Quinazolinone and benzoxazine derivatives as progesterone receptor modulators

A compound of the formula:

• 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, heterocyclic, substituted heterocyclic, CORA, and NRBCORA;
• or R1 and R2 are fused to form:
• a) a carbon-based 3 to 8 membered saturated spirocyclic ring;
• b) a carbon-based 3 to 8 membered spirocyclic ring having at least one carbon-carbon double bond;
• or
• c) a 3 to 8 membered heterocyclic ring having in its backbone one to three heteroatoms selected from the group consisting of O, S and N;
• the rings of a), b) and c) being optionally substituted by from 1 to 4 groups selected from the group consisting of fluorine, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 thioalkoxy, —CF3, —OH, —CN, —NH2, —NH(C1 to C6 alkyl), and —N(C1 to C6 alkyl)2;
• RA is 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, or substituted C1 to C3 aminoalkyl;
• RB is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
• R3 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C1 to C6 alkenyl, alkynyl, substituted alkynyl, or CORC;
• RC is 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, or substituted C1 to C4 aminoalkyl;
• R4 is H, halogen, CN, NO2, C1 to C6 alkyl, substituted C1 to C6 alkyl, alkynyl, substituted alkynyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, amino, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
• R5 is a benzene ring having the structure:
• X is selected from the group consisting of halogen, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, alkynyl, substituted alkynyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 thioalkoxy, substituted C1 to C3 thioalkoxy, amino, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, 5 or 6 membered heterocyclic ring having in its backbone 1 to 3 heteroatoms, CORD, OCORD, and NRECORD;
• Y and Z are independent substituents selected from the group consisting of H, halogen, CN, NO2, amino, aminoalkyl, C1 to C3 alkoxy, C1 to C4 alkyl, and C1 to C3 thioalkoxy;
• RD is 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, or substituted C1 to C3 aminoalkyl;
• RE is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
• RF is 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, or substituted C1 to C3 aminoalkyl;
• RG is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
• R6 is H, C1 to C3 alkyl, or C1 to C4 CO2 alkyl;
• G1 is O;
• G2 is CR7R8;
• R7 and R8 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;
• or pharmaceutically acceptable salt thereof.

A compound of the formula:

• wherein:
• R1 is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, CORA, and NRBCORA;
• R2 is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, CORA, and NRBCORA;
• or R1 and R2 are fused to form:
• a) a carbon-based 3 to 8 membered saturated spirocyclic ring;
• b) a carbon-based 3 to 8 membered spirocyclic ring having at least one carbon-carbon double bond;
• or
• c) a 3 to 8 membered heterocyclic ring containing one to three heteroatoms selected from the group consisting of O, S and N;
• the spirocyclic rings of a), b) and c) being optionally substituted by from 1 to 4 groups selected from the group consisting of fluorine, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 thioalkoxy, —CF3, —OH, —CN, —NH2, —NH(C1 to C6 alkyl), and —N(C1 to C6 alkyl)2;
• RA is 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, or substituted C1 to C3 aminoalkyl;
• RB is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
• R3 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C1 to C6 alkenyl, alkynyl, substituted alkynyl, or CORC;
• RC is H, C1 to C4 alkyl, substituted C1 to C4 alkyl, aryl, substituted aryl, C1 to C alkoxy, substituted C1 to C4 alkoxy, C1 to C4 aminoalkyl, or substituted C1 to C4 aminoalkyl;
• R4 is H, halogen, CN, NO2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, amino, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
• R5 is selected from the group consisting of a) and b):
• a) a substituted benzene ring having the structure:
• 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 thioalkoxy, substituted C1 to C3 thioalkoxy, amino, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, 5 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, CORD, OCORD, and NRECORD;
• RD is 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, or substituted C1 to C3 aminoalkyl;
• RE is H, C1 to C3 alkyl, or 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, C1 to C3 alkyl, and C1 to C3 thioalkoxy;
• or
• b) a five or six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2, and NR6 and containing one or two independent substituents selected from the group consisting of H, halogen, CN, NO2, amino, C1 to C3 alkyl, and C1 to C3 alkoxy;
• R6 is H or C1 to C3 alkyl,
• G1 is O;
• G2 is CR7R8;
• R7 and R8 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;
• or pharmaceutically acceptable salt thereof.

A compound of the formula:

• wherein:
• R1═R2 and is C1 to C3 alkyl or substituted C1 to C6 alkyl;
• or R1 and R2 are fused to form a carbon-based 3 to 8 membered saturated spirocyclic ring;
• R3 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, or CORC;
• RC is H, C1 to C4 alkyl, or C1 to C alkoxy;
• R4 is H, halogen, NO2, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
• R5 is selected from the group consisting of a), b), and c):
• a) a substituted benzene ring of the structure:
• X is selected from the group consisting of halogen, CN, C1 to C3 alkyl C1 to C3 alkoxy, C1 to C3 thioalkoxy, NO2, C1 to C3 perfluoroalkyl, or 5 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms;
• Y is on the 4′ or 5′ position and is selected from the group consisting of H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, and C1 to C3 thioalkoxy;
• b) a five membered ring of the structure:
• wherein:
• U is O, S, or NR6;
• X′ is selected from the group consisting of halogen, CN, NO2, C1 to C3 alkyl, and C1 to C3 alkoxy;
• Y′ is selected from the group consisting of H and C1 to C4 alkyl;
• R6 is H, C1 to C3 alkyl, or C1 to C4 CO2 alkyl;
• and
• c) a six membered ring of the structure:
• wherein:
• X1 is N or CX2;
• X2 is halogen, CN, NO2, or C1 to C3 alkoxy;
• G1 is O;
• G2 is CR7R8;
• R7 and R8 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;
• or pharmaceutically acceptable salt thereof.

A compound of the formula:

• wherein:
• R1═R2 and are CH3;
• or R1 and R2 are fused to form a carbon-based 3 to 8 membered saturated spirocyclic ring;
• R3 is H, OH, NH2, C1 alkyl, substituted C1 alkyl, or CORC;
• RC is H, C1 to C3 alkyl, or C1 to C alkoxy;
• R4 is H, halogen, or C1 to C3 alkyl;
• R5 is selected from the group consisting of a) and b):
• a) a substituted benzene ring of the structure:
• X is selected from the group consisting of halogen, CN, C1 alkoxy, NO2, and 5 membered heterocyclic ring;
• wherein said heterocyclic ring is a 2-thiazole;
• Y is on the 4′ or 5′ position and is selected from the group consisting of H and halogen;
• wherein said halogen is F;
• and
• b) a five membered ring of the structure:
• wherein:
• U is O, S, or NH;
• X′ is selected from the group consisting of halogen, CN, or NO2;
• Y′ is selected from the group consisting of H and C1 to C4 alkyl;
• G1 is O;
• G2 is CR7R8;
• R7 and R8 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;
• or pharmaceutically acceptable salt thereof.