Heterocyclic degronimers for target protein degradation

1. A compound of Formula:

or a pharmaceutically acceptable salt thereof;

wherein:

A is CR 8 R 9 , C=O, C=S, or C═CH 2 ;

A′ is C═O, C=S, C═CH 2 , SO 2 , or S(O);

A″ is CR 3 R 4 , C═O, C=S, C═CH 2 , SO 2 , or S(O);

X is independently selected from NH and NR 11 ;

Z is O, S, CH 2 , CH(C 1 -C 4 alkyl), or C(C 1 -C 4 alkyl) 2 ;

n is 0, 1, 2, 3, 4, or 5;

m is 1 or 3;

is a single or double bond;

R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , and R 13 are independently selected from hydrogen, alkyl, hydroxyl, alkoxy, amine, —NHalkyl, and —Nalkyl 2 ;

or R 3 and R 4 form a 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;

or R 8 and R 9 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 and O;

or R 3 and R 7 form a 1 or 2 carbon bridged ring;

or R 13 and R 4 form a 1 or 2 carbon bridged ring;

or R 13 and R 5 form a 3, 4, 5, or 6 carbon fused ring wherein R 5 is on the carbon alpha to R 13 or a 1, 2, 3, or 4 carbon bridged ring wherein R 5 is not on the carbon alpha to R 13 ;

R 5 is selected at each instance from: alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, —NHalkyl, —N(alkyl) 2 , —NHSO 2 alkyl, —N(alkyl)SO 2 alkyl, —NHSO 2 aryl, —N(alkyl)SO 2 aryl, —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, and haloalkyl;

or two R 5 substituents together with the carbon atom(s) to which they are bound can form a 3 membered ring:

Q 1 , Q 2 , Q 3 , and Q 4 are independently selected from CH, CR 12 , and N; and wherein no more than two of Q 1 , Q 2 , Q 3 , and Q 4 are N;

R 11 is independently selected from alkyl, alkenyl, alkynyl, C(O)H, —C(O)OH, —C(O)alkyl, and —C(O)Oalkyl; and

R 12 is independently selected from alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, azide, amino, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, —NHalkyl, —N(alkyl) 2 , —NHSO 2 alkyl, —N(alkyl)SO 2 alkyl, —NHSO 2 aryl, —N(alkyl)SO 2 aryl, —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, cyano, nitro, nitroso, —SH, —Salkyl, and haloalkyl;

wherein for compounds of Formula IV and Formula V at least one of: a, b, c, d, or e is satisfied:

a. R 3 and R 4 form a 4, 5, or 6 membered spiroheterocycle or 4, 5, or 6 membered spirocarbocycle;

b. R 8 and R 9 form a 4, 5, or 6 membered spiroheterocycle or 3, 4, 5, or 6 membered spirocarbocycle;

c. R 4 and R 13 form a 1 or 2 carbon bridged ring;

d. A′ is SO 2 or S(O); or

e. A″ is SO 2 or S(O); and

wherein for compounds of Formula VI at least one of: f, g, h, i, j, k, l, or m is satisfied:

f. m is 3 and n is not 0;

g. R 3 and R 4 form a spirocycle;

h. R 8 and R 9 form a spirocycle;

i. R 4 and R 13 form a 1 or 2 carbon bridged ring;

j. R 13 and R 5 form a 3, 4, 5, or 6 carbon fused ring;

k. R 13 and R 5 form a 1 or 2 carbon bridged ring;

l. A′ is SO 2 or S(O); or

m. A″ is SO 2 or S(O).

2. The compound of claim 1 , wherein the compound is of Formula:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound is of Formula:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound is of Formula:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein A is C═O or CH 2 .

6. The compound of claim 1 , wherein A′ is C=O, C=S, or C═CH 2 .

7. The compound of claim 1 , wherein A″ is C=O, C=S, or C═CH 2 .

8. The compound of claim 1 , wherein X is NH.

9. The compound of claim 1 , wherein Q 1 , Q 2 , Q 3 , and Q 4 are CH.

10. The compound of claim 1 , wherein Q 1 is CR 12 and one of Q 2 , Q 3 , and Q 4 is N.

11. The compound of claim 10 , wherein R 12 is amino.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. A method for treating a patient with abnormal cellular proliferation comprising administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, to a patient in need thereof.

19. The method of claim 18 , wherein the patient is a human.

20. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.