SUBSTITUTED DIPYRIDO-PYRIMIDO-DIAZEPINE AND BENZO-PYRIDO-PYRIMIDO COMPOUNDS

• US 20100249108A1
• Filed: 03/31/2010
• Published: 09/30/2010
• Est. Priority Date: 03/31/2009
• Status: Active Grant

• Current Assignee: ArQule, Inc. (Merck & Co., Inc.)
• Original Assignee: ArQule, Inc. (Merck & Co., Inc.)
• Inventors: Tandon, Manish, Ashwell, Mark A., Liu, Yanbin, Palma, Rocio, Namdev, Nivedita
• Granted Patent: US 8,349,827 B2
• Time in Patent Office: Days
• US Class Current: 514/215
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 471/14 Ortho-condensed systems
• CPC Class Codes: C07D 471/22 in which the condensed systems contains four or more hetero rings

Abstract

The present invention relates to substituted dipyrido-pyrimido-diazepine compounds, substituted benzo-pyrido-pyrimido-diazepine compounds and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing substituted dipyrido-pyrimido-diazepine compounds, substituted benzo-pyrido-pyrimido-diazepine compounds and methods of treating cell proliferative disorders, such as cancer, by administering these compounds and pharmaceutical compositions to subjects in need thereof.

Claims

1. A compound having formula I:

2. The compound of claim 1 having formula II:

3. The compound of claim 2 having the formula:

4. The compound of claim 3, wherein Q is a bond or unsubstituted or substituted C₁-C₆ alkyl linker.

5. The compound of claim 3, wherein both R₂ and R₃ are H.

6. The compound of claim 3, wherein at least one of R₂ and R₃ is -Q-T.

7. The compound of claim 3, wherein T is C₁-C₆ alkyl and is optionally substituted with hydroxyl.

8. The compound of claim 3, wherein T is dimethylamino, diethylamino or dipropylamino.

9. The compound of claim 3, wherein T is phenyl and is optionally substituted with one, two or more groups selected from hydroxyl, halogen, nitro, cyano, unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxy, amino, C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, and unsubstituted or substituted C₆-C₁₀ aryl.

10. The compound of claim 3, wherein T is heteroaryl selected from pyridinyl, pyrazinyl, indolyl and pyrrolopyridinyl, and is optionally substituted with unsubstituted or substituted C₁-C₆ alkyl.

11. The compound of claim 3, wherein T is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and is optionally substituted with hydroxyl.

12. The compound of claim 3, wherein T is heterocycle selected from pyrrolidinyl, pyrrolidinone and piperidinyl, and is optionally substituted with unsubstituted or substituted C₁-C₆ alkyl.

13. The compound of claim 3, wherein R₂ and R₃, together with the atom to which they attach, form a piperazinyl ring which is optionally substituted with unsubstituted or substituted C₁-C₆ alkylcarbonyl.

14. The compound of claim 1 having formula III:

15. The compound of claim 14 having the formula:

16. The compound of claim 15, wherein Q_R is a bond or unsubstituted or substituted C₁-C₆ alkyl linker.

17. The compound of claim 15, wherein T_R is phenyl and is optionally substituted with one, two or more groups selected from hydroxyl, halogen, nitro, cyano, unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxy, amino, C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, and unsubstituted or substituted C₆-C₁₀ aryl.

18. The compound of claim 1, selected from:

19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a salt, solvate, hydrate or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

20. A method of treating a cell proliferative disorder comprising administering to a subject in need thereof a therapeutically effective amount of the composition of claim 19.

21. The method of claim 20, wherein said cell proliferative disorder is selected from a precancerous condition, a hematologic tumor or malignancy, a solid tumor and a cancer.