Selective androgen receptor degrader (SARD) ligands and methods of use thereof
This invention provides novel 3-amino propanamide selective androgen receptor degrader (SARD) compounds, pharmaceutical compositions and uses thereof in treating prostate cancer, advanced prostate cancer, castration resistant prostate cancer, androgenic alopecia or other 5 hyperandrogenic dermal diseases, Kennedy's disease, amyotrophic lateral sclerosis (ALS), 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 method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of a hyperandrogenic hormonal condition in a male 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 IA:
wherein
T is OH, OR, —NHCOCH 3 , or NHCOR;
Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
Y is CF 3 , F, I, Br, Cl, CN, C(R) 3 or Sn(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, C 1 -C 12 -alkyl, —SO 2 -aryl, —SO 2 -phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
Q 1 , Q 4 , and Q 5 are each independently selected from hydrogen, substituted or unsubstituted linear or branched alkyl, substituted aryl, F, Cl, Br, I, CF 3 , CN, NO 2 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted 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;
Q 2 and Q 3 are each independently selected from hydrogen, substituted or unsubstituted linear or branched alkyl, substituted aryl, F, Cl, Br, I, CF 3 , CN, NO 2 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted 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;
wherein at least two of Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are not hydrogens; or
Q 1 and Q 2 are joined together to form a substituted or unsubstituted C 5 -C 8 carbocyclic or heterocyclic ring, and Q 3 , Q 4 , and Q 5 are as defined above; or
Q 2 and Q 3 are joined together to form a substituted or unsubstituted C 5 -C 8 carbocyclic or heterocyclic ring, and Q 1 , Q 4 , and Q 5 are as defined above; and
wherein said formed carbocyclic or heterocyclic ring is not dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole;
or its optical isomer, its racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof.
2. The method according to claim 1 , wherein the compound is represented by the structure of formula III:
wherein
Z is NO 2 or CN;
Y is CF 3 , F, I, Br, Cl, or CN;
R 2 is hydrogen, C 1 -C 12 -alkyl, —SO 2 -aryl, —SO 2 -phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
Q 1 is substituted or unsubstituted aryl, substituted or unsubstituted phenyl, substituted or unsubstituted arylalkyl, F, Cl, Br, I, CF 3 , CN, NO 2 , or substituted or unsubstituted heterocycloalkyl;
Q 2 is hydrogen, substituted aryl, substituted phenyl, F, Cl, Br, I, CF 3 , CN, NO 2 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted arylalkyl;
Q 3 is hydrogen, substituted aryl, substituted phenyl, F, Cl, Br, I, CF 3 , CN, NO 2 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted arylalkyl;
wherein at least one of Q 1 , Q 2 and Q 3 is a substituted aryl, substituted phenyl, or substituted or unsubstituted arylalkyl; or
Q 1 and Q 2 are joined together to form a substituted or unsubstituted C 5 -C 8 carbocyclic or heterocyclic ring and Q 3 is as defined above; or
Q 2 and Q 3 are joined together to form a substituted or unsubstituted C 5 -C 8 non-aromatic carbocyclic or a heterocyclic ring and Q 1 is as defined above; and
wherein said formed carbocyclic or heterocyclic ring is not dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole;
or its optical isomer, its racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof.
3. The method according to claim 1 , wherein Q 1 is CN.
4. The method according to claim 1 , wherein Q 2 and Q 3 are joined together to form a substituted or unsubstituted C 5 -C 8 non-aromatic carbocyclic or a substituted or unsubstituted C 5 -C 8 heterocyclic ring.
5. The method according to claim 1 , wherein the compound is represented by the structure of any one of the following compounds:
6. The method according to claim 1 , wherein said condition is hypergonadism, hypersexuality, sexual dysfunction, gynecomastia, precocious puberty in a male, hair loss, hyperandrogenic dermatological disorders, pre-cancerous lesions of the prostate, benign prostate hyperplasia, prostate cancer and/or other androgen-dependent cancers.
7. A method of treating prostate cancer in a subject in need thereof, wherein said subject has AR overexpressing prostate cancer, castration-resistant prostate cancer, castration-sensitive prostate cancer, AR-V7 expressing prostate cancer, or d567ES expressing 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 IA:
wherein
T is OH, OR, —NHCOCH 3 , or NHCOR;
Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
Y is CF 3 , F, I, Br, Cl, CN, C(R) 3 or Sn(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, C 1 -C 12 -alkyl, —SO 2 -aryl, —SO 2 -phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are each independently selected from hydrogen, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CF 3 , CN, NO 2 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted 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; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof;
wherein at least two of Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are not hydrogens; or
Q 1 and Q 2 are joined together to form a substituted or unsubstituted C 5 -C 8 carbocyclic or heterocyclic ring, and Q 3 , Q 4 , and Q 5 are as defined above; or
Q 2 and Q 3 are joined together to form a substituted or unsubstituted C 5 -C 8 carbocyclic or heterocyclic ring, and Q 1 , Q 4 , and Q 5 are as defined above; and
wherein said formed carbocyclic or heterocyclic ring is not dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole.
