WO2008112674A1 - Compounds and compositions as inhibitors of cannabinoid receptor 1 activity - Google Patents

Abstract

The invention provides compounds of formula (I), pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of Cannabinoid Receptor 1 (CB 1).

Description

COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF CANNABINOID RECEPTOR 1 ACTIVITY

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. provisional application serial number 60/894,331, filed March 12, 2007, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Field of the Invention

[0002] The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of Cannabinoid Receptor 1 (CBl).

Background

[0003] The cannabinoids are psychoactive ingredients of marijuana, principally delta-9-tetrahydrocannabinol. Two cannabinoid receptors have been cloned, CBl and CB2. CBl is predominantly expressed in the central nervous system whereas CB2 is expressed in peripheral tissues, principally in the immune system. Both receptors are members of the G-protein coupled class and their inhibition is linked to adenylate cyclase activity.

[0004] The novel compounds of this invention inhibit the activity of CBl and are, therefore, expected to be useful in the treatment of CBl-associated diseases or disorders such as, but not limited to, psychosis, memory deficit, cognitive disorders, migraine, neuropathy, neuroinflammatory disorders, cerebral vascular accidents, head trauma, anxiety disorders, substance abuse (such as smoking cessation), stress, epilepsy, Parkinson's disease, schizophrenia, osteoporosis, constipation, chronic intestinal pseudoobstruction, cirrhosis of the liver, asthma, obesity, and other eating disorders associated with excessive food intake. SUMMARY OF THE INVENTION

[0005] In one aspect, the present invention provides a compound of Formula I:

[0006] in which:

[0007] Y₁ is selected from N and CR_n ;

[0008] Y₂ is selected from N and CR₈;

[0009] Y₃ is selected from N and CR₆; wherein R₆ is selected from hydrogen, halo, nitro, Ci_₆alkyl, Ci_₆alkoxy, halo-substituted-Ci_₆alkyl, halo-substituted-Ci_₆alkoxy,

S(0)o-2Ri6 and -C(O)R]₆; wherein R]₆ is selected from Ci_6alkyl, Cδ-ioaryl, C_{1- l}oheteroaryl, C₃_iocycloalkyl and C₃_₈heterocycloalkyl; wherein said aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R]₆ is optionally substituted with 1 to 3 radicals independently selected from halo and Ci_₆alkyl;

[0010] Z₁ is selected from S, S(O), SCH₂, S(O)CH₂, CH₂S(O), CH₂S and NR₂; wherein R₂ is selected from hydrogen, -C(O)X₂Ri₈, -C(O)OX₂Ri₈, -S(OV₂X₂Ri₈, ; wherein X₂ is selected from a bond and Ci^alkylene; Ri₈ is independently selected from hydrogen, Ci_₆alkyl, Ci_ioheteroaryl and C₃_₈heterocycloalkyl; wherein said heteroaryl or heterocycloalkyl of Ri₈ is optionally substituted with 1 to 3 radicals independently selected from halo and Ci_₆alkyl;

[0011] Z₂ is selected from O, NH, N(OH), N(CN) and S;

[0012] Ri is selected from hydrogen, C_1-6alkyl, -XiC(O)NRi_7aRi_7b, -

XiC(O)NRn₃; wherein Xi is selected from a bond and Ci^alkylene; R_17a and R₁₇b are independently selected from hydrogen, Ci_₆alkyl, C₃_i₂cycloalkyl and C₃_ sheterocycloalkyl; wherein said cycloalkyl or heterocycloalkyl of R_17a or R_17b can be optionally substituted with 1 to 3 radicals independently selected from halo, C]_₆alkyl, C_{1- δ}alkoxy, halo-substituted-Ci_₆alkyl and halo-substituted-Ci_₆alkoxy; [0013] R₃, R₅, and R₇ are selected from hydrogen, halo, hydroxy, nitro, Ci_₆alkyl,

Ci_₆alkoxy, halo-substituted-Ci_₆alkyl, halo-substituted-Ci_₆alkoxy, -S(0)o_-2Ri₆ and - C(O)R]₆; wherein R]₆ is selected from Ci_₆alkyl, C_δ-ioaryl, Ci_ioheteroaryl, C₃_iocycloalkyl and C₃_sheterocycloalkyl; wherein said aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R₁₆ is optionally substituted with 1 to 3 radicals independently selected from halo and Ci-₆alkyl;

[0014] R₄ is selected from halo, nitro, cyano, Ci_₆alkyl, Ci_₆alkoxy, halo- substituted- Ci _6alkyl, halo-substituted-Ci_6alkoxy, -Ri3a, -NRi3_aRi3b, -OX₄OC(O)R₁₃₃, - ₄OC(O)R_13a, -C(O)Ri₃₈, -C(O)ORi₃₈, -OX₄OR₁₃₃, -OX₄R₁₃₃, -X₄NR₁₃₃C(O)R₁₃₃, - X₄NRi_3aS(0)o-2Ri3₃, -OR]₃₃, ; wherein X₄ is selected from a bond and Ci^alkylene; R]₃₃ and R]_3b are independently selected from hydrogen, Ci_₆alkyl, C_6-10aryl, Ci_ioheteroaryl, C₃_i₂cycloalkyl and C₃_sheterocycloalkyl; or R₄ and R₅ together with the carbon atoms to which R₄ and R₅ are attached form C₃_sheterocycloalkyl or Ci_ioheteroaryl; wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R₄ or the combination of R₄ and R₅ is optionally substituted with 1 to 3 radicals independently selected from Ci_₆alkyl, C_{1- 6}alkoxy, halo-substituted-Ci_₆alkyl, halo-substituted-Ci_₆alkoxy, -C(O)NR]_4aRi_4b and - C(O)OR]₄₃; wherein R₁₄₃ and R_14b are independently selected from hydrogen and C_{1- 6}alkyl;

[0015] Rg, R₉, Rn and R₁₂ are independently selected from hydrogen, halo, hydroxyl, cyano, Ci_₆alkyl, Ci_₆alkoxy, halo-substituted-Ci_₆alkyl, halo-substituted-Ci_ βalkoxy, -S(O)_0-2R_1S, -OR₁₅ and -R₁₅; wherein R₁₅ is selected from hydrogen, Ci_₆alkyl, halo-substituted-Ci_₆alkyl and C₆-i₀aryl; wherein said aryl of R₁₅ is optionally substituted with 1 to 3 radicals independently selected from halo, Ci_₆alkyl, Ci_₆alkoxy, halo- substituted- Ci _₆alkyl and halo-substituted-Ci_₆alkoxy; or Rn and R_]2 together with he carbon atoms to which Rn and R₁₂ are attached form phenyl;

[0016] R]₀ is selected from halo, cyano, hydroxy, Ci_₆alkyl, Ci_₆alkoxy, halo- substituted- Ci -₆alkyl, halo-substituted-Ci_₆alkoxy, -X₃ORi₉, -X₃S(O)₀-2Ri₉, -X₃NR₂₀Ri₉ and -X₃Ri₉; wherein X₃ is selected from a bond and Ci^alkylene; R₂₀ is selected from hydrogen and C^alkyl; and R]₉ is selected from C₆-i₀aryl and Ci_i₀heteroaryl; wherein Rj₉ is optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, nitro, amino, Ci_₆alkyl, Ci_₆alkoxy, halo-substituted-Ci_₆alkyl and halo- substituted- Ci _₆alkoxy;

[0017] Ri₃ is selected from hydrogen and Ci_₆alkyl; and the pharmaceutically acceptable salts, hydrates, solvates and isomers thereof.

[0018] In a second aspect, the present invention provides a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.

[0019] In a third aspect, the present invention provides a method of treating a disease in an animal in which modulation of CB 1 activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.

[0020] In a fourth aspect, the present invention provides the use of a compound of

Formula I in the manufacture of a medicament for treating a disease in an animal in which CB 1 activity contributes to the pathology and/or symptomology of the disease. [0021] In a fifth aspect, the present invention provides a process for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof, and the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0022] "Alkyl" as a group and as a structural element of other groups, for example halo-substituted-alkyl and alkoxy, can be either straight-chained or branched. Ci_₆alkoxy includes, methoxy, ethoxy, and the like. Halo-substituted alkyl includes trifluoromethyl, pentafluoroethyl, and the like. [0023] "Aryl" means a monocyclic or fused bicyclic aromatic ring assembly containing six to ten ring carbon atoms. For example, aryl can be phenyl or naphthyl, preferably phenyl. "Arylene" means a divalent radical derived from an aryl group. "Heteroaryl" is as defined for aryl where one or more of the ring members are a heteroatom selected from -O-, -N=, -NR-, -C(O) -, -S-, -S(O) - or -S(O)₂-, wherein R is hydrogen, Ci^alkyl or a nitrogen protecting group. For example C]_ioheteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[l,3]dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, lH-pyridin-2-onyl, 6-oxo-l,6-dihydro-pyridin-3-yl, etc. "C_δ-ioarylCo^alkyl" means an aryl as described above connected via a alkylene grouping. For example, C_δ-ioarylCo^alkyl includes phenethyl, benzyl, etc. Heteroaryl also includes the N-oxide derivatives, for example, pyridine-N-oxide derivatives with the following structure:

[0024] "Cycloalkyl" means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing the number of ring atoms indicated. For example, C₃_iocycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. "Heterocycloalkyl" means cycloalkyl, as defined in this application, provided that one or more of the ring carbons indicated, are replaced by a moiety selected from -O-, -N=, -NR-, -C(O) -, -S-, -S(O) - or -S(O)₂-, wherein R is hydrogen, Ci^alkyl or a nitrogen protecting group. For example, C₃_₈heterocycloalkyl as used in this application to describe compounds of the invention includes morpholino, pyrrolidinyl, piperazinyl, piperidinyl, piperidinylone, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, 2-oxo- pyrrolidin-1-yl, 2-oxo-piperidin-l-yl, etc.

[0025] "Halogen" (or halo) preferably represents chloro or fluoro, but can also be bromo or iodo.

[0026] "Treat", "treating" and "treatment" refer to a method of alleviating or abating a disease and/or its attendant symptoms. Description of the Preferred Embodiments

[0027] The present invention provides compounds, compositions and methods for the treatment of diseases in which inhibition of CB 1 activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I.

[0028] In one embodiment, with reference to compounds of Formula I, Y] is selected from N and CRn; Y₂ is selected from N and CRs; or Rn and R]₂ together with the carbon atoms to which Rn and R]₂ are attached form a phenyl ring optionally substituted with 1 to 3 halo radicals.

[0029] In a further embodiment, Y₃ is selected from N and CR₆; wherein R₆ is selected from hydrogen, halo, methyl, methoxy, acetyl, nitro, trifluoromethyl, trifluoro- methoxy, benzyl-oxy, phenyl-sulfanyl and furanyl-methyl-sulfanyl; wherein said phenyl- sulfanyl is optionally substituted with 1 to 3 radicals independently selected from halo. [0030] In a further embodiment, Z₁ is selected from S, S(O), SCH₂, S(O)CH₂,

CH₂S(O), CH₂S and NR₂; wherein R₂ is selected from hydrogen, acetyl, methyl-sulfonyl, ethoxy-carbonyl, 4-methyl-piperazinyl, methyl-carbonyl and morpholino-methyl- carbonyl; Z₂ is selected from O and S; and R₈, R_n and R_]2 are independently selected from hydrogen, halo, ethyl, hydroxy, cyano, methyl-sulfanyl, methyl, trifluoromethoxy, methoxy, phenoxy and phenyl; wherein said phenyl or phenoxy is optionally substituted with 1 to 3 radicals independently selected from halo.

[0031] In another embodiment, R₉ is selected from hydrogen, halo, ethyl, hydroxy, cyano, methyl-sulfanyl, methyl, trifluoromethoxy, methoxy, phenoxy and phenyl; wherein said phenyl or phenoxy is optionally substituted with 1 to 3 radicals independently selected from halo.

[0032] In another embodiment, Ri is selected from hydrogen, methyl, ethyl, propyl-amino-carbonyl-methyl, butyl-amino-carbonyl-methyl, trifluoroethyl-amino- carbonyl-methyl, cyclopropyl-amino-carbonyl-methyl, 2,6-dimethyl-morpholino- carbonyl-methyl, pyrrolidinyl-carbonyl-methyl and morpholino-ethyl-amino-carbonyl- methyl.

