Oxadiazoline ligands for modulating the expression of exogenous genes via an ecdysone receptor complex

1. An in vitro method for producing a polypeptide comprising:

a) selecting a cell;

b) introducing into the cell:

1) a DNA construct comprising:

i) an exogenous gene encoding the polypeptide; and

ii) a response element;

wherein the gene is under the control of the response element; and

2) a DNA construct encoding an ecdysone receptor complex comprising:

i) a DNA binding domain;

ii) an ecdysone receptor ligand binding domain; and

iii) a transactivation domain; and

c) exposing the cell to the ligand,

wherein the ligand is a compound having the formula:

wherein X and X′ are independently O or S;

R 1 is

a) H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )cyanoalkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or benzyloxy;

b) unsubstituted or substituted phenyl wherein the substituents are independently 1 to 5H; halo;nitro; cyano; hydroxy; amino (—NR a R b ); (C 1 -C 6 )alkyl; (C 1 -C 6 )haloalkyl; (C 1 -C 6 )cyanoalkyl;(C 1 -C 6 )hydroxyalkyl; (C 1 -C 6 )alkoxy; phenoxy; (C 1 -C 6 )haloalkoxy; (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl; (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy; (C 1 -C 6 )alkanoyloxy(C 1 -C 6 )alkyl; (C 2 -C 6 )alkenyl optionally substituted with halo, cyano, (C 1 -C 4 ) alkyl, or (C 1 -C 4 )alkoxy; (C 2 -C 6 )alkynyl optionally substituted with halo or (C 1 -C 4 )alkyl; formyl; carboxy; (C 1 -C 6 )alkylcarbonyl; (C 1 -C 6 )haloalkylcarbonyl; benzoyl; (C 1 -C 6 )alkoxycarbonyl; (C 1 -C 6 )haloalkoxycarbonyl; (C 1 -C 6 )alkanoyloxy (—OCOR a );carboxamido (—CONR a R b ); amido (—NR a COR b ); alkoxycarbonylamino (—NR a CO 2 R b ); alkylaminocarbonylamino (—NR a CONR b R c ); mercapto; (C 1 -C 6 )alkylthio; (C 1 -C 6 ) alkylsulfonyl; (C 1 -C 6 )alkylsulfoxido (—S(O)R a ); sulfamido (—SO 2 NR a R b ); or unsubstituted or substituted phenyl wherein the substituents are independently 1 to 3 halo, nitro, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )alkyl, or amino; or when two adjacent positions on the phenyl ring are substituted with alkoxy groups, these groups, together with the carbon atoms to which they are attached, may be joined as a linkage (—OCH 2 O—) or (—OCH 2 CH 2 O—) to form a 5- or 6-membered dioxolano or dioxano heterocyclic ring;

c) unsubstituted or substituted naphthyl wherein the substituents are independently 1 to 3 halo, nitro, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )alkyl, or amino;

d) unsubstituted or substituted benzothiophene-2-yl, benzothiophene-3-yl, benzofuran-2-yl, or benzofuran-3-yl wherein the substituents are independently 1 to 3 halo, nitro, hydroxy, (C 1 -C 6 )alkyl, (C 1 - 6 )alkoxy, carboxy, or (C 1 -C 6 )alkoxycarbonyl (—CO 2 R a );

e) unsubstituted or substituted 2,3, or 4-pyridyl wherein the substituents are independently 1 to 3 halo, cyano, nitro, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )haloalkoxy;

f) unsubstituted or substituted 5-membered heterocycle selected from furyl, thiophenyl, triazolyl, pyrrolyl, isopyrrolyl, pyrazolyl, isoimidazolyl, thiazolyl, isothiazolyl, oxazolyl, or isooxazolyl wherein the substituents are independently 1 to 3 halo, nitro, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, carboxy, (C 1 -C 6 )alkoxycarbonyl (—CO 2 R a ), or unsubstituted or substituted phenyl wherein the substituents are independently 1 to 3 halo, nitro, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, carboxy, (C 1 -C 4 )alkoxycarbonyl (—CO 2 R a ), or amino (—NR a R b );

g) aromatic-substituted or unsubstituted phenyl(C 1 -C 6 )alkyl, phenyl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, or phenoxy(C 1 -C 6 )alkyl wherein the aromatic substituents are independently 1 to 3 halo, nitro, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )alkyl, or amino; or

h) aromatic-substituted or unsubstituted phenylamino, phenyl(C 1 -C 6 )alkylamino, or phenylcarbonylamino wherein the aromatic substituents are independently 1 to 3 halo, nitro, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )alkyl, or amino;

wherein R a , R b , and R c are independently H, (C 1 -C 6 )alkyl, or phenyl;

