Degraders and degrons for targeted protein degradation

A compound of Formula:

• or a pharmaceutically acceptable salt thereof;
• wherein:
• W1 is C═O;
• W2 is C═O;
• R2 is selected at each instance from the group consisting of hydrogen, alkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, —C(O)(aryl or heteroaryl), —C(O)O(aryl or heteroaryl), alkene, and alkyne;
• R4 is selected from the group consisting of hydrogen, alkyl, and heterocyclic;
• R5 is selected at each instance from the group consisting of hydrogen, alkyl, alkene, alkyne, F, Cl, hydroxyl, alkylhydroxyl, alkoxy, azide, amino, alkylamino, cyano, —NH(alkyl), —N(alkyl)2, —NHSO2(alkyl), —N(alkyl)SO2alkyl, —NHSO2(aryl, heteroaryl, or heterocyclic), —N(alkyl)SO2(aryl, heteroaryl, or heterocyclic), —NHSO2alkenyl, —N(alkyl)SO2alkenyl, —NHSO2alkynyl, —N(alkyl)SO2alkynyl, haloalkyl, heteroalkyl, carbocyclic, C(O)R40, aryl, aryloxy, heterocyclo, heteroaryl, arylalkyl, O-arylalkyl, nitro, nitroso, sulfone, sulfoxide, thioalkyl, thiol, haloalkyl, and cycloalkyl;
• R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, carbocyclic, heterocyclic, aryl, heteroaryl, F, Cl, azide, cyano, hydroxyl, alkoxy, amine, —NH(alkyl), and —N(alkyl)2;
• or R10 and R11 together with the carbon to which they are bound form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S;
• R13 and R14 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxy, amino, —NHalkyl, and —N(alkyl)2;
• or R13 and R14 together with the carbon atom to which they are attached form C(O), C(S), C═CH2, a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;
• R16 is selected from the group consisting of:
• or R16 is a 4, 5, 6, 7, 8, 9, or 10 membered carbocyclo or aryl moiety, wherein the carbocyclo or aryl moiety is substituted with R12 at any desired position;
• wherein the carbocyclo or aryl moiety is optionally further substituted with one, two, or three substituents selected from R5;
• and wherein the carbocyclo or aryl moiety is attached through a carbon atom;
• or R16 is
• R17 is selected from the group consisting of R17a, R17b, and R17c,
• R17a is selected from the group consisting of:
• or R17a is selected from the group consisting of
• or R17a is selected from the group consisting of:
• R17b is selected from the group consisting of:
• or R17b is —NR2aryl, —NR2heteroaryl, or NR2carbocycle, wherein the aryl, heteroaryl, and carbocycle moieties are substituted with a R12 at any desired position, wherein the aryl, heteroaryl, and carbocycle moieties are optionally further substituted with one, two, or three substituents selected from R5;
• and wherein the aryl, heteroaryl, and carbocycle moieties are optionally further substituted with one oxo group at a position allowed by valence;
• R17c is selected from the group consisting of:
• or R17c is —O-aryl, —O-heteroaryl, or —O-carbocycle, wherein the aryl, heteroaryl, and carbocycle moieties are substituted with a R12 at any desired position, wherein the aryl, heteroaryl, and carbocycle moieties are optionally further substituted with one, two, or three substituents selected from R5;
• and wherein the aryl, heteroaryl, and carbocycle moieties are optionally further substituted with one oxo group at a position allowed by valence;
• R40 is selected at each instance from the group consisting of:
• hydrogen, alkyl, alkene, alkyne, F, Cl, hydroxyl, alkoxy, azide, amino, cyano, —NH(alkyl), —N(alkyl)2, —NHSO2(alkyl), —N(alkyl)SO2alkyl, —NHSO2(aryl, heteroaryl or heterocyclic), —N(alkyl)SO2(aryl, heteroaryl or heterocyclic), —NHSO2alkenyl, —N(alkyl)SO2alkenyl, —NHSO2alkynyl, —N(alkyl) SO2alkynyl, haloalkyl, aryl, heteroaryl, heteroalkyl, heterocyclic, and carbocyclic;
• is selected from the group consisting of a single and a double bond;
• Y is independently selected from the group consisting of N, CH, and CR5;
• Z1 is selected from the group consisting of CH2, CHR2, C(R2)2, NR2, O, and S;
• Z2 is selected from the group consisting of NH, O, S, NR2, C=O, S=O, and SO2;
• wherein when R12 is bonded to a Y, then Y is CR12;
• when R12 is bonded to a Z1 that is nitrogen, then Z1 is NR12;
• when R12 is bonded to Z1 that is carbon, then Z1 is CR2R12;
• when R12 is bonded to a Z2, then Z2 is NR12;
• R12 is -(Linker)A- Targeting Ligand;
• (Linker)A is
• X1 and X2 are independently selected from the group consisting of bond, NH, NR2, CH2, CHR2, C(R2)2, O, and S;
• R20, R21, R22, R23, and R24 are independently selected from the group consisting of bond, alkyl, —C(O)—, —C(O)O—, —OC(O)—, —C(O) alkyl, —C(O)Oalkyl, —SO2-, —S(O)—, —C(S)-, —C(O)NH-, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—, —S—, —NH-, —N(alkyl)-, —CH(—O-R26)-, —CH(—NHR2)-, —CH(—NH2)-, —C(—O-R26) alkyl-, —C(—NHR2)alkyl-, —C(R40R40)-, —alkyl(R27)-alkyl(R28)-, —C(R27R28)-, —NHC(O)NH-, —N(R2)C(O)N(R2)-, —N(H)C(O)N(R2)-, alkene, haloalkyl, alkoxy, alkyneheteroarylalkyl, aryl, arylalkyl, heterocycle, heteroaryl, and carbocycle;
• each of which R20, R21, R22, R23, and R24 is optionally substituted with one, two, or three substituents selected from R101;
• R101 is independently selected at each occurrence from the group consisting of hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, —COOalkyl, COOH, NO2, F, Cl, CF3, NH2, NHalkyl, and N(alkyl)2;
• R26 is selected from the group consisting of hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, and heterocyclic;
• R27 and R28 are independently selected from the group consisting of hydrogen, alkyl, amine, or together with the carbon atom to which they are attached, form C(O), C(S), C═CH2, a C3-C6 spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O, or form a 1 or 2 carbon bridged ring;
• and
• Targeting Ligand is a means for binding a Target Protein that mediates a disease.