Tyrosine kinase inhibitors

• US 7,223,757 B2
• Filed: 11/30/2005
• Issued: 05/29/2007
• Est. Priority Date: 03/28/2001
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Sang, Xiaopeng, Zimmermann, Kurt, Velaparthi, Upender, Liu, Peiying, Wittman, Mark D., Saulnier, Mark G., Frennesson, David B., Marinier, Anne, Roy, Stephan, Balasubramanian, Neelakantan, Tarrant, James G., Stoffan, Karen M.
• Primary Examiner(s): McKane; Joseph K.
• Assistant Examiner(s): Freistein; Andrew B.
• Application Number:
  US11/289,834
• Publication Number:
  US 20060079518A1
• Time in Patent Office: 545 Days
• Field of Search: 544/365, 514/253.09
• US Class Current: 514/235.8
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

The present invention provides compounds of formula I

and pharmaceutically acceptable salts thereof.

The formula I compounds inhibit tyrosine kinase enzymes thereby making them useful as anti-cancer agents. The formula I compounds are also useful for the treatment of other diseases which can be treated by inhibiting tyrosine kinase enzymes.

Claims

1. A compound according to formula I

2. The compound according to claim 1 wherein

R¹, R⁷, R⁸ and R⁹ are H;

R² and R⁴ are H or F;

Y is O;

R⁵ is selected from the group consisting of H, methyl, ethyl, isopropyl, secondary butyl, cyclopropyl, F, and CF₃; and

R⁶ is selected from the group consisting of H, NHCH₂CH(OH)aryl, and NHCH(CH₂OH)CH₂aryl.

3. The compound according to claim 2 wherein R³ is piperazine, homopiperazine, 3-methylpiperazine, or 3,5-dimethylpiperazine being optionally substituted at the 4-N position with a compound selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkyl-R²⁵, —

C(O)—

R¹⁵, or —

CO₂R¹⁵ wherein R¹⁵ is hydrogen, alkyl, aryl, alkyl-R²⁵.

4. The compound according to claim 3 wherein said piperazine is substituted with methyl, ethyl, CH₂-cyclopropyl, hydroxyethyl, 2-dimethylaminoethyl, 2-diethylaminoethyl, 2-aminoethyl, 2-methylaminoethyl, 2-ethylaminoethyl, methoxyethyl, ethoxyethyl, thiomethoxyethyl, morpholine, and morpholinylethyl.

5. The compound according to claim 1 wherein R⁹ is —

SO₂R⁶³ and R⁶³ is a haloalkyl.

6. The compound according to claim 2 wherein R⁶ is selected from the group consisting of H, NHCH₂CH(OH)aryl, and NHCH(CH₂OH)CH₂aryl.

7. The compound according to claim 6 wherein said aryl is an optionally substituted phenyl.

8. The compound according to claim 7 wherein said phenyl is substituted with at least one Br, Cl, F, —

CN, methoxy, or —

NHSO₂CH₃.

9. The compound according to claim 7 wherein said substituent is 3-Br, 3-Cl or 3-F.

10. The compound according to claim 7 wherein said substituent is 4-F or 4-methoxy.

20. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

21. A compound according to claim 1 which is (S)-4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-{6-[4-(2-methoxy-ethyl)-piperazin-1-yl]-4-methyl-1H-benzimidazol-2-yl}-1H-pyridin-2-one bis hydrochloride.

11. A compound having the formula

12. The compound according to claim 11 wherein R⁵¹ is methoxyethyl and R⁶ is —

NHCH₂CHOH-aryl.

13. The compound according to claim 11 wherein R⁵¹ is hydrogen, methyl, ethyl, or (CH₂)_nCH₂—

R²⁵ wherein R²⁵ is OH, OMe, F, CN, CF₃, SOCH₃ or SO₂CH₃, wherein n is 0 or 1.

14. The compound according to claim 11 wherein R⁵¹ is cyanoethyl, hydroxyethyl, CH₂CH₂SOCH₃, CH₂CH₂CH₂F, CH₂CH₂CH₂CN, or CH₂CH₂CF₃;

R¹⁶ and R¹⁹ are H;

R¹⁷ is Br, or Cl; and

R¹⁸ is hydrogen or methoxy.

15. A compound having the formula:

16. The compound according to claim 15 wherein R¹⁵ is hydrogen or methyl;

R¹⁷ is bromo, chloro or fluoro;

R¹⁸ is hydrogen or methoxy; and

R¹⁹ is hydrogen.

17. A compound having the formula

18. The compound according to claim 17 wherein R¹⁵ is hydrogen, methyl, ethyl, or —

(CH₂)_nCH₂—

R²⁵ wherein n is 0, 1, or 2; and

R²⁵ is OH, OMe, F, CN, CF₃, SOCH₃ or SO₂CH₃, —

NR³⁰COR³¹, —

NR³⁰COOR³¹, —

NR³⁰SO₂R³¹, or —

C(O)NR³⁰R³¹.

19. The compound according to claim 17 wherein R¹⁵ is ethyl, methoxyethyl, CH₂CH₂F, or CH₂CH₂CN;

R¹⁷ is bromo or chloro;

R¹⁸ is methoxy or hydrogen; and

R¹⁹ is hydrogen.