SUBSTITUTED BENZOPYRAZIN DERIVATIVES AS FGFR KINASE INHIBITORS FOR THE TREATMENT OF CANCER DISEASES

• US 20130267525A1
• Filed: 11/29/2011
• Published: 10/10/2013
• Est. Priority Date: 11/29/2010
• Status: Active Grant

• Current Assignee: Astex Therapeutics Limited (Otsuka Holdings Company Limited)
• Original Assignee: Astex Therapeutics Limited (Otsuka Holdings Company Limited)
• Inventors: Saxty, Gordon, Murray, Christopher William, Berdini, Valerio, Besong, Gilbert Ebai, Hamlett, Christopher Charles Frederick, Woodhead, Steven John, Ligny, Yannick Aime Eddy, Angibaud, Patrick Ren
• Granted Patent: US 9,290,478 B2
• Time in Patent Office: Days
• US Class Current: 514/249
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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

Abstract

The invention relates to new quinoxaline derivative compounds, to pharmaceutical compositions comprising said compounds, to processes for the preparation of said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

Claims

1. A compound of formula (I):

2. A compound according to claim 1 wherein the compound is a compound of formula (I^o):

3. A compound according to claim 1 wherein n is 0, 1 or 2;

a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

4. A compound according to claim 1 wherein R¹ is C_1-6alkyl;

a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

5. A compound according to claim 1 wherein R² is C_1-4alkoxy;

a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

6. A compound according to claim 1 wherein R^3a is —

NR¹⁰R¹¹, hydroxyl, hydroxyC_1-6alkyl, cyanoC_1-6alkyl, C_1-6alkyl substituted with —

C(═

O)—

C_1-6alkyl, C_1-6alkyl substituted with —

C(═

O)—

O—

C_1-6alkyl, C_1-6alkyl substituted with R⁹, C_1-6alkyl substituted with —

NR¹⁰R¹¹, C_1-6alkyl substituted with hydroxyl and —

NR¹⁰R¹¹, C_1-6alkyl substituted with —

C(═

O)—

NR¹⁰R¹¹;

a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

7. A compound according to claim 1 wherein R^3a and R^3b are taken together to form ═

O, to form cyclopropyl together with the carbon atom to which they are attached, to form ═

CH—

C_0-4alkyl substituted with R^3c, or to form

8. A compound according to claim 1 wherein R^3c represents hydroxyl, —

NR¹⁰R¹¹, cyano, or —

C(═

O)—

C_1-6alkyl;

a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

9. A compound according to claim 1 wherein R⁹ is a monocyclic heterocyclyl containing at least one heteroatom selected from N, O and S, said monocyclic heterocyclyl optionally being substituted with 1 substituent selected from ═

O and C_1-4alkyl;

a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

10. A compound according to claim 1 wherein R¹⁰ and R¹¹ each independently represent hydrogen, C_1-6alkyl, C_1-6alkyl substituted with —

NR¹⁴R¹⁵ or haloC_1-6alkyl;

a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

11. A compound according to claim 1 wherein R¹⁴ and R¹⁵ each independently represent hydrogen or C_1-4alkyl;

a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

12. A compound according to claim 1 wherein the compound is selected from

{(Z)-3-(3,5-Dimethoxy-phenyl)-3-[3-(1-methyl-1H-pyrazol-4-yl)-quinoxalin-6-yl]-allyl}-dimethyl-amine;

{(Z)-3-(3,5-Dimethoxy-phenyl)-3-[3-(1-methyl-1H-pyrazol-4-yl)-quinoxalin-6-yl]-allyl}-isopropyl-amine;

{(Z)-3-(3,5-Dimethoxy-phenyl)-3-[3-(1-methyl-1H-pyrazol-4-yl)-quinoxalin-6-yl]-allyl}-(2,2,2-trifluoro-ethyl)-amine;

{(S)-3-(3,5-Dimethoxy-phenyl)-3-[3-(1-methyl-1H-pyrazol-4-yl)-quinoxalin-6-yl]-propyl}-isopropyl-amine; and

{3-(3,5-Dimethoxy-phenyl)-3-[3-(1-methyl-1H-pyrazol-4-yl)-quinoxalin-6-yl]-propyl}-isopropyl-amine;

a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

13. A compound as defined in claim 1 or a pharmaceutically acceptable salt or solvate thereof.

14. A compound according to claim 12 or a pharmaceutically acceptable salt or solvate thereof.

15. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1;

a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

16. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 12;

a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

17. A method for the prophylaxis or treatment of cancer, which method comprises administerinq to a subject in need thereof a compound of the formula (I) as defined in claim 1;

a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

19. A method for the prophylaxis or treatment of cancer, which method comprises administering to a subject in need thereof a compound of the formula (I) as defined in claim 12;

a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

21. A method for the prophylaxis or treatment of a disease state or condition mediated by a FGFR kinase, which method comprises administering to a subject in need thereof a compound of the formula (I) as defined in claim 1;

a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

22. A process for the preparation of a compound of formula (I) as defined in claim 1, a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, which process comprises

(I) reacting an intermediate of formula (IV) wherein W₁ represents a suitable leaving group, with an intermediate of formula (V) in the presence of a suitable catalyst, a suitable base, and a suitable solvent or solvent mixture,

18. (canceled)

20. (canceled)