Deuterated compounds as inhibitors of the BCL6 BTB domain protein-protein interaction and/or as BCL6 degraders
View Patent ↗The present application relates to compounds of Formula I (I) or pharmaceutically acceptable salts, solvates and/or prodrugs thereof, to compositions comprising these compounds or pharmaceutically acceptable salts, solvates and/or prodrugs thereof, and various uses in the treatment of diseases, disorders or conditions that are treatable by inhibiting interactions with BCL6 BTB and/or by degrading BCL6, such as cancer.
1. A compound of formula I, or a pharmaceutically acceptable salt, thereof:
A is selected from O and NR 11 ;
X is selected from CH 2 , CF 2 , CD 2 , CHF, CDF and CHD;
R 1 and R 2 are independently selected from H, D, C 1-4 alkyl and deuterium-substituted C 1-4 alkyl;
R 3 , R 4 , R 5 , R 6 , R 9 and R 10 are independently selected from H and D;
R 7 and R 8 are independently CR 12 R 13 R 14 ,
R 11 is selected from H, C 1-4 alkyl and deuterium-substituted C 1-4 alkyl;
R 12 , R 13 and R 14 are independently selected from H, D and F; and
all alkyl groups are optionally fluoro-substituted and the compound of Formula I comprises at least one D.
2. The compound of claim 1 , wherein A is NR 11 and R 11 is selected from H, CH 3 and CD 3 .
3. The compound of claim 2 , wherein A is NCH 3 .
4. The compound of claim 1 , wherein X is selected from CH 2 , and CF 2 .
5. The compound of claim 1 , wherein R 1 and R 2 are independently selected from CH 3 and CD 3 .
6. The compound of claim 1 , wherein R 3 , R 4 , R 5 , R 6 , R 9 and R 10 are all H, or R 3 , R 4 , R 5 , R 6 , R 9 and R 10 are all D.
7. The compound of claim 1 , wherein R 3 and R 4 are D and R 5 , R 6 , R 9 and R 10 are all H.
8. The compound of claim 1 , wherein R 7 and R 8 are the same and are selected from CH 3 , CF 3 , CD 3 and CD 2 F.
9. The compound of claim 1 , wherein the stereochemistry in the compounds of Formula I is as follows:
10. The compound of claim 1 selected from:
No
Structure
Ia
Ib
Ic
Ie
If
Ig
Ih
Ii
Ij
Ik
Il
Im
In
Io
Ip
Iq
Ir
Is
It
Iu
Iv
Iw
Ix
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , selected from:
No
Structure
Ia
Ib
Ih
Ig
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising one of more compounds of claim 1 and a pharmaceutically acceptable carrier.
13. A method for inhibiting interactions with BCL6 BTB and/or degrading BCL6 in a cell, comprising administering an effective amount of one or more compounds of claim 1 to the cell.
14. A method of treating a lymphoma comprising administering a therapeutically effective amount of one or more compounds of claim 1 to a subject in need thereof.
15. The method of claim 14 , wherein the lymphoma is a B-cell lymphoma, a non-Hodgkins lymphoma, or a follicular lymphoma.
16. The method of claim 14 , wherein the lymphoma is diffuse large B cell lymphoma (DLBCL).