SELECTIVE ANDROGEN RECEPTOR DEGRADER (SARD) LIGANDS AND METHODS OF USE THEREOF

摘要

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 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.

主权项

1. A selective androgen receptor degrader (SARD) compound represented by the structure of formula I: wherein
T is OH, OR, —NHCOCH3, or NHCOR;Z is NO2, CN, COOH, COR, NHCOR or CONHR;Y is CF3, F, I, Br, Cl, CN, C(R)3 or Sn(R)3;R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3;R2 is hydrogen, C1-C12-alkyl, —SO2-aryl, —SO2-phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C3-C7-cycloalkyl;Q1, Q2, Q3, Q4, and Q5 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, CF3, CN, NO2, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)3, N(R)2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, or OCN;wherein at least two of Q1, Q2, Q3, Q4, and Q5 are not hydrogens; orQ1 and Q2 are joined together to form a substituted or unsubstituted C5-C8 carbocyclic or heterocyclic ring, and Q3, Q4, and Q5 are as defined above; orQ2 and Q3 are joined together to form a substituted or unsubstituted C5-C8 carbocyclic or heterocyclic ring, and Q1, Q4, and Q5 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.