Modulators of phosphoinositide 3-kinase

• US 20030149074A1
• Filed: 10/24/2002
• Published: 08/07/2003
• Est. Priority Date: 10/24/2001
• Status: Active Grant

• Current Assignee: Entelos Holding Corp. (SilkRoad Inc.)
• Original Assignee: Iconix Biosciences, Inc. (SilkRoad Inc.)
• Inventors: Nguyen, Allen T.Q., Sun, Dongxu, Perkins, Edward L., Melese, Teri
• Granted Patent: US 6,908,932 B2
• Time in Patent Office: Days
• US Class Current: 514/312
• CPC Class Codes: C07D 215/22 attached in position 2 or 4
• CPC Class Codes: C07D 215/38 Nitrogen atoms nitro radicals C07D215/18
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

Compounds of formula 1 are effective modulators of PI3 kinase:

wherein R₁ is H, hydroxy, amino, lower alkyl, or trihalomethyl;

R₂ is amino, lower alkylamino, lower acylamino, arylamino, arylacyl-amino, heteroaryl-amino, heteroaryl-acyl amino, where aryl and heteroaryl are substituted with 0-3 substituents selected from the group consisting of halo, trihalomethyl, hydroxy, lower alkyl and lower alkoxy, or a substituent of the form —(CH₂)_n—C(═X)—R₈, where n is 0-3 inclusive and X is O or NR₉, where R₉ is H, lower alkyl, or R₁, and R₂ together form —CH═N—X—where X is CH, NH, O, or S, and R₈ is H, lower alkyl, lower alkoxy, aryl, aralkyl, or —(CH₂)_mCR₁₀R₁₁R₁₂, where m is 0-3 inclusive, and R₁₀, R₁₁, and R₁₂ are each independently H, lower alkyl, aryl, aralkyl, hydroxy, lower alkoxy, aryloxy, aralkoxy, amino, lower alkyl-amino, arylamino, aralkylamino, heteroaryl amino, or heteroaralkyl amino, where aryl and heteroaryl are substituted with 0-3 substituents selected from the group consisting of halo, hydroxy, and lower alkyl;

R₃ is H or lower alkyl; and

R₄, R₅, R₆, R₇ are each independently H, halo, hydroxy, amino, nitro, lower alkyl, or lower alkoxy;

and pharmaceutically acceptable salts thereof.

Claims

1. ) A compound of formula 1:

2. ) The compound of claim 1, wherein R₁ is hydroxy.

3. ) The compound of claim 2, wherein R₃ is lower alkyl.

4. ) The compound of claim 3, wherein R₄, R₅, R₆, and R₇ are each H.

5. ) The compound of claim 4, wherein R₂ is lower acylamino.

6. ) The compound of claim 5, wherein R₂ is hexanoylamino.

7. ) The compound of claim 4, wherein R₂ is heteroaryl-acyl amino.

8. ) The compound of claim 7, wherein R₂ is 4-pyridoylamino.

9. ) The compound of claim 7, wherein R₂ is —

(CH₂)_n—

C(═

X)—

R₈, where X is O, and R₈ is H, lower alkoxy, or —

(CH₂)_mCR₁₀R₁₁R₁₂.

10. ) The compound of claim 9, wherein n is 1 and R₈ is lower alkoxy.

11. ) The compound of claim 10, wherein R₈ is ethoxy.

12. ) The compound of claim 9, wherein n is 0 and R₈ is —

(CH₂)_mCR₁₀R₁₁R₁₂.

13. ) The compound of claim 12, wherein m is 1, R₁₀ is arylamino, R₁₁ is aryl, and R₁₂ is H, wherein arylamino and aryl are substituted with 0-3 substituents selected from the group consisting of hydroxy, lower alkyl, halo, and nitro.

14. ) The compound of claim 13, wherein R₁₀ is naphthylamino.

15. ) The compound of claim 14, wherein R₁₁ is 4-chlorophenyl.

16. ) The compound of claim 1, wherein R₁ and R₂ together form a ring.

17. ) The compound of claim 16, wherein R₁ and R₂ together form an isoxazole ring.

18. ) The compound of claim 17, wherein R₃ is lower alkyl.

19. ) The compound of claim 18, wherein R₄, R₅, R₆, and R₇ are each H.

20. ) A method for modulating the activity of a PI3 kinase, comprising:

contacting said PI3 kinase with an effective amount of a compound of formula

wherein R₁ is H, hydroxy, amino, lower alkyl, or trihalomethyl;

R₂ is amino, lower alkylamino, lower acylamino, arylamino, arylacyl-amino, heteroaryl-amino, heteroaryl-acyl amino, where aryl and heteroaryl are substituted with 0-3 substituents selected from the group consisting of halo, trihalomethyl, hydroxy, lower alkyl and lower alkoxy, or a substituent of the form —

(CH₂)_n—

C(═

X)—

R₈, where n is 0-3 inclusive and X is O or NR₉, where R₉ is H, lower alkyl, or R₁ and R₂ together form —

CH═

N—

X—

, where X is CH, NH, O, or S, and R₈ is H, lower alkyl, lower alkoxy, aryl, aralkyl, or —

(CH₂)_mCR₁₀R₁₁R₁₂, where m is 0-3 inclusive, and R₁₀, R₁₁, and R₁₂ are each independently H, lower alkyl, aryl, aralkyl, hydroxy, lower alkoxy, aryloxy, aralkoxy, amino, lower alkyl-amino, arylamino, aralkylamino, heteroaryl amino, or heteroaralkyl amino, where aryl and heteroaryl are substituted with 0-3 substituents selected from the group consisting of halo, hydroxy, and lower alkyl;

R₃ is H or lower alkyl; and

R₄, R₅, R₆, R₇ are each independently H, halo, hydroxy, amino, nitro, lower alkyl, or lower alkoxy;

and pharmaceutically acceptable salts thereof.

21. ) A composition for modulating the activity of a PI3 kinase, said composition comprising:

a therapeutic amount of a compound of formula 1

wherein R₁ is H, hydroxy, amino, lower alkyl, or trihalomethyl;

R₂ is amino, lower alkylamino, lower acylamino, arylamino, arylacyl-amino, heteroaryl-amino, heteroaryl-acyl amino, where aryl and heteroaryl are substituted with 0-3 substituents selected from the group consisting of halo, trihalomethyl, hydroxy, lower alkyl and lower alkoxy, or a substituent of the form —

(CH₂)_n—

C(═

X)—

R₈, where n is 0-3 inclusive and X is O or NR₉, where R₉ is H, lower alkyl, or R₁ and R₂ together form —

CH═

N—

X—

, where X is CH, NH, O, or S, and R₈ is H, lower alkyl, lower alkoxy, aryl, aralkyl, or —

(CH₂)_mCR₁₀R₁₁R₁₂, where m is 0-3 inclusive, and R₁₀, R₁₁, and R₁₂ are each independently H, lower alkyl, aryl, aralkyl, hydroxy, lower alkoxy, aryloxy, aralkoxy, amino, lower alkylamino, arylamino, aralkylamino, heteroaryl amino, or heteroaralkyl amino, where aryl and heteroaryl are substituted with 0-3 substituents selected from the group consisting of halo, hydroxy, and lower alkyl;

R₃ is H or lower alkyl; and

R₄, R₅, R₆, R₇ are each independently H, halo, hydroxy, amino, nitro, lower alkyl, or lower alkoxy;

and pharmaceutically acceptable salts thereof;

and a pharmaceutically acceptable excipient.