[0033] In another embodiment, R₃, R₅ and R₇ are selected from hydrogen, halo, methyl, methoxy, acetyl, nitro, trifluoromethyl, trifluoro-methoxy, benzyl-oxy, phenyl- sulfanyl and furanyl-methyl-sulfanyl; wherein said phenyl- sulfanyl is optionally substituted with 1 to 3 radicals independently selected from halo. [0034] In another embodiment, R₄ is selected from amino, methyl-carboxy- ethoxy, methyl-carbonyl-amino, trifluoro-methyl, hydroxy-ethoxy, methyl-sulfonyl- amino, benzyl-oxy, cyclopropyl, morpholino, phenoxy, phenyl, phenyl-carbonyl, phenyl- amino, isoxazolyl-methoxy, oxazolyl-methoxy, methoxy-carbonyl, trifluoro-methoxy, nitro, cyano, ethoxy, acetate, hydroxy, methyl, halo, pyrrolyl and methoxy; or R₄ and R₅ together with the carbon atoms to which R₄ and R₅ are attached form a ring selected from 1,3-dioxolane and pyrrole; wherein said benzyl, phenyl, oxazolyl or isoxazolyl of R₄ or the combination of R₄ and R₅ is optionally substituted with 1 to 3 radicals independently selected from amino-carbonyl, methyl, methoxy-carbonyl and methoxy. [0035] In another embodiment, Rio is selected from hydroxy, methyl, methyl- sulfanyl, trifluoromethyl-sulfanyl, isopropyl, trifluoromethyl, methoxy, phenyl, phenyl- amino, phenyl-sulfanyl, phenyl-sulfinyl, phenyl-sulfonyl, pyridinyl-oxy, halo, phenoxy, pyridazinyl-oxy and pyrimidinyl-oxy; wherein said phenyl, phenyl-sulfonyl, phenyl- amino, phenoxy, pyridazinyl-oxy and pyrimidinyl-oxy can be optionally substituted with 1 to 3 radicals independently selected from ethyl, nitro, trifluoromethoxy, methoxy, halo, amino and hydroxyl.In another embodiment, compounds of Formula I are selected from: 3-(4-Methoxy-phenyl)-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro- phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Bromo-phenyl)- 2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4'-Ethyl-biphenyl-4-yl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Fluoro-phenoxy)-phenyl]-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(3'-Trifluoromethoxy-biphenyl-4-yl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Hydroxy-phenyl)-2-(3-trifluoromethyl- phenyl)-thiazolidin-4-one; 3-(4'-Chloro-biphenyl-4-yl)-2-(3-trifluoromethyl-phenyl)- thiazolidin-4-one; 3-[4-(4-Methoxy-phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)- thiazolidin-4-one; 3-[4-(4-Nitro-phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)- thiazolidin-4-one; 3-(4-Phenoxy-phenyl)-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(3-Trifluoromethoxy-phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4- one; 3-[4-(4-Bromo-phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3- [4-(4-Ethyl-phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(3- Fluoro-phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(3-Nitro- phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(Pyridin-4- yloxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(3-Hydroxy-phenyl)-2- (3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4'-Chloro-biphenyl-3-yl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(3-Methoxy-phenyl)-2-(3-trifluoromethyl- phenyl)-thiazolidin-4-one; 3-[3-(4-Chloro-phenoxy)-phenyl]-2-(3-trifluoromethyl- phenyl)-thiazolidin-4-one; 3-(4-Iodo-phenyl)-2-(3-trifluoromethyl-phenyl)-thiazolidin-4- one; 3-[3-(3-Chloro-phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3- [3-(3,5-Dichloro-phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[3- (3,4-Dichloro-phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4- (3,5-Dichloro-phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4- (3,4-Dichloro-phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(4- Chloro-phenoxy)-phenyl]-l-oxo-2-(3-trifluoromethyl-phenyl)-lλ⁴-thiazolidin-4-one; 3- (3-Trifluoromethoxy-phenyl)-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 2-Methyl- 5-[4-oxo-2-(3-trifluoromethyl-phenyl)-thiazolidin-3-yl]-benzonitrile; 3-(4-Isopropyl- phenyl)-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(2-Bromo-4-chloro-phenyl)-2- (3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Methoxy-2-methyl-phenyl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 2-(3-Trifluoromethyl-phenyl)-3-(4- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(3-Methylsulfanyl-phenyl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Bromo-2-methyl-phenyl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Methylsulfanyl-phenyl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 2-(3-Trifluoromethyl-phenyl)-3-(4- trifluoromethylsulfanyl-phenyl)-thiazolidin-4-one; 3-(4-Bromo-2-ethyl-phenyl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Bromo-3-methoxy-phenyl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-5-methyl-2- (3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Bromo-naphthalen-l-yl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Bromo-2-fluoro-phenyl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Bromo-3-methyl-phenyl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Bromo-2-chloro-phenyl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-phenyl- thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-o-tolyl-thiazolidin-4-one; 3-[4-(4- Chloro-phenoxy)-phenyl]-2-p-tolyl-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]- 2-(2-fluoro-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3-fluoro- phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(4-fluoro-phenyl)- thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3-methoxy-phenyl)-thiazolidin-4- one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(4-methoxy-phenyl)-thiazolidin-4-one; 2-(4- Acetyl-phenyl)-3-[4-(4-chloro-phenoxy)-phenyl]-thiazolidin-4-one; 3-[4-(4-Chloro- phenoxy)-phenyl]-2-(4-nitro-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)- phenyl]-2-(4-trifluoromethyl-phenyl)-thiazolidin-4-one; 2-(4-Bromo-phenyl)-3-[4-(4- chloro-phenoxy) -phenyl] -thiazolidin-4-one ; 3 - [4-(4-Chloro-phenoxy)-phenyl] -2-(3 - trifluoromethyl-phenyl)-[l,3]thiazinan-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3- trifluoromethoxy-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(4- trifluoromethoxy-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3- trifluoromethyl-phenyl)-imidazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-methyl- 2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2- ethyl-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]- 2-(3-hydroxy-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-m-tolyl- thiazolidin-4-one; 2-Benzo[l,3]dioxol-5-yl-3-[4-(4-chloro-phenoxy)-phenyl]-thiazolidin- 4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3-ethoxy-phenyl)-thiazolidin-4-one; 3-(3-(4- (4-chlorophenoxy)phenyl)-4-oxothiazolidin-2-yl)phenyl acetate; 3-[4-(4-Chloro- phenoxy)-phenyl]-2-(3-pyrrol-l-yl-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)- phenyl]-2-(3,5-dimethoxy-phenyl)-thiazolidin-4-one; 3-{3-[4-(4-Chloro-phenoxy)- phenyl]-4-oxo-thiazolidin-2-yl}-benzonitrile; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3- nitro-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3,4-dimethoxy- phenyl)-thiazolidin-4-one; Methyl 3-(3-(4-(4-chlorophenoxy)phenyl)-4-oxothiazolidin-2- yl)benzoate; 4-(3-{3-[4-(4-Chloro-phenoxy)-phenyl]-4-oxo-thiazolidin-2-yl}- phenoxymethyl)-benzamide; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-[3-(5-methyl-isoxazol- 3-ylmethoxy)-phenyl]-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(lH-indol- 5-yl)-thiazolidin-4-one; Methyl 2-((3-(3-(4-(4-chlorophenoxy)phenyl)-4-oxothiazolidin- 2-yl)phenoxy)methyl)oxazole-4-carboxylate; 2-(3-(4-(4-chlorophenoxy)phenyl)-4-oxo-2- (3-(trifluoromethyl)phenyl)thiazolidin-5-yl)-N-propylacetamide; 2-(3-(4-(4- chlorophenoxy)phenyl)-4-oxo-2-(3-(trifluoromethyl)phenyl)thiazolidin-5-yl)-N-(2,2,2- trifluoroethyl)acetamide; 2-(3-(4-(4-chlorophenoxy)phenyl)-4-oxo-2-(3- (trifluoromethyl)phenyl)thiazolidin-5-yl)-N-cyclopropylacetamide; 3-(4-(4- chlorophenoxy)phenyl)-5-(2-(2,6-dimethylmorpholino)-2-oxoethyl)-2-(3- (trifluoromethyl)phenyl)thiazolidin-4-one; N-Butyl-2-[3-[4-(4-chloro-phenoxy)-phenyl]- 4-oxo-2-(3-trifluoromethyl-phenyl)-thiazolidin-5-yl]-acetamide; (2R,5S)-3-(4-(4- chlorophenoxy)phenyl)-5-(2-oxo-2-(pyrrolidin-l-yl)ethyl)-2-(3-

(trifluoromethyl)phenyl)thiazolidin-4-one; (2S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(2- oxo^-Cpyrrolidin-l-y^ethy^^-CS-CtrifluoromethyOpheny^thiazolidin^-one; 2-[3-[4-(4- Chloro-phenoxy)-phenyl]-4-oxo-2-(3-trifluoromethyl-phenyl)-thiazolidin-5-yl]-N-(2- morpholin-4-yl-ethyl)-acetamide; 3-[4-(4-Chloro-phenoxy)-phenyl]-(5S)-methyl-2-(3- trifluoromethyl-phenyl)-imidazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3- methoxy-phenyl)-(5S)-methyl-imidazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2- (3-fluoro-phenyl)-(5S)-methyl-imidazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]- (5R)-methyl-2-(3-trifluoromethyl-phenyl)-imidazolidin-4-one; 3-[4-(4-Chloro-phenoxy)- phenyl]-2-(3,5-difluoro-phenyl)-thiazolidin-4-one; 3-[5-(4-Chloro-phenoxy)-pyridin-2- yl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[6-(4-Chloro-phenoxy)-pyridin-3- yl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[5-(4-Chloro-phenoxy)-pyrazin-2- yl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2- (2,5-dimethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3,4- dimethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3,5-dimethyl- phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3,5-dibromo-phenyl)- thiazolidin-4-one; 2-(3,5-Bis-trifluoromethyl-phenyl)-3-[4-(4-chloro-phenoxy)-phenyl]- thiazolidin-4-one; 2-(3,5-Bis-benzyloxy-phenyl)-3-[4-(4-chloro-phenoxy)-phenyl]- thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3-fluoro-5-trifluoromethyl- phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(2,3-dimethyl-phenyl)- thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(2,4-dimethyl-phenyl)-thiazolidin- 4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(2,6-dimethyl-phenyl)-thiazolidin-4-one; 3- (4-(4-chlorophenoxy)phenyl)-2-(3-chlorophenyl)thiazolidin-4-one; 2-(3-bromophenyl)- 3-(4-(4-chlorophenoxy)phenyl)thiazolidin-4-one; 3-(4-(4-chlorophenoxy)phenyl)-2-(3- iodophenyl)thiazolidin-4-one; 3-(4-(4-chlorophenoxy)phenyl)-2-(3,5- dichlorophenyl)thiazolidin-4-one; 2-(3-chloro-5-(trifluoromethyl)phenyl)-3-(4-(4- chlorophenoxy)phenyl)thiazolidin-4-one; 2-(3-chloro-5-(trifluoromethoxy)phenyl)-3-(4- (4-chlorophenoxy)phenyl)thiazolidin-4-one; 2-biphenyl-3-yl-3-[4-(4-chloro-phenoxy)- phenyl]-thiazolidin-4-one; 3-(4-(4-chlorophenoxy)phenyl)-2-(3- cyclopropylphenyl)thiazolidin-4-one; 3-[4-(4-chloro-phenoxy)-phenyl]-2-(3-morpholin- 4-yl-phenyl)-thiazolidin-4-one; 3-(4-(4-chlorophenoxy)phenyl)-2-(3-fluoro-5- methylphenyl)thiazolidin-4-one; 2-(3-chloro-5-fluorophenyl)-3-(4-(4- chlorophenoxy)phenyl)thiazolidin-4-one; 3-(4-(4-chlorophenoxy)phenyl)-2-(pyridin-3- yl)thiazolidin-4-one; 3-(4-(4-chlorophenoxy)phenyl)-2-(3-phenoxyphenyl)thiazolidin-4- one; l-acetyl-3-(4-(4-chlorophenoxy)phenyl)-2-(3-(trifluoromethyl)phenyl)imidazolidin- 4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-l-methanesulfonyl-2-(3-trifluoromethyl- phenyl)-imidazolidin-4-one; ethyl 3-(4-(4-chlorophenoxy)phenyl)-4-oxo-2-(3- (trifluoromethyl)phenyl)imidazolidine- 1-carboxylate; 3-(4-(4-chlorophenoxy)phenyl)- 1- (2-(4-methylpiperazin-l-yl)acetyl)-2-(3-(trifluoromethyl)phenyl)imidazolidin-4-one; 3- [4-(4-Chloro-phenoxy)-phenyl]-l-(2-morpholin-4-yl-acetyl)-2-(3-trifluoromethyl- phenyl)-imidazolidin-4-one; 3-(4-(4-nitrophenylsulfonyl)phenyl)-2-(3- (trifluoromethyl)phenyl)thiazolidin-4-one; 3-[4-(4-chlorophenoxy)phenyl]-2-(3- mesylaminophenyl)thiazolidin-4-one; 3-[4-(4-chlorophenoxy)phenyl]-2-[3- (trifluoromethyl)phenyl]thiazolidine-4-thione; 3-(4-(4-chlorophenoxy)phenyl)-2-(3-(2- hydroxyethoxy)phenyl)thiazolidin-4-one; 3-(4-benzoylphenyl)-2-(3- (trifluoromethyl)phenyl)thiazolidin-4-one; 3-(4-(4-methoxyphenylamino)phenyl)-2-(3- (trifluoromethyl)phenyl)thiazolidin-4-one; 2-(5-bromopyridin-3-yl)-3-(4-(4- chlorophenoxy)phenyl)thiazolidin-4-one; 3-(4-(phenylsulfonyl)phenyl)-2-(3- (trifluoromethyl)phenyl)thiazolidin-4-one; 3-[4-(4-chlorophenoxy)phenyl]-2-(3- aminophenyl)thiazolidin-4-one; N-{3-[3-[4-(4-chlorophenoxy)phenyl]-4-oxothiazolidin- 2-yl]phenyl}acetamide; 3-(4-(4-aminophenylamino)phenyl)-2-(3- (trifluoromethyl)phenyl)thiazolidin-4-one; 3-(4-(4-chlorophenoxy)phenyl)-2-(2-(4- chlorophenylthio)-5-nitrophenyl)thiazolidin-4-one; 3-(4-(4-chlorophenoxy)phenyl)-2-(4- (furan-2-ylmethylthio)-3-nitrophenyl)thiazolidin-4-one; 2-(2-chloro-5-nitrophenyl)-3-(4- (4-chlorophenoxy)phenyl)thiazolidin-4-one; 3-(4-(4-chlorophenoxy)phenyl)-2-(2-fluoro- 5-nitrophenyl)thiazolidin-4-one; 3-(4-(4-chlorophenoxy)phenyl)-2-(4-fluoro-3- nitrophenyl)thiazolidin-4-one; 3-(4-(4-chlorophenylthio)phenyl)-2-(3- (trifluoromethyl)phenyl)thiazolidin-4-one; 3-(4-(4-chlorophenylsulfinyl)phenyl)-2-(3- (trifluoromethyl)phenyl)thiazolidin-4-one; 3-(4-(4-chlorophenylsulfonyl)phenyl)-2-(3- (trifluoromethyl)phenyl)thiazolidin-4-one; 3-[4-(4-hydroxyphenoxy)phenyl]-2-[3- (trifluoromethyl)phenyl]thiazolidin-4-one; and 2-(3-(3-(4-(4-chlorophenoxy)phenyl)-4- oxothiazolidin-2-yl)phenoxy)ethyl acetate.

