Arginine methyltransferase 5 (PRMT5) degraders and uses thereof

1 . A bifunctional compound having a structure represented by formula (I):

wherein

R represents

wherein the squiggle ( ) represents the attachment point to the carbonyl group (C(O)) and the double-squiggle ( ) represents the attachment point to

X represents CH 2 , NH or O;

R 1 and R 3 each independently represents hydrogen, halo, methoxy, NO 2 , CN, —C(O)OR′ 1 or —C(O)NR′ 1 R′ 2 ;

R 2 and R 4 each independently represents halo, methoxy, NO 2 , CN, —C(O)OR′ 1 or —C(O)NR′ 1 R′ 2 , wherein R′ 1 and R′ 2 are independently H or optionally substituted C 1 -C 6 alkyl; R 5 represents H, biotinyl, or a solubility enhancing group;

the linker comprises an alkylene chain which may be interrupted by and/or terminate at either or both termini in at least one of —O—, —S—, —N(R′)—, —C≡C—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(NOR′)—, —C(O)N(R′)—, —C(O)N(R′)C(O)—, —C(O)N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —C(NR′)—, —N(R′)C(NR′)—, —C(NR′)N(R′)—, —N(R′)C(NR′)N(R′)—, —OB(Me)O—, —S(O) 2 —, —OS(O)—, —S(O)O—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —N(R′)S(O) 2 —, —S(O) 2 N(R′)—, —N(R′)S(O)—, —S(O)N(R′)—, —N(R′)S(O) 2 N(R′)—, —N(R′)S(O)N(R′)—, C 3-12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof,

wherein R′ is H or C 1 -C 6 alkyl, wherein the interrupting and the one or both terminating groups may be the same or different, or

comprises a polyethylene glycol chain which may terminate at either or both termini in at least one of —S—, —N(R′)—, —C≡C—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(NOR′)—, —C(O)N(R)—, —C(O)N(R)C(O)—, —C(O)N(R′)C(O)N(R)—, —N(R′)C(O)—, N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′), —C(NR′)—, —N(R′)C(NR′)—, —C(NR′)N(R′)—, —N(R′)C(NR′)N(R′)—, —OB(Me)O—, —S(O) 2 —, —OS(O)—, —S(O)O—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —N(R′)S(O) 2 —, —S(O) 2 N(R′)—, —N(R′)S(O)—, —S(O)N(R′)—, —N(R′)S(O) 2 N(R′)—, —N(R′)S(O)N(R′)—, C 3-12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof, wherein R′ is H or C 1 -C 6 alkyl, wherein the one or both terminating groups may be the same or different;

and the targeting ligand is represented by TL1 or TL2:

or a pharmaceutically acceptable salt or stereoisomer thereof.

2 . The bifunctional compound of claim 1 , wherein the targeting ligand is represented by TL1:

3 . The bifunctional compound of claim 1 , which is represented by any one of structures (I-1) to (I-4):

or a pharmaceutically acceptable salt or stereoisomer thereof.

4 . The bifunctional compound of claim 3 , wherein each of R 1 , R 2 , R 3 and R 4 represents Cl.

5 . The bifunctional compound of claim 3 , wherein each of R 1 and R 3 represents CN, and each of R 2 and R 4 represents Cl.

6 . The bifunctional compound of claim 3 , wherein each of R 1 and R 3 represents Cl, and each of R 2 and R 4 represents methoxy.

7 . The bifunctional compound of claim 3 , wherein each of R 1 and R 3 represents H, and each of R 2 and R 4 represents NO 2 .

8 . The bifunctional compound of claim 3 , which is represented by any one of structures (I-1a) to (I-5d):

or a pharmaceutically acceptable salt or stereoisomer thereof.

9 . The bifunctional compound of claim 8 , wherein R 5 is H.

10 . The bifunctional compound of claim 8 , wherein R 5 is biotynyl or a solubility enhancing group.

11 . The bifunctional compound of claim 10 , wherein the solubility enhancing group is alpha-chloro acetyl.

12 . The bifunctional compound of claim 1 , wherein the linker comprises an alkylene chain which may be interrupted by and/or terminate at either or both termini in at least one of —O—, —S—, —N(R′)—, —C≡C—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(NOR′), —C(O)N(R′), —C(O)N(R′)C(O)—, —C(O)N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′), —N(R′)C(O)O—, —OC(O)N(R′)—, —C(NR′)—, —N(R′)C(NR′)—, —C(NR′)N(R′)—, —N(R′)C(NR′) N(R′)—, —OB(Me)O—, —S(O) 2 —, —OS(O)—, —S(O)O—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —N(R′)S(O) 2 —, —S(O) 2 N(R′)—, —N(R′)S(O)—, —S(O)N(R′)—, —N(R′)S(O) 2 N(R′)—, —N(R′)S(O)N(R′)—, C 3-12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof, wherein R′ is H or C 1 -C 6 alkyl, wherein the interrupting and the one or both terminating groups may be the same or different.

13 . The bifunctional compound of claim 12 , wherein the linker comprises an alkylene chain having 2-20 alkylene units.

14 . The bifunctional compound of claim 1 , wherein the linker comprises a polyethylene glycol chain which may terminate at either or both termini in at least one of —S—, —N(R′)—, —C≡C—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(NOR′)—, —C(O)N(R′)—, —C(O)N(R′)C(O)—, —C(O)N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —C(NR′)—, —N(R′)C(NR)—, —C(NR′)N(R′)—, —N(R′)C(NR′)N(R′)—, —OB(Me)O—, —S(O) 2 —, —OS(O)—, —S(O)O—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —N(R′)S(O) 2 —, —S(O) 2 N(R′)—, —N(R′)S(O)—, —S(O)N(R′)—, —N(R′)S(O) 2 N(R′)—, —N(R′)S(O)N(R′)—, C 3-12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof, wherein R′ is H or C 1 -C 6 alkyl, wherein the one or both terminating groups may be the same or different.

15 . The bifunctional compound of claim 14 , wherein the linker comprises 1-6 polyethylene glycol units.

16 . The bifunctional compound of claim 1 , wherein the linker is represented by any one of structures:

17 . The bifunctional compound of claim 1 , which is represented by any one of structures 1-14:

or a pharmaceutically acceptable salt or stereoisomer thereof.

18 . A pharmaceutical composition, comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomer of claim 1 , and a pharmaceutically acceptable carrier.

19 . A method of treating a disease or disorder that is characterized or mediated by aberrant activity of PRMT5, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomer of claim 1 .

20 . The method of claim 19 , wherein the disease or disorder is a cancer.

21 . The method of claim 20 , wherein the cancer is breast cancer, colorectal cancer, lung cancer, gastric cancer, nasopharyngeal cancer, ovarian cancer, germ cell tumors, B-cell lymphoma, T-cell lymphoma, metastatic melanoma, neuroblastoma or glioblastoma.

22 . The method of claim 21 , wherein the breast cancer is triple-negative breast cancer.

23 . The method of claim 20 , wherein the cancer is myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).

24 . The bifunctional compound of claim 1 , wherein the targeting ligand is represented by TL2: