Methods to induce targeted protein degradation through bifunctional molecules

Patent metadata

Field	Value
Publication number	US-10849980-B2
Application number	US-201916264266-A
Country	US
Kind code	B2
Filing date	Jan 31, 2019
Priority date	Dec 23, 2014
Publication date	Dec 1, 2020
Grant date	Dec 1, 2020

Abstract

The present application provides bifunctional compounds which act as protein degradation inducing moieties. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of the bifunctional compounds that link a cereblon-binding moiety to a ligand that is capable of binding to the targeted protein which can be utilized in the treatment of proliferative disorders. The present application also provides methods for making compounds of the application and intermediates thereof.

First claim

We claim:

1. A compound selected from:

or a pharmaceutically acceptable salt thereof;
wherein:
Y is a bond, (CH 2 ) 1-6 , (CH 2 ) 0-6 —O, (CH 2 ) 0-6 —C(O)NR 2 ′, (CH 2 ) 0-6 —NR 2 ′C(O), (CH 2 ) 0-6 —NH or (CH 2 ) 0-6 —NR 2 ;
X is C(O) or C(C 1 -C 3 alkyl) 2 ;
m is 0, 1, 2 or 3;
n is 0, 1 or 2;
wherein at least one of the following is present:
a. X is C(C 1 -C 3 alkyl) 2 ; or
b. m is 1, 2 or 3; or
c. n is 1 or 2;

each R 1 is C 1 -C 6 alkoxy;
R 2 is C 1 -C 6 alkyl, C(O)—C 1 -C 6 alkyl, or C(O)—C 3 -C 6 cycloalkyl;
R 2 ′ is H or C 1 -C 6 alkyl;
R 3 is H or C 1 -C 3 alkyl;
each R 3 ′ is independently C 1 -C 3 alkyl;
each R 4 is independently H or C 1 -C 3 alkyl; or two R 4 groups, together with the carbon to which they are attached, form a C(O), a C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
R 5 is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
the Linker is a group that covalently binds to Y and the Targeting Ligand; and
the Targeting Ligand is a moiety that binds to a Target Protein, wherein the Target Protein is a mediator of abnormal cellular proliferation in a host in need of such therapy.

2. The compound of claim 1 , wherein the Targeting Ligand binds to a Target Protein selected from TRIM24, AATK, AXL, BLK, BMX, CSF1R, DDR1, DDR2, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6, ERBB2, ERBB4, FER, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1, FLT3, FLT4, FRK, FYN, GSG2, HCK, ILK, INSR, INSRR, ITK, KSR1, LMTK2, LMTK3, LTK, LYN, MATK, MERTK, MLTK, MST1R, MUSK, NPR1, NTRK1, NTRK2, NTRK3, PDGFRA, PDGFRB, PLK4, PTK2, PTK2B, PTK6, PTK7, ROR1, ROR2, ROS1, RYK, SGK493, SRMS, STYK1, TEC, TEK, TEX14, TIE1, TNK1, TNK2, TNNI3K, TXK, TYK2, TYRO3, YES1, ZAP70, casein kinase 2, AKT1, AKT2, AKT3, ALK1, ALK2, ALK3, ALK4, CLK1, CLK2, CLK3, DAPK1, DAPK2, DAPK3, DMPK, GCK, GSK3, HIPK, KHS1, LKB1, LOK, MAPKAPK2, MAPKAPK, MNK1, MSSK1, MST1, MST2, MST4, NDR, NEK2, NEK3, NEK6, NEK7, NEK9, NEK11, PAK1, PAK2, PAK3, PAK4, PAK5, PAK6, PIM1, PIM2, PLK1, RIP2, RIPS, RSK1, RSK2, SGK2, SGK3, SIK1, STK33, TAO1, TAO2, TLK2, TSSK1, TSSK2, ULK1, ULK2, LRRK2, BRCA1, BRCA2, FANCA, FANCD2, FANCE, FANCF, Her3, Bcl2, PPAR-gamma, DOT1L, BRD4, ERK1, ERK2, RET, and BRD9.

3. The compound of claim 2 , wherein the Target Protein selected from KSR1, TNK1, TNK2, TRIM24, FLT1, FLT3, FLT4, and PAK4.

4. The compound of claim 2 , wherein the Target Protein is selected from FGFR1, FGFR2, FGFR3, FGFR4, NTRK1, DOT1L, LMTK2, LMTK3, BRD4, ERK1, ERK2, RET, Her3, Bcl2, PPAR-gamma, and BRD9.

5. The compound of claim 2 , wherein the Target Protein is selected from AKT1, AKT2, AKT3, ALK1, ALK2, ALK3, and ALK4.

6. The compound of claim 2 , wherein X is C(O).

7. The compound of claim 2 , wherein X is C(CH 3 ) 2 .

8. The compound of claim 2 , wherein X is C(CH 2 CH 3 ) 2 .

9. The compound of claim 2 , wherein R 5 is H or deuterium.

10. The compound of claim 2 , wherein n is 0.

11. The compound of claim 2 , wherein m is 1.

12. The compound of claim 11 , wherein R 1 is methoxy, ethoxy, or propoxy.

13. The compound of claim 2 , wherein m is 0.

14. The compound of claim 2 , wherein R 3 is hydrogen.

15. The compound of claim 2 , wherein R 3 is C 1 -C 3 alkyl.

16. The compound of claim 2 , wherein R 3 ′ is methyl, ethyl, or propyl.

17. The compound of claim 2 , wherein the Linker is:

wherein:
each W is independently absent, CH 2 , O, S, NH or NR 5 ;
Z is absent, CH 2 , O, NH or NR 5 ;
Q is absent or —CH 2 C(O)NH—;
p1 is selected from 0, 1, 2, 3, 4, 5 and 6;
p2 is selected from 0, 1, 2, 3, 4, 5, and 6; and
p3 is selected from 1, 2, 3, 4 and 5.

18. The compound of claim 2 , wherein Linker-Targeting Ligand is selected from L1 or L2:

wherein:
each W is independently absent, CH 2 , O, S, NH or NR 5 ;
Z is absent, CH 2 , O, NH or NR 5 ;
p1 is selected from 0, 1, 2, 3, 4, 5 and 6;
p2 is selected from 0, 1, 2, 3, 4, 5, and 6;
p3 is selected from 1, 2, 3, 4 and 5; and
TL is the Targeting Ligand.

19. The compound of claim 2 , wherein Linker-Targeting Ligand is selected from L6, L7, L8, or L9:

wherein:
each of Q 1 and Q 2 independently is 3- to 8-membered heterocycloalkylene or 5- to 10-membered heteroarylene;
each W is independently absent, CH 2 , O, S, NH or NR 5 ;
Z is absent, CH 2 , O, NH or NR 5 ;
p1 is selected from 0, 1, 2, 3, 4, 5 and 6;
p2 is selected from 0, 1, 2, 3, 4, 5, and 6;
p3 is selected from 1, 2, 3, 4 and 5; and
TL is the Targeting Ligand.

20. The compound of claim 2 , wherein the abnormal cellular proliferation is a neoplasm.

21. The compound of claim 2 , wherein the abnormal cellular proliferation is a cancer.

22. The compound of claim 2 , wherein the abnormal cellular proliferation is a leukemia or lymphoma.

23. The compound of claim 2 , wherein the abnormal cellular proliferation is a benign tumor, an in situ tumor, or a sarcoma.

24. A compound selected from:

or a pharmaceutically acceptable salt thereof;
wherein:
Y is a bond, (CH 2 ) 1-6 , (CH 2 ) 0-6 —O, (CH 2 ) 0-6 —C(O)NR 2 ′, (CH 2 ) 0.6 —NR 2 ′C(O), (CH 2 ) 0-6 —NH or (CH 2 ) 0-6 —NR 2 ;
X is C(O) or C(C 1 -C 3 alkyl) 2 ;
m is 0, 1, 2 or 3;
n is 0, 1 or 2;
each R 1 is independently halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
R 2 is C 1 -C 6 alkyl, C(O)—C 1 -C 6 alkyl, or C(O)—C 3 -C 6 cycloalkyl;
R 2 ′ is H or C 1 -C 6 alkyl;
R 3 is H or C 1 -C 3 alkyl;
each R 3 ′ is independently C 1 -C 3 alkyl;
each R 4 is independently H or C 1 -C 3 alkyl; or two R 4 groups, together with the carbon to which they are attached, form a C(O), a C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
R 5 is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
the Linker is a group that covalently binds to Y and the Targeting Ligand; and
the Targeting Ligand is a moiety that binds to a Target Protein, wherein the Target Protein is a mediator of abnormal cellular proliferation in a host in need of such therapy, and wherein the Target Protein is selected from TRIM24, AATK, AXL, BLK, BMX, CSF1R, DDR1, DDR2, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6, ERBB2, ERBB4, FER, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1, FLT3, FLT4, FRK, FYN, GSG2, HCK, ILK, INSR, INSRR, ITK, KSR1, LMTK2, LMTK3, LTK, LYN, MATK, MERTK, MLTK, MST1R, MUSK, NPR1, NTRK1, NTRK2, NTRK3, PDGFRA, PDGFRB, PLK4, PTK2, PTK2B, PTK6, PTK7, ROR

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• Bradner James
• Buckley Dennis
• Winter Georg

Classifications

• C07J43/003 Primary

  not condensed · CPC title

• A61K47/542 Primary

  Carboxylic acids, e.g. a fatty acid or an amino acid · CPC title

• C07J3/005

  the carbon atom being part of a carboxylic function · CPC title

• A61K47/545

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

• A61K47/54

  the modifying agent being an organic compound · CPC title