[0036] The compounds of Formula (I), pharmaceutically acceptable salts, solvates, N- oxides, prodrugs and isomers thereof, and pharmaceutical compositions provided herein also includes all suitable isotopic variations of such compounds, and pharmaceutically acceptable salts, solvates, N-oxides, prodrugs and isomers thereof, and pharmaceutical compositions. An isotopic variation of a compound of the invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that may be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include but are not limited to isotopes of hydrogen, carbon, nitrogen and oxygen such as as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷0, ¹⁸0, ³⁵S, ¹⁸F, ³⁶Cl and ¹²³I. Certain isotopic variations of the compounds of the invention and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as ³H or ¹⁴C is incorporated, are useful in drug and/or substrate tissue distribution studies. In particular examples, ³H and ¹⁴C isotopes may be used for their ease of preparation and detectability. In other examples, substitution with isotopes such as H may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopic variations of the compounds, and pharmaceutically acceptable salts, solvates, N-oxides, prodrugs and isomers thereof, and pharmaceutical compositions provided herein are prepared by conventional procedures using appropriate isotopic variations of suitable reagents. [0037] Another embodiment provides for a method of treating a disease mediated by the Cannabinoid- 1 receptor (for example, an eating disorder associated with excessive food intake like obesity, bulimia nervosa, and compulsive eating disorders) comprising administration of to a patient in need of such treatment of a therapeutically effective amount of a compound selected from the Summary of the Invention (supra). [0038] Another embodiment provides for a method of preventing obesity in a person at risk for obesity comprising administration to said person of about 0.001 mg to about 100 mg per kg of a compound selected from the Summary of the Invention (supra). [0039] Further compounds of the invention are detailed in the Examples and Table

I, infra.

Pharmacolθ2V and Utility

[0040] Compounds of the invention inhibit the activity of CB 1 and, as such, are useful for treating diseases or disorders in which the activity of CB 1 contributes to the pathology and/or symptomology of the disease. This invention further provides compounds of this invention for use in the preparation of medicaments for the treatment of diseases or disorders in which CB 1 activity contributes to the pathology and/or symptomology of the disease. CB 1 mediated diseases or conditions include, but are not limited to, metabolic disorders as well as conditions associated with metabolic disorders including obesity, bulimia nervosa, compulsive eating disorders, diabetes, arteriosclerosis, hypertension, polycystic ovary disease, osteoporosis, cardiovascular disease, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, cholelithiasis and sleep disorders, and hyperlipidemic conditions; or psychiatric disorders such as substance abuse, psychosis, depression, anxiety, stress, epilepsy, mania and schizophrenia; or cognitive disorders such as dementia including Alzheimer's disease, memory deficits, short term memory loss and attention deficit disorders; or neurodegenerative disorders such as Parkinson's Disease, cerebral apoplexy and craniocerebral trauma, hypotension, catabolism in connection with pulmonary dysfunction and ventilator dependency; or cardiac dysfunction including valvular disease, myocardial infarction, cardiac hypertrophy and congestive heart failure); or the overall pulmonary dysfunction, transplant rejection, rheumatoid arthritis, migraine, neuropathy, multiple sclerosis, Guillain-Barre syndrome, the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, inflammatory bowel disease, lupus, graft vs. host disease, T-cell mediated hypersensitivity disease, psoriasis, asthma, Hashimoto's thyroiditis, Guillain-Barre syndrome, cancer, contact dermatitis, allergic rhinitis, ischemic or reperfusion injury, head trauma and movement disorders. 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 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, osteopororsis, and cirrhosis of the liver. [0041] Marijuana 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 Δ9-Tetrahydrocannabinol (Δ9-THC). The biological action of Δ9-THC and other members of the cannabinoid family occurs through two G-protein coupled receptors termed CBl and CB2. The CBl receptor is primarily found in the central and peripheral nervous systems and to a lesser extent in several peripheral organs. [0042] 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 Δ9-THC, including sedation, hypothermia, intestinal immobility, antinociception, analgesia, catalepsy, anti-emesis, and appetite stimulation.

[0043] The genes for the respective cannabinoid receptors have each been disrupted in mice. The CB 1 receptor knockout mice appeared normal and fertile. They were resistant to the effects of Δ9-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 Δ9-THC. There were some effects on immune cell activation, reinforcing the role for the CB2 receptor in immune system functions. [0044] Excessive exposure to Δ9-THC can lead to overeating, psychosis, hypothermia, memory loss, and sedation.

[0045] Treatment of asthma with CB 1 receptor modulators (such as CB 1 inverse agonists) is supported by the finding that presynaptic cannabinoid CBl receptors mediate the inhibition of noradrenalin release.

[0046] 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.

[0047] In accordance with the foregoing, the present invention further provides a method for preventing or treating any of the diseases or disorders described above in a subject in need of such treatment, which method comprises administering to said subject a therapeutically effective amount (See, "Administration and Pharmaceutical Compositions ", infra) of a compound of Formula I or a pharmaceutically acceptable salt thereof. For any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.

Administration and Pharmaceutical Compositions

[0048] In general, compounds of the invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5mg/kg per body weight. An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5mg to about lOOmg, conveniently administered, e.g. in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral administration comprise from ca. 1 to 50mg active ingredient.

[0049] Compounds of the invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form. Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods. For example, oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrollidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions. The compositions can be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they can also contain other therapeutically valuable substances. Suitable formulations for transdermal applications include an effective amount of a compound of the present invention with a carrier. A carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. Matrix transdermal formulations can also be used. Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. [0050] Compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations). For example, synergistic effects can occur with other substances used in the treatment of diseases or disorders, such as, psychosis, memory deficit, cognitive disorders, migraine, neuropathy, neuroinflammatory disorders, cerebral vascular accidents, head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, schizophrenia, substance abuse disorders such as smoking cessation, osteoporosis, constipation, chronic intestinal pseudo-obstruction, cirrhosis of the liver, asthma, obesity, and other eating disorders associated with excessive food intake, obesity, etc. (see "Pharmacology and Utility", supra). Where the compounds of the invention are administered in conjunction with other therapies, dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth. [0051] A combined preparation or pharmaceutical composition can comprise a compound of the invention as defined above or a pharmaceutical acceptable salt thereof and at least one active ingredient selected from: a) anti-diabetic agents such as insulin, insulin derivatives and mimetics; insulin secretagogues such as the sulfonylureas, e.g., Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide; insulin sensitizer such as protein tyrosine phosphatase- IB (PTP-IB) inhibitors such as PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors such as SB-517955, SB-4195052, SB-216763, NN-57-05441 and NN-57-05445; RXR ligands such as GW-0791 and AGN- 194204; sodium-dependent glucose co-transporter inhibitors such as T- 1095; glycogen phosphorylase A inhibitors such as BAY R3401; biguanides such as metformin; alpha-glucosidase inhibitors such as acarbose; GLP-I (glucagon like peptide-1), GLP-I analogs such as Exendin-4 and GLP-I mimetics; DPPIV (dipeptidyl peptidase IV) inhibitors such as DPP728, LAF237 (vildagliptin - Example 1 of WO 00/34241), MK-0431, saxagliptin, GSK23A ; an AGE breaker; a thiazolidone derivative (glitazone) such as pioglitazone, rosiglitazone, or (R)-l-{4-[5-methyl-2-(4-trifluoromethyl- phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-lH-indole-2- carboxylic acid described in the patent application WO 03/043985, as compound 19 of Example 4, a non- glitazone type PPAR gamma agonist e.g. GI-262570; Diacylglycerol acetyltransferase (DGAT) inhibitors such as those disclosed in WO 2005044250, WO 2005013907, WO 2004094618 and WO 2004047755; ypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, e.g., lovastatin and related compounds such as those disclosed in U.S. Pat. No. 4,231,938, pravastatin, simvastatin and related compounds such as those disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171, pravastatin and related compounds such as those disclosed in U.S. Pat. No.4,346,227, cerivastatin, mevastatin and related compounds such as those disclosed in U.S. Pat. No. 3,983,140, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and related statin compounds disclosed in U.S. Pat. No. 5,753,675, rivastatin, pyrazole analogs of mevalonolactone derivatives as disclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactone derivatives as disclosed in PCT application WO 86/03488, 6-[2- (substituted-pyrrol-l-yl)-alkyl)pyran-2-ones and derivatives thereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a 3- substituted pentanedioic acid derivative) dichloroacetate, imidazole analogs of mevalonolactone as disclosed in PCT application WO 86/07054, 3- carboxy- 2- hydroxy-propane-phosphonic acid derivatives as disclosed in French Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan and thiophene derivatives as disclosed in European Patent Application No. 0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat. No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No. 4, 499,289, keto analogs of mevinolin (lovastatin) as disclosed in European Patent Application No.0,142,146 A2, and quinoline and pyridine derivatives disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322. In addition, phosphinic acid compounds useful in inhibiting HMG CoA reductase suitable for use herein are disclosed in GB 2205837; squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; cholestyramine; fibrates; nicotinic acid and aspirin; c) an anti-obesity agent or appetite regulating agent such as melanocortin receptor (MC4R) agonists, melanin-concentrating hormone receptor (MCHR) antagonists, growth hormone secretagogue receptor (GHSR) antagonists, galanin receptor modulators, orexin antagonists, CCK agonists, GLP-I agonists, and other Pre-proglucagon-derived peptides; NPYl or NPY5 antagonsist, NPY2 and NPY4 modulators, corticotropin releasing factor agonists, histamine receptor-3 (H3) modulators, aP2 inhibitors, PPAR gamma modulators, PPAR delta modulators, acetyl-CoA carboxylase (ACC) inihibitors, 11-β-HSD-l inhibitors, adinopectin receptor modulators; beta 3 adrenergic agonists, such as AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other known beta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5, 491,134, 5,776,983 and 5,488,064, a thyroid receptor beta modulator, such as a thyroid receptor ligand as disclosed in WO 97/21993 (U. CaI SF), WO 99/00353 (KaroBio) and GB98/284425 (KaroBio), a SCD-I inhibitor as disclosed in WO2005011655, a lipase inhibitor, such as orlistat or ATL-962 (Alizyme), serotonin receptor agonists, (e.g., BVT- 933 (Biovitrum)), monoamine reuptake inhibitors or releasing agents, such as fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex, clortermine, picilorex, sibutramine, dexamphetamine, phentermine, phenylpropanolamine or mazindol, anorectic agents such as topiramate (Johnson & Johnson), CNTF (ciliary neurotrophic factor)/AXOKINE® (Regeneron), BDNF (brain-derived neurotrophic factor), leptin and leptin receptor modulators, phentermine, leptin, bromocriptine, dexamphetamine, amphetamine, fenfluramine, dexfenfluramine, sibutramine, orlistat, dexfenfluramine, mazindol, phentermine, phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate, diethylpropion, benzphetamine, phenylpropanolamine or ecopipam, ephedrine, pseudoephedrine; d) anti-hypertensive agents such as loop diuretics such as ethacrynic acid, furosemide and torsemide; diuretics such as thiazide derivatives, chlorithiazide, hydrochlorothiazide, amiloride; angiotensin converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril and trandolapril; inhibitors of the Na-K-ATPase membrane pump such as digoxin; neutralendopeptidase (NEP) inhibitors e.g. thiorphan, terteo-thiorphan, SQ29072; ECE inhibitors e.g. SLV306; ACE/NEP inhibitors such as omapatrilat, sampatrilat and fasidotril; angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, in particular valsartan; renin inhibitors such as aliskiren, terlakiren, ditekiren, RO 66-1132, RO-66-1168; beta-adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol; inotropic agents such as digoxin, dobutamine and milrinone; calcium channel blockers such as amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine and verapamil; aldosterone receptor antagonists; aldosterone synthase inhibitors; and dual ET/AII antagonist such as those disclosed in WO 00/01389. e) a HDL increasing compound; f) Cholesterol absorption modulator such as ZETIA® and KT6-971; g) Apo-Al analogues and mimetics; h) thrombin inhibitors such as Ximelagatran; i) aldosterone inhibitors such as anastrazole, fadrazole, eplerenone; j) Inhibitors of platelet aggregation such as aspirin, clopidogrel bisulfate; k) estrogen, testosterone, a selective estrogen receptor modulator, a selective androgen receptor modulator;

1) a chemotherapeutic agent such as aromatase inhibitors e.g. femara, anti- estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, alkylating agents, antineoplastic antimetabolites, platin compounds, compounds decreasing the protein kinase activity such as a PDGF receptor tyrosine kinase inhibitor preferably Imatinib ( { N-{5-[4-(4- methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2- pyrimidine- amine }) described in the European patent application EP-A-O 564 409 as example 21 or 4-Methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide described in the patent application WO 04/005281 as example 92; and m) an agent interacting with a 5-HT₃ receptor and/or an agent interacting with 5- HT₄ receptor such as tegaserod described in the US patent No. 5510353 as example 13, tegaserod hydrogen maleate, cisapride, cilansetron; n) an agent for treating tobacco abuse, e.g., nicotine receptor partial agonists, bupropion hypochloride (also known under the tradename ZYB AN®) and nicotine replacement therapies; o) an agent for treating erectile dysfunction, e.g., dopaminergic agents, such as apomorphine), ADD/ ADHD agents (e.g., RITALIN®, STRATTERA®, CONCERTA® and ADDERALL®); p) an agent for treating alcoholism, such as opioid antagonists (e.g., naltrexone (also known under the tradename REVIA®) and nalmefene), disulfiram (also known under the tradename ANTABUSE®), and acamprosate (also known under the tradename CAMPRA1®)). In addition, agents for reducing alcohol withdrawal symptoms may also be co-administered, such as benzodiazepines, beta- blockers, clonidine, carbamazepine, pregabalin, and gabapentin (NEURONTIN®); q) other agents that are useful including anti-inflammatory agents (e.g., COX-2 inhibitors) ; antidepressants (e.g., fluoxetine hydrochloride (PROZAC®)); cognitive improvement agents (e.g., donepezil hydrochloride (ARICEPT®) and other acetylcholinesterase inhibitors); neuroprotective agents (e.g., memantine) ; antipsychotic medications (e.g., ziprasidone (GEODON®), risperidone (RISPERDAL®), and olanzapine (ZYPREXA®)); or, in each case a pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable carrier. [0052] The invention also provides for a pharmaceutical combinations, e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent. The kit can comprise instructions for its administration.

[0053] The terms "co- administration" or "combined administration" or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. [0054] The term "pharmaceutical combination" as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non- fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound of Formula I and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non- fixed combination" means that the active ingredients, e.g. a compound of Formula I and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of 3 or more active ingredients.

Processes for Makin2 Compounds of the Invention

[0055] The present invention also includes processes for the preparation of compounds of the invention. In the reactions described, it can be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups can be used in accordance with standard practice, for example, see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991.

[0056] In the following schemes, several methods of preparing the compounds of the present invention are illustrative. One of skill in the art will appreciate that these methods are representative, and in no way inclusive of all methods for preparing the compounds of the present invention. The radicals in the schemes are as described in the Summary of the Invention {supra).

[0057] An illustration of the synthesis of the compounds in the present invention of Formula I is given in the following reaction schemes:

Scheme 1

1-1 1-2 1-3 1-4

[0058] An illustration of the synthesis of the compounds in the present invention of formula I, in which Z₂ =0 and Z] = NR₂, Ari and Ar₂ represent the aryl groups containing Y₁ZY₂ and Y₃ respectively (according to the Summary of the Invention), is given in Scheme 1. Carboxylic acid of N-Boc glycine can be activated by forming mix anhydride with isobutyl chloroformate and condensed with aniline NH₂Ar] to provide amide 1-2. t-Boc group can be easily removed under acidic condition to give amine 1-3. The 2,3-diarylimidazolidin-4-one 1-4 can be formed from 1-3 through a two step process: The formation of imine intermediate with aniline Ar₂CHO and the intramolecular cyclization of imine.

[0059] For other variations of the procedure described above, see: Microwave- assisted synthesis and anti-HIV activity of 2,3-diaryl-l,3-thiazolidin-4-ones. Sriram, D.; Yogeeswari, P.; Kumar, T. G. Ashok Indian Journal of Pharmaceutical Sciences (2005), 67(4), 496-499. Microwave- assisted synthesis and anti-YFV activity of 2,3- diaryl-l,3-thiazolidin-4-ones. Sriram, Dharmarajan; Yogeeswari, Perumal; Kumar, T. G. Ashok. Journal of Pharmacy & Pharmaceutical Sciences (2005), 8(3), 426-429. Synthesis and antiinflammatory activity of 3-(3-chloro-4-fluorophenyl)-2-substituted phenyl-4-thiazolidinones. Murthy, M. Srinivasa; Rao, Gopala Krishna; Pai, P. N. Sanjay; Nargund, L. V. G. Asian Journal of Chemistry (2005), 17(3), 2052-2054. Novel bridgehead nitrogen bisheterocyclic systems. Synthesis, stereochemistry and antimicrobial activity of p-bis[2H,5H-4-oxothiazol-3-yl]phenylenes and p-bis[cis-5H- 3,3a-dihydropyrazolo[3,4-d]thiazol-6-yl]phenylenes. Mohan, Jag; Kumar, Ashok. Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (2005), 44B(3), 631-634. Transformation of Schiff bases derived from α - naphthaldehyde. Synthesis, spectral data and biological activity of new-3-aryl-2-(α - naphthyl)-4-thiazolidinones and N-aryl-N-[l-(α -naphthyl)but-3-enyl]amines. Kouznetsov, Vladimir; Rodriguez, William; Stashenko, Elena; Ochoa, Carmen; Vega, Celeste; Rolon, Miriam; Pereira, David Montero; Escario, Jose A.; Barrio, Alicia Gomez. Journal of Heterocyclic Chemistry (2004), 41(6), 995-999. An expeditious synthesis of thiazolidinones and tetrahydro-l,3-thiazin-4-ones. Rawal, Ravindra. K.; Srivastava, Tumul; Haq, W.; Katti, S. B. Journal of Chemical Research (2004), (5), 368-369. Thiazolidin-4-one formation. Mechanistic and synthetic aspects of the reaction of imines and mercaptoacetic acid under microwave and conventional heating. Bolognese, Adele; Correale, Gaetano; Manfra, Michele; Lavecchia, Antonio; Novellino, Ettore; Barone, Vincenzo. Organic & Biomolecular Chemistry (2004), 2(19), 2809-2813.

Scheme 2

π-i π-2

[0060] An illustration of the synthesis of the compounds in the present invention of formula I, in which Z₂ =0 and Z] = S, is given in Scheme 2. Aniline Ar]NH₂ and an adehyde Ar₂CHO are mixed in appropriate solvent, followed by addition of mercaptopropionic acid II- 1. The mixture is (1) heated at 110 ⁰C (e.g. reflux toluene) for 2-50 h, or (2) in presence of dehydrating agents (e.g. dicyclohexylcarbodiimide and etc.) to consummate the three-component cyclization reaction to yield II-2. [0061] For alternative synthesis of 2,3 diaryl-imidazolidin-4-one, see: New examples of the penicillin-penillonic acid rearrangement. Bird, C. W. Tetrahedron Lett. 1964, (11-12), 609-12; The rearrangement of 3-acylaminoazetidinones. Bird, C. W. Tetrahedron 1966, 22(8), 2489-91. [0062] For copper mediated N-arylation reactions, see: Buchwald, S. L. et al.

(2001). "A general and efficient copper catalyst for the amidation of aryl halides and the Ν-arylation of nitrogen heterocycles." J. Am. Chem. Soc. 123(31): 7727-9. [0063] Detailed descriptions of the synthesis of compounds of the Invention are given in the Examples, infra.

Additional Processes for Makin2 Compounds of the Invention

[0064] A compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Alternatively, the salt forms of the compounds of the invention can be prepared using salts of the starting materials or intermediates.

[0065] The free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from, respectively. For example a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound of the invention in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).

[0066] Compounds of the invention in unoxidized form can be prepared from Ν- oxides of compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 ⁰C.

[0067] Prodrug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., lj-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).

[0068] Protected derivatives of the compounds of the invention can be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, "Protecting Groups in Organic Chemistry", 3^rd edition, John Wiley and Sons, Inc., 1999.

[0069] Compounds of the present invention can be conveniently prepared, or formed during the process of the invention, as solvates (e.g., hydrates). Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.

[0070] Compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981.

[0071] In summary, the compounds of Formula I can be made by a process, which involves:

(a) that of reaction scheme 1 and 2; and (b) optionally converting a compound of the invention into a pharmaceutically acceptable salt;

(c) optionally converting a salt form of a compound of the invention to a non- salt form;

(d) optionally converting an unoxidized form of a compound of the invention into a pharmaceutically acceptable N-oxide;

(e) optionally converting an N-oxide form of a compound of the invention to its unoxidized form;

(f) optionally resolving an individual isomer of a compound of the invention from a mixture of isomers;

(g) optionally converting a non-derivatized compound of the invention into a pharmaceutically acceptable prodrug derivative; and

(h) optionally converting a prodrug derivative of a compound of the invention to its non-derivatized form.

[0072] Insofar as the production of the starting materials is not particularly described, the compounds are known or can be prepared analogously to methods known in the art or as disclosed in the Examples hereinafter.

[0073] One of skill in the art will appreciate that the above transformations are only representative of methods for preparation of the compounds of the present invention, and that other well known methods can similarly be used.

Examples

[0074] The present invention is further exemplified, but not limited, by the following Examples that illustrate the preparation of compounds of the invention.

Example 6

3-(3'-Trifluoromethoxy-biphenyl-4-yl)-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one

[0075] To a solution of 3-(4-bromo-phenyl)-2-(3-trifluoromethyl-phenyl)- thiazolidin-4-one (24 mg, 0.06 mmol) and 3-trifluoro-phenylboronic acid (25 mg, 0.12 mmol) in 1 mL of toluene is added palladium tetrakis(triphenylphosphine) (6.9 mg, 0.006 mmol) and 2.0 M Na₂CO₃ solution. The reaction mixture is heated on microwave at 170 ⁰C for 20 min before cooling down to room temperature. Concentration followed by purification with HPLC (20-100 % acetonitrile/water) yields 3-(3'-trifluoromethoxy- biphenyl-4-yl)-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one as the product. ¹H NMR (CDCl₃) δ(ppm) 7.49 (m, 8H), 7.32 (m, IH), 7.27 (m, 2H), 7.18 (m, IH), 6.20 (d, IH), 3.97 (m, 2H); HPLC-MS calculated for C₂₃H₁₅F₆NO₂S (M+H⁺): 484.1, found 484.1.

Example 14

3-r4-(4-Ethyl-phenoxy)-phenyll-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one

[0076] To a solution of p-anisidine (130 μL, 0.98 mmol) and mercaptoacetic acid

(136 μL, 1.95 mmol) in 3 mL of toluene is added α,β,β-trifluoro-m-tolualdehyde (120 mg, 0.98 mmol). The solution is heated at 110 ⁰C for 15 h. The resulting solution is cooled down to room temperature and concentrated. Purification with flash chromatography (silica gel, 0 - 30 % ethyl acetate/hexanes) yields (4-methoxy-phenyl)-2- (3-trifluoromethyl-phenyl)-thiazolidin-4-one as a syrup. ¹H NMR (CDCI₃) δ (ppm) 7.61 (m, 2H), 7.45 (m, 2H), 7.05(d, 2H), 6.78 (d, 2H), 6.32 (d, IH), 3.95 (m, 2H), 3.66 (s, 3H); HPLC-MS calculated for Ci₇H₁₄F₃NO₂S (M+H⁺): 354.1, found 354.1. [0077] A solution of (4-methoxy-phenyl)-2-(3-trifluoromethyl-phenyl)- thiazolidin-4-one (270 mg, 0.76 mmol) in 5 mL of dichloromethane is cooled down to - 78 ⁰C. Boron tribromide solution (1.0 M in dichloromethane, 3.82 mL, 3.82 mmol) is added dropwise. After addition, the reaction mixture is slowly warmed to room temperature. The solution is quenched with water after being stirred at room temperature for 4 h, then extracted with ethyl acetate. The organics are combined and washed with saturated aq. NaHCO₃ solution, brine and dried over MgSO₄. Concentration gives 3-(4- hydroxy-phenyl)-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one as a yellow solid. HPLC-MS calculated for Ci₆H₁₂F₃NO₂S (M+H⁺): 340.1, found 340.1. [0078] 3-[4-(4-Ethyl-phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-

4-one: A dry flask charged with 3-(4-hydroxy-phenyl)-2-(3-trifluoromethyl-phenyl)- thiazolidin-4-one (22 mg, 0.065 mmol), copper(II) acetate (11.8 mg, 0.065 mmol), 4- ethyl phenyl boronic acid (19.5 mg, 0.13 mmol) and 4A molecular sieve powder is diluted with dichloromethane to yield 0.1 M in phenol. Triethylamine is added and the suspension is stirred at room temperature for 18 h. Filtration and concentration followed by purification with HPLC (eluent: 20-100% acetonitrile/water) gives 3-[4-(4-ethyl- phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one as a syrup. ¹H NMR (CDCl₃) δ (ppm) 7.49 (m, 4H), 7.14 (d, 2H), 6.87 (d, 2H), 6.86 (m, 4H), 6.07 (d, IH), 3.95 (m, 2H), 2.62 (m, 2H), 1.22 (t, 3H); HPLC-MS calculated for C₂₄H₂₀F₃NO₂S (M+H⁺): 444.1, found 444.1. Two enantiomers are separated by chial column (ChiralPak AD column, hexane: ethanol = 70:30, flow rate 1 mL/min).

Example 28 -r4-(4-Chloro-phenoxy)-phenyll- l-oxo-2-(3-trifluoromethyl-phenyl)- 1 D ⁴-thiazolidin-4-one mCPBA

[0079] A solution of 3-[4-(4-chloro-phenoxy)-phenyl]-2-(3-trifluoromethyl- phenyl)-thiazolidin-4-one (8.2 mg, 0.018 mmol) in dichloromethane is cooled to 0 ⁰C. m-Chloroperoxybenzoic acid (9.0 mg, 0.04 mmol) is added, the reaction mixture is warmed to room temperature and stirred overnight. Concentration followed by purification with HPLC (20-100 % acetonitrile/water) gives 3-[4-(4-chloro-phenoxy)- phenyl]-l-oxo-2-(3-trifluoromethyl-phenyl)-l D⁴-thiazolidin-4-one as product. ¹H NMR (CDCl₃) δ (ppm) 7.66 (m, 4H), 7.31 (m, 4H), 6.95 (m, 4H), 5.95 (s, IH), 3.91 (d, IH), 3.65 (d, IH); HPLC-MS calculated for C₂₂H₁₅ClF₃NO₃S (M+H⁺): 466.0, found 466.0.

Example 58

3-r4-(4-Chloro-phenoxy)-phenyll-2-(3-trifluoromethyl-phenyl)-ri,31thiazinan-4-one

[0080] A solution of 4-(4-chlorophenoxy)aniline (50 mg, 0.228 mmol) and a,a,a- trifluoro-m-tolualdehyde (61 μL, 0.457 mmol) in THF is stirred at ice cooled temperatures for 5 min, followed by addition of 3-mercaptopropionic acid (60 μL, 0.684 mmol). After stirring for another 5 min, dicyclohexylcarbodiimide (71 mg, 0.342 mmol) is added. The resulting reaction mixture is then warmed to room temperature and stirred overnight. Filtration and concentration followed by purification with HPLC (20-100 % water/acetonitrile) gives 3-[4-(4-chloro-phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)- [l,3]thiazinan-4-one as the product. ¹H NMR (CDCl₃) δ (ppm) 7.56 (m, 4H), 7.27 (d, 2H), 7.11 (d, 2H), 6.88 (m, 4H), 5.92 (d, IH), 2.96 (m, 4H); HPLC-MS calculated for C₂₃H₁₇ClF₃NO₂S (M+H⁺): 464.1, found 464.1.

Example 61

3-r4-(4-Chloro-phenoxy)-phenyll-2-(3-trifluoromethyl-phenyl)-imidazolidin-4-one

[0081] {[4-(4-Chloro-phenoxy)-phenylcarbamoyl]-methyl}-carbamic acid tert- butyl ester: To a cold solution (-15 ⁰C) of feTt-butoxycarbonylamino-acetic acid (350 mg, 2.0 mmol) and 4-methylmorpholine (220 μL, 2.0 mmol) in anhydrous THF (10 mL), isobutyl chloroformate (261 μL, 2.0 mmol) in 1 mL of THF is added dropwise. After addition, the resulting solution is stirred for 15 min before adding 4-(4- chlorophenoxy) aniline (438 mg, 2.0 mmol) in one portion. The reaction mixture is allowed to warm to room temperature and stirred for 15 h. Quenched with water, the organic phase is separated and washed with water and dried over MgSO₄. Concentration followed by purification with flash chromatography (silica gel, 0-20 % ethyl acetate/hexanes) yields { [4-(4-chloro-phenoxy)-phenylcarbamoyl]-methyl}-carbamic acid tert-butyl ester as the desired product. ¹H NMR (CDCl₃) δ (ppm) 7.15 (b, IH), 7.47 (d, 2H), 7.27 (d, 2H), 6.96 (d, 2H), 6.90 (d, 2H), 5.25 (b, IH), 3.93 (d, 2H), 1.48 (s, 9H). [0082] 2-Amino-N-[4-(4-chloro-phenoxy)-phenyl]-acetamide: To {[4-(4-chloro- phenoxy)-phenylcarbamoyl]-methyl}-carbamic acid tert-buty\ ester is added trifluoroacetic acid solution (1:1 TFA:dichloromethane). The solution is stirred at room temperature for 30 min, then diluted with ethyl acetate and washed with IN NaOH, water and brine. Dried over MgSO₄, the solution is concentrated to yield 2-amino-N-[4-(4- chloro-phenoxy)-phenyl]-acetamide. HPLC-MS calculated for C₂₃H₁₇ClF₃NO₂S (M+H⁺): 277.1, found 277.1.

[0083] 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)- imidazolidin-4-one: A suspension of 2-amino-N-[4-(4-chloro-phenoxy)-phenyl]- acetamide (20 mg, 0.072 mmol) and potassium carbonate (19.9 mg, 0.144 mmol) in 3 mL of methanol is stirred at room temperature for 1 h. a,a, α-Trifluoro-m-tolualdehyde (19.2 DL, 0.144 mmol) is added and the resulting solution is heated at 80 ⁰C for 3 h. Concentration followed by purification with HPLC (eluent: 20-100 % acetonitrile /water) gives 3-[4-(4-chloro-phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-imidazolidin-4-one as white solid. ¹H ΝMR (CDCl₃) δ (ppm) 7.56 (m, 5H), 7.25 (m, 4H), 6.88 (q, 4H), 6.14 (d, IH), 3.86 (m, 4H); HPLC-MS calculated for C₂₂H₁₆ClF₃N₂O₂ (M+H⁺): 433.1, found 433.1.

Example 84 and 85

3-[4-(4-Chloro-phenoxy)-phenyll-5-(2-oxo-2-pyrrolidin-l-yl-ethyl)-2-(3-trifluoromethyl- phenyl)-thiazolidin-4-one

[0084] [3-[4-(4-Chloro-phenoxy)-phenyl]-4-oxo-2-(3-trifluoromethyl-phenyl)- thiazolidin-5-yl] -acetic acid: A solution of 4-(4-chlorophenoxy)aniline (1.1 g, 5.0 mmol) in toluene is added mercaptosuccinic acid (0.75 g, 10.0 mmol), followed by α,α,α- trifluoro-m-tolualdehyde (0.67 mL, 5.0 mmol). The solution is heated at 110 ⁰C for 2 days before cooling down to room temperature. After diluting with ethyl acetate, the solution is washed with IN HCl, saturated NaHCθ₃, and water and dried over MgSO₄. Filtration and concentration followed by purification with HPLC (eluent: 20-90 % acetonitrile/water) gives the desired product as a yellow syrup. ¹H NMR (CDCI₃) δ (ppm) 7.54 (m, 3H), 7.42 (m, IH), 7.27 (m, 2H), 7.05 (m, 2H), 6.86 (m, 4H), 6.12 (s, IH), 4.50 (m, IH), 3.15 (m, 2H); HPLC-MS calculated for C₂₄H₁₇ClF₃NO₄S (M+H⁺): 508.1, found 508.1.

[0085] 3-[4-(4-Chloro-phenoxy)-phenyl]-5-(2-oxo-2-pyrrolidin-l-yl-ethyl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one: A solution of [3-[4-(4-chloro-phenoxy)- phenyl]-4-oxo-2-(3-trifluoromethyl-phenyl)-thiazolidin-5-yl]-acetic acid (32 mg, 0.064 mmol) in thionyl chloride (1 mL) is heated at 80 ⁰C for 1 h. After cooling, the reaction mixture is concentrated on vacuum, and then diluted with dichloromethane. To the solution, pyrrolidine (9.2 mg, 0.13 mmol) is added followed by triethylamine (27 μL, 0.19 mmol). After stirring at room temperature for 18 h, the resulting solution is concentrated and purified with TLC (silica gel 60 A, eluent: ethyl acetate: hexanes 4: 1). Two isomers are separated. Isomer one has R_f= 0.4, ¹H NMR (CDCI₃) δ (ppm) 7.47 (m, 3H), 7.35 (m, IH), 7.17 (m, 2H), 7.05 (m, 2H), 6.80 (m, 4H), 6.05 (s, IH), 4.44 (m, IH), 3.44 (m, 4H), 3.05 (m, 2H), 1.86 (m, 4H); HPLC-MS calculated for C₂₈H₂₄ClF₃N₂O₃S (M+H⁺): 561.1, found 561.1. Isomer two has R_f = 0.3, ¹H NMR (CDCl₃) δ (ppm) 7.46 (m, 3H), 7.33 (m, IH), 7.17 (m, 2H), 7.01 (m, 2H), 6.80 (m, 4H), 6.03 (s, IH), 4.47(m, IH), 3.40 (m, 5H), 2.82 (m, IH), 1.92 (m, 2H), 1.81 (m, IH); HPLC-MS calculated for C₂₈H₂₄ClF₃N₂O₃S (M+H⁺): 561.1, found 561.1.

Example 92 -r5-(4-Chloro-phenoxy)-pyridin-2-yll-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one

[0086] A mixture of 3-(5-bromo-pyridin-2-yl)-2-(3-trifluoromethyl-phenyl)- thiazolidin-4-one (20 mg, 0.05 mmol, prepared using method from example 14), 4- chlorophenol (40 mg, 0.31 mmol), CS₂CO₃ (50 mg, 0.15 mmol) and catalytic amount of N,N-dimethylglycine-HCl and CuI in dioxane (0.5 mL) is degassed and heated to 120 ⁰C under Ν₂ for 14 h. The mixture is then cooled to room temperature and treated with saturated aqueous NH₄Cl solution (3 mL) and extracted with EtOAc (3 x 3 mL). The combined organic layer is concentrated and purified by flash column chromatography (silica gel, EtOAc/hexane 0-50%) to provide the titled compound 3-[5-(4-chloro- phenoxy)-pyridin-2-yl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one as white solid (10 mg, 45%). ¹H NMR (CDCl₃, 400 MHz) δ 8.04 (d, IH), 7.98 (s, IH), 7.56 (s, IH), 7.48- 7.52 (m, 2H), 7.41 (t, IH), 7.31 (d, IH), 7.29 (d, 2H), 6.89 (d, 2H), 6.83 (s, IH), 4.04 (d, IH), 3.86 (d, IH); HPLC-MS calculated for C₂]H₁₄ClF₃N₂O₂S (M +H⁺) 451.0, found 451.0.

Example 111

2-biphenyl-3-yl-3-r4-(4-chloro-phenoxy)-phenvH-thiazolidin-4-one

[0087] A reaction tube charged with 2-(3-bromo-phenyl)-3-[4-(4-chloro- phenoxy)-phenyl]-thiazolidin-4-one (20.0 mg, 0.043 mmol), phenylboronic acid (10.6 mg, 0.086 mmol), and Pd(PPh₃)₄ (5.0 mg, 0.0043 mmol) is purged with nitrogen. Toluene (1.0 mL) and Na₂CO₃ aqueous solution (2.0 M, 0.20 mL) are added via syringe. The reaction mixture is heated at 100 ⁰C overnight and then partitioned between water and ethyl acetate. The organic phase is concentrated and purified by preparative TLC followed by preparative LC/MS to provide the title compound; HPLC-MS calculated for C₂₇H₂₀ClNO₂S (M +H⁺) 458.1, found 458.1. Example 113

3-r4-(4-chloro-phenoxy)-phenyll-2-(3-morpholin-4-yl-phenyl)-thiazolidin-4-one

[0088] A reaction tube charged with 3-[4-(4-chloro-phenoxy)-phenyl]-2-(3-iodo- phenyl)-thiazolidin-4-one (20.0 mg, 0.039 mmol), Pd₂(dba)₃ (3.6 mg, 0.0039 mmol), BINAP (4.9 mg, 0.0078 mmol), and Cs₂CO₃ (25.7 mg, 0.078 mmol) is purged with nitrogen. A solution of morpholine (6.86 μL, 0.078 mmol) in anhydrous toluene (1.0 mL) is added via syringe. The reaction mixture is heated at 100 ⁰C overnight and then partitioned between water and ethyl acetate. The organic phase is concentrated and purified by preparative LC/MS followed by preparative TLC to provide the title compound; HPLC-MS calculated for C₂₅H₂₃ClN₂O₃S (M +H⁺) 467.1, found 467.1.

Example 119

3 - [4-(4- Chloro-phenoxy ) -pheny 11 - 1 -methanesulf onyl-2 - (3 -trifluoromethyl-phenyl) - imidazolidin-4-one

[0089] Step A: To a solution of N-Boc glycine (175 mg, 1.0 mmol) in anhydrous

THF (10 mL) is added 4- methyl morpholine (101 mg, 1.0 mmol) at 0 ⁰C. After stirring at 0 ⁰C for 5 min., isobutyl chloroformate (136.6 mg, 1.0 mmol) is added. After the addition, the mixture is allowed to warm up to room temperature and stirred for 15 min when 4-(4-chloro-phenoxy)-phenylamine (219.7 mg, 1.0 mmol) is added and stirred for 14 h. The reaction mixture is then poured into water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layer is washed with brine and dried (MgSO₄). After removing the drying agent, the solution is concentrated and purified by flash column chromatography (silica gel, EtOAc/hexane) to provide the desired product {[4-(4-Chloro- phenoxy)-phenylcarbamoyl]-methyl}-carbamic acid tert-butyl ester. [0090] Step B: { [4-(4-Chloro-phenoxy)-phenylcarbamoyl]-methyl}-carbamic acid tert-butyl ester from above is treated with TFA (1.5 ml) in CH₂Cl₂ (6 mL) at room temperature for 30 min and then concentrated. The residue is treated with saturated NaHCθ₃ aqueous solution (10m L) and EtOAc (25 mL). The resultant precipitate is collected by filtration to provide the desired product 2-smino-N-[4-(4-chloro-phenoxy)- phenyl]-acetamide as a white solid. HPLC-MS calculated for Ci₄Hi₃ClN₂O₂ (M +H⁺) 277.1, found 277.1.

[0091] Step C: To a solution of 2-amino-N-[4-(4-chloro-phenoxy)-phenyl]- acetamide (100 mg, 0.36 mmol) in anhydrous EtOH (1 mL) is added 3-trifluoromethyl- benzaldehyde (76 mg, 0.43 mmol). The resultant solution is stirred at room temperature for 14 h and concentrated to provide the crude N-[4-(4-chloro-phenoxy)-phenyl]-2-[(3- trifluoromethyl-benzylidene)-amino]-acetamide.

