Spirocyclic degronimers for target protein degradation

Patent metadata

Field	Value
Publication number	US-2021106688-A1
Application number	US-202016882236-A
Country	US
Kind code	A1
Filing date	May 22, 2020
Priority date	May 10, 2016
Publication date	Apr 15, 2021
Grant date	—

Abstract

This invention provides compounds that have spirocyclic E3 Ubiquitin Ligase targeting moieties (Degrons), which can be used as is or 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.

First claim

We claim:

1 . A method for treating a human with a disorder mediated by ABL, BRD4, BRD9, CBP, DOT1L, ERK1, ERK2, EZH2, FGFR3, FGFR4, FKBP, IRAK4, JAK2, MDM2, NTRK1, PIK3CA, RET, WDR5, bromodomain containing protein, glucocorticoid receptor, androgen receptor, or estrogen receptor, comprising administering an effective amount of a compound optionally in a pharmaceutically acceptable carrier, to a patient in need thereof, wherein the compound is of Formula:

or a pharmaceutically acceptable salt thereof;
wherein:
W 1 is C═O;
W 2 is C═O;
X is independently NH, NR 12 , CH 2 , CHR 12 , C(R 12 ) 2 , O, or S;
n is 0, 1, 2, or 3;
is a single or double bond;
Y and Z are each independently selected from the group consisting of CH 2 , CHR 12 , C(R 12 ) 2 , C(O), N, NH, NR 13 , O, S, and S(O) as permitted by valency;
R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 , are independently selected from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, carbocyclic, hydroxyl, alkoxy, amine, —NHalkyl, or —Nalkyl 2 ;
or R 1 and R 2 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 3 and R 4 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 7 and R 8 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 1 and R 3 form a 1, 2, 3 or 4 carbon bridged ring;
or R 1 and R 7 form a 1, 2, 3 or 4 carbon bridged ring;
or R 3 and R 7 form a 1, 2, 3, or 4 carbon bridged ring;
R 5 is selected at each instance from the group consisting of: alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano, aryl, heteroaryl, heteroaliphatic, hetercyclic, —NHalkyl, —N(alkyl) 2 , —NHSO 2 alkyl, —N(alkyl)SO 2 alkyl, —NHSO 2 aryl, aliphatic, —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 6 is a bond wherein Y or Z is substituted with R 10 ;
or R 6 is a divalent moiety attached to Y and Z that contains 1 to 5 contiguous carbon atoms that form a 3 to 8-membered ring wherein 1, 2, or 3 carbon atoms can be replaced with a nitrogen, oxygen or sulfur atom wherein one of the ring atoms is substituted with R 10 and the others are optionally substituted with R 11 ;
wherein the contiguous atoms of R 6 can be attached through a single or double bond;
or

forms a bicyclic moiety which is substituted with R 10 and optionally substituted with one or more groups independently selected from R 11 and oxo;
R 10 is Linker-Targeting Ligand;
R 11 is selected at each instance from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, aliphatic, heteroaliphatic, carbocyclic, halogen, hydroxyl, amino, cyano, alkoxy, aryl, heteroaryl, heterocyclic, carbocyclic, alkylamino, alkylhydroxyl, and haloalkyl;
R 12 is selected from the group consisting of alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, —C(O)H, —C(O)OH, —C(O)(aliphatic), —C(O)O(aliphatic), —NH(aliphatic), —N(independently aliphatic) 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, aliphatic, heteroaliphatic, aryl, heteroaryl, hetercyclic, carbocyclic, cyano, nitro, nitroso, —SH, —Salkyl, and haloalkyl;
R 13 is selected from the group consisting of alkyl, alkenyl, alkynyl, —C(O)H, —C(O)OH, —C(O)alkyl, and —C(O)Oalkyl;
Linker is a chemical group that covalently attaches the Degron to the Targeting Ligand;
and Targeting Ligand binds to a Targeted Protein, wherein the Targeted Protein is selected from the group consisting of ABL, BRD4, BRD9, CBP, DOT1L, ERK1, ERK2, EZH2, FGFR3, FGFR4, FKBP, IRAK4, JAK2, MDM2, NTRK1, PIK3CA, RET, WDR5, bromodomain containing protein, glucocorticoid receptor, androgen receptor, or estrogen receptor.

2 . The method of claim 1 , wherein X is NH.

3 . The method of claim 1 , wherein n is 0.

4 . The method of claim 1 , wherein X is NH and n is 0.

5 . The method of claim 1 , wherein R 7 and R 8 are hydrogen.

6 . The method of claim 1 , wherein R 6 is a divalent moiety attached to Y and Z that contains 1 to 5 contiguous carbon atoms that form a 3 to 8-membered ring wherein 1, 2, or 3 carbon atoms can be replaced with a nitrogen, oxygen or sulfur atom wherein one of the ring atoms is substituted with R 10 and the others are optionally substituted with R 11 ; wherein the contiguous atoms of R 6 can be attached through a single or double bond.

7 . The method of claim 1 , wherein

forms a bicyclic moiety which is substituted with R 10 and optionally substituted with one or more groups independently selected from R 11 and oxo.

8 . The method of claim 1 , wherein

is selected from:

9 . The method of claim 1 , wherein the disorder is a cancer.

10 . The method of claim 9 , wherein the cancer is a solid tumor.

11 . The method of claim 9 , wherein the cancer is a hematological cancer.

12 . The method of claim 9 , wherein the cancer is multiple myeloma.

13 . The method of claim 9 , wherein the cancer is leukemia.

14 . The method of claim 9 , wherein the cancer is T-cell lineage acute lymphoblastic leukemia.

15 . The method of claim 9 , wherein the cancer is large granular lymphocytic leukemia.

16 . The method of claim 9 , wherein the cancer is Hodgkin's lymphoma.

17 . The method of claim 9 , wherein the cancer is non-Hodgkin's lymphoma.

18 . The method of claim 9 , wherein the cancer is sarcoma.

19 . The method of claim 9 , wherein the cancer is synovial sarcoma.

20 . The method of claim 9 , wherein the cancer is Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, or myosarcoma.

Assignees

• C4 Therapeutics Inc

Inventors

• Phillips Andrew J
• Nasveschuk Chris G
• Henderson James A
• Liang Yanke
• Lazarski Kiel
• Michael Ryan E

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D498/20

  Spiro-condensed systems · CPC title

• A61K31/438

  The ring being spiro-condensed with carbocyclic or heterocyclic ring systems · CPC title

• A61K47/554

  the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid · CPC title

• C07D471/10

  Spiro-condensed systems · CPC title