C3-carbon linked glutarimide degronimers for target protein degradation

Patent metadata

Field	Value
Publication number	US-11992531-B2
Application number	US-202017107781-A
Country	US
Kind code	B2
Filing date	Nov 30, 2020
Priority date	May 10, 2016
Publication date	May 28, 2024
Grant date	May 28, 2024

Abstract

This invention provides Degronimers that have carbon-linked E3 Ubiquitin Ligase targeting moieties (Degrons), which can be 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 compound of Formula:

or a pharmaceutically acceptable salt thereof;
wherein:
W 1 is C═O;
W 2 is C═O;
X is NH;
n is 0, 1, 2, or 3;
is a single or double bond;
R 6 is selected from:

Y is independently selected from N, CH, and CR 11 , wherein 0, 1, or 2 instances of Y are selected to be N;
R 7 , R 8 , and R 15 are independently selected from hydrogen, alkyl, heterocyclic, carbocyclic, aryl, heteroaryl, hydroxyl, halo, azide, CN—, alkoxy, amine, —NHalkyl, and Nalkyl 2 ;
or R 7 and R 8 together with the carbon to which they are attached form a 3-, 4-, 5-, or 6-membered spiro-carbocycle, or a 4-, 5-, or 6-membered spiro-heterocycle comprising 1 or 2 heteroatoms selected from N and O;
or R 15 and R 7 form a 3, 4, 5, or 6 carbon fused ring;
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: 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 halo(alkyl);
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 a linker-targeting ligand;
linker is selected from:

wherein:
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 heteroarylalkyl, aryl, arylalkyl, heterocycle, heteroaryl, carbocycle, bond, alkyl, —C(O)— —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —SO 2 —, —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-, -alkyl(R 27 )-alkyl(R 28 )—, —C(R 27 R 28 )—, —NHC(O)NH—, —N(R 25 )C(O)N(R 25 )—, —N(H)C(O)N(R 25 )—, polyethylene glycol, alkene, haloalkyl, alkoxy, and alkyne, each of which is optionally substituted with one or more substituents independently 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, and alkynyl;
R 26 is hydrogen, alkyl, arylalkyl, heteroarylalkyl, 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═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;

R 101 is independently selected at each occurrence from the group consisting of hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, —COOalkyl, COOH, NO 2 , F, Cl, Br, I, CF 3 , NH 2 , NHalkyl, and N(alkyl) 2 ;
R 11 is selected at each instance from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, hydroxyl, heterocyclic, heteroalkyl, carbocyclic, alkoxy, aryl, heteroaryl, alkylamino, alkylhydroxyl, —NHalkyl, —Nalkyl 2 , amino, cyano, nitro, thioalkyl, thiol, and haloalkyl;
targeting ligand is a means for binding the targeted protein that mediates a disorder;
wherein the targeted protein selected from the group consisting of AKT1, AXL, ABL, ABL1, ABL2, AKT2, AP1, AP2, ASH1L, ATAD2, androgen receptor, ATF2, BMX, BCR-ABL, Bcl-2, Bel-XL, BAZ2A, BAZ2B, BRPF1, BMX, CSF1R, CECR2, cathepsin, cyclin dependent kinase, DDR1, DOT1L, dihydrofolate reductase, EPHA2, EPHA3, EPHA4, EPHA7, EPHB4, EZH2, EED, EHMT1, EHMT2, estrogen receptor, FLT3, FES, FYN, FKBP, fatty acid binding protein, factor Xa, FLAP, GSG2, HIV integrase, HIV reverse transcriptase, HIV protease, HCV protease, HDM2, HBV, HCK, histone deacetylase, histone acetyltransferase, heat shock protein, IGF1R, INSR, IDO1, IDH1, ITK, KIT, KSR1, kringle domain V, 4BVV, kallikrein 7, KSR receptor, lactoylglutathione lyase, L3MBTL3, lysine-specific histone demethylase, lysine methyltransferase, LCK, LYN, mPGES-1, MERTK, MEK1, MDM2, MDM4, MEN1, MTH1, MCL-1, MER, MET, mast/stem cell growth factor receptor, MST1R, NTRK, NTRK1, NTRK2, NTRK3, PDZ, phospholipase A2 domain, PB1, PHIP, protein S100-A7, PAK1, PAK4, PPAR-gamma, PDGFR receptor, PNET, ROS1 receptor, RCC receptor, RAML receptor, SETD2, SETD7, SETD8, SETDB1, SMYD2, SMYD3, SUV4-20H1, saposin-B, Sec7, SH2 domain, SEGA receptor, TNIK, TRIM24, TAF1, TAF1L, mTORC1, mTORC2, TANK1, TRKB, tie 2 receptor, TEC, SF6D, U09-CX-5279, VEGF receptor, and YES.

2. The compound of claim 1 , wherein n is O.

3. The compound of claim 1 , wherein R 7 and R 8 are hydrogen.

4. The compound of claim 1 , wherein R 15 is hydrogen.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein R 6 is

10. The compound of claim 1 , wherein R 11 is F, Cl, Br, alkyl, or haloalkyl.

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

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

13. The compound of claim 1 , wherein the linker is selected from the group consisting of:

14. The compound of claim 1 , wherein X 1 is bond.

15. The compound of claim 1 , wherein X 2 is bond.

16. The compound of claim 1 , wherein R 21 is bond.

17. The compound of claim 16 , wherein R 22 is bond.

18. The compound of claim 17 , wherein R 23 is bond.

19. The compound of claim 1 ,

Assignees

• C4 Therapeutics Inc

Inventors

• Phillips Andrew J
• Nasveschuk Christopher G
• Henderson James A
• Liang Yanke
• He Minsheng
• Lazarski Kiel
• Veits Gesine Kerstin
• Vora Harit U

Classifications

• A61K47/55

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title

• A61K47/545 Primary

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title

• A61K31/45 Primary

  having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide · CPC title

• A61K31/451

  having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title