Selective androgen receptor degrader (SARD) ligands and methods of use thereof
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.
1. 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, or 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;
or its optical isomer or a racemic mixture thereof, isomer, pharmaceutically acceptable salt, pharmaceutical product, or any combination thereof;
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.
2. The selective androgen receptor degrader (SARD) compound of claim 1 , represented by the structure of formula IA:
or its isomer, pharmaceutically acceptable salt, pharmaceutical product, or any combination thereof.
3. The selective androgen receptor degrader (SARD) compound of claim 1 , represented by the structure of formula IB:
or its isomer, pharmaceutically acceptable salt, pharmaceutical product, or any combination thereof.
4. The SARD compound of claim 1 , 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, or 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, or imidazolidine ring, said ring 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;
or its optical isomer or a racemic mixture thereof, isomer, pharmaceutically acceptable salt, pharmaceutical product, or any combination thereof;
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.
5. The SARD compound of claim 4 , represented by the structure of formula IIA:
or its isomer, pharmaceutically acceptable salt, pharmaceutical product, or any combination thereof.
6. The SARD compound of claim 4 , represented by the structure of formula IIB:
or its isomer, pharmaceutically acceptable salt, pharmaceutical product, or any combination thereof.
7. The SARD compound of claim 1 , 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, or 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 or 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, isomer, pharmaceutically acceptable salt, pharmaceutical product, or any combination thereof.
8. The SARD compound of claim 7 , represented by the structure of formula VIIA:
or its isomer, pharmaceutically acceptable salt, pharmaceutical product, or any combination thereof.
9. The SARD compound of claim 7 , represented by the structure of formula VIIB:
or its isomer, pharmaceutically acceptable salt, pharmaceutical product, or any combination thereof.
10. The SARD compound of claim 1 , wherein Q 1 , Q 2 , Q 3 or Q 4 is hydrogen, CN, NO 2 , CF 3 , F, Cl, Br, I, NHCOOR, N(R) 2 , NHCOR, COR, or substituted or unsubstituted phenyl.
11. The SARD compound of claim 1 , represented by the structure of any one of the following compounds:
12. The compound according to claim 1 , wherein the compound exhibits at least one of AR-splice variant (AR-SV) degradation activity, full length (AR-FL) degradation activity, AR-SV inhibitory, or AR-FL inhibitory activity.
13. A pharmaceutical composition comprising a SARD compound according to claim 1 , or its optical isomer or a racemic mixture thereof, isomer, pharmaceutically acceptable salt, pharmaceutical product, or any combination thereof; and a pharmaceutically acceptable carrier.
14. The pharmaceutical composition according to claim 13 , wherein the composition is formulated for topical use.
15. The pharmaceutical composition according to claim 14 , wherein the 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, or shampoo.