Tetrahydroisoquinoline compounds as estrogen agonists/antagonists

A compound of claim 29 wherein:

• p is 0;
• X is CO;
• R1 is (C1-C4)alkyl, (C4-C7)cycloalkyl, adamantyl, phenyl, pyridyl, or thienyl, wherein each of said phenyl, pyridyl, or thienyl groups is optionally substituted with one to three fluoro, or optionally substituted with one substituent selected from iodo, chloro, bromo, hydroxy, methoxy, dimethylamino, OCH2CH2NR8R9, COOR7, or ethenyl-CONR4R5 wherein R4 and R5 are both methyl, or R4 and R5 taken together with the nitrogen atom to which they are attached form pyrrolidino, piperidino, hexamethyleneimino, or morpholino;
• and
• R2 is (C5-C7)cycloalkyl, (C3-C7)alkyl, napthyl, or trifluoromethyl, wherein said (C3-C7)alkyl is optionally substituted with one to three fluoro.

A compound of the formula:

• wherein:
• A1 is hydrogen, hydroxy, (C1-C4)alkoxy, or (C1-C4)alkanoyloxy, said (C1-C4)alkoxy or said (C1-C4)alkanoyloxy being optionally substituted by hydroxy, halo, di(C1-C4alkyl)amino or a partially saturated, fully saturated, or fully unsaturated five to twelve membered ring optionally comprising one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen;
• A2, A3, and A4 are independently selected from hydrogen, hydroxy, (C1-C4)alkoxy, and halo;
• R1 is (C1-C7)alkyl;
• adamantyl;
• a partially saturated, fully saturated, or fully unsaturated three to twelve membered ring optionally comprising one to four heteroatoms selected independently from oxygen, sulfur, and nitrogen;
• a bicyclic ring consisting of two fused independently partially saturated, fully saturated, or fully unsaturated five to six membered rings, said bicyclic ring optionally comprising one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen;
• or a bicyclic ring system consisting of two rings joined by a covalent bond, said rings being independently partially saturated, fully saturated, or fully unsaturated three to eight membered rings, said bicyclic ring system optionally comprising one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen;
• wherein each of the above R1 groups is optionally substituted with one to seven fluoro, or optionally substituted with one to three substituents independently selected from Group A, wherein Group A consists of hydroxy, chloro, bromo, iodo, (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C8)cycloalkyl, R3—(C1-C4)alkoxy, (C2-C4)alkenyl-COOR7, (C0-C4)alkyl-COOR7, (C1-C4)alkanoyloxy-(C2-C4)alkenyl, (C2-C4)alkenyl-CONR4R5, (C0-C4)alkyl-CONR4R5, (C0-C4)alkyl-NR4R5, OCH2CH2NR8R9, propyl-R8R9, and SO2—R6;
• X is (C0-C1)alkylene-phenylene-(C0-C1)alkylene, CO2, CO, (C1-C3)alkylene-CO—(C1-C3)alkylene, (C0-C3)alkylene-CO—(C2-C3)alkylene, (C2-C3)alkylene-CO—(C0-C3)alkylene, or (C0-C4)alkylene-SO2—(C0-C4)alkylene;
• R2 is (C1-C9)alkyl;
• (C2-C4)alkenyl;
• benzhydryl;
• a partially saturated, fully saturated, or fully unsaturated three to eight membered ring optionally comprising one to four heteroatoms selected independently from oxygen, sulfur, and nitrogen;
• a bicyclic ring consisting of two fused independently partially saturated, fully saturated, or fully unsaturated five to six membered rings, and said bicyclic ring optionally comprising one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen;
• or a bicyclic ring system consisting of two rings joined by a covalent bond said rings being independently partially saturated, fully saturated, or fully unsaturated three to eight membered rings, and said bicyclic ring system optionally comprising one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen;
• wherein said (C1-C9)alkyl is optionally substituted with one to seven fluoro, or optionally substituted with one to three substituents independently selected from Group B, wherein Group B consists of chloro, (C1-C4)alkoxy, amino, and (C1-C4)alkylcarbonyl;
• wherein said (C2-C4)alkenyl is optionally substituted with one to three substituents independently selected from Group C, wherein Group C consists of halo, (C1-C4)alkoxy, amino, and (C1-C4)alkylcarbonyl;
• and wherein said benzhydryl, said three to eight membered ring, said bicyclic ring, and said bicyclic ring system are each optionally substituted with one to three substituents independently selected from Group D, wherein Group D consists of halo, hydroxy, (C1-C4)alkyl, (C1-C4alkoxy, imidazolyl, amino, (C1-C4)alkylcarbonylamino, and (C1-C4)alkylcarbonyl;
• R3 at each occurrence is independently pyrrolidino, piperidino, morpholino, or dimethylamino;
• R4 and R5 at each occurrence are independently hydrogen, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkylene, or (C3-C8)cycloalkyl, or R4 and R5 taken together with the nitrogen atom to which they are attached are pyrrolidino, piperidino, morpholino, or hexamethyleneimino;
• R6 at each occurrence is independently imidazolyl, thienyl, benzathienyl, or isoxazyl, each optionally substituted with one to three substituents independently selected from (C1-C4)alkyl;
• R7 at each occurrence is independently hydrogen or (C1-C4)alkyl;
• R8 and R9 are independently methyl or ethyl, or R8 and R9 taken together with the nitrogen atom to which they are attached are pyrrolidino, piperidino, morpholino, or hexamethyleneimino;
• and
• p is 0, 1, or 2.

A compound of the formula:

• wherein:
• A1 is hydrogen, hydroxy, (C1-C4)alkoxy, or (C1-C4)alkanoyloxy, said (C1-C4)alkoxy or said (C1-C4)alkanoyloxy being optionally substituted by hydroxy, halo, di(C1-C4alkyl)amino or a partially saturated, fully saturated, or fully unsaturated five to twelve membered ring optionally having up to four heteroatoms independently selected from oxygen, sulfur, and nitrogen;
• A2, A3, and A4 are independently selected from hydrogen, hydroxy, (C1-C4)alkoxy, and halo;
• R1 is (C1-C7)alkyl;
• adamantyl;
• a partially saturated, fully saturated, or fully unsaturated three to twelve membered ring optionally comprising one to four heteroatoms selected independently from oxygen, sulfur, and nitrogen;
• a bicyclic ring consisting of two fused independently partially saturated, fully saturated, or fully unsaturated five to six membered rings, said bicyclic ring optionally comprising one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen;
• or a bicyclic ring system consisting of two rings joined by a covalent bond, said rings being independently partially saturated, fully saturated, or fully unsaturated three to eight membered rings, said bicyclic ring system optionally comprising one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen;
• wherein each of the above R1 groups is optionally substituted with one to seven fluoro, or optionally substituted with one to three substituents independently selected from Group A, wherein Group A consists of hydroxy, chloro, bromo, iodo, (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C8)cycloalkyl, R3—(C1-C4)alkoxy, (C2-C4)alkenyl-COOR7, (C0-C4)alkyl-COOR7, (C1-C4)alkanoyloxy-(C2-C4)alkenyl, (C2-C4)alkenyl-CONR4R5, (C0-C4)alkyl-CONR4R5, (C0-C4)alkyl-NR4R5, OCH2CH2NR8R9, propyl-R8R9 and SO2—R6;
• X is a covalent bond, (CH2)n wherein n is 1, 2, or 3, (C0-C1)alkylene-phenylene-(C0-C1)alkylene, CO2, (C0-C3)alkylene-CO—(C0-C3)alkylene, or (C0-C4)alkylene-SO2—(C0-C4alkylene;
• R2 is (C1-C9)alkyl;
• (C2-C4)alkenyl;
• benzhydryl;
• a partially saturated, fully saturated, or fully unsaturated four to five membered ring optionally comprising one to three heteroatoms selected independently from oxygen, sulfur, and nitrogen;
• a partially saturated, fully saturated, or fully unsaturated seven to eight membered ring optionally comprising one to four heteroatoms selected independently from oxygen, sulfur, and nitrogen;
• a bicyclic ring consisting of two fused independently partially saturated, fully saturated, or fully unsaturated five to six membered rings, said bicyclic ring optionally comprising one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen;
• or a bicyclic ring system consisting of two rings joined by a covalent bond, said rings being independently partially saturated, fully saturated, or fully unsaturated three to eight membered rings, wherein said bicyclic ring system optionally comprises one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen;
• wherein said (C1-C9)alkyl is optionally substituted with one to seven fluoro, or optionally substituted with one to three substituents independently selected from Group B, wherein Group B consists of chloro, (C1-C4)alkoxy, amino, and (C1-C4)alkylcarbonyl;
• wherein said (C2-C4)alkenyl is optionally substituted with one to three substituents independently selected from Group C, wherein Group C consists of halo, (C1-C4)alkoxy, amino, and (C1-C4)alkylcarbonyl;
• and wherein said benzhydryl, said four to five membered ring, said seven to eight membered ring, said bicyclic ring, and said bicyclic ring system are optionally substituted with one to three substituents independently selected from Group D, wherein Group D consists of halo, hydroxy, (C1-C4)alkyl, (C1-C4)alkoxy, imidazolyl, amino, (C1-C4)alkylcarbonylamino, and (C1-C4)alkylcarbonyl;
• R3 at each occurrence is independently pyrrolidino, piperidino, morpholino, or dimethylamino;
• R4 and R5 at each occurrence are independently hydrogen, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkylene, or (C3-C8)cycloalkyl, or R4 and R5 taken together with the nitrogen atom to which they are attached form pyrrolidino, piperidino, morpholino, or hexamethyleneimino;
• R6 at each occurrence is independently imidazolyl, thienyl, benzathienyl, or isoxazyl, said imidazolyl, thienyl, benzathienyl, or isoxazyl each optionally substituted with one to thee substituents independently selected from (C1-C4)alkyl;
• R7 at each occurrence is independently hydrogen or (C1-C4)alkyl;
• R8 and R9 at each occurrence are independently methyl or ethyl, or R8 and R9 taken together with the nitrogen atom to which they are attached are pyrrolidino, piperidino, morpholino, or hexamethyleneimino;
• and
• p is 0, 1, or 2;
• with the proviso that when X is (CH2)2 or (CH2)3, p is 0, and R1 is phenyl or phenyl substituted with a single chloro, fluoro, bromo, hydroxy, methoxy, pyrrolidinoethoxy, piperidinoethoxy or morpholinoethoxy substituent, then R2 is not tert-butyl or cyclopentyl.

A compound of the formula:

• wherein:
• A1 is hydrogen, hydroxy, (C1-C4)alkoxy, or (C1-C4)alkanoyloxy, said (C1-C4)alkoxy or said (C1-C4)alkanoyloxy optionally substituted by hydroxy, halo, di(C1-C4alkyl)amino or a partially saturated, fully saturated, or fully unsaturated five to twelve membered ring optionally comprising one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen;
• A2, A3, and A4 are independently selected from hydrogen, hydroxy, (C1-C4)alkoxy, and halo;
• R1 is (C1-C7)alkyl;
• adamantyl;
• a partially saturated, fully saturated, or fully unsaturated three to twelve membered ring optionally comprising one to four heteroatoms selected independently from oxygen, sulfur, and nitrogen;
• a bicyclic ring consisting of two fused independently partially saturated, fully saturated, or fully unsaturated five to six membered rings, said bicyclic ring optionally comprising one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen;
• or a bicyclic ring system consisting of two rings joined by a covalent bond, said rings being independently partially saturated, fully saturated, or fully unsaturated three to eight membered rings, said bicyclic ring system optionally comprising one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen;
• wherein each of the above R1 groups is optionally substituted with one to seven fluoro, or optionally substituted with one to three substituents independently selected from Group A, wherein Group A consists of hydroxy, chloro, bromo, iodo, (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C8)cycloalkyl, R3—(C1-C4)alkoxy, (C2-C4)alkenyl-COOR7, (C0-C4alkyl-COOR7, (C1-C4)alkanoyloxy-(C2-C4)alkenyl, (C2-C4)alkenyl-CONR4R5, (C0-C4)alkyl-CONR4R5, (C0-C4)alkyl-NR4R5, OCH2CH2NR8R9, propyl-R8R9 and SO2—R6;
• X is a covalent bond, (CH2)n where n is 1, 2, or 3, (C0-C1)alkylene-phenylene-(C0-C1)alkylene, CO2, (C0-C3)alkylene-CO—(C0-C3)alkylene, or (C0-C4)alkylene-SO2—(C0-C4)alkylene;
• R2 is a partially saturated or fully saturated six membered ring optionally comprising one to three heteroatoms selected independently from oxygen, sulfur, and nitrogen;
• wherein said six membered ring is optionally substituted with one to three substituents independently selected from Group D, wherein Group D consists of halo, hydroxy, (C1-C4)alkyl, (C1-C4)alkoxy, imidazolyl, amino, (C1-C4)alkylcarbonylamino, and (C1-C4)alkylcarbonyl;
• R3 at each occurrence is independently pyrrolidino, piperidino, morpholino, or dimethylamino;
• R4 and R5 at each occurrence are independently hydrogen, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkylene, or (C3-C8)cycloalkyl, or R4 and R5 taken together with the nitrogen atom to which they are attached form pyrrolidino, piperidino, morpholino, or hexamethyleneimino;
• R6 at each occurrence is independently imidazolyl, thienyl, benzathienyl, or isoxazyl, each optionally substituted with one to three substituents independently selected from (C1-C4)alkyl;
• R7 at each occurrence is independently hydrogen or (C1-C4)alkyl;
• R8 and R9 at each occurrence are independently methyl or ethyl, or R8 and R9 taken together with the nitrogen atom to which they are attached form pyrrolidino, piperidino, morpholino, or hexamethyleneimino;
• and
• p is 0, 1, or 2.

A compound of the formula:

• wherein:
• A1 is hydrogen, hydroxy, (C1-C4)alkoxy, or (C1-C4)alkanoyloxy, said (C1-C4)alkoxy or said (C1-C4)alkanoyloxy being optionally substituted by hydroxy, halo, di(C1-C4alkyl)amino or a partially saturated, fully saturated, or fully unsaturated five to twelve membered ring optionally comprising one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen;
• A2, A3, and A4 are independently selected from hydrogen, hydroxy, (C1-C4)alkoxy, and halo;
• R1 is (C1-C7)alkyl;
• adamantyl;
• a partially saturated, fully saturated, or fully unsaturated three to twelve membered ring optionally comprising one to four heteroatoms selected independently from oxygen, sulfur, and nitrogen;
• a bicyclic ring consisting of two fused independently partially saturated, fully saturated, or fully unsaturated five to six membered rings, said bicyclic ring optionally comprising one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen;
• or a bicyclic ring system consisting of two rings joined by a covalent bond, said rings being independently partially saturated, fully saturated, or fully unsaturated three to eight membered rings, said bicyclic ring system optionally comprising one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen;
• wherein each of the above R1 groups is optionally substituted with one to seven fluoro, or optionally substituted with one to three substituents independently selected from Group A, wherein Group A consists of hydroxy, chloro, bromo, iodo, (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C8)cycloalkyl, R3—(C1-C4)alkoxy, (C2-C4)alkenyl-COOR7, (C0-C4)alkyl-COOR7, (C1-C4)alkanoyloxy-(C2-C4)alkenyl, (C2-C4)alkenyl-CONR4R5, (C0-C4)alkyl-CONR4R5, (C0-C4)alkyl-NR4R5, OCH2CH2NR8R9, propyl-R8R9 and SO2—R6;
• X is a covalent bond, (CH2)n where n is 1, 2, or 3, (C0-C1)alkylene-phenylene-(C0-C1)alkylene, CO2, (C0-C3)alkylene-CO—(C0-C3)alkylene, or (C0-C4)alkylene-SO2—(C0-C4)alkylene;
• R2 is (C1-C9)alkyl;
• (C2-C4)alkenyl;
• benzhydryl;
• a partially saturated, fully saturated, or fully unsaturated three to eight membered ring optionally comprising one to four heteroatoms selected independently from oxygen, sulfur, and nitrogen;
• a bicyclic ring consisting of two fused independently partially saturated, fully saturated, or fully unsaturated five to six membered rings, wherein said bicyclic ring optionally comprises one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen;
• or a bicyclic ring system consisting of two rings joined by a covalent bond, said rings being independently partially saturated, fully saturated, or fully unsaturated three to eight membered rings, wherein said bicyclic ring system optionally comprises one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen;
• wherein said (C1-C9)alkyl is optionally substituted with one to seven fluoro, or optionally substituted with one to three substituents independently selected from Group B, wherein Group B consists of chloro, (C1-C4)alkoxy, amino, and (C1-C4)alkylcarbonyl;
• wherein said (C2-C4)alkenyl is optionally substituted with one to three substituents independently selected from Group C, wherein Group C consists of halo, (C1-C4)alkoxy, amino, and (C1-C4)alkylcarbonyl;
• and wherein said benzhydryl, said three to eight membered ring, said bicyclic ring, and said bicyclic ring system is optionally substituted with one to three substituents independently selected from Group D, wherein Group D consists of halo, hydroxy, (C1-C4)alkyl, (C1-C4)alkoxy, imidazolyl, amino, (C1-C4)alkylcarbonylamino, and (C1-C4)alkylcarbonyl;
• R3 at each occurrence is independently pyrrolidino, piperidino, morpholino, or dimethylamino;
• R4 and R5 at each occurrence are independently hydrogen, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkylene, or (C3-C8)cycloalkyl, or R4 and R5 taken together with the nitrogen atom to which they are attached form pyrrolidino, piperidino, morpholino, or hexamethyleneimino;
• R6 at each occurrence is independently imidazolyl, thienyl, benzathienyl, or isoxazyl, each optionally substituted with one to three substituents independently selected from (C1-C4)alkyl;
• R7 at each occurrence is independently hydrogen or (C1-C4)alkyl;
• R8 and R9 at each occurrence are independently methyl or ethyl, or R8 and R9 taken together with the nitrogen atom to which they are attached form pyrrolidino, piperidino, morpholino, or hexamethyleneimino;
• and
• p is 0,1, or 2.