Cereblon ligands

Abstract

The disclosure provides compds. of formula I,​and the salts and solvates thereof. The disclosure also relates to uses of the compds. as cereblon (CRBN) ubiquitination inhibitors, as synthetic intermediates that can be used to prep. PROTAC mols., or as PROTAC mols. The disclosure also relates to uses of the compds., e.g., in treating or preventing cancer and other diseases. Compds. of formula I wherein when A1 is CR2a and N; then A is CR2b; A2 is CR2c; A3 is CR2' and N; R2a and R2' are independently H, halo, C1-​3 alkyl, amino and C1-​3 alkoxy; R2bR2c are taken together to form (CH2)​1-​3 NR1a(CH2)​1-​3, (CH2)​1-​3 CR1bR1c(CH2)​1-​3, CONR1'(CH2)​1,​-​2, etc.; when A1 is CR2a and N; then A is CR2b; A2 is CR2c; A3 is CR2' and N; R2c and R2' are independently H, halo, C1-​3 alkyl, amino and C1-​3 alkoxy; R2aR2b are taken together to form (CH2)​1-​3 NR1a(CH2)​1-​3, (CH2)​1-​3 CR1bR1c(CH2)​1-​3, CONR1'(CH2)​1,​-​2, etc.; R1a is H, C1-​3 alkyl, aryl, heteroaryl, etc.; R1b is H, CHO, CO2H, NH2, etc.; R1c is H; R1bR1c may be taken together to form :O and azacycle; R1' is H, heterocyclyl, heterocycloalkyl, etc.; R3 is H, D, F and C1-​3 alkyl; Z and Z1 are CO; Z is CO and Z1 is CR4aR4b and N:C(CH3)​; Z is CR4aR4b and N:C(CH3) and Z1 is CO; Z is a bond and Z1 is NHCO and derivs.; Z is NHCO and derivs. and Z1 is a bond; R4a and R4b are independently H and C1-​3 alkyl R4aR4b may be taken together to form C3-​6 cycloalkyl; and pharmaceutically acceptable salts and solvates thereof, are claimed. Example compd. II was prepd. by a multistep procedure (procedure given)​. The invention compds. were evaluated for their cereblon binding activity