# US 10,865,184 B2 · Selective androgen receptor degrader (SARD) ligands and methods of use thereof

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- Number: US 10,865,184 B2
- Document ID: US10865184B2
- Status: Granted
- Kind: B2
- Application number: 16/122,862
- Filed: 2018-09-05
- Published: 2019-05-16
- Granted: 2020-12-15
- Earliest claimed: 2015-04-21
- Assignees: University of Tennessee Research Foundation
- Applicants: University of Tennessee Research Foundation
- Inventors: Ramesh Narayanan; Duane D. Miller; Thamarai Ponnusamy; Dong-Jin Hwang; Yali He
- Web page: https://patentgrep.com/patent/US10865184B2

## CPC

- C07D 209/08: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
- A61K 31/403: condensed with carbocyclic rings, e.g. carbazole
- A61K 31/404: Indoles, e.g. pindolol
- 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 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/472: Non-condensed isoquinolines, e.g. papaverine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 5/26: Androgens
- A61P 17/10: Anti-acne agents
- A61P 17/14: for baldness or alopecia
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- C07D 209/42: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 209/86: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
- C07D 209/88: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
- C07D 215/06: having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
- C07D 217/04: with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
- C07D 231/56: Benzopyrazoles; Hydrogenated benzopyrazoles
- C07D 235/06: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D 249/18: Benzotriazoles
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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 selective androgen receptor degrader (SARD) compound represented by the structure of formula XVII:
wherein
X1, X2, X3, X4, and X5 are each independently N or CH, wherein if any one of X1, X2, X3, X4, and X5 is CH, then the H is optionally replaced with R2, Y, or Z in the respective position, and if any one of X1, X2, X3, X4, and X5 is not CH, then the respective position is unsubstituted; wherein at least one of X1, X2, X3, X4, or X5 is nitrogen;
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 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 2 (depends on 1)

The compound of claim 1, wherein the compound is a compound of formula XVII(1):

### Claim 3 (depends on 1)

The compound of claim 1, wherein the compound is a compound of formula XVII(2):

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 1)

The compound of claim 1, wherein only one of X1, X2, X3, X4, and X5 is N.

### Claim 8 (depends on 1)

The compound of claim 1, wherein X1 or X5 is N.

### Claim 9 (depends on 1)

The compound of claim 1, wherein X2 or X4 is N.

### Claim 10 (depends on 1)

The compound of claim 1, wherein X3 is N.

### Claim 11 (depends on 1)

The compound of claim 1, wherein X4 is N and X1, X2, X3, and X5 are CH.

### Claim 12 (depends on 1)

The compound of claim 1, wherein the compound is represented by the structure of formula XIX:

### Claim 13 (depends on 1)

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

### Claim 14 (depends on 1)

The compound of claim 1, wherein Z is CN.

### Claim 15 (depends on 1)

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

### Claim 16 (depends on 1)

The compound of claim 1, wherein said compound is represented by compound 47 or compound 99:

### Claim 17 (depends on 1)

A pharmaceutical composition comprising a SARD compound according to claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof, and a pharmaceutically acceptable carrier.

### Claim 18 (depends on 1)

A method of treating prostate cancer (PCa) or increasing the survival of a male subject suffering from prostate cancer comprising administering to the subject a therapeutically effective amount of a compound according to claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

### Claim 19 (depends on 18)

The method according to claim 18, wherein the prostate cancer is at least one of advanced prostate cancer, refractory prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), or high-risk nmCRPC.

### Claim 20 (depends on 18)

The method according to claim 18 further comprising administering androgen deprivation therapy (ADT).

### Claim 21 (depends on 18)

The method according to claim 18, wherein the prostate cancer is resistant to treatment with an androgen receptor antagonist(s).

### Claim 22 (depends on 21)

The method according to claim 21, wherein the androgen receptor antagonist is at least one of enzalutamide, apalutamide, bicalutamide, abiraterone, ODM-201, EPI-001, EPI-506, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, or spironolactone.

### Claim 23 (depends on 1)

A method of treating enzalutamide resistant prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

### Claim 24 (depends on 1)

A method of treating apalutamide resistant prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

### Claim 25 (depends on 1)

A method of treating abiraterone resistant prostate cancer comprising administering to the subject a therapeutically effective amount of a compound according to claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

### Claim 26 (depends on 1)

A method of treating triple negative breast cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

### Claim 27 (depends on 1)

A method of reducing the levels of AR-splice variants in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

### Claim 28 (depends on 27)

The method according to claim 27, wherein the method further reduces the levels of AR-full length (AR-FL) in the subject.