8. The method according to claim 7 , represented by the structure of formula III:
wherein
Z is NO 2 or CN;
Y is CF 3 , F, I, Br, Cl, or CN;
R 2 is hydrogen, C 1 -C 12 -alkyl, —SO 2 -aryl, —SO 2 -phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl Q 1 is substituted or unsubstituted aryl, substituted or unsubstituted phenyl, substituted or unsubstituted arylalkyl, CN, or NO 2 ;
Q 2 is hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CF 3 , CN, NO 2 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted arylalkyl;
Q 3 is hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CF 3 , CN, NO 2 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted arylalkyl;
wherein at least one of Q 2 and Q 3 is a substituted or unsubstituted aryl, substituted or unsubstituted phenyl, or substituted or unsubstituted arylalkyl; or
Q 2 and Q 3 are joined together to form a substituted or unsubstituted C 5 -C 8 carbocyclic or heterocyclic ring and Q 1 is as defined above;
or its optical isomer, its racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof.
9. The method according to claim 7 , wherein Q 1 is CN.
10. The method according to claim 7 , wherein Q 2 and Q 3 are joined together to form a substituted or unsubstituted C 5 -C 8 non-aromatic carbocyclic or a substituted or unsubstituted C 5 -C 8 heterocyclic ring.
11. The method according to claim 7 , represented by the structure of any one of the following compounds:
12. The method of claim 7 , wherein said castration-resistant prostate cancer is AR overexpressing castration-resistant prostate cancer, F876L mutation expressing castration-resistant prostate cancer, F876L_T877A double mutation expressing castration-resistant prostate cancer, AR-V7 expressing castration-resistant prostate cancer, d567ES expressing castration-resistant prostate cancer, and/or castration-resistant prostate cancer characterized by intratumoral androgen synthesis.
13. The method of claim 7 , wherein said castration-sensitive prostate cancer is F876L mutation expressing castration-sensitive prostate cancer, F876L_T877A double mutation castration-sensitive prostate cancer, and/or castration-sensitive prostate cancer characterized by intratumoral androgen synthesis.
14. The method of claim 7 , wherein said treating of castration-sensitive prostate cancer is conducted in a non-castrate setting, or as monotherapy, or when said castration-sensitive prostate cancer tumor is resistant to enzalutamide, apalutamide, and/or abiraterone.
15. A method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting triple negative breast cancer 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 IA:
wherein
T is OH, OR, —NHCOCH 3 , or NHCOR;
Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
Y is CF 3 , F, I, Br, Cl, CN, C(R) 3 or Sn(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, C 1 -C 12 -alkyl, —SO 2 -aryl, —SO 2 -phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
Q 1 , Q 4 , and Q 5 are each independently selected from hydrogen, substituted or unsubstituted linear or branched alkyl, substituted aryl, F, Cl, Br, I, CF 3 , CN, NO 2 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted 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;
Q 2 and Q 3 are each independently selected from hydrogen, substituted or unsubstituted linear or branched alkyl, substituted aryl, F, Cl, Br, I, CF 3 , CN, NO 2 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted 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;
wherein at least two of Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are not hydrogens; or
Q 1 and Q 2 are joined together to form a substituted or unsubstituted C 5 -C 8 carbocyclic or heterocyclic ring, and Q 3 , Q 4 , and Q 5 are as defined above; or
Q 2 and Q 3 are joined together to form a substituted or unsubstituted C 5 -C 8 carbocyclic or heterocyclic ring, and Q 1 , Q 4 , and Q 5 are as defined above; and
wherein said formed carbocyclic or heterocyclic ring is not dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole;
or its optical isomer, its racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof.
16. The method according to claim 15 , wherein the compound is represented by the structure of formula III:
wherein
Z is NO 2 or CN;
Y is CF 3 , F, I, Br, Cl, or CN;
R 2 is hydrogen, C 1 -C 12 -alkyl, —SO 2 -aryl, —SO 2 -phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
Q 1 is substituted or unsubstituted aryl, substituted or unsubstituted phenyl, substituted or unsubstituted arylalkyl, F, Cl, Br, I, CF 3 , CN, NO 2 , or substituted or unsubstituted heterocycloalkyl;
Q 2 is hydrogen, substituted aryl, substituted phenyl, F, Cl, Br, I, CF 3 , CN, NO 2 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted arylalkyl;
Q 3 is hydrogen, substituted aryl, substituted phenyl, F, Cl, Br, I, CF 3 , CN, NO 2 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted arylalkyl;
wherein at least one of Q 1 , Q 2 and Q 3 is a substituted aryl, substituted phenyl, or substituted or unsubstituted arylalkyl; or
Q 1 and Q 2 are joined together to form a substituted or unsubstituted C 5 -C 8 carbocyclic or heterocyclic ring and Q 3 is as defined above; or
Q 2 and Q 3 are joined together to form a substituted or unsubstituted C 5 -C 8 non-aromatic carbocyclic or a heterocyclic ring and Q 1 is as defined above; and
wherein said formed carbocyclic or heterocyclic ring is not dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole;
or its optical isomer, its racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof.
17. The method according to claim 15 , wherein Q 1 is CN.
18. The method according to claim 15 , wherein Q 2 and Q 3 are joined together to form a substituted or unsubstituted C 5 -C 8 non-aromatic carbocyclic or a substituted or unsubstituted C 5 -C 8 heterocyclic ring.
19. The method according to claim 15 , wherein the compound is represented by the structure of any one of the following compounds:
20. A method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of a hyperandrogenic hormonal condition in a male in need thereof; prostate cancer in a subject in need thereof, wherein said subject has AR overexpressing prostate cancer, castration-resistant prostate cancer, castration-sensitive prostate cancer, AR-V7 expressing prostate cancer, or d567ES expressing prostate cancer; or triple negative breast cancer 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: