SUBSTITUTED INDOLO-PYRIDINONE COMPOUNDS

• US 20100249127A1
• 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., Vensel, David, Wang, Jianqiang, Westlund, Neil, Palma, Rocio, Namdev, Nivedita, Dalton, Audra
• Granted Patent: US 8,410,144 B2
• Time in Patent Office: Days
• US Class Current: 514/233.200
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond

Abstract

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

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein Y is C(O)R⁴, W, X and Z are each H, R² and R³ are each H, R¹ is unsubstituted or substituted C₅-C₁₀ aryl, and R⁴ is NR⁵R⁶, further wherein said R⁵ is unsubstituted or substituted C₁-C₆ alkyl.

3. The compound of claim 1, wherein Y is C(O)R⁴, W, X and Z are each H, R² and R³ are each H, R¹ is unsubstituted or substituted C₅-C₁₀ aryl, and R⁴ is NR⁵R⁶, further wherein said R⁵ is unsubstituted or substituted C₅-C₁₀ aryl.

16. The compound of claim 1, selected from the group consisting of:

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

18. 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.

19. A method of treating cancer 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 cancer is treated.

20. A method of selectively inducing cell death in precancerous or cancerous cells by contacting a cell with an 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 contacting the cell results in selective induction of cell death in the precancerous or cancer cells.

4. A compound of formula II:

5. The compound of claim 4, wherein Y is C(O)R⁴ and R² and R³ are each H.

6. The compound of claim 5, wherein R¹ is unsubstituted or substituted C₅-C₁₀ aryl.

7. The compound of claim 6, wherein R⁴ is NR⁵R⁶ and further wherein said R⁵ is unsubstituted or substituted C₁-C₆ alkyl.

8. The compound of claim 6, wherein R⁴ is NR⁵R⁶ and further wherein said R⁵ is unsubstituted or substituted C₅-C₁₀ aryl.

9. A compound of formula III:

10. The compound of claim 9, wherein R^2a and R^3a are each H.

11. The compound of claim 10, wherein m is 1 or 2 and each R¹⁰ is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, methoxyl, ethoxyl, propyloxyl, iso-propyloxyl, fluorine, chlorine, bromine, iodine or unsubstituted or substituted phenyl.

12. The compound of claim 10, wherein m is 0 and R⁵ is unsubstituted or substituted methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, or unsubstituted or substituted heterocycle comprising 1-4 heteroatoms selected from N, O and S.

13. The compound of claim 10, wherein m is 0 and R⁵ is —

(CH₂)_n—

R⁹.

14. The compound of claim 10, wherein m is 0 and R⁵ and R⁶, together with the nitrogen atom to which they are attached, form a 6-member ring which optionally comprises 1-2 additional heteroatoms selected from N and O and optionally is substituted.

15. The compound of claim 10, wherein m is 0 and R⁵ and R⁶, together with the nitrogen atom to which they are attached, form an unsubstituted or substituted piperazinyl or piperidinyl ring.