AMINE-LINKED C3-GLUTARIMIDE DEGRONIMERS FOR TARGET PROTEIN DEGRADATION

1 . A Degronimer consisting of a Degron covalently linked to a Targeting Ligand, wherein the Degronimer is of Formula:

or a pharmaceutically acceptable salt or N-oxide thereof;

wherein:

W 1 is CR 6 R 7 , C═O, C═S, C═CH 2 , SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH, or P(O)NH 2 ;

W 2 is CR 8 R 9 , C═O, C═S, C═CH 2 , SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH, or P(O)NH 2 ;

X is NH, NR 3 , CH 2 , CHR 3 , C(R 3 ) 2 , O, or S;

n is 0, 1, or 2;

is a single or double bond;

R 1 is selected from:

R 2 is alkyl or hydrogen;

or R 1 and R 2 are combined to form a 4, 5, 6, 7, 8, 9, or 10 membered heterocyclo or heteroaryl species, wherein the heterocyclo or heteroaryl species is substituted with R 12 at any desired position, and wherein the heterocyclo or heteroaryl species is optionally further substituted with one or more substituents selected from R 5 ;

R 3 is selected at each instance from: alkyl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, alkene, and alkyne;

R 4 is selected at each instance from: alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, —NHalkyl, —N(alkyl) 2 , —NHSO 2 alkyl, —N(alkyl)SO 2 alkyl, —NHSO 2 aryl, —N(alkyl)SO 2 aryl, —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, and haloalkyl;

or two R 4 substituents together with the carbon atom(s) to which they are bound can form a 3, 4, 5 or 6 membered ring;

R 5 and R 14 are independently selected at each instance from: hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, —NHalkyl, —N(alkyl) 2 , —NHSO 2 alkyl, —N(alkyl)SO 2 alkyl, —NHSO 2 aryl, —N(alkyl)SO 2 aryl, —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, and haloalkyl;

R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 , are independently selected from hydrogen, alkyl, hydroxyl, alkoxy, amine, —NHalkyl, and —Nalkyl 2 ;

or R 6 and R 7 together with the carbon to which they are bound form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;

or R 8 and R 9 together with the carbon to which they are bound form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;

or R 10 and R 11 together with the carbon to which they are bound form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;

or R 6 and R 8 form a 1 or 2 carbon bridged ring;

or R 6 and R 10 form a 1 or 2 carbon bridged ring;

or R 8 and R 10 form a 1 or 2 carbon bridged ring;

or R 14 and R 6 form a 3, 4, 5, or 6 carbon fused ring;

or R 14 and R 10 form a 3, 4, 5, or 6 carbon fused ring;

or R 14 and R 8 form a 1 or 2 carbon bridged ring;

or R 14 and R 4 form a 3, 4, 5, or 6 carbon fused ring wherein R 5 is on the carbon alpha to R 13 or a 1, 2, 3, or 4 carbon bridged ring wherein R 5 is not on the carbon alpha to R 13 ;

R 12 is Linker-Targeting Ligand;

Linker is a chemical group that covalently attaches the Degron to a Targeting Ligand;

and Targeting Ligand is a small molecule that binds to a Targeted Protein, wherein the Targeted Protein is a mediator of abnormal cellular proliferation in a host in need of such therapy.

2 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

3 . The pharmaceutical composition of claim 2 , wherein the compound is selected from:

4 . A method for treating a patient with abnormal cellular proliferation comprising administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

5 . The method of claim 4 , wherein the compound is selected from:

6 . The method of claim 5 , wherein the abnormal cellular proliferation is a cancer.

7 . The method of claim 6 , wherein the cancer is a solid tumor.

8 . The method of claim 6 , wherein the cancer is a hematological cancer.

9 . The method of claim 5 , wherein the Targeted Protein is the androgen receptor.

10 . The method of claim 5 , wherein the Targeted Protein is the estrogen receptor.

11 . The method of claim 5 , wherein the Targeted Protein is the epidermal growth factor receptor.