### Claim 29 (depends on 1)

A method of treating Kennedy's disease in a subject comprising administering to the subject a therapeutically effective amount of the compound of claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

### Claim 30 (depends on 1)

A method of treating acne in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

### Claim 31 (depends on 30)

The method according to claim 30, wherein the acne is acne vulgaris.

### Claim 32 (depends on 1)

A method of decreasing sebum production in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

### Claim 33 (depends on 32)

The method according to claim 32, wherein decreasing sebum production treats at least one of seborrhea, seborrheic dermatitis, or acne.

### Claim 34 (depends on 1)

A method of treating hirsutism or alopecia in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

### Claim 35 (depends on 34)

The method according to claim 34, wherein the alopecia is at least one of androgenic alopecia, alopecia areata, alopecia secondary to chemotherapy, alopecia secondary to radiation therapy, alopecia induced by scarring, or alopecia induced by stress.

### Claim 36 (depends on 1)

A method of treating a hyperandrogenic hormonal condition in a female comprising administering to the female a therapeutically effective amount of a compound according to claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

### Claim 37 (depends on 36)

The method according to claim 36, wherein the hormonal condition is at least one of precocious puberty, dysmenorrhea, amenorrhea, multilocular uterus syndrome, endometriosis, hysteromyoma, abnormal uterine bleeding, early menarche, fibrocystic breast disease, fibroids of the uterus, ovarian cysts, polycystic ovary syndrome, pre-eclampsia, eclampsia of pregnancy, preterm labor, premenstrual syndrome, or vaginal dryness.

### Claim 38 (depends on 1)

A method of treating sexual perversion, hypersexuality, or paraphilias in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

### Claim 39 (depends on 1)

A method of treating virilization in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

### Claim 40 (depends on 1)

A method of treating androgen insensitivity syndrome in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

### Claim 41 (depends on 1)

A method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

### Claim 42 (depends on 41)

The method according to claim 41, wherein the cancer is at least one of breast cancer, testicular cancer, cancers associated with partial androgen insensitivity syndromes (PAIS) such as gonadal tumors and seminoma, uterine cancer, ovarian cancer, cancer of the fallopian tubes or peritoneum, salivary gland cancer, bladder cancer, urogenital cancer, brain cancer, skin cancer, lymphoma, mantle cell lymphoma, liver cancer, hepatocellular carcinoma, renal cancer, renal cell carcinoma, osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer, non-small cell lung cancer (NSCLC), gastric cancer, colon cancer, perianal adenoma, or central nervous system cancer.

### Claim 43 (depends on 42)

The method according to claim 42, wherein the breast cancer is triple negative breast cancer.

### Claim 44 (depends on 1)

A method of reducing the levels of polyglutamine (polyQ) AR polymorphs in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

### Claim 45 (depends on 44)

The method according to claim 44, wherein the polyQ-AR is a short polyQ polymorph or a long polyQ polymorph.

### Claim 46 (depends on 45)

The method according to claim 45, wherein the polyQ-AR is a short polyQ polymorph and the method further treats dermal disease.

### Claim 47 (depends on 46)

The method according to claim 46, wherein the dermal disease is at least one of alopecia, seborrhea, seborrheic dermatitis, or acne.

### Claim 48 (depends on 45)

The method according to claim 45, wherein the polyQ-AR is a long polyQ polymorph and the method further treats Kennedy's disease.

### Claim 49 (depends on 1)

A method of treating uterine fibroids in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

### Claim 50 (depends on 1)

A method of treating abdominal aortic aneurysm (AAA) in a subject comprising administering a therapeutically effective amount of a compound according to claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

### Claim 51 (depends on 1)

A method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of a hyperandrogenic hormonal condition in a male in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

### Claim 52 (depends on 51)

The method of claim 51, wherein said condition is hypergonadism, hypersexuality, sexual dysfunction, gynecomastia, precocious puberty in a male, alterations in cognition and mood, depression, hair loss, hyperandrogenic dermatological disorders, precancerous lesions of the prostate, benign prostate hyperplasia, prostate cancer and/or other androgen-dependent cancers.