Compounds and methods for the targeted degradation of androgen receptor

A compound represented by the structure:

• ABM-L-CLM,
• or a pharmaceutically acceptable salt thereof, wherein:
• (a) CLM is
• wherein:
• W is CH2 or C═O;
• A is H;
• n is an integer from 1 to 4;
• wherein when n is 1, R is an aryl, heteroaryl, cycloalkyl, or heterocyclyl covalently joined to the linker group (L);
• and when n is 2, 3, or 4, one R is an aryl, heteroaryl, cycloalkyl, or heterocyclyl covalently joined to the linker group (L) and the remaining R are selected from OR′, —NR′R″, —SR′, —C1-6 alkyl, —Cl, —F, —Br, —I, —CF3, —CN, and —OCF3;
• R′ and R″ are each independently selected from H, C1-6 alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;
• and
• represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific;
• (b) L is a chemical linker group that is covalently bound to the ABM and the CLM, and has the chemical structure -(AL)q-, wherein:
• q is an integer greater than or equal to 1;
• each AL is selected from CRL1RL2, O, S, NRL3, CO, CRL1═CRL2, C≡C, C3-11 cycloalkyl optionally substituted with 1-6 RL1, C5-13 spirocycloalkyl optionally substituted with 1-9 RL1, C3-11 heterocyclyl optionally substituted with 1-6 RL1, C5-13 spiroheterocycloalkyl optionally substituted with 1-8 RL1, aryl optionally substituted with 1-4 RL1, and heteroaryl optionally substituted with 1-4 RL1;
• and
• RL1, RL2, and RL3 are each, independently, H, halogen, C1-8alkyl, OC1-8alkyl, NHC1-8alkyl, N(C1-8alkyl)2, C3-11cycloalkyl, aryl, heteroaryl, C3-11heterocyclyl, OC3-8cycloalkyl, NHC3-8cycloalkyl, N(C3-8cycloalkyl)2, N(C3-8cycloalkyl)(C1-8alkyl), OH, NH2, COC1-8alkyl, CO2H, CN, CF3, CHF2, CH2F, NO2, CONHC1-8alkyl, or CON(C1-8alkyl)2, or RL1 and RL2 are linked to form a cycloalkyl or a heterocyclyl moiety;
• and
• (c) ABM is:
• wherein:
• W1 is aryl optionally substituted by 1 or more halogen;
• hydroxyl;
• nitro;
• CN;
• C1-6 alkyl optionally substituted by 1 or more halogen or C1-6 alkoxyl;
• or C1-6 alkoxyl optionally substituted by 1 or more halogen;
• each Y3 is independently a bond, O, NRY2, CRY1RY2, or C═O;
• Q is a 6-membered alicyclic substituted with 0-6 RQ;
• each RQ is independently halogen;
• C1-6 alkoxy;
• or C1-6 alkyl optionally substituted by 1 or more halogen or C1-6 alkoxyl;
• RY1 and RY2 are each, independently, H, halogen, C1-6 alkoxy, or C1-6 alkyl optionally substituted by 1 or more halogen or C1-6 alkoxyl;
• W2 is aryl optionally substituted by 1-4 RW2 or heteroaryl optionally substituted by 1-4 RW2;
• each RW2 is, independently, halogen;
• C1-6 alkyl optionally substituted by 1 or more —F;
• OH;
• NRY1RY2;
• CN;
• or OC1-3alkyl optionally substituted by 1 or more —F;
• and
• is the point of attachment of the ABM to the chemical linker group (L).