A method of treating dysfunctional bleeding, uterine leiomyomata, endometriosis, or polycystic ovary syndrome, comprising the step of delivering to a female in need thereof a composition comprising a compound of formula I or 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 I is:
- 31
- wherein:
- R1 and R2 are independent substituents selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, carbon-based heterocyclic ring having in its backbone 1 to 3 heteroatoms, substituted carbon-based heterocyclic ring having in its backbone 1 to 3 heteroatoms, CORA, and NRBCORA;
- or R1 and R2 are fused to form a ring selected from the group consisting of a), b) and c), wherein said ring is optionally substituted by from 1 to 3 substituents selected from the group consisting of H and C1 to C3 alkyl;
- a) a carbon-based 3 to 8 membered saturated spirocyclic ring;
- b) a carbon-based 3 to 8 membered spirocyclic ring having one or more carbon-carbon double bonds;
- and
- c) a 3 to 8 membered spirocyclic ring having in its backbone one to three heteroatoms selected from the group consisting of O, S and N;
- RA 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, amino, C1 to C3 aminoalkyl, and substituted C1 to C3 aminoalkyl;
- RB is selected from the group consisting of H, C1 to C3 alkyl, and substituted C1 to C3 alkyl;
- 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 CORC;
- RC is selected from the group consisting of H, C1 to C4 alkyl, substituted C1 to C4 alkyl, aryl, substituted aryl, C1 to C4 alkoxy, substituted C1 to C4 alkoxy, C1 to C4 aminoalkyl, and substituted C1 to C4 aminoalkyl;
- R4 is selected from the group consisting of H, halogen, CN, NO2, 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 (i) and (ii):
- (i) a substituted benzene ring having the structure:
- 32
- X is selected from the group consisting of halogen, 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, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, substituted C1 to C3 perfluoroalkyl, 5 or 6 membered carbon-based heterocyclic ring having in its backbone 1 to 3 heteroatoms, substituted 5 or 6 membered carbon-based heterocyclic ring having in its backbone 1 to 3 heteroatoms, CORD, OCORD, and NRECORD;
- RD 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;
- RE is selected from the group consisting of H, C1 to C3 alkyl, and substituted C1 to C3 alkyl;
- Y and Z are independent substituents 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;
- and
- b) a five or six membered carbon-based heterocyclic ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2, and NR6 and having one or two independent substituents selected 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, C1 to C3 perfluoroalkyl, substituted C1 to C3 perfluoroalkyl, 5 or 6 membered carbon-based heterocyclic ring having in its backbone 1 to 3 heteroatoms, substituted 5 or 6 membered carbon-based heterocyclic ring having in its backbone 1 to 3 heteroatoms, C1 to C3 thioalkyl, substituted C1 to C3 thioalkyl, CORF, and NRGCORF;
- RF 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;
- RG is selected from the group consisting of H, C1 to C3 alkyl, and substituted C1 to C3 alkyl;
- R6 is selected from the group consisting of H, C1 to C3 alkyl, and C1 to C4CO2alkyl;
- Q1 is selected from the group consisting of S, NR7, and 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, carbon-based heterocyclic ring having in its backbone 1 to 3 heteroatoms, substituted carbon-based heterocyclic ring having in its backbone 1 to 3 heteroatoms, 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, carbon-based heterocyclic ring having in its backbone 1 to 3 heteroatoms, substituted carbon-based heterocyclic ring having in its backbone 1 to 3 heteroatoms, NO2, CN, and CO2R10;
- R10 is selected from the group consisting of C1 to C3 alkyl and substituted C1 to C3 alkyl;
- or CR8R9 comprise a six membered ring having the structure:
- 33
- R11 and R12 are independently selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, aryl, substituted aryl, carbon-based heterocyclic ring having in its backbone 1 to 3 heteroatoms, substituted carbon-based heterocyclic ring having in its backbone 1 to 3 heteroatoms, acyl, substituted acyl, sulfonyl, and substituted sulfonyl;
- and formula II is:
- 34
- wherein:
- 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, carbon-based heterocyclic ring having in its backbone 1 to 3 heteroatoms, substituted carbon-based heterocyclic ring having in its backbone 1 to 3 heteroatoms, 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, carbon-based heterocyclic ring having in its backbone 1 to 3 heteroatoms, substituted carbon-based heterocyclic ring having in its backbone 1 to 3 heteroatoms, NO2, CN, and CO2R10;
- R10 is selected from the group consisting of C1 to C3 alkyl and substituted C1 to C3 alkyl;
- or CR8R9 comprise a six membered ring having the structure:
- 35
- R11 and R12 are independently selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, aryl, substituted aryl, carbon-based heterocyclic ring having in its backbone 1 to 3 heteroatoms, substituted carbon-based heterocyclic ring having in its backbone 1 to 3 heteroatoms, acyl, substituted acyl, sulfonyl, and substituted sulfonyl;
- and formula II is:
- 36
- wherein:
- R1′ is selected from the group methyl, ethyl, trifluoromethyl;
- R2′ is selected from the group methyl, ethyl, trifluoromethyl;
- or
- R1′ and R2′ are joined to form a spirocyclic ring containing 3 to 7 carbon atoms;
- and R3′ is selected from the group C1 to C4 alkyl;
- and
- a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.