[0092] To a suspension of crude N-[4-(4-chloro-phenoxy)-phenyl]-2-[(3- trifluoromethyl-benzylidene)-amino]-acetamide from above in toluene (2 mL) is added methane sulfonyl chloride (82 mg, 0.72 mmol). The resultant mixture is stirred at room temperature for 3 h and then concentrated. The residue is purified by preparative LC/MS to provide the desired product 3-[4-(4-chloro-phenoxy)-phenyl]-l-methanesulfonyl-2-(3- trifluoromethyl-phenyl)-imidazolidin-4-one. ¹H NMR (CDC13, 400 MHz) δ 7.51-7.66 (m, 4H), 7.28 (d, 2H), 7.22 (d, 2H), 6.91 (d, 2H), 6.89 (d, 2H), 6.51 (d, IH), 4.45 (d, IH), 4.20 (dd, IH), 2.71 (s, 3H); HPLC-MS calculated for C₂₃H₁₈ClF₃N₂O₄S (M +H⁺) 511.1, found 511.1.

Example 122

3-r4-(4-Chloro-phenoxy)-phenyll-l-(2-morpholin-4-yl-acetyl)-2-(3-trifluoromethyl- phenyl)-imidazolidin-4-one

[0093] To a solution of l-(2-chloro-acetyl)-3-[4-(4-chloro-phenoxy)-phenyl]-2-(3- trifluoromethyl-phenyl)-imidazolidin-4-one (20mg, 0.039 mmol, prepared using the same method described in example 119) in anhydrous MeCN (1 mL) is added morpholine (lOmg, 0.12 mmol) followed by KI (catalytic amount). The resultant mixture is stirred at room temperature for 2 hr and then concentrated. The residue is purified by preparative LC/MS to provide the desired product 3-[4-(4-chloro-phenoxy)-phenyl]-l-(2-morpholin- 4-yl-acetyl)-2-(3-trifluoromethyl-phenyl)-imidazolidin-4-one. HPLC-MS calculated for C₂₈H₂₅ClF₃N₃O₄ (M +H⁺) 560.2, found 560.2.

Example 124

3-r4-(4-chlorophenoxy)phenvH-2-(3-mesylaminophenyl)thiazolidin-4-one

[0094] A solution of 4-(4-chlorophenoxy)benzenamine (220 mg, 1.0 mmol) and mercaptoacetic acid (140 μL, 2 mmol) in 3mL of toluene is added 3- (mesylamino)benzaldehyde (262 mg, 1.0 mmol). The resulting solution is stirred and heated at 110 ⁰C for 15 h. The reaction mixture is cooled down to room temperature and concentrated. The residue is purified on silica gel (0-30% ethyl acetate in hexane) to yield 3-[4-(4-chlorophenoxy)phenyl]-2-(3-mesylaminophenyl)thiazolidin-4-one as a white foam. ¹H NMR (CDCl₃) δ (ppm) 7.31-7.23 (m, 3H), 7.22-7.14 (m, 2H), 7.13-7.08 (m, 4H), 6.89-6.82 (m, 4H), 6.02 (d, J=1.2 Hz, IH), 4.00 (dd, J=16.0, 1.6 Hz, IH), 3.88 (d, J=15.6 Hz, IH), 2.90 (s, 3H). HPLC-MS calculated C₂₂H₁₉ClN₂O₄S₂ (M+H⁺) 475.05, found 475.00.

Example 125

3-r4-(4-chlorophenoxy)phenyll-2-r3-(trifluoromethyl)phenyllthiazolidine-4-thione

Lawesson's Reagent toluene/pyridine reflux

[0095] The mixture of 3-[4-(4-chlorophenoxy)phenyl]-2-[3-

(trifluoromethyl)phenyl]-thiazolidin-4-one (210 mg, 0.47 mmol), Lawesson's reagent (220mg, 0.504 mmol), toluene (2 mL) and pyridine (2 mL) is stirred under reflux for 22 h. The reaction mixture is cooled to room temperature and concentrated. The residue is purified on silica gel (0-20% ethyl acetate in hexane) to yield 3-[4-(4- chlorophenoxy)phenyl]-2-[3-(trifluoromethyl)phenyl] thiazolidine-4-thione as a brown oil. ¹H NMR (CDCl₃) δ (ppm) 7.60-7.52 (m, 2H), 7.50-7.44 (m, 2H), 7.31-7.27 (m, 2H), 6.99-6.94 (m, 2H), 6.93-6.86 (m, 4H), 6.27 (m, IH), 4.65 (dd, J=17.0, 2.2 Hz, IH), 4.55 (dd, J=17.0, 1.0 Hz, IH). HPLC-MS calculated C₂₂H₁₅ClF₃NOS₂ (M+H⁺) 466.03, found 466.00.

Example 131 & 132

3-r4-(4-chlorophenoxy)phenyll-2-(3-aminophenyl)thiazolidin-4-one

& N- { 3- [3- r4-(4-chlorophenoxy)phenvH-4-oxothiazolidin-2-yllphenyl 1 acetamide

[0096] 3-[4-(4-Chlorophenoxy)phenyl]-2-(3-nitrophenyl)thiazolidin-4-one (106 mg, 0.25 mmol), ethanol (1.25 niL), NH₄Cl (137 mg), H₂O (0.625 niL) and indium (119 mg) are successively added to the reaction tube. The resulting mixture is stirred and heated under reflux for 2.5 h. The reaction mixture is then cooled to room temperature, diluted with 2 mL of H₂O and filtered. The filtrate is extracted with DCM (4 x 10 niL); the combined organic phases are washed with brine (10 mL) and dried over Na₂SO₄. After concentration the residue is purified on silica gel (0-33% ethyl acetate in hexane) to give 3-[4-(4-chlorophenoxy)phenyl]-2-(3-aminophenyl)thiazolidin-4-one as a colorless syrup. ¹H NMR (CDCl₃) δ (ppm) 7.30-7.24 (m, 2H), 7.16-7.07 (m, 3H), 6.93-6.85 (m, 4H), 6.72-6.59 (m, 3H), 5.91 (d, J=1.2 Hz, IH), 3.99 (dd, J=15.6, 1.6 Hz, IH), 3.84 (d, J=16.0 Hz, IH). HPLC-MS calculated C₂]H₁₇ClN₂O₂S (M+H⁺): 397.07, found: 397.00. [0097] To the solution containing 3-[4-(4-chlorophenoxy)phenyl]-2-(3- aminophenyl)thiazolidin-4-one (38 mg, 0.096 mmol), DCM (2 mL) and Et₃N (50μL) is added acetic chloride (9.0 mg, 0.115 mmol) dropwise at room temperature. After the addition, the resulting mixture is further stirred for 2 h at room temperature. After concentration the residue is purified on silica gel (0-40% ethyl acetate in hexane) to give 3-[4-(4-chlorophenoxy)phenyl]-2-(3-aminophenyl)thiazolidin-4-one as a white foam. HPLC-MS calculated C₂₃H₁₉ClN₂O₃S (M+H⁺) 439.08, found 439.00. Example 142

3 - r4-(4-hydroxyphenoxy)phenyll -2- [3 -(trifluoromethyl)phenyll thiazolidin-4-one

BBrVDCM/rt

[0098] The mixture of 3-[4-(4-methoxyphenoxy)phenyl]-2-[3-(trifluoromethyl)- phenyl]thiazolidin-4-one (70 mg, 0.157 mmol), DCM (3 mL) and BBr₃ (1 M in DCM, 0.80 mL) is stirred at room temperature for 2.5 h. The reaction mixture is then dissolved in DCM (60 mL), washed with saturated NaHCO₃ (20 mL) and brine (20 mL) and dried over Na₂SO₄. After concentration the residue is purified on slilica gel (0-45% ethyl acetate in hexane) to give 3-[4-(4-hydroxyphenoxy)phenyl]-2-[3- (trifluoromethyl)phenyl]thiazolidin-4-one as a white solid. HPLC-MS calculated for C₂₂H₁₇F₃N₂O₂S (M+H⁺) 431.10, found 430.90.

[0099] By repeating the procedures described in the above examples, using appropriate starting materials, the following compounds of Formula I, as identified in Table 1, are obtained.

Table 1

CBl Biological Assays

Homogenized membranes are prepared from CHO cell clones stably expressing a human cannabinoid receptor 1 (CBl) or human cannabinoid receptor 2 (CB2). Cells are grown and scrapped from 15cm tissue culture plates, and then subsequently centrifuged down. Cells are washed once with cold PBS, and resuspended in <20 ml of Buffer A (20 mM HEPES, pH 7.4, 10 mM EDTA, EDTA-free complete protease inhibitor cocktail [1 tablet/25 ml]). The cell suspension is homogenized on ice, using a Polytron homogenizer at 25000 rpm at three intervals of 15 seconds each. The homogenate is first centrifuged at 2000 rpm on a tabletop low speed centrifuge for 10 minutes. The supernatant, after passing through a cell strainer, is then centrifuged at 50,000 x g for 25 minutes at 4⁰C. The pellet is resuspended into buffer B (15% glycerol, 20 mM HEPES, pH 7.4, 0.1 mM EDTA, EDTA-free complete protease inhibitor cocktail [1 tablet/10 ml]). Protein concentration of the prep is determined using the BCA Protein Assay kit using BSA as standard. The membranes are aliquoted and kept frozen at - 8O⁰C.

[00100] [³H]-CP55940 ligand binding assay: Solutions of test compounds ranging from 100 μM to 0.01 nM are prepared in DMSO. The desired amount of membrane prep is diluted with ice-cold assay buffer (5OmM Tris-HCl, 2.5mM EDTA, 5 mM MgCl₂, 0.05% BSA, pH 7.4) and vortexed well. 2 Dl or less of compound is distributed into each well of a round-bottom 96- well polystyrene assay plate, followed by addition of 100 Dl of diluted membranes (3-10 Dg/well) and the mixture is kept on ice until the addition of hot CP55940 (final concentration of 0.5nM). [³H]-CP55940 is diluted 1:6300 (v/v) with cold assay buffer and 100 Dl is added into each well. The reaction is carried out at room temperature for 120 minutes before the membranes are harvested onto a PerkinElmer Unifilter GF/B-96 filter plate using a Packard Filtermate Harvester. After nine washes with wash buffer (5OmM Tris-HCl, 2.5mM EDTA, 5 mM MgCl₂, 0.05% BSA, pH 7), the filter is dried in a 37°C oven for 30 minutes. MicroScint- 20 is added and the plate sealed for scintillation counting on TopCount. EC₅₀ values are obtained by fitting the data with the sigmoidal dose response curve-fitting tool of GraphPad Prism. Eight or twelve different concentrations are used to generate a concentration response curve (using three data points per concentration).

[00101] GTPDS binding assay: Solutions of test compounds ranging from 100 μM to 0.01 nM are prepared in DMSO. The desired amount of membrane prep is diluted with ice-cold assay buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl₂, 0.1% Fatty acid- free BSA, 5 DM GDP) and vortexed well. 2 Dl or less of compound is distributed into each well of a round-bottom 96- well polystyrene assay plate, followed by addition of 100 Dl of diluted membranes (3-10 Dg/well) and the mixture is kept on ice until the addition of hot GTPDS. [³⁵S]-GTPDS (Perkin Elmer NEG030H; 1 DCi/Dl, 1250 Ci/mmol) is diluted 1:1000 (v/v) with cold assay buffer and 100 Dl is added into each well. The reaction is carried out at room temperature for 90 minutes before the membranes are harvested onto PerkinElmer Unifilter GF/B-96 filter plate using a Packard Filtermate Harvester. After several washes with wash buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl₂₎, and a rinse with 95% ethanol, the filter is dried in a 37°C oven for 30 minutes. MicroScint-20 is added and the plate sealed for scintillation counting on TopCount. EC₅₀ values are obtained by fitting the GTP [D-³ S] binding data with the sigmoidal dose response curve-fitting tool of GraphPad Prism. Six or twelve different concentrations are used to generate a concentration response curve (using three data points per concentration).

[00102] For each assay, a Cheng-Prusoff correction (Cheng and Prusoff, 1973,

Biochem. Pharmacol., 22: 3099-3103) is used to convert the EC₅₀ to inhibition constant K₁. Thus,

EC 50

K₁ =

1 + [L] / K_d where [L] is the concentration of the radio-ligand used in the assay, and K_d is the equilibrium binding dissociation constant for the radio-ligand.

Food Intake and Body Weight Gain

[00103] To evaluate the efficacy of compounds of the invention on inhibition of food intake and body weight gain, genetically obese (Lep^ob/Lep^ob) mice and diet-induced obese (DIO) mice are used in acute and sub-chronic models, respectively. [00104] Male ob/ob mice (age 7-8 weeks old, Jackson Labs, Bar Harbor, Maine) are housed in groups of four and fed commercial standard pellet diet (Lab Diet 5001, PMI Nutrition International, LLC). Diet-induced obese mice are generated using 6-7 weeks old C57BL6 mice (Jackson Labs, Bar Harbor, Maine) placed on high fat diet (D12331, Research Diets) for 12-17 weeks. All mice are maintained on a 12-hour light/dark cycle (lights on at 06:00) in a humidity- and temperature-controlled environment with free access to food and water.

[00105] The week prior to the start of each study, mice are singly housed and a habituation to treatment is performed to establish baseline food consumption and body weight. Animals are randomized into treatment groups based on their initial body weight and food consumption.

[00106] To determine the acute effects of a single administration of a compound of the invention (test compound) on food consumption, ob/ob mice are treated with either vehicle, a known antagonist as a positive control, or with test compound(s). Similarly, to determine more chronic effects of test compound on food consumption and body weight gain, DIO mice are treated with either vehicle, a known antagonist as a positive control, or with test compound(s) for up to 7-35 days. Test compounds are dosed at ranges between 0.1 up to 100 mg/kg. Animals are treated one hour prior to the start of the dark cycle. Food intake and body weight are recorded manually using an electronic balance prior to treatment, 16 hours post-treatment, followed by daily measurements for up to 7- 35 days after the start of study. Compound efficacy is determined by comparing food intake and body weight data between vehicle treated, standard positive control treated, and test compound treated mice.

[00107] Compounds of Formula I, in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, for example, as indicated by the in vitro tests described in this application. Compound of the invention show a K₁ of between 1x10^" and Ix 10^"10M, preferably less than 50OnM, more preferably less than 10OnM. Additionally, compounds of the invention show a 10 fold, preferably 20, 50 and 100 fold, selectivity for CBl over CB2.

[00108] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

Claims

WE CLAIM:

1. A compound of Formula I:

in which:

Y] is selected from N and CRn ;

Y₂ is selected from N and CRs;

Y₃ is selected from N and CR₆; wherein R₆ is selected from hydrogen, halo, nitro, Ci_₆alkyl, Ci_₆alkoxy, halo-substituted-Ci_₆alkyl, halo-substituted-Ci_₆alkoxy, -S(O)_{0- 2}R₁6 and -C(O)R]₆; wherein R]₆ is selected from Ci_6alkyl, C6-i₀aryl, Ci_i₀heteroaryl, C₃_ iocycloalkyl and C₃_sheterocycloalkyl; wherein said aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R]₆ is optionally substituted with 1 to 3 radicals independently selected from halo and Ci_₆alkyl;

Z₁ is selected from S, S(O), SCH₂, S(O)CH₂, CH₂S(O), CH₂S and NR₂; wherein R₂ is selected from hydrogen, -C(O)X₂RiS, -C(O)OX₂RiS, -S(O)₀_₂X₂Ris, ; wherein X₂ is selected from a bond and Ci_₄alkylene; Ris is independently selected from hydrogen, Ci_₆alkyl, Ci_i₀heteroaryl and C₃_sheterocycloalkyl; wherein said heteroaryl or heterocycloalkyl of Ris is optionally substituted with 1 to 3 radicals independently selected from halo and Ci_₆alkyl;

Z₂ is selected from O, NH, N(OH), N(CN) and S;

Ri is selected from hydrogen, C_1-6alkyl, -XiC(O)NRi_7aRi7b, -XiC(0)NRi_7a; wherein Xi is selected from a bond and Ci^alkylene; Rπ_a and R_17b are independently selected from hydrogen, Ci_₆alkyl, C₃_i₂cycloalkyl and C₃_sheterocycloalkyl; wherein said cycloalkyl or heterocycloalkyl of Ri_7a or Ri_7b can be optionally substituted with 1 to 3 radicals independently selected from halo, C]_₆alkyl, C]_₆alkoxy, halo-substituted-C]_₆alkyl and halo-substituted-Ci_₆alkoxy;

R₃, R₅, and R₇ are selected from hydrogen, halo, hydroxy, nitro, C]_₆alkyl, C_1- δalkoxy, halo-substituted-Ci_6alkyl, halo-substituted-Ci_6alkoxy, -S(0)o_-2Ri6 and -C(O)R]₆; wherein R]₆ is selected from Ci_₆alkyl, C_δ-ioaryl, Ci_ioheteroaryl, C₃_iocycloalkyl and C₃_ sheterocycloalkyl; wherein said aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R]₆ is optionally substituted with 1 to 3 radicals independently selected from halo and Ci_₆alkyl;

R₄ is selected from halo, nitro, cyano, Ci_₆alkyl, Ci_₆alkoxy, halo-substituted- Ci_₆alkyl, halo-substituted-Ci_₆alkoxy, -R_13a, -NRi_3aRi3b, -OX₄OC(O)Ri₃₃, -₄OC(O)Ri_3a, - C(O)Ri₃₃, -C(O)ORi₃₃, -OX₄ORi₃₃, -OX₄Ri₃₃, -X₄NRi₃₃C(O)Ri₃₃, -X₄NRi₃₃S(OV₂Ri₃₃, - ORi₃₃, ; wherein X₄ is selected from a bond and Ci_₄alkylene; Ri₃₃ and Ri_3b are independently selected from hydrogen, Ci_₆alkyl, C₆-i₀aryl, Ci_ioheteroaryl, C₃_i₂cycloalkyl and C₃_₈heterocycloalkyl; or R₄ and R₅ together with the carbon atoms to which R₄ and R₅ are attached form C₃_sheterocycloalkyl or Ci_ioheteroaryl; wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R₄ or the combination of R₄ and R₅ is optionally substituted with 1 to 3 radicals independently selected from Ci_₆alkyl, Ci_₆alkoxy, halo- substituted-Ci_6alkyl, halo-substituted-Ci_6alkoxy, -C(O)NRi_4aRi₄b and -C(O)ORi₄₃; wherein Ri₄₃ and Ri_4b are independently selected from hydrogen and Ci_₆alkyl;

Rs, R₉, Rn and R₁₂ are independently selected from hydrogen, halo, hydroxyl, cyano, Ci_₆alkyl, Ci_₆alkoxy, halo-substituted-Ci_₆alkyl, halo-substituted-Ci_₆alkoxy, -S(O)₀. ₂R₁5, -OR₁5 and -R₁5; wherein R₁5 is selected from hydrogen, Ci_6alkyl, halo-substituted-Ci_ ₆alkyl and C₆-i₀aryl; wherein said aryl of R₁₅ is optionally substituted with 1 to 3 radicals independently selected from halo, Ci_₆alkyl, C^alkoxy, halo-substituted-Ci_₆alkyl and halo- substituted-Ci_₆alkoxy; or Rn and R₁₂ together with he carbon atoms to which Rn and R₁₂ are attached form phenyl;

Ri₀ is selected from halo, cyano, hydroxy, Ci_₆alkyl, Ci-₆alkoxy, halo- substituted-Ci_6alkyl, halo-substituted-Ci_6alkoxy, -X₃ORi₉, -X₃S(O)₀_₂Ri₉, -X₃NR₂₀Ri₉ and -X₃Ri₉; wherein X₃ is selected from a bond and C^alkylene; R₂₀ is selected from hydrogen and Ci-₆alkyl; and Ri₉ is selected from C₆-i₀aryl and Ci_i₀heteroaryl; wherein Ri₉ is optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, nitro, amino, C]_₆alkyl, C]_₆alkoxy, halo-substituted-C]_₆alkyl and halo-substituted-C]_₆alkoxy;

Ri₃ is selected from hydrogen and Ci_₆alkyl; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 in which: Y] is selected from N and CRn ;

Y₂ is selected from N and CRs; or Rn and R]₂ together with the carbon atoms to which Rn and R]₂ are attached form a phenyl ring optionally substituted with 1 to 3 halo radicals;

Y₃ is selected from N and CR₆; wherein R₆ is selected from hydrogen, halo, methyl, methoxy, acetyl, nitro, trifluoromethyl, trifluoro-methoxy, benzyl-oxy, phenyl- sulfanyl and furanyl-methyl-sulfanyl; wherein said phenyl-sulfanyl is optionally substituted with 1 to 3 radicals independently selected from halo.

Z₁ is selected from S, S(O), SCH₂, S(O)CH₂, CH₂S(O), CH₂S and NR₂; wherein R₂ is selected from hydrogen, acetyl, methyl-sulfonyl, ethoxy-carbonyl, 4-methyl- piperazinyl, methyl-carbonyl and morpholino-methyl-carbonyl;

Z₂ is selected from O and S; and

Rs, Rn and R]₂ are independently selected from hydrogen, halo, ethyl, hydroxy, cyano, methyl-sulfanyl, methyl, trifluoromethoxy, methoxy, phenoxy and phenyl; wherein said phenyl or phenoxy is optionally substituted with 1 to 3 radicals independently selected from halo.

3. The compound of claim 2 in which R₉ is selected from hydrogen, halo, ethyl, hydroxy, cyano, methyl-sulfanyl, methyl, trifluoromethoxy, methoxy, phenoxy and phenyl; wherein said phenyl or phenoxy is optionally substituted with 1 to 3 radicals independently selected from halo.

4. The compound of claim 3 in which Ri is selected from hydrogen, methyl, ethyl, propyl-amino-carbonyl-methyl, butyl-amino-carbonyl-methyl, trifluoroethyl-amino- carbonyl-methyl, cyclopropyl-amino-carbonyl-methyl, 2,6-dimethyl-morpholino-carbonyl- methyl, pyrrolidinyl-carbonyl-methyl and morpholino-ethyl-amino-carbonyl-methyl.

5. The compound of claim 4 in which R₃, R₅ and R₇ are selected from hydrogen, halo, methyl, methoxy, acetyl, nitro, trifluoromethyl, trifluoro-methoxy, benzyl-oxy, phenyl- sulfanyl and furanyl-methyl-sulfanyl; wherein said phenyl-sulfanyl is optionally substituted with 1 to 3 radicals independently selected from halo.

6. The compound of claim 5 in which R₄ is selected from amino, methyl-carboxy- ethoxy, methyl-carbonyl-amino, trifluoro-methyl, hydroxy-ethoxy, methyl- sulfonyl- amino, benzyl-oxy, cyclopropyl, morpholino, phenoxy, phenyl, phenyl-carbonyl, phenyl-amino, isoxazolyl-methoxy, oxazolyl-methoxy, methoxy-carbonyl, trifluoro-methoxy, nitro, cyano, ethoxy, acetate, hydroxy, methyl, halo, pyrrolyl and methoxy; or R₄ and R₅ together with the carbon atoms to which R₄ and R₅ are attached form a ring selected from 1,3-dioxolane and pyrrole; wherein said benzyl, phenyl, oxazolyl or isoxazolyl of R₄ or the combination of R₄ and R₅ is optionally substituted with 1 to 3 radicals independently selected from amino- carbonyl, methyl, methoxy-carbonyl and methoxy.

7. The compound of claim 6 in which Rio is selected from hydroxy, methyl, methyl-sulfanyl, trifluoromethyl-sulfanyl, isopropyl, trifluoromethyl, methoxy, phenyl, phenyl-amino, phenyl-sulfanyl, phenyl-sulfinyl, phenyl-sulfonyl, pyridinyl-oxy, halo, phenoxy, pyridazinyl-oxy and pyrimidinyl-oxy; wherein said phenyl, phenyl-sulfonyl, phenyl-amino, phenoxy, pyridazinyl-oxy and pyrimidinyl-oxy can be optionally substituted with 1 to 3 radicals independently selected from ethyl, nitro, trifluoromethoxy, methoxy, halo, amino and hydroxyl.

8. The compound of claim 1 selected from: 3-(4-Methoxy-phenyl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Bromo-phenyl)-2-(3-trifluoromethyl- phenyl)-thiazolidin-4-one; 3-(4'-Ethyl-biphenyl-4-yl)-2-(3-trifluoromethyl-phenyl)- thiazolidin-4-one; 3-[4-(4-Fluoro-phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)- thiazolidin-4-one; 3-(3'-Trifluoromethoxy-biphenyl-4-yl)-2-(3-trifluoromethyl-phenyl)- thiazolidin-4-one; 3-(4-Hydroxy-phenyl)-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3- (4'-Chloro-biphenyl-4-yl)-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Methoxy- phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Nitro-phenoxy)- phenyl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Phenoxy-phenyl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(3-Trifluoromethoxy-phenoxy)-phenyl]-2- (3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Bromo-phenoxy)-phenyl]-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Ethyl-phenoxy)-phenyl]-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(3-Fluoro-phenoxy)-phenyl]-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(3-Nitro-phenoxy)-phenyl]-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(Pyridin-4-yloxy)-phenyl]-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(3-Hydroxy-phenyl)-2-(3-trifluoromethyl- phenyl)-thiazolidin-4-one; 3-(4'-Chloro-biphenyl-3-yl)-2-(3-trifluoromethyl-phenyl)- thiazolidin-4-one; 3-(3-Methoxy-phenyl)-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3- [3-(4-Chloro-phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Iodo- phenyl)-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[3-(3-Chloro-phenoxy)-phenyl]-2- (3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[3-(3,5-Dichloro-phenoxy)-phenyl]-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[3-(3,4-Dichloro-phenoxy)-phenyl]-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(3,5-Dichloro-phenoxy)-phenyl]-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(3,4-Dichloro-phenoxy)-phenyl]-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-l-oxo-2-(3- trifluoromethyl-phenyl)-lλ⁴-thiazolidin-4-one; 3-(3-Trifluoromethoxy-phenyl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 2-Methyl-5-[4-oxo-2-(3-trifluoromethyl-phenyl)- thiazolidin-3-yl]-benzonitrile; 3-(4-Isopropyl-phenyl)-2-(3-trifluoromethyl-phenyl)- thiazolidin-4-one; 3-(2-Bromo-4-chloro-phenyl)-2-(3-trifluoromethyl-phenyl)-thiazolidin-4- one; 3-(4-Methoxy-2-methyl-phenyl)-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 2-(3- Trifluoromethyl-phenyl)-3-(4-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(3- Methylsulfanyl-phenyl)-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Bromo-2- methyl-phenyl)-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Methylsulfanyl- phenyl)-2-(3-trifluoromethyl-phenyl)-thiazolidin-4-one; 2-(3-Trifluoromethyl-phenyl)-3-(4- trifluoromethylsulfanyl-phenyl)-thiazolidin-4-one; 3-(4-Bromo-2-ethyl-phenyl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Bromo-3-methoxy-phenyl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-5-methyl-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Bromo-naphthalen-l-yl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Bromo-2-fluoro-phenyl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Bromo-3-methyl-phenyl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-(4-Bromo-2-chloro-phenyl)-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-phenyl- thiazolidin-4-one ; 3 - [4-(4-Chloro-phenoxy)-phenyl] -2-o-tolyl-thiazolidin-4-one ; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-p-tolyl-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)- phenyl]-2-(2-fluoro-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3- fluoro-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(4-fluoro-phenyl)- thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3-methoxy-phenyl)-thiazolidin-4- one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(4-methoxy-phenyl)-thiazolidin-4-one; 2-(4- Acetyl-phenyl)-3-[4-(4-chloro-phenoxy)-phenyl]-thiazolidin-4-one; 3-[4-(4-Chloro- phenoxy)-phenyl]-2-(4-nitro-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2- (4-trifluoromethyl-phenyl)-thiazolidin-4-one; 2-(4-Bromo-phenyl)-3-[4-(4-chloro-phenoxy)- phenyl]-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)- [l,3]thiazinan-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3-trifluoromethoxy-phenyl)- thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(4-trifluoromethoxy-phenyl)- thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)- imidazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-methyl-2-(3-trifluoromethyl- phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-ethyl-2-(3-trifluoromethyl- phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3-hydroxy-phenyl)- thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-m-tolyl-thiazolidin-4-one; 2- Benzo[l,3]dioxol-5-yl-3-[4-(4-chloro-phenoxy)-phenyl]-thiazolidin-4-one; 3-[4-(4-Chloro- phenoxy)-phenyl]-2-(3-ethoxy-phenyl)-thiazolidin-4-one;

3-(3-(4-(4-chlorophenoxy)phenyl)-4-oxothiazolidin-2-yl)phenyl acetate; 3-[4-(4-Chloro- phenoxy)-phenyl]-2-(3-pyrrol-l-yl-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)- phenyl]-2-(3,5-dimethoxy-phenyl)-thiazolidin-4-one; 3-{3-[4-(4-Chloro-phenoxy)-phenyl]- 4-oxo-thiazolidin-2-yl}-benzonitrile; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3-nitro-phenyl)- thiazolidin-4-one ; 3 - [4-(4-Chloro-phenoxy)-phenyl] -2-(3 ,4-dimethoxy-phenyl)-thiazolidin- 4-one; Methyl 3-(3-(4-(4-chlorophenoxy)phenyl)-4-oxothiazolidin-2-yl)benzoate; 4-(3-{3- [4-(4-Chloro-phenoxy)-phenyl]-4-oxo-thiazolidin-2-yl}-phenoxymethyl)-benzamide; 3-[4- (4-Chloro-phenoxy)-phenyl]-2-[3-(5-methyl-isoxazol-3-ylmethoxy)-phenyl]-thiazolidin-4- one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(lH-indol-5-yl)-thiazolidin-4-one; Methyl 2-((3-(3- (4-(4-chlorophenoxy)phenyl)-4-oxothiazolidin-2-yl)phenoxy)methyl)oxazole-4-carboxylate; 2-(3-(4-(4-chlorophenoxy)phenyl)-4-oxo-2-(3-(trifluoromethyl)phenyl)thiazolidin-5-yl)-N- propylacetamide; 2-(3-(4-(4-chlorophenoxy)phenyl)-4-oxo-2-(3- (trifluoromethyl)phenyl)thiazolidin-5-yl)-N-(2,2,2-trifluoroethyl)acetamide; 2-(3-(4-(4- chlorophenoxy)phenyl)-4-oxo-2-(3-(trifluoromethyl)phenyl)thiazolidin-5-yl)-N- cyclopropylacetamide; 3-(4-(4-chlorophenoxy)phenyl)-5-(2-(2,6-dimethylmorpholino)-2- oxoethyl)-2-(3-(trifluoromethyl)phenyl)thiazolidin-4-one; N-Butyl-2-[3-[4-(4-chloro- phenoxy)-phenyl]-4-oxo-2-(3-trifluoromethyl-phenyl)-thiazolidin-5-yl]-acetamide; (2R,5S)- 3-(4-(4-chlorophenoxy)phenyl)-5-(2-oxo-2-(pyrrolidin-l-yl)ethyl)-2-(3- (trifluoromethyl)phenyl)thiazolidin-4-one; (2S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(2- oxo^-Cpyrrolidin-l-y^ethy^^-CS-Ctrifluoromethy^pheny^thiazolidin^-one; 2-[3-[4-(4- Chloro-phenoxy)-phenyl]-4-oxo-2-(3-trifluoromethyl-phenyl)-thiazolidin-5-yl]-N-(2- morpholin-4-yl-ethyl)-acetamide; 3-[4-(4-Chloro-phenoxy)-phenyl]-(5S)-methyl-2-(3- trifluoromethyl-phenyl)-imidazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3- methoxy-phenyl)-(5S)-methyl-imidazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3- fluoro-phenyl)-(5S)-methyl-imidazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-(5R)- methyl-2-(3-trifluoromethyl-phenyl)-imidazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]- 2-(3,5-difluoro-phenyl)-thiazolidin-4-one; 3-[5-(4-Chloro-phenoxy)-pyridin-2-yl]-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[6-(4-Chloro-phenoxy)-pyridin-3-yl]-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[5-(4-Chloro-phenoxy)-pyrazin-2-yl]-2-(3- trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(2,5- dimethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3,4-dimethyl- phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3,5-dimethyl-phenyl)- thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-2-(3,5-dibromo-phenyl)-thiazolidin-4- one; 2-(3,5-Bis-trifluoromethyl-phenyl)-3-[4-(4-chloro-phenoxy)-phenyl]-thiazolidin-4-one; 2-(3,5-Bis-benzyloxy-phenyl)-3-[4-(4-chloro-phenoxy)-phenyl]-thiazolidin-4-one; 3-[4-(4- Chloro-phenoxy)-phenyl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-thiazolidin-4-one; 3-[4-(4- Chloro-phenoxy)-phenyl]-2-(2,3-dimethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro- phenoxy)-phenyl]-2-(2,4-dimethyl-phenyl)-thiazolidin-4-one; 3-[4-(4-Chloro-phenoxy)- phenyl]-2-(2,6-dimethyl-phenyl)-thiazolidin-4-one; 3-(4-(4-chlorophenoxy)phenyl)-2-(3- chlorophenyl)thiazolidin-4-one; 2-(3-bromophenyl)-3-(4-(4- chlorophenoxy)phenyl)thiazolidin-4-one; 3-(4-(4-chlorophenoxy)phenyl)-2-(3- iodophenyl)thiazolidin-4-one; 3-(4-(4-chlorophenoxy)phenyl)-2-(3,5- dichlorophenyl)thiazolidin-4-one; 2-(3-chloro-5-(trifluoromethyl)phenyl)-3-(4-(4- chlorophenoxy)phenyl)thiazolidin-4-one; 2-(3-chloro-5-(trifluoromethoxy)phenyl)-3-(4-(4- chlorophenoxy)phenyl)thiazolidin-4-one; 2-biphenyl-3-yl-3-[4-(4-chloro-phenoxy)-phenyl]- thiazolidin-4-one; 3-(4-(4-chlorophenoxy)phenyl)-2-(3-cyclopropylphenyl)thiazolidin-4-one; 3-[4-(4-chloro-phenoxy)-phenyl]-2-(3-morpholin-4-yl-phenyl)-thiazolidin-4-one; 3-(4-(4- chlorophenoxy)phenyl)-2-(3-fluoro-5-methylphenyl)thiazolidin-4-one; 2-(3-chloro-5- fluorophenyl)-3-(4-(4-chlorophenoxy)phenyl)thiazolidin-4-one; 3-(4-(4- chlorophenoxy)phenyl)-2-(pyridin-3-yl)thiazolidin-4-one; 3-(4-(4-chlorophenoxy)phenyl)-2- (3-phenoxyphenyl)thiazolidin-4-one; l-acetyl-3-(4-(4-chlorophenoxy)phenyl)-2-(3- (trifluoromethyl)phenyl)imidazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-l- methanesulfonyl-2-(3-trifluoromethyl-phenyl)-imidazolidin-4-one; ethyl 3-(4-(4- chlorophenoxy)phenyl)-4-oxo-2-(3-(trifluoromethyl)phenyl)imidazolidine-l-carboxylate; 3- (4-(4-chlorophenoxy)phenyl)-l-(2-(4-methylpiperazin-l-yl)acetyl)-2-(3- (trifluoromethyl)phenyl)imidazolidin-4-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-l-(2- morpholin-4-yl-acetyl)-2-(3-trifluoromethyl-phenyl)-imidazolidin-4-one; 3-(4-(4- nitrophenylsulfonyl)phenyl)-2-(3-(trifluoromethyl)phenyl)thiazolidin-4-one; 3-[4-(4- chlorophenoxy)phenyl]-2-(3-mesylaminophenyl)thiazolidin-4-one; 3-[4-(4- chlorophenoxy)phenyl] -2- [3 -(trifluoromethyl)phenyl] thiazolidine-4-thione; 3 -(4-(4- chlorophenoxy)phenyl)-2-(3-(2-hydroxyethoxy)phenyl)thiazolidin-4-one; 3-(4- benzoylphenyl)-2-(3-(trifluoromethyl)phenyl)thiazolidin-4-one; 3-(4-(4- methoxyphenylamino)phenyl)-2-(3-(trifluoromethyl)phenyl)thiazolidin-4-one; 2-(5- bromopyridin-3-yl)-3-(4-(4-chlorophenoxy)phenyl)thiazolidin-4-one; 3-(4- (phenylsulfonyl)phenyl)-2-(3-(trifluoromethyl)phenyl)thiazolidin-4-one; 3-[4-(4- chlorophenoxy)phenyl]-2-(3-aminophenyl)thiazolidin-4-one; N-{3-[3-[4-(4- chlorophenoxy)phenyl]-4-oxothiazolidin-2-yl]phenyl}acetamide; 3-(4-(4- aminophenylamino)phenyl)-2-(3-(trifluoromethyl)phenyl)thiazolidin-4-one; 3-(4-(4- chlorophenoxy)phenyl)-2-(2-(4-chlorophenylthio)-5-nitrophenyl)thiazolidin-4-one; 3-(4-(4- chlorophenoxy)phenyl)-2-(4-(furan-2-ylmethylthio)-3-nitrophenyl)thiazolidin-4-one; 2-(2- chloro-5-nitrophenyl)-3-(4-(4-chlorophenoxy)phenyl)thiazolidin-4-one; 3-(4-(4- chlorophenoxy)phenyl)-2-(2-fluoro-5-nitrophenyl)thiazolidin-4-one; 3-(4-(4- chlorophenoxy)phenyl)-2-(4-fluoro-3-nitrophenyl)thiazolidin-4-one; 3-(4-(4- chlorophenylthio)phenyl)-2-(3-(trifluoromethyl)phenyl)thiazolidin-4-one; 3-(4-(4- chlorophenylsulfinyl)phenyl)-2-(3-(trifluoromethyl)phenyl)thiazolidin-4-one; 3-(4-(4- chlorophenylsulfonyl)phenyl)-2-(3-(trifluoromethyl)phenyl)thiazolidin-4-one; 3-[4-(4- hydroxyphenoxy)phenyl]-2-[3-(trifluoromethyl)phenyl]thiazolidin-4-one; and 2-(3-(3-(4-(4- chlorophenoxy)phenyl)-4-oxothiazolidin-2-yl)phenoxy)ethyl acetate.

9. A method of treating a disease mediated by the Cannabinoid-1 receptor comprising administration of to a patient in need of such treatment of a therapeutically effective amount of a compound of claim 1.

10. The method according to claim 9 wherein the disease mediated by the Cannabinoid-1 receptor is an eating disorder associated with excessive food intake.

11. The method according to Claim 10 wherein the eating disorder associated with excessive food intake is selected from obesity, bulimia nervosa, and compulsive eating disorders.

12. The method according to Claim 11 wherein the eating disorder associated with excessive food intake is obesity.

13. A method of preventing obesity in a person at risk for obesity comprising administration to said person of about 0.001 mg to about 100 mg per kg of a compound selected from a compound of claim 1.

14. A composition comprising a pharmaceutically acceptable carrier and a compound selected from a compound of claim 1.

15. The use of a compound for the manufacture of a medicament useful for the treatment of a disease mediated by the Cannabinoid- 1 receptor in a human patient in need of such treatment, said compound being selected from a compound of claim 1.

16. The use according to Claim 15 wherein the disease mediated by the Cannabinoid- 1 receptor is selected from: metabolic disorders as well as conditions associated with metabolic disorders including obesity, bulimia nervosa, compulsive eating disorders, diabetes, arteriosclerosis, hypertension, osteoporosis, polycystic ovary disease, cardiovascular disease, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, cholelithiasis and sleep disorders, and hyperlipidemic conditions; or psychiatric disorders such as substance abuse, psychosis, depression, anxiety, stress, epilepsy, mania and schizophrenia; or cognitive disorders such as dementia including Alzheimer's disease, memory deficits, short term memory loss and attention deficit disorders; or neurodegenerative disorders such as Parkinson's Disease, cerebral apoplexy and craniocerebral trauma, hypotension, catabolism in connection with pulmonary dysfunction and ventilator dependency; or cardiac dysfunction including valvular disease, myocardial infarction, cardiac hypertrophy and congestive heart failure); or the overall pulmonary dysfunction, transplant rejection, rheumatoid arthritis, migraine, neuropathy, multiple sclerosis, Guillain-Barre syndrome, the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, inflammatory bowel disease, lupus, graft vs. host disease, T-cell mediated hypersensitivity disease, psoriasis, osteoporosis, asthma, Hashimoto's thyroiditis, Guillain-Barre syndrome, cancer, contact dermatitis, allergic rhinitis, ischemic or reperfusion injury, head trauma and movement disorders.

17. The use according to Claim 16 wherein the disease mediated by the Cannabinoid- 1 receptor is an eating disorder associated with excessive food intake.

18. The use according to Claim 17, wherein the eating disorder associated with excessive food intake is selected from obesity, bulimia nervosa, and compulsive eating disorders.

19. The use according to Claim 18 wherein the eating disorder associated with excessive food intake is obesity.

20. The use of a compound according to Claim 1 for the manufacture of a medicament for the prevention of obesity in a person at risk therefore.