OXADIAZOLINE LIGANDS FOR MODULATING THE EXPRESSION OF EXOGENOUS GENES VIA AN ECDYSONE RECEPTOR COMPLEX
The present invention relates to non-steroidal ligands for use in nuclear receptor-based inducible gene expression system, and a method to modulate exogenous gene expression in which an ecdysone receptor complex comprising: a DNA binding domain; a ligand binding domain; a transactivation domain; and a ligand is contacted with a DNA construct comprising: the exogenous gene and a response element; wherein the exogenous gene is under the control of the response element and binding of the DNA binding domain to the response element in the presence of the ligand results in activation or suppression of the gene.
1 . A compound of the general 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; p 2 b) unsubstituted or substituted phenyl wherein the substituents are independently 1 to 5 H; 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;
e) 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 -C 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 5 H; 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 compound 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-trifluromethoxyphenyl;
provided that when R 4 is phenyl, then R 1 is not phenyl.
5 . The compound of claim 4 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)-5-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 . A method of modulating the expression of a target gene in a host cell, wherein the host cell includes a first gene expression cassette comprising a first polynucleotide encoding a first polypeptide comprising:
(i) a transactivation domain;
(ii) a DNA-binding domain; and
(iii) a Group H nuclear receptor ligand binding domain;
a second gene expression cassette comprising:
(i) a response element capable of binding to said DNA binding domain;
(ii) a promoter that is activated by the transactivation domain; and
(iii) said target gene;
the method comprising contacting said host cell with a compound of 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 5 H; 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 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;
f) 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 -C 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 5 H; 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, cyanio, (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.
7 . The method of claim 6 wherein the compound is of the specified formula and:
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.
8 . The method of claim 7 wherein the compound is of the specified formula and:
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.
9 . The method of claim 8 wherein the compound is of the specified formula and:
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-trifluromethoxyphenyl;
provided that when R 4 is phenyl, then R 1 is not phenyl.
10 . The method of claim 9 , wherein the compound is 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)-5-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.
11 . A method to modulate the expression of one or more exogenous genes in a subject, comprising administering to the subject an effective amount of a ligand of 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 5 H; 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 -C 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 5 H; 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.
12 . A method for regulating endogenous or heterologous gene expression in a transgenic subject comprising contacting a ligand with an ecdysone receptor complex within the cells of the subject, wherein the cells further contain a DNA binding sequence for the ecdysone receptor complex when in combination with the ligand and wherein formation of an ecdysone receptor complex-ligand-DNA binding sequence complex induces expression of the gene, and where the ligand has the following 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 5 H; 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;
g) 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 -C 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 5 H; 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.
13 . The method of claim 12 , wherein the ecdysone receptor complex is a chimeric ecdysone receptor complex and the DNA construct further comprises a promoter.
14 . The method of claim 12 , wherein the subject is a plant.
15 . The method of claim 12 , wherein the subject is a mammal.
16 . A method of modulating the expression of a gene in a host cell comprising the steps of:
a) introducing into the host cell a gene expression modulation system comprising:
i) a first gene expression cassette that is capable of being expressed in a host cell comprising a polynucleotide sequence that encodes a first hybrid polypeptide comprising:
(a) a DNA-binding domain that recognizes a response element associated with a gene whose expression is to be modulated; and
(b) an ecdysone receptor ligand binding domain;
ii) a second gene expression cassette that is capable of being expressed in the host cell comprising a polynucleotide sequence that encodes a second hybrid polypeptide comprising:
(a) a transactivation domain; and
(b) a chimeric retinoid X receptor ligand binding domain; and
iii) a third gene expression cassette that is capable of being expressed in a host cell comprising a polynucleotide sequence comprising:
(a) a response element recognized by the DNA-binding domain of the first hybrid polypeptide;
(b) a promoter that is activated by the transactivation domain of the second hybrid polypeptide; and
(c) a gene whose expression is to be modulated; and
b) introducing into the host cell a ligand of 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 5 H; 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 -C 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 ) z —), 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; 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.
17 . A method for producing a polypeptide comprising the steps of:
a) selecting a cell which is substantially insensitive to exposure to a ligand comprising 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 5 H; 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 -C 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 5 H; 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;
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) an ecdysone receptor complex comprising:
i) a DNA binding domain;
ii) a binding domain for the ligand; and
iii) a transactivation domain; and
c) exposing the cell to the ligand.