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

Patent metadata

Field	Value
Publication number	US-10035763-B2
Application number	US-201615331777-A
Country	US
Kind code	B2
Filing date	Oct 21, 2016
Priority date	Apr 21, 2015
Publication date	Jul 31, 2018
Grant date	Jul 31, 2018

Abstract

This invention provides novel indole, indazole, benzimidazole, indoline, quinolone, isoquinoline, and carbazole selective androgen receptor degrader (SARD) compounds, pharmaceutical compositions and uses thereof in treating 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 selected from N or CH;
W 3 , W 4 , W 5 and W 6 are each independently selected from CH;
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 an integer between 1-3; and
m is an integer between 1-3; or its pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, isomer, optical isomer or any mixture of optical isomers including a racemic mixture, or any combination thereof.

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

or its pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, isomer, optical isomer or any mixture of optical isomers including a racemic mixture, or any combination thereof.

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

or its pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, isomer, optical isomer or any mixture of optical isomers including a racemic mixture, or any combination thereof.

4. The SARD compound according to claim 1 , wherein W 1 , W 2 , W 3 , W 4 , W 5 , and W 6 are CH.

5. The SARD compound according to claim 1 , wherein W 2 is N and W 1 , W 3 , W 4 , W 5 , and W 6 are CH.

6. The SARD compound according to claim 1 , wherein W 1 =N and W 2 , W 3 , W 4 , W 5 , and W 6 are CH.

7. The SARD compound according to claim 1 , represented by the structure of formula III:

or its pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, isomer, optical isomer or any mixture of optical isomers including a racemic mixture, or any combination thereof.

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

9. The SARD compound of claim 1 , wherein Z is CN.

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

11. The SARD compound of claim 1 , represented by the structure of the following compound:

12. A pharmaceutical composition comprising a SARD compound according to claim 1 , or its pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, isomer, optical isomer or any mixture of optical isomers including a racemic mixture, or any combination thereof, and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12 , wherein said composition is formulated for topical use.

14. The pharmaceutical composition of claim 12 , wherein said composition is in the form of a solution, lotion, salve, cream, ointment, liposome, spray, gel, foam, roller stick, cleansing soap or bar, emulsion, mousse, aerosol, shampoo, or any combination thereof.

15. A method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of prostate cancer (PCa) and its symptoms, or increasing the survival of a male subject suffering from prostate cancer comprising administering to said subject a therapeutically effective amount of a compound according to claim 1 , or its pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, isomer, optical isomer or any mixture of optical isomers including a racemic mixture, or any combination thereof.

16. The method of claim 15 , wherein the prostate cancer is advanced prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combination thereof.

17. The method of claim 15 , wherein said subject further receives androgen deprivation therapy (ADT).

18. The method of claim 15 , wherein said subject has failed androgen deprivation therapy (ADT).

19. The method of claim 15 , wherein said cancer is resistant to treatment with an androgen receptor antagonist and/or lyase inhibitor.

20. The method of claim 15 , wherein said administering reduces the levels of AR, AR-full length (AR-FL), AR-FL with anti-androgen resistance-conferring AR-LBD mutations, AR-splice variant (AR-SV), or any combination thereof, in said subject.

21. A method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of hyperandrogenic acne in a subject, comprising administering to said subject a therapeutically effective

Assignees

• Gtx Inc
• Univ Tennessee Res Found

Inventors

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

Classifications

• C07D209/08 Primary

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring · CPC title

• C07D209/86

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system · CPC title

• C07D215/00

  Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems · CPC title

• C07D209/42

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D235/04

  Benzimidazoles; Hydrogenated benzimidazoles · CPC title