Granted Patent B2

US 12,605,450 · App. 18/642,602 · Granted Apr 21, 2026

Inventors: Andrew J. Phillips (Littleton, CO); Christopher G. Nasveschuk (Stoneham, MA); James A. Henderson (Weston, MA); Yanke Liang (Belmont, MA); Minsheng He (Andover, MA); Kiel Lazarski (Boston, MA); Gesine Kerstin Veits (Somerville, MA); Harit U. Vora (Andover, MA)

Assignee: C4 THERAPEUTICS, INC.

A61K47/545A61K31/45A61K31/451A61K31/454A61K31/4545C07D211/86C07D211/88C07D211/90C07D221/22C07D401/04C07D401/06C07D401/12C07D401/14C07D405/14C07D413/04C07D413/14C07D417/04C07D417/14C07D471/04C07D471/08C07D487/04C07D495/04C07D495/14C07D519/00C07K14/47C07K14/72

Abstract

Claims (48)

1 . A compound of Formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

W 1 is C═O;

W 2 is C═O;

X is NH;

n is 0 or 1;

 is a single or double bond;

R 6 is selected from:

Y is independently selected from the group consisting of N, CH, and CR 11 , wherein 0, 1, or 2 instances of Y are selected to be N;

Z is NH, O, S, or NR 12 ;

Z 2 is NH or NR 12 ;

and when R 10 is bonded to a Y that is carbon, then Y is CR 10 , and when R 10 is bonded to a Z or Z 2 that is nitrogen, then Z or Z 2 is NR 10 ;

R 15 is selected from the group consisting of hydrogen, alkyl, heterocyclic, carbocyclic, aryl, heteroaryl, hydroxyl, F, Cl, azide, CN-, alkoxy, amine, —NHalkyl, and —Nalkyl 2 ;

or R 15 and R 5 form a 3, 4, 5, or 6 carbon fused ring wherein R 5 is on the carbon alpha to R 15 or a 1, 2, 3, or 4 carbon bridged ring wherein R 5 is not on the carbon alpha to R 15 ;

R 5 is selected at each instance from the group consisting of alkyl, alkene, alkyne, heterocyclic, aryl, heteroaryl, halogen, hydroxyl, alkoxy, azide, amino, —NH (alkyl), —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 5 substituents together with the carbon atom(s) to which they are bound can form a 3, 4, 5 or 6 membered ring;

R 10 is -Linker-Targeting Ligand;

R 11 is selected at each instance from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxyl, heterocyclic, carbocyclic, alkoxy, aryl, heteroaryl, alkylamino, alkylhydroxyl, —NHalkyl, —Nalkyl 2 , amino, cyano, nitro, nitroso, sulfone, sulfoxide, thioalkyl, thiol, and haloalkyl;

R 12 is selected at each instance from the group consisting of hydrogen, alkyl, heterocyclic, heteroaryl, aryl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, —C(O)(aryl, —C(O)O(aryl), alkene, and alkyne;

R 13 and R 14 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxy, amino, —NHalkyl, and —N(alkyl) 2 ;

or R 13 and R 14 together with the carbon atom to which they are attached, form C(O), C(S), C═CH 2 , 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;

Linker is

X 1 and X 2 are independently selected from the group consisting of 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 the group consisting of bond, alkyl, alkene, haloalkyl, alkoxy, alkyne, aryl, heterocycle, heteroaryl, carbocycle, —C(O)—, —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —C(S)—, —SO 2 —, —S(O)—, —C(O)NH—, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—, —S—, —NH—, —N(alkyl)-, —CH(—O—R 26 )—, —CH(—NHR 25 )—, —CH(—NH 2 )—, —CH(—NR 25 2 )—, —C(—O—R 26 )alkyl-, —C(—NHR 25 )alkyl-, —C(—NH 2 )alkyl-, —C(—NR 25 2 )alkyl-, -alkyl(R 27 )-alkyl(R 28 )—, —C(R 27 R 28 )—, —NHC(O)NH—, —N(R 25 )C(O)N(R 25 )—, and —N(H)C(O)N(R 25 )—, wherein each of R 20 , R 21 , R 22 , R 23 , and R 24 is optionally substituted with one or two substituents selected from R 101 ;

R 25 is selected at each instance from the group consisting of alkyl, —C(O) H, —C(O) OH, —C(O)alkyl, —C(O)Oalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclic;

R 26 is hydrogen, alkyl, alkene, alkyne, aryl, heteroaryl, or heterocyclic;

R 27 and R 28 are independently selected from the group consisting of hydrogen, alkyl, and 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, or form a 1 or 2 carbon bridged ring;

R 101 is independently selected at each occurrence from the group consisting of hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl, heterocycle, aryloxy, heteroaryloxy, CN, —COOalkyl, COOH, NO 2 , F, Cl, CF 3 , NH 2 , NHalkyl, and N(alkyl) 2 ; and

Targeting Ligand is a means for binding the Targeted Protein that mediates a disorder, wherein the Targeting Ligand is selected from those in FIGS. 1 A through 8 PPPPP.

2 . The compound of claim 1 , wherein:

n is 0; and

 is a single bond.

3 . The compound of claim 1 , wherein R 6 is selected from the group consisting of

4 . The compound of claim 3 , wherein Re is selected from the group consisting of

5 . The compound of claim 1 , wherein Re is selected from the group consisting of

6 . The compound of claim 1 , wherein Re is selected from the group consisting of

7 . The compound of claim 1 , wherein R 6 is selected from the group consisting of

8 . The compound of claim 2 , wherein the compound is selected from the group consisting of

9 . The compound of claim 2 , wherein the compound is selected from the group consisting of

10 . The compound of claim 1 , wherein the Linker is

11 . The compound of claim 1 , wherein the Linker is

12 . The compound of claim 1 , wherein the Linker is

13 . The compound of claim 1 , wherein one of R 20 , R 21 , R 22 , R 23 , and R 24 is selected from the group consisting of

14 . The compound of claim 1 , wherein the Linker is selected from the group consisting of

15 . The compound of claim 1 , wherein the Linker is selected from the group consisting of

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

17 . A method for treating a patient with a disorder mediated by the targeted protein comprising administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein the disorder mediated by the targeted protein is a tumor or cancer.

Assignments (2)

Continuity (5)

References Cited (207)