochromane-3-carboxylic acid, ethyl ester.

To a solution of 2, 3-dihydro-4H-chromen-4-one (5.0 g, 34 mmol) in 100 mL of anhydrous tetrahydrofuran at-78 °C was added lithium hexamethyldisilazide (1 M in tetrahydrofuran, 37 mL, 37 mmol). After stirring at- 78 °C for 30 min, a solution of ethyl cyanoformate (4.0 g, 40 mmol) in 10 mL of

tetrahydrofuran was added. After stirring at-78 °C for another 30 min, the reaction mixture was diluted with ether (200 mL), washed with aqueous saturated ammonium chloride (200 mL) and water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography eluted with 3% ethyl acetate in hexane to give the title compound.

Step B Chromane-3-carboxylic acid, ethyl ester.

A mixture of 4-oxochromane-3-carboxylic acid, ethyl ester (4.0 g, 18 mmol) and 10% palladium on carbon (0.4 g) in 100 mL of acetic acid was degassed and filled with hydrogen using a balloon. After stirring at 70 °C overnight, the reaction mixture was filtered through CELITE diatomaceous earth, and the CELITE cake was washed with ethyl acetate (200 mL). The filtrate was washer with water (2 x 200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD30D) : 8 7.2-7. 0 (m, 2H), 6.84 (t, 1H), 6.74 (d, 1H), 4.36 (dd, 1H), 4.21-4. 13 (m, 3H), 3.03 (m, 3H), 1.26 (t, 3H).

Step C Chromane-3-carboxylic acid.

Chromane-3-carboxylic acid, ethyl ester was converted to the title compound following the procedure described for Reference Example 5, Step C, substituting methyl 2-methyl-2,3-dihydrofuran-2-carboxylate with chromane-3- carboxylic acid, ethyl ester (Step B). 1H NMR (500 MHz, CD30D) : 8 7.15-7. 05 (m, 2H), 6.84 (t, 1H), 6.76 (d, 1H), 4.40 (dd, 1H), 4.15 (dd, 1H), 3.02 (m, 3H).

REFERENCE EXAMPLE 9 3-Methylchromane-3-carboxylic acid.

Step A 3-Methyl-4-oxochromane-3-carboxylic acid, ethyl ester.

The title compound was prepared following the procedures described for Reference Example 5, Step B substituting 2,3-dihydrofuran-2-carboxylic acid, methyl ester with 4-oxochromane-3-carboxylic acid, ethyl ester. 1H NMR (500 MHz, CD30D) : b 7.88 (dd, 1H), 7.56 (ddd, 1H), 7.10 (t, 1H), 7.02 (d, 1H), 4.79 (d, 1H), 4.30 (d, 1H), 4.16 (m, 2H), 1.42 (s, 3H), 1.17 (t, 3H).

Step B 3-Methylchromane-3-carboxylic acid.

The title compound was prepared following the procedures described for Reference Example 8, Steps B and C substituting 4-oxochromane-3-carboxylic acid, ethyl ester with ethyl 3-methyl-4-oxochromane-3-carboxylic acid, ethyl ester.

1H NMR (500 MHz, CD30D) : 8 7.07 (m, 2H), 6.82 (t, 1H), 6.76 (d, 1H), 4.27 (d, 1H), 3.95 (d, 1H), 3.22 (d, 1H), 2.68 (d, 1H), 1.28 (s, 3H).

REFERENCE EXAMPLE 10 2-Methyl-2, 3-dihydro-1, 4-benzodioxane-2-carboxylic acid.

The title compound was prepared following the procedures of Salimbeni and Manghisi J. Heterocyclic Chenil. 1980, 17, 489). 1H NMR (500 MHz, CD30D): 6 6.94-6. 80 (m, 4H), 4.56 (d, 1H), 3.90 (d, 1H), 1.58 (s, 3H).

REFERENCE EXAMPLE 11 6-Chloro-2-methyl-2 3-dihydro-1 4-benzodioxane-2-carboxylic Acid and 7-Chloro-2- methyl-2 3-dihydro-1, 4-benzodioxane-2-carboxylic Acid (1: 1).

The title compounds were prepared following the procedures of Salimbeni and Manghisi J. Heterocyclic Chem. 1980, 17, 489). 1H NMR (500 MHz, CD30D): & 6.94-6. 80 (m, 3H), 4. 57/4. 56 (d, 1H), 3.91/3. 89 (d, 1H), 1.57 (s, 3H).

REFERENCE EXAMPLE 12

6,7, 8, 9-Tetrahydro-5H-benzofalr7lannulene-6-carboxylic acid.

The title compound was obtained from Americana Advanced Organics.

REFERENCE EXAMPLE 13

6,7, 8, 9-Tetrahydro-5H-benzofalf7lannulene-7-carboxylic acid.

The title compound was obtained from Americana Advanced Organics.

REFERENCE EXAMPLE 14

N-{[2-(3-Bromophenyl)-3-(4-chlorophenyl)-1,2-dimethylpropyl} amine, hydrochloride (Diastereomer a and n Step A : 1-(3-bromophenyl) acetone To a solution of N-methoxy-N-methylacetamide (10 g, 0.10 mol) in 200 mL of ether at 0°C was added 3-bromobenzylmagnesium bromide (0.25 M, 200 mL, 50 mmol). After stirring at 0°C for 2 h, the reaction mixture was partitioned between hexane and saturated aqueous ammonium chloride. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated

to dryness to give the title compound, which was used without further purification. 1H NMR (500 MHz, CD30D) : 8 7.5-7. 1 (m, 4H), 3.78 (s, 2H), 2.19 (s, 3H).

Step B : 3- (3-Bromophenyl)-2-butanone.

To a solution of 3-bromophenylacetone (4.7 g, 22 mmol) in acetonitrile (100 mL) was added methyl iodide (1. 4 mL, 22 mmol) and cesium carbonate (14 g, 44 mmol). After stirring at room temperature for 17 h, the reaction mixture was poured into ether (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer extracted with ether. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to dryness to give the title compound.

1H NMR (400 MHz, CD30D) : 6 7.45-7. 40 (m, 2H), 7.3-7. 2 (m, 2H), 3.87 (q, 1H), 2.06 (s, 3H), 1.34 (d, 3H).

Step C: 3- (3-Bromophenyl)-4- (4-chlorophenyl)-3-methyl-2-butanone.

To a solution of 3- (3-bromophenyl)-2-butanone (2.0 g, 8.8 mmol) in methylene chloride (100 mL) was added 4-chlorobenzyl chloride (1.4 g, 8.8 mmol), tetrabutylammonium iodide (0.16 g, 0.44 mmol) and cesium hydroxide monohydrate (5.9 g, 35 mmol). After stirring at room temperature for 3.5 h, the reaction mixture was poured into ethyl acetate (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness to give the title compound. 1H NMR (400 MHz, CD30D): 6 7.5-7. 1 (m, 4 H), 7.08 (d, 2H), 6.68 (d, 2H), 3.16 (ABq, 2H), 1.98 (s, 3H), 1.42 (s, 3H).

Step D : 3-(3-Bromophenyl)-4-(4-chlorophenvl)-3-methyl-2-butanol.

To a solution of 3- (3-bromophenyl)-4- (4-chlorophenyl)-3-methyl-2-butanone (1.6 g, 4.6 mmol) in methanol (50 mL) was added sodium borohydride (0.26 g, 6.8 mmol).

After stirring at room temperature for 10 min, the reaction was quenched by addition of saturated aqueous ammonium chloride (25 mL). The precipitate was filtered off and washed with ethyl acetate (25 mL). The organic layer of the filtrate was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluted with 5% ethyl acetate in hexane to afford the title compound as two separate diastereomers. Faster eluting diastereomer (Diastereomer a) 1H NMR (400 MHz, CD30D) : 6 7.63 (s, 1H), 7.42-7. 18 (m, 3H), 7.05 (d, 2H), 6.80 (d, 2H), 3.92 (q, 1H), 3.19 (d, 1H), 2.86 (d, 1H), 1.13 (s, 3H), 1.02 (d, 3H). Slower eluting

diastereomer (Diastereomer (3) 1H NMR (400 MHz, CD30D): 7.40-7. 18 (m, 4H), 7.04 (d, 2H), 6.64 (d, 2H), 4.12 (q, 1H), 3.04 (ABq, 2H), 1.17 (s, 3H), 0.84 (d, 3H).

Step E: 2-Azido-3- (3-bromophenyl)-4- (4-chlorophenyl)-3-methylbutane.

To a solution of 3- (3-bromophenyl)-4- (4-chlorophenyl)-3-methyl-2-butanol (fasting eluting diastereomer, 0.90 g, 2.5 mmol) in ethyl acetate (80 mL) at 0°C was added triethyl amine (dried over activated molecular sieves, 0.42 mL. 3.1 mmol) and methanesulfonyl chloride (0.22 mL, 2.8 mmol). After stirring at 0°C for 2 h, the reaction was quenched by addition of saturated aqueous sodium bicarbonate (10 mL).

After stirring at room temperature for 0.5 h, the organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness to give the crude sulfonate, which was used without further purification.

Thus, a mixture of the sulfonate and sodium azide (0.83 g, 0.13 mol) in dimethylformamide (5 mL) was heated at 120°C for 4 h. The reaction mixture was cooled to room temperature and was poured into water (40 mL), and the product was extracted with ether (2 x 20 mL). The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to dryness, and the residue was purified on a silica gel column eluting with hexane to give the title compound (Diastereomer a). 1H NMR (400 MHz, CD30D): 6 7.43-7. 20 (m, 4H), 7.04 (d, 2H), 6.64 (d, 2H), 4.10 (q, 1H), 3.10 (d, 1H), 3.00 (d, 1H), 1.10 (s, 3H), 1.02 (d, 3H).

The slower eluting diastereomer was converted to the other diastereomer (Diastereomer P) of the title compound following the same procedure as described for the faster eluting diastereomer. 1H NMR (400 MHz, CD30D): 8 7.60- 7.20 (m, 4H), 7.07 (d, 2H), 6.80 (d, 2H), 3.90 (q, 1H), 3.17 (d, 1H), 2.92 (d, 1H), 1.22 (d, 3H), 1.20 (s, 3H).

Step F: 2-(N-tert-Butoxycarbonel) amino-3-(3-bromophenel)-4-(4- chlorophenyl)-3-methylbutane To a solution of 2-azido-3- (3-bromophenyl)-4- (4-chlorophenyl)-3-methylbutane (Diastereomer oc, 0.26 g, 0.68 mmol) in ethyl acetate (5 mL) was added di (tert- butyl) dicarbonate (0.18 g, 0.82 mmol) and platinum dioxide (0.025 g). The mixture was degassed and charged with hydrogen with a balloon. After stirring for 1 day, the reaction mixture was filtered through CELITE, diatomaceous earth, and the filtrate was concentrated to give diastereomer a of the title compound.

Diastereomer ß of 2-azido-3- (3-bromophenyl)-4- (4-chlorophenyl)-3- methylbutane was converted to the Diastereomer (3 of the title compound following the same procedure as described for Diastereomer α.

Step G: N-[3-(4-Chlorophenyl)-2-(3-bromophenyl)-1,2-dimethylpropyl]- amine hydrochloride (Diastereomer a and ß).

2- (N-tert-Butoxycarbonyl) amino-3- (3-bromophenyl)-4- (4-chlorophenyl)-3- methylbutane (Diastereomer oc, 0.35 g, 0.76 mmol) was treated with 4 M hydrogen chloride in dioxane (5 mL) at room temperature for 2 h. The mixture was concentrated to dryness to give Diastereomer oc of the title compound. LC-MS: m/e 352 (M + H) + (3. 0 min).

Diastereomer (3 of 2-azido-3- (3-bromophenyl)-4- (4-chlorophenyl)-3- methylbutane was converted to Diastereomer ß of the title compound following the same procedure as described for Diastereomer a. LC-MS: m/e 352 (M + H) + (3.0 min).

REFERENCE EXAMPLE 15 N-{r3-(4-Chlorophenyl)-2-phenel-2-cyano-1-methyllpropYllamin en hydrochloride<BR> <BR> <BR> <BR> Step A : 4-(4-Chlorophenel)-3-cyano-3-phenyl-2-butanone.

To a solution of a-acetylphenylacetonitrile (1.0 g, 6.3 mmol) in acetonitrile (25 mL) was added 4-chlorobenzyl bromide (1.3 g, 6.3 mmol) and cesium carbonate (8.2 g, 25 mmol). After stirring at room temperature for 2 h, the reaction mixture was poured into ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness, and the residue was purified on a silica gel column eluting with 1 to 5% ethyl acetate in hexane to give the title compound. 1H NMR (400 MHz, CD30D) : 8 7.5-6. 9 (m, 9H), 3.56 (d, 1H), 3.37 (d, 1H), 2.22 (s, 3H). LC-MS: m/e 306 (M + Na) + (3.0 min).

Step B : N-r4- (4-Chlorophenvl)-3-cyano-3-phenyl-2-butylidenel-2- methylpropane- (S)-sulfinamide.

To a solution of 4- (4-chlorophenyl)-3-cyano-3-phenyl-2-butanone (1.9 g, 6.7 mmol) and (S) -2-methylsulfinamide (0.74 g, 6.1 mmol) in tetrahydrofuran (25 mL) was added titanium tetraethoxide (4.0 mL, 18 mmol). After stirring at 60°C for 6 h and 75°C for 18 h, the reaction mixture was poured into a well-stirred brine solution (50 mL). The resulting mixture was filtered through CELITE diatomaceous earth and washed with ethyl acetate (20 mL), and the filtrate was extracted with ethyl acetate (2 x 50 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 10 to 20% ethyl acetate in hexane to give the title compound as a 1: 1 mixture of diastereomers. LC-MS: m/e 387 (M + H) + (3.6 min).

Step C: N- r3-(4-Chlorophenyl)-2-cyano-2-phenyl-1-methyllpropyl}-2- methylpropane- (S)-sulfinamide To a solution of N- [4- (4-chlorophenyl)-3-cyano-3-phenyl-2- butylidene]-2-methylpropane- (S)-sulfinamide (0.50 g, 1.3 mmol) in methanol (25 mL) at 0°C was added sodium borohydride (0.075 g, 1.9 mmol). After stirring for 15 min, the reaction was quenched by addition of saturated aqueous ammonium chloride (25 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give the title compound. LC-MS: m/e 389 (M + H) + (3. 4 min).

Step D: Nj r3- (4-Chlorophenyl)-2-cyano-2-phenyl-1-methylpropyllamine} hydrochloride salt N-{[3-(4-Chlorophenyl)-2-cyano-2-phenyl-1-methyl]propyl}-2- methylpropane- (S)-sulfinamide (0.55 g, 1.4 mmol) in methanol (20 mL) was added 4 M hydrogen chloride in dioxane (25 mL). After stirring for 30 min, the mixture was concentrated to dryness to give the title compound as a mixture of diastereomers (a and (3). LC-MS: m/e 285 (M + H) + (Major diastereomer: 2.0 ; Minor diastereomer: 2.1 min).

REFERENCE EXAMPLE 16

N- [3-(4-Chlorophenyl)-2-(3-bromophenyl)-2-hydroxylpropyl} amine hydrochloride Step A: 1-Bromo-3-{[(N-tert-butoxycarbonyl)amino]acetyl}benzene To a solution of 1-bromo-3-iodobenzene (8.8 mL, 69 mmol) in 200 mL of ether at-78°C was added tert-butyllithium (1.7 M in pentane, 40 mL, 69 mmol).

After stirring at-78°C for 30 min, a solution of N- (tert-butoxycarbonyl) glycine N'- methoxy-N'-methylamide (5.0 g, 23 mmol) in 100 mL of tetrahydrofuran was added.

After stirring at-78°C for 2 h, the reaction was allowed to warm up to 0°C, and was quenched with dilute aqueous ammonium chloride (200 mL). The organic layer was separated, 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 eluted with 5-10% ethyl acetate in hexane to give the title compound. 1H NMR (400 MHz, CD30D) : 8 8.12 (s, 1H), 7.97 (d, 1H), 7.80 (d, 1H), 7.43 (t, 1H), 4.50 (s, 2H), 1.42 (s, 9H).

Step B : 3-(4-Chlorophenyl)-2-(3-bromophenyl)-l-[(N-butoxycarbonyl) amino- 2-hydroxyl propane To a solution of l-bromo-3-{[(N-tert-butoxycarbonyl) amino] acetyl} benzene (0.65 g, 2.1 mmol) in 25 mL of ether at-78°C was added 4-chlorobenylmagnesium chloride (0.25 M in ether, 21 mL, 5.2 mmol). The reaction was allowed to warm up to-10°C over 3.5 h and was quenched at-10°C with saturated aqueous ammonium chloride (50 mL). The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluted with 5-10% ethyl acetate in hexane to give the title compound. 1H NMR (400 MHz, CD30D) : 8 7.5-7. 1 (m, 4H), 7.10 (d, 2H), 6.92 (d, 2H), 3.55 (d, 2H), 3.40 (d, 2H), 3.02 (ABq, 2H), 1.38 (s, 9H). <BR> <BR> <BR> <P>Step C: N-T r3-(4-Chlorophenyl)-2-(3-bromophenyl)-2-hydroXvlpropyliamine hydrochloride To a solution of 3- (4-chlorophenyl)-2- (3-bromophenyl)-1- [ (N-butoxycarbonyl) amino- 2-hydroxy] propane (0.38 g, 0.86 mmol) in ethyl acetate (10 mL) was added 4 M

hydrogen chloride in dioxane (20 mL). After stirring for 1 h, the mixture was concentrated to dryness to give the title compound. LC-MS: m/e 340 (M + H) + (2.8 min).

REFERENCE EXAMPLE 17 N-f r3-(4-Chlorophenel)-2-(3-bromophenyl)-2-fluoro-1 (S)-methyllpropyl} amine hydrochloride Step A: 3-(3-Bromophenyl)-2(S)-[(N-butoxycarbonyl)amino-4-(4- chlorophenyl)-3-hydroxyl butane The title compound was prepared following the same procedure described for Reference Example 8, Step A and B substituting N- (tert-butoxycarbonyl) glycine N'- methoxy-N'-methylamide with N- (tert-butoxycarbonyl)-L-alanine N'-methoxy-N'- methylamide. 1H NMR (500 MHz, CD30D) : 6 7.5-7. 0 (m, 6H), 6.82 (d, 2H), 4.11 (m, 1H), 3.07 (ABq, 2H), 1.50 (s, 9H), 0. 87 (d, 3H).

Step B : 3- (3-Bromophenyl)-2 (S)-f (N-butoxvcarbonyl) amino-4- (4- chlorophenyl)-3-fluorol butane To a solution of 3- (3-bromophenyl)-2 (S)- [ (N-butoxycarbonyl) amino-4- (4- chlorophenyl) -3-hydroxy] butane (2.0 g, 4.4 mmol) in 15 mL of methylene chloride at - 78°C was added (dimethylamino) sulfur trifluoride (1.1 mL, 8. 8 mmol), and the reaction was allowed to warm up to room temperature over 2.5 h. The reaction was quenched by carefully transferring to a well-stirred saturated aqueous sodium bicarbonate (50 mL). The mixture was extracted with ether (2 x 50 mL), and the combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. The residue was purified on a silica gel column eluting with 4-20% ethyl acetate in hexane to give the title compound as one major diastereomer and some contamination of the corresponding dehydration product. 1H NMR (500

MHz, CD30D) : 8 7.4-7. 1 (m, 4H), 7.06 (d, 2H), 6.85 (d, 2H), 4.19 (m, 1H), 3.43 (dd, 1H), 3.10 (dd, 1H), 1.50 (s, 9H), 0.93 (d, 3H).

Step C: N-{[3-(4-Chlorophenyl)-2-(3-bromophenyl)-2-fluoro-1(S)- methyllpropvl} amine hydrochloride To a solution of 3- (3-bromophenyl)-2 (S)- [ (N-butoxycarbonyl) amino-4- (4- chlorophenyl)-3-fluoro] butane (0.16 g, 0.35 mmol) in ethyl acetate (1 mL) was added 4 M hydrogen chloride in dioxane (4 mL). After stirring for 2 h, the mixture was concentrated to dryness to give the title compound. LC-MS: m/e 356 (M + H) + (3.1 min).

The amines of Reference Examples 18-25 were prepared by the same procedures described in Reference Example 1 : REFERENCE EXAMPLE 18 2-Amino-3, 4-diphenylbutane hydrochloride salt Diastereomer α : LC-MS: calculated for C16Hl9N 225, observed m/e 226 (M + H) + (2.0 min).

