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

Patent metadata

Field	Value
Publication number	US-10654809-B2
Application number	US-201815923668-A
Country	US
Kind code	B2
Filing date	Mar 16, 2018
Priority date	Jun 10, 2016
Publication date	May 19, 2020
Grant date	May 19, 2020

Abstract

This invention is directed to pyrrole, pyrazole, imidazole, triazole, and morpholine based selective androgen receptor degrader (SARD) compounds including heterocyclic anilide rings and their synthetic precursors, R-isomers, and non-hydroxylated and/or non-chiral propanamides, and pharmaceutical compositions and uses thereof in treating prostate cancer, advanced prostate cancer, castration resistant prostate cancer, triple negative breast cancer, other cancers expressing the androgen receptor, androgenic alopecia or other hyperandrogenic dermal diseases, Kennedy's disease, amyotrophic lateral sclerosis (ALS), abdominal aortic aneurysm (AAA), and uterine fibroids, and to methods for reducing the levels of androgen receptor-full length (AR-FL) including pathogenic 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 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 selective androgen receptor degrader (SARD) compound represented by the structure of formula I:

wherein
T is OH, OR, OCOR, CH 3 , —NHCOCH 3 , or NHCOR;
R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
or T and R 1 form a 3-8 carbocyclic or heterocyclic ring;

Y is H, CF 3 , F, I, Br, Cl, CN, or C(R) 3 ;
Z is H, NO 2 , CN, halide, COOH, COR, NHCOR, CONHR,
or Y and Z form a 5 to 8 membered fused ring;
X is CH or N;
R is H, alkyl, alkenyl, haloalkyl, alcohol, CH 2 CH 2 OH, CF 3 , CH 2 Cl, CH 2 CH 2 Cl, aryl, F, Cl, Br, I, or OH;
A is R 2 or R 3 ;
R 2 is a five-membered saturated or five or six-membered unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q 1 , Q 2 , Q 3 or Q 4 , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO 2 , hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR;
R 3 is halide, N 3 , CF 3 , COR 4 , COCl, COOCOR 4 , COOR 4 , OCOR 4 , OCONHR 4 , NHCOOR 4 , NHCONHR 4 , OCOOR 4 , CN, CONH 2 , CONH(R 4 ), CON(R 4 ) 2 , SO 3 H, SO 2 NH 2 , SO2NH(R 4 ), SO 2 N(R 4 ) 2 , NH 2 , CO(N-heterocycle), NO 2 , cyanate, isocyanate, thiocyanate, isothiocyanate, mesylate, tosylate, triflate, PO(OH) 2 or OPO(OH) 2 ; and
R 4 is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionally substituted;
wherein if A is Br or I, R 1 is CH 3 , and T is OH, then X is N or the aniline ring forms a fused heterocyclic ring,
or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

2. The method according to claim 1 , 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.

3. The method according to claim 1 further comprising administering androgen deprivation therapy (ADT).

4. The method according to claim 1 , wherein the prostate cancer is resistant to treatment with an androgen receptor antagonist(s).

5. The method according to claim 4 , wherein the androgen receptor antagonist is at least one of enzalutamide, bicalutamide, abiraterone, ARN-509, ODM-201, EPI-001, EPI-506, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, or spironolactone.

6. A method of treating enzalutamide resistant prostate cancer in a subject 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
T is OH, OR, OCOR, CH 3 , —NHCOCH 3 , or NHCOR;
R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
or T and R 1 form a 3-8 carbocyclic or heterocyclic ring;

Y is H, CF 3 , F, I, Br, Cl, CN, or C(R) 3 ;
Z is H, NO 2 , CN, halide, COOH, COR, NHCOR, CONHR,
or Y and Z form a 5 to 8 membered fused ring;
X is CH or N;
R is H, alkyl, alkenyl, haloalkyl, alcohol, CH 2 CH 2 OH, CF 3 , CH 2 Cl, CH 2 CH 2 Cl, aryl, F, Cl, Br, I, or OH;
A is R 2 or R 3 ;
R 2 is a five-membered saturated or five or six-membered unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q 1 , Q 2 , Q 3 or Q 4 , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO 2 , hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR;
R 3 is halide, N 3 , CF 3 , COR 4 , COCl, COOCOR 4 , COOR 4 , OCOR 4 , OCONHR 4 , NHCOOR 4 , NHCONHR 4 , OCOOR 4 , CN, CONH 2 , CONH(R 4 ), CON(R 4 ) 2 , SO 3 H, SO 2 NH 2 , SO 2 NH(R 4 ), SO 2 N(R 4 ) 2 , NH 2 , CO(N-heterocycle), NO 2 , cyanate, isocyanate, thiocyanate, isothiocyanate, mesylate, tosylate, triflate, PO(OH) 2 or OPO(OH) 2 ; and
R 4 is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionally substituted;
wherein if A is Br or I, R 1 is CH 3 , and T is OH, then X is N or the aniline ring forms a fused heterocyclic ring,
or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

7. A method of treating abiraterone resistant 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
T is OH, OR, OCOR, CH 3 , —NHCOCH 3 , or NHCOR;
R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
or T and R 1 form a 3-8 carbocyclic or heterocyclic ring;

Y is H, CF 3 , F, I, Br, Cl, CN, or C(R) 3 ;
Z is H, NO 2 , CN, halide, COOH, COR, NHCOR, CONHR,
or Y and Z form a 5 to 8 membered fused ring;
X is CH or N;
R is H, alkyl, alkenyl, haloalkyl, alcohol, CH 2 CH 2 OH, CF 3 , CH 2 Cl, CH 2 CH 2 Cl, aryl, F, Cl, Br, I, or OH;
A is R 2 or R 3 ;
R 2 is a five-membered saturated or five or six-membered unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q 1 , Q 2 , Q 3 or Q 4 , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO 2 , hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR;
R 3 is halide, N 3 , CF 3 , COR 4 , COCl, COOCOR 4 , COOR 4 , OCOR 4 , OCONHR 4 , NHCOOR 4 , NHCONHR 4 , OCOOR 4 , CN, CONH 2 , CONH(R 4 ), CON(R 4 ) 2 , SO 3 H, SO 2 NH 2 , SO 2 NH(R 4 ), SO 2 N(R 4 ) 2 , NH 2 , CO(N-heterocycle), NO 2 , cyanate, isocyanate, thiocyanate, isothiocyanate, mesylate, tosylate, triflate, PO(OH) 2 or OPO(OH) 2 ; and
R 4 is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionally substituted;
wherein if A is Br or I, R 1 is CH 3 , and T is OH, then X is N or the aniline ring forms a fused heterocyclic ring,
or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

8. The method of claim 1 , wherein the SARD compound is represented by the structure of formula IA:

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

9. The method of claim 6 , wherein the S

Assignees

• Univ Tennessee Res Found

Inventors

• Narayanan Ramesh
• Miller Duane D
• Ponnusamy Thamarai
• Hwang Dong-Jin
• He Yali

Classifications

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• C07D207/34

  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 ring carbon atoms · CPC title

• A61K31/4164

  1,3-Diazoles · CPC title

• C07D233/68

  Halogen atoms · CPC title

• C07D207/06

  with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms · CPC title