Quinoxalines as B Baf Inhhibitors

• US 20080207616A1
• Filed: 10/13/2005
• Published: 08/28/2008
• Est. Priority Date: 10/15/2004
• Status: Abandoned Application

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Lee, Stephen, Lyne, Paul, Aquila, Brian, Pontz, Timothy, Su, Mei, Ioannidis, Stephanos, Deegan, Tracy, Dakin, Les
• Application Number:
  US11/577,132
• Publication Number:
  US 20080207616A1
• Time in Patent Office: Days
• US Class Current: 514/234.8
• 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 241/42 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings

Abstract

The invention relates to chemical compounds of the formula (I) or pharmaceutically acceptable salts thereof, which possess B Raf inhibitory activity and are accordingly useful for their anti cancer activity and thus in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cancer effect in a warm blooded animal such as man.

Claims

1. A compound of formula (I):

2. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 wherein Ring A is phenyl, pyrazolyl, benzimidazolyl, pyridyl, thienyl, furyl, 2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-1-benzofuranyl, pyrimidinyl, imidazolyl, indolyl, pyrrolyl or pyrazinyl;

wherein said pyrrolyl, pyrazolyl or imidazolyl may be optionally substituted on nitrogen by a group selected from R⁹;

wherein R⁹ is selected from C_1-6alkyl.

3. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to either claim 1 or claim 2 wherein R¹ is a substituent on carbon and is selected from halo, nitro, hydroxy, amino, sulphamoyl, C_1-6alkyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkanoyl, N,N—

(C_1-6alkyl)₂amino, C_1-6alkanoylamino, C_1-6alkylS(O)_a wherein a is 0 to 2, C_1-6alkoxycarbonylamino, N,N—

(C_1-6alkyl)₂sulphamoyl, C_1-6alkylsulphonylamino, carbocyclyl-R¹⁰—

or heterocyclyl-R¹¹—

;

wherein R¹ may be optionally substituted on carbon by one or more R¹²;

R¹² is selected from halo, cyano, hydroxy, C_1-6alkyl, C_1-6alkoxy, carbocyclyl-R²⁶—

or heterocyclyl-R²⁷—

;

wherein R¹² may be optionally substituted on carbon by one or more R²⁸; and

wherein if said heterocyclyl contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from R²⁹;

R¹⁰, R¹¹, R²⁶ and R²⁷ are a direct bond;

R²⁹ is C_1-6alkyl;

R²⁸ is selected from hydroxy and methyl.

4. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-3 wherein n is selected from 0-2;

wherein the values of R¹ may be the same or different.

5. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-4 wherein Z is —

C(O)NH—

.

6. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-4 wherein Z is —

NHC(O)—

.

7. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-4 wherein Z is —

CH₂NH—

.

8. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7 wherein R² is selected from hydrogen or halo.

9. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-8 wherein R³ is selected from halo, methyl or methoxy.

10. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-9 wherein X is —

NHC(O)—

, —

NH—

or —

NHCH₂—

.

11. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-10 wherein R⁴, R⁵, R⁶, R⁷ and R⁸ are independently selected from hydrogen, halo, C_1-6alkyl, N—

(C_1-6alkyl)amino, N,N—

(C_1-6alkyl)₂amino or heterocyclyl-R²²—

;

wherein R⁴, R⁵, R⁶, R⁷ and R⁸ independently of each other may be optionally substituted on carbon by one or more R²³;

wherein

R²³ is selected from hydroxy, amino, N—

(C_1-6alkyl)amino, N,N—

(C_1-6alkyl)₂amino or heterocyclyl-R²⁷—

; and

R²² and R²⁷ are selected from a direct bond.

14. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof which process, wherein variable are, unless otherwise specified, as defined in claim 1, comprises of:

Process a) for compounds of formula (I) wherein Z is —

C(O)NH—

;

reacting an amine of the formula (II)

15. A pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-13, in association with a pharmaceutically-acceptable diluent or carrier.

16. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-13, for use as a medicament.

17. The use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-13, in the manufacture of a medicament for use in the production of a B-Raf inhibitory effect in a warm-blooded animal such as man.

18. The use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-13, in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded animal such as man.

19. The use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-13, in the manufacture of a medicament for use in the treatment of melanoma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries.

20. A method for producing a B-Raf inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-13.

21. A method for producing an anti-cancer effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-13.

22. A method of treating melanoma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-13.

23. A pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-13, in association with a pharmaceutically-acceptable diluent or carrier for use in the production of a B-Raf inhibitory effect in a warm-blooded animal such as man.

24. A pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-13, in association with a pharmaceutically-acceptable diluent or carrier for use in the production of an anti-cancer effect in a warm-blooded animal such as man.

25. A pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-13, in association with a pharmaceutically-acceptable diluent or carrier for use in the treatment of melanoma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries in a warm-blooded animal such as man.

12. A compound of formula (I) wherein:

Ring A is phenyl, 1-methylpyrazol-3-yl, 1-methylpyrazol-5-yl, 1-t-butylpyrazol-5-yl, benzimidazol-2-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thien-2-yl, thien-3-yl, fur-2-yl, 2,3-dihydro-1,4-benzodioxin-5-yl, 2,3-dihydro-1-benzofuran-7-yl, pyrimidin-4-yl, pyrimidin-5-yl, 1-methylimidazol-2-yl, indol-4-yl, indol-7-yl, 1-methylpyrrol-2-yl or pyrazin-2-yl;

R¹ is a substituent on carbon and is selected from fluoro, chloro, iodo, nitro, hydroxy, amino, sulphamoyl, methyl, trifluoromethyl, cyanomethyl, 3,5-dimethylpyrazol-1-ylmethyl, ethyl, 1-methyl-1-cyanoethyl, propyl, isopropyl, t-butyl, (1-hydroxycyclopentyl)ethynyl, cyclopropylethynyl, 3-hydroxyprop-1-yn-1-yl, 3-(1-methylpiperazin-4-yl)prop-1-yn-1-yl, 3-(cyclopentyl)prop-1-yn-1-yl, 3,3-dimethylprop-1-yn-1-yl, benzyloxy, 2-pyrrolidin-1-ylethoxy, propoxy, isopropoxy, butoxy, isobutoxy, methylthio, difluoromethylthio, mesyl, dimethylamino, N-methyl-N-(2-methoxyethyl)amino, acetyl, N,N-dimethylsulphamoyl, acetylamino, t-butoxycarbonylamino, 2,2-dimethylpropionylamino, mesylamino, cyclopropyl, 1-cyanocyclopropyl, 1-cyanocyclobutyl, 1-cyano-tetrahydro-2H-pyran-4-yl, thien-2-yl, pyrrol-1-yl, 2,5-dimethylpyrrol-1-yl, pyrid-3-yl, 2-methylthiazol-4-yl, morpholino and piperidin-1-yl;

n is selected from 0-2;

wherein the values of R¹ may be the same or different;

Z is —

C(O)NH—

, —

NHC(O)—

or —

CH₂NH—

;

R¹ is selected from hydrogen or bromo;

R³ is selected from fluoro, chloro, bromo, methyl or methoxy;

X is —

NHC(O)—

, —

NH—

or —

NHCH₂—

;

R⁴, R⁵, R⁶, R⁷ and R⁸ are independently selected from hydrogen, chloro, methyl, 3-(piperidin-1-yl)propylamino, 2-hydroxyethylamino, 2-(dimethylamino)ethylamino, 2-(morpholino)ethylamino, methylamino, N-methyl-N-ethylamino, N-methyl-N-(2-methylaminoethyl)amino, morpholino, 3-aminopropylamