# US 10,441,570 B2 · Selective androgen receptor degrader (SARD) Ligands and methods of use thereof

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- Number: US 10,441,570 B2
- Document ID: US10441570B2
- Status: Granted
- Kind: B2
- Application number: 15/981,636
- Filed: 2018-05-16
- Published: 2018-12-20
- Granted: 2019-10-15
- Earliest claimed: 2015-04-21
- Assignees: University of Tennessee Research Foundation; GTx, Inc.
- Applicants: GTx, Inc.; University of Tennessee Research Foundation
- Inventors: Ramesh Narayanan; Duane D. Miller; Thamarai Ponnusamy; Dong-Jin Hwang; Yali He; Jayaprakash Pagadala; Charles B. Duke; Christopher C. Coss; James T. Dalton
- Web page: https://patentgrep.com/patent/US10441570B2

## CPC

- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/403: condensed with carbocyclic rings, e.g. carbazole
- A61K 31/416: condensed with carbocyclic ring systems, e.g. indazole
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/4192: 1,2,3-Triazoles
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/472: Non-condensed isoquinolines, e.g. papaverine
- A61P 35/00: Antineoplastic agents
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention provides novel indole, indazole, benzimidazole, benzotriazole, indoline, quinolone, isoquinoline, and carbazole selective androgen receptor degrader (SARD) compounds, pharmaceutical compositions and uses thereof in treating hyperproliferations of the prostate including pre-malignancies and benign prostatic hyperplasia, prostate cancer, advanced prostate cancer, castration resistant prostate cancer, other AR-expressing cancers, androgenic alopecia or other hyper androgenic dermal diseases, Kennedy's disease, amyotrophic lateral sclerosis (ALS), abdominal aortic aneurysm (AAA), and uterine fibroids, and to methods for reducing the levels (through degradation) and/or activity (through inhibition) of any androgen receptor including androgen receptor-full length (AR-FL) including pathogenic and/or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.

## Claims

### Claim 1

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 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.

### Claim 2 (depends on 1)

The method of claim 1, wherein said compound is a compound of formula I(1):

### Claim 3 (depends on 1)

The method of claim 1, wherein said compound is a compound of formula I(2):

### Claim 4 (depends on 1)

The method of claim 1, wherein W1, W2, W3, W4, W5, and W6 are CH.

### Claim 5 (depends on 1)

The method of claim 1, wherein W2 is N and W1, W3, W4, W5, and W6 are CH.

### Claim 6 (depends on 1)

The method of claim 1, wherein W1 is N and W2, W3, W4, W5, and W6 are CH.

### Claim 7 (depends on 1)

The method of claim 1, represented by the structure of formula III:

### Claim 8 (depends on 1)

The method of claim 1, wherein Q is H, NO2, COR, alkyl, alkoxy, aryl, CN, CF3, F, Cl, Br or I.

### Claim 9 (depends on 1)

The method of claim 1, wherein Z is CN.

### Claim 10 (depends on 1)

The method of claim 1, wherein Y is Cl or CF3.

### Claim 11 (depends on 1)

The method of claim 1, represented by one of the following compounds:
indoles:
benzimidazoles:
indazoles:
benzotriazoles:

### Claim 12 (depends on 1)

The method of claim 1, wherein said castration-resistant prostate cancer is AR overexpressing castration-resistant prostate cancer, F876L mutation expressing castration-resistant prostate cancer, F876L_T877A double mutation expressing castration-resistant prostate cancer, AR-V7 expressing castration-resistant prostate cancer, d567ES expressing castration-resistant prostate cancer, and/or castration-resistant prostate cancer characterized by intratumoral androgen synthesis.

### Claim 13 (depends on 1)

The method of claim 1, wherein said castration-sensitive prostate cancer is F876L mutation expressing castration-sensitive prostate cancer, F876L_T877A double mutation castration-sensitive prostate cancer, and/or castration-sensitive prostate cancer characterized by intratumoral androgen synthesis.

### Claim 14 (depends on 1)

The method of claim 1, wherein said treating of castration-sensitive prostate cancer is conducted in a non-castrate setting, or as monotherapy, or when castration-sensitive prostate cancer tumor is resistant to enzalutamide, apalutamide, and/or abiraterone.

### Claim 15

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.

### Claim 16 (depends on 15)

The method of claim 15, wherein said compound is a compound of formula V(1):

### Claim 17 (depends on 15)

The method of claim 15, wherein said compound is a compound of formula V(2):

### Claim 18 (depends on 15)

The method of claim 15, wherein said compound is represented by the structure of formula VI:

### Claim 19 (depends on 15)

The method of claim 15, wherein said compound is represented by the structure of formula VII:

### Claim 20 (depends on 15)

The method of claim 15, wherein said compound is represented by the structure of formula IV:

### Claim 21 (depends on 15)

The method of claim 15, wherein Q is H, F, Cl, Br, I, NO2, CN, and aryl.

### Claim 22 (depends on 15)

The method of claim 15, wherein said compound is represented by the following structures:
indolines:
isoquinolines and quinolines:

### Claim 23 (depends on 15)

The method of claim 15, wherein said castration-resistant prostate cancer is AR overexpressing castration-resistant prostate cancer, F876L mutation expressing castration-resistant prostate cancer, F876L_T877A double mutation expressing castration-resistant prostate cancer, AR-V7 expressing castration-resistant prostate cancer, d567ES expressing castration-resistant prostate cancer, and/or castration-resistant prostate cancer characterized by intratumoral androgen synthesis.

### Claim 24 (depends on 15)

The method of claim 15, wherein said castration-sensitive prostate cancer is F876L mutation expressing castration-sensitive prostate cancer, F876L_T877A double mutation castration-sensitive prostate cancer, and/or castration-sensitive prostate cancer characterized by intratumoral androgen synthesis.

### Claim 25 (depends on 15)

The method of claim 15, wherein said treating of castration-sensitive prostate cancer is conducted in a non-castrate setting, or as monotherapy, or when castration-sensitive prostate cancer tumor is resistant to enzalutamide, apalutamide, and/or abiraterone.

### Claim 26

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.

### Claim 27 (depends on 26)

The method of claim 26, wherein said compound is a compound of formula I(1):

### Claim 28 (depends on 26)

The method of claim 26, wherein said compound is a compound of formula I(2):

### Claim 29 (depends on 26)

The method of claim 26, wherein W1, W2, W3, W4, W5, and W6 are CH.

### Claim 30 (depends on 26)

The method of claim 26, wherein W2 is N and W1, W3, W4, W5, and W6 are CH.

### Claim 31 (depends on 26)

The method of claim 26, wherein W1 is N and W2, W3, W4, W5, and W6 are CH.

### Claim 32 (depends on 26)

The method of claim 26, represented by the structure of formula III:

### Claim 33 (depends on 26)

The method of claim 26, wherein Q is H, NO2, COR, alkyl, alkoxy, aryl, CN, CF3, F, Cl, Br or I.

### Claim 34 (depends on 26)

The method of claim 26, wherein Z is CN.

### Claim 35 (depends on 26)

The method of claim 26, wherein Y is Cl or CF3.

### Claim 36 (depends on 26)

The method of claim 26, represented by the structure of anyone of the following compounds:
indoles:
benzimidazoles:
indazoles:
benzotriazoles:

### Claim 37

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.

### Claim 38 (depends on 37)

The method of claim 37, wherein said compound is a compound of formula V(1):

### Claim 39 (depends on 37)

The method of claim 37, wherein said compound is a compound of formula V(2):

### Claim 40 (depends on 37)

The method of claim 37, wherein said compound is represented by the structure of formula VI:

### Claim 41 (depends on 37)

The method of claim 37, wherein said compound is represented by the structure of formula VII:

### Claim 42 (depends on 37)

The method of claim 37, wherein said compound is represented by the structure of formula IV:

### Claim 43 (depends on 37)

The method of claim 37, wherein Q is H, F, Cl, Br, I, NO2, CN, and aryl.

### Claim 44 (depends on 37)

The method of claim 37, wherein said compound is represented by the following structures:
indolines:
isoquinolines and quinolines:

### Claim 45

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.

### Claim 46 (depends on 45)

The method of claim 45, wherein said compound is a compound of formula I(1):

### Claim 47 (depends on 45)

The method of claim 45, wherein said compound is a compound of formula I(2):

### Claim 48 (depends on 45)

The method of claim 45, wherein W1, W2, W3, W4, W5, and W6 are CH.

### Claim 49 (depends on 45)

The method of claim 45, wherein W2 is N and W1, W3, W4, W5, and W6 are CH.

### Claim 50 (depends on 45)

The method of claim 45, wherein W1 is N and W2, W3, W4, W5, W6 are CH.

### Claim 51 (depends on 45)

The method of claim 45, represented by the structure of formula III:

### Claim 52 (depends on 45)

The method of claim 45, wherein Q is H, NO2, COR, alkyl, alkoxy, aryl, CN, CF3, F, Cl, Br or I.

### Claim 53 (depends on 45)

The method of claim 45, wherein Z is CN.

### Claim 54 (depends on 45)

The method of claim 45, wherein Y is Cl or CF3.

### Claim 55 (depends on 45)

The method of claim 45, represented by the structure of any one of the following compounds:
indoles:
benzimidazoles:
indazoles:
benzotriazoles:

### Claim 56

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.

### Claim 57 (depends on 56)

The method of claim 56, wherein said compound is a compound of formula V(1):

### Claim 58 (depends on 56)

The method of claim 56, wherein said compound is a compound of formula V(2):

### Claim 59 (depends on 56)

The method of claim 56, wherein said compound is represented by the structure of formula VI:

### Claim 60 (depends on 56)

The method of claim 56, wherein said compound is represented by the structure of formula VII:

### Claim 61 (depends on 56)

The method of claim 56, wherein said compound is represented by the structure of formula IV:

### Claim 62 (depends on 56)

The method of claim 56, wherein Q is H, F, Cl, Br, I, NO2, CN, and aryl.

### Claim 63 (depends on 56)

The method of claim 56, wherein said compound is represented by the following structures:
indolines:
isoquinolines and quinolines:

### Claim 64

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:
or its isomer, racemic mixture containing the SARD compound, a metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal of said selective androgen receptor degrader, or any combination thereof.

### Claim 65

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:
or its isomer, racemic mixture containing the SARD compound, a metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal of said selective androgen receptor degrader, or any combination thereof.

### Claim 66

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:
or its isomer, racemic mixture containing the SARD compound, a metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal of said selective androgen receptor degrader, or any combination thereof.