Inhibitors of the notch transcriptional activation complex kinase (“NACK”) and methods for use of the same

Patent metadata

Field	Value
Publication number	US-11649214-B2
Application number	US-201916967652-A
Country	US
Kind code	B2
Filing date	Feb 6, 2019
Priority date	Feb 6, 2018
Publication date	May 16, 2023
Grant date	May 16, 2023

Abstract

Disclosed herein are Notch transcriptional activation complex kinase (“NACK”) inhibitors, and methods for their use in treating or preventing diseases, such as cancer. The inhibitors described herein include compounds of Formula (la) and pharmaceutically acceptable salts thereof: wherein the substituents are as described.

First claim

We claim:

1. A compound of Formula (Ia), or a pharmaceutically acceptable salt thereof:

wherein:
A is C 1-4 alkyl or

X is CH or N;
Y is CH 2 or N, and when X is N, then Y is CH 2 ;
m is 0 or 1, and when m is 1 then Y is CH 2 ;
n is 0 or 1;
R 1 is H, C 1-6 alkyleneC(═O)R 6 , halo, cyano, aryloxy, amino, C 0-3 alkylene-amido, carbamyl, S-thiocarbamyl, or ureido;
R 2 is H, halo, C 1-6 alkyl, C 3-8 cycloalkyl, or heteroaryl;
each R 3 and R 4 independently is H, C 1-6 alkyl, or C 1-3 aralkyl, or R 3 and R 4 and the nitrogen to which they are attached join together to form a 3-6 membered ring optionally comprising 1 to 3 additional heteroatoms selected from N, 0, and S;
R 5 is H, or R 1 and R 5 together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring comprising 1 to 3 ring heteroatoms selected from N, O, and S;
R 6 is OH, C 1-6 alkyl, or OC 1-6 alkyl; and
R 7 is H, halo or amino;
with the proviso that the compound is not

2. The compound of claim 1 , wherein A is methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, or t-butyl.

3. The compound or salt of claim 1 , wherein A is

4. The compound or salt of claim 3 , wherein n is 0.

5. The compound or salt of claim 3 , wherein R 1 and R 5 together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring comprising 1 to 3 ring heteroatoms selected from N, O, and S.

6. The compound of claim 5 , wherein A is selected from the group consisting of

7. The compound or salt of claim 3 , wherein R 5 is H.

8. The compound or salt of claim 7 , wherein R 1 is:
(i)H;
(ii) methyl, ethyl, fluoromethyl, or trifluoromethyl;
(iii)

(iv) F;
(v) CN or —OPh;
(vi) NH 2 , —N(CH 3 ) 2 or —NH 2 Ph; or
(vii)

9. The compound or salt of claim 1 , wherein A is selected from the group consisting of CH 3 ,

10. The compound or salt of claim 1 , wherein m is 1.

11. The compound or salt of claim 1 , wherein R 2 is:
H;
(ii) Br or Cl;
(iii) CH 3 , CF 3 , CH 2 OH, or CH 2 OCH 3 ;
(iv) cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or
(v) 3-furanyl.

12. The compound or salt of claim 1 , wherein each of R 3 and R 4 independently is H, C 1-6 alkyl, or C 1-3 aralkyl.

13. The compound or salt of claim 12 , wherein each of R 3 and R 4 independently is H, CH 3 , CH 2 CH 3 , ‘Bu, or CH 2 Ph.

14. The compound or salt of claim 1 , wherein

is selected from the group consisting of:
(i)

or
(ii)

15. The compound or salt of claim 1 ,
wherein R 7 is:
(i) H; or
(ii) NH 2 , Br, CI, or F.

16. A compound listed in Table A, Table B, Table C, or a pharmaceutically acceptable salt thereof.

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

18. A method of inhibiting the Notch activation complex kinase (“NACK”) in a cell, comprising contacting the cell with a compound of claim 1 ,

or a pharmaceutically acceptable salt of any of the foregoing, in an amount effective to inhibit NACK.

19. The method of claim 18 , wherein the contacting comprises administering to a patient in need thereof, wherein the patient suffers from a disease associated with deregulation of the Notch transcriptional activation complex, and the disease is:
(i) Tetralogy of Fallot (“TOF”) or Alagille syndrome;
(ii) cancer; or
(iii) multiple sclerosis (“MS”).

20. A method of inhibiting kinase activity, ATPase activity, or both in a cell, comprising contacting the cell with a compound of claim 1 ,

or a pharmaceutically acceptable salt of any of the foregoing in an amount effective to inhibit kinase activity, ATPase activity, or both in the cell.

Assignees

• Univ Miami

Inventors

• Capobianco Anthony J
• Schürer Stephan C
• Zhu Xiaoxia
• Kelley Tanya T

Classifications

• C12Y207/00

  Transferases transferring phosphorus-containing groups (2.7) · CPC title

• C12Y306/01003

  Adenosine triphosphatase (3.6.1.3) · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D231/54 Primary

  condensed with carbocyclic rings or ring systems · CPC title