Selective androgen receptor degrader (SARD) Ligands and methods of use thereof

A method of treating prostate cancer in a subject in need thereof, wherein said subject has AR overexpressing prostate cancer, castration-resistant prostate cancer, castration-sensitive prostate cancer, AR-V7 expressing prostate cancer, or d567ES expressing prostate cancer, comprising administering to the subject a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by the structure of formula V:

• wherein
• T is OH, OR, —NHCOCH3, NHCOR or
• Z is NO2, CN, COOH, COR, NHCOR or CONHR;
• Y is CF3, F, I, Br, Cl, CN or C(R)3;
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
• R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
• R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O—C1-C12-alkyl, O—C1-C12-haloalkyl, —SO2-aryl, —SO2-phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
• Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
• R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
• R4 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, keto (═O), alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
• n is 1, 2 or 3;
• m 1, 2 or 3;
• l is 0 or 1;
• and
• k is 0, 1 or 2;
• or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

A method of treating breast cancer in a subject in need thereof, wherein said subject has AR expressing breast cancer, AR-SV expressing breast cancer, and/or AR-V7 expressing breast cancer, comprising administering to the subject a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by the structure of formula I:

• wherein
• W1 and W2 are each independently selected from N or CH;
• W3, W4, W5 and W6 are each independently CH;
• wherein if any one of W1, W2, W3, W4, W5, and W6 is CH, then the H is optionally replaced with R4, Q or R3 in the respective position, and if any one of W1, and W2, is not CH, then the respective position is unsubstituted;
• T is OH, OR, —NHCOCH3, NHCOR or
• Z is NO2, CN, COOH, COR, NHCOR or CONHR;
• Y is CF3, F, I, Br, Cl, CN or C(R)3;
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
• R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
• R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O—C1-C12-alkyl, O—C1-C12-haloalkyl, —SO2-aryl, —SO2-phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
• Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
• R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
• R4 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
• n is 1, 2 or 3;
• and
• m is 1, 2 or 3;
• or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

A method of treating breast cancer in a subject in need thereof, wherein said subject has AR expressing breast cancer, AR-SV expressing breast cancer, and/or AR-V7 expressing breast cancer, comprising administering to the subject a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by the structure of formula V:

• wherein
• T is OH, OR, —NHCOCH3, NHCOR or
• Z is NO2, CN, COOH, COR, NHCOR or CONHR;
• Y is CF3, F, I, Br, Cl, CN or C(R)3;
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
• R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
• R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O—C1-C12-alkyl, O—C1-C12-haloalkyl, —SO2-aryl, —SO2-phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
• Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
• R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
• R4 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, keto (═O), alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
• n is 1, 2 or 3;
• m is 1, 2 or 3;
• l is 0 or 1;
• and
• k is 0, 1 or 2;
• or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

A method of treating, suppressing, reducing the incidence of, reducing the severity of, or inhibiting the progression of an androgen-dependent disease or condition in a male in need thereof, wherein said disease or condition is hypergonadism, hypersexuality, sexual dysfunction, gynecomastia, precocious puberty in a male, hair loss, hyperandrogenic dermatological disorders, pre-cancerous lesions of the prostate, benign prostate hyperplasia, prostate cancer and/or other androgen-dependent cancers,

• comprising administering to the subject a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by the structure of formula I:
• wherein
• W1 and W2 are each independently selected from N or CH;
• W3, W4, W5 and W6 are each CH;
• wherein if any one of W1, W2, W3, W4, W5, and W6 is CH, then the H is optionally replaced with R4, Q or R3 in the respective position, and if any one of W1, W2, is not CH, then the respective position is unsubstituted;
• T is OH, OR, —NHCOCH3, NHCOR or
• Z is NO2, CN, COOH, COR, NHCOR or CONHR;
• Y is CF3, F, I, Br, Cl, CN or C(R)3;
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
• R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
• R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O—C1-C12-alkyl, O—C1-C12-haloalkyl, —SO2-aryl, —SO2-phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
• Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
• R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
• R4 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
• n is 1, 2 or 3;
• and
• m is 1, 2 or 3;
• or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

A method of treating, suppressing, reducing the incidence of, reducing the severity of, or inhibiting the progression of an androgen-dependent disease or condition in a male in need thereof, wherein said disease or condition is hypergonadism, hypersexuality, sexual dysfunction, gynecomastia, precocious puberty in a male, hair loss, hyperandrogenic dermatological disorders, pre-cancerous lesions of the prostate, benign prostate hyperplasia, prostate cancer and/or other androgen-dependent cancers,

• comprising administering to the subject a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by the structure of formula V:
• wherein
• T is OH, OR, —NHCOCH3, NHCOR or
• Z is NO2, CN, COOH, COR, NHCOR or CONHR;
• Y is CF3, F, I, Br, Cl, CN or C(R)3;
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
• R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;
• R2 is hydrogen, halogen, CN, NO2, COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH2, NHR, NR2, C1-C12-alkyl, C1-C12-haloalkyl, O—C1-C12-alkyl, O—C1-C12-haloalkyl, —SO2-aryl, —SO2-phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;
• Q is hydrogen, F, Cl, Br, I, CF3, CN, NO2, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
• R3 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
• R4 is hydrogen, F, Cl, Br, I, CF3, CN, NO2, NH2, SH, COOH, COOR, keto (═O), alkoxy, haloalkyl, optionally substituted linear or branched alkyl, optionally substituted linear or branched heteroalkyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO or OCN;
• n is 1, 2 or 3;
• m is 1, 2 or 3;
• l is 0 or 1;
• and
• k is 0, 1 or 2;
• or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.