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

Patent metadata

Field	Value
Publication number	US-11273147-B2
Application number	US-201916556828-A
Country	US
Kind code	B2
Filing date	Aug 30, 2019
Priority date	Apr 21, 2015
Publication date	Mar 15, 2022
Grant date	Mar 15, 2022

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.

First claim

What is claimed is:

1. A selective androgen receptor degrader (SARD) compound represented by the structure of formula I:

wherein
W 1 and W 2 are each independently N;
W 3 , W 4 , W 5 and W 6 are each independently selected from CH or N;
wherein if any one of W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 is CH, then the H is optionally replaced with R 4 , Q or R 3 in the respective position, and if any one of W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 is not CH, then the respective position is unsubstituted;
T is OH, OR, —NHCOCH 3 , NHCOR or

Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
Y is CF 3 , F, I, Br, Cl, CN or C(R) 3 ;
R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
R 2 is hydrogen, halogen, CN, NO 2 , COOH, COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH 2 , NHR, NR 2 , C 1 -C 12 -alkyl, C 1 -C 12 -haloalkyl, O—C 1 -C 12 -alkyl, O—C 1 -C 12 -haloalkyl, —SO 2 -aryl, —SO 2 -phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
Q is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , 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 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
R 3 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , 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 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
R 4 is hydrogen, F, Cl, Br, I, CF 3 , CN, NO 2 , NH 2 , 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 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO or OCN;
n is 1, 2, or 3; and
m is 1, 2, or 3,

or its optical isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

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

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

4. The compound of claim 1 , wherein Q is H, NO 2 , COR, alkyl, alkoxy, aryl, CN, CF 3 , F, Cl, Br or I.

5. The compound of claim 1 , wherein Z is CN.

6. The compound of claim 1 , wherein Y is Cl or CF 3 .

7. The compound of claim 1 , represented by the structure of any one of the following compounds:

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

9. A method of treating an androgen receptor dependent disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or its optical isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, wherein said androgen receptor dependent disease or condition is acne, overproduction of sebum, hirsutism, alopecia, a hormonal disease or condition in a female, virilization, androgen insensitivity syndrome, AR-expressing cancer, or uterine fibroids, wherein said hormonal disease or condition in a female is 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.

10. The method of claim 9 , wherein said acne is acne vulgaris.

11. The method of claim 9 , wherein reducing said overproduction of sebum treats at least one of seborrhea, seborrheic dermatitis, or acne.

12. The method of claim 9 , wherein said 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.

13. The method of claim 9 , wherein said AR-expressing 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.

14. A SARD compound, represented by the structure of any one of the following compounds:

or its optical isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

15. A pharmaceutical composition comprising a SARD compound according to claim 14 , or its optical isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof, and a pharmaceutically acceptable carrier.

16. A method of treating an androgen receptor dependent disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 14 , or its optical isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, wherein said androgen receptor dependent disease or condition is acne, overproduction of sebum, hirsutism, alopecia, a hormonal disease or condition in a female, virilization, androgen insensitivity syndrome, AR-expressing cancer, or uterine fibroids,

Assignees

• Univ Tennessee Res Found

Inventors

• Narayanan Ramesh
• Miller Duane D
• Ponnusamy Thamarai
• Hwang Dong-Jin
• He Yali
• Pagadala Jayaprakash
• Coss Christopher C
• Dalton James T
• Duke Charles B

Classifications

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/47

  Quinolines; Isoquinolines · CPC title

• A61K31/404 Primary

  Indoles, e.g. pindolol · CPC title

• A61K31/403

  condensed with carbocyclic rings, e.g. carbazole · CPC title

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title