R 2 and R 3 are independently H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )cyanoalkyl, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, phenyl, or together as an alkane linkage (—(CH 2 ) x —), an alkyloxylalkyl linkage (—(CH 2 ) y O(CH 2 ) z —), an alkylaminoalkyl linkage (—(CH 2 ) y NR a (CH 2 ) z —), or an alkylbenzoalkyl linkage (—(CH 2 ) y -1-benzo-2-(CH 2 ) z —) form a ring with the carbon atom to which they are attached,

wherein x=3 to 7, y=1 to 3, z=1 to 3, and R a is H, (C 1 -C 6 )alkyl, or phenyl; and

R 4 is unsubstituted or substituted phenyl wherein the substituents are independently 1 to 5H; halo; nitro; cyano; hydroxy; amino (—NR a R b ); (C 1 -C 6 )alkyl; (C 1 -C 6 )haloalkyl; (C 1 -C 6 )cyanoalkyl; (C 1 -C 6 )hydroxyalkyl; (C 1 -C 6 )alkoxy; phenoxy; (C 1 -C 6 )haloalkoxy; (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl; (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy; (C 1 -C 6 )alkanoyloxy(C 1 -C 6 )alkyl; (C 2 -C 6 )alkenyl optionally substituted with halo, cyano, (C 1 -C 4 ) alkyl, or (C 1 -C 4 )alkoxy; (C 2 -C 6 )alkynyl optionally substituted with halo or (C 1 -C 4 )alkyl; formyl; carboxy; (C 1 -C 6 )alkylcarbonyl; (C 1 -C 6 )haloalkylcarbonyl; benzoyl; (C 1 -C 6 )alkoxycarbonyl; (C 1 -C 6 )haloalkoxycarbonyl; (C 1 -C 6 )alkanoyloxy (—OCOR a ); carboxamido (—CONR a R b ); amido (—NR a COR b ); alkoxycarbonylamino (—NR a CO 2 R b ); alkylaminocarbonylamino (—NR a CONR b R c ); mercapto; (C 1 -C 6 )alkylthio; (C 1 -C 6 ) alkylsulfonyl; (C 1 -C 6 )alkylsulfoxido (—S(O)R a ); sulfamido (—SO 2 NR a R b ); or unsubstituted or substituted phenyl wherein the substituents are independently 1 to 3 halo, nitro, (C 1 -C 6 ) alkoxy,(C 1 -C 6 )alkyl, or amino; or when two adjacent positions on the phenyl ring are substituted with alkoxy groups, these groups, together with the carbon atoms to which they are attached, may be joined to form a 5- or 6-membered dioxolano (—OCH 2 O—) or dioxano (—OCH 2 CH 2 O—) heterocyclic ring; wherein R a , R b , and R c are independently H, (C 1 -C 6 )alkyl, or phenyl;

provided that R 4 is not 3-nitrophenyl or 4-nitrophenyl, and

when R 4 is phenyl, then R 1 is not phenyl,

when R 4 is 3-chlorophenyl, then R 1 is not phenylamino, or

when R 4 is 4-chlorophenyl, then R 1 is not methyl.

2. The compound of claim 1 wherein:

X and X′ are independently O or S;

R 1 is

a) H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )cyanoalkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or benzyloxy;

b) unsubstituted or substituted phenyl wherein the substituents are independently 1 to 5 H; halo; nitro; cyano; hydroxy; (C 1 -C 6 )alkyl; (C 1 -C 6 )haloalkyl; (C 1 -C 6 )cyanoalkyl; (C 1 -C 6 )hydroxyalkyl; (C 1 -C 6 )alkoxy; (C 1 -C 6 )haloalkoxy; (C 1 -C 6 ) alkoxy(C 1 -C 6 )alkyl; (C 1 -C 6 )alkanoyloxy(C 1 -C 6 )alkyl;(C 2 -C 6 )alkenyl optionally substituted with halo, cyano, (C 1 -C 4 ) alkyl, or (C 1 -C 4 )alkoxy; (C 2 -C 6 ) alkynyl optionally substituted with halo or (C 1 -C 4 )alkyl; formyl; carboxy; (C 1 -C 6 )alkylcarbonyl; (C 1 -C 6 )haloalkylcarbonyl; benzoyl; (C 1 -C 6 )alkoxycarbonyl; (C 1 -C 6 )alkanoyloxy (—OCOR a ); carboxamido (—CONR a R b ); amido (—NR a COR b ); (C 1 -C 6 ) alkylsulfonyl; (C 1 -C 6 )alkylsulfoxido (—S(O)R a ); sulfamido (—SO 2 NR a R b ); or unsubstituted or substituted phenyl wherein the substituents are independently 1 to 3 halo, nitro, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )alkyl, or amino; or when two adjacent positions on the phenyl ring are substituted with alkoxy groups, these groups, together with the carbon atoms to which they are attached, may be joined as a linkage (—OCH 2 O—) or (—OCH 2 CH 2 O—) to form a 5- or 6-membered dioxolano or dioxano heterocyclic ring;

