2-oxo-2,3,4,5-tetrahydro-1 H-benzo[B]diazepines and their use in the treatment of cancer

Patent metadata

Field	Value
Publication number	US-9422331-B2
Application number	US-201314428407-A
Country	US
Kind code	B2
Filing date	Sep 16, 2013
Priority date	Sep 19, 2012
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

Abstract

Disclosed are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein W, Y, Z, R1, R2, R3, R4 and R5 are described herein, and methods of using said compounds in the treatment of cancer.

First claim

The invention claimed is:

1. A compound of Formula I

wherein
W is selected from H and C 1-6 -alkyl that optionally may be substituted with 1-3 deuterium atoms;
Y is C 1-6 -alkyl that optionally may be substituted with OR6,
R1, R2 and R3 are the same or different and each is independently selected from H and cyano;
R4 is C 1-6 -alkyl;
R5 is selected from the group
a) C 1-6 -alkyl that optionally may be substituted with SO 2 R6 and OR6,
b) heterocyclyl, and
c) aryl that optionally may be substituted with C(O)R7, halo and cyano;
Z is selected from the group
a) aryl that optionally may be substituted with C 1-6 -alkyl, OR6, halogen and aryl that optionally may be substituted with halogen,
b) heteroaryl that optionally may be substituted with C 1-6 -alkyl, C 3-7 -cycloalkyl, OR6, halogen, oxo and aryl that optionally may substituted with cyano, and
c) aryl fused with heterocyclyl, wherein the aryl optionally may be substituted with OR6 and halogen, and the heterocyclyl optionally may be substituted with oxo, and
d) heterocyclyl;
R6 is selected from H and C 1-6 -alkyl that optionally may be substituted with halogen and deuterium; and
R7 is C 1-6 -alkyl;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein W is C 1-6 -alkyl, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 wherein W is methyl.

4. The compound according to claim 1 wherein Y is C 1-6 -alkyl, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 wherein Y methyl or ethyl, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 wherein R1, R2 and R3 are H, or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 wherein R1 is H and either R2 or R3 is cyano and other is H, or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 wherein R4 is methyl, or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 wherein R5 is C 1-6 -alkyl that optionally may be substituted with SO 2 R6 or OR6 and R6 is methyl, or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 wherein R5 is heterocyclyl, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10 wherein R5 is tetrahydropyran.

12. The compound according to claim 1 wherein R5 is aryl that optionally may be substituted with C(O)R7, halogen and cyano, or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12 wherein R5 is phenyl that optionally may be substituted with C(O)CH 3 and cyano.

14. The compound according to claim 1 wherein Z is aryl, or a pharmaceutically acceptable salt thereof.

15. The compound of claim 14 wherein Z is phenyl that optionally may be substituted with OCH 3 , halogen and phenyl that optionally may be substituted with halogen.

16. The compound of claim 14 wherein Z is naphthalenyl that optionally may be substituted with OCH 3 , halogen, CH3 and OCHF 2 .

17. The compound according to claim 1 wherein Z is heteroaryl, or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17 wherein Z is selected from quinolinyl, indazolyl, chromenyl and bensoisoxazolyl.

19. The compound of claim 1 wherein Z is aryl fused with heterocyclyl, or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 1 wherein R6 is methyl, or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 1 wherein R7 is methyl, or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1 wherein W and Y are each methyl, R1 is H, R2 and R3 are each independently H or cyano, R4 is methyl and R5 is aryl, or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1 wherein W and Y are each methyl, R1 is H, R2 and R3 are each independently H or cyano, R4 is methyl, R5 is C 1-6 -alkyl that optionally may be substituted with OCH 3 or SO 2 CH 3 , or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1 wherein W and Y are each methyl, R1 is H, R2 and R3 are each independently H or cyano, R4 is methyl and R5 is heterocyclyl, or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1 wherein W and Y are each methyl, R1 is H, R2 and R3 are each independently H or cyano, R4 is methyl, R5 is C 1-6 -alkyl that optionally may be substituted with SO 2 CH 3 or OCH 3 and Z is aryl, or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1 wherein W and Y are each methyl, R1 is H, R2 and R3 are each independently H or cyano, R4 is methyl, R5 is C 1-6 -alkyl that optionally may be substituted with SO 2 CH 3 or OCH 3 and Z heteroaryl, or a pharmaceutically acceptable salt thereof.

27. The compound of claim 1 wherein W and Y are each methyl, R1 is H, R2 and R3 are each independently H or cyano, R4 is methyl, R5 is heterocyclyl and Z is aryl, or a pharmaceutically acceptable salt thereof.

28. The compound of claim 1 wherein W and Y are each methyl, R1 is H, R2 and R3 are each independently H or cyano, R4 is methyl, R5 is aryl and Z is aryl or heteroaryl, or a pharmaceutically acceptable salt thereof.

29. The compound of claim 1 wherein W and Y are each methyl, R1 is H, R2 and R3 are each independently H or cyano, R4 is methyl, R5 is C 1-6 -alkyl and Z is aryl fused with heterocyclyl, or a pharmaceutically acceptable salt thereof.

30. The compound of claim 1 wherein said compound is:
(S)-N-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride;
(S)-N-((3S,4S)-1-((5-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride;
(S)-N-((3S,4S)-1-((7-methoxy-2-oxo-2H-chromen-4-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide 2,2,2-trifluoroacetate;
(S)-N-((3S,4S)-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride;
(S)-N-((2S,3S)-2-methyl-5-((3-methylquinolin-4-yl)methyl)-1-(2-(methyl sulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride;
(S)-N-((3S,4S)-1-((2-chloro-3-methylquinolin-4-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride;
(S)-N-((2S,3S)-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-5-(quinolin-4-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride;
(S)-N-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-5-(3-methoxypropanoyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride;
(S)-N-((2S,3S)-1-acetyl-5-((3-cyclopropylquinolin-4-yl)methyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide;
(S)-N-((2S,3S)-1-acetyl-5-((1-(2-cyanophenyl)-1H-indazol-3-yl(met

Assignees

• Hoffmann La Roche

Inventors

• Donnell Andrew Forrest
• Kester Robert
• Lou Yan
• Anthony John
• Remiszewski Stacy

Classifications

• C07D243/26

  Preparation from compounds already containing the benzodiazepine skeleton · CPC title

• A61K31/5513

  1,4-Benzodiazepines, e.g. diazepam {or clozapine} · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K5/06026 Primary

  the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala · CPC title

• A61K38/05

  Dipeptides · CPC title