Tetrahydroisoquinoline estrogen receptor modulators and uses thereof

A compound selected from Formula I:

• and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:
• Y1is —C(Rb)—or N;
• Y2 is —CH2— or —N(Ra)—;
• Y3 is —N(Ra)—or —C(Rb)2—;
• where one of Y2 and Y3 is N or —N(Ra)—;
• Ra and Rc are independently selected from H, C1-C6 alkyl, C1-C6 fluoroalkyl, allyl, propargyl, C3-C6 cycloalkyl, and C3-C6 heterocyclyl, optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, OH, OCH3, and SO2CH3;
• Rb is independently selected from H, —O(C1-C3 alkyl), C1-C6 alkyl, C1-C6 fluoroalkyl, allyl, propargyl, C3-C6 cycloalkyl, and C3-C6 heterocyclyl, optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, OH, OCH3, and SO2CH3;
• where at least one of Ra and Rb is —CH2Cl, —CH2F, —CHF2, —CF3, —CH2CH2F, —CH2CHF2, —CH2CF3, CH2CH2Cl, CH2CH2CH2F, CH2CH2CHF3, CH2CH2, CF3, or CH2CH2CH2Cl;
• X1, X2, X3, and X4 are independently selected from CR5 and N;
• where none, one, or two of X1, X2, X3, and X4 is N;
• Z is selected from O, S, S(O), S(O)2, C(═O), CH(OH), C1-C6 alkyldiyl, CH(OH)—(C1-C6 alkyldiyl), C1-C6 fluoro alkyldiyl, NRc, NRc—(C1-C6 alkyldiyl), NRc—(C1-C6 fluoro alkyldiyl), O—(C1-C6 alkyldiyl), and O—(C1-C6 fluoroalkyldiyl);
• R1 and R2 are independently selected from H, F, Cl, Br, I, —CN, —CH3, —CH2CH3, —CH(CH3)2, —CH2CH(CH3)2, —CH2OH, —CH2OCH3, —CH2CH2OH, —C(CH3)2OH, —CH(OH), CH(CH3)2, —C(CH3)2CH2OH, —CH2CH2SO2CH3, —CH2OP(O)(OH)2, —CH2Cl, —CH2F, —CHF2, —CH2NH3, —CH2NHSO2CH3, —CH2NHCH3, —CH2N(CH3)2, —CF3—CH3, —CH2CF3, —CH2CHF2, —C(CH3)CN, —C(CH3)2CN, —CH2CN, —CO2H, —COCH3, —CO2CH3, —CO2C(CH3)3, —COCH(OH)CH3, —CONH2, —CONHCH3, —CONHCH2CH3, —CONHCH(CH3)2, —CON(CH3)2CONH2, —NH2, —NHCH3, —N(CH3)2, —NHCOCH3, —N(CH3)COCH3, —NHS(O)2CH3, —N(CH3)C(CH3)2CONH2, —N(CH3)CH2CH2S(O)2CH3, —NO2, ═O, —OH, —OCH3, —OCH2CH3, —OCH2CH2OCH3, —OCH2CH2OH, —OCH2CH2N(CH3)2, —OP(O)(OH)2, —S(O)2N(CH3)2, —SCH3, —S(O)2CH3, —S(O)3H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazine-1-yl, morpholinomethyl, morpholino-methanone, and morpholino;
• R3 is selected from C1-C6 alkyl, C1-C6 fluoroalkyl, allyl, propargyl, C3-C6 cycloalkyl, phenyl, C3-C6 heterocyclyl, C6-C20 aryl or C1-C6 heteroaryl, —CO—(C1-C6 alkyl), —CO—(C3-C6 cycloalkyl), —S(O)2—(C1-C6 alkyl), and —S(O)2—(C3-C6 cycloalkyl), optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, OH, OCH3, and SO2CH3;
• R4 is independently selected from F, Cl, Br, I, —CN, —CH3, —CH2CH3, —CH(CH3)2, —CH2CH(CH3)2, —CH2OH, —CH2OCH3, —CH2CH2OH, —C(CH3)2OH, —CH(OH)CH(CH3)2, —C(CH3)2CH2OH, —CH2CH2SO2CH3, —CH2OP(O)(OH)2, —CH2F, —CHF2, —CH2NH2, —CH2NHSO2CH3, —CH2NHCH3, —CH2N(CH3)2, —CF3, —CH2CF3, —CH2CHF2, —CH(CH3)CN, —C(CH3)2CN, —CH2CN, —CO2H, —COCH3, —CO2CH3, —CO2C(CH3)3, —COCH(OH)CH3, —CONH2, —CONHCH3, —CONHCH2CH3, —CONHCH(CH3)2, —CON(CH3)2, —C(CH3)2CONH2, —NH2, —NHCH3, —N(CH3)2, —NHCOCH3, —N(CH3)COCH3, —NHS(O)2CH3, —N(CH3)C(CH3)2CONH2, —N(CH3)CH2CH2S(O)2CH3, —NO2, ═O, —OH, —OCH3, —OCH2CH3, —OCH2CH2OCH3, —OCH2CH2OH, —OCH2CH2N(CH3)2, —OP(O)(OH)2, —S(O)2N(CH3)2, —SCH3,—S(O)2CH3, —S(O)3H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl -methanone, piperazine-1-yl, morpholinomethyl, morpholino-methanone, and morpholino;
• or two R4 groups on vicinal carbon atoms form a five- or six-membered, fused carbocyclyl, heterocyclyl, or heteroaryl ring;
• R5 is selected from H, F, Cl, Br, I, —CN, —CH3, —CH2CH3, —CH(CH3)2, —CH2CH(CH3)2, —CH2OH, —CH2OCH3, —CH2CH2OH, —C(CH3)2OH, —CH(OH)CH(CH3)2, —C(CH3)2CH2OH, —CH2CH2SO2CH3, —CH2OP(O)(OH)2, —CH2F, —CHF2, —CH2NH2, —CH2NHSO2CH3, —CH2NHCH3, —CH2N(CH3)2, —CF3, —CH2CF3, —CH2CHF2, —(CH3)CN, —C(CH3)2CN, —CH2CN, —CO2H, —COCH3, -CO2CH3, -CO2C(CH3)3, COCH(OH)CH3, —CONH2, —CONHCH3, —CONHCH2CH3, —CONHCH(CH3)2, -CON(CH3)2, —C(CH3)2CONH2, —NH2, —NHCH3, —N(CH3)2, -NHCOCH3, —N(CH3)COCH3, —NHS(O)2CH3, —N(CH3)C(CH3)2CONH2, —N(CH3)CH2CH2S(O)2CH3, —NO2, ═O, —OH, —OCH3, —OCH2CH3, —OCH2CH2OCH3, —OCH2CH2OH, —OCH2CH2N(CH3)2, —OP(O)(OH)2, —S(O)2N(CH3)2, —SCH3, —S(O)2CH3, —(O)3H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-methyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl -methanone, piperazine- 1-yl, morpholinomethyl, morpholino-methanone, and morpholino;
• R6 is selected from H, F, and C1-C6 alkyl optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, OH, OCH3, and SO2CH3;
• R7 is independently selected from F, and C1-C6 alkyl optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, OH, OCH3, and SO2CH3;
• m is selected from 0, 1, 2, 3, and 4;
• n is selected from 0, 1, 2, 3, and 4;
• and
• p is 1 or 2;
• where alkyldiyl, fluoro alkyldiyl, aryl, carbocyclyl, heterocyclyl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CN, —CH3, —CH2CH3, —(CH3)2, —CH2CH(CH3)2, —CH2OH, —CH2CH3, —CH2CH2OH, —C(CH3)2OH, —CH(OH)CH(CH3)2, —C(CH3)2CH2OH, —CH2CH2SO2CH3, —CH2OP(O)(OH)2, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH(CH3)CN, —C(CH3)2CN, —CH2CN, —CH2NH2, —CH2NHSO2CH3, —CH2NHCH3, —CH2N(CH3)2, —CO2H, —COCH3, —CO2CH3, —CO2C(CH3)3, —COCH(OH)CH3, —CONH2, —CONHCH3, —CON(CH3)2, —C(CH3)2CONH2, —NH2, —NHCH3, —N(CH3)2, —NHCOCH3, —N(CH3)COCH3, —NHS(O)2CH3, —N(CH3)C(CH3)2CONH2, —N(CH3)CH2CH2S(O)2CH3, —NO2, ═O, —OH, —OCH3, —OCH2CH3, —OCH2CH2OCH3, —OCH2CH2OH, —OCH2CH2N(CH3)2, —OP(O)(OH)2, —S(O)2N(CH3)2, —SCH3, —S(O)2CH3, —S(O)3H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methyl azetidin-3-yl)oxy, N-methyl-N-oxetan-3-yl)amino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrroli din-1-yl, pyrroli din-1-yl -methanone, piperazine-1-yl, morpholinomethyl, morpholino-methanone, and morpholino.