c) unsubstituted or substituted benzothiophene-2-yl, or benzofuran-2-yl wherein the substituents are independently 1 to 3 halo, nitro, hydroxy, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxy;

d) unsubstituted or substituted 2,3, or 4-pyridyl wherein the substituents are independently 1 to 3 halo, cyano, nitro, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )haloalkoxy;

e) unsubstituted or substituted 5-membered heterocycle selected from furyl, thiophenyl, triazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, or isooxazolyl wherein the substituents are independently 1 to 3 halo, nitro, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, carboxy, (C 1 -C 6 )alkoxycarbonyl (—CO 2 R a ), or unsubstituted or substituted phenyl wherein the substituents are independently 1 to 3 halo, nitro, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, carboxy, or (C 1 -C 4 )alkoxycarbonyl (—CO 2 R a );

f) aromatic-substituted or unsubstituted phenyl(C 1 -C 6 )alkyl, phenyl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, or phenoxy(C 1 -C 6 )alkyl wherein the aromatic substituents are independently 1 to 3 halo, nitro,(C 1 -C 6 ) alkoxy, or (C 1 -C 6 )alkyl; or

g) aromatic-substituted or unsubstituted phenylamino, phenyl(C 1 -C 6 )alkylamino, or phenylcarbonylamino wherein the aromatic substituents are independently 1 to 3 halo, nitro, (C 1 -C 6 ) alkoxy, or (C 1 -C 6 )alkyl;

wherein R a and R b are independently H, (C 1 -C 6 )alkyl, or phenyl;

R 2 and R 3 are independently H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )cyanoalkyl, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, phenyl, or together as an alkane linkage (—(CH 2 ) x —), an alkyloxylalkyl linkage (—(CH 2 ) y O(CH 2 ) z —), an alkylaminoalkyl linkage (—(CH 2 ) y NR a (CH 2 ) z —), or an alkylbenzoalkyl linkage (—(CH 2 ) y -1-benzo-2-(CH 2 ) z —) form a ring with the carbon atom to which they are attached,

wherein x=3 to 7, y=1 to 3, z=1 to 3, and R a is H, (C 1 -C 6 )alkyl, or phenyl; and

R 4 is unsubstituted or substituted phenyl wherein the substituents are independently 1 to 5 H; halo; nitro; cyano; hydroxy; (C 1 -C 6 )alkyl; (C 1 -C 6 )haloalkyl; (C 1 -C 6 )cyanoalkyl; (C 1 -C 6 )hydroxyalkyl; (C 1 -C 6 )alkoxy; (C 1 -C 6 )haloalkoxy; (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl; (C 1 -C 6 )alkanoyloxy(C 1 -C 6 )alkyl; (C 2 -C 6 )alkenyl optionally substituted with halo, cyano, (C 1 -C 4 ) alkyl, or (C 1 -C 4 )alkoxy; (C 2 -C 6 )alkynyl optionally substituted with halo or (C 1 -C 4 )alkyl; formyl; carboxy; (C 1 -C 6 )alkylcarbonyl; (C 1 -C 6 )haloalkylcarbonyl; benzoyl; (C 1 -C 6 )alkoxycarbonyl; (C 1 -C 6 )alkanoyloxy (—OCOR a ); carboxamido(—CONR a R b ); amido (—NR a COR b ); (C 1 -C 6 ) alkylsulfonyl; (C 1 -C 6 )alkylsulfoxido (—S(O)R a ); sulfamido (—SO 2 NR a R b ); or unsubstituted or substituted phenyl wherein the substituents are independently 1 to 3 halo, nitro, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )alkyl, or amino; or when two adjacent positions on the phenyl ring are substituted with alkoxy groups, these groups, together with the carbon atoms to which they are attached, may be joined as a linkage (—OCH 2 O—) or (—OCH 2 CH 2 O—) to form a 5- or 6-membered dioxolano or dioxano heterocyclic ring; wherein R a and R b are independently H, (C 1 -C 6 )alkyl, or phenyl;

provided that R 4 is not 3-nitrophenyl or 4-nitrophenyl, and

when R 4 is phenyl, then R 1 is not phenyl,

when R 4 is 3-chlorophenyl, then R 1 is not phenylamino, or

when R 4 is 4-chlorophenyl, then R 1 is not methyl.

