DEGRADERS AND DEGRONS FOR TARGETED PROTEIN DEGRADATION

1 . A compound of Formula:

or a pharmaceutically acceptable salt thereof;

wherein:

W 1 is C═O;

W 2 is C═O;

X is NH, NR 2 , O, S(O), S(O) 2 , or S;

R 2 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;

R 4 is selected from the group consisting of hydrogen, aliphatic, heterocyclic, and heteroaliphatic;

R 5 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 , —NHSO 2 (aliphatic), —N(aliphatic)SO 2 alkyl, —NHSO 2 (aryl, heteroaryl, or heterocyclic), —N(alkyl)SO 2 (aryl, heteroaryl, or heterocyclic), —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, haloalkyl, aliphatic, heteroaliphatic, heteroalkyl, carbocyclic, C(O)R 40 , aryl, aryloxy, heterocyclo, heteroaryl, arylalkyl, O-arylalkyl, nitro, nitroso, sulfone, sulfoxide, thioalkyl, thiol, haloalkyl, and cycloalkyl;

R 10 and R 11 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 R 10 and R 11 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;

R 16 is selected from the group consisting of:

or R 16 is a 4, 5, 6, 7, 8, 9, or 10 membered carbocyclo or aryl moiety, wherein the carbocyclo or aryl moiety is substituted with R 12 at any desired position; wherein the carbocyclo or aryl moiety is optionally further substituted with one or more substituents selected from R 5 ; and wherein the carbocyclo or aryl moiety is attached through a carbon atom;

or R 16 is

R 13 and R 14 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxy, amino, —NHalkyl, and —N(alkyl) 2 ;

or R 13 and R 14 together with the carbon atom to which they are attached form C(O), C(S), C═CH 2 , 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;

R 17 is selected from the group consisting of R 17a , R 17b , and R 17c ;

R 17a is selected from the group consisting of:

or R 17a is selected from the group consisting of

or R 17a 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 R 12 at any desired position, wherein the heterocyclo or heteroaryl moiety is optionally further substituted with one or more substituents selected from R 5 ; and the heterocyclo or heteroaryl moiety is optionally further substituted with one or more oxo groups at a position allowed by valence;

or R 17a is selected from the group consisting of:

R 17b is selected from the group consisting of:

or R 17b is -NR 2 aryl, —NR 2 heteroaryl, or NR 2 carbocycle, wherein the aryl, heteroaryl, and carbocycle moieties are substituted with a R 12 at any desired position, wherein the aryl, heteroaryl, and carbocycle moieties are optionally further substituted with one or more substituents selected from R 5 ; and the aryl, heteroaryl, and carbocycle moieties are optionally further substituted with one or more oxo groups at a position allowed by valence;

R 17c is selected from the group consisting of:

or R 17c is selected from the group consisting of

or R 17c is —O-aryl, —O-heteroaryl, or —O-carbocycle, wherein the aryl, heteroaryl, and carbocycle moieties are substituted with a R 12 at any desired position, wherein the aryl, heteroaryl, and carbocycle moieties are optionally further substituted with one or more substituents selected from R 5 ; and the aryl, heteroaryl, and carbocycle moieties are optionally further substituted with one or more oxo groups at a position allowed by valence;

R 40 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 , —NHSO 2 (aliphatic), —N(aliphatic)SO 2 alkyl, —NHSO 2 (aryl, heteroaryl or heterocyclic), —N(alkyl)SO 2 (aryl, heteroaryl or heterocyclic) —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl, heterocyclic, and carbocyclic;

is a single or double bond;

Y is independently N, CH, or CR 5 ;

Z 1 is CH 2 , CHR 2 , C(R 2 ) 2 , NR 2 , O, or S;

Z 2 is NH, O, S, NR 2 , C═O, S═O, or SO 2 ;

when R 12 is bonded to a Y, then Y is CR 12 ; when R 12 is bonded to a Z 1 that is nitrogen, then Z 1 is NR 12 ; when R 12 is bonded to Z 1 that is carbon, then Z 1 is CR 2 R 12 ; when R 12 is bonded to a Z 2 , then Z 2 is NR 12 ;

R 12 is -(Linker) B ;

(Linker) B is selected from the group consisting of:

X 1 is selected from the group consisting of bond, NH, NR 2 , CH 2 , CHR 2 , C(R 2 ) 2 , O, and S;

X 22 is selected from the group consisting of hydrogen, halo, —NH 2 , —NHR 2 , —N(R 2 ) 2 , alkyl, —CH 2 R 2 , —CH(R 2 ) 2 , —C(R 2 ) 3 , hydroxyl, thiol, —B(OH) 2 , —Sn(R 2 ) 3 , —Si(R 2 ) 3 , —OS(O) 2 alkyl, —OS(O) 2 haloalkyl, ethynyl, ethenyl, —C(O)H, and —C(O)OH;

R 20 , R 21 , R 22 , R 23 , and R 24 are independently selected from the group consisting of bond, alkyl, —C(O)—, —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —SO 2 —, —S(O)—, —C(S)—, —C(O)NH—, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—, —S—, —NH—, —N(alkyl)-, —CH(—O—R 26 )—, —CH(—NHR 2 )—, —CH(—NH 2 )—, —CH(—NR 2 2 )—, —C(—O—R 26 )alkyl-, —C(—NHR 2 )alkyl-, —C(—NH 2 )alkyl-, —C(—NR 2 2 )alkyl-, —C(R 40 R 40 )—, -alkyl(R 27 )-alkyl(R 28 )—, —C(R 27 R 28 )—, —P(O)(OR 26 )O—, —P(O)(OR 26 )—, —NHC(O)NH—, —N(R 2 )C(O)N(R 2 )—, —N(H)C(O)N(R 2 )—, 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—(CH 2 ) 1-12 —O—, —NH—(CH 2 ) 1-12 —NH—, —NH—(CH 2 ) 1-12 —O—, —O—(CH 2 ) 1-12 —NH—, —S—(CH 2 ) 1-12 —O—, —O—(CH 2 ) 1-12 —S—, —S—(CH 2 ) 1-12 —S—, —S—(CH 2 ) 1-12 —NH—, and —NH—(CH 2 ) 1-12 —S—;

each of which R 20 , R 21 , R 22 , R 23 , and R 24 is optionally substituted with one or more substituents selected from R 101 ;

R 26 is selected from the group consisting of hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic;

R 27 and R 28 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═CH 2 , a C 3 -C 6 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

R 101 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, NO 2 , F, Cl, Br, I, CF 3 , NH 2 , NHalkyl, N(alkyl) 2 , aliphatic, and heteroaliphatic.

2 . The compound of claim 1 , wherein R 4 is hydrogen.

3 . The compound of claim 1 , wherein R 10 and R 11 are both hydrogen.

4 . The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

5 . The compound of claim 1 , wherein the compound is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

6 . The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

7 . The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

8 . The compound of claim 7 , wherein X is NH.

9 . The compound of claim 7 , wherein X is O.

10 . The compound of claim 7 , wherein X is S.

11 . The compound of claim 1 , wherein -(Linker) B is selected from the group consisting of:

12 . The compound of claim 1 , wherein -(Linker) B is selected from the group consisting of:

13 . The compound of claim 1 , wherein X 22 is bromine.

14 . The compound of claim 1 , wherein X 22 is —NH 2 .

15 . The compound of claim 1 , wherein X 22 is hydroxyl.

16 . The compound of claim 1 , wherein X 22 is —B(OH) 2 .

17 . The compound of claim 1 , wherein X 22 is ethynyl.

18 . The compound of claim 1 , wherein X 22 is —C(O)H or —C(O)OH.

19 . The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

20 . The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

21 . The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

22 . A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

23 . A method for treating a human with a medical disorder comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein the medical disorder is treated by binding the compound to the cereblon protein in vivo.

24 . The method of claim 23 , wherein the disorder is cancer or tumor.