Substituted Benzo-Pyrimido-Tetrazolo-Diazepine Compounds

• US 20110166127A1
• Filed: 12/29/2010
• Published: 07/07/2011
• Est. Priority Date: 12/30/2009
• Status: Active Grant

• Current Assignee: ArQule, Inc. (Merck & Co., Inc.)
• Original Assignee: ArQule, Inc. (Merck & Co., Inc.)
• Inventors: Link, Jeffrey S., Yang, Rui-Yang
• Granted Patent: US 8,470,812 B2
• Time in Patent Office: Days
• US Class Current: 514/219
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 487/14 Ortho-condensed systems
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention relates to substituted benzo-pyrimido-tetrazolo-diazepine compounds and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing substituted benzo-pyrimido-tetrazolo-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 of Formula I or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof:

2. The compound of claim 1, wherein R is SR_S or S(O)₂R_S.

3. The compound of claim 1, wherein R is NR₁R₂.

4. The compound of claim 3, wherein R₁ is H or unsubstituted or substituted C₁-C₆ alkyl and R₂ is unsubstituted or substituted C₁-C₆ alkyl.

5. The compound of claim 3, wherein R₁ is H or unsubstituted or substituted C₁-C₆ alkyl and R₂ is -T_g-R_q.

6. The compound of claim 5, wherein R_q is unsubstituted or substituted di-C₁-C₆ alkylamino, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀ carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.

7. The compound of claim 3, wherein R₁ and R₂, together with the nitrogen atom to which they are attached, form a 4- to 8-member ring which optionally comprises 1-3 additional heteroatoms selected from N, O and S and optionally is substituted.

8. The compound of claim 3, wherein R₄ is H.

9. The compound of claim 3, wherein R₁ and R₂, together with the nitrogen atom to which the are attached, form a ring having the formula:

10. The compound of claim 9, wherein X₁, X₂, X₄ and X₅ are each CH and X₃ is N, O or CH.

11. The compound of claim 9, wherein X₁ is absent.

12. The compound of claim 9, wherein R₄ is H.

13. The compound of claim 9, wherein R₄ is -T_r-R_r.

14. The compound of claim 13, wherein T_r is a methyl linker and R_r is unsubstituted or substituted phenyl.

15. The compound of claim 1, wherein R₄ is -T_r-R_r;

T_r is a methyl linker; and

R_r has the formula;

16. The compound of claim 15, wherein R₁ is H or unsubstituted or substituted C₁-C₆ alkyl and R₂ is -T_g-R_q.

17. The compound of claim 15, wherein R₁ and R₂, together with the nitrogen atom to which they are attached, form a 4- to 8-member ring which optionally comprises 1-3 additional heteroatoms selected from N, O and S and optionally is substituted.

18. A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable carriers.

19. A method of treating a cell proliferative disorder by administering to a subject in need thereof, a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, such that the disorder is treated.

20. The method of claim 19, further comprising administering to the subject in need thereof, a second anti-proliferative agent.