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

13 . The compound of claim 12 , wherein Linker is selected from:

wherein:

X 1 and X 2 are independently selected from bond, NH, NR 25 , CH 2 , CHR 25 , C(R 25 ) 2 , O, and S;

R 20 , R 21 , R 22 , R 23 , and R 24 are independently selected from bond, alkyl, —C(O)— —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —C(S)—, —SO 2 —, —S(O)—, —C(S)—, —C(O)NH—, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—, —S—, —NH—, —N(alkyl)-, —C(—O—R 26 )H—, —C(—NHR 25 )H—, —C(—NH 2 )H—, —C(—NR 25 2 )H—, —C(—O—R 26 )alkyl-, —C(—NHR 25 )alkyl-, —C(—NH 2 )alkyl-, —C(—NR 25 2 )alkyl-, -alkyl(R 27 )-alkyl(R 28 )—, —CR 27 R 28 —, —P(O)(OR 26 )O—, —P(O)(OR 26 )—, —NHC(O)NH—, —N(R 25 )C(O)N(R 25 )—, —N(H)C(O)N(R 25 )—, polyethylene glycol, poly(lactic-co-glycolic acid), alkene, haloalkyl, alkoxy, and alkyne;

R 25 is selected at each instance from: alkyl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, alkenyl, and alkynyl;

R 26 is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, and alkyne; and

R 27 and R 28 are independently selected from hydrogen, alkyl, amine, or together with the carbon atom to which they are attached, form C(O), C(S), C═CH 2 , a C 3 -C 6 spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O.

14 . The compound of claim 13 , wherein the Targeted Protein is the androgen receptor.

15 . The compound of claim 13 , wherein the Targeted Protein is the estrogen receptor.

16 . The compound of claim 13 , wherein the Targeted Protein is the epidermal growth factor receptor.

17 . The compound of claim 13 , wherein R 27 and R 28 are hydrogen.

18 . The compound of claim 13 , wherein the Linker is:

19 . The compound of claim 13 , wherein the Linker is selected from:

20 . The compound of claim 13 , wherein the Linker is selected from:

21 . The compound of claim 13 , wherein the compound is selected from:

22 . The compound of claim 13 , wherein the compound is selected from:

23 . The compound of claim 13 , wherein the compound is selected from:

24 . The compound of claim 13 , wherein the compound is selected from:

25 . The compound of claim 13 , wherein the compound is:

26 . A Degronimer consisting of a Degron covalently linked to a Targeting Ligand, wherein the Degronimer is selected from:

or a pharmaceutically acceptable salt or N-oxide thereof;

wherein R 12 is Linker-Targeting Ligand;

Linker is a chemical group that covalently attaches the Degron to a Targeting Ligand;

and Targeting Ligand is a small molecule that binds to a Targeted Protein, wherein the Targeted Protein is a mediator of abnormal cellular proliferation in a host in need of such therapy.

27 . The compound of claim 26 , wherein the Linker is selected from:

wherein:

X 1 and X 2 are independently selected from bond, NH, NR 25 , CH 2 , CHR 25 , C(R 25 ) 2 , O, and S;

R 20 , R 21 , R 22 , R 23 , and R 24 are independently selected from bond, alkyl, —C(O)— —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —C(S)—, —SO 2 —, —S(O)—, —C(S)—, —C(O)NH—, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—, —S—, —NH—, —N(alkyl)-, —C(—O—R 26 )H—, —C(—NHR 25 )H—, —C(—NH 2 )H—, —C(—NR 25 2 )H—, —C(—O—R 26 )alkyl-, —C(—NHR 25 )alkyl-, —C(—NH 2 )alkyl-, —C(—NR 25 2 )alkyl-, -alkyl(R 27 )-alkyl(R 28 )—, —CR 27 R 28 —, —P(O)(OR 26 )O—, —P(O)(OR 26 )—, —NHC(O)NH—, —N(R 25 )C(O)N(R 25 )—, —N(H)C(O)N(R 25 )—, polyethylene glycol, poly(lactic-co-glycolic acid), alkene, haloalkyl, alkoxy, and alkyne;

R 25 is selected at each instance from: alkyl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, alkenyl, and alkynyl;

R 26 is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, and alkyne; and

R 27 and R 28 are independently selected from hydrogen, alkyl, amine, or together with the carbon atom to which they are attached, form C(O), C(S), C═CH 2 , a C 3 -C 6 spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O.

28 . The compound of claim 27 , wherein the Targeted Protein is the androgen receptor.

29 . The compound of claim 27 , wherein the Targeted Protein is the estrogen receptor.

30 . The compound of claim 27 , wherein the Targeted Protein is the epidermal growth factor receptor.

31 . The compound of claim 27 , wherein the Linker is:

32 . The compound of claim 27 , wherein the Linker is selected from:

33 . The compound of claim 27 , wherein the Linker is selected from:

34 . The compound of claim 27 , wherein the compound is selected from:

35 . The compound of claim 27 , wherein the compound is selected from:

36 . The compound of claim 27 , wherein the compound is selected from