Cereblon binders for the degradation of ikaros

1. A compound selected from the following Formulas:

or a pharmaceutically acceptable salt thereof;

wherein:

R 1 is selected from:

a. haloalkyl and alkyl; either of which is optionally substituted with 1, 2, or 3 substituents independently selected from aryl, cycloalkyl, heteroaryl, —SO 2 R 5 , —NR 2 —C(O)—R 3 , —C(O)OR 4 , and —C(O)—R 3 ; wherein when the haloalkyl or alkyl group has two or more carbons it can additionally be optionally substituted with 1, 2, 3, or 4 substituents independently selected from —OC(O)—R 3 , —NR 4 R 4 , and —OR 4 , wherein these additional substituents are not on the carbon alpha to the pyrazole;

b. cycloalkyl and aryl; either of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, heterocycle, —NR 2 R 2 , —OR 2 , —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , and —C(O)—R 3 ;

c. heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, —NR 4 R 4 , —OR 4 , —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , and —C(O)—R 3 ; wherein the heteroaryl group is only substituted such that no N—O or N—N bonds are formed;

d. heterocycle substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, heterocycle, —NR 2 R 2 , —OR 2 , —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , —C(O)—R 3 , —SO 2 R 5 , —C(O)—R 5 , and R 5 ; wherein the heterocycle group is only substituted such that no N—O or N—N bonds are formed;

e. (CR 4 R 2 )—(CR 2 R 2 ) o -heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, heterocycle, —NR 2 R 2 , —OR 2 , —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , —C(O)—R 3 , —SO 2 R 5 , —C(O)—R 5 , and R 5 ; wherein the heterocycle group is only substituted such that no N—O or N—N bonds are formed; and

f. bicyclic heterocycle or multicyclic heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, heterocycle, —NR 2 R 2 , —OR 2 , —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , —C(O)—R 3 , —SO 2 R 5 , —C(O)—R 5 , and R 5 ; wherein the bicyclic heterocycle group is only substituted such that no N—O or N—N bonds are formed;

R 2 at each instance is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocycle, heteroaryl, and cycloalkyl;

R 3 is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocycle, heteroaryl, —NR 2 R 2 , and —OR 4 ;

R 4 at each instance is independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, haloalkyl, aryl, heterocycle, heteroaryl, and alkynyl;

R 5 is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heteroaryl, heterocycle, aryl, —O-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycle, —O-alkyl, —NR 2 — cycloalkyl, —NR 2 -aryl, —NR 2 -heteroaryl, —NR 2 -heterocycle, —NR 2 -alkyl, —CH 2 -cycloalkyl, —CH 2 -aryl, —CH 2 -heteroaryl, —CH 2 -heterocycle, —OR 2 , and —NR 2 R 2 ; each of which except for hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, halogen, —OR 2 , and —NR 2 R 2 ;

m and o are independently selected from 0, 1, 2, 3, 4, and 5;

x is 0, 1, 2, 3, or 4;

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

y is 1, 2, 3, 4, 5, or 6;

R 11 is selected from

a. haloalkyl and alkyl; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , and —C(O)—R 3 ; wherein when the haloalkyl or alkyl group has two or more carbons it can additionally be optionally substituted with 1, 2, 3, or 4 substituents independently selected from —OC(O)—R 3 , —NR 4 R 4 , and —OR 4 , wherein these additional substituents are not on the carbon alpha to the pyrazole;

b. cycloalkyl, heteroaryl, and aryl; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, F, Cl, Br, I, cyano, heteroaryl, aryl, cycloalkyl, —NR 4 R 4 , —OR 4 , —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , and —C(O)—R 3 ;

c. (CR 2 R 2 ) n -heterocycle substituted with 1, 2, 3, or 4 substituents independently selected from alky, alkenyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, —NR 4 R 4 , —OR 4 , —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , —C(O)—R 3 , and —SO 2 R 5 ; wherein the heterocycle group is only substituted such that no N—O or N—N bonds are formed; and

d. bicyclic heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, heterocycle, —NR 2 R 2 , —OR 2 , —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , —C(O)—R 3 , —SO 2 R 5 , —C(O)—R 5 , and R 5 ; wherein the bicyclic heterocycle group is only substituted such that no N—O or N—N bonds are formed;

R 12 is selected from alkyl, haloalkyl, alkenyl, alkynyl, heteroaryl, aryl, cycloalkyl, heterocycle, —C(O)—R 3 , —SO 2 R 5 , and —C(O)—R 5 ;