3. The compound of claim 2 wherein:

X is O;

X′ is O or S;

R 1 is

a) H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, or (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl;

b) unsubstituted or substituted phenyl wherein the substituents are independently 1 to 5 H; halo; nitro; cyano; (C 1 -C 6 )alkyl; (C 1 -C 6 )haloalkyl; (C 1 -C 6 )alkoxy; (C 1 -C 6 )haloalkoxy; (C 1 -C 6 )alkylcarbonyl; (C 1 -C 6 )alkoxycarbonyl; carboxamido (—CONR a R b ); amido (—NR a COR b ); or phenyl; or when two adjacent positions on the phenyl ring are substituted with alkoxy groups, these groups, together with the carbon atoms to which they are attached, may be joined as a linkage (—OCH 2 O—) or (—OCH 2 CH 2 O—) to form a 5- or 6-membered dioxolano or dioxano heterocyclic ring;

c) unsubstituted or substituted benzothiophene-2-yl, or benzofuran-2-yl wherein the substituents are independently 1 to 3 halo, nitro, hydroxy, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxy;

d) unsubstituted or substituted furyl or thiophenyl wherein the substituents are independently 1 to 3 halo, nitro, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, carboxy, (C 1 -C 6 )alkoxycarbonyl (—CO 2 R a ), or phenyl;

e) aromatic-substituted or unsubstituted phenyl(C 1 -C 6 )alkyl, phenyl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, or phenoxy(C 1 -C 6 )alkyl wherein the aromatic substituents are independently 1 to 3 halo, nitro, (C 1 -C 6 ) alkoxy, or (C 1 -C 6 )alkyl; or

f) aromatic-substituted or unsubstituted phenylamino, phenyl(C 1 -C 6 )alkylamino, or phenylcarbonylamino wherein the aromatic substituents are independently 1 to 3 halo, nitro, (C 1 -C 6 ) alkoxy, or (C 1 -C 6 )alkyl;

wherein R a and R b are independently H, (C 1 -C 6 )alkyl, or phenyl;

R 2 and R 3 are independently H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, phenyl, or together as an alkane linkage (—(CH 2 ) x —), an alkyloxylalkyl linkage (—(CH 2 ) y O(CH 2 ) z —), an alkylaminoalkyl linkage (—(CH 2 ) y NR a (CH 2 ) z —), or an alkylbenzoalkyl linkage (—(CH 2 ) y -1-benzo-2-(CH 2 ) z —) form a ring with the carbon atom to which they are attached,

wherein x=3 to 7, y=1 to 3, z=1 to 3, and R a is H, (C 1 -C 6 )alkyl, or phenyl; and

R 4 is unsubstituted or substituted phenyl wherein the substituents are independently 1 to 5 H; halo; nitro; cyano; (C 1 -C 6 )alkyl; (C 1 -C 6 )haloalkyl; (C 1 -C 6 )alkoxy; (C 1 -C 6 )haloalkoxy; (C 1 -C 6 )alkylcarbonyl; (C 1 -C 6 )alkoxycarbonyl; carboxamido (—CONR a R b ); amido (—NR a COR b ); or phenyl; or when two adjacent positions on the phenyl ring are substituted with alkoxy groups, these groups, together with the carbon atoms to which they are attached, may be joined as a linkage (—OCH 2 O—) or (—OCH 2 CH 2 O—) to form a 5- or 6-membered dioxolano or dioxano heterocyclic ring; wherein R a and R b are independently H, (C 1 -C 6 )alkyl, or phenyl;

provided that R 4 is not 3-nitrophenyl or 4-nitrophenyl, and

when R 4 is phenyl, then R 1 is not phenyl,

when R 4 is 3-chlorophenyl, then R 1 is not phenylamino, or

when R 4 is 4-chlorophenyl, then R 1 is not methyl.

4. The method of claim 3 wherein:

X and X′ are O;

R 1 is

phenyl, 4-chlorophenyl-, 4-ethylphenyl-, 2-ethyl-3,4-ethylenedioxyphenyl, 3-fluorophenyl-, 2-fluoro-4-ethylphenyl-, 2-methyl-3-methoxyphenyl-, 2-ethyl-3-methoxyphenyl, 3-methylphenyl-, 2-methoxyphenyl-, 2-nitrophenyl-, 3-nitrophenyl-, 2-furanyl-, benzyl-, benzothiophene-2-yl-, phenylamino-, benzyloxymethyl, phenoxymethyl-, 3-toluoylamino-, benzylamino-, benzoylamino-,ethoxycarbonylethyl-, or 3-chloro-2,2,3,3-tetrafluoroethyl;

R 2 and R 3 are independently methyl, ethyl, or together as a tetramethylene (—(CH 2 ) 4 —), 4-pyrano (—CH 2 CH 2 OCH 2 CH 2 —), or methylenebenzoethylene (—CH 2 -1-benzo-2-CH 2 CH 2 —) linkage form a ring with the carbon atom to which they are attached; and

R 4 is phenyl, 4-biphenyl, 4-chlorophenyl, 2,4-dimethoxyphenyl, 3,5-dimethylphenyl, 2-methoxyphenyl, 3,4-methylenedioxyphenyl, 3-trifluoromethylphenyl, or 4-trifluoromethoxyphenyl;

provided that when R 4 is phenyl, then R 1 is not phenyl.

5. An in vitro method for producing a polypeptide comprising:

a) selecting a cell,

b) introducing into the cell:

1) a DNA construct comprising:

i) an exogenous gene encoding the polypeptide; and

ii) a response element;

wherein the gene is under the control of the response element; and

2) a DNA construct encoding an ecdysone receptor complex comprising:

i) a DNA binding domain;

ii) an ecdysone receptor ligand binding domain; and

iii) a transactivation domain; and

c) exposing the cell to the ligand,

wherein the ligand is a compound selected from the group consisting of:

1-Benzyl-3-[3-(3,5-dimethyl-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-urea;

1-Benzoyl-3-[3-(3,5-dimethyl-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-urea;

N-[3-(4-Chloro-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-4-ethyl-benzamide;

3-Chloro-N-[3-(4-chloro-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-2,2,3,3-tetrafluoro-propionamide;

N-[3-(4-Chloro-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-benzamide;

Benzo[b]thiophene-2-carboxylic acid [3-(4-chloro-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-amide;

N-[3-(4-Chloro-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-succinamic acid ethyl ester;

1-[3-(4-Chloro-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-3-phenyl-urea;

N-[3-(4-Chloro-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-2-phenoxy-acetamide;

2-Benzyloxy-N-[3-(4-chloro-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-acetamide;

Furan-2-carboxylic acid [3-(4-chloro-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-amide;

N-[3-(4-Chloro-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-2-phenyl-acetamide;

N-[3-(4-Chloro-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-2-ethyl-3-methoxy-benzamide;

N-[5,5-Dimethyl-3-(4-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-4-yl]-benzamide;

N-[5,5-Dimethyl-3-(4-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-4-yl]-4-ethyl-benzamide;

Benzo[b]thiophene-2-carboxylic acid [5,5-dimethyl-3-(4-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-4-yl]-amide;

1-[5,5-Dimethyl-3-(4-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-4-yl]-3-phenyl-urea;

N-[5,5-Dimethyl-3-(4-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-4-yl]-2-phenoxy-acetamide;

2-Benzyloxy-N-[5,5-dimethyl-3-(4-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-4-yl]-acetamide;

N-[5,5-Dimethyl-3-(4-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-4-yl]-2-phenyl-acetamide;

Furan-2-carboxylic acid [5,5-dimethyl-3-(4-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-4-yl]-amide;

N-[5,5-Dimethyl-3-(4-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-4-yl]-2-ethyl-3-methoxy-benzamide;

N-[5,5-Dimethyl-3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-4-yl]-4-ethyl-benzamide;

N-[5,5-Dimethyl-3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-4-yl]-benzamide;

3-Chloro-N-[5,5-dimethyl-3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-4-yl]-2,2,3,3-tetrafluoro-propionamide;

N-[5,5-Dimethyl-3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-4-yl]-succinamic acid ethyl ester;

1-[5,5-Dimethyl-3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-4-yl]-3-phenyl-urea;

2-Benzyloxy-N-[5,5-dimethyl-3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-4-yl]-acetamide;

Furan-2-carboxylic acid [5,5-dimethyl-3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-4-yl]-amide;

4-Ethyl-N-[3-(2-methoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-benzamide;

N-[3-(2-Methoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-benzamide;

