1-6. (canceled)
7. 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 compound of the formula:
wherein:
X and X\u2032 are independently O or S;
A is unsubstituted or substituted phenyl wherein the substituents are independently 1 to 5H; halo; nitro; cyano; hydroxy; amino (\u2014NRaRb); alkylaminoalkyl (\u2014(CH2)nNRaRb); (C1-C6)alkyl; (C1-C6)haloalkyl; (C1-C6)cyanoalkyl; (C1-C6)hydroxyalkyl; (C1-C6)alkoxy; phenoxy; (C1-C6)haloalkoxy; (C1-C6)alkoxy(C1-C6)alkyl; (C1-C6)alkenyloxy(C1-C6)alkyl; (C1-C6)alkoxy(C1-C6)alkoxy; (C1-C6)alkanoyloxy(C1-C6)alkyl; (C2-C6)alkenyl optionally substituted with halo, cyano, (C1-C4)alkyl, or (C1-C4)alkoxy; (C2-C6)alkynyl optionally substituted with halo or (C1-C4)alkyl; formyl; carboxy; (C1-C6)alkylcarbonyl; (C1-C6)haloalkylcarbonyl; benzoyl; (C1-C6)alkoxycarbonyl; (C1-C6)haloalkoxycarbonyl; (C1-C6)alkanoyloxy (\u2014OCORa); carboxamido (\u2014CONRaRb); amido (\u2014NRaCORb); alkoxycarbonylamino (\u2014NRaCO2Rb); alkylaminocarbonylamino (\u2014NRaCONRbRa); mercapto; (C1-C6)alkylthio; (C1-C6)alkylsulfonyl; (C1-C6)alkylsulfonyl(C1-C6)alkyl; (C1-C6)alkylsulfoxido (\u2014S(O)Ra); (C1-C6)alkylsulfoxido(C1-C6)alkyl-(CH2)S(O)Ra); sulfamido (\u2014SO2NRaRb); \u2014SO3H; or unsubstituted or substituted phenyl wherein the substituents are independently 1 to 3 halo, nitro, (C1-C6)alkoxy, (C1-C6)alkyl, or amino; or when one or both of two adjacent positions on the phenyl ring are substituted, the attached atoms may form the phenyl-connecting termini of a linkage selected from the group consisting of (\u2014OCH2O\u2014), (\u2014OCH(CH3)O\u2014), (\u2014OCH2CH2O\u2014), (\u2014OCH(CH3)CH2O\u2014), (\u2014S\u2014CH\u2550N\u2014), (\u2014CH2OCH2O\u2014), (\u2014O(CH2)3\u2014), (\u2550N\u2014O\u2014N\u2550), (\u2014CH\u2550CH\u2014NH\u2014), (\u2014OCF2O\u2014), (\u2014NH\u2014CH\u2550N\u2014), (\u2014CH2CH2O\u2014), and (\u2014(CH2)4\u2014);
B is:
(a) unsubstituted or substituted phenyl wherein the substituents are independently 1 to 5H; halo; nitro; cyano; hydroxy; amino (\u2014NRaRb); alkylaminoalkyl (\u2014(CH2)nNRaRb); (C1-C6)alkyl; (C1-C6)haloalkyl; (C1-C6)cyanoalkyl; (C1-C6)hydroxyalkyl; (C1-C6)alkoxy; phenoxy; (C1-C6)haloalkoxy; (C1-C6)alkoxy(C1-C6)alkyl; (C1-C6)alkenyloxy(C1-C6)alkyl; (C1-C6)alkoxy(C1-C6)alkoxy; (C1-C6)alkanoyloxy(C1-C6)alkyl; (C2-C6)alkenyl optionally substituted with halo, cyano, (C1-C4)alkyl, or (C1-C4)alkoxy; (C2-C6)alkynyl optionally substituted with halo or (C1-C4)alkyl; formyl; carboxy; (C1-C6)alkylcarbonyl; (C1-C6)haloalkylcarbonyl; -benzoyl; (C1-C6)alkoxycarbonyl; (C1-C6)haloalkoxycarbonyl; (C1-C6)alkanoyloxy (\u2014OCORa); carboxamido (\u2014CONRaRb); amido (\u2014NRaCORb); alkoxycarbonylamino (\u2014NRaCO2Rb); alkylaminocarbonylamino (\u2014NRaCONRbRc); mercapto; (C1-C6)alkylthio; (C1-C6)alkylsulfonyl; (C1-C6)alkylsulfonyl(C1-C6)alkyl; (C1-C6)alkylsulfoxido (\u2014S(O)Ra); (C1-C6)alkylsulfoxido(C1-C6)alkyl (\u2014CH2)nS(O)Ra); sulfamido (\u2014SO2NRaRb); \u2014SO3H; \u2014CH\u2550N\u2014NHC(O)NRaRb; \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb; or unsubstituted or substituted phenyl wherein the substituents are independently 1 to 3 halo, nitro, (C1-C6)alkoxy, (C1-C6)alkyl, or amino; or when one or both of two adjacent positions on the phenyl ring are substituted with C, N, O, or S, these atoms may form the phenyl-connecting termini of a linkage selected from the group consisting of (\u2014OCH2O\u2014), (\u2014OCH(CH3)O\u2014), (\u2014OCH2CH2O\u2014), (\u2014OCH(CH3)CH2O\u2014), (\u2014S\u2014CH\u2550N\u2014), (\u2014CH2OCH2O\u2014), (\u2014O(CH2)3\u2014), (\u2550N\u2014O\u2014N\u2550), (\u2014CH\u2550CH\u2014NH\u2014), (\u2014OCF2O\u2014), (\u2014NH\u2014CH\u2550N\u2014), (\u2014CH2CH2O\u2014), and (\u2014(CH2)4\u2014);
(b) unsubstituted 6-membered heterocycle or substituted 6-membered heterocycle having 1-3 nitrogen atoms and 3-5 nuclear carbon atoms where the substituents are from one to three of the same or different halo; nitro; hydroxy; (C1-C6)alkyl; (C1-C6)alkoxy; (C1-C6)thioalkoxy; carboxy; (C1-C6)alkoxycarbonyl; (C1-C6)carbocyalkyl; (C1-C6)alkoxycarbonylalkyl having independently the stated number of carbon atoms in each alkyl group; \u2014CONRaRb; amino; (C1-C6)alkylamino; (C1-C6)dialkylamino having independently the stated number of carbon atoms in each alkyl group; haloalkyl; CH\u2550N\u2014NHC(O)NRaRb; or \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb; or
(c) 5-benzimidazolyl; 1-trityl-5-benzimidazolyl; 3-trityl-5-benzimidazolyl; 1H-indazole-3-yl; 1-trityl-1H-indazole-3-yl; or 1-(C1-C6)alkyl-1H-indole-2-yl;
E is unsubstituted or substituted (C4-C10) branched alkyl wherein the substituents are independently 1-4 cyano; halo; (C5-C6)cycloalkyl; phenyl; (C2-C3)alkenyl; hydroxy, (C1-C6)alkoxy; carboxy; (C1-C6)alkoxycarbonyl; formyl; (C1-C6)trialkylsilyloxy having independently the stated number of carbon atoms in each alkyl group; \u2014CH\u2550N\u2014ORa; \u2014CH\u2550N\u2014Rd; \u2014CH\u2550N\u2014NHC(O)NRaRb; or \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb;
wherein Ra, Rb, and Rc are independently H, (C1-C6)alkyl, or phenyl; Rd is hydroxy(C1-C6)alkyl;
and n=1-4; and
G is H or CN;
provided that:
1) when E is unsubstituted or substituted (C4-C10) branched alkyl wherein the substituents are independently 1-4 cyano; halo; (C2-C3)alkenyl; carboxy; or (C1-C6)alkoxycarbonyl;
then B is:
(a) substituted phenyl which bears at least one \u2014CH\u2550N\u2014NHC(O)NRaRb or \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb group;
(b) substituted 6-membered heterocycle having 1-3 nitrogen atoms and 3-5 nuclear carbon atoms which bears at least one haloalkyl group; or
(c) 5-benzimidazolyl; 1-trityl-5-benzimidazolyl; 3-trityl-5-benzimidazolyl; 1H-indazole-3-yl; 1-trityl-1H-indazole-3-yl; or 1-(C1-C6)alkyl-1H-indole-2-yl;
2) when E is a substituted (C4-C10) branched alkyl which bears at least one of phenyl; hydroxy; (C1-C6)alkoxy; or formyl;
then B is:
(a) substituted phenyl which bears at least one \u2014CH\u2550N\u2014NHC(O)NRaRb or \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb group;
(b) substituted or unsubstituted 6-membered heterocycle having 1-3 nitrogen atoms and 3-5 nuclear carbon atoms; or
(c) 5-benzimidazolyl; 1-trityl-5-benzimidazolyl; 3-trityl-5-benzimidazolyl; 1H-indazole-3-yl; 1-trityl-1H-indazole-3-yl; or 1-(C1-C6)alkyl-1H-indole-2-yl.
8. 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 is
a compound of the formula:
wherein:
X and X\u2032 are independently O or S;
A is unsubstituted or substituted phenyl wherein the substituents are independently 1 to 5H; halo; nitro; cyano; hydroxy; amino (\u2014NRaRb); alkylaminoalkyl((CH2)nNRaRb); (C1-C6)alkyl; (C1-C6)haloalkyl; (C1-C6)cyanoalkyl; (C1-C6)hydroxyalkyl; (C1-C6)alkoxy; phenoxy; (C1-C6)haloalkoxy; (C1-C6)alkoxy(C1-C6)alkyl; (C1-C6)alkenyloxy(C1-C6)alkyl; (C1-C6)alkoxy(C1-C6)alkoxy; (C1-C6)alkanoyloxy(C1-C6)alkyl; (C2-C6)alkenyl optionally substituted with halo, cyano, (C1-C4)alkyl, or (C1-C4)alkoxy; (C2-C6)alkynyl optionally substituted with halo or (C1-C4)alkyl; formyl; carboxy; (C1-C6)alkylcarbonyl; (C1-C6)haloalkylcarbonyl; benzoyl; (C1-C6)alkoxycarbonyl; (C1-C6)haloalkoxycarbonyl; (C1-C6)alkanoyloxy (\u2014OCORa); carboxamido (\u2014CONRaRb); amido (\u2014NRaCORb); alkoxycarbonylamino (\u2014NRaCO2Rb); alkylaminocarbonylamino (\u2014NRaCONRbRc); mercapto; (C1-C6)alkylthio; (C1-C6)alkylsulfonyl; (C1-C6)alkylsulfonyl(C1-C6)alkyl; (C1-C6)alkylsulfoxido (\u2014S(O)Ra); (C1-C6)alkylsulfoxido(C1-C6)alkyl \u2014(CH2)S(O)Ra); sulfamido (\u2014SO2NRaRb); \u2014SO3H; or unsubstituted or substituted phenyl wherein the substituents are independently 1 to 3 halo, nitro, (C1-C6)alkoxy, (C1-C6)alkyl, or amino; or when one or both of two adjacent positions on the phenyl ring are substituted, the attached atoms may form the phenyl-connecting termini of a linkage selected from the group consisting of (\u2014OCH2O\u2014), (\u2014OCH(CH3)O\u2014), (\u2014OCH2CH2O\u2014), (\u2014OCH(CH3)CH2O\u2014), (\u2014S\u2014CH\u2550N\u2014), (\u2014CH2OCH2O\u2014), (\u2014O(CH2)3\u2014), (\u2550N\u2014O\u2014N\u2550), (\u2014CH\u2550CH\u2014NH\u2014), (\u2014OCF2O\u2014), (\u2014NH\u2014CH\u2550N\u2014), (\u2014CH2CH2O\u2014), and (\u2014(CH2)4\u2014);
B is:
(a) unsubstituted or substituted phenyl wherein the substituents are independently 1 to 5H; halo; nitro; cyano; hydroxy; amino (\u2014NRaRb); alkylaminoalkyl (\u2014(CH2)nNRaRb); (C1-C6)alkyl; (C1-C6)haloalkyl; (C1-C6)cyanoalkyl; (C1-C6)hydroxyalkyl; (C1-C6)alkoxy; phenoxy; (C1-C6)halo alkoxy; (C1-C6)alkoxy(C1-C6)alkyl; (C1-C6)alkenyloxy(C1-C6)alkyl; (C1-C6)alkoxy(C1-C6)alkoxy; (C1-C6)alkanoyloxy(C1-C6)alkyl; (C2-C6)alkenyl optionally substituted with halo, cyano, (C1-C4)alkyl, or (C1-C4)alkoxy; (C2-C6)alkynyl optionally substituted with halo or (C1-C4)alkyl; formyl; carboxy; (C1-C6)alkylcarbonyl; (C1-C6)haloalkylcarbonyl; benzoyl; (C1-C6)alkoxycarbonyl; (C1-C6)haloalkoxycarbonyl; (C1-C6)alkanoyloxy (\u2014OCORa); carboxamido (\u2014CONRaRb); amido (\u2014NRaCORb); alkoxycarbonylamino (\u2014NRaCO2Rb); alkylaminocarbonylamino (\u2014NRaCONRbRc); mercapto; (C1-C6)alkylthio; (C1-C6)alkylsulfonyl; (C1-C6)alkylsulfonyl(C1-C6)alkyl; (C1-C6)alkylsulfoxido (\u2014S(O)Ra); (C1-C6)alkylsulfoxido(C1-C6)alkyl (\u2014CH2)nS(O)Ra); sulfamido (\u2014SO2NRaRb); \u2014SO3H; \u2014CH\u2550N\u2014NHC(O)NRaRb; \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb; or unsubstituted or substituted phenyl wherein the substituents are independently 1 to 3 halo, nitro, (C1-C6)alkoxy, (C1-C6)alkyl, or amino; or when one or both of two adjacent positions on the phenyl ring are substituted with C, N, O, or S, these atoms may form the phenyl-connecting termini of a linkage selected from the group consisting of (\u2014OCH2O\u2014), (\u2014OCH(CH3)O\u2014), (\u2014OCH2CH2O\u2014), (\u2014OCH(CH3)CH2O\u2014), (\u2014S\u2014CH\u2550N\u2014), (\u2014CH2OCH2O\u2014), (\u2014O(CH2)3\u2014), (\u2550N\u2014O\u2014N\u2550), (\u2014CH\u2550CH\u2014NH\u2014), (\u2014OCF2O\u2014), (\u2014NH\u2014CH\u2550N\u2014), (\u2014CH2CH2O\u2014), and (\u2014(CH2)4\u2014);
(b) unsubstituted 6-membered heterocycle or substituted 6-membered heterocycle having 1-3 nitrogen atoms and 3-5 nuclear carbon atoms where the substituents are from one to three of the same or different halo; nitro; hydroxy; (C1-C6)alkyl; (C1-C6)alkoxy; (C1-C6)thioalkoxy; carboxy; (C1-C6)alkoxycarbonyl; (C1-C6)carbocyalkyl; (C1-C6)alkoxycarbonylalkyl having independently the stated number of carbon atoms in each alkyl group; \u2014CONRaRb; amino; (C1-C6)alkylamino; (C1-C6)dialkylamino having independently the stated number of carbon atoms in each alkyl group; haloalkyl; \u2014CH\u2550N\u2014NHC(O)NRaRb; or \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb; or
(c) 5-benzimidazolyl; 1-trityl-5-benzimidazolyl; 3-trityl-5-benzimidazolyl; 1H-indazole-3-yl; 1-trityl-1H-indazole-3-yl; or 1-(C1-C6)alkyl-1H-indole-2-yl;
E is unsubstituted or substituted (C4-C10) branched alkyl wherein the substituents are independently 1-4 cyano; halo; (C5-C6)cycloalkyl; phenyl; (C2-C3)alkenyl; hydroxy, (C1-C6)alkoxy; carboxy; (C1-C6)alkoxycarbonyl; formyl; (C1-C6)trialkylsilyloxy having independently the stated number of carbon atoms in each alkyl group; \u2014CH\u2550N\u2014ORa; \u2014CH\u2550N\u2014Rd; \u2014CH\u2550N\u2014NHC(O)NRaRb; or \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb;
wherein Ra, Rb, and Rc are independently H, (C1-C6)alkyl, or phenyl; Rd is hydroxy(C1-C6)alkyl;
and n=1-4; and
G is H or CN;
provided that:
1) when E is unsubstituted or substituted (C4-C10) branched alkyl wherein the substituents are independently 1-4 cyano; halo; (C2-C3)alkenyl; carboxy; or (C1-C6)alkoxycarbonyl;
then B is:
(a) substituted phenyl which bears at least one \u2014CH\u2550N\u2014NHC(O)NRaRb or \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb group;
(b) substituted 6-membered heterocycle having 1-3 nitrogen atoms and 3-5 nuclear carbon atoms which bears at least one haloalkyl group; or
(c) 5-benzimidazolyl; 1-trityl-5-benzimidazolyl; 3-trityl-5-benzimidazolyl; 1H-indazole-3-yl; 1-trityl-1H-indazole-3-yl; or 1-(C1-C6)alkyl-1H-indole-2-yl;
2) when E is a substituted (C4-C10) branched alkyl which bears at least one of phenyl; hydroxy; (C1-C6)alkoxy; or formyl;
then B is:
(a) substituted phenyl which bears at least one \u2014CH\u2550N\u2014NHC(O)NRaRb or \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb group;
(b) substituted or unsubstituted 6-membered heterocycle having 1-3 nitrogen atoms and 3-5 nuclear carbon atoms; or
(c) 5-benzimidazolyl; 1-trityl-5-benzimidazolyl; 3-trityl-5-benzimidazolyl; 1H-indazole-3-yl; 1-trityl-1H-indazole-3-yl; or 1-(C1-C6)alkyl-1H-indole-2-yl.
9. The method of claim 8, wherein the ecdysone receptor complex is a chimeric ecdysone receptor complex and the DNA construct further comprises a promoter.
10. The method of claim 8, wherein the subject is a plant.
11. The method of claim 8, wherein the subject is a mammal.
12. 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 compound of the formula:
wherein X and X\u2032 are independently O or S;
A is unsubstituted or substituted phenyl wherein the substituents are independently 1 to 5H; halo; nitro; cyano; hydroxy; amino (\u2014NRaRb); alkylaminoalkyl (\u2014(CH2)nNRaRb); (C1-C6)alkyl; (C1-C6)haloalkyl; (C1-C6)cyanoalkyl; (C1-C6)hydroxyalkyl; (C1-C6)alkoxy; phenoxy; (C1-C6)haloalkoxy; (C1-C6)alkoxy(C1-C6)alkyl; (C1-C6)alkenyloxy(C1-C6)alkyl; (C1-C6)alkoxy(C1-C6)alkoxy; (C1-C6)alkanoyloxy(C1-C6)alkyl; (C2-C6)alkenyl optionally substituted with halo, cyano, (C1-C4)alkyl, or (C1-C4)alkoxy; (C2-C6)alkynyl optionally substituted with halo or (C1-C4)alkyl; formyl; carboxy; (C1-C6)alkylcarbonyl; (C1-C6)haloalkylcarbonyl; benzoyl; (C1-C6)alkoxycarbonyl; (C1-C6)haloalkoxycarbonyl; (C1-C6)alkanoyloxy (\u2014OCORa); carboxamido (\u2014CONRaRb); amido (\u2014NRaCORb); alkoxycarbonylamino (\u2014NRaCO2Rb); alkylaminocarbonylamino (\u2014NRaCONRbRc); mercapto; (C1-C6)alkylthio; (C1-C6)alkylsulfonyl; (C1-C6)alkylsulfonyl(C1-C6)alkyl; (C1-C6)alkylsulfoxido (\u2014S(O)Ra); (C1-C6)alkylsulfoxido(C1-C6)alkyl \u2014(CH2)nS(O)Ra); sulfamido (\u2014SO2NRaRb); \u2014SO3H; or unsubstituted or substituted phenyl wherein the substituents are independently 1 to 3 halo, nitro, (C1-C6)alkoxy, (C1-C6)alkyl, or amino; or when one or both of two adjacent positions on the phenyl ring are substituted, the attached atoms may form the phenyl-connecting termini of a linkage selected from the group consisting of (\u2014OCH2O\u2014), (\u2014OCH(CH3)O\u2014), (\u2014OCH2CH2O\u2014), (\u2014OCH(CH3)CH2O\u2014), (\u2014S\u2014CH\u2550N\u2014), (\u2014CH2OCH2O\u2014), (\u2014O(CH2)3\u2014), (\u2550N\u2014O\u2014N\u2550), (\u2014CH\u2550CH\u2014NH\u2014), (\u2014OCF2O\u2014), (\u2014NH\u2014CH\u2550N\u2014), (\u2014CH2CH2O\u2014), and (\u2014(CH2)4\u2014);
B is:
(a) unsubstituted or substituted phenyl wherein the substituents are independently 1 to 5H; halo; nitro; cyano; hydroxy; amino (\u2014NRaRb); alkylaminoalkyl (\u2014(CH2)nNRaRb); (C1-C6)alkyl; (C1-C6)haloalkyl; (C1-C6)cyanoalkyl; (C1-C6)hydroxyalkyl; (C1-C6)alkoxy; phenoxy; (C1-C6)haloalkoxy; (C1-C6)alkoxy(C1-C6)alkyl; (C1-C6)alkenyloxy(C1-C6)alkyl; (C1-C6)alkoxy(C1-C6)alkoxy; (C1-C6)alkanoyloxy(C1-C6)alkyl; (C2-C6)alkenyl optionally substituted with halo, cyano, (C1-C4)alkyl, or (C1-C4)alkoxy; (C2-C6)alkynyl optionally substituted with halo or (C1-C4)alkyl; formyl; carboxy; (C1-C6)alkylcarbonyl; (C1-C6)haloalkylcarbonyl; benzoyl; (C1-C6)alkoxycarbonyl; (C1-C6)haloalkoxycarbonyl; (C1-C6)alkanoyloxy (\u2014OCORa); carboxamido (\u2014CONRaRb); amido (\u2014NRaCORb); alkoxycarbonylamino (\u2014NRaCO2Rb); alkylaminocarbonylamino (\u2014NRaCONRbRc); mercapto; (C1-C6)alkylthio; (C1-C6)alkylsulfonyl; (C1-C6)alkylsulfonyl(C1-C6)alkyl; (C1-C6)alkylsulfoxido (\u2014S(O)Ra); (C1-C6)alkylsulfoxido(C1-C6)alkyl (\u2014CH2)nS(O)Ra); sulfamido (\u2014SO2NRaRb); \u2014SO3H; \u2014CH\u2550N\u2014NHC(O)NRaRb; \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb; or unsubstituted or substituted phenyl wherein the substituents are independently 1 to 3 halo, nitro, (C1-C6)alkoxy, (C1-C6)alkyl, or amino; or when one or both of two adjacent positions on the phenyl ring are substituted with C, N, O, or S, these atoms may form the phenyl-connecting termini of a linkage selected from the group consisting of (\u2014OCH2O\u2014), (\u2014OCH(CH3)O\u2014), (\u2014OCH2CH2O\u2014), (\u2014OCH(CH3)CH2O\u2014), (\u2014S\u2014CH\u2550N\u2014), (\u2014CH2OCH2O\u2014), (\u2014O(CH2)3\u2014), (\u2550N\u2014O\u2014N\u2550), (\u2014CH\u2550CH\u2014NH\u2014), (\u2014OCF2O\u2014), (\u2014NH\u2014CH\u2550N\u2014), (\u2014CH2CH2O\u2014), and (\u2014(CH2)4\u2014);
(b) unsubstituted 6-membered heterocycle or substituted 6-membered heterocycle having 1-3 nitrogen atoms and 3-5 nuclear carbon atoms where the substituents are from one to three of the same or different halo; nitro; hydroxy; (C1-C6)alkyl; (C1-C6)alkoxy; (C1-C6)thioalkoxy; carboxy; (C1-C6)alkoxycarbonyl; (C1-C6)carbocyalkyl; (C1-C6)alkoxycarbonylalkyl having independently the stated number of carbon atoms in each alkyl group; \u2014CONRaRb; amino; (C1-C6)alkylamino; (C1-C6)dialkylamino having independently the stated number of carbon atoms in each alkyl group; haloalkyl; \u2014CH\u2550N\u2014NHC(O)NRaRb; or \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb; or
(c) 5-benzimidazolyl; 1-trityl-5-benzimidazolyl; 3-trityl-5-benzimidazolyl; 1H-indazole-3-yl; 1-trityl-1H-indazole-3-yl; or 1-(C1-C6)alkyl-1H-indole-2-yl;
E is unsubstituted or substituted (C4-C10) branched alkyl wherein the substituents are independently 1-4 cyano; halo; (C5-C6)cycloalkyl; phenyl; (C2-C3)alkenyl; hydroxy, (C1-C6)alkoxy; carboxy; (C1-C6)alkoxycarbonyl; formyl; (C1-C6)trialkylsilyloxy having independently the stated number of carbon atoms in each alkyl group; \u2014CH\u2550N\u2014ORa; \u2014CH\u2550N\u2014Rd; \u2014CH\u25a1N\u2014NHC(O)NRaRb; or \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb;
wherein Ra, Rb, and Rc are independently H, (C1-C6)alkyl, or phenyl; Rd is hydroxy(C1-C6)alkyl; and n=1-4; and
G is H or CN;
provided that:
1) when E is unsubstituted or substituted (C4-C10) branched alkyl wherein the substituents are independently 1-4 cyano; halo; (C2-C3)alkenyl; carboxy; or (C1-C6)alkoxycarbonyl;
then B is:
(a) substituted phenyl which bears at least one \u2014CH\u2550N\u2014NHC(O)NRaRb or \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb group;
(b) substituted 6-membered heterocycle having 1-3 nitrogen atoms and 3-5 nuclear carbon atoms which bears at least one haloalkyl group; or
(c) 5-benzimidazolyl; 1-trityl-5-benzimidazolyl; 3-trityl-5-benzimidazolyl; 1H-indazole-3-yl; 1-trityl-1H-indazole-3-yl; or 1-(C1-C6)alkyl-1H-indole-2-yl;
2) when E is a substituted (C4-C10) branched alkyl which bears at least one of phenyl; hydroxy; (C1-C6)alkoxy; or formyl;
then B is:
(a) substituted phenyl which bears at least one \u2014CH\u2550N\u2014NHC(O)NRaRb or \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb group;
(b) substituted or unsubstituted 6-membered heterocycle having 1-3 nitrogen atoms and 3-5 nuclear carbon atoms; or
(c) 5-benzimidazolyl; 1-trityl-5-benzimidazolyl; 3-trityl-5-benzimidazolyl; 1H-indazole-3-yl; 1-trityl-1H-indazole-3-yl; or 1-(C1-C6)alkyl-1H-indole-2-yl.
13. A method for producing a polypeptide comprising the steps of:
a) selecting a cell which is substantially insensitive to exposure to
a compound of the formula:
wherein X and X\u2032 are independently O or S;
A is unsubstituted or substituted phenyl wherein the substituents are independently 1 to 5H; halo; nitro; cyano; hydroxy; amino (\u2014NRaRb); alkylaminoalkyl (\u2014(CH2)nNRaRb); (C1-C6)alkyl; (C1-C6)haloalkyl; (C1-C6)cyanoalkyl; (C1-C6)hydroxyalkyl; (C1-C6)alkoxy; phenoxy; (C1-C6)haloalkoxy; (C1-C6)alkoxy(C1-C6)alkyl; (C1-C6)alkenyloxy(C1-C6)alkyl; (C1-C6)alkoxy(C1-C6)alkoxy; (C1-C6)alkanoyloxy(C1-C6)alkyl; (C2-C6)alkenyl optionally substituted with halo, cyano, (C1-C4)alkyl, or (C1-C4)alkoxy; (C2-C6)alkynyl optionally substituted with halo or (C1-C4)alkyl; formyl; carboxy; (C1-C6)alkylcarbonyl; (C1-C6)haloalkylcarbonyl; benzoyl; (C1-C6)alkoxycarbonyl; (C1-C6)haloalkoxycarbonyl; (C1-C6)alkanoyloxy (\u2014OCORa); carboxamido (\u2014CONRaRb); amido (\u2014NRaCORb); alkoxycarbonylamino (\u2014NRaCO2Rb); alkylaminocarbonylamino (\u2014NRaCONRbRc); mercapto; (C1-C6)alkylthio; (C1-C6)alkylsulfonyl; (C1-C6)alkylsulfonyl(C1-C6)alkyl; (C1-C6)alkylsulfoxido (\u2014S(O)Ra); (C1-C6)alkylsulfoxido(C1-C6)alkyl \u2014(CH2)S(O)Ra); sulfamido (\u2014SO2NRaRb); \u2014SO3H; or unsubstituted or substituted phenyl wherein the substituents are independently 1 to 3 halo, nitro, (C1-C6)alkoxy, (C1-C6)alkyl, or amino; or when one or both of two adjacent positions on the phenyl ring are substituted, the attached atoms may form the phenyl-connecting termini of a linkage selected from the group consisting of (\u2014OCH2O\u2014), (\u2014OCH(CH3)O\u2014), (\u2014OCH2CH2O\u2014), (\u2014OCH(CH3)CH2O\u2014), (\u2014S\u2014CH\u2550N\u2014), (\u2014CH2OCH2O\u2014), (\u2014O(CH2)3\u2014), (\u2550N\u2014O\u2014N\u2550), (\u2014CH\u2550CH\u2014NH\u2014), (\u2014OCF2O\u2014), (\u2014NH\u2014CH\u2550N\u2014), (\u2014CH2CH2O\u2014), and (\u2014(CH2)4\u2014);
B is:
(a) unsubstituted or substituted phenyl wherein the substituents are independently 1 to 5H; halo; nitro; cyano; hydroxy; amino (\u2014NRaRb); alkylaminoalkyl (\u2014(CH2)nNRaRb); (C1-C6)alkyl; (C1-C6)haloalkyl; (C1-C6)cyanoalkyl; (C1-C6)hydroxyalkyl; (C1-C6)alkoxy; phenoxy; (C1-C6)haloalkoxy; (C1-C6)alkoxy(C1-C6)alkyl; (C1-C6)alkenyloxy(C1-C6)alkyl; (C1-C6)alkoxy(C1-C6)alkoxy; (C1-C6)alkanoyloxy(C1-C6)alkyl; (C2-C6)alkenyl optionally substituted with halo, cyano, (C1-C4)alkyl, or (C1-C4)alkoxy; (C2-C6)alkynyl optionally substituted with halo or (C1-C4)alkyl; formyl; carboxy; (C1-C6)alkylcarbonyl; (C1-C6)haloalkylcarbonyl; benzoyl; (C1-C6)alkoxycarbonyl; (C1-C6)haloalkoxycarbonyl; (C1-C6)alkanoyloxy (\u2014OCORa); carboxamido (\u2014CONRaRb); amido (\u2014NRaCORb); alkoxycarbonylamino (\u2014NRaCO2Rb); alkylaminocarbonylamino (\u2014NRaCONRbRc); mercapto; (C1-C6)alkylthio; (C1-C6)alkylsulfonyl; (C1-C6)alkylsulfonyl(C1-C6)alkyl; (C1-C6)alkylsulfoxido (\u2014S(O)Ra); (C1-C6)alkylsulfoxido(C1-C6)alkyl (\u2014CH2)nS(O)Ra); sulfamido (\u2014SO2NRaRb); \u2014SO3H; \u2014CH\u2550N\u2014NHC(O)NRaRb; \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb; or unsubstituted or substituted phenyl wherein the substituents are independently 1 to 3 halo, nitro, (C1-C6)alkoxy, (C1-C6)alkyl, or amino; or when one or both of two adjacent positions on the phenyl ring are substituted with C, N, O, or S, these atoms may form the phenyl-connecting termini of a linkage selected from the group consisting of (\u2014OCH2O\u2014), (\u2014OCH(CH3)O\u2014), (\u2014OCH2CH2O\u2014), (\u2014OCH(CH3)CH2O\u2014), (\u2014S\u2014CH\u2550N\u2014), (\u2014CH2OCH2O\u2014), (\u2014O(CH2)3\u2014), (\u2550N\u2014O\u2014N\u2550), (\u2014CH\u2550CH\u2014NH\u2014), (\u2014OCF2O\u2014), (\u2014NH\u2014CH\u2550N\u2014), (\u2014CH2CH2O\u2014), and (\u2014(CH2)4\u2014);
(b) unsubstituted 6-membered heterocycle or substituted 6-membered heterocycle having 1-3 nitrogen atoms and 3-5 nuclear carbon atoms where the substituents are from one to three of the same or different halo; nitro; hydroxy; (C1-C6)alkyl; (C1-C6)alkoxy; (C1-C6)thioalkoxy; carboxy; (C1-C6)alkoxycarbonyl; (C1-C6)carbocyalkyl; (C1-C6)alkoxycarbonylalkyl having independently the stated number of carbon atoms in each alkyl group; \u2014CONRaRb; amino; (C1-C6)alkylamino; (C1-C6)dialkylamino having independently the stated number of carbon atoms in each alkyl group; haloalkyl \u2014CH\u2550N\u2014NHC(O)NRaRb; or \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb; or
(c) 5-benzimidazolyl; 1-trityl-5-benzimidazolyl; 3-trityl-5-benzimidazolyl; 1H-indazole-3-yl; 1-trityl-1H-indazole-3-yl; or 1-(C1-C6)alkyl-1H-indole-2-yl;
E is unsubstituted or substituted (C4-C10) branched alkyl wherein the substituents are independently 1-4 cyano; halo; (C5-C6)cycloalkyl; phenyl; (C2-C3)alkenyl; hydroxy, (C1-C6)alkoxy; carboxy; (C1-C6)alkoxycarbonyl; formyl; (C1-C6)trialkylsilyloxy having independently the stated number of carbon atoms in each alkyl group; \u2014CH\u2550N\u2014ORa; \u2014CH\u2550N\u2014Rd; \u2014CH\u2550N\u2014NHC(O)NRaRb; or \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb;
wherein Ra, Rb, and Rc are independently H, (C1-C6)alkyl, or phenyl; Rd is hydroxy(C1-C6)alkyl;
and n=1-4; and
G is H or CN;
provided that:
1) when E is unsubstituted or substituted (C4-C10) branched alkyl wherein the substituents are independently 1-4 cyano; halo; (C7-C3)alkenyl; carboxy; or (C1-C6)alkoxycarbonyl;
then B is:
(a) substituted phenyl which bears at least one \u2014CH\u2550N\u2014NHC(O)NRaRb or \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb group;
(b) substituted 6-membered heterocycle having 1-3 nitrogen atoms and 3-5 nuclear carbon atoms which bears at least one haloalkyl group; or
(c) 5-benzimidazolyl; 1-trityl-5-benzimidazolyl; 3-trityl-5-benzimidazolyl; 1H-indazole-3-yl; 1-trityl-1H-indazole-3-yl; or 1-(C1-C6)alkyl-1H-indole-2-yl;
2) when E is a substituted (C4-C10) branched alkyl which bears at least one of phenyl; hydroxy; (C1-C6)alkoxy; or formyl;
then B is:
(a) substituted phenyl which bears at least one \u2014CH\u2550N\u2014NHC(O)NRaRb or \u2014CH\u2550N\u2014NHC(O)C(O)NRaRb group;
(b) substituted or unsubstituted 6-membered heterocycle having 1-3 nitrogen atoms and 3-5 nuclear carbon atoms; or
(c) 5-benzimidazolyl; 1-trityl-5-benzimidazolyl; 3-trityl-5-benzimidazolyl; 1H-indazole-3-yl; 1-trityl-1H-indazole-3-yl; or 1-(C1-C6)alkyl-1H-indole-2-yl;
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.