R 13 at each instance is independently selected from alkyl, alkenyl, alkynyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, heterocycle, —NR 2 R 2 , —OR 2 , —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , —C(O)—R 3 , —SO 2 R 5 , —C(O)—R 5 , and R 5 ; or two R 13 s may together with the carbon(s) to which they are attached be replaced with a spiro or fused, heterocycle or carbocycle ring, or two R 13 s may together with the carbon to which they are attached be replaced with an aryl ring;

R 20 is heterocycle substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, heterocycle, —NR 2 R 2 , —OR 2 , —NR 2 —C(O)—R 24 , —O—C(O)—R 24 , —C(O)—R 24 , —SO 2 R 24 , and R 24 ; wherein the heterocycle group is only substituted such that no N—O or N—N bonds are formed;

R 21 and R 22 are independently selected from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, —(C 2 -C 6 alkenylene)-cycloalkyl, —(C 2 -C 6 alkynylene)-cycloalkyl, halogen, and cyano;

R 23a and R 23b are independently selected from hydrogen, alkyl, cycloalkyl, and —(C 1 -C 6 alkylene)-NR 2 R 2 ;

or R 21 and R 23a are joined together with the carbons to which they are attached to form a 5- to 6-membered carbocyclic ring;

or R 22 and R 23a are joined together with the carbons to which they are attached to form a 5- to 6-membered carbocyclic ring;

R 24 is selected at each occurrence from alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heteroaryl, heterocycle, aryl, —O-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycle, —O-alkyl, —NR 2 -cycloalkyl, —NR 2 -aryl, —NR 2 -heteroaryl, —NR 2 -heterocycle, —NR 2 -alkyl, —CH 2 -cycloalkyl, —CH 2 -aryl, —CH 2 -heteroaryl, —CH 2 -heterocycle, —OR 2 , and —NR 2 R 2 ; wherein each R 24 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R 25 ; and

R 25 is selected at each occurrence from: alkyl; alkenyl; alkynyl; haloalkyl; cycloalkyl; heterocycle; aryl optionally substituted with 1, 2, or 4 groups independently selected from alkyl, alkoxy, or halogen; heteroaryl optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkoxy, or halogen; —CH 2 -cycloalkyl; —CH 2 -aryl optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkoxy, or halogen; —CH 2 -heteroaryl optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkoxy, or halogen; —CH 2 -heterocycle; —CH 2 —NH—C(O)CH 3 ; —C(O)-cycloalkyl; —C(O)-aryl optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkoxy, or halogen; —C(O)-heteroaryl optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkoxy, or halogen; —C(O)-heterocycle; —C(O)-alkyl; —(C 2 -C 6 alkenylene)-aryl; —(C 2 -C 6 alkynylene)-aryl; —(C 2 -C 6 alkenylene)-cycloalkyl; —(C 2 -C 6 alkynylene)-cycloalkyl; —C(O)—(C 1 -C 6 alkylene)-O-alkyl; —C(O)—(C 1 -C 6 alkylene)-aryl; cyano; halogen; —OR 2 ; and —NR 2 R 2 ; or

two R 25 groups may join together with the atoms to which they are attached to form a 3- to 7-membered carbocyclic ring.

2. The compound of claim 1 , wherein m is 0.

3. The compound of claim 1 , wherein R 1 is heterocycle substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, heterocycle, —NR 2 R 2 , —OR 2 , —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , —C(O)—R 3 , —SO 2 R 5 , —C(O)—R 5 , and R 5 ; and wherein the heterocycle group is only substituted such that no N—O or N—N bonds are formed.

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 the compound is of formula:

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein R 5 is alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, halogen, —OR 2 , and —NR 2 R 2 .

9. The compound of claim 1 , wherein R 5 is cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, halogen, —OR 2 , and —NR 2 R 2 .

10. The compound of claim 1 , wherein R 5 is —CH 2 -cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, halogen, —OR 2 , and —NR 2 R 2 .

11. The compound of claim 1 , wherein R 5 is heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, halogen, —OR 2 , and —NR 2 R 2 .

12. The compound of claim 1 , wherein R 5 is —CH 2 -heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, halogen, —OR 2 , and —NR 2 R 2 .

13. The compound of claim 1 , wherein R 5 is —OR 2 .

14. The compound of claim 1 , wherein x is 0, 1, or 2.

15. The compound of claim 1 , wherein R 13 is alkyl.

16. A compound selected from:

or a pharmaceutically acceptable salt thereof.

17. A compound of claim 1 selected from:

or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound of claim 1 with a pharmaceutically acceptable carrier or diluent.

19. A compound of claim 1 of formula:

or a pharmaceutically acceptable salt thereof.