N-[5,5-Dimethyl-3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-4-yl]-2-ethyl-3-methoxy-benzamide;

N-[5,5-Dimethyl-3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-4-yl]-2-phenyl-acetamide;

N-[5,5-Dimethyl-3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-4-yl]-2-phenoxy-acetamide;

Benzo[b]thiophene-2-carboxylic acid [5,5-dimethyl-3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-4-yl]-amide;

3-Chloro-2,2,3,3-tetrafluoro-N-[3-(2-methoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-propionamide;

N-[3-(2-Methoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-succinamic acid ethyl ester;

Benzo[b]thiophene-2-carboxylic acid [3-(2-methoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-amide;

1-[3-(2-Methoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-3-phenyl-urea;

N-[3-(2-Methoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-2-phenoxy-acetamide;

2-Benzyloxy-N-[3-(2-methoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-acetamide;

N-[3-(2-Methoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-2-phenyl-acetamide;

Furan-2-carboxylic acid [3-(2-methoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-amide;

2-Ethyl-3-methoxy-N-[3-(2-methoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-benzamide;

N-(3-Benzo[1,3]dioxol-5-yl-5,5-dimethyl-[1,2,4]oxadiazol-4-yl)-4-ethyl-benzamide;

N-(3-Benzo[1,3]dioxol-5-yl-5,5-dimethyl-[1,2,4]oxadiazol-4-yl)-benzamide;

N-(3-Benzo[1,3]dioxol-5-yl-5,5-dimethyl-[1,2,4]oxadiazol-4-yl)-succinamic acid ethyl ester;

Benzo[b]thiophene-2-carboxylic acid (3-benzo[1,3]dioxol-5-yl-5,5-dimethyl-[1,2,4]oxadiazol-4-yl)-amide;

1-(3-Benzo[1,3]dioxol-5-yl-5,5-dimethyl-[1,2,4]oxadiazol-4-yl)-3-phenyl-urea;

N-(3-Benzo[1,3]dioxol-5-yl-5,5-dimethyl-[1,2,4]oxadiazol-4-yl)-2-phenoxy-acetamide;

N-(3-Benzo[1,3]dioxol-5-yl-5,5-dimethyl-[1,2,4]oxadiazol-4-yl)-2-benzyloxy-acetamide;

N-(3-Benzo[1,3]dioxol-5-yl-5,5-dimethyl-[1,2,4]oxadiazol-4-yl)-2-phenyl-acetamide;

Furan-2-carboxylic acid (3-benzo[1,3]dioxol-5-yl-5,5-dimethyl-[1,2,4]oxadiazol-4-yl)-amide;

N-(3-Benzo[1,3]dioxol-5-yl-5,5-dimethyl-[1,2,4]oxadiazol-4-yl)-2-ethyl-3-methoxy-benzamide;

N-[3-(2,4-Dimethoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-4-ethyl-benzamide;

N-[3-(2,4-Dimethoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-benzamide;

N-[3-(2,4-Dimethoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-succinamic acid ethyl ester;

Benzo[b]thiophene-2-carboxylic acid [3-(2,4-dimethoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-amide;

1-[3-(2,4-Dimethoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-3-phenyl-urea;

N-[3-(2,4-Dimethoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-2-phenoxy-acetamide;

2-Benzyloxy-N-[3-(2,4-dimethoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-acetamide;

N-[3-(2,4-Dimethoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-2-phenyl-acetamide;

Furan-2-carboxylic acid [3-(2,4-dimethoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-amide;

N-[3-(2,4-Dimethoxy-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-2-ethyl-3-methoxy-benzamide;

N-(3-Biphenyl-4-yl-5,5-dimethyl-[1,2,4]oxadiazol-4-yl)-4-ethyl-benzamide;

N-(3-Biphenyl-4-yl-5,5-dimethyl-[1,2,4]oxadiazol-4-yl)-2-ethyl-3-methoxy-benzamide;

4-Ethyl-N-(5-ethyl-5-methyl-3-phenyl-[1,2,4]oxadiazol-4-yl)-benzamide;

N-(5-Ethyl-5-methyl-3-phenyl-[1,2,4]oxadiazol-4-yl)-benzamide;

Benzo[b]thiophene-2-carboxylic acid (5-ethyl-5-methyl-3-phenyl-[1,2,4]oxadiazol-4-yl)-amide;

1-(5-Ethyl-5-methyl-3-phenyl-[1,2,4]oxadiazol-4-yl)-3-phenyl-urea;

