Methods of treating hormone-related conditions using thio-oxindole derivatives

A method of inducing contraception comprising the step of delivering to a female of child-bearing age a composition comprising a compound of formula II, or a tautomer thereof, in a regimen which involves delivering a pharmaceutically effective amount of one or more of a selective estrogen receptor modulator to said female, wherein formula II is:

• 41
• wherein:
• R11 is selected from the group consisting of H, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl;
• R5 is (i), (ii), or (iii):
• (i) a substituted benzene ring having the structure:
• 42
• wherein:
• X is selected from the group consisting of halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CON(alkyl)2, CSN(alkyl)2, CNHNHOH, CNH2NOH, C1 to C3 alkoxy, C1 to C3 alkyl, NO2, C to C3 perfluoroalkyl, 5 membered heterocyclic ring having 1 to 3 heteroatoms, and C1 to C3 thioalkyl;
• Y is selected from the group consisting of H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, and C1 to C3 thioalkyl;
• (ii) a five membered ring having the structure:
• 43
• wherein:
• U is O, S, or NR6;
• R6 is H, C1 to C3 alkyl, or C1 to C4 CO2alkyl;
• X′ is selected from the group consisting of halogen, CN, NO2, CONH2, CNHNHOH, CNH2NOH, CSNH2, CONHalkyl, CSNHalkyl, CON(alkyl)2, CSN(alkyl)2, C1 to C3 alkyl, and C1 to C3 alkoxy;
• Y′ is selected from the group consisting of H, F, and C1 to C4 alkyl;
• or
• (iii) a six membered ring having the structure:
• 44
• wherein:
• X1 is N or CX2;
• X2 is halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CON(alkyl)2, CSN(alkyl)2 or NO2;
• or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.

A method of inducing contraception comprising the step of delivering to a female of child-bearing age a composition comprising a compound of formula III in a regimen which involves delivering a pharmaceutically effective amount of one or more of a selective estrogen receptor modulator to said female, wherein formula III is:

• 45
• wherein:
• R5 is (i), (ii), or (iii):
• (i) a substituted benzene ring having the structure:
• 46
• wherein:
• X is selected from the group consisting of halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CON(alkyl)2, CSN(alkyl)2, CNHNOH, C1 to C3 alkoxy, C1 to C3 alkyl, NO2, C1 to C3 perfluoroalkyl, 5 membered heterocyclic ring having 1 to 3 heteroatoms, and C1 to C3 thioalkyl;
• Y is selected from the group consisting of H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, and C1 to C3 thioalkyl;
• (ii) a five membered ring having the structure:
• 47
• wherein:
• U is O, S, or NR6;
• R6 is H, C1 to C3 alkyl, or C1 to C4 CO2alkyl;
• X′ is selected from the group consisting of halogen, CN, NO2, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CON(alkyl)2, CSN(alkyl)2, C1 to C3 alkyl, and C1 to C3 alkoxy;
• Y′ is selected from the group consisting of H, F and C1 to C4 alkyl;
• or
• (iii) a six membered ring having the structure:
• 48
• wherein:
• X1 is N or CX2;
• X2 is halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CON(alkyl)2, CSN(alkyl)2 or NO2;
• or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.

A method of inducing contraception comprising the step of delivering to a female of child-bearing age a composition comprising a compound of formula IV in a regimen which involves delivering a pharmaceutically effective amount of one or more of a selective estrogen receptor modulator to said female, wherein formula IV is:

• 49
• wherein:
• R8 is selected from the group consisting of H, CO2R10, acyl, substituted acyl, aroyl, substituted aroyl, alkyl, substituted alkyl, and CN;
• R10 is C1 to C3 alkyl;
• R5 is (i), (ii), or (iii):
• (i) a substituted benzene ring having the structure:
• 50
• wherein:
• X is selected from the group consisting of halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CON(alkyl)2, CSN(alkyl)2, CNHNOH, C1 to C3 alkoxy, C1 to C3 alkyl, NO2, C1 to C3 perfluoroalkyl, 5 membered heterocyclic ring having 1 to 3 heteroatoms, and C1 to C3 thioalkyl;
• Y is selected from the group consisting of H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, and C1 to C3 thioalkyl;
• (ii) a five membered ring having the structure:
• 51
• wherein:
• U is O, S, or NR6;
• R6 is H, C1 to C3 alkyl, or C1 to C4 C0-2alkyl;
• X′ is selected from the group consisting of halogen, CN, NO2, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CON(alkyl)2, CSN(alkyl)2, C1 to C3 alkyl, and C1 to C3 alkoxy;
• Y′ is selected from the group consisting of H, F and C1 to C4 alkyl;
• (iii) a six membered ring having the structure:
• 52
• wherein:
• X1 is Nor CX2;
• X2 is halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CON(alkyl)2, CSN(alkyl)2 or NO2;
• or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.

A method of inducing contraception comprising the step of delivering to a female of child-bearing age a composition comprising a compound of formula V in a regimen which involves delivering a pharmaceutically effective amount of one or more of a selective estrogen receptor modulator to said female, wherein formula V is:

• 53
• R5 is (i), (ii), or (iii):
• (i) a substituted benzene ring having the structure:
• 54
• wherein:
• X is selected from the group consisting of halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CON(alkyl)2, CSN(alkyl)2 CNHNOH, C1 to C3 alkoxy, C1 to C3 alkyl, NO2, C1 to C3 perfluoroalkyl, 5 membered heterocyclic ring having 1 to 3 heteroatoms, and C1 to C3 thioalkyl;
• Y is selected from the group consisting of H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, and C1 to C3 thioalkyl;
• (ii) a five membered ring having the structure:
• 55
• wherein:
• U is O, S, or NR6;
• R6 is H, C1 to C3 alkyl, or C1 to C4 CO2alkyl;
• X′ is selected from the group consisting of halogen, CN, NO2, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CON(alkyl)2, CSN(alkyl)2, C1 to C3 alkyl, and C1 to C3 alkoxy;
• Y′ is selected from the group consisting of H, F, and C1 to C4 alkyl;
• (iii) a six membered ring having the structure:
• 56
• wherein:
• X1 is N or CX2;
• X2 is halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CON(alkyl)2, CSN(alkyl)2 or NO2;
• or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.

A method of providing hormone replacement therapy comprising the step of delivering to a female a composition comprising a compound of formula I, or a tautomer thereof, in a regimen which involves delivering a pharmaceutically effective amount of one or more of a selective estrogen receptor modulator to said female, wherein formula I is:

• 57
• wherein:
• R1 and R2 are selected from the group consisting of H, alkyl, substituted alkyl, OH, O(alkyl), O(substituted alkyl), O(Acetyl), aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, alkylaryl, substituted alkylaryl, alkylheteroaryl, substituted alkylheteroaryl, 1-propynyl, substituted 1-propynyl, 3-propynyl, and substituted 3-propynyl;
• or R1 and R2 are joined to form a ring selected from the group consisting of —CH2(CH2)nCH2—, —CH2CH2C(CH3)2CH2CH2—, —O(CH2)mCH2—, —O(CH2)pO—, —CH2CH2OCH2CH2—, —CH2CH2N(H)CH2CH2—, and —CH2CH2N(alkyl)CH2CH2—;
• m is an integer from 1 to 4;
• n is an integer from 1 to 5;
• p is an integer from 1 to 4;
• or R1 and R2 form a double bond to C(CH3)2, C(cycloalkyl), O, or C(cycloether);
• R3 is selected from the group consisting of H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C3 to C6 alkenyl, alkynyl, substituted alkynyl, and CORA;
• RA is selected from the group consisting of H, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, and substituted C1 to C3 aminoalkyl;
• R4 is selected from the group consisting of H, halogen, CN, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, and substituted C1 to C6 aminoalkyl;
• R5 is selected from the group consisting of a), b) and c):
• a) a substituted benzene ring having the structure:
• 58
• X is selected from the group consisting of halogen, OH, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 thioalkyl, substituted C1 to C3 thioalkyl, S(O)alkyl, S(O)2alkyl, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, substituted C1 to C3 perfluoroalkyl, 5 or 6 membered heterocyclic ring having 1 to 3 heteroatoms, CONH2, CSNH2, CNHNHOH, CNH2NOH, CNHNOH, CORB, CSRB, OCORB, and NRCCORB;
• RB is selected from the group consisting of H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, and substituted C1 to C3 aminoalkyl;
• RC is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
• Y and Z are independently selected from the group consisting of H, halogen, CN, NO2, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C4 alkyl, substituted C1 to C4 alkyl, C1 to C3 thioalkyl, and substituted C1 to C3 thioalkyl;
• b) a five or six membered heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6 and having one or two independent substituents from the group consisting of H, halogen, CN, NO2, C1 to C4 alkyl, substituted C1 to C4 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, CORD, CSRD, and NRECORD;
• RD is H, NH2, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
• RE is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
• R6 is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, or C1 to C4CO2alkyl;
• or
• c) an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, wherein said moiety is optionally substituted by from 1 to 3 substituents selected from the group consisting of halogen, alkyl, substituted alkyl, CN, NO2, alkoxy, substituted alkoxy, and CF3;
• Q1 is S, NR7, or CR8R9;
• R7 is selected from the group consisting of CN, C1 to C6 alkyl, substituted C, to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, SO2CF3, OR11, and NR11R12;
• R8 and R9 are independent substituents selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, NO2, CN, and CO2R10;
• R10 is C1 to C3 alkyl or substituted C1 to C3 alkyl;
• or CR8R9 comprise a six membered ring having the structure:
• 59
• R11 and R12 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl;
• or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.

A method of treating carcinomas comprising the step of delivering to a mammal in need thereof a composition comprising a compound of formula I, or a tautomer thereof, in a regimen which involves delivering a pharmaceutically effective amount of one or more of a selective estrogen receptor modulator to said mammal, wherein formula I is:

• 60
• wherein:
• R1 and R2 are selected from the group consisting of H, alkyl, substituted alkyl, OH, O(alkyl), O(substituted alkyl), O(Acetyl), aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, alkylaryl, substituted alkylaryl, alkylheteroaryl, substituted alkylheteroaryl, 1-propynyl, substituted 1-propynyl, 3-propynyl, and substituted 3-propynyl;
• or R1 and R2 are joined to form a ring selected from the group consisting of —CH2(CH2)nCH2—, —CH2CH2C(CH3)2CH2CH2—, O(CH2)mCH2—, —O(CH2)pO—, —CH2CH2OCH2CH2—, —CH2CH2N(H)CH2CH2—, and —CH2CH2N(alkyl)CH2CH2—;
• m is an integer from 1 to 4;
• n is an integer from 1 to 5;
• p is an integer from 1 to 4;
• or R1 and R2 form a double bond to C(CH3)2, C(cycloalkyl), O, or C(cycloether);
• R3 is selected from the group consisting of H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C3 to C6 alkenyl, alkynyl, substituted alkynyl, and CORA;
• RA is selected from the group consisting of H, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, and substituted C1 to C3 aminoalkyl;
• R4 is selected from the group consisting of H, halogen, CN, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, and substituted C1 to C6 aminoalkyl;
• R5 is selected from the group consisting of a), b) and c):
• a) a substituted benzene ring having the structure:
• 61
• X is selected from the group consisting of halogen, OH, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 thioalkyl, substituted C1 to C3 thioalkyl, S(O)alkyl, S(O)2alkyl, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, substituted C1 to C3 perfluoroalkyl, 5 or 6 membered heterocyclic ring having 1 to 3 heteroatoms, CONH2, CSNH2, CNHNHOH, CNH2NOH, CNHNOH, CORB, CSRB, OCORB, and NRCCORB;
• RB is selected from the group consisting of H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, and substituted C1 to C3 aminoalkyl;
• RC is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
• Y and Z are independently selected from the group consisting of H, halogen, CN, NO2, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C4 alkyl, substituted C1 to C4 alkyl, C1 to C3 thioalkyl, and substituted C1 to C3 thioalkyl;
• b) a five or six membered heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6 and having one or two independent substituents from the group consisting of H, halogen, CN, NO2, C1 to C4 alkyl, substituted C1 to C4 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, CORD, CSRD, and NRECORD;
• RD is H, NH2, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
• RE is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
• R6 is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, or C1 to C4CO2alkyl;
• or
• c) an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, wherein said moiety is optionally substituted by from 1 to 3 substituents selected from the group consisting of halogen, alkyl, substituted alkyl, CN, NO2, alkoxy, substituted alkoxy, and CF3;
• Q1 is S, NR7, or CR8R9;
• R7 is selected from the group consisting of CN, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, SO2CF3, OR11, and NR11R12;
• R8 and R9 are independent substituents selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, NO2, CN, and CO2R10;
• R10 is C1 to C3 alkyl or substituted C1 to C3 alkyl;
• or CR8R9 comprise a six membered ring having the structure:
• 62
• R11 and R12 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl;
• or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.

