N/O-LINKED DEGRONS AND DEGRONIMERS FOR PROTEIN DEGRADATION
This invention provides Degronimers that have E3 Ubiquitin Ligase targeting moieties (Degrons) that can be linked to a targeting ligand for a protein that has been selected for in vivo degradation, and methods of use and compositions thereof as well as methods for their preparation. The invention also provides Degrons that can be used to treat disorders mediated by cereblon or an Ikaros family protein, and methods of use and compositions thereof as well as methods for their preparation.
1 . A compound of Formula:
or a pharmaceutically acceptable salt thereof;
wherein:
n is 0 or 1;
R 5 is hydrogen, C 1 -C 3 alkyl, F, Cl, Br, hydroxyl, C 1 -C 3 alkoxy, amino, cyano, —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl) 2 , C(O)R 4 , or C 1 -C 3 haloalkyl;
R 4 is hydrogen, C 1 -C 3 alkyl, hydroxyl, C 1 -C 3 alkoxy, amino, —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl) 2 , or C 1 -C 3 haloalkyl;
R 12 is Linker-Targeting Ligand;
Linker is a chemical group of formula:
wherein:
X 1 and X 2 are independently selected from the group consisting of bond, NH, and NC 1 -C 3 alkyl;
R 20 , R 21 , R 22 , R 23 , and R 24 are independently selected from the group consisting of bond, C 1 -C 3 alkyl, —C(O)—, —C(O)O—, —OC(O)—, —C(O)C 1 -C 3 alkyl, —C(O)OC 1 -C 3 alkyl, —C(O)NH—, —NHC(O)—, —N(C 1 -C 3 alkyl)C(O)—, —C(O)N(C 1 -C 3 alkyl)-, —O—, —NH—, —N(C 1 -C 3 alkyl)-, C 1 -C 3 alkoxy, phenyl, and 6-membered heterocycle with one or two nitrogen atoms;
each of which R 20 , R 21 , R 22 , R 23 , and R 24 is optionally substituted with one substituent selected from R 101 ;
R 101 is independently selected at each occurrence from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and F; and
Targeting Ligand is a ligand that binds to an androgen receptor, wherein the Targeting Ligand is of formula:
wherein:
R is the point at which the Linker is attached.
2 . The compound of claim 1 , wherein n is 0.
3 . The compound of claim 1 , wherein the Linker is
wherein:
Aryl is phenyl optionally substituted with R 101 , wherein X 1 is attached to the Targeting Ligand.
4 . The compound of claim 1 , wherein the Linker is selected from the group consisting of
wherein:
Heterocycle is a 6-membered heterocycle with one or two nitrogen atoms optionally substituted with R 101 .
5 . The compound of claim 1 , wherein R 20 , R 21 , R 22 , R 23 , and R 24 are independently selected from the group consisting of bond, C 1 -C 2 alkyl, —C(O)—, —C(O)C 1 -C 3 alkyl, —C(O)NH—, —NHC(O)—, —O—, —NH—, phenyl, and 6-membered heterocycle with one or two nitrogen atoms.
6 . The compound of claim 2 , wherein X 1 is NH.
7 . The compound of claim 6 , wherein X 2 is attached to the Targeting Ligand.
8 . The compound of claim 7 , wherein X 2 is bond.
9 . The compound of claim 8 , wherein R 24 is —C(O)C 1 -C 3 alkyl.
10 . The compound of claim 9 , wherein R 23 is piperazinyl substituted with R 101 , wherein the R 101 substituent on R 23 is methyl.
11 . The compound of claim 10 , wherein R 22 is
12 . The compound of claim 11 , wherein R 21 is —O—.
13 . The compound of claim 12 , wherein R 20 is
wherein the R 101 substituent on R 20 is ethyl.
14 . The compound of claim 8 , wherein R 24 is
15 . The compound of claim 14 , wherein R 23 is
16 . The compound of claim 15 , wherein R 22 is piperazinyl substituted with R 101 , wherein the R 101 substituent on R 22 is methyl.
17 . The compound of claim 16 , wherein R 21 is
18 . The compound of claim 17 , wherein R 20 is
wherein the R 101 substituent on R 20 is ethyl.
19 . The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof;
wherein:
X 1 is NH;
X 2 is attached to the Targeting Ligand and wherein X 2 is bond;
R 24 is —C(O)C 1 -C 3 alkyl;
R 23 is piperazinyl substituted with methyl;
R 22 is
R 21 is —O—; and
R 20 is
wherein R 101 is ethyl.
20 . The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof;
wherein:
X 1 is NH or NCH 3 ;
X 2 is attached to the Targeting Ligand and wherein X 2 is bond;
R 23 is
R 23 is
R 22 is piperazinyl substituted with methyl;
R 21 is
and
R 20 is
wherein R 101 is ethyl.
21 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
22 . A method for the treatment of a medical disorder in a human patient that can be treated by degrading an androgen receptor, wherein the method comprises administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to the patient.
23 . The method of claim 22 , wherein the disorder is a tumor or cancer.
24 . The method of claim 22 , wherein the disorder is prostate cancer.