US 11,753,397 B2
Cereblon binders for the degradation of ikaros
James A. Henderson, Weston, MA (US); Gesine Kerstin Veits, Somerville, MA (US); Minsheng He, Watertown, MA (US); Christopher G. Nasveschuk, Stoneham, MA (US); Andrew J. Phillips, Arlington, MA (US); and Andrew Charles Good, Watertown, MA (US)
Assigned to C4 Therapeutics, Inc., Watertown, MA (US)
Filed by C4 Therapeutics, Inc., Watertown, MA (US)
Filed on Sep. 24, 2020, as Appl. No. 17/31,550.
Application 17/031,550 is a continuation of application No. PCT/US2019/024094, filed on Mar. 26, 2019.
Claims priority of provisional application 62/648,238, filed on Mar. 26, 2018.
Prior Publication US 2021/0009559 A1, Jan. 14, 2021
Int. Cl. C07D 401/14 (2006.01)
CPC C07D 401/14 (2013.01) 19 Claims
 
1. A compound selected from the following Formulas:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof;
wherein:
R1 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, —SO2R5, —NR2—C(O)—R3, —C(O)OR4, and —C(O)—R3; 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)—R3, —NR4R4, and —OR4, 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, —NR2R2, —OR2, —NR2—C(O)—R3, —O—C(O)—R3, and —C(O)—R3;
c. heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, —NR4R4, —OR4, —NR2—C(O)—R3, —O—C(O)—R3, and —C(O)—R3; 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, —NR2R2, —OR2, —NR2—C(O)—R3, —O—C(O)—R3, —C(O)—R3, —SO2R5, —C(O)—R5, and R5; wherein the heterocycle group is only substituted such that no N—O or N—N bonds are formed;
e. (CR4R2)—(CR2R2)o-heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, heterocycle, —NR2R2, —OR2, —NR2—C(O)—R3, —O—C(O)—R3, —C(O)—R3, —SO2R5, —C(O)—R5, and R5; 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, —NR2R2, —OR2, —NR2—C(O)—R3, —O—C(O)—R3, —C(O)—R3, —SO2R5, —C(O)—R5, and R5; wherein the bicyclic heterocycle group is only substituted such that no N—O or N—N bonds are formed;
R2 at each instance is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocycle, heteroaryl, and cycloalkyl;
R3 is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocycle, heteroaryl, —NR2R2, and —OR4;
R4 at each instance is independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, haloalkyl, aryl, heterocycle, heteroaryl, and alkynyl;
R5 is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heteroaryl, heterocycle, aryl, —O-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycle, —O-alkyl, —NR2— cycloalkyl, —NR2-aryl, —NR2-heteroaryl, —NR2-heterocycle, —NR2-alkyl, —CH2-cycloalkyl, —CH2-aryl, —CH2-heteroaryl, —CH2-heterocycle, —OR2, and —NR2R2; 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, —OR2, and —NR2R2;
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;
R11 is selected from
a. haloalkyl and alkyl; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from —NR2—C(O)—R3, —O—C(O)—R3, and —C(O)—R3; 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)—R3, —NR4R4, and —OR4, 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, —NR4R4, —OR4, —NR2—C(O)—R3, —O—C(O)—R3, and —C(O)—R3;
c. (CR2R2)n-heterocycle substituted with 1, 2, 3, or 4 substituents independently selected from alky, alkenyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, —NR4R4, —OR4, —NR2—C(O)—R3, —O—C(O)—R3, —C(O)—R3, and —SO2R5; 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, —NR2R2, —OR2, —NR2—C(O)—R3, —O—C(O)—R3, —C(O)—R3, —SO2R5, —C(O)—R5, and R5; wherein the bicyclic heterocycle group is only substituted such that no N—O or N—N bonds are formed;
R12 is selected from alkyl, haloalkyl, alkenyl, alkynyl, heteroaryl, aryl, cycloalkyl, heterocycle, —C(O)—R3, —SO2R5, and —C(O)—R5;
R13 at each instance is independently selected from alkyl, alkenyl, alkynyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, heterocycle, —NR2R2, —OR2, —NR2—C(O)—R3, —O—C(O)—R3, —C(O)—R3, —SO2R5, —C(O)—R5, and R5; or two R13s may together with the carbon(s) to which they are attached be replaced with a spiro or fused, heterocycle or carbocycle ring, or two R13s may together with the carbon to which they are attached be replaced with an aryl ring;
R20 is heterocycle substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, heterocycle, —NR2R2, —OR2, —NR2—C(O)—R24, —O—C(O)—R24, —C(O)—R24, —SO2R24, and R24; wherein the heterocycle group is only substituted such that no N—O or N—N bonds are formed;
R21 and R22 are independently selected from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, —(C2-C6alkenylene)-cycloalkyl, —(C2-C6alkynylene)-cycloalkyl, halogen, and cyano;
R23a and R23b are independently selected from hydrogen, alkyl, cycloalkyl, and —(C1-C6alkylene)-NR2R2;
or R21 and R23a are joined together with the carbons to which they are attached to form a 5- to 6-membered carbocyclic ring;
or R22 and R23a are joined together with the carbons to which they are attached to form a 5- to 6-membered carbocyclic ring;
R24 is selected at each occurrence from alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heteroaryl, heterocycle, aryl, —O-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycle, —O-alkyl, —NR2-cycloalkyl, —NR2-aryl, —NR2-heteroaryl, —NR2-heterocycle, —NR2-alkyl, —CH2-cycloalkyl, —CH2-aryl, —CH2-heteroaryl, —CH2-heterocycle, —OR2, and —NR2R2; wherein each R24 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R25; and
R25 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; —CH2-cycloalkyl; —CH2-aryl optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkoxy, or halogen; —CH2-heteroaryl optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkoxy, or halogen; —CH2-heterocycle; —CH2—NH—C(O)CH3; —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; —(C2-C6alkenylene)-aryl; —(C2-C6alkynylene)-aryl; —(C2-C6alkenylene)-cycloalkyl; —(C2-C6alkynylene)-cycloalkyl; —C(O)—(C1-C6alkylene)-O-alkyl; —C(O)—(C1-C6alkylene)-aryl; cyano; halogen; —OR2; and —NR2R2; or
two R25 groups may join together with the atoms to which they are attached to form a 3- to 7-membered carbocyclic ring.