Granted Patent B2

US 12,264,157 · App. 17/931,814 · Granted Apr 1, 2025

Inventors: Andrew P. Crew (Guilford, CT); Craig M. Crews (New Haven, CT); Xin Chen (Trumbull, CT); Hanqing Dong (Madison, CT); Caterina Ferraro (Stamford, CT); Yimin Qian (Plainsboro, NJ); Kam Siu (Milford, CT); Jing Wang (Milford, CT); Meizhong Jin (East Northport, NY); Michael Berlin (Flemington, NJ); Kurt Zimmermann (Durham, CT); Lawrence Snyder (Killingworth, CT)

Assignees: Arvinas Operations, Inc.; Yale University

C07D471/04A61K45/06C07D401/14C07D403/06C07D403/14C07D405/14C07D413/14C07D417/12C07D417/14C07D495/04

Abstract

Claims (97)

1. A compound according to the following structure:

or a pharmaceutically acceptable salt thereof, wherein:

R is

and

ULM is

wherein:

one of R 5 and R 6 is —OH, and the other is H;

R 7 is H;

E is C═O or C═S;

G is C═J;

J is 0;

M is:

R 9 and R 10 are each independently H or optionally substituted alkyl;

R 11 is optionally substituted heterocyclic, optionally substituted heteroaryl, or optionally substituted aryl;

each R 14 is independently H or alkyl;

R 15 is optionally substituted heteroaryl, optionally substituted aryl, or optionally substituted heterocyclyl;

each R 16 is independently halo, optionally substituted alkyl, CN, or optionally substituted haloalkoxy;

each R 25 is H;

R 23 is H;

o is 0, 1, 2, 3, or 4; and

L is:

—(A) q —,

wherein:

q is an integer from 1 to 20;

each A is independently selected from a bond, CR L1 R L2 , O, S, SO 2 , NR L3 , SO 2 NR L3 CONR L3 , C 0 , CR L 1CR L2 , C═C, C 311 cycloalkyl optionally substituted with 0-6 R L1 , C 3-11 heteocyclyl optionally substituted with 0-6 R L1 , aryl optionally substituted with 0-6 R L1 heteroaryl optionally substituted with 0-6 R L1 , wherein R L1 or R L2 , each independently, can be linked to other groups to form cycloalkyl and/or heterocyclyl; and

R L1 , R L2 , and R L3 are, each independently, selected from H, halo, C 1-8 alkyl, OC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OH, NH 2 , CC—C 1-8 alkyl, CCH, CH═CH(C 1-8 alkyl), C(C 1-8 alkyl)═CH(C 1-8 alkyl), C(C 1-8 alkyl)═C(C 1-8 alkyl) 2 , COC 1-8 alkyl, CO 2 H, halogen, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NHC 1-8 alkyl, SO 2 N(C 1-8 alkyl) 2 , SONHC 1-8 alkyl, SON(C 1-8 alkyl) 2 , CONHC 1-8 alkyl, and CON(C 1-8 alkyl) 2 ;

or L is optionally substituted polyethylene glycol that contains between 2 and 10 ethylene glycol units; and

the chemical linker group (L) is covalently attached to the ULM via R S , R 10 , or R 11 .

2. The compound of claim 1 , wherein:

E is C═O;

G is C═J;

J is O;

R 7 is H;

o is 0;

R 15 is:

and

R 17 is selected from H, halo, optionally substituted cycloalkyl, optionally substituted alkyl, and optionally substituted alkenyl.

3. The compound of claim 1 , wherein R 15 is selected from:

wherein R 30 is H or alkyl.

4. The compound of claim 1 , wherein

E is C═O;

M is:

and

R 11 is:

wherein:

each R 18 is independently halo, optionally substituted alkoxy, cyano, or optionally substituted alkyl; and

p is 0, 1, 2, 3, or 4.

5. The compound of claim 1 , wherein R 11 is selected from:

6. The compound of claim 1 , wherein

E is C═O;

M is:

and

R 11 is optionally substituted heteroaryl, or optionally substituted heterocyclic wherein:

q is 1 or 2;

R 20 is H, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted aryl.

7. The compound of claim 1 , wherein

E is C═O;

M is:

and

R 11 is an optionally substituted heteroaryl or an optionally substituted aryl.

8. The compound of claim 1 , wherein R 11 is selected from:

9. The compound of claim 1 , wherein ULM is:

wherein

X is O or S;

Y is H, methyl, or ethyl;

R 17 is H, methyl, ethyl, hydroxymethyl, or cyclopropyl;

M is:

R 9 is H;

R 10 is H or optionally substituted alkyl; and

R 11 is optionally substituted heteroaryl or optionally substituted aryl.

10. The compound of claim 1 , wherein ULM is:

wherein:

Y is H, methyl, or ethyl;

R 9 is H;

R 10 is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl; and

R 11 is optionally substituted isoindolinone, optionally substituted isoxazole, and optionally substituted heterocyclic.

11. The compound of claim 1 , wherein ULM is:

wherein:

R 17 is methyl or ethyl;

R 9 is H; and

R 10 is alkyl.

12. The compound of claim 1 , wherein R 10 is isopropyl, tert-butyl, or sec-butyl.

13. The compound of claim 1 , wherein ULM is selected from:

14. The compound of claim 1 , wherein L is selected from:

15. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

16. A compound selected from:

or a pharmaceutically acceptable salt thereof.

17. A compound selected from:

or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient.

19. A pharmaceutical composition comprising an effective amount of a compound according to claim 16 in combination with a pharmaceutically acceptable carrier, additive or excipient.

20. A method of treating prostate cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of claim 16 .

21. A pharmaceutical composition comprising an effective amount of a compound according to claim 17 in combination with a pharmaceutically acceptable carrier, additive or excipient.

22. A method of treating prostate cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of claim 17 .

23. A method of treating prostate cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of claim 1 .

24. A method of treating prostate cancer in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of claim 1 .

Assignments (3)

Continuity (4)

References Cited (186)