Carbonylamino pyrrolopyrazoles, potent kinase inhibitors

• US 7,884,117 B2
• Filed: 12/12/2006
• Issued: 02/08/2011
• Est. Priority Date: 12/21/2005
• Status: Expired due to Fees

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Li, Haitao, Hong, Yufeng, Zhang, Junhun, Johnson, Mary Catherine, Guo, Chuangxing, McAlpine, Indrawan James, Kephart, Susan Elizabeth, Tikhe, Jayashree, Dong, Liming, Yang, Anle
• Primary Examiner(s): Saeed; Kamal A
• Assistant Examiner(s): Shterengarts; Samantha L
• Application Number:
  US12/158,241
• Publication Number:
  US 20090318440A1
• Time in Patent Office: 1,519 Days
• Field of Search: 514/378, 514/406, 548/248, 548/360.5
• US Class Current: 514/378
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Carbonylamino Pyrrolopyrazole compounds of formula I, compositions including these compounds and methods of their use are provided. Preferred compounds of formula I have activity as protein kinase inhibitors, including as inhibitors of PAK4.

Claims

1. A compound of formula I,

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R² is unsubstituted methyl and R³ is unsubstituted methyl.

3. The compound of claim 2, or a pharmaceutically acceptable thereof, wherein R¹ is selected from the group consisting of C₁-C₈ alkyl, —

(C₁-C₃ alkylene)_m-phenyl, —

(C₃-C₇ cycloalkylene)-phenyl, —

(C₁-C₃ alkylene)_m-(C₃-C₁₂ cycloalkyl), —

(C₃-C₇ cycloalkylene)-(C₃-C₁₂ cycloalkyl), —

(C₁-C₃ alkylene)_m-(C₃-C₁₂ unsaturated nonaromatic carbocyclyl), —

(C₃-C₇ cycloalkylene)-(C₃-C₁₂ unsaturated nonaromatic carbocyclyl)-(C₁-C₃ alkylene)_m-(5-10 member heteroaryl), —

(C₃-C₇ cycloalkylene)-(5-10 member heteroaryl), —

(C₁-C₃ alkylene)_m-(3-10 member heterocyclyl) and —

(C₃-C₇ cycloalkylene)-(3-10 member heterocyclyl), and R¹ is optionally further substituted by 1-6 groups selected from the group consisting of C₁-C₃ alkyl, —

(C₁-C₃ alkylene)_m-(C₃-C₅ cycloalkyl), —

(C₁-C₃ alkylene)_m-(3-6 member heterocyclyl optionally further substituted by 1-2 methyl), F, Cl, —

CN, C₁-C₃ perfluoroalkyl, —

(C₁-C₃ alkylene)_m-NH₂, —

(C₁-C₃ alkylene)_m-NH(C₁-C₄ alkyl), —

(C₁-C₃ alkylene)_m-N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —

(C₁-C₃ alkylene)_m-NH—

(C₃-C₅ cycloalkyl)-(C₁-C₃ alkylene)_m-OH, —

(C₁-C₃ alkylene)_m-O—

(C₁-C₄ alkyl), —

(C₁-C₃ alkylene)_m-O—

(C₃-C₅ cycloalkyl), —

(C₁-C₃ alkylene)_m-C(O)—

NH₂, —

(C₁-C₃ alkylene)_m-C(O)—

NH—

(C₁-C₄ alkyl) and —

(C₁-C₃ alkylene)_m-C(O)—

N(C₁-C₄ alkyl)(C₁-C₄ alkyl).

4. The compound of claim 2, or a pharmaceutically acceptable thereof, wherein R¹ is selected from the group consisting of C₁-C₈ alkyl, C₃-C₈ cycloalkyl, phenyl, —

(C₁-C₃ alkylene)-phenyl, -(cyclopropylene)-phenyl, -pyridinyl, —

(C₁-C₃ alkylene)-pyridinyl, —

(cyclopropylene)-pyridinyl, -pyrimidinyl, —

(C₁-C₃ alkylene)-pyrimidinyl, -(cyclopropylene)-pyrimidinyl, thiophenyl, —

(C₁-C₃ alkylene)-thiophenyl, -(cyclopropylene)-thiophenyl, pyrazolyl, —

(C₁-C₃ alkylene)-pyrazolyl, -(cyclopropylene)-pyrazolyl, tetrahydrofuranyl, —

(C₁-C₃ alkylene)-tetrahydrofuranyl, —

(C₁-C₃ cyclopropylene)-tetrahydrofuranyl, tetrahydropyranyl, —

(C₁-C₃ alkylene)-tetrahydropyranyl, —

(C₁-C₃ cyclopropylene)-tetrahydropyranyl, morpholinyl, —

(C₁-C₃ alkylene)-morpholinyl, -(cyclopropylene)-morpholinyl, imidazolyl, —

(C₁-C₃ alkylene)-imidazolyl, -(cyclopropylene)-imidazolyl, thiazolyl, —

(C₁-C₃ alkylene)-thiazolyl, -(cyclopropylene)-thiazolyl, isothiazolyl, —

(C₁-C₃ alkylene)-isothiazolyl, -(cyclopropylene)-isothiazolyl, oxazolyl, —

(C₁-C₃ alkylene)-oxazolyl, -(cyclopropylene)-oxazolyl, isoxazolyl, —

(C₁-C₃ alkylene)-isoxazolyl, -(cyclopropylene)-isoxazolyl, benzothiophenyl, —

(C₁-C₃ alkylene)-benzothiophenyl, -(cyclopropylene)-benzothiophenyl, benzothiazolyl, —

(C₁-C₃ alkylene)-benzothiazolyl, -(cyclopropylene)-benzothiazolyl, dihydrobenzofuranyl, —

(C₁-C₃ alkylene)-dihydrobenzofuranyl, -(cyclopropylene)-dihydrobenzofuranyl, pyrazinyl, —

(C₁-C₃ alkylene)-pyrazinyl and -(cyclopropylene)-pyrazinyl, wherein R¹ is optionally further substituted by 1-3 groups selected from F, Cl, C₁-C₃ alkyl, C₁-C₃ perfluoroalkyl and C₁-C₃ alkoxyl.

19. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof.

20. A method to treat abnormal cell growth in a mammal, comprising administering to the mammal the compound of claim 1, or a pharmaceutically acceptable salt thereof.

21. A method of inhibiting a PAK4 protein kinase comprising contacting the PAK4 kinase with the compound of claim 1 or with a pharmaceutically acceptable salt thereof.

5. A compound of formula II,

6. The compound of claim 5, or a pharmaceutically acceptable thereof, wherein R² is methyl;

R³ is methyl;

B is —

O—

, —

NH—

or —

CH₂—

;

R¹ is selected from the group consisting of C₁-C₈ alkyl, phenyl, —

(C₁-C₃ alkylene)-phenyl, -(cyclopropylene)-phenyl, C₃-C₁₀ cycloalkyl, —

(C₁-C₃ alkylene)-(C₃-C₁₀ cycloalkyl), 3-10 member heterocyclyl, —

(C₁-C₃ alkylene)-(3-10 member heterocyclyl), -(cyclopropylene)-(3-10 member heterocyclyl), 5-12 member heteroaryl, —

(C₁-C₃ alkylene)-(5-12 member heteroaryl) and -(cyclopropylene)-(5-12 member heteroaryl), and R¹ is optionally further substituted by 1-6 groups selected from F, Cl, hydroxyl, CN, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl and —

(C₁-C₃ alkylene)_m-(C₁-C₆ alkoxyl).

7. The compound of claim 6, or a pharmaceutically acceptable thereof, where R⁶ is unsubstituted cyclopropylene.

8. The compound of claim 6, or a pharmaceutically acceptable thereof, wherein R⁶ is cyclopropylene substituted by 1-3 groups selected from F, Cl, C₁-C₃ alkyl and C₁-C₃ perfluoalkyl.

9. The compound of claim 6, or a pharmaceutically acceptable thereof, wherein R⁷ is selected from the group consisting of phenyl, 5-6 member heteroaryl and 4-7 member heterocyclyl, and R⁷ is optionally further substituted by 1-3 groups selected from F, Cl, C₁-C₃ alkyl, C₁-C₃ perfluoalkyl and C₁-C₃ alkoxyl.

10. A compound of formula III,

11. The compound of claim 10, or a pharmaceutically acceptable thereof, wherein R² is methyl;

R³ is methyl;

B is —

O—

, —

NH—

or —

CH₂—

;

R¹ is selected from the group consisting of C₁-C₈ alkyl, phenyl, —

(C₁-C₃ alkylene)-phenyl, -(cyclopropylene)-phenyl, C₃-C₁₀ cycloalkyl, —

(C₁-C₃ alkylene)-(C₃-C₁₀ cycloalkyl), 3-10 member heterocyclyl, —

(C₁-C₃ alkylene)-(3-10 member heterocyclyl), -(cyclopropylene)-(3-10 member heterocyclyl), 5-12 member heteroaryl, —

(C₁-C₃ alkylene)-(5-12 member heteroaryl) and -(cyclopropylene)-(5-12 member heteroaryl), and R¹ is optionally further substituted by 1-6 groups selected from F, Cl, hydroxyl, CN, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl and —

(C₁-C₃ alkylene)_m-(C₁-C₆ alkoxyl).

12. The compound of claim 11, or a pharmaceutically acceptable thereof, wherein R⁸ is —

(C₁-C₆ alkylene)_m-NR^pR^q, wherein each R^p and R^q is independently H or C₁-C₃ alkyl.

13. The compound of claim 12, or a pharmaceutically acceptable thereof, wherein R⁸ is selected from —

CH₂—

N—

(CH₃)₂, —

CH₂—

NH—

CH₃ and —

CH₂—

NH₂.

14. The compound of claim 11, or a pharmaceutically acceptable thereof, wherein R⁸ is —

(C₁-C₆ alkylene)_m-NR^pR^q, and R^p and R^q, together with the nitrogen atom they attach to, form a 3-7 member heterocyclyl, the said 3-7 member heterocyclyl is optionally further substituted by 1-6 groups selected from halide, C₁-C₃ alkyl and C₁-C₃ perfluoroalkyl.

15. The compound of claim 11, or a pharmaceutically acceptable thereof, wherein R⁹ is selected from the group consisting of C₁-C₈ alkyl, phenyl, —

(C₁-C₃ alkylene)-phenyl, 5-6 member heteroaryl and 3-7 member cycloalkyl, and R⁹ is optionally further substituted with 1-6 groups selected from F, Cl, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl, —

OH, C₁-C₆ alkoxy, —

(C₁-C₆ alkylene)-(C₁-C₆ alkoxy) and CN.

16. A compound selected from the group consisting of

17. A compound selected from the group consisting of

18. A compound selected from the group consisting of

22. A compound of the formula

23. A pharmaceutical composition comprising the compound of claim 22, or a pharmaceutically acceptable salt thereof.