A method of treating dysfunctional bleeding, uterine leiomyomata, endometriosis, and/or polycystic ovary syndrome, comprising the step of delivering to a female in need thereof a composition comprising a compound of formula I, or a tautomer thereof, in a regimen which involves delivering a pharmaceutically effective amount of one or more of a selective estrogen receptor modulator to said female, wherein formula I is:

• 63
• wherein:
• R1 and R2 are selected from the group consisting of H, alkyl, substituted alkyl, OH, O(alkyl), O(substituted alkyl), O(Acetyl), aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, alkylaryl, substituted alkylaryl, alkylheteroaryl, substituted alkylheteroaryl, 1-propynyl, substituted 1-propynyl, 3-propynyl, and substituted 3-propynyl;
• or R1 and R2 are joined to form a ring selected from the group consisting of —CH2(CH2)nCH2—, CH2CH2C(CH3)2CH2CH2—, O(CH2)mCH2—, —O(CH2)pO—, —CH2CH2OCH2CH2—, —CH2CH2N(H)CH2CH2—, and —CH2CH2N(alkyl)CH2CH2—;
• m is an integer from 1 to 4;
• n is an integer from 1 to 5;
• p is an integer from 1 to 4;
• or R1 and R2 form a double bond to C(CH3)2, C(cycloalkyl), O, or C(cycloether);
• R3 is selected from the group consisting of H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C3 to C6 alkenyl, alkynyl, substituted alkynyl, and CORA;
• RA is selected from the group consisting of H, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, and substituted C1 to C3 aminoalkyl;
• R4 is selected from the group consisting of H, halogen, CN, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, and substituted C1 to C6 aminoalkyl;
• R5 is selected from the group consisting of a), b) and c):
• a) a substituted benzene ring having the structure:
• 64
• X is selected from the group consisting of halogen, OH, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 thioalkyl, substituted C1 to C3 thioalkyl, S(O)alkyl, S(O)2alkyl, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, 5 or 6 membered heterocyclic ring having 1 to 3 heteroatoms, CONH2, CSNH2, CNHNHOH, CNH2NOH, CNHNOH, CORB, CSRB, OCORB, and NRCCORB;
• RB is selected from the group consisting of H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, and substituted C1 to C3 aminoalkyl;
• RC is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
• Y and Z are independently selected from the group consisting of H, halogen, CN, NO2, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C4 alkyl, substituted C1 to C4 alkyl, C1 to C3 thioalkyl, and substituted C1 to C3 thioalkyl;
• b) a five or six membered heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6 and having one or two independent substituents from the group consisting of H, halogen, CN, NO2, C1 to C4 alkyl, substituted C1 to C4 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, CORD, CSRD, and NRECORD;
• RD is H, NH2, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
• RE is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
• R6 is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, or C1 to C4CO2alkyl;
• or
• c) an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, wherein said moiety is optionally substituted by from 1 to 3 substituents selected from the group consisting of halogen, alkyl, substituted alkyl, CN, NO2, alkoxy, substituted alkoxy, and CF3;
• Q1 is S, NR7, or CR8R9;
• R7 is selected from the group consisting of CN, C1 to C6 alkyl, substituted C, to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, SO2CF3, OR11 and NR11R12;
• R8 and R9 are independent substituents selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, NO2, CN, and CO2R10;
• R10 is C1 to C3 alkyl or substituted C1 to C3 alkyl;
• or CR8R9 comprise a six membered ring having the structure:
• 65
• R11 and R12 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl;
• or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.