Cyclocarbamate derivatives as progesterone receptor modulators

A method of synchronizing estrus in a mammal, the method comprising administering to said mammal in need thereof about 0.5 to about 50 mg/kg of said mammal's body weight of a compound selected from the group consisting of 4,4-Dimethyl-6-[3-(1H-tetrazol-5-yl)-phenyl]-1,4-dihydrobenzo[d][1,3]oxazin-2-one;

• 4,4-Dimethyl-6-(3-trimethylsilanylethynyl-phenyl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one;
• 6-(5-Bromo-1-oxy-pyridin-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;
• N-[4-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2-fluoro-phenyl]-acetamide, 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]-oxazin-6-yl)benzenesulfonamide;
• 5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]-oxazin-6-yl)-thiophene-2-sulfonamide;
• and 4-(1,4-Dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)-2-furancarboxaldehyde oxime;
• or pharmaceutically acceptable salt thereof.

A method of synchronizing estrus in a mammal, the method comprising administering to said mammal in need thereof about 0.5 to about 50 mg/kg of said mammal's body weight of a compound of the formula (I):

• 39
• 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 in its backbone one or more carbon-carbon double bonds;
• or
• c) a carbon-based 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 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 thioalkyl, 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;
• R3is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C3 to C6 alkenyl, alkynyl, substituted alkynyl, or CORC;
• RC 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;
• R4is 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;
• R5is selected from the group consisting of (i) and (ii):
• (i) a substituted benzene ring having the substituents X, Y and Z as shown below:
• 40
• wherein:
• X is selected from the group consisting of H, halogen, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, alkenyl, substituted alkenyl, 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 containing in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, and N, 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, amino, aminoalkyl, C1 to C3 alkoxy, C1 to C3 alkyl, and C1 to C3 thioalkoxy;
• wherein X, Y, and Z are not all H;
• and
• (ii) 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, C1 to C3 alkoxy, C1 to C3 aminoalkyl, CORF, and NRGCORF;
• 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 or C1 to C3 alkyl;
• wherein when R5 is a five-membered ring having in its backbone a NR6 heteroatom, and when R5 is attached at the two position of said ring, there is no CN substituent in the five position on said ring;
• and wherein:
• said substituted alkyl, alkenyl, and alkynyl groups have one to three substituents selected from the group consisting of halogen, CN, OH, NO2, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio;
• said substituted alkoxy, aminoalkyl, and thioalkoxy groups have one to three substituents selected from the group consisting of alkyl and substituted alkyl;
• said substituted aryl group has one to four substituents selected from the group consisting of halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio;
• said substituted cycloalkyl group has one to three substituents selected from the group consisting of halogen, CN, OH, NO2, amino, aryl, heterocyclic, aryloxy, aryl alkoxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio;
• said substituted heterocyclic group has one to four substituents selected from the group consisting of halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio;
• said substituted alkyloxy group has one to three substituents selected from the group consisting of halogen, CN, OH, NO2, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio;
• said aryl group is selected from the group consisting of phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, and phenanthryl;
• said heterocyclic group is a five-membered ring, a six-membered ring, or a multicyclic ring;
• said five-membered heterocyclic ring is selected from the group consisting of tetrahydrofuran, pyrrolidinyl, imidazolyl, oxazolyl, isooxazolyl, thienyl, furyl, and thiazolyl;
• said six-membered heterocyclic ring is selected from the group consisting of piperidinyl, piperazinyl, 2-oxopiperidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiomorpholinyl, azepinyl, and thiomorpholinyl sulfoxide;
• said multicyclic heterocyclic ring is selected from the group consisting of indolyl, quinolinyl, benzofuranyl, benzothienyl, and isoquinolinyl;
• or pharmaceutically acceptable salt thereof.

A method of synchronizing estrus in a mammal, the method comprising administering to said mammal in need thereof about 0.5 to about 50 mg/kg of said mammal's body weight of a compound of the formula (I):

• 41
• wherein:
• R1 and R2 are independent substituents selected from the group consisting of H and C1 to C6 alkyl;
• R3 is H;
• R4 is H;
• R5 is selected from the group consisting of (i) and (ii):
• (i) a substituted benzene ring having the substituents X, Y and Z as shown below:
• 42
• wherein:
• X is selected from the group consisting of halogen, CN, 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, and C1 to C3 alkyl;
• and
• (ii) 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, and CN;
• wherein when R5 is a five-membered ring having in its backbone a NR6 heteroatom, and when R5 is attached at the two position of said ring, there is no CN substituent in the five position on said ring;
• wherein:
• said five-membered heterocyclic ring is selected from the group consisting of tetrahydrofuran, pyrrolidinyl, imidazolyl, oxazolyl, isooxazolyl, thienyl, furyl, and thiazolyl;
• said six-membered heterocyclic ring is selected from the group consisting of piperidinyl, piperazinyl, 2-oxopiperidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiomorpholinyl, azepinyl, and thiomorpholinyl sulfoxide;
• or pharmaceutically acceptable salt thereof.

A compound selected from the group consisting of 6-(3-Methoxyphenyl)spiro[4H-3,1-benzoxazine-4,1-cyclobutan]-2(1H)-one;

• 8-Bromo-6-(3-chloro-4-fluorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;
• 3-(8-Bromo-4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile;
• 3-(8-Bromo-4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile;
• 5-(8-Bromo-4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2-fluorobenzonitrile;
• 6-(3-Bromophenyl)-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;
• 6-(3-Fluorophenyl)-4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;
• 3-(4,4-Dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile;
• 3-(4,4-Dimethyl-8-hydroxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile;
• 6-(2,3-Difluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;
• 3-(1-Ethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluoro-benzonitrile;
• [6-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)pyridin-2-yl]acetonitrile;
• 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]-oxazin-6-yl)-5-fluoro-phenylacetonitrile;
• 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]-oxazin-6-yl)-4-fluoro-phenylacetonitrile;
• 4-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2-fluorophenylacetonitrile;
• 2-(4,4-Dimethyl 2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)phenylacetonitrile;
• 6-(3-Fluoro-4-methoxy-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;
• 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]-oxazin-6-yl)phenylacetonitrile;
• 6-(6-Amino-pyridin-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;
• 6-(5-Diethoxymethyl-furan-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;
• 4-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbaldehyde;
• N-[4-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2-fluoro-phenyl]-acetamide, 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]-oxazin-6-yl) benzenesulfonamide;
• 5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]-oxazin-6-yl)-thiophene-2-sulfonamide;
• and 4-(1,4-Dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)-2-furancarboxaldehyde oxime;
• or a pharmaceutically acceptable salt thereof.