N-(5-Ethyl-5-methyl-3-phenyl-[1,2,4]oxadiazol-4-yl)-2-phenoxy-acetamide;

2-Benzyloxy-N-(5-ethyl-5-methyl-3-phenyl-[1,2,4]oxadiazol-4-yl)-acetamide;

N-(5-Ethyl-5-methyl-3-phenyl-[1,2,4]oxadiazol-4-yl)-2-phenyl-acetamide;

Furan-2-carboxylic acid (5-ethyl-5-methyl-3-phenyl-[1,2,4]oxadiazol-4-yl)-amide;

2-Ethyl-N-(5-ethyl-5-methyl-3-phenyl-[1,2,4]oxadiazol-4-yl)-3-methoxy-benzamide;

N-[3-(3,5-Dimethyl-phenyl)-5-ethyl-5-methyl-[1,2,4]oxadiazol-4-yl]-4-ethyl-benzamide;

N-[3-(3,5-Dimethyl-phenyl)-5-ethyl-5-methyl-[1,2,4]oxadiazol-4-yl]-benzamide;

3-Chloro-N-[3-(3,5-dimethyl-phenyl)-5-ethyl-5-methyl-[1,2,4]oxadiazol-4-yl]-2,2,3,3-tetrafluoro-propionamide;

N-[3-(3,5-Dimethyl-phenyl)-5-ethyl-5-methyl-[1,2,4]oxadiazol-4-yl]-succinamic acid ethyl ester;

Benzo[b]thiophene-2-carboxylic acid [3-(3,5-dimethyl-phenyl)-5-ethyl-5-methyl-[1,2,4]oxadiazol-4-yl]-amide;

1-[3-(3,5-Dimethyl-phenyl)-5-ethyl-5-methyl-[1,2,4]oxadiazol-4-yl]-3-phenyl-urea;

N-[3-(3,5-Dimethyl-phenyl)-S-ethyl-5-methyl-[1,2,4]oxadiazol-4-yl]-2-phenoxy-acetamide;

2-Benzyloxy-N-[3-(3,5-dimethyl-phenyl)-5-ethyl-5-methyl-[1,2,4]oxadiazol-4-yl]-acetamide;

N-[3-(3,5-Dimethyl-phenyl)-5-ethyl-5-methyl-[1,2,4]oxadiazol-4-yl]-2-phenyl-acetamide;

Furan-2-carboxylic acid [3-(3,5-dimethyl-phenyl)-5-ethyl-5-methyl-[1,2,4]oxadiazol-4-yl]-amide;

N-[3-(3,5-Dimethyl-phenyl)-5-ethyl-5-methyl-[1,2,4]oxadiazol-4-yl]-2-ethyl-3-methoxy-benzamide;

4-Ethyl-N-(3-phenyl-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl)-benzamide;

N-(3-Phenyl-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl)-benzamide;

3-Chloro-2,2,3,3-tetrafluoro-N-(3-phenyl-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl)-propionamide;

N-(3-Phenyl-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl)-succinamic acid ethyl ester;

Benzo[b]thiophene-2-carboxylic acid (3-phenyl-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl)-amide;

1-Phenyl-3-(3-phenyl-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl)-urea;

2-Phenoxy-N-(3-phenyl-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl)-acetamide;

2-Benzyloxy-N-(3-phenyl-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl)-acetamide;

2-Phenyl-N-(3-phenyl-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl)-acetamide;

Furan-2-carboxylic acid (3-phenyl-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl)-amide;

2-Ethyl-3-methoxy-N-(3-phenyl-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl)-benzamide;

N-[3-(3,5-Dimethyl-phenyl)-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl]-4-ethyl-benzamide;

N-[3-(3,5-Dimethyl-phenyl)-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl]-benzamide;

3-Chloro-N-[3-(3,5-dimethyl-phenyl)-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl]-2,2,3,3-tetrafluoro-propionamide;

N-[3-(3,5-Dimethyl-phenyl)-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl]-succinamic acid ethyl ester;

Benzo[b]thiophene-2-carboxylic acid [3-(3,5-dimethyl-phenyl)-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl]-amide;

1-[3-(3,5-Dimethyl-phenyl)-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl]-3-phenyl-urea;

N-[3-(3,5-Dimethyl-phenyl)-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl]-2-phenoxy-acetamide;

2-Benzyloxy-N-[3-(3,5-dimethyl-phenyl)-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl]-acetamide;

N-[3-(3,5-Dimethyl-phenyl)-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl]-2-phenyl-acetamide;

Furan-2-carboxylic acid [3-(3,5-dimethyl-phenyl)-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl]-amide;

N-[3-(3,5-Dimethyl-phenyl)-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl]-2-ethyl-3-methoxy-benzamide;

4-Ethyl-N-(3-phenyl-1,8-dioxa-2,4-diaza-spiro[4.5]dec-2-en-4-yl)-benzamide;

N-(3-Phenyl-1,8-dioxa-2,4-diaza-spiro[4.5]dec-2-en-4-yl)-benzamide;

1-Phenyl-3-(3-phenyl-1,8-dioxa-2,4-diaza-spiro[4.5]dec-2-en-4-yl)-urea;

2-Phenoxy-N-(3-phenyl-1,8-dioxa-2,4-diaza-spiro[4.5]dec-2-en-4-yl)-acetamide;

2-Benzyloxy-N-(3-phenyl-1,8-dioxa-2,4-diaza-spiro[4.5]dec-2-en-4-yl)-acetamide;

2-Phenyl-N-(3-phenyl-1,8-dioxa-2,4-diaza-spiro[4.5]dec-2-en-4-yl)-acetamide;

2-Ethyl-3-methoxy-N-(3-phenyl-1,8-dioxa-2,4-diaza-spiro[4.5]dec-2-en-4-yl)-benzamide;

N-[3-(3,5-Dimethyl-phenyl)-1,8-dioxa-2,4-diaza-spiro[4.5]dec-2-en-4-yl]-4-ethyl-benzamide;

N-[3-(3,5-Dimethyl-phenyl)-1,8-dioxa-2,4-diaza-spiro[4.5]dec-2-en-4-yl]-benzamide;

1-[3-(3,5-Dimethyl-phenyl)-1,8-dioxa-2,4-diaza-spiro[4.5]dec-2-en-4-yl]-3-phenyl-urea;

N-[3-(3,5-Dimethyl-phenyl)-1,8-dioxa-2,4-diaza-spiro[4.5]dec-2-en-4-yl]-2-phenoxy-acetamide;

2-Benzyloxy-N-[3-(3,5-dimethyl-phenyl)-1,8-dioxa-2,4-diaza-spiro[4.5]dec-2-en-4-yl]-acetamide;

N-[3-(3,5-Dimethyl-phenyl)-1,8-dioxa-2,4-diaza-spiro[4.5]dec-2-en-4-yl]-2-phenyl-acetamide;

Furan-2-carboxylic acid [3-(3,5-dimethyl-phenyl)-1,8-dioxa-2,4-diaza-spiro[4.5]dec-2-en-4-yl]-amide;

N-[3-(3,5-Dimethyl-phenyl)-1,8-dioxa-2,4-diaza-spiro[4.5]dec-2-en-4-yl]-2-ethyl-3-methoxy-benzamide;

N-[3-(3,5-Dimethyl-phenyl)-1-oxa-2,4-diaza-spiro[4.5]-7,8-benzo-dec-2-en-4-yl]-3-methoxy-2-methyl-benzamide;

N-[3-(3,5-Dimethyl-phenyl)-1,8-dioxa-2,4-diaza-spiro[4.5]dec-2-en-4-yl]-3-methoxy-2-methyl-benzamide;

N-[3-(3,5-Dimethyl-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-3-methoxy-2-methyl-benzamide;

N-[3-(3,5-Dimethyl-phenyl)-5-ethyl-5-methyl-[1,2,4]oxadiazol-4-yl]-4-ethyl-2-fluoro-benzamide;

4-Ethyl-2-fluoro-N-(3-phenyl-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl)-benzamide;

N-[3-(3,5-Dimethyl-phenyl)-1-oxa-2,4-diaza-spiro[4,4]non-2-en-4-yl]-4-ethyl-2-fluoro-benzamide;

N-(5,5-Dimethyl-3-phenyl-[1,2,4]oxadiazol-4-yl)-4-ethyl-2-fluoro-benzamide;

5-Ethyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid (5,5-dimethyl-3-phenyl-[1,2,4]oxadiazol-4-yl)-amide; and

5-Ethyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid [3-(3,5-dimethyl-phenyl)-5-ethyl-5-methyl-[1,2,4]oxadiazol-4-yl]-amide.

6. The method of claim 1 , wherein said cell is a eucaryotic cell.

7. The method of claim 5 , wherein said cell is a eucaryotic cell.

8. The method of claim 6 , wherein said eucaryotic cell is a vertebrate cell.

9. The method of claim 7 , wherein said eucaryotic cell is a vertebrate cell.