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;
• X is NH, NR2, O, S(O), S(O)2, or S;
• R2 is selected at each instance from the group consisting of hydrogen, alkyl, heteroalkyl, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, —C(O)(aliphatic, aryl, heteroaliphatic or heteroaryl), —C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne;
• R4 is selected from the group consisting of hydrogen, aliphatic, heterocyclic, and heteroaliphatic;
• R5 is selected at each instance from the group consisting of hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkylhydroxyl, alkoxy, azide, amino, alkylamino, cyano, —NH(aliphatic), —N(aliphatic)2, —NHSO2(aliphatic), —N(aliphatic)SO2alkyl, —NHSO2(aryl, heteroaryl, or heterocyclic), —N(alkyl)SO2(aryl, heteroaryl, or heterocyclic), —NHSO2alkenyl, —N(alkyl)SO2alkenyl, —NHSO2alkynyl, —N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, 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, aliphatic, heteroaliphatic, carbocyclic, heterocyclic, aryl, heteroaryl, halo, azide, cyano, hydroxyl, alkoxy, amine, —NH(aliphatic), and —N(aliphatic)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 the group consisting of N, O, and S;
• 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 or more substituents selected from R5;
• and wherein the carbocyclo or aryl moiety is attached through a carbon atom;
• or R16 is
• 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 the group consisting of N and O;
• 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 a 3, 4, 5, 6, 7, 8, or 10 membered heterocyclo or heteroaryl moiety containing at least one nitrogen atom through which it is directly attached, wherein the heterocyclo or heteroaryl moiety is substituted with R12 at any desired position, wherein the heterocyclo or heteroaryl moiety is optionally further substituted with one or more substituents selected from R5;
• and the heterocyclo or heteroaryl moiety is optionally further substituted with one or more oxo groups at a position allowed by valence;
• 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 or more substituents selected from R5;
• and the aryl, heteroaryl, and carbocycle moieties are optionally further substituted with one or more oxo groups at a position allowed by valence;
• R17c is selected from the group consisting of:
• or 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 R12at any desired position, wherein the aryl, heteroaryl, and carbocycle moieties are optionally further substituted with one or more substituents selected from R5;
• and the aryl, heteroaryl, and carbocycle moieties are optionally further substituted with one or more oxo groups at a position allowed by valence;
• R40 is selected at each instance from the group consisting of hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano, —NH(aliphatic), —N(aliphatic)2, —NHSO2(aliphatic), —N(aliphatic)SO2alkyl, —NHSO2(aryl, heteroaryl or heterocyclic), —N(alkyl)SO2(aryl, heteroaryl or heterocyclic) —NHSO2alkenyl, —N(alkyl)SO2alkenyl, —NHSO2alkynyl, —N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl, heterocyclic, and carbocyclic;
• is a single or double bond;
• Y is independently N, CH, or CR5;
• Z1 is CH2, CHR2, C(R2)2, NR2, O, or S;
• Z2 is NH, O, S, NR2, C═O, S═O, or SO2;
• 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)B;
• (Linker)B is selected from the group consisting of:
• X1 is selected from the group consisting of bond, NH, NR2, CH2, CHR2, C(R2)2, O, and S;
• X22 is selected from the group consisting of hydrogen, halo, —NH2, —NHR2, —N(R2)2, alkyl, —CH2R2, —CH(R2)2, —C(R2)3, hydroxyl, thiol, —B(OH)2, —Sn(R2)3, —Si(R2)3, —OS(O)2alkyl, —OS(O)2haloalkyl, ethynyl, ethenyl, —C(O)H, and —C(O)OH;
• 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)—, —CH(—NR22)—, —C(—O—R26)alkyl-, —C(—NHR2)alkyl-, —C(—NH2)alkyl-, —C(—NR22)alkyl-, —C(R40R40)—, -alkyl(R27)-alkyl(R28)—, —C(R27R28)—, —P(O)(OR26)O—, —P(O)(OR26)—, —NHC(O)NH—, —N(R2)C(O)N(R2)—, —N(H)C(O)N(R2)—, polyethylene glycol, poly(lactic-co-glycolic acid), alkene, haloalkyl, alkoxy, alkyneheteroarylalkyl, aryl, arylalkyl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, polypropylene glycol, lactic acid, glycolic acid, carbocycle, —O—(CH2)1-12—O—, —NH—(CH2)1-12—NH—, —NH—(CH2)1-12—O—, —O—(CH2)1-12—NH—, —S—(CH2)1-12—O—, —O—(CH2)1-12—S—, —S—(CH2)1-12—S—, —S—(CH2)1-12—NH—, and —NH—(CH2)1-12—S—;
• each of which R20, R21, R22, R23, and R24 is optionally substituted with one or more substituents selected from R101;
• R26 is selected from the group consisting of hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic;
• R27 and R28 are independently selected from the group consisting of hydrogen, alkyl, and 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 the group consisting of N and O, or form a 1 or 2 carbon bridged ring;
• and
• 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, Br, I, CF3, NH2, NHalkyl, N(alkyl)2, aliphatic, and heteroaliphatic.