Inhibitors of the notch transcriptional activation complex kinase ("nack") and methods for use of the same

Patent metadata

Field	Value
Publication number	US-2021171469-A1
Application number	US-201916967652-A
Country	US
Kind code	A1
Filing date	Feb 6, 2019
Priority date	Feb 6, 2018
Publication date	Jun 10, 2021
Grant date	—

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 alkyl, C 0-6 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, O, 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 2 , wherein A is methyl.

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

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

6 . The compound or salt of claim 4 , wherein n is 1.

7 . The compound or salt of any one of claims 4 - 6 , 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.

8 . The compound of claim 7 , wherein A is selected from the group consisting of

9 . The compound or salt of any one of claims 4 - 6 , wherein R 5 is H.

10 . The compound or salt of claim 9 , wherein R 1 is H.

11 . The compound or salt of claim 9 , wherein R 1 is C 1-6 alkyl.

12 . The compound or salt of claim 11 , wherein R 1 is methyl, ethyl, fluoromethyl, or trifluoromethyl.

13 . The compound or salt of claim 9 , wherein R 1 is C 0-6 alkyleneC(═O)R 6 .

14 . The compound of claim 13 , wherein, R 1 is

15 . The compound or salt of claim 9 , wherein R 1 is halo.

16 . The compound or salt of claim 15 , wherein R 1 is F.

17 . The compound or salt claim 9 , wherein R 1 is cyano or aryloxy.

18 . The compound or salt of claim 17 , wherein R 1 is CN or —OPh.

19 . The compound or salt of claim 9 , wherein R 1 is amino.

20 . The compound or salt of claim 19 , wherein R 1 is —NH 2 , —N(CH 3 ) 2 or —NH 2 Ph.

21 . The compound or salt of claim 9 , wherein R 1 is C 0-3 alkylene-amido, carbamyl, S-thiocarbamyl, or ureido.

22 . The compound or salt of claim 21 , wherein R 1 is selected from the group consisting of

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

24 . The compound or salt of any one of claims 1 - 23 , wherein X is CH.

25 . The compound or salt of any one of claims 1 - 23 , wherein X is N.

26 . The compound or salt of any one of claims 1 - 25 , wherein Y is CH 2 .

27 . The compound or salt of any one of claims 1 - 24 , wherein Y is N.

28 . The compound or salt of any one of claims 1 - 27 , wherein m is 0.

29 . The compound or salt of any one of claims 1 - 27 , wherein m is 1.

30 . The compound or salt of any one of claims 1 - 29 , wherein R 2 is H.

31 . The compound or salt of any one of claims 1 - 29 , wherein R 2 is Br or Cl.

32 . The compound or salt of any one of claims 1 - 29 , wherein R 2 is CH 3 , CF 3 , CH 2 OH, or CH 2 OCH 3 .

33 . The compound or salt of any one of claims 1 - 29 , wherein R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

34 . The compound or salt of any one of claims 1 - 29 , wherein R 2 is 3-furanyl.

35 . The compound or salt of any one of claims 1 - 29 , wherein R 2 is selected from the group consisting of H, CH 3 , CF 3 , and cyclopropyl.

36 . The compound or salt of any one of claims 1 - 35 , wherein each of R 3 and R 4 independently is H, C 1-6 alkyl, or C 1-3 aralkyl.

37 . The compound or salt of claim 36 , wherein each of R 3 and R 4 independently is H, CH 3 , CH 2 CH 3 , i Bu, or CH 2 Ph.

38 . The compound or salt of claim 35 , wherein

is selected from the group consisting of

39 . The compound or salt of any one of claims 1 - 35 , wherein R 3 and R 4 and the nitrogen to which they are attached join together to form a 5-6 membered ring.

40 . The compound or salt of claim 39 , wherein

is selected from the group consisting of

41 . The compound or salt of any one of claims 1 - 35 , wherein

is selected from the group consisting of

42 . The compound or salt of any one of claims 1 - 41 , wherein R 7 is H.

43 . The compound or salt of any one of claims 1 - 41 , wherein R 7 is NH 2 , Br, Cl, or F.

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

45 . A pharmaceutical composition comprising a compound of any one of claims 1 - 44 and a pharmaceutically acceptable excipient.

46 . A method of inhibiting the Notch activation complex kinase (“NACK”) in a cell, comprising contacting the cell with a compound of any one of claims 1 - 44 , the pharmaceutical composition of claim 45 ,

Assignees

• Univ Miami

Inventors

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

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D231/54 Primary

  condensed with carbocyclic rings or ring systems · CPC title