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

Patent metadata

Field	Value
Publication number	US-11230523-B2
Application number	US-201916425865-A
Country	US
Kind code	B2
Filing date	May 29, 2019
Priority date	Jun 10, 2016
Publication date	Jan 25, 2022
Grant date	Jan 25, 2022

Abstract

This invention is directed to pyrrole, pyrazole, imidazole, triazole, and morpholine based selective androgen receptor degrader (SARD) compounds including cyclic and heterocyclic anilide rings and their synthetic precursors, and mono-, di-, or multi-substituted N-heterocyclic rings, R-isomers, non-hydroxylated and/or non-chiral propanamides in treating androgen receptor dependent diseases and conditions such as hyperproliferations of the prostate including pre-malignancies and benign prostatic hyperplasia, 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 an androgen receptor dependent disease or condition in a subject in need thereof, 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 or six-membered saturated or 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 and 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 , OR 4 , 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 , SR 4 , SO 2 R 4 , SOR 4 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;
or its optical isomer or a racemic mixture thereof, pharmaceutically acceptable salt, pharmaceutical product, or any combination thereof.

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

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

3. The method of claim 1 , wherein said SARD compound is represented by the structure of formula IB:

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

4. The method of claim 1 , wherein said SARD compound is represented by the structure of formula II:

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 pyrrole, pyrrolidine, pyrazole, pyrazolidine, triazole, imidazole, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q 1 , Q 2 , Q 3 and 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 , OR 4 , 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 , SR 4 , SO 2 R 4 , SOR 4 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;
or its optical isomer or a racemic mixture thereof, pharmaceutically acceptable salt, pharmaceutical product, or any combination thereof.

5. The method of claim 4 , wherein said SARD compound is represented by the structure of formula IIA:

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

6. The method of claim 4 , wherein said SARD compound is represented by the structure of formula IIB:

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

7. The method of claim 1 , wherein said SARD compound is represented by the structure of formula VII:

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

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; and
Q 2 , Q 3 and Q 4 are 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, arylalkyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR;
or its optical isomer or a racemic mixture thereof, pharmaceutically acceptable salt, pharmaceutical product, or any combination thereof.

8. The method of claim 7 , wherein said SARD compound is represented by the structure of formula VIIA:

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

9. The method of claim 7 , wherein said SARD compound is represented by the structure of formula VIIB:

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

10. The method of claim 1 , wherein Q 1 , Q 2 , Q 3 and Q 4 is hydrogen, CN, NO 2 , CF 3 , F, Cl, Br, I, NHCOOR, N(R) 2 , NHCOR, COR, alkyl, alkoxy, or substituted or unsubstituted phenyl.

11. The method of claim 1 , wherein said SARD compound is represented by the structure of any one of the following compounds:

Assignees

• Univ Tennessee Res Found

Inventors

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

Classifications

• C07D207/34 Primary

  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

• C07D233/58

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

• A61K31/5375

  1,4-Oxazines, e.g. morpholine · CPC title

• C07D213/75

  Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates · CPC title

• C07D303/48

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