Methods to induce targeted protein degradation through bifunctional molecules
The present application provides bifunctional compounds which act as SMARCA2 and Ras protein degradation inducing moieties. The present application also relates to methods for the targeted degradation of SMARCA2 and Ras through the use of the bifunctional compounds that link a cereblon-binding moiety to a ligand that is capable of binding to SMARCA2 or Ras. The application also provides compounds of Formula:
1. A compound selected from:
or an enantiomer or diastereomer thereof, wherein:
Y is a bond, Y 1 , O, NH, NR 2 , C(O)O, OC(O), C(O)NR 2 ′, NR 2 ′C(O), Y 1 —O, Y 1 —NH, Y 1 —NR 2 , Y 1 —C(O), Y 1 —C(O)O, Y 1 —OC(O), Y 1 —C(O)NR 2 ′, or Y 1 —NR 2 ′C(O);
Y 1 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene;
X is C(O) or C(R 3 ) 2 ;
X 1 -X 2 is C(R 3 )═N or C(R 3 ) 2 —C(R 3 ) 2 ;
each R 1 is independently halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
R 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C(O)—C 1 -C 6 alkyl, C(O)—C 2 -C 6 alkenyl, C(O)—C 3 -C 8 cycloalkyl, or C(O)-3- to 8-membered heterocycloalkyl, and R 2 is optionally substituted with one or more of halogen, N(R a ) 2 , NHC(O)R a , NHC(O)OR a , OR b , C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each of the C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally further substituted with one or more of halogen, NH 2 , CN, nitro, OH, C(O)OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 2 ′ is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; wherein each R 2 ′ other than H is optionally substituted with one or more of halogen, N(R a ) 2 , NHC(O)R a , NHC(O)R a , OR b , C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each of the C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally further substituted with one or more of halogen, NH 2 , CN, nitro, OH, C(O)OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
each R 3 is independently H or C 1 -C 3 alkyl optionally substituted with C 6 -C 10 aryl or 5- to 10-membered heteroaryl;
each R 3 ′ is independently C 1 -C 3 alkyl;
two R 4 , together with the carbon atom to which they are attached, form C(O), a C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
R 5 is H, C 1 -C 3 alkyl, F, or Cl;
each R a independently is H or C 1 -C 6 alkyl;
R b is H or tosyl;
m is 0, 1, 2, or 3;
n is 0, 1, or 2;
the Linker is a group that covalently binds to the Targeting Ligand and Y; and
the Targeting Ligand binds to a targeted protein selected from SMARCA2 and Ras;
wherein the Targeting Ligand is selected from:
R is the attachment point to the Linker;
o is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and
A is N or CH.
2. The compound of claim 1 , wherein Linker is of Formula:
wherein
p1 is an integer selected from 0 to 12;
p2 is an integer selected from 0 to 12;
p3 is an integer selected from 0 to 6;
each W is independently absent, CH 2 , O, S, NH or NR 5 ;
Z is absent, CH 2 , O, NH or N(C 1 -C 3 alkyl); and
Q is absent, —C(O)NH—, —C(O)O—, —CH 2 C(O)NH—, or —CH 2 C(O)O—;
wherein the Linker is covalently bonded to the Y with the
next to Q, and covalently bonded to the Targeting Ligand with the
next to Z.
3. The compound of claim 2 , wherein X is CH 2 .
4. The compound of claim 2 , wherein the compound is of Formula
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 4 , wherein n is 0, R 5 is H, each R 3 is H, and two R 4 , together with the carbon atom to which they are attached, form C(O).
6. The compound of claim 5 , wherein X is C(O).
7. The compound of claim 6 , wherein Y is a O, NH, or NR 2 .
8. The compound of claim 1 , wherein n is 0, R 5 is H, each R 3 is H, and two R 4 , together with the carbon atom to which they are attached, form C(O).
9. The compound of claim 2 , wherein n is 0, R 5 is H, each R 3 is H, and two R 4 , together with the carbon atom to which they are attached, form C(O).
10. The compound of claim 2 , wherein the compound is of Formula:
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 10 , wherein n is 0, R 5 is H, and two R 4 , together with the carbon atom to which they are attached, form C(O).
12. The compound of claim 11 , wherein X 1 -X 2 is C(R 3 )═N.
13. The compound of claim 1 , wherein the Targeting Ligand is selected from:
14. The compound of claim 1 , wherein the Targeting Ligand is selected from:
15. The compound of claim 1 , wherein the Targeting Ligand is selected from:
16. The compound of claim 1 , wherein the Targeting Ligand is selected from:
17. The compound of claim 2 , wherein p1 is an integer selected from 0 to 3; p2 is an integer selected from 0 to 3; and p3 is an integer selected from 0 to 3.
18. The compound of claim 17 , wherein Q is —C(O)NH—.
19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.