14. A process for the preparation of a compound of formula (IV) comprising the steps of:
i reacting a compound of formula (I) with a base selected from NaH, KH, or an amide MNRaRb to produce a product II, wherein M is Li, Na, or K, and Ra and Rb are independently (C1-C6)alkyl or phenyl; and
ii reacting the product (II) of step (i) with a compound of formula (III) wherein R is phenyl substituted with three to five of the same or different chloro, fluoro, or trifluoromethyl;
wherein
A and B are independently
(a) unsubstituted or substituted phenyl wherein the substituents are independently 1 to 5H; halo; nitro; cyano; amino (\u2014NRaRb); alkylaminoalkyl (\u2014(CH2)nNRaRb); (C1-C6)alkyl; (C1-C6)haloalkyl; (C1-C6)cyanoalkyl; (C1-C6)alkoxy; phenoxy; (C1-C6)haloalkoxy; (C1-C6)alkoxy(C1-C6)alkyl; (C1-C6)alkenyloxy(C1-C6)alkyl; (C1-C6)alkoxy(C1-C6)alkoxy; (C2-C6)alkenyl optionally substituted with halo, cyano, (C1-C4)alkyl, or (C1-C4)alkoxy; (C2-C6)alkynyl optionally substituted with halo or (C1-C4)alkyl; formyl; (C1-C6)haloalkylcarbonyl; benzoyl; (C1-C6)alkoxycarbonyl; (C1-C6)haloalkoxycarbonyl; (C1-C6)alkanoyloxy (\u2014OCORa); carboxamido (\u2014CONRaRb); amido (\u2014NRaCORb); alkoxycarbonylamino (\u2014N(CH2)nCO2Rb); alkylaminocarbonylamino (\u2014N(CH2)nCONRbRc); (C1-C6)alkylthio; sulfamido (\u2014SO2NRaRb); or unsubstituted or substituted phenyl wherein the substituents are independently 1 to 3 halo, nitro, (C1-C6)alkoxy, (C1-C6)alkyl, or (\u2014NRaRb); or when one or both of two adjacent positions on the phenyl ring are substituted, the attached atoms may form the phenyl-connecting termini of a linkage selected from the group consisting of (\u2014OCH2O\u2014), (\u2014OCH(CH3)O\u2014), (\u2014OCH2CH2O\u2014), (\u2014OCH(CH3)CH2O\u2014), (\u2014S\u2014CH\u2550N\u2014), (\u2014CH2OCH2O\u2014), (\u2014O(CH2)3\u2014), (\u2550N\u2014O\u2014N\u2550), (\u2014CH\u2550CH\u2014NH\u2014), (\u2014OCF2O\u2014), (\u2014NH\u2014CH\u2550N\u2014), (\u2014CH2CH2O\u2014), and (\u2014(CH2)4\u2014); or
(b) unsubstituted 5- or 6-membered heterocycle or substituted 5 or 6-membered heterocycle having 1-3 nitrogen atoms where the substituents are from one to four of the same or different halo; nitro; (C1-C6)alkyl; (C1-C6)alkeyl; (C1-C6)alkoxy; (C1-C6)thioalkoxy; (C1-C6)alkoxycarbonyl; (C1-C6)carbocyalkyl; \u2014CONRaRb; amino(\u2014NRaRb); haloalkyl including CF3; -trialkylsilyl (\u2014SiRaRbRc); trityl(C(Ph)3); or unsubstituted or substituted phenyl wherein the substituents are independently 1 to 3 halo, nitro, (C1-C6)alkoxy, (C1-C6)alkyl, or (\u2014NRaRb); or when two adjacent positions are substituted, these positions may form a benzo ring fusion; and
E is phenyl, or unsubstituted or substituted (C1-C10) straight or branched alkyl wherein the substituents are independently 1-4 cyano; halo; (C5-C6)cycloalkyl; phenyl; (C2-C3)alkenyl; (C1-C6)alkoxy; (C1-C6)alkoxycarbonyl; (C1-C6)alkanoyloxy (\u2014OCORa); formyl; (C1-C6)trialkylsilyloxy having independently the stated number of carbon atoms in each alkyl group; or \u2014CH\u2550N\u2014ORa;
wherein Ra, Rb, and Re are independently (C1-C6)alkyl or phenyl, and n=1-4.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A battery, comprising:
a nickel cathode;
an iron anode comprising an iron active material that is metal iron or an iron oxide material and a binder; and
an electrolyte comprising 6 to 7.5 M sodium hydroxide, 0.5 to 2.0 M lithium hydroxide, and 1-2 wt % sodium sulfide based on the weight of the electrolyte,
with the battery exhibiting a cycle life of at least about 10,000 cycles.
2. The battery of claim 1, further comprising a polyolefin battery separator.
3. The battery of claim 1, which is a sealed battery.
4. The battery of claim 1, wherein the iron anode is comprised of a single layer of a conductive substrate coated on at least one side with a coating comprising the iron active material and the binder.
5. The battery of claim 4, wherein the substrate is coated on both sides.
6. The battery of claim 1, further exhibiting a specific energy of at least about 105 watt hourskg.
7. The battery of claim 1, further exhibiting an energy density of at least about 183 watt hoursliter.
8. The battery of claim 1, further exhibiting a specific power of at least about 2100 wattskg.
9. The battery of claim 1, further exhibiting a power density of at least about 3660 wattsliter.
10. The battery of claim 1, further exhibiting a watt hour efficiency of at least about 95%.
11. The battery of claim 1, further exhibiting a charge retention, measured as capacity at 28 days 20\xb0 C., of at least about 95%.
12. The battery of claim 1, exhibiting
a specific energy of at least about 105 watt hourskg;
an energy density of at least about 183 watt hoursliter;
a watt hour efficiency of at least about 95%; and
a charge retention of at least about 95%.
13. The battery of claim 1, wherein the binder is a polyvinyl alcohol binder.
14. A battery, comprising:
a nickel cathode;
an iron anode comprising an iron active material that is metal iron or an iron oxide material and a binder; and
an electrolyte comprising sodium hydroxide, lithium hydroxide, and a concentration of 0.23 wt % to 0.75 wt % sulfide based on the weight of the electrolyte,
with the battery exhibiting a cycle life of at least about 10,000 cycles.
15. The battery of claim 14, wherein electrolyte comprises sodium sulfide.
16. The battery of claim 14, wherein the binder is a polyvinyl alcohol binder.