Diastereomer P : LC-MS: calculated for C16Hl9N 225, observed m/e 226 (M + H) + (1. 9 min).

REFERENCE EXAMPLE 19

3-Amino-1, 2-diphenylpentane hydrochloride salt Diastereomer oc : LC-MS: calculated for C17H2lN 239, observed m/e 240 (M + H) + (2.1 min).

Diastereomer P : LC-MS: calculated for C17H2lN 239, observed m/e 240 (M + H) + (2.0 min).

REFERENCE EXAMPLE 20 1-Amino-1, 2, 3-triphenylpropane p-toluenesulfonate salt Diastereomer a : LC-MS: calculated for C21H21N 287, observed m/e 288 (M + H)+ (2. 3 min).

Diastereomer (3 : LC-MS: calculated for C2lH2lN 287, observed m/e 288 (M + H) + (2.3 min).

REFERENCE EXAMPLE 21

2-Amino-4- (4-chlorophenyl)-3-phenylbutane hydrochloride salt Diastereomer oc : LC-MS: calculated for C16Hl8ClN 259, observed m/e 260 (M + H) + (2.3 min).

Diastereomer P : LC-MS: calculated for C16H18ClN 259, observed m/e 260 (M + H) + (2.2 min).

REFERENCE EXAMPLE 22

2-Amino-3-(4-chlorophenyl)-4-phenylbutane hydrochloride salt Diastereomer a : LC-MS: calculated for C16HlgClN 259, observed m/e 260 (M + H)+ (2.3 min).

Diastereomer P : LC-MS: calculated for C16HlgCIN 259, observed m/e 260 (M + H) + (2.1 min).

REFERENCE EXAMPLE 23

2-Amino-4-(4-methoxycarbonylphenyl)-3-phenylbutane hydrochloride salt Diastereomer oc : LC-MS: calculated for C1gH21N02 283, observed m/e 284 (M + H) + (2.0 min).

Diastereomer (3 : LC-MS: calculated for C1gH21N02 283, observed m/e 284 (M + H) + (1.9 min).

REFERENCE EXAMPLE 24 2-Amino-3-(2-Chlorophenyl)-4-phenylbutane (mixture of diastereomers α/ß 1: 2) LC-MS: calculated for C16H18ClN 259, observed m/e 260 (M + H) + (1.9/2. 0 min).

REFERENCE EXAMPLE 25 2-Amino-3- (4-methoxyphenyl)-4-phenylbutane (mixture of diastereomers oye 2 : 5) LC-MS: m/e 256 (M + H) + (1.7 min).

REFERENCE EXAMPLE 26

2-Amino-4- (4-chlorophenyl)-3- (3-fluorophenyl) butane hydrochloride salt (mixture of diastereomers c/ß 5: 1) Step A Methyl 3-(4-Chlorophenyl)-2-(3-flurophenyl) propionate.

To a solution of 3-fluorophenylacetic acid (5.0 g, 32 mmol) in MeOH (25 mL) and CH2C12 (25 mL) at 0°C was added trimethylsilyldiazomethane (2 M in hexane, 30 mL, 60 mmol). After stirring at room temperature for 15 min, the reaction mixture was concentrated to dryness, and the residue was azeotroped with toluene to give the crude methyl 3-fluorophenylacetate (5.6 g), which was used without further purification. Thus, the crude methyl 3-fluorophenylacetate obtained above (2.5 g, 15 mmol) was converted to the title compound (purified on silica gel) by reacting with 4- chlorobenzyl bromide (4.6 g, 22 mmol) and sodium hexamethyldisilazide (1 M in THF, 15 mL, 15 mmol) following the procedure described in Reference Example 2, Step A. 1H NMR (400 MHz, CD30D): 6 7.35-6. 88 (m, 8H), 3.92 (t, 1H), 3.60 (s, 3H), 3.34 (dd, 1H), 3.00 (dd, 1H). LC-MS: m/e 305 (M + Na) + (3.9 min). <BR> <BR> <BR> <BR> <P>Step B N-Methoxy-N-methyl-3- (4-chlorophenyl)-2- (3-fluororophenyl)<BR> <BR> <BR> <BR> <BR> <BR> propanamide.

To a suspension N-methoxy-N-methylamine hydrochloride (2.0 g, 21 mmol) in 50 mL CH2C12 at 0°C was added dimethylaluminum chloride (1 M in hexane, 21 mL, 21 mmol). After stirring at room temperature for 1 h, a solution of methyl 3- (4- chlorophenyl)-2- (3-flurophenyl) propionate (Step A, 2.0 g, 10 mmol) in CH2C12 (10 mL) was added, and the resulting mixture was stirred overnight. The reaction mixture was quenched by addition of MeOH (5 mL), and the resulting mixture was

concentrated with silica gel (50 g). The material was loaded onto a silica gel column, which was eluted with 10% EtOAc in hexane to 2% ammonia in MeOH (2 M) in 10% EtOAc/hexane to give the title compound. 1H NMR (400 MHz, CD30D): 6 7. 35- 6.90 (m, 8H), 4.39 (br, 1H), 3.41 (s, 3H), 3.38-3. 30 (m, 1H), 3.08 (s, 3H), 2.92 (dd, 1H). LC-MS: m/e 322 (M + H) + (3.6 min).

Step C 4- (4-Chlorophenyl)-3- (3-fluorophenyl)-2-butanol.

The product of Step B (N-methoxy-N-methyl-3- (4-chlorophenyl)-2- phenylpropionamide) (0.74 g, 2.3 mmol) was converted to the title compound (a 5: 1 mixture of diastereomers) following the procedure described in Reference Example 2, Steps D-E. 1H NMR (400 MHz, CD30D): 8 7.22-6. 78 (m, 8H), 3.98 (m, 1H), 3.11 (dd, 1H), 2.94 (dd, 1H), 2.85 (m, 1H), 1.08 (d, 3H).

Step D 2-Azido-4- (4-chlorophenyl)-3- (3-fluorophenyl) butane.

To a mixture of 4- (4-chlorophenyl)-2- (3-fluorophenyl)-2-butanol (Step C, 0.65 g, 2.3 mmol), triphenylphosphine (1.2 g, 4.7 mmol), imidazole (0.32 g, 4.7 mmol) and zinc azide dipyridine complex (Viaud, M. C.; Rollin, P. Synthesis 1990,130) (0.72 g, 2.3 mmol) in 10 mL CH2C12 was added diethylazodicarboxylate (0.73 mL, 4.7 mmol) at 0°C. After stirring at room temperature for 30 min, the resulting mixture was concentrated with silica gel (20 g) and loaded onto a silica gel column, which was eluted with 2% ether in hexane to 2% ammonia in MeOH (2 M) in 2% ether/hexane to give the title compound. 1H NMR (400 MHz, CD30D): 8 7.25-6. 85 (m, 8H), 3.76 (m, 1H), 3.33 (m, 1H), 2.92 (m, 2H), 1.15 (d, 3H).

Step E 2-Amino-4- (4-Chlorophenyl)-3- (3-fluorophenyl) butane hydrochloride salt (mixture of diastereomers oc/ 5 5 1).

The product of Step D (2-azido-4- (4-chlorophenyl)-3- (3-fluorophenyl) butane) (0.49 g, 1.6 mmol) was converted to the title compound following the steps described in Reference Example 2, Steps H-1. 1H NMR (400 MHz, CD30D): 8 7.32-6. 90 (m, 7H), 3.61 (m, 1H), 3.20 (dd, 1H), 3.11 (m, 1H), 2.92 (dd, 1H), 1.19 (d, 3H). LC-MS: m/e 278 (M + H) + (2.4 min).

The amines of Reference Examples 27-29 were prepared according to the procedures described in Reference Example 26: REFERENCE EXAMPLE 27

2-Amino-4- (4-chlorophenyl)-3- (2-fluorophenyl) butane hydrochloride salt (mixture of diastereomers oc/ß 10 : 1) LC-MS: m/e 278 (M + H) + (2.3 min).

REFERENCE EXAMPLE 28 2-Amino-4-(4-chlorophenyl)-3-(4-fluorophenyl) butane hydrochloride salt (mixture of diastereomers o/ß 10: 1) LC-MS: m/e 278 (M + H) + (2.5 min).

REFERENCE EXAMPLE 29 2-Amino-4-(4-chlorophenyl)-3-(4-pyridyl) butane hydrochloride salt (mixture of diastereomers azid 10: 1) Trimethyl aluminum was used in place of dimethylaluminum chloride at Step B of Reference Example 26. LC-MS: m/e 261 (M + H) +.

REFERENCE EXAMPLE 30

2-Amino-4- (4-cyanophenyl)-3-phenylbutane hydrochloride salt (mixture of diastereomers ot/ß 10: 1) Step A 4- (4-Cyanophenyl)-3-phenyl-2-butanone.

To a solution of phenylacetone (1.2 g, 9.0 mmol) and 4-cyanobenzyl chloride (1.4 g, 9.0 mmol) in 20 mL CH2Cl2at-78°C was added cesium hydroxide monohydrate (4.5 g, 27 mmol) and tetrabutyl ammonium iodide (20 mg). The reaction was allowed to warm to room temperature over 6 h, and the resulting mixture partitioned between brine (100 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 20-50% EtOAc in hexane to give the title compound. 1H NMR (500 MHz, CD30D) : 8 7.52 (d, 2H), 7.34-7. 16 (m, 7H), 4.12 (dd, 1H), 3.41 (dd, 1H), 3.00 (dd, 1H). LC-MS: m/e 250 (M + H) + (3. 2 min).

Step B 2-Amino-4- (3-cyanophenyl)-3-phenylbutane hydrochloride salt (mixture of diastereomers α/ß 10 : 1).

The product of Step A (4- (4-cyanophenyl)-3-phenyl-2-butanone) (1.0 g, 4.0 mmol) was converted to the title compound following the procedure described in Reference Example 2, Steps E-I. LC-MS: m/e 251 (M + 1-1) + (1.9 min).

REFERENCE EXAMPLE 31

2-Amino-4- (5-chloro-2-pyridyl)-3-phenylbutane hydrochloride salt (mixture of diastereomers cc/ß 10 : 1) 5-Chloro-2-choromethylpyridine (Weidmann, K. et al. J. Med. Chem. 1992, 35, 438) was used in place of 4-cyanobenzyl bromide in Step A of Reference Example 30. LC-MS: m/e 261 (M + H) +.

REFERENCE EXAMPLE 32 2-Amino-4- (2, 4-dichlorophenyl)-3- (4-chlorophenyl) butane hydrochloride salt (3 isomers) Step A Methyl 3-(2,4-Dichlorophenyl)-2-(4-chlorophenyl)propionate.

A sample of 4-chlorophenylacetic acid (4.2 g, 25 mmol) was converted to the title compound (6.5 g) following the procedure in Reference Example 26, Step A substituting 4-chlorophenylacetic acid for 3-fluorophenylacetic acid and 2,4- dichlorobenzyl bromide for 4-chlorobenzyl bromide following the procedures described in Reference Example 2, Step A. 1H NMR (500 MHz, CD30D): 8 7.40 (d, 1H), 7.32-7. 22 (m, 4 H), 7.15 (dd, 1H), 7.08 (d, 1H), 4.00 (t, 1H), 3.62 (s, 3H), 3.44 (dd, 1H), 3.12 (dd, 1H).

Step B 3-(2, 4-Dichlorophenyl)-2-(4-chlorophenyl) propanol.

To a solution of methyl 3- (2, 4-dichlorophenyl)-2- (4-chorophenyl) propionate (6.4 g, 8.6 mmol) in 50 mL ether at-40°C was added lithium aluminum hydride (1.4 g, 37

mmol), and the reaction was allowed to warm to room temperature over 2 h. The reaction was quenched by addition of MeOH (3 mL) dropwise at - 10°C, and the mixture was partitioned between 100 mL saturated ammonium chloride and EtOAc (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the title compound, which was used without further purification. 1H NMR (400 MHz, CD30D) : 8 7.4- 6.9 (m, 7H), 3.72 (m, 2H), 3.24 (dd, 1H), 3.16 (m, 1H), 2.85 (dd, 1H).

Step C 3- (2, 4-Dichlorophenyl)-2- (4-chorophenyl) propanal.

To a solution of 3- (2, 4-dichlorophenyl)-2- (4-chorophenyl) propanol (Step B, 0.89 g, 2.8 mmol) in 20 mL CH2C12was added crushed activated molecular sieves (4 g).

After stirring at room temperature for 10 min, pyridinium chlorochromate (0.90 g, 4.2 mmol) was added. After stirring at room temperature for 1 h, CELITE diatomaceous earth (4 g) was added followed by 100 mL ether. The resulting mixture was filtered through a silica gel pad, which was washed with ether (2 x 50 mL). The filtrate was concentrated to dryness and azeotroped with toluene to give the title compound, which was used without further purification.

Step D N-r3- (2, 4-Dichlorophenyl)-2- (4-chorophenyl) propylidenel-2- propanesulfinamde.

To a solution of 3- (2, 4-dichlorophenyl)-2- (4-chorophenyl) propanal (Step C, 0.90 g, 2.8 mmol) in 6 mLTHF was added (R)- (+)-2-methyl-2-propane-sulfinamide (0.5 gm, 4.1 mmol) followed by the addition of titanium tetraethoxide (1.5 mL, 8. 0 mmol).

After stirring at room temperature overnight, the reaction mixture was added to a well-stirred brine solution (50 mL). The resulting mixture was filtered through CELITE diatomaceous earth and washed with EtOAc (20 mL), and the filtrate was extracted with EtOAc (2 x 50 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 10% ether in hexane to give the title compound as a 1: 1 mixture of diastereomers. 1H NMR (500 MHz, CD30D): 8 8. 11 (m, 1H), 7.41 (m, 1H), 7.35-7. 31 (m, 4 H), 7.16-7. 06 (m, 2H), 4.26 (m, 1H), 3.78-3. 58 (m, 1H), 3.22-3. 14 (m, 1H), 1.13/1. 12 (s, 9H).

Step E N-f3(2, 4-Dichlorophenyl)-2- (4-chorophenyl)-1-methylpropyll-2- methylpropanesulfinamide (3 isomers).

To a solution of N- [3- (2, 4-dichlorophenyl)-2- (4-chorophenyl)-1-methylpropylidene]- 2-methylpropanesulfinamde (Step D, 0.51 g, 1.3 mmol) in 6 mL CH2Cl2at-60°C was added methylmagnesium bromide (3 M in ether, 0.90 mL, 2.7 mmol). After stirring at - 60°C for 6 h, the reaction was allowed to warm to room temperature overnight. The resulting mixture was partitioned between saturated aqueous ammonium chloride (50 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 50 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 30 to 50% EtOAc in hexane to give the title compound as one pure faster eluting enantiomer and a 1: 1 mixture of slower co-eluting diastereomers. The addition of the methyl Grignard reagent was apparently stereoselective for one of the sulfinamide diastereomers.

Faster eluting isomer: 1H NMR (500 MHz, CD30D): 8 7.30 (d, 1H), 7.22 (d, 2H), 7.12 (d, 2H), 7.03 (dd, 1H), 6.94 (d, 1H), 3.62 (m, 1H), 3.56 (dd, 1H), 2.97 (dd, 1H), 1.23 (s, 9H), 1.04 (d, 3H). LC-MS: m/e 432 (M + Fizz (4.2 min).

Slower eluting isomers (1: 1): 1H NMR (500 MHz, CD30D) : 8 7.33/7. 30 (d, 1H), 7.21/7. 18 (d, 2H), 7.06/7. 04 (d, 2H), 6.99/6. 97 (dd, 1H), 6.79/6. 75 (d, 1H), 3.70-3. 55 (m, 1H), 3.07/2. 97 (m, 1H), 2.90/2. 80 (dd, 1H), 1.32/0. 95 (s, 9H), 1.49/1. 10 (d, 3H).

Step F 2-Amino-4- (2, 4-dichlorophenyl)-3- (4-chorophenyl) butane hydrochloride (3 isomers).

To a solution of N- [3- (2, 4-dichlorophenyl)-2- (4-chorophenyl)-1-methylpropyl]-2- methylpropanesulfinamde (Step F, faster eluting isomer, 50 mg, 0.11 mmol) in 5 mL MeOH was added hydrogen chloride in dioxane (4 M, 2 mL). After stirring at room temperature for 10 min, the reaction mixture was concentrated to dryness to give the title compound as one pure isomer.

Isomer 1 : 1H NMR (500 MHz, CD30D) : 8 7.35 (d, 1H), 7.29 (d, 2H), 7.15 (d, 2H), 7.06 (dd, 1H), 6.91 (d, 1H), 3.68 (m, 1H), 3.36 (dd, 1H), 3.06 (dd, 1H), 1.18 (d, 3H).

LC-MS: m/e 328 (M + H) + (2.8 min).

The two slower co-eluting isomers were treated in the same fashion to give two other isomers of the title compound. Isomer 2 and 3 (1 : 1) : LC-MS: m/e 328 (M + H) + (2.7/2. 8 min).

REFERENCE EXAMPLE 33

2-Amino-4- (4-chloro-2-fluorophenyl)-3- (4-chlorophenyl) butane hydrochloride sal (Isomers, 1, 2 and 3).

The title compound was prepared according to the procedures of Reference Example 32 substituting 2,5-dichlorobenzyl bromide with 4-chloro-2- fluorobenzyl bromide.

Isomer 1: LC-MS: m/e 312 (M + H) + (2.6 min).

Isomer 2 and 3 (1: 1): LC-MS: m/e 312 (M + 1-1) + (2.5/2. 6 min).

REFERENCE EXAMPLE 34 2- (4-Chlorophenyloxy)-2- (4-chlorophenyl) ethylamine hydrochloride salt.

Step A 2- (4-Chlorophenyloxy)-2- (4-chlorophenyl) ethanol.

To a suspension of 2- (4-chlorophenyloxy)-2- (4-chlorophenyl) acetic acid (Newman et al J. Amer. Chem. Soc. 1947, 69, 718) (1.0 g, 3.4 mmol) in 10 mLTHF at 0°C was added borane (1 M in THF, 6.8 mL, 6.8 mmol). After stirring at room temperature for 2 h, the reaction was quenched by addition of 2 M hydrochloric acid (10 mL). The volatile materials were removed on a rotary evaporator, and the resulting mixture was partitioned between brine (20 mL) and EtOAc (30 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 20 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to

dryness to give the title compound, which was used without further purification. LC- MS: m/e 283 (M + H) + (3.4 min).

Step B 2- (4-Chlorophenoylxv)-2- (4-chlorophenyl) ethyl Azide 2- (4-Chlorophenyloxy)-2- (4-chlorophenyl) ethanol (Step A, 0.45 g, 2.4 mmol) was converted to the title compound (0.29 g) following the procedure described in Reference Example 26, Step D. 1H NMR (500 MHz, CD30D) : 8 7.41 (d, 2H), 7.37 (d, 2H), 7.18 (d, 2H), 6.86 (d, 2H), 5.42 (dd, 1H), 3.69 (dd, 1H), 3.45 (dd, 1H). LC-MS: m/e 308 (M + H) + (4.3 min).

Step C 2- (4-Chlorophenoylxy)-2- (4-chlorophenyl) ethylamine.

To a solution of 2- (4-chlorophenoylxy)-2- (4-chlorophenyl) ethyl azide (Step B, 0.23 g, 0.75 mmol) in 4 mLTHF at-20°C was added trimethylphosphine (0.18 mL, 1.8 mmol), and the reaction was allowed to warm to room temperature over 2 h. Lithium hydroxide monohydrate (61 mg, 1.5 mmol) was added followed by 2 mL water. After stirring at room temperature for 30 min, the reaction was quenched by addition of 2 M hydrochloric acid (final pH = 2). The volatile materials were removed on a rotary evaporator, and the resulting mixture was partitioned between brine (20 mL), 5 N aqueous sodium hydroxide (20 mL), ether (20 mL) and toluene (20 mL). The organic layer was separated and the aqueous layer extracted with ether (40 mL). The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the title compound (0.43 g), which was contaminated with trimethylphosphine oxide and was used without further purification. 1H NMR (500 MHz, CD30D): 5 7.46-7. 40 (m, 4H), 7.20 (d, 2H), 6.91 (d, 2H), 5.53 (m, 2H), 3.36 (m, 2H). LC-MS: m/e 282 (M + H) + (2.5 min).

REFERENCE EXAMPLE 35 2fl2-Bis (4-chlorophenyl) ethylamine hydrochloride salt

Step A Methyl 3. 3-Bis (4-chlorophenyl) propenoate A mixture of di (4-chlorophenyl) ketone (7. 5 g, 30 mmol) and methyl (triphenylphosphoranylidene) acetate (10 g, 30 mmol) in 20 mL toluene was heated at 130°C while allowing the solvent to slowly evaporate overnight. The resulting mixture was dissolved in CH2C12 (20 mL) and toluene (20 mL) and was concentrated with 30 g silica gel. The material was loaded onto a silica gel column, which was eluted with 6: 3: 1 hexane/CH2Cl2/ether to give the title compound.

Step B Methyl 3,3-Bis (4-chlorophenyl) propionate A suspension of methyl 3,3-bis (4-chlorophenyl) propenoate (Step A, 3.0 g, 14 mmol) and platinum dioxide (0.30 g) in MeOH (20 mL) and 2 M aqueous hydrochloric acid (1 mL) was degassed and filled with hydrogen with a balloon. After stirring at room temperature for 2 h, the reaction mixture was filtered through CELITE diatomaceous earth, and the filtrate was concentrated to dryness. The residue was dissolved in 50 mL ether and was concentrated with 20 g silica gel. The material was loaded onto a silica gel column, which was eluted with 10% ether in hexane to give the title compound. 1H NMR (500 MHz, CD30D): 8 7.29-7. 22 (m, 4H), 4.50 (t, 1H), 3.56 (s, 3H), 3.07 (d, 2H). LC-MS: m/e 309 (M + H) + (4.1 min).

Step C 3,3-Bis (4-chlorophenyl) propionic Acid A mixture of methyl 3,3-bis (4-chlorophenyl) propionate (Step B, 0. 78 g, 3.9 mmol), lithium hydroxide monohydrate (0.33 g, 7.8 mmol) in 1: 1: 1 MeOH/ THF/water (15 mL) was stirred at room temperature overnight. The resulting mixture was partitioned between 2 M aqueous hydrochloric acid (50 mL) and ether (50 mL).

The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 50 mL). The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD30D): 8 7. 29-7.23 (m, 4H), 4.49 (t, 1H), 3.02 (d, 2H).

Step D N-F2, 2-Bis (4-chlorophenyl) ethyllallylcarbamate.

To a solution of 3, 3-bis (4-chlorophenyl) propionic acid (Step C, 0.32 g, 1. 1 mmol) and triethyl amine (0.60 mL, 4.3 mmol) in 4 mLTHF at 0 °C was added ethyl chloroformate (0.31 mL, 3.3 mmol). After stirring at room temperature for 30 min, the reaction was cooled to 0°C, and was added sodium azide (0.35 g, 5.4 mmol) in 2 mLwater. After stirring at room temperature for 1 h, the reaction mixture was partitioned between brine (20 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 20 mL). The combined

extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was dissolved in allylic alcohol (1 mL) and toluene (1 mL).

After stirring at 80°C overnight, the reaction mixture was concentrated to dryness, and the residue was purified by flash column chromatography on silica gel column eluted with 20% EtOAc in hexane to give the title compound. 1H NMR (500 MHz, CD30D) : 8 7.30-7. 21 (m, 4H), 5.84 (m, 1H), 5.17 (dd, 1H), 5.10 (dd, 1H), 4.46 (d, 2H), 4.22 (t, 1H), 3.68 (d, 2H). LC-MS: m/e 350 (M + H) + (3.9 min).

Step E 2, 2-Bis (4-chlorophenyl) ethylamine hydrochloride salt.

To a solution of N- [2, 2-bis (4-chlorophenyl) ethyl] allylcarbamate (Step D, 0.26 g, 0.73 mmol) in 1.5 mLTHF at 0°C was added tetrakis (triphenylphosphine) palladium (85 mg, 0.073 mmol) and triphenylsilane (0.18 mL, l. lmmol). After stirring at 0°C for 1 h, the reaction mixture was partitioned between ether (20 mL) and 2 M hydrochloric acid (20 mL). The aqueous layer was separated, and was added 5 N aqueous sodium hydroxide (final pH > 12). The product was extracted with ether (3 x 30 mL), and the combined extracts were dried over sodium hydroxide, and filtered through CELITE, diatomaceous earth. After addition of 4 M hydrogen chloride in dioxane (2 mL), the filtrate was concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD30D): 8 7.40-7. 34 (m, 4H), 4. 28 (m, 1H), 3.62 (d, 2H). LC-MS: m/e 266 (M + H) + (2.3 min).

REFERENCE EXAMPLE 36 2-Amino-3- (4-chlorophenylthio)-3- (4-chlorophenyl) propane hydrochloride salt (two diastereomers) Step A Methyl 2- (4-Chlorophenylthio)-2- (4-chlorophenyl) acetate.

To a solution of 2- (4-chlorophenylthio)-2- (4-chlorophenyl) acetic acid (Nicolaescu et al Rev. Roum. Chim. 1979, 24, 137) (1.0 g, 3.0 mmol) in MeOH (10 mL) and CH2C12 (10 mL) at 0°C was added trimethylsilyldiazomethane (2 M in

hexane) until a yellow color persisted. Concentration afforded the title compound, which was used without further purification.

Step B 2-Amino-3- (4-chlorophenylthio)-3- (4-chlorophenyl) propane hydrochloride salt (two diastereomers) The product of Step A (methyl 2- (4-chlorophenylthio)-2- (4- chlorophenyl) acetate) (1.1 g, 3.0 mmol) was converted to the title compound following the procedures described in Reference Example 26 Steps B-E.

LC-MS: m/e 312 (M + H) + (2. 7 min).

REFERENCE EXAMPLE 37 2-Amino-3, 4-bis (4-chlorophenyl)-2-methylbutane hydrochloride salt Step A Methyl 2,3-Bis (4-chlorophenyl) propionate.

The title compound was prepared following the procedure described in Reference Example 2, Step A, substituting methyl phenylacetate with methyl 4- chlorophenylacetate. 1H NMR (500 MHz, CD30D): 8 7. 30-7. 22 (m, 4H), 7.19 (d, 2H), 7.09 (d, 2H), 3.90 (t, 1H), 3.58 (s, 3H), 3.32 (dd, 1H), 2.98 (dd, 1H).

Step B 3,4-Bis (4-chlorophenyl)-2-methyl-2-butanol.

To a solution of methyl 2,3-bis (4-chlorophenyl) propionate (2.6 g, 8.4 mmol) in ether (20 mL) was added methylmagnesium bromide (3 M in ether, 8.4 mL, 25 mmol) at-10°C, and the reaction was allowed to warm to room temperature over 2 h. The reaction mixture was poured into saturated aqueous ammonium chloride (100 mL), and the product was extracted with EtOAc (3 x 100mL). The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the title compound, which was used without further purification. 1H NMR (500 MHz, CD30D): 8 7.17 (ABq, 4H), 7.06 (d, 2H), 6.93 (d, 2H), 3.32 (dd, 1H), 2.94 (dd, 1H), 2.84 (dd, 1H), 1.20 (s, 3H), 1.16 (s, 3H).

Step C N-r2, 3-Bis (4-chlorophenyl)-1, 1-dimethylpropyllchloroacetamide.

To a solution of 3,4-bis (4-chlorophenyl) -2-methyl-2-butanol (Step B, 1.4 g, 4.5 mmol) and chloroacetonitrile (0.57 mL, 9.1 mmol) in acetic acid (0.7 mL) at - 10°C was added concentrated sulfuric acid (0.31 mL, 14 mmol). After stirring at- 10°C for 15 min and room temperature for 2 h, the reaction mixture was poured onto ice (20 g), and the product was extracted with EtOAc (3 x 20 mL). The combined extracts were washed with brine/saturated aqueous sodium bicarbonate, dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the title compound.

1H NMR (500 MHz, CD30D) : 8 7.19 (ABq, 4H), 7.06 (d, 2H), 6.95 (d, 2H), 3.93 (ABq, 2H), 3.89 (dd, 1H), 3.10 (dd, 1H), 2.99 (dd, 1H), 1.43 (s, 3H), 1.25 (s, 3H). LC- MS: m/e 384 (M + H) + (3.9 min).

Step D 2-Amino-3,4-bis (4-chlorophenyl) -2-methylbutane hydrochloride To a solution of N [2, 3-bis (4-chlorophenyl)-1, 1-dimethylpropyl] chloroacetamide (Step C, 1.3 g, 3.8 mmol) in ethanol (10 mL) and acetic acid (2 mL) was added thiourea (0.34 g, 4.5 mmol). The reaction was stirred at 80°C overnight to give a white precipitate. The precipitate was removed by filtration and washed with ethanol (10 mL), and the filtrate was diluted with dilute aqueous sodium hydroxide and extracted with hexane (2 x 50 mL). The combined extracts were dried over sodium hydroxide, filtered, and concentrated to dryness, and the residue was taken up by hydrogen chloride in dioxane (4 M, 5 mL) and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD30D): (free amine) 8 7.22-7. 14 (m, 4H), 7.06 (d, 2H), 6.96 (d, 2H), 3.22 (dd, 1H), 2.95 (dd, 1H), 2.86 (dd, 1H), 1.16 (s, 3H), 1.10 (s, 3H).

REFERENCE EXAMPLE 38 2-Amino-5-methyl-3-phenylhexane hydrochloride salt Step A 4-Methyl-2-phenylpentanoic acid

A solution of 0.25 g (1.84 mmol) of phenylacetic acid in 3.6 mL dry THF was cooled in ice bath and 4 mL 1M lithium bis (trimethylsilyl) amide was added. After 15 min, 0.23 mL (2.02 mmol) of isobutyliodide was added and the cold bath was removed. After stirring the reaction overnight, it was quenched with water and extracted once with EtOAc. The aqueous layer was acidified with 1.2 N HC1 and extracted with EtOAc. The EtOAc solution was washed with brine, dried and concentrated to furnish the title compound which was used in the next step without purification. 1H NMR : (500 MHz, CDC13) : 80. 92 (d, 6H), 1.51 (m, 1H), 1.72 (m, 1H), 1.98 (m, 1H), 3.67 (m, 1H), 7.0-7. 4 (m, 5H).

Step B N-Methoxy-N-methyl-4-methyl-2-phenylpentanamide To a solution of 0.234 g (1.22 mmol) of 4-methyl-2-phenylpentanoic acid in 6 mL CH2C12 and 2 drops of DMF, 0.12 mL (1.34 mmol) of oxalyl chloride was added. The solution was stirred for 1 h and concentrated. The residue was dissolved in 1 mL CH2C12 and added to a mixture of 0.142 g N, O- dimethylhydroxylamine hydrochloride in 4 mL CH2Cl2and 4 mL saturated NaHCO3.

After stirring for 4 h, the layers were separated and the aqueous layer was extracted with CH2C12. The combined CH2C12 layer was washed with brine, dried and concentrated to give the title compound which was used in the next step without purification. 1H NMR : (500 MHz, CDC13) : 8 0.94 and 0.96 (2d, 6H), 1.5 (m, 1H), 1.67 (m, 1H), 2.0 (m, 1H), 3.19 (s, 3H), 3.54 (s, 3H), 4.18 (br, 1H), 7.2-7. 4 (m, 5H).

Step C 5-Methyl-3-phenyl-2-hexanone To a solution of 75 mg (0.317 mmol) N-methoxy-N-methyl-4-methyl- 2-phenylpentanamide in 1 mL dry THF, 0.45 mL 1.4 M methylmagnesium bromide was added. The reaction was stirred for 1 h, quenched with 1.2 N HC1 and extracted with EtOAc. The EtOAc solution was washed with brine, dried and concentrated leaving the title compound. 1H NMR: (500 MHz, CDC13) : 8 0.95 (2d, 6H), 1.42 (m, 1H), 1.67 (m, 1H), 1.9 (m, 1H), 2.06 (s, 3H), 3.73 (m, 1H), 7.0-7. 4 (m, 5H).

Step D 5-Methyl-3-phenyl-2-hexanol A solution of 66 mg (0.345 mmol) of 5-methyl-3-phenyl-2-hexanone in 1 mL MeOH was treated with 16 mg sodium borohydride. After 1.5 h, the reaction was quenched with 1.2 N HCl and concentrated. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried and concentrated to yield the crude title compound which was used without purification. 1H NMR: (500 MHz, CDC13) : 8 0.88 (2d, 6H), 1.0-1. 8 (m, 4H), 1.2 (d, 3H), 2.64 (m, 1H), 3.9 (m, 1H), 7.2-7. 4 (m, 5H).

Step E 2-Azido-5-methyl-3-phenylhexane.

To a solution of 60 mg 5-methyl-3-phenyl-2-hexanol in 2 mL CH2C12, 0.163 g (0.62 mmol) of triphenylphosphine and 96 mg (0.31 mmol) of zinc azide pyridine were added. The reaction mixture was cooled in an ice bath and 98 mL (0.62 mmol) of DEAD was added. The cold bath was removed and the solution was stirred for 3 h. The reaction mixture was filtered through a pad of CELITE diatomaceous earth and the pad was rinsed with CH2C12. The filtrate was concentrated and the residue was purified by prep-TLC using 20% EtOAc-hexane to isolate the title compound. 1H NMR : (500 MHz, CDC13) : 8 0.88 (2d, 6H), 1.12 (d, 3H), 1.31 (m, 1H), 1.72 (m, 2H), 2.68 (m, 1H), 3.53 (m, 1H), 7.2-7. 4 (m, 5H).

Step F 2-Amino-5-methyl-3-phenylhexane.

To a solution of 32 mg 2-azido-5-methyl-3-phenylhexane in 1 mL MeOH and 2 drops of 1.2 N HCI, 4 mg Pt02 was added and the solution was stirred under H2 atmosphere for 2 h. The reaction was filtered through a pad of CELITE diatomaceous earth and the pad was rinsed with MeOH. The combined filtrate was concentrated to give the desired product. 1H NMR: (500 MHz, CDC13) : 8 0.86 (m, 6H), 0.99 (d, 3H), 1.25 (m, 1H), 1.54 (m, 1H), 1.77 (m, 1H), 2.73 (m, 1H), 3.19 (m, 1H), 7.2-7. 4 (m, 5H).

REFERENCE EXAMPLE 39 N-r3-(4-Chlorophenyl)-2-(3, 5-difluorophenyl)-1-methylpropYllamine hydrochloride (Diastereomer a) The title compounds was prepared following the procedures described for Reference Example 2 substituting methyl phenylacetate with methyl 3,5- difluorophenylacetate (prepared from 3,5-difluorophenylacetic acid and trimethylsilyldiazomethane) at Step A and sodium borohydride in MeOH with lithium tri (sec-butylborohydride in THF at Step E. LC-MS: m/e 296 (M + H) + (2.39 min).

REFERENCE EXAMPLE 40

N-[2-(3-Bromophenyl)-3-(4-chlorophenyl)-1-methylpropyl]amine hydrochloride (Diastereomer ot) The title compounds was prepared following the procedures described for Reference Example 2 substituting methyl phenylacetate with methyl 3- bromophenylacetate (prepared from 3-bromophenylacetic acid and trimethylsilyldiazomethane) at Step A and sodium borohydride in MeOH with lithium tri (sec-butylborohydride in THF at Step E. LC-MS: m/e 338 (M + H) + (2. 5 min).

REFERENCE EXAMPLE 41

N-r3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyllamine hydrochloride (Diastereomer (x) Step A 2-(N-tert-Butoxycarbonyl)amino-4-(4-chlorophenyl)-3-(3- cyanophenyl)butane

To a solution of 2- (N-tert-butoxycarbonyl) amino-3-bromophenyl-4- (4- chlorophenyl) butane (Intermediate of Reference Example 40 1.0 g, 2.3 mmol) in 5 mL DMF was added zinc cyanide (0.16 g, 1.4 mmol), tris (dibenzylidene- acetone) dipalladium chloroform complex (3.0 mg, 2.8 tmol), 1, 1'-bis (diphenylp- hosphino) ferrocene (5.0 mg, 9.0 Amol) and water (0.1 mL). After heating at 120°C for 6 h under nitrogen, another batch of zinc cyanide (0.16 g, 1.4 mmol), tris (dibenzylideneacetone) dipalladium chloroform complex (5.0 mg, 4.8 mol), 1,1'- bis (diphenylphosphino) ferrocene (5.0 mg, 9.0 pool) and water (0.05 mL) was added, and heating was continued for another 18 h. 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 extracted with ether (2 x 50 mL).

The combined extracts were dried over anhydrous MgSO4, filtered and concentrated, and the residue was purified by flash column chromatography on silica gel eluted with 20% EtOAc in hexane to afford the title compound. 1H NMR (400 MHz, CD30D) : 8 7.6-7. 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) + (3.9 min).

Step B N-r3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyllamine hydrochloride (Diastereomer a) The title compound was prepared following the procedure described for Reference Example 2, Step I. LC-MS: m/e 285 (M + H) + (2.2 min).

REFERENCE EXAMPLE 42 N-r2- (3-Chlorophenyl)-3 (4-chlorophenyl)-1-methylpropyllamine hydrochloride (Diastereomer a) <BR> <BR> Step A 2-(N-tert-Butoxycarbonyl) amino-4-(4-chlorophenyl)-3-(3-<BR> <BR> trimethvlstannylphenyl) butane

To a solution of 2-(N-tert-butoxycarbonyl) amino-3-(3-bromophenyl)-4-(4- chlorophenyl) butane (intermediate of Reference Example 40,1. 5 g, 3.4 mmol) in 15 mL anhydrous dioxane was added hexamethylditin (1.6 g, 4.8 mmol), triphenylphosphine (18 mg, 0.068 mmol), lithium chloride (0.16 g, 3.8 mmol) and tetrakis (triphenyl-phosphine) palladium (0.20 g, 0.17 mmol). After heating at 95°C for 7.5 h under nitrogen, the reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with 10% aqueous potassium fluoride and brine, dried over anhydrous MgSO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluted with 20% EtOAc in hexane to afford the title compound. 1H NMR (500 MHz, CD30D) : 8 7.3-7. 2 (m, 2H), 7.07 (d, J=8.5 Hz, 2H), 7.06-6. 99 (m, 2H), 6.86 (d, J=8.5 Hz, 2H), 3.93 (m, 1H), 3.18 (m, 1H), 2.76 (m, 2H), 1.51 (s, 9H), 0.94 (d, J=7.0 Hz, 3H), 0.21 (s, 9H).

Step B 2- (N-tert-Butoxycarbonyl) amino-3- (3-chlorophenyl)-4- (4- chlorophenyl) butane To a solution of 2- (N-tert-butoxycarbonyl) amino-4- (4-chlorophenyl)-3- (3- trimethylstanylphenyl) butane (0.55 g, 1.0 mmol) in 5 mL CH2C12 at 0°C was added tert-butoxychloride (freshly prepared, 0.20 mL, 1.1 mmol). The reaction was allowed to warm to room temperature over 2 h, and the resulting mixture was concentrated with 2 g silica gel. The residue was purified by flash column chromatography on silica gel eluted with 10% ether in hexane to afford the title compound. 1H NMR (500 MHz, CD30D): 5 7.25-7. 15 (m, 2H), 7.11 (d, J=8.5 Hz, 2H), 7.09 (m, 1H), 6.99 (d, J=7.5 Hz, 1H), 6. 92 (d, J=8.5 Hz, 2H), 3.88 (m, 1H), 3.19 (dd, J=13.0, 3.5 Hz, 1H), 2.90-2. 75 (m, 2H), 1.50 (s, 9H), 0.94 (d, J=6.5 Hz).

Step C N-r2- (3-Chloroophenyl)-3- (4-chlorophenyl)-1-methylpropyllamine hydrochloride (Diastereomer a) The title compound was prepared following the procedure described for Reference Example 2, Step I. LC-MS: m/e 294 (M + H) + (2.82 min).

REFERENCE EXAMPLE 43

N-r2-(3-Bromophenyl)-3-(4-chlorophenyl)-1-methylpropYllamine hydrochloride and N-r3- (4-Chlorophenyl)-2- (3-iodophenyl)-l-methylpropyllamine hydrochloride (1: 1 mixture) (Diastereomer a) <BR> <BR> <BR> Step A 2- (N-tert-Butoxycarbonyl) amino-3- (3-bromophenyl)-4- (4-<BR> <BR> <BR> <BR> <BR> chlorophenyl)-butane and 2- (N-tert-Butoxycarbonyl) amino-4- (4-<BR> <BR> <BR> <BR> <BR> chlorophenyl)-3- (3-iodophenyl) butan To a solution of 2-(N-tert-butoxycarbonyl)amino-3-(3-bromophenyl)-4-(4- chlorophenyl) butane (intermediate of Reference Example 40,2. 6 g, 5.9 mmol) in 7 mL anhydrous THF at 0°C was added methylmagnesium chloride (3 M in THF, 3.9 mL, 12 mmol). After 30 min, the reaction mixture was cooled to-78°C, and was added tert-butyllithium (1.7 M, 10 mL, 17 mmol). After stirring at-78°C for 2 h, the reaction was allowed to warm to 0°C, and half of the resulting mixture was added to a suspension of iodine (5.0 g, mmol) in 10 mL THF at-40°C. The reaction mixture was allowed to warm to room temperature over 2 h, and was partitioned between ether (100 mL) and saturated aqueous ammonium chloride (100 mL). The organic layer was separated and the aqueous layer extracted with ether (2 x 50 mL). The combined extracts were washed with dilute aqueous sodium thiosulfate (2x) and brine, dried over anhydrous MgS04, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluted with 10% EtOAc in hexane to afford the title compounds as a 1: 1 mixture. <BR> <BR> <BR> <P>Step B N-r2-(3-Bromophenyl)-3-(4-chlorophenyl)-1-methylpropyllamine <BR> <BR> <BR> <BR> <BR> hydrochloride and N-r3- (4-chlorophenyl)-2- (3-iodophen. yl)-1- methylpropyll amine hydrochloride (1: 1 mixture) (Diastereomer oc) The title compound was prepared following procedure described for Reference Example 2, Step I. LC-MS: m/e 338/386/ (M + H) + (2. 6 min).

REFERENCE EXAMPLE 44

2-Amino-4- (4-chlorophenyl)-3-cyclobutylmethoxybutane.

Step A Methyl 2-diazo-3- (4-chlorophenyl) propanoat DL-4-Chlorophenylalanine methyl ester (5.0 g, 23.36 mmol) was dissolved in 120 mL chloroform and placed into an oven-dried 3-neck flask equipped with a condenser and an addition funnel. Glacial acetic acid (0.267 mL, 4.672 mmol) was added. Finally, isoamylnitrite (3.8 mL, 28 mmol) was added dropwise while slowly bringing the reaction to reflux (73°C). The reaction was refluxed for 30 minutes and then cooled to 0°C. The reaction mixture was washed with cold 1 N sulfuric acid solution, cold water, cold saturated aqueous sodium bicarbonate solution, and then cold water again. The organic extracts were dried over MgS04, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (Biotage 40M cartridge, gradient elution using hexane and EtOAc (100: 1 to 50: 1) to provide a yellow oil, homogeneous by TLC, Rf=0. 48 (4: 1 hexanes: EtOAc). 500 MHz 1H NMR (CDC13): 8 3.65 (s, 2H) ; 3. 83 (s, 3H); 7.22 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.5, 2H).

Step B Methyl 3-(4-chlorophenyl)-2-cyclobutylmethoxypropanoate.

To a solution of 500 mg (2.23 mmol) of methyl-2-diazo-3- (4- chlorophenyl) propanoate (obtained from Step A) and 1.05 mL (5 eq; 11.1 mmol) of cyclobutanemethanol in 5 mL benzene in a pressure tube was added 10 mg (1 mole %) of Rh2 (OAc) 4 catalyst. The tube was sealed and heated to 90°C for 1.5 h. The solvents were evaporated under reduced pressure and the crude material was taken up in CH2C12 and purified by flash chromatography via gradient elution using mixtures of hexane and EtOAc (100: 1 to 50: 1). This provided the title compound as a clear oil.

TLC Rf=0. 53 (4: 1 hexanes: EtOAc). 500 MHz 1H NMR (CDC13) : 5 1. 68 (m, 2H);

1.85 (m, 1H); 1.88 (m, 1H) ; 2.01 (m, 2H); 2.53 (sep, 1H) ; 2.98 (m, 2H); 3.24 (dd, 1H); 3.58 (dd, 1H) ; 3.76 (s, 3H); 3. 98 (dd, 1H) ; 7.20 (d, 2H) ; 7.28 (d, 2H).

Step C 4- (4-Chlorophenyl)-3-cyclobutylmethoxybutan-2-one.

At 0° C, under anhydrous conditions, to a stirred suspension of N, O- dimethylhydroxylaminehydrochloride (732 mg, 7.50 mmol) in 60 mL CH2Cl2 was added dimethylaluminum chloride (7.5 mL, 1M solution in hexanes). The solution was allowed to warm to room temperature over a period of one hour. At that point a solution of methyl 2-cyclobutylmethoxy-3- (4-chlorophenyl) propanoate (531 mg, 1.88 mmol, obtained from Step B) in CH2C12 (8 mL) was added dropwise. The reaction was allowed to stir overnight at room temperature when TLC indicated completion of reaction. The reaction was worked up by the addition of pH=8 phospate buffer (25 mL, approx. 3 mL/mmol of Me2AlCl) and allowed to stir at room temperature for 30 minutes, diluted with chloroform (75 mL), and the phases were separated. The organic layer was washed with water and dried over MgSO4. The solvents were evaporated under reduced pressure and the crude product was purified by flash chromatography (gradient elution using hexane and EtOAc, 20: 1 to 5: 1) to give the Weinreb amide as a clear oil). This purified material (424 mg, 1.36 mmol) was dissolved in 10 mL THF, injected into an oven dried flask, and cooled to 0°C under nitrogen. Methyl magnesium bromide (1.4 mL 3M solution in ether) was added to the solution dropwise. The reaction was allowed to warm to room temperature. After 4 h the TLC indicated a complete reaction. The reaction was quenched with enough 10% citric acid to bring the pH of the solution to approximately 3. The aqueous layer was extract with ether. The combined organics were washed with water and then dried over MgSO4. The solvents were evaporated under reduced pressure and the crude material was purified by flash chromatography (hexane: EtOAc, 100: 1 to 50: 1), resulting in 250 mg the title compound as a clear oil. TLC Rf=0. 55 (4: 1 hexanes: EtOAc). 500 MHz 1H NMR (CDC13) : 5 1. 71 (m, 2H); 1.84 (m, 1H) ; 1.91 (m, 1H); 2.01 (m, 2H); 2.17 (s, 3H) ; 2.53 (sep, 1H) ; 2.90 (m, 2H) ; 3.28 (dd, 1H) ; 3.43 (dd, 1H); 3. 81 (dd, 1H).

Step D 2-Amino-4-(4-chlorophenyl)-3-cyclobutylmethoxybutane.

A solution of 3-cyclobutylmethoxy-4- (4-chlorophenyl) butan-2-one (247 mg, 0.925 mmol, obtained from Step C) in 0.5 mL CH2C12 was added to a stirred suspension of NH40Ac (715 mg, 9.25 mmol) and NaBH3CN (35 mg, 0.555 mmol) at room temperature and allowed to stir overnight. The reaction was quenched by the addition of 2.2 mL conc. HCl allowed to stir for 30 minutes. The solvents were

evaporated under reduced pressure and the residue was partitioned between ether and water. The aqueous layer was washed two more times with ether. The combined organics were dried over Na2SO4. The crude product mixture obtained after filtration and removal of volatiles was purified by flash chromatography, eluting using mixtures of mixtures of CH2C12 and MeOH (100% CH2C12, to 5% MeOH in CH2CI2) to provide the title compound as a yellow oil, homogeneous by TLC Rf=0. 12 (5% MeOH in CH2C12). 500 MHz 1H NMR (CDC13) : 8 1.16 (t, 3H); 1.67 (m, 2H); 1.85 (m, 3H); 2.01 (m, 2H); 2.48 (m, 1H) ; 2.74 (m, 2H); 2.90 (dd, 1H) ; 3.15 (d quint, 2H); 3.37 (m, 2H). <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> 2-Amino-4- (4-chlorophenyl)-3-methoxy-butane, 2-amino-4- (4-<BR> <BR> <BR> <BR> <BR> <BR> chlorophenyl) -3-ethoxy-butane, 2-amino-4- (4-chlorophenyl)-3-n-propyloxy-butane, 2- amino-4- (4-chlorophenyl)-3-n-pentyloxy-butane, and 2-amino-4- (4-chlorophenyl)-3- cyclopentylmethoxy-butane were prepared according to the procedures described in Reference Example 44 substituting an appropriate alcohol for cyclobutylmethanol in Step B.

REFERENCE EXAMPLE 45 2-Amino-4-t4-chlorophenYl)-3-(1-pyrrolidinyl)-butane hedrochloride.

Step A Ethyl 3- (4-chlorophenyl)-2-pyrrolidin-N-yl-propanoate.

While stirring rapidly, to a mixture of DL-4-chlorophenylalanine methyl ester hydrochloride (2.5 g, 10 mmole), 40 mL ethanol and sodium carbonate (3. 18 g, 30 mmole) was added dropwise a solution of 1,4-dibromobutane (2.16 g, 10 mmol) dissolved in 20 mL ethanol. The mixture was refluxed overnight. The volatiles were removed under reduced pressure, and the residue was partitioned between water and EtOAc. The aqueous layer was re-extracted with EtOAc thrice.

The organic layers were combined and washed tieh water and brine and dried over anhydrous MgSO4. The crude product obtained after filtration and removal of

volatiles was purified via flash chromatography using mixtures of CH2C12 and MeOH to provide the titled compound as an oil, homogeneous by TLC, Rf = 0.55 in 95: 5 CH2C12 : MeOH. LC/MS m/e = 282.1 (M+1). 400 MHz 1H NMR (CDC13) 8 1.12 (t, J = 7.2 Hz, 3H), 1.72 (m, 4H), 2.67 (m, 1H), 2.76 (m, 1H), 3.05 (m, 4H), 3.43 (m, 1H), 4.05 (m, 2H), 7.13 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H) Step B 4-(4-Chlorophenyl)-3-(1-pyrrolidinyl)-butan-2-one.

The title compound was prepared according to the procedure of Reference Example 2, Step C except that ethyl 3- (4-chlorophenyl)-2- (l-pyrrolidinyl)- propanoate (from Step A) was the ester used (two steps). TLC Rf = 0.7 (95: 5 CH2C12 : MeOH). LC/MS m/e = 252 (M+1). 500 MHz 1H NMR (CDC13) 6 1.86 (br s, 4H), 2.03 (s, 3H), 2.66 (m, 2H), 2.78 (m, 2H), 2.98 (dd, J=2.9, 10.3 Hz, 1H), 3.08 (m, 1H), 3.43 (m, 1H), 7.12 (d, J = 8. 3 Hz, 2H), 7.26 (d, J = 8. 3 Hz, 2H) Step C 4- (4-Chlorophenyl)-3-pyrrolidin-N-yl-butan-2-one oxime.

To a solution of 4- (4-chlorophenyl)-3-pyrrolidin-N-yl-butan-2-one (200 mg, 0.79 mmol, from Step B) dissolved in ethanol (2 mL), was added pyridine (63 mg, 0.79 mmol), and hydroxylamine hydrochloride (78 mg, 1.12 mmol). The mixture was refluxed for 24h when LC/MS indicated disappearance of all starting material. The mixture was cooled to room temperature, concentrated under reduced pressure, treated with 33% aqueous potassium carbonated, and extracted with chloroform 5 times. The organic layers were combined and filtered over glass wool and dried over potassium carbonate. The filtrated obtained after passing through sintered glass was concentrated to give the oxime, homogeneous by TLC, Rf = 0.3 in 95: 5 CH2C12 : MeOH. LC/MS m/e = 267 (M+1). 500 MHz 1H NMR (CDC13) 8 1.73 (m, 4H), 1.76 (s, 3H), 2.40 (m, 2H), 2.60 (m, 2H), 2. 72 (dd, J=2.7, 10.8 Hz, 1H), 2.94 (dd, J=4. 3,8. 8 Hz, 1H), 3.03 (dd, J = 4.4, 13.3Hz, 1H), 3.8 (s, 1H), 6.96 (d, J = 8. 3 Hz, 2H), 7.11 (d, J = 8. 3 Hz, 2H) Step D 2-Amino-4- (4-chlorophenyl)-3-pyrrolidin-N-yl-butane hydrochloride.

At room temperature, to a solution of 4- (4-chlorophenyl)-3-pyrrolidin- N-yl-butan-2-one oxime (173 mg, 0.648 mmol, from Step C) in 1.8 mL anhydrous THF was added dropwise a 1M solution of lithium aluminum hydride in THF (0.778 mmole). The mixture was refluxed for 20 h. The reaction was quenched by addition of saturated aqueous sodium sulfate (0.1 mL), and stirred overnight. This mixture was filtered over a pad of CELITE diatomaceous earth, and the filtrate was concentrated to dryness. The mass spectrum of this material looked very messy, so the HCl salt was

prepared (by addition of a HCl (g) in ether solution) in attempt to clean up the mess.

By NMR, the reductive amination provided a-1 : 1 mixture of the two diastereomeric pairs of amines. This HCl salt was rather sticky and difficult to work with and therefore was used in the ensuing coupling experiment without further purification.

LC/MS m/e = 253 (M+1). 500 MHz 1H NMR (CD30D) 8 1.56, 1.59 (2 d, J = 7.2 Hz, 3H), 2.03 (m, 6H), 2.08 (m, 2H), 3.20-4. 00 (m, 3H), 7.43 (m, 4H) REFERENCE EXAMPLE 46 Benzyl 3-amino-2-(4-chlorobenzyl) butyrate.

Step A Benzyl 2- (4-chlorobenzyl)-3-ketobulyrate.

Benzyl acetoacetate (1.92 g, 10 mmole) and 4-chlorobenzylbromide (2.05 g, 10 mmole) were dissolved in 40mL anhydrous THF and cooled to-10°C. To this mixture was added dropwise slowly a solution of solution of sodium hexamethyl disilazide (0.5M solution in THF). Monoalkylation occurred almost exclusively of bisalkylation between-10 and 5°C. After quenching with water, the organics were extracted with EtOAc three times. The combined organic layer was washed with brine and dried over anhydrous MgS04. The crude product obtained after filtration and removal of volatiles was purified via flash chromatography using gradient elution (mixtures of hexane and EtOAc) to provide of the title compound as a clear yellow liquid, homogeneous by TLC, Rf=0. 4 in 4: 1 hexane: EtOAc. By NMR, this compound, this compound exists in a-4 : 1 ratio of the keto: enol forms. 400 MHz 1H NMR (CDC13) 8 2.08, 2.18 (2 s, 3H), 3.15 (m, 2H), 3.80 (t, J = 7. 5 Hz, 0. 8 H), 5.14, 5.17 (2 s, 2H), 7.05-7. 39 (m, 9H).

Step B Benzyl 3-amino-2-(4-chlorobenzyl) butyrate.

Benzyl 2- (4-chlorobenzyl)-3-ketobutyrate (317 mg, 1 mmole, obtained from Step A) was added to a cooled mixture of 7M ammonia in MeOH (2.42 mL) and

glacial acetic acid (1.6 mL). To this solution, at-10 °C, was added sodium cyanoborohydride (101 mg, 1.75 mmol) in small portions. This mixture was stirred at room temperature for 40 h. The excess sodium cyanoborohydride was destroyed by the addition of 6M HC1 (to pH 1). The residue obtained after removal of volatiles was taken up in a minimal amount of water and extracted with ether. The aqueous layer was basified to pH 10 using solid KOH. This layer was then saturated with sodium chloride and then extracted with EtOAc. Further analyses of the ether and the EtOAc layers suggest that the desired product resides the EtOAc layer. This material was used in the ensuing coupling reaction without further purification. Proton NMR spectrum show that the two pairs of diastereomers are obtained in-1 : 1 ratio, homogeneous by TLC, Rf = 0.4 in 95: 5 CH2C12 : MeOH. LC/MS m/e = 318 (M+1).

400 MHz 1H NMR (CDC13) 8 1.27, 1.29 (2 d, J=7Hz, 3H), 2.85 (m, 1H), 3.03 (m, 1H), 3.15 (m, 1H), 3.55 (m, 1H), 4.85 (br, 2H), 5.00-5. 18 (m, 2H), 7.0-7. 2 (m, 9H).

REFERENCE EXAMPLE 47 2-Amino-4- (4-chlorophenyl)-3-cyclopentylbutane.

Step A Methyl 3- (4-chlorophenyl)-2-cyclopentylpropanoate.

A mixture of methyl cyclopentylacetate (3.52 g, 25 mmol) and 4- chlorobenzyl bromide (4.75 g, 23 mmol) was dissolved in 100 mL THF in an oven- dried flask. The solution was cooled to-40°C and 23 mL 1M NaHMDS solution in hexanes was added slowly over an hour while maintaining the temperature at-40°C.

The solution was then stirred for an additional 3 h at-40°C. The reaction was quenched at-40°C with enough 10% citric acid solution to bring the pH to-3. 5. The aqueous layer was extracted with ether three times. The combined organics were washed with water and dried over MgSO4. The solvents were evaporated under reduced pressure and the crude material was purified by flash chromatography [Biotage 40 M, gradient elution using mixtures of hexane and EtOAc (from 0-1% EtOAc) ]. This provided a light brown oil, which is a 3: 1 ratio of the title compound:

methyl cyclopentylacetate based on the methyl ester peak integrations. TLC of the desired product: Rf=0. 34 in 20: 1 hexane: EtOAc. The complete separation of the title compound from the starting material was not practical in this case, as they had overlapping Rf's on the TLC. Therefore, this mixture was carried on to the next step.

Step B 3-(4-Chlorophenyl)-2-cYclopentylpropanioc acid.

The mixture of methyl esters from Step A (3.41 g, 14.48 mmol of methyl 3- (4-chlorophenyl)-2-cyclopentylpropanoate--assuming 3: 1 mixture obtained in Step A. ) was dissolved in 10 mL DMSO and 4 mL distilled water. Then powdered KOH (3.25 g, 57.92 mmol) was added and the solution was stirred overnight at room temperature. The next day the pH was brought to 2 with 2 N HC1. The aqueous layer was extracted 3 times with ether. The combined organic extracts were dried over anhydrous sodium sulfate. Filtration and evaporation of volatiles provided the mixture of acids as an oil. 500 MHz 1H NMR (CDC13): 8 1.28 (m, 2H), 1.64 (m, 6H), 2.06 (m, 1H), 2.47 (m, 1H), 2.86 (t, 2H).

Step C 3- (4-Chlorophenyl)-2-cyclopentyl-N, O-dimethyl-propanamide.

The mixture of acids obtained in Step B (3.21 g, 14.48 mmol of the desired acid--based on assumption of 3: 1 mixture from Step B) was dissolved in 75 mL CH2C12. While being stirred rigorously, N, O-dimethylhydroxylamine hydrochloride (1.56 g, 15.95 mmol), l-ethyl-3- (3-dimethylaminopropyl) carbodiimide (3.06 g, 16.0 mmol), diisopropylethylamine (5.56 mL, 31.90 mmol), and a catalytic amount of 4- (dimethylaminopyridine) were added sequentially. Stirring was continued overnight at room temperature. The next day the reaction mixture was diluted with EtOAc, treated with water, and the phases were separated. The aqueous layer was re-extracted with EtOAc twice. The combined organic layers were washed with water three times and then with saturated brine. The organic layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The crude material was purified by flash chromatography [Biotage 40 M column, gradient elution using mixtures or hexanes and EtOAc (100: 1 to 20: 1] to provide the title compound cleanly as an oil. TLC Rf=0. 31 (4: 1 hexanes: EtOAc). LC/MS m/e 295.9 (M+1). 500 MHz 1H NMR (CDC13) : 8 1.27 (m, 2H), 1.64 (m, 6H), 1.97 (m, 1H), 2.13 (q, 1H), 2.81 (d, 1H), 2.97 (d, 1H), 3.07 (s, 3H), 3.17 (s, 3H). LC/MS m/e 295.9 (M+1).

Step D 4-(4-Chlorophenyl)-3-cyclopentylbutan-2-one.

3- (4-Chlorophenyl)-2-cyclopentyl-N, O-dimethyl-propanamide (514 mg, 1.737 mmol, obtained from Step C) was dissolved in 15 mL anhydrous THF and

injected into an oven dried flask under nitrogen. The solution was cooled to 0°C and CH3MgBr (1 M in ether) was added dropwise. The ice bath was removed and the reaction was allowed to warm to room temperature and stirred for a total of 4h. TLC indicated a nearly complete reaction. The reaction was quenched with enough 10 % citric acid to bring the pH of the solution to 3. The aqueous layer was extracted 3 times with ether and the extracts were dried over anhydrous MgSO4. The solution was filtered and the solvents were removed under reduced pressure. The crude material was purified by flash chromatography (30 mL silica; 100: 1 to 50: 1 hexanes: EtOAc) to provide 351 mg the title compound as an oil. TLC Rf=0. 49 (4: 1 hexanes: EtOAc). 500 MHz 1H NMR (CDC13): S 1.23 (m, 3H), 1.58 (m, 1H), 1.71 (m, 3H), 1.91 (s, 3H), 1.93 (m, 1H), 2.05 (m, 1H), 2.68 (m, 1H), 2.84 (m, 2H).

Step E 2-Amino-4- (4-chlorophenyl)-3-cyclopentylbutan.

The title compound was prepared according to the procedure of Reference Example 2, Step D, exceptthat 4- (4-chlorophenyl)-3-cyclopentylbutan-2- one (obtained from Step D) was used as the starting material. LC/MS m/e 251.9 (M+1) ; 500 MHz 1H NMR (CDC13) : 8 0.93 (m, 1H), 1.29 (q, 3H), 1.29 (m, 2H), 1.61 (m, 4H), 1.87 (m, 3H), 2.62 (m, 1H), 2.80 (m, 1H), 3.26 and 3.48 (m, 1H).

2-Amino-4- (4-chlorophenyl)-3-ethyl-butane and 2-amino-4- (4- chlorophenyl) -3-isopropyl-butane were also prepared according to the procedures described in Reference Example 47 substituting the appropriate ester for methyl cyclopentylacetate in Step A.

REFERENCE EXAMPLE 48 2-Amino-3-(1-(1, 2, 3-triazolyl) ?-4-(4-chlorophenyl) butane: Step A Benzyl 2- (l- (1, 2, 3-triazolyl)) acetate: A mixture of 1,2, 3-triazole (2.07 g, 30 mmol), benzyl bromoacetate (6.9 g, 30 mmol), and diisopropylethylamine (5,1 mL, 30 mmol) in 40 mL CH2C12

was stirred overnight at room temperature. This mixture was then diluted with ether until no further precipitate formed. The solid was filtered and washed with ether.

The filtrate was concentrated and the residue was purified on silica gel using 10% hexane in CH2C12 to give the title compound's isomer, benzyl 2- (2- (1, 2,3- triazolyl) acetate as amorphous solid. Further elution with a solvent mixture containing equal amounts of ether and CH2Cl2gave the title compound as amorphous solid. 1H NMR (400 MHz, CDC13) : 8 2.251 (s, 2HO, 7.267-7. 390 (m, 5H), 7.723 (s, 1H), 7.785 (s, lH) Step B 2- (1- (1, 2, 3-triazolyl)) acetic acid : Palladium hydroxide (20% on carbon, 800 mg) was added to a solution of benzyl 2- (1- (1, 2,3-triazolyl)) acetate (Step A, 8.68 g, 39.9 mmol) in 150 mL MeOH and the mixture was hydrogenated overnight on a Parr shaker under an atmosphere of hydrogen at room temperature and 45 psi. The catalyst was filtered through a bed of CELITE diatomaceous earth and washed with MeOH. The filtrate was concentrated to give a solid, which was dried in vacuo at 50°C for 36 h resulting in the title compound. 1H NMR (400 MHz, CD30D): 8 5.3 (s, 2H), 7,75 (s, 1HO, 8.016 (s, 1H).

Step C N-Methoxy-N-methyl-2- (1- (1, 2, 3-triazolyl)) acetamide: Oxalyl chloride (0.95 mL, 11 mmol) was added dropwise to a suspension of 2- (1-1, 2,3-triazolyl)) acetic acid (Step B, 1.27 g, 10 mmol) in 10 mL CH2C12 containing 0.05 mL DMF. Vigorous effervescence was observed. This mixture was stirred at room temperature for 4 h and cooled to-78°C. A solution of N. O-dimethylhydroxylamine hydrochloride (1.2 g, 13 mmol) and diisopropylethyl amine (6.0 mL, 35 mmol) in 10 mL CH2C12 was added slowly over 3 min. The mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was then diluted with ether until no additional 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 solvent to provide the title compound as amorphous solid. 1H NMR (400 MHz, CDC13) : 8 3.252 (s, 3H0, 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 Lithium hexamethyldisilazide (lmolar in THF, 8.4 mL, 8.4 mmol) was added dropwise 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. After additional 30 min stirring, a solution of 4-chlorobenzyl bromide (1.65 g, 8 mmol) in 5 mL THF was added

dropwise. The mixture was allowed to warm to room temperature and stirred 5.5 h.

This mixture was purified on silica gel using 40% EtOAc in hexane to give the title compound. 1H NMR (400 MHz, CDC13.) : 8 3.186 (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: The product of Step D, N-methoxy-N-methyl-3- (4-chlorophenyl)-2- (l- (1, 2,3-triazolyl) propionamide was converted to the title compound following the procedures described in Reference Example 2, Step D-E and Reference Example 26, Step D. 1H NMR (400 MHz, CDC13) : 8 1.219-1. 246 (d's 3H), 3.253-4. 754 (m, 4H0, 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: Platinum oxide (14 mg) was added 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 MeOH.

This mixture was hydrogenated in an atmosphere of hydrogen using a hydrogen filled balloon for 3 h at room temperature. The catalyst was filtered through a bed of CELITE diatomaceous earth and washed with MeOH. The filtrate was concentrated to give the title compound as oil. 1H NMR (400 MHz, CDC13) : 8 1.085-1. 174 (d's 3H), 3.220-3. 361 (m, 2H), 3.517-3. 563 (m, 1H), 4.379-4. 431 (m, 1H), 6.679-7. 179 (d's, 4H), 7.297, 7.40, 7.592 & 7.607 (s's, 2H).

REFERENCE EXAMPLE 49 2-Amino-3- (1- (1, 2, 4-triazolyl)-4- 4-chlorophenyl) butane : The title compound was prepared according to the procedures described in Reference Example 48 substituting 1,2, 4-triazole for 1,2, 3-triazole in Step A. The azide was separated by column chromatography on silica gel eluted with 20% hexane in EtOAc.

REFERENCE EXAMPLE 50

N-r3- (4-Chlorophenyl)-2- (3-methylphenyl)-l-methylpropyllamine hydrochloride (Diastereomer 0) Step A 2- (N-tert-Butoxycarbonyl) amino-4- (4-chlorophenyl)-3- (3- methylphenyl) butane A mixture of 2- (N-tert-butoxycarbonyl) amino-3- (3-bromophenyl)-4- (4- chlorophenyl) butane (intermediate of Reference Example 40,0. 50 g, 1. 1 mmol), tetramethyltin (0.41 g, 2.3 mmol), triphenylphosphine (0.12 g, 0.46 mmol), lithium chloride (0.38 g, 9.1 mmol) and dichlorobis (triphenylphosphine) palladium (0.12 g, 0.17 mmol) in 20 mL anhydrous DMF was heated at 100°C under nitrogen for 18 h.

The reaction mixture was cooled to room temperature, and was partitioned between water (100 mL) and ether (100 mL). The organic layer was separated and the aqueous layer was extracted with ether (100 mL). The combined extracts were dried over anhydrous MgSO4, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 10% EtOAc in hexane to afford the title compound. 1H NMR (400 MHz, CD30D): 5 7.2-6. 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) + (4.4 min).

Step B N-F3-(4-Chlorophenyl)-2-(3-methylphenel)-l-methylpropyllamin e hydrochloride (Diastereomer a) The title compound was prepared following the procedure described for Reference Example 2, Step I. LC-MS: m/e 274 (M + H) + (2.5 min).

REFERENCE EXAMPLE 51

N-r3- (4-Chlorophenyl)-2- (3-trifluoromethylphenyl)-l-methylpropyllamine hydrochloride (Diastereomer a) The title compound was prepared following the procedure described in Reference Example 26 substituting fluorophenylacetic acid with 3- trifluoromethylphenylacetic acid at Step A. LC-MS: m/e 328 (M + H) + (2. 6 min).

REFERENCE EXAMPLE 52 N-[3-(5-Chloro-2-pyridyl)-2(S)-phenyl-1(S)-methylpropyl]amin e hydrochloride (Diastereomer a) Step A 5-Chloro-2-methylpyridine A mixture of 2,5-dichloropyridine (15 g, 0.10 mol), tetramethyltin (15 mL, 0.11 mol), and dichlorobis (triphenylphosphine) palladium (2.0 g, 2.8 mmol) in 200 mL anhydrous DMF was heated at 110°C under nitrogen for 72 h. The reaction mixture was cooled to room temperature, and was 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

MgSO4, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 2 to 10% ether in hexane to afford the title compound. 1H NMR (500 MHz, CD30D) : 8 8.41 (d, 1H), 7.75 (dd, 1H), 7.30 (d, 1H), 2.53 (s, 3H).

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

To a solution of 5-chloro-2-methylpyridine (Step A, 1.1 g, 8.7 mmol) in 15 mL anhydrous ether was added phenyl lithium (1.8 M in cyclohexane/ether, 7.2 mL, 13 mmol) at 0°C, and the reaction was stirred at room temperature for 30 min. The resulting mixture was cooled back to 0°C, and was added (lR, 2R)-l-phenylpropylene oxide (2.3 g, 17 mmol), and the reaction was allowed to warm 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 extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 10 to 40% EtOAc in hexane to afford the title compound. 1H NMR (500 MHz, CD30D): 8 8.28 (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 a mixture of 4- (5-chloro-2-pyridyl)-3-phenyl-2-butanol (Step B, 0.24 g, 0.92 mmol), triphenylphosphine (1.5 g, 1.4 mmol) and diphenylphosphoryl azide (0.30 mL, 1.4 mmol) in 5 mL anhydrous THF was added diethylazodicarboxylate (0.24 mL, 1.4 mmol). After stirring at room temperature overnight, the resulting mixture was concentrated with silica gel (10 g) and the residue was loaded onto a silica gel column. Elution with 5 to 15% EtOAc in hexane afforded the title compound. 1H NMR (500 MHz, CD30D) : 6 8.35 (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-r3- (5-Chloro-2-pyridyl)-2 (S)-phenyl-1 (S)-methylpropyllamine, hydrochloride The product of Step C (0.20 g, 0.70 mmol) was converted to the title compound following the procedure described in Reference Example 2, Steps H-1, except hydrogen chloride in dioxane (4 M) was used in place of hydrogen chloride in EtOAc. 1H NMR (500 MHz, CD30D) : 8 8.75 (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) + (2.2 min).

REFERENCE EXAMPLE 53

N-r2-(3-Bromophenyl)-3-(5-chloro-2-pyridyl)-l-methylpropylla mine hydrochloride (Diastereomer oc) Step A 3-Bromophenylacetone To a solution of N-methoxy-N-methylacetamide (10 g, 100 mmol) in 100 mL anhydrous ether at 0°C was added 3-bromobenzylmagnesium bromide (0.25 M in ether, 200 mL, 50 mmol). The reaction was allowed to warm to room temperature overnight and was 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 MgSO4, filtered and concentrated to dryness to afford the title compound. 1H NMR (500 MHz, CD30D): 8 7.45-7. 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-methylpyridine (Reference Example 52, Step A, 6.4 g, 50 mmol) and N-bromosuccinimide (12.5 g, 70 mmol) in 100 mL carbon tetrachloride was heated to gentle reflux (bath temperature 90°C), and 2,2'- azobisisobutyronitrile (0. 74 g) was added in several portions over 30 min. After stirring at this temperature for 5 h, the reaction mixture was concentrated. The resulting slurry was diluted with EtOAc (100 mL) and was 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, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 2 to 15% ether in CH2Cl2/hexane (1 : 1) to afford 2-

bromomethyl-5-chloropyridine (6.0 g, 60%), which was used immediately for the ensuing reaction. Thus, to a vigorously stirred solution of 2-bromomethyl-5- chloropyridine (6.0 g, 29 mmol) and 3-bromophenyl acetone (Step A, 6.0 g, 28 mmol) and tetrabutylammonium iodide (20 mg) in 30 mL CH2C12 at-78°C was added cesium hydroxide monohydrate (10 g, 60 mmol), and the reaction was allowed to slowly warm to room temperate overnight. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer 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 eluted with 5 to 40% EtOAc in hexane to afford the title compound. 1H NMR (500 MHz, CD30D) : 6 8.44 (d, 1H), 7.66 (dd, 1H), 7.46-7. 41 (m, 2H), 7.24 (t, 1H), 7.22 (d, 1H), 7.15 (d, Ih), 4.42 (dd, 1H), 3.54 (dd, 1H), 3.07 (dd, 1H), 2.12 (s, 3H). LC-MS: m/e 338 (M + H) + (3.0 min).

Step C 3-(3-Bromophenyl)-4-(5-chloro-2-pyndyl)-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 anhydrous THF at-78°C was added lithium tri (sec- butyl) borohydride (1.0 M in THF, 30 mL, 30 mmol), and the reaction was allowed to warm to room temperature overnight. The reaction was cooled to 0°C, and was carefully added 2 M hydrochloric acid (50 mL), and the resulting mixture was partitioned between hexane (200 mL) and water (200 mL). The aqueous layer was separated and the organic layer extracted with 2 M hydrochloric acid (2 x 100 mL).

The combined aqueous extracts were neutralized with 5 N aqueous sodium hydroxide (pH > 12), and was extracted with EtOAc (2x200 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to afford the title compound.

Step D N-r2-(3-Bromophenyl)-3-(5-chloro-2-pyridyl)-1-methylpropylla mine, hydrochloride The product of Step C (5.9 g, 17 mmol) was converted to the title compound following the procedure described in Reference Example 52, Steps C-D. LC-MS: m/e 338 (M + H) + (2.3 min).

REFERENCE EXAMPLE 54

N-[3-(5-Chloro-2-pyridyl)-2-(3-chlorophenyl)-1-methylpropyl] amine hydrochloride (Diastereomer a) The title compound was prepared following the procedure described in Reference Example 42 substituting 2- (N-tert-butoxycarbonyl) amino-3-bromophenyl- <BR> <BR> 4- (4-chlorophenyl) butane with 2- (N-tert-butoxycarbonyl) amino-3-bromophenyl-4- (5- chloro-2-pyridyl) butane (intermediate of Reference Example 53, Step D) at Step A.

LC-MS: m/e 295 (M + H) + (2.0 min).

REFERENCE EXAMPLE 55 Step A 5-Bromo-3-pyn A mixture of 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- (diphenylphosphino)-2' (N, N-dimethylamino) biphenyl (1.6 g, 4.2 mmol) in 400 mL toluene was heated at 100°C under nitrogen for 2 h. The reaction mixture was cooled to room temperature, and was concentrated to about 100 mL. The resulting mixture was loaded onto a silica gel column, which was eluted with 0 to 60% EtOAc in

hexane to afford the title compound. 1H NMR (500 MHz, CD30D) : 8 8.54 (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-pyndyl)-4-(4-chlorophenyl)-2-butanol The title compound was prepared following the procedure described in Reference Example 53, Step B-C, substituting 2-bromomethyl-5-chloropyridine with 4-chlorobenzyl chloride and 3-bromophenylaceatone with 5-bromo-3-pyridylacetone (Step A). 1H NMR (500 MHz, CD30D) : 6 8.43 (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-r2-(5-Bromo-3-pyridyl)-3-(4-chlorophenyl ?-l-methylpropyllamine hydrochloride (Diastereomer a) The title compound was prepared following the procedure described for Reference Example 3, Step B. LC-MS: m/e 339 (M + H) + (2.5 min).

REFERENCE EXAMPLE 56 N-[2-(5-Bromo-3-pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]a mine hydrochloride (Diastereomer oc) The title compound was prepared following the procedure described for Reference Example 55 substituting 4-chlorobenzyl chloride with 4-flurobenzyl chloride at Step B. LC-MS: m/e 323 (M + H) + (2.3 min).

REFERENCE EXAMPLE 57

N-[3-(4-Chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]a mine hydrochloride (Diastereomer oc Step A 5-Cyano-3-pyndylacetone The title compound was prepared following the procedure described for Reference Example 55 substituting 3,5-dibromopyridine with 5-bromonicotinonitrile (5-bromo-3-cyanopyridine) at Step A. 1H NMR (400 MHz, CD30D) : 8 8.89 (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-2-pyridyl)-1-methylpropyl]a mine hydrochloride (Diastereomer ot/ß 5: 1) The title compound was prepared following the procedure described for Reference Example 4 substituting 3-pyridylacetone with 5-cyano-3-pyridylacetone (Step A). LC-MS: m/e 286 (M + H) + (1.9 min).

REFERENCE EXAMPLE 58 N-f2- (5-Cyano-3-pyridyl)-3- (4-fluorophenyl)-1-methylpropyllamine hydrochloride (Diastereomer oc)

The title compound was prepared following the procedure described for Reference Example 57 substituting 4-chlorobenzyl chloride with 4-fluorobenzyl chloride at Step B. LC-MS: m/e 270 (M + H) + (2.2 min).

REFERENCE EXAMPLE 59

N-r2-(5-Cyano-3-pyridyl)-3-(3, 4-difluorophenyl)-1-methylpropyllamine hydrochloride (Diastereomer ex) The title compound was prepared following the procedure described for Reference Example 58 substituting 4-fluorobenzyl chloride with 3,4-difluorobenzyl chloride at Step B. LC-MS: m/e 288 (M + H) + (2.3 min).

REFERENCE EXAMPLE 60

N-f3- (3-Chlorophenvl)-2- (5-cyano-3-pyridyl)-l-methylpropyllamine hydrochloride (Diastereomer a)

The title compound was prepared following the procedure described for Reference Example 58 substituting 4-fluorobenzyl chloride with 3-chlorobenzyl chloride at Step B. LC-MS: m/e 286 (M + H) + (2.4 min).

REFERENCE EXAMPLE 61 N-r3-(4-Chlorophenyl)-2-(5-chloro-3-pvridyl)-1-methylpropyll amine hydrochloride (Diastereomer oc) Step A 5-Chloro-3-pyr The title compound was prepared following the procedure described for Reference Example 55 substituting 3,5-dibromopyridine with 3,5-dichloropyrdine and 2- (diphenylphosphino)-2' (N, N-dimethylamino) biphenyl with 2- (di-t-butylphosphino) biphenyl at Step A. 1H NMR (500 MHz, CD30D) : b 8.42 (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 oc) The title compound was prepared following the procedure described for Reference Example 55, Step B-C substituting 5-bromo-3-pyridylacetone with 5- chloro-3-pyridylacetone at Step B. LC-MS: m/e 295 (M + H) + (1. 9 min).

REFERENCE EXAMPLE 62

N-[2-(5-Chloro-3-pyridyl)-3-(4-fluorophenyl)-1-methylpropyl] amine hydrochloride (Diastereomer a) The title compound was prepared following the procedure described for Reference Example 61 substituting 4-chlorobenzyl chloride with 4-fluorobenzyl chloride at Step B. LC-MS: m/e 279 (M + H) + (2.3 min).

REFERENCE EXAMPLE 63

2-Amino-3-(5-chloro-3-pyridyl)-5-methylhane, Hydrochloride Salt (Diastereome cc/ß 6 : 1) The title compound was prepared following the procedure described for Reference Example 61 substituting 4-chlorobenzyl chloride with 1-iodo-2- methylpropane at Step B. LC-MS: m/e 227 (M + H) + (2. 2 min).

REFERENCE EXAMPLE 64

N-[2-(5-Chloro-3-pyridyl)-3-cyclobutyl-1-methylpropyl]amine hydrochloride (Diastereomer oc/ß 6: 1) The title compound was prepared following the procedure described for Reference Example 61 substituting 4-chlorobenzyl chloride with (bromomethyl) cyclobutane at Step B. LC-MS: m/e 239 (M + H) + (2. 3 min).

REFERENCE EXAMPLE 65

N-[3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]amine hydrochloride (Diastereomer a) Step A 3-Cyanophenylacetone The title compound was prepared following the procedure described for Reference Example 55 substituting 3,5-dibromopyridine with 3-bromobenzonitrile and 2- (diphenylphosphino)-2'- (N, N-dimethylamino) biphenyl with 2- (dicyclohexylphosphino)-2'- (N, N-dimethylamino) biphenyl at Step A. 1H NMR (500 MHz, CD30D): 8 7.6 (m, 1H), 7.56 (br s, 1H), 7.50-7. 48 (m, 2H), 3. 88 (s, 2H), 2.21 (s, 3H).

Step B N-f3- (4-Chlorophenyl)-2- 3-cyanophenyl)-l-methylpropyllamine hydrochloride (Diastereomer a) The title compound was prepared following the procedure described for Reference Example 55 substituting 5-bromo-3-pyridylacetone with 3- canophenylacetone at Step B. LC-MS: m/e 285 (M + H) + (2.2 min).

REFERENCE EXAMPLE 66 N-F3-(4-Chlorophenyl)-2-(5-fluoro-3-pvndyl)-l-methylpropylla mine hydrochloride (Diastereomer a) Step A 5-fluoro-3-pyridylacetone The title compound was prepared following the procedure described for Reference Example 55 substituting 3,5-dibromopyridine with 3-fluoro-5- trifluoromethanesulfonyloxypyridine (prepared form 3-fluoro-5-hydroxypyrdine and triflic anhydride) and 2- (diphenylphosphino)-2' (N, N-dimethylamino) biphenyl with 2- (dicyclohexylphosphino)-2' (N, N-dimethylamino) biphenyl at Step A. 1H NMR (500 MHz, CD30D) : 8 8.34 (d, 1H), 8.22 (br s, 1H), 7.50 (ddd, 1H), 3.93 (s, 2H), 2.25 (s, 3H).

Step B N-[3-(4-Chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl] amine hydrochloride (Diastereomer a) The title compound was prepared following the procedure described for Reference Example 55, Step B-C substituting 5-bromo-3-pyridylacetone with 5-fluoro-3- pyridylacetone at Step B. LC-MS: m/e 279 (M + H) + (2. 4 min).

REFERENCE EXAMPLE 67

p dl)-l-methylpropyllamine hydrochloride (Diastereomer oc) The title compound was prepared following the procedure described for Reference Example 50 substituting 2- (N-tert-butoxycarbonyl) amino-3- (3- bromophenyl)-4- (4-chlorophenyl) butane with 2- (N-tert-butoxycarbonyl) amino-3- (5- bromo-3-pyridyl)-4- (4-chlorophenyl) butane (intermediate ot Reference Example 55, Step B) at Step A. LC-MS: m/e 275 (M + H) + (1.3 min).

REFERENCE EXAMPLE 68

N-r2- (3-Bromo-5-fluorophenyl)-3- (4-Chlorophenvl)-l-methylpropyllamine hydrochloride (Diastereomer oc) Step A 3-Bromo-5-fluorophenylacetone The title compound was prepared following the procedure described for Reference Example 55 substituting 3,5-dibromopyridine with 1, 3-dibromo-5- fluorobenzene and 2- (diphenylphosphino)-2'- (N, N-dimethylamino) biphenyl with 1, 1'-bis (diphenylphosphino) ferrocene at Step A. 1H NMR (500 MHz, CD30D) : 6 7.23 (d, 1H), 7.22 (s, 1H), 6.96 (d, 1H), 3.81 (s, 2H), 2.20 (s, 3H).

Step B N-[2-(3-Bromo-5-fluorophenyl)-3-(4-chlorophenyl)-1- methylpropyllamine hydrochloride (Diastereomer oc) The title compound was prepared following the procedure described for Reference Example 55, Step B substituting 5-bromo-3-pyridylacetone with 3-bromo- 5-fluorophenylacetone (Step A). LC-MS: m/e 356 (M + H) + (2.9 min).

REFERENCE EXAMPLE 69

N-l 2-(3-Bromo-5-fluorophenyl)-3-(4-fluorophenyl)-1-methylpropyl lamine hydrochloride (Diastereomer a) The title compound was prepared following the procedure described for Reference Example 68 substituting 4-chlorobenzyl chloride with 4-fluorobenzyl chloride at Step B. LC-MS: m/e 340 (M + H) + (2.8 min).

REFERENCE EXAMPLE 70

2-Amino-3-indolin-N-yl-4 (4-chloro) phenylbutane Step A. Ethyl 3- (4-chlorophenyl)-2-indolin-N-ylpropanoate.

In an oven-dried flask under an atmosphere of nitrogen, l. lg LiOH-H20 (26.25 mmol) in DMF (20 mL) was added to a stirring suspension of 4

angstrom molecular sieves. After 30 minutes of stirring at room temperature 2.8 mL (25 mmol) indoline was added dropwise. After one hour at room temperature 2.9 mL (26.25 mmol) Ethyl bromoacetate was added dropwise. After 1.5 h the solid material was filtered and the residue was washed with copious amounts of EtOAc. The organics were washed 3 times with water and the organic material was dried over MgSO4. The solvents were evaporated under reduced pressure. The crude material was then dissolved in 75 mL anhydrous THF, charged into an oven dried round bottom under an atmosphere of nitrogen, cooled to-78°C, and then treated with 26.25 mL a 1M solution of NaHMDS. The solution was allowed to stir for 30 minutes at- 78°C after which the enolate was quenched with 5.4 g (26.25 mmol) of parachlorobenzyl bromide (solution in 25 mL anhydrous THF). The reaction was allowed to warm to room temperature overnight. The next day the reaction was quenched with water. The aqueous layer was extracted with 3 large portions of EtOAc. The combined organics were dried over MgSO4. The solvents were removed under reduced pressure and the residue was purified by flash chromatography which yielded the title compound as a yellow oil. LC/MS m/e=331 (M+1). TLC Rf=0. 22 (20: 1 hexanes: EtOAc). 1H NMR (500 MHz, CDC13) : 8 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=3.75 Hz, 1H).

Step B. N, O-dimethyl-3- (4-chlorophenyl)-2-indolin-N-ylpropanamid In an oven-dried flask under an atmosphere of nitrogen, 11.75 mL 1 M solution of (CH3) 2AlCl in CH2C12 was added via addition funnel to a stirring suspension of 1. 15 g (11.75 mmol) N, O-dimethylhydroxylamine hydrochloride at 0°C.

After warming to room temperature a solution of 970 mg (2.94 mmol) of Ethyl 3- (4- chlorophenyl) -2-indolinylpropanoate in 10 mL was added via addition funnel. After stirring at room temperature for 5 h, 35 mL pH=8 phospate buffer solution was added and the resulting solution was stirred vigorously for 30 minutes. The phases were separated and the aqueous layer was extracted 2 times with chloroform. The combined organics were washed with water and then dried over MgSO4. A brown oil was collected. The crude material was carried on to the next step. ). TLC Rf=0. 12 (10: 1 hexanes: EtOAc). 1H NMR (500 MHz, CDC13) : 8 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=7.1 Hz, 1H), 7.07 (t, J=7.1 Hz, 2H), 7.18 (d, J=8.5 Hz, 2H), 7.24 (d, J=8.5 Hz, 2H) Step C. 4- (4-chlorophenyl)-3-indolin-N-ylbutan-2-one.

In an oven dried flask under an atmosphere of nitrogen, 2.8 mL 1 M solution of CH3MgBr in THF was added dropwise to a stirring solution of N, O- dimethyl-3- (4-chlorophenyl)-2-indolinylpropanamide (965 mg) in 25 mL anhydrous THF. The solution was stirred for 4 h while being allowed to warm to room temperature. Then approximately 20 mL water were added. The solution was extract three times with 50 mL ether. The combined extracts were dried over MgSO4. The solvents were removed under reduced pressure yielding a brown oil which was carried on to the next step without purification. LC/MS m/e=301 (M+1). TLC Rf=0. 5 (4: 1 hexanes: EtOAc). 1H NMR (500 MHz, CDC13) : 8 2.14 (s, 3H), 2.81 (dd, J=14. 6, 6.6 Hz, 1H), 2.97 (t, J=8.5 Hz, 2H), 3.26 (m, 2H), 3.5 (m, 1H), 4.21 (dd, J=6.6, 6.6 Hz), 6.39 (d, J=8 Hz, 1H), 6.66 (dd, J=7,7 Hz, 1H), 7.07 (m, 2H), 7.13 (d, J=8.5 Hz), 7.22 (d, J=8.3 Hz).

Step D. 4- (4-chlorophenyl)-3-indolin-N-ylbutan-2-one methoxime.

A solution of 472 mg (1.573 mmol) of the product of Step C and 263 mg (3.147 mmol) of methoxylamine hydrochloride in anhydrous ethanol was treated with 255 ! 1L (3.147 mmol) of pyridine. The solution was stirred for 2 h at room temperature. Solvent was removed under reduced pressure and the residue was partitioned between water and ether. The water was extracted with ether again. The extracts were then combined and dried over MgSO4, filtered and concentrate to obtain crude material. obtained. Both the E and Z isomers were carried onto the next step.

LC/MS m/e=330 (M+1). TLC Rf=. 77 and. 65 (4: 1 hexanes: EtOAc). 1H NMR (500 MHz, CDC13) : 8 1.78 (2s, 1H), 2.88 (dd, J=6.2, 13.8 Hz, 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, 7.8 Hz, 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 In an oven-dried flask equipped with a water condenser under an atmosphere of nitrogen, a solution of 301 mg (0.914 mmol) 4- (4-chlorophenyl)-3- indolinylbutan-2-one methoxime in 1.5 mL anhydrous THF was treated with 3.7 mL (3.7 mmol) of 1M BH3-THF at room temperature. The solution was then heated to 75°C for 2 days. The solution was then cooled to 0°C and treated with chips of ice until bubbling subsided. 500, ut of 20% KOH were then added and the solution was heated at 45°C for 2h. The solution was then cooled to room temperature and extracted with ether 3x. The combined extracts were dried over MgS04, filtered, and concentrated to afford crude amine which was used in the next experiment without further purification. LC/MS m/e=302 (M+1). 1H NMR (500 MHz, CDC13) : 8 1.13,

1.14 (2d, J=6.5 Hz, 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=7.9 Hz, 1H), 6.50-6. 78 (m, 2H), 6.95-7. 24 (m, 5H) REFERENCE EXAMPLE 71 2-Amino-3-indol-N-yl-4 (4-chloro) phenylbutane This compound was prepared in an analogous manner to Reference Example 70 except that during Step A, sodium hydride was used as the base instead of the lithium hydroxide monohydrate/molecular sieves combination. LC/MS : calculated for C18HIgCIN2 299, observed m/e 300 (M + H) + (2.4 min).

REFERENCE EXAMPLE 72 2-Amino-3- (N-methyl, N-phenyl) amino-4 (4-chloro) phenylbutane This compound was prepared in an analogous manner to Reference Example 70. LC/MS: calculated for C17H21ClN2 289, observed m/e 290 (M + Fizz (2.4 min).

REFERENCE EXAMPLE 73

2-Amino-3- (7-azaindol-N-yl)-4 (4-chloro) phenylbutane This compound was prepared in an analogous manner to Reference Example 70. LC/MS : calculated for C17H18ClN3 300, observed m/e 301 (M + H) + (2.7 min).

REFERENCE EXAMPLE 74 2-Amino-3-(benzisoxazol-3-yl)-4 (4-chloro) phenylbutane This compound was prepared in an analogous manner to Reference Example 70 except starting with ethyl (benzisoxazol-3-yl) acetate. LC/MS: calculated for C17Hl7ClN20 300, observed m/e 301 (M + H) + (2.2 min).

REFERENCE EXAMPLE 75 4- (4-Methylphenyl)-3-phenylbutan-2-amine (mixture of 4 isomers) Step A 1-Phenylacetone

To a solution of N-methyl-N-methoxyacetamide (9.9mL. 97 mmol) in ether (300 mL) at 0°C was added benzylmagnesium chloride (97 mL a 1M solution in ether). The cloudy, white reaction mixture was warmed to room temperature for 2 h and then quenched by careful addition of 1N hydrochloric acid (100 mL). The organic phase was separated, washed with brine, dried over MgS04 and concentrated.

The crude material was purified by column chromatography on silica gel eluting from 0-10% EtOAc/hexane to give the title compound. 1H NMR (500 MHz, CDC13) : 6 7.36 (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/e 135 (M + H) + (1.95 min).

Step B 4- (4-Methylphenyl)-3-phenylbutan-2-one 1-Phenylacetone (200 mg, 1.49 mmol) was mixed with powdered potassium hydroxide (167 mg, 2.98 mmol) and tetra-n-butylammonium bromide (lmol %, 5 mg) in a flask without solvent. This mixture was stirred at room temperature for 90 min. before the addition of 1- (chloromethyl)-4-methylbenzene (198 1, 1.49 mmol). The reaction mixture was then stirred overnight before diluting with water and CH2C12. The aqueous layer was separated and neutralized to pH 7 with 2N hydrochloric acid and extracted again into CH2C12. The combined organic washes were dried with MgS04 and concentrated. The crude material was purified by column chromatography on silica gel eluting from 0-10% EtOAc/hexane to give the title compound. 1H NMR (500 MHz, CDC13) : 8 7.35 (t, J = 7.0 Hz, 2H), 7.29 (t, J = 7. 4 Hz, 1H), 7.23 (d, J = 7. 1 Hz, 2H), 7.05 (d, 7. 8 Hz, 2H), 6.98 (d, J = 7. 8 Hz, 2H), 3.94 (t, J = 7.3 Hz, 1H), 3.43 (dd, J = 13.9, 7.5 Hz, 1H), 2.91 (dd, J = 14,7. 1 Hz, 1H), 2.32 (s, 3H), 2.08 (s, 3H). LC-MS: m/e 239 (M + H) + (3.61 min).

Step C 4-(4-Methylphenyl)-3-phenYlbutan-2-amine To a solution of the 4- (4-methylphenyl)-3-phenylbutan-2-one (308 mg, 1.29 mmol) in 7M ammonia in MeOH (5 mL) and acetic acid (3 mL) was added sodium cyanoborohydride (130 mg, 2.06 mmol) and the reaction stirred at room temperature overnight. The reaction was quenched by pouring into 2M sodium carbonate solution and extracted into EtOAc. The aqueous layer was salted and re-extracted. The combined organic extracts were dried over MgS04 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) + (2.22 min).

REFERENCE EXAMPLE 76

4- (4-Methoxyphenyl)-3-phenylbutan-2-amine Prepared using the procedures described in Example 75, Steps A through C using 1- (chloromethyl)-4-methoxybenzene as the alkylating agent in Step B. LC-MS: m/e 256 (M + H) + (1.90 and 2.03 min).

REFERENCE EXAMPLE 77

3-f2-Amino-l- (4-fluorobenzyl) propyllbenzonitrile Prepared using the procedures described in Example 65 using 3- (2- oxopropyl) benzonitrile and 1- (chloromethyl)-4-fluorobenzene as the reactants in Step B. LC-MS: m/e 269 (M + H) + (2.87 min).

REFERENCE EXAMPLE 78

N-F2-Phenyl-3- (4-fluorophenyl)-l-methylpropyllamine hydrochloride (Diastereomer a)

The title compound was obtained by the method described in Reference Example 38, substituting 4-fluorobenzyl bromide for isobutyl iodide. LC- MS, Rt = 2.2 min, m/e = 244.

REFERENCE EXAMPLE 79 2-(2, 3-Dihydro-1-H-indol-1-yl)-1, 4-dimethylpentylamine<BR> <BR> <BR> <BR> <BR> Step A Ethyl (2-(2, 3-dihydro-lH-indol-l-yl)-4-methylpentanoate A solution of 0.53 g (3.3 mmol) of ethyl (S) -2-hydroxyisocaproate in 8 mL dly CH2Cl2was cooled in a-78 oC bath and 0.73 mL (4.34 mmol) of triflic anhydride and 0.6 mL (5.36 mmol) of 2,6 lutidine were added. After 15 min 2 mL (11.5 mmol) of diisopropylethylamine was added and stirred for 10 min. To this solution 0.36 mL (3.21 mmol) of 2,3-dihydroindoline was added and stirred overnight as it slowly warmed to room temperature. The reaction was quenched with saturated NaHC03 solution and extracted with ether. The combined organic layer was washed with water, brine, dried and concentrated. The residue was purified on a flash column using a gradient of 5-10% EtOAc/hexane to isolate the title compound. 1H NMR: (500 MHz, CDC13) : 8 0.99 (d, 3H), 1.03 (d, 3H), 1.22 (t, 3H), 1.81 (m, 3H), 3.04 (m, 2H), 3.57 (m, 1H), 3.66 (m, 1H), 4.14 (q, 2H), 4.24 (t, 1H), 6.4-7. 1 (m, 4H).

Step B 3-(2 3-Dihydro-lH-indol-l-yl)-5-methylhexan-2-one To a solution of 0.54 g (2.07 mmol) of ethyl (2- (2, 3-dihydro-lH-indol- 1-yl)-4-methylpentanoate in 10 mL CH2C12, 1. 98 g (10 mmol) of N, O- dimethylhydroxylamine hydrochloride and 1.4 mL triethylamine were added. The mixture was cooled in an ice bath and 10 mL (10 mmol) 1 M diethylaluminium chloride in toluene was added. The reaction was stirred overnight as it warmed to room temperature then carefully quenched by pouring into 1.2 N HCI. The solution was extracted with CH2C12. The organic layer was washed with brine, dried and concentrated leaving amide which was used without purification. This amide was dissolved in 5 mL THF and 2.5 mL (3.5 mmol) of 1.4 M methylmagnesium bromide

was added. After 1 h, the solution was quenched with 1.2 N HC1 and extraced with EtOAc. The EtOAc layer was washed with brine, dried and concentrated. The residue was chromatographed using a gradient of 5-10% EtOAc-hexane to isolate the title compound. 1H NMR: (500 MHz, CDC13) : 8 0.96 (d, 3H), 0.99 (d, 3H), 1.7 (m, 3H), 2.17 (s, 3H), 3.06 (m, 2H), 3.04 (q, 1H), 3.52 (m, 1H), 4.11 (m, 1H) 6.4-7. 1 (m, 4H).

Step C 2-(2, 3-Dihydro-1-H-indol-1-yl)-1, 4-dimethylpentylamine To a solution of 0.185 g (0.8 mmol) of 3-(2, 3-dihydro-lH-indol-1-yl)- 5-methylhexan-2-one in 2 mL ethanol, 0. 135 g O-methylhydroxylamine hydrochloride and 0.13 mL (1.6 mmol) of pyridine were added. After stirring for 2 h, the solution was concentrated and the residue was partitioned between water and EtOAc. The organic layer was washed with brine, dried and concentrated to give 0.2 g O- methyloxime as a mixture of isomers. This mixture was dissolved in 2 mLTHF and 1.5 mL 1 M BH3 in THF was added. After gas evolution ceased, the reaction was heated in a 50 oc bath. After 2 h another 1.5 mL1 M BH3 in THF was added and heating was continued overnight. The reaction mixture was cooled and quenched with MeOH and concentrated. The residue was dissolved in 6 mL CH2C12 and 2 mL1 N NaOH was added. After stirring for 15 min the layers were separated and the aqueous layer was extracted with CH2C12. The combined organic layer was washed with water, brine dried and concentrated to isolate title compound as a mixture of diastereomers which was used without purification. LC-MS, Rt = 2.24 min, m/e = 233.

The following amines were synthesized by the method of Reference Example 79.

REFERENCE EXAMPLE 80 3-Cyclobutyl-2-(3, 4-dihydroquinoline-1 (2H)-yl)-l-methylpropylamine LC-MS, Rt = 2., 8 min, m/e = 259.

REFERENCE EXAMPLE 81

2- (3, 4-Dihydroquinoline-1 (2H)-yl)-1, 4-dimethylpentylamine LC-MS, Rt = 2.74 min, m/e = 248.

REFERENCE EXAMPLE 82 2- (lH-1, 2, 3-Benzotriazol-1-yl)-3 (4-chlorophenyl)-1-methylpropylamine<BR> <BR> <BR> <BR> <BR> Step A 2- (lH-1, 2, 3-Benzotriazol-1-yl)-N-methoxy-N-methylacetamide A mixture of 1.77 g (10 mmol) of 2-(lH-1, 2, 3-benzotriazol-1-yl) acetic acid, 1.07 g (11 mmoles) of N, O-dimethylhydroxylamine hydrochloride, 5.8 g (11 mmol) of PyBOP, and 3.4 mL (24.2 mmol) of diisopropylethylamine in 50 mL CH2C12 was stirred overnight at RT. This mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous MgS04. Solvent removal afforded a crude product which was purified on silica gel using 60% EtOAC in hexane as solvent to give 2.01 g the desired amide as a solid.

1H NMR: (CDC13) : 8 3.26 (s, 3H), 3.84 (s, 3H), 5.63 (s, 2H), 7.35-8. 2 (m, 4H). <BR> <BR> <BR> <BR> <P>Step B 2-(lH-1, 2. 3-Benzotriazol-l-yl)-3-(4-chlorophenyl)-N-methoxy-N-<BR&g t; <BR> <BR> <BR> <BR> methyl-propanamide.

To a solution of 2.0 g (9 mmol) of 2-(lH-1, 2, 3-benzotriazol-1-yl)-N- methoxy-N-methylacetamide in 15 mL anhydrous THF at-78 °C, 10 mL (10 mmol) of 1M lithium bis (trimethylsilyl) amide was added dropwise. After stirring for 25 min,

a solution of 2.06 g (10 mmol) of 4-chlorobenzyl bromide in 2 mL anhydrous THF was added. The resulting reaction mixture was allowed to warm to RT and stirred for 6 h. This reaction was quenched, diluted with 75 mL EtOAc and washed 3 times with 10 mL each of brine, After drying the organic phase solvent removal afforded a crude product which was purified on silica gel using 40% EtOAc in hexane as solvent to afford the desired product as a solid. 1H NMR: (CDC13) : 8 3.2 (s, 3H), 3.34 (s, 3H), 3.52 (m, 1H), 3.7 (m, 1H), 6.32 (t, 1H), 6.9-8. 2 (m, 8H).

Step C 2-(lH-1, 2, 3-Benzotriazol-l-yl)-3-(4-chlorophenyl)-butan-2-one.

To a solution of 1.73 g (5 mmol) of 2-(lH-1, 2, 3-benzotriazol-1-yl)-3- (4-chlorophenyl) -N-methoxy-N-methyl-propanamide in 10 mL anhydrous THF at 0 °C, 4 mL (10 mmol) of 2.5M methyl magnesium bromide in ether was added. The reaction mixture was stirred for 4 h as it warmed to RT. The reaction was quenched by adding 10 mL 1N HC1 and the resulting mixture was partitioned between EtOAc and water. The organic phase was washed with brine and dried over anhydrous MgSO4. Solvent removal gave a crude ketone, which was purified on silica gel using 40% EtOAc in hexane to provide the desired ketone.

Step D 2- (lH-1, 2, 3-Benzotriazol-1-yl)-3- (4-chlorophenyl)-l-methyl propylamine To a solution of 1.18 g (4 mmol) of 2-(lH-1, 2, 3-benzotriazol-1-yl)-3- (4-chlorophenyl) -butan-2-one in 8.5 mL (60 mmol) of 7N ammonia in MeOH at 0 °C, 4 mL (964 mmol) of glacial acetic acid was added followed by 410 mg (6.5 mmol) of sodium cyanoborohydride. The reaction mixture was allowed to warm to RT and stirred overnight. The reaction was partitioned between EtOAc and saturated NaHCO3 solution. The organic phase was dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue was purified on silica gel using a mixture of 5% 2N methanolic ammonia solution and 95% CH2C12 to give the desired amine as a mixture of diastereomers. LC-MS, Rt = 2.0 min, m/e = 301.

REFERENCE EXAMPLE 83

3-(4-Chlorophenyl)-2-(thiophene-3-yl)-1-methylpropelamine The title amine was prepared by the method described in Reference Example 82, substituting thiophene-3-acetic acid for 2-(lH-1, 2, 3-benzotriazol-l- yl) acetic acid in Step A. LC-MS, Rt = 2.19 min, m/e = 266.

REFERENCE EXAMPLE 84 3-(4-Chlorophenyl)-2-(thiophene-2-yl)-1-methylpropylamine Step A 3- (4-Chlorophenyl)-2- (thiophen-2-yl)-butan-2-one.

The title compound was obtained from 2-thiopheneacetic acid according to the procedure described in Reference Example 38, Steps A-C.

Step B 3-(4-Chlorophenyl)-2-(thiophene-2-yl)-1-methylpropylamine This amine was synthesized by the method of Reference Example 82, Step D. LC-MS, Rt = 2.18 min, m/e = 266.

REFERENCE EXAMPLE 85 3-(4-Chlorophenyl)-l-methyl-2-(1-methyl-1H-indol-3-yl) propylamine The title compound was prepared according to the method described in Reference Example 84. LC-MS: Rt = 2.5 min, m/e = 313.

REFERENCE EXAMPLE 86

3-(4-Chlorophenyl)-l-methyl-2-(lH-indazol-l-yl) propylamine Step A 3-(4-Chlorophenyl)-2-(lH-indazol-l-yl)-butan-2-one.

The title compound was obtained from indazol-1-yl-acetic acid by following the procedure of Reference Example 2, Steps A-D.

Step B 3-(4-Chlorophenyl)-l-methyl-2-(lH-indazol-l-yl) propylamine.

The title amine was prepared according to the procedure of Reference Example 79, Step C. LC-MS: Rt = 2.24 min, m/e = 300.

REFERENCE EXAMPLE 87 3-(4-Chlorophenyl)-1-methyl-2-(1-methyl-1H-indol-4-yl)propyl amine Step A 4-Chloro-1-methylindole In a 100 mL flask, 0.3 g (7.5 mmol) sodium hydride was washed twice with dry hexane. The solid was suspended in 15 mL dry THF and lg (6.6 mmol) 4- chloroindole was drop wise added. After 15 min, 0.5 mL (7.9 mmol) methyl iodide was added and the solution was stirred overnight. The reaction was quenched with 1.2 N HCl and partitioned between ether and water. The organic layer was washed with brine, dried and concentrated keeping the bath temperature below 30 °C. The residue was purified on a flash column using a gradient of 5-10% EtOAc/hexane to isolate the desired product. 1H NMR : (500 MHz, CDC13) : 83. 84 (s, 3H), 6.63 (d, 1H), 7-7.3 (m, 4H).

Step B 1-(1-Methyl-lH-indol-4-yl) acetone

To a solution of 0.852 g (5.14 mmol) of 4-chloro-1-methylindole in 15 mL dry toluene, 0.85 mL (7.73 mmol) isopropenyl acetate and 2.3 mL (8 mmol) tributyltin methoxide were added. The solution was heated to 100 °C. After 15 min, 0.24 g (0.61 mmol) 2-dicyclohexylphospino-2'- (N, N-dimethylamino) biphenyl and 0.14 g (0.153 mmol) tris (dibenzylidineacetone) dipalladium were added and heating was continued. After 2 h the solution was cooled, filtered through a pad of CELITE diatomaceous earth and the filtrate was concentrated to ca. 5 mL. This solution was purified on a silica column using a gradient of 5-20% EtOAc/hexane to obtain the title compound. 1H NMR: (500 MHz, CDC13) : 8 2.14 (s, 3H), 3.84 (s, 3H), 3.97 (s, 2H), 6.51 (d, 1H), 7-7.3 (m, 4H).

Step C 4-(4-Chlorophenyl)-3-(1-methyl-lH-indol-4-yl)-butan-2-one To a suspension of 135 mg (3.38 mmol) of sodium hydride in 8 mL dry THF, a solution of 605 mg (3.23 mmol) 1- (l-methyl-lH-indol-4-yl) acetone in 2 mL THF was added. The mixture was stirred for 45 min during which time the sodium hydride dissolved and a yellow orange solution resulted. The reaction was cooled in ice bath and 660 mg (3.24 mmol) 4-chlorobenzyl bromide in 1 mL THF was added.

The cold bath was removed and the solution was stirred for 1.5 h. The reaction was quenched with 1. 2 N HCl and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was chromatographed using a gradient of 10-20% EtOAc/hexane to isolate the desired product. 1H NMR: (500 MHz, CDC13) : 8 2.03 (s, 3H), 3.07 (m, 1H), 3.58 (m, 1H), 3.84 (s, 3H), 4.23 (t, 1H), 6.52 (d, 1H), 6. 9-7. 3 (m, 8H).

Step D 3- (4-Chlorophenyl)- l-methyl-2- (l-methyl-lH-indol-4-yl) propylamine The title compound was prepared from 4- (4-chlorophenyl)-3- (1- methyl-lH-indol-4-yl)-butan-2-one by following the procedure of Reference Example 79, Step C. LC-MS, Rt = 2.4 min, m/e = 313.

REFERENCE EXAMPLE 88 3-(4-Chlorophenyl)-1-methyl-2-(pyridazin-3-yl)propylamine

Step A 4- (4-Chlorophenyl)-3- (pyr This compound was synthesized from 3-iodopyridazine by the procedure of Reference Example 87, Steps B-C. <BR> <BR> <BR> <P>Step B N-2, 4-Dimethoxybenzyl-N (3- (4-chlorophenyl)- 1-methyl-2- (pyridazin- 3-yl) propyl) amine A solution of 300 mg (1.15 mmol) 4- (4-chlorophenyl)-3- (pyridazin-3-yl)-butan-2-one in 4 mL dichloroethane was treated with 234 mg (1.15 mmol) 2,4-dimethoxybenzyl amine hydrochloride, 0.16 mL (1.15 mmol) triethylamine and 488 mg (2.3 mmol) sodium triacetoxyborohydride. After stirring the reaction overnight, it was partitioned between water and CH2C12. The organic layer was washed with brine, dried and concentrated and the residue was purified on a flash column using 3% MeOH- CH2Cl2to isolate the desired amine.

Step C 3-(4-Chlorophenyl)-1-methyl-2-(pyridazin-3-yl)propylamine A solution of 300 mg N-2,4-dimethoxybenzyl-N (3- (4-chlorophenyl)- 1-methyl-2- (pyridazin-3-yl) propyl) amine in 5 mL trifluoroacetic acid was heated in a 70 °C bath over night followed by 6 h in a 100 °C bath. The reaction was cooled, concentrated and the residue was diluted with EtOAc. This solution was quenched (to pH 10) with IN NaOH and the layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was purified on a prepTLC using 10% MeOH/CH2Cl2with 1% NH4OH to isolate the title compound (mixture of diastereomers), starting material was also recovered. LC-MS, Rt = 1.63 min, m/e = 262.

REFERENCE EXAMPLE 89 3-(4-Chlorophenyl)-l-methyl-2-(pyrimidin-5-yl) propylamine<BR> <BR> Step A 4-(4-Chlorophenvl)-3-(pynmidin-5-yl)-butan-2-one The title compound was obtained from 5-bromopyrimidine following the method of Reference Example 87, Steps B-C except that 2- (di-t-butylphosphino) biphenyl was used in place of dicyclohexylphospino-2'- (N, N-dimethylamino) biphenyl in Step B.

Step B 3-(4-Chlorophenyl)-1-methyl-2-(perimidin-5-yl) propylamine The title compound was prepared by the procedure described in Reference Example 18, Steps E-1. LC-MS, Rt = 1.57 min, m/e = 262.

REFERENCE EXAMPLE 90 2- (3-Cyanophenyl)-3-cyclobutyl-l-methylpropylamine Step A 1-(3-Cyanophenyl) acetone The title compound was prepared from 3-bromobenzonitrile and isopropenyl acetate by the procedure of Reference Example 87, Step B.

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 acetonitrile, 1.1 mL (9.5 mmol) cyclobutyl bromide and 5.91 g (18.1 mmol) cesium carbonate were added. 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 layer was washed with brine, dried and concentrated. The residue was purified on a flash column using a gradient of 5-10% EtOAc/hexane to isolate the title compound. 1H NMR: (500 MHz, CDCl3) : 81. 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 This amine was prepared by following the method of Reference Example 2, Steps E-I. LC-MS, Rt = 2.48 min, m/e = 229.

The compounds of Reference Examples 91-93 were obtained by procedures described in Reference Example 90.

REFERENCE EXAMPLE 91

2-(3-Cyanophenyl)-3-cyclopropyl-1-methylpropylamine LC-MS, Rt = 1.8 min, m/e = 215.

REFERENCE EXAMPLE 92 2-(3-Cyanophenyl)-3-cyclopentyl-1-methylpropylamine LC-MS, Rt = 2.7 min, m/e = 243.

REFERENCE EXAMPLE 93 2-(3-Cyanophenyl)-3-cyclohexyl-1-methylpropylamine LC-MS, Rt = 2.8 min, m/e = 257.

REFERENCE EXAMPLE 94

2-(3-Cyanophenyl)-3-(1-tert-butyloxycarbonyl-piperidin-4-yl) -1-methylpropylamine<BR> <BR> <BR> <BR> <BR> Step A 3-(3-Cyanophenyl)-4-(1-tert-butyloxycarbonyl-piperidin-4-yl) -butan-2- one The title compound was synthesized by the method of Reference Example 90, Steps A-B.

Step B 2- (3-Cyanophenyl)-3- (1-tert-butyloxycarbonyl-piperidin-4-yl)-1- methylpropylamine The title amine was obtained by the method of Reference Example 2, steps E-G except that di-tert-butyl dicarbonate was not added in Step G. LC-MS, Rt = 2.72 min, m/e = 258 (M-99).

REFERENCE EXAMPLE 95 The title compound was prepared following the same procedure as described in Reference Example 66 substituting 3,5-dibromopyridine with 3- bromothioanisole at Step A. LC-MS: m/e 306 (M + H) + (2. 68 min).

EXAMPLE 1 Automated Synthesis of a One Dimensional Amide Library

The following synthesis of a 1-dimensional, single, pure compound library was performed on a Myriad Core System. All reaction vessels were dried under a stream of nitrogen at 120°C for 12 hours prior to use. All solvents were dried over sieves for at least 12 hours prior to use. An appropriate stock solution of N- [2, 3- bis (4-chlorophenyl)-1-methylpropyl]-amine hydrochloride (alpha isomer) was prepared immediately prior to use in pyridine with 0.05 equivalents (relative to N- [2,3-bis (4-chlorophenyl)-1-methylpropyl]-amine hydrochloride (alpha isomer) ) of dimethylaminopyridine added; the diversity carboxylic acids were dissolved immediately prior to use in DMSO. The relative amounts of reactants and coupling reagents are listed in Table 1. Compounds of the present invention that were prepared by this method of automated synthesis are listed in Table 2.

Table 1. Substance Amount MW Concentration mmols Equivs. per reaction vessel Aryl Acid in 1 mL N/A 0. 2 M 0.2 1.67 DMSO EDC/HOBt 0.8 mL EDC: 0.25 M each 0.2 1.67 Cocktail in 191.71 each each Deuterated HOBt : Chloroform 135. 13 Amine in Pyridine 0.6 mL 294.22 0. 2M 0.12 1.0 with catalytic 7 dimethylaminopyri dine (-0. 05 eq.) Procedure To vessel one of a total of 192 dry, 10 mL fritted Myriad reaction vessels under nitrogen was added the appropriate diversity acid subunit (1.0 mL, 0.2 mmoles, 0.2 M in DMSO); this was repeated for the remaining 191 reactions until the diversity acids had been enumerated to all 192 reaction vessels. To each of 192 reaction vessels under nitrogen was then added the EDC/HOBt cocktail (0.8 mL, 0.2 mmoles, 0.25 M each in deuterated chloroform). Finally, to each of the 192 reaction

vessels was added N- [2, 3-bis (4-chlorophenyl)-1-methylpropyl]-amine hydrochloride (alpha isomer) (0.6 mL, 0.12 mmoles, 0. 2M in pyridine). The reactions were then aged for 4 hours at room temperature (20-25° C) followed by 16 hours at 65°C with nitrogen sparging agitation (ls pulse of nitrogen every 30 minutes. ) The crude reactions were analyzed by HPLC-MS Method 1.

Analytical LC Method 1: Column: MetaChem Polaris C-18A, 30 mm X 4.6 mm, 5.0 Fm Eluent A: 0.1% TFA in Water Eluent B: 0. 1 % TFA in Acetonitrile Gradient: 5% B to 95% B in 3.3 minutes, ramp back to 5% B in 0.3 min Flow: 2.5 mL/min.

Column Temp.: 50° C Injection amount: 5 pL of undiluted crude reaction mixture.

Detection: UV at 220 and 254 nm.

MS: API-ES ionization mode, mass scan range (100-700) ELSD: Light Scattering Detector All 192 crude reactions were purified by preparative HPLC using UV based detection (Preparative method 2). The collected fractions were then analyzed for purity by LC-MS (Analytical method 3); fractions found to be greater than 90% purity were pooled into tared 40 mL EPA vials and lyophilized.

Preparative LC Method 2: Column: MetaChem Polaris C-18A, 100 mm X 21.2 mm, 10 m Eluent A: 0. 1% TEA in Water Eluent B: 0. 1% TFA in Acetonitrile Pre-inject Equilibration: 1.0 min Post-Inject Hold: 0.0 min Gradient: 10% B to 100% B in 6.0 minutes, hold at 100% B for an additional 2.0 minutes, ramp back from 100% B to 10% B in 1.5 minutes.

Flow: 25 mL/min.

Column Temp.: ambient Injection amount: 1.5 mL of undiluted crude reaction mixture.

Detection: UV at 220 and 254 nm.

Analytical LC Method 3: Column: MetaChem Polaris C-18A, 30 mm X 2.0 mm, 3. 0 mi Eluent A: 0. 1% TFA in Water Eluent B: 0. 1% TFA in Acetonitrile Gradient: 5% B to 95% B in 2.0 minutes, ramp back to 5% B in 0.1 min Flow: 1. 75 mL/min.

Column Temp.: 60° C Injection amount: 5 uL of undiluted fraction.

Detection: UV at 220 and 254 nm.

MS: API-ES ionization mode, mass scan range (100-700) ELSD: Light Scattering Detector Lyophilization Parameters Initial Freeze Setpoint: 1 hour at-70° C Drying Phase Condenser Setpoint :-50° C Drying Phase Table : Shelf Temperature Duration (minutes) Vacuum Setpoint (C) (mTorr) -60° 240 25 -40° 240 25 5O 480 25 20° 1000 25 Table 2. Compounds prepared by automated synthesis. retention HPLC-mass Exp. Name Structure time spectrum No. (min) rnle ......................, _ _ _ ~ _"''~"""""'ei-~~--~ ~--",.", _, 1 N- (2, 3-bis (4- 0 1. 449 456. 1 jchlorophenyl)-l- ! ti oX I I methylpropyl)-1, 4 ( benzodioxane-2- E de jcarbpxamide 2. N- (2, 3-bis (4-i C Nw ! 1. 45 | 438. 1 5 ; 1 N v/I chlorophenyl)-1- methylpropyl)-indane- 1-carboxamide i3. N-(2, 3-bis (4-CU J9 | 1. 5 1 440. 2 |chlorophenyl)-l- f<NJ 04 Ij |methylpropyl)-2, 3-| ClX ; Y P PY ; dihydrobenzofuran-2- carboxamide 4. N- (2, 3-bis (4- °'TJkA."t '''''''-'' : N ; i chlorophenyl)-l- |methylpropyl)-1, 2, 3, 4-cox |tetrahydrocarbazole-l- icarboxamide EXAMPLES 5 and 6

N-[2,3-Bis(4-Chlorophenyl)-1-methylpropyl]-1,2,3,4-tetrahydr o-2-naphthamide (Diastereomers I and In.

To a solution of 1, 2,3, 4-tetrahydro-2-naphthoic acid (Aldrich, 0.50 g, 2.8 mmol) in methylene chloride (10 mL) at 0 °C was added a drop of dimethylformamide and oxalyl chloride (2 M in methylene chloride, 4.3 mL, 8.5 mmol). After stirring at room temperature for 2 h, the reaction mixture was concentrated on a rotary evaporator and dried under vacuum, and the resulting crude acyl chloride (0.55 g) was used without further purification. Thus, the crude acyl chloride (88 mg, 0.45 mmol) was dissolved in 1 mL of methylene chloride and was added 3,4-bis (4-chlorophenyl)-1-methylpropyl-amine hydrochloride salt (Reference Example 1) (Diastereomer oc, 0.10 g, 0.30 mmol) and diisopropylethylamine (0.16 mL, 0.91 mmol). After stirring at room temperature for 6 h, the reaction mixture was loaded onto a silica gel column, which was eluted with 10% ethyl acetate to give a faster eluting diastereomer (Diastereomer I) and a slower eluting diastereomer (Diastereomer II) along with some mixed fractions.

Diastereomer 1 : LC-MS: m/e 452 (M + H) + (4. 36 min).

Diastereomer II : LC-MS: m/e 452 (M + H) + (4.34 min).

EXAMPLES 7 and 8 N-f2, 3-Bis (4-Chlorophenyl)-1-methylpropyll-1, 2, 3, 4-tetrahydro-2-naphthamide (Diastereomers III and IV).

The title compounds were prepared following the procedures described for Examples 5 and 6 substituting Diastereomer oc of 3,4-bis (4-chlorophenyl)-1- methylpropyl-amine hydrochloride salt (Reference Example 1) with Diastereomer P of 3,4-bis (4-chlorophenyl)-1-methylpropyl-amine hydrochloride salt (Reference Example 1).

Diastereomer III (fasting eluting diastereomer on silica gel): LC-MS: m/e 452 (M + H) + (4.30 min).

Diastereomer IV (slower eluting diastereomer on silica gel): LC-MS: m/e 452 (M + H) + (4.29 min).

The following Examples (Table 3) were prepared by the procedures described in Examples 5-6 (Method B) substituting 3,4-bis (4-chlorophenyl)-1- methylpropyl-amine hydrochloride salt with the appropriate amines described in Reference Examples 1-4 and substituting 1, 2,3, 4-tetrahydro-2-naphthoic acid with the appropriate carboxylic acids described in Reference Examples 5-13. In some cases, commercial acids were employed.

Table 3. Compounds prepared by Method B. retention ! HPLC- e mass Diaster i . ; Ex., Name Structure j tim No. (min) spectrum-eomer title 19. N- [3- (4- a |Chlorophenyl)-l-S methy-2- 'a methy-2- ' 3. 97 406 phenylpropylj-2, 3- j ! J'= ci ofuran i de i s -2-carboxamide __. _. m.... _.... _.... __......-.. _.. 10. N- [3- (4- T^ y i ; i ) Chlorophenyl)-l- i imethy-2- D6 11 i t ; N o r v 3. 95 406 II (I i a phenylpropyl]-2, 3-1, ( dihydrobenzofuran -2-carboxamide 1 l. N- [3- (4- v N [3 (4 l Chlorophenyl)- !- methy-2-I", Y 3. 96 406 1 , J - 3. 96 406 phenylpropyll dihydrobenzofuran amide )-2arbpxamidej 12. N- [2, 3-Bis (4- chlorophenyl)-1- CI \ I N O methypropyl]-2-X N 4. 15 454 methyl-2, 3-CI dihydrobenzofuran '-2-caiboxamide 13. N- [2, 3-Bis (4- tchiorophenyl)-l-| Cl\nl o F i methypropyl]-2-N i 4. 13 454 ethyl-2, 3- ci |-2-ca boxa de_ 2 14. V- [2, 3-Bis (4- i ; chlorophenyl)-1- CI/ 4 |methypropyl]-2-e NJ I 4. 14 454 I : II N o r v 4. 14'454 methyl-2, 3-l : 1 CI dihydrobenzofuran ij l l - 2-carboxamide dihydrobenzofuran Chlorophenyl)- !- ! methy-2- Iphenylpropyl]-2-i, Ci o<3 1 4. 15 1 420 | I methyl-2, 3 1 ci dihydrobenzofuran ; 2 carboxamide ; .. ; {Chlorophenyl)-1- methoxy-2- o r v 4. 13 420 II phenylpropyl]-2- y methyl-2, 3-' dihydrobenzofuran 'I 17. N- [3- (4- Chlorophenyl)-l- methoxy-2- o r 4. 14 420 methoxy-2- 1 : 1 methyl-2, 3-Cl dihydrobenzofuran 2 carboxamide j... _.. 18. N-[2, 3-Bis (4- t chlorophenyl)- !- e, r i ° ichlorophenyl)-l- 1 cri ! mcthyl-1, 2, 3, 4-ClX l 4. 54 466 j tetrahydro-2- < < - [2, 3-Bis (4- chlorophenyl)- O N ichlorophenyl)-l-ci 4. 50 ? 466 II |methyl-1, 2, 3, 4- t tetrahydro-2- tetrahydro-2- Chlorophenyl)-1- i j/o a |Chlorophenyl)-l- ! | ii ! methy-2- j'I : B 4. 31 432 Imethy-2- j ! j Id methyl-1, 2, 3, 4-cW tetrahydro-2- "". _. naphthamide 21. N [3- (4- I I Chlorophenyl)-1- met-2- methy-2--YYfT) t methy-2- phenylpropyl]- 1, 2, 3, 4-tetrahydro- 2naphthamide -phthami 22. N- [3- (4- Chlorophenyl)-1- methoxy-2- 'J UU 4. 14 418 n phenylpropyl]-ClX . 1, 2, 3, 4-tetrahydro- na hthamide 23. iN-. [3 (4_-.. _. _.. __. _....... __ I 1 I Chlorophenyl)- !- 23. N- [3- (4- 4. 14'418 phenylpropyl]- I s '1, 2, 3, 4-tetrahydro- ; j 2-na hthamide E ! 24 ! F-[2, 3-Bis (4-ii chlorophenyl)- !- T ! j t cri i chlorophenyl) _ I- mane-2-| Cl ! (carboxamide : ..... i am' : E 25. mane-2- i Chlorophenyl)- !- I : n imethy-2-1 WNX ! 4. 16 0 T I : II | phenylpropyl] chro 1 : 1 I mane-2- , t 1 ci |chlorophenyl)-l- ! C143s 1N) ; E P Y) y o ; , methylpropyl]-2-J UU 4. 53 468 | I | i methylchromane- ;-carboxamide ! 27. lN-[2, 3-Bis (4-l ! ! jchlorophenyl)- !-"Y).) N 127. N- [2, 3-Bis (4- YP PY) t |methylchromane-cl 'cboxamide 28. N- [2, 3-Bis (4- chlorophenyl)-t-ci 0 methylpropyl]-2-J kJU 4. 45 468 Y P PY ' 1 : 1 methylchromane-ci 2-carboxamide Chlorophenyl)- !- ' r, 4. 34 434 phenylpropyl]-2-J methylchromane- j - 30. IN- [3- (4- 30. iN [3 (4 l l ! Chlorophenyl)- !- |methy-2-iNe ! 4. 24 434 | II 'J J 4. 24 434 n , ; phenylpropyl]-2- methylchromane- ; ; . ! 2- _. . _ ; _. _boxamide. ) Chlorophenyl)-1- r ; UU 4. 29 434 i ! o I E I : II methy-2-i "' 4. 29'434' [phenylpropyl]-2-Ij Cli methylchromane- L. _. __i. boxamide 32. N [2, 3-Bis (4- I chlorophenyl)- !- °'1) t ? 'I : II ' \ 4. 20 454 |methylpropyl] chro t oJSi 4. 20 1 454 j ; Imane-3- ! C carboxamide 3 i33. IN [3 (4 Chlorophenyl)- !- icarboxamide 4. 00 420 . 1 : 1 phenylpropyl] chro Cl mante-3- mane-3- i' acarboxamide' mane-3- 34. N- [2, 3-Bis (4- chlorophenyl)-1-°' ', p 1 : 11 methylpropyl]-3-) 3) 4. 31 468 Y P PY '1 : 1 methylchromane-Cl methylehromane-ci 3-carboxamide 35. A- [3- (4- Chlorophenyl)- !- N jmethy-2- 4. 11 434 henylpropyl]-3- 1 v 1 ; ! phenylpropyl]-3-Jkd L 1 : l methylchromane- zinc . ! 36. N- [2, 3-Bis (4- 36 chlorophenyl)- !- i ; a ci methyl-2, 3- J JU 4. 36 470 I idihydro-1, 4 Cl | ! l 3 |benzodioxane-2-i d ci dihydro-1, 4- i chlorophenyl)- !- l f |methylpropyl]-2-| cl, i chlorophenyl)-l- i 't y'I ! methylpropyll-2- benzodioxane-2- icarboxamide ! chlorophenyl)- !- ibenzodioxane-2- tchlorophenyl)-l I ! ! 3 meth 1 ro 1-2-c'' E YP PY . o ° I : II methyl-2, 3- J JU 4. 32 470 dihydro-1, 4 c, benzodioxane-2- ! icarboxamide 39. N- [3- (4- Chlorophenyl)-1- methoxy-2- methy-2- phenylpropyl]-2-4. 17 436 1 methyl-2, 3- E dihydro-1, 4- benzodioxane-2- s I 3 I carboxamide j i I-, Chlorophenyl)- !- methoxy-2- 0 methoxy-2- 4. 08 436 II n 4. Uo 4jo U methyl-2, 3-cl4 dihydro-1, 4- ; i 1 |benzodioxane-2- ! ;, ; ___ ! 41 ty-[3-(4- ! | ! i j j Chlorophenyl)- !- t carboxam |phenylpropyl]-2-, 033 4. 12 1 436 Chlorophenyl)-l- methy-2- ; ( dihydro-1, 4- , I i benzodioxane-2- i icarboxamide 42. iN-[2, 3-Bis (4- ! ! |chlorophenyl)-l-cz l I methylpropyl]-2, 3- 4. 22 456 in ; dihyclro-1, 4- ( benzodioxane-2- carboxamide Icarbox. I j43., N [2, 3-Bis (4 s I o J LJU 4. 20 456 IV Imethylprop 112 3 Idihvdro-14- ! i J 0 j -'- I.......... benzodioxane-2- carboxamide 44. N- [3- (4- I t Chlorophenyl)- !- 1 methy-2-0 4. 04 422 I phenylpropyl]-2, 3- tdihydro-1, 4 Clw benzodioxane-2- t benzodioxane-2- 45. N- [3- (4- Chlorophenyl)-1- methy-2- N 0 : 0 a ' (dihydro-1, 4- °'/ i benzodioxane-2- 3 (i benzodioxane-2- 46. N- [3- (4- Chlorophenyl)- !- methy-2-) ? j methy-2-_ I No ' I : II 'ko 1 : 11 phenylpropyl]-2, 3- J o 4. 01 422 l : l i dihydro-1, 4 Cl benzodioxane-2- tcarboxamide, l ! ! I _ ___.. __.. 47. jN- [3- (4-. Chlorophenyl)- !- ! methy-3-. methy-3-NeOg 1 : 11 methoxy-3- methyl-2, 3-Cl l ! 3 : 1 E dihydro-1, 4- !' I Jcarboxamide benzodioxane-2- 48. N- [3- (4- Chlorophenyl)-1- methyl- pyridylpropyl]-2- I : II 2. 61/2. 52 437 methyl-2, 3-Cl dihydro-1, 4- benzodioxane-2- carboxamide I 149 jN-[3-(4-j T ; Chlorophenyl)-1- methy-3- pyddylpropyl]-2-YN°) 2. 52 1 ! methyl-2, 3- ! Cl methyl-2, tdihydro-1, 4- Ibenzodioxane-2- i s I i ; , E I i i ; E j i I chlorophenyl i I f i ci i 6, 7, 8, 9-tetrahydro- I ISH-I ClL} benzol [7] annule r... _.. _. _. ne,-6-carboxamide I E ! 51. N- [2, 3-Bis (4- j chlorophenyl)-1- a chlorophenyl)-l methylpropyll- N--Cp ! ! 5ff-I Cl benzo [a] [7] annule 5H-ci ne-6-carboxamide 52. N- [2, 3-Bis (4- ci 4. 43 466 i I : II s -J 1 : 1 e methylpropyl]-' CI ci 5H- benzo [a] [7] annule ne-6-carboxamide 53. N- [3- (4- Chlorophenyl)-l- methyl- phenylpropyl]-TJ\NS 4. 24 432 I 4. 24, 432 I 6, 7, 8, 9-tetrahydro- ; 5H- benzo [a] [7] annule ) ! I I 54. N- [3- (4- S4. N-[3-(4-1 i i ') Chlorophenyl)- !- I methoxy-2-) henylpropyll- "'"", J k/"4. 23 432 n 6, 7, 8, 9-tetrahydro- I ISH- Ibenzo [a] [7] annule .., ( __.. _. _ne-6carboxamide I -IN [3 (4 Chlorophenyl)- !- Method-2- methy-2- a I iphenylpropyl i 1 : 1 6, 7, 8, 9-tetrahydro-c, l ! ! 1 : 1 5H- i benzo [a] [7] annule ne-6-carboxamide i 56. N-[2, 3-Bis (4- f chlorophenyl)-l-c, O i t Imethypropyl]-N I : II 4. 41 466 |6, 7, 8, 9-tetrahydro-. E C I i benzo [a] [7] annule ;. _.. ne-7-carboxamide 57. N- [3- (4- Chlorophenyl)-1- methy-2- !.. j o methoxy-2- phenylpropyl N 4. 21 432 su- ! f t benzo [a] [7] annule |ne-7-carboxamide ! EXAMPLES 58 and 59

N-r3- (4-Chlorophenyl)-l-methy-2-phenylpropyll-2-methyl-2, 3-dihydro-1, 4- benzodioxane-2-carboxamide (Diastereomer I, Enantiomers A and B) Preparative HPLC was performed on a Gilson HPLC system for the separation of enantiomers. Thus, a solution of N [3- (4-chlorophenyl)-1-methy-2- phenylpropyl]-2-methyl-2, 3-dihydro-1, 4-benzodioxane-2-carboxamide (Example 39, Diastereomer 1) (51 mg) in hexane (1.7 mL) /ethanol (0.3 rnL) was loaded onto a CHIRALCEL OJ column (2 cm x 25 cm), which was eluted with 7% ethanol in hexane (flow rate 8 mL/min, 1.0 mL per injection) to give the two pure enantiomers.

Faster eluting enantiomer (Enantiomer A): Analytical HPLC : retention time = 8. 28 min (CHIRALCEL OJ column, flow rate = 0.75 mL/min, 10% ethanol/hexane).

LC-MS: m/e 436 (M + H) + (4.17 min).

Slower eluting enantiomer (Enantiomer B) : Analytical HPLC : retention time = 10.16 min (Chiralcel OJ column, flow rate = 0.75 mL/min, 10% ethanol/hexane).

LC-MS: m/e 436 (M + H) + (4.17 min).

EXAMPLES 60 and 61

N-f3- (4-Chlorophenyl)-1-methy-3-pyridylpropyll-2-methyl-2, 3-dihydro-1, 4- benzodioxane-2-carboxamide (Diastereomer I, Enantiomers A and B) Preparative HPLC was performed on a GILSON HPLC system for the separation of enantiomers. Thus, a solution of N [3- (4-chlorophenyl)-1-methy-3- pyridylpropyl]-2-methyl-2, 3-dihydro-1, 4-benzodioxane-2-carboxamide (Example 47, Diastereomers 1 : II 3 : 1) (0.10 g) in hexane (1.65 mL)/ethanol (0.35 mL) was loaded onto a CHIRALPAK AD column (2 cm x 25 cm), which was eluted with 60% ethanol in hexane (flow rate 8 mL/min, 1.0 mL per injection). The two major peaks were collected to give two pure enantiomers.

Faster eluting enantiomer (Enantiomer A): Analytical HPLC : retention time = 17.5 min (CHIRALPAK AD column, flow rate = 0.75 mL/min, 15% ethanol/hexane). LC- MS: m/e 437 (M + H) + (2.49 min).

Slower eluting enantiomer (Enantiomer B): Analytical HPLC : retention time = 23.6 min (CHIRALPAK AD column, flow rate = 0.75 mL/min, 15% ethanol/hexane). LC- MS: m/e 437 (M + H) + (2.49 min).

EXAMPLES 62 and 63

N-f 3- (4-chlorophenyl)-2 (S)-phenyl-1 (S)-methylpropyll-3-methylchromane-3-<BR> carboxamide (Diastereomers I and 11).

The title compounds were prepared as a 1: 1 mixture of diastereomers following the procedures described for Examples 5 and 6 substituting 2-amino-3,4- bis (4-chlorophenyl) butane hydrochloride salt (Reference Example 1) with N- [3- (4- chlorophenyl) -2 (S)-phenyl-l (S)-methylpropyl]-amine hydrochloride (Reference Example 3) and substituting 1, 2,3, 4-tetrahydro-2-naphthoic acid with 3- methylchromane-3-carboxylic acid (Reference Example 9). LC-MS: m/e 434 (M + 1-1) + (4.06 min).

EXAMPLES 64 and 65 N-F3-(4-chlorophenyl)-2 (S)-phenyl-1 (S)-methylpropyll-2-methyl-2, 3-dihydro-1, 4- benzodioxane-2-carboxamide (Diastereomers I and IT).

The title compounds were prepared as a 1: 1 mixture of diastereomers following the procedures described for Examples 5 and 6 substituting 2-amino-3,4- bis (4-chlorophenyl) butane hydrochloride salt (Reference Example 1) with N [3- (4- chlorophenyl) -2 (S)-phenyl-l (S)-methylpropyl]-amine hydrochloride (Reference Example 3) and 1, 2,3, 4-tetrahydro-2-naphthoic acid with 2-methyl-2, 3-dihydro-1, 4- benzodioxane-2-carboxylic acid (Reference Example 10). The mixture of diastereomers was separated into two pure diastereomers by eluting on a silica gel column with 15% ethyl acetate in hexane. Faster eluting diastereomer: Analytical HPLC : retention time = 10.10 min (Chiralcel OJ column, flow rate = 0.75 mL/min, 10% ethanol/hexane). LC-MS: m/e 436 (M + H) + (4.14 min).

Slower eluting diastereomer: Analytical HPLC : retention time = 7.13 min (Chiralcel OJ column, flow rate = 0.75 mL/min, 10% ethanol/hexane). LC-MS: m/e 436 (M + EI) + (4. 05 min).

EXAMPLES 66 and 67

N-r3- (4-chlorophenyl)-2 (S)-phenyl-l (S)-methylpropyll-6-chloro-2-methyl-2, 3- dihydro-1, 4-benzodioxane-2-carboxamide and N-f3- (4-chlorophenyl)-2 (S)-phenyl- <BR> <BR> <BR> 1 (S)-methylpropyll-7-chloro-2-methyl-2, 3-dihydro-1, 4-benzodioxane-2-carboxamide (Diastereomers I and II, each a mixture of 6-and 7-chloro regioisomers).

The title compounds were prepared as a 1: 1 mixture of diastereomers following the procedures described for Examples 5 and 6 substituting 2-amino-3,4- bis (4-chlorophenyl) butane hydrochloride salt (Reference Example 1) with N- [3- (4- chlorophenyl) -2 (S)-phenyl-1 (S)-methylpropyl]-amine hydrochloride (Reference Example 3) and 1, 2,3, 4-tetrahydro-2-naphthoic acid with 6-chloro-2-methyl-2,3- dihydro-1, 4-benzodioxane-2-carboxylic acid and 7-chloro-2-methyl-2, 3-dihydro-1, 4- benzodioxane-2-carboxylic acid (1: 1 mixture of regioisomers) (Reference Example 11). The mixture of regioisomers was separated into two diastereomers by eluting on silica gel with 10% ethyl acetate in hexane.

Faster eluting component: LC-MS: m/e 470 (M + H) + (4. 34 min).

Slower eluting component: LC-MS: m/e 470 (M + H) + (4.20 min).

EXAMPLE 68 Cannabinoid Receptor-1 (CB1) Binding Assay.

Binding affinity determination is based on recombinant human CB 1 receptor expressed in Chinese Hamster Ovary (CHO) cells (Felder et al, Mol.

Pharmacol. 48: 443-450,1995). Total assay volume is 250 Ill (240 RI CB 1 receptor membrane solution plus 5 1 test compound solution plus 5 ul [3H] CP-55940 solution). Final concentration of [3H] CP-55940 is 0.6 nM. Binding buffer contains 50mM Tris-HCl, pH7.4, 2.5 mM EDTA, 5mM MgC12, 0. 5mg/mL fatty acid free bovine serum albumin and protease inhibitors (Cat#P8340, from Sigma). To initiate the binding reaction, 5 Ill of radioligand solution is added, the mixture is incubated with gentle shaking on a shaker for 1.5 hours at 30°C. The binding is terminated by

using 96-well harvester and filtering through GF/C filter presoalced in 0. 05% polyethylenimine. The bound radiolabel is quantitated using scintillation counter.

Apparent binding affinities for various compounds are calculated from IC50 values (DeBlasi et al., Trends Pharmacol Sci 10: 227-229,1989).

The binding assay for CB2 receptor is done similarly with recombinant human CB2 receptor expressed in CHO cells.

EXAMPLE 69 Cannabinoid Receptor-1 (CB1) Functional Activity Assay.

The functional activation of CB 1 receptor is based on recombinant human CB 1 receptor expressed in CHO cells (Felder et al, Mol. Pharmacol. 48 : 443- 450,1995). To determine the agonist activity or inverse agonist activity of any test compound, 50 u. l of CB1-CHO cell suspension are mixed with test compound and 70 ul assay buffer containing 0. 34 mM 3-isobutyl-1-methylxanthine and 5.1 tM of forskolin in 96-well plates. The assay buffer is comprised of Earle's Balanced Salt Solution supplemented with 5 mM MgCl2, 1 mM glutamine, 10 mM HEPES, and 1 mg/mL bovine serum albumin. The mixture is incubated at room temperature for 30 minutes, and terminated by adding 301l1/well of 0. 5M HCl. The total intracellular cAMP level is quantitated using the New England Nuclear Flashplate and cAMP radioimmunoassay kit.

To determine the antagonist activity of test compound, the reaction mixture also contains 0.5 nM of the agonist CP55940, and the reversal of the CP55940 effect is quantitated. Alternatively, a series of dose response curves for CP55940 is performed with increasing concentration of the test compound in each of the dose response curves.

The functional assay for the CB2 receptor is done similarly with recombinant human CB2 receptor expressed in CHO cells.

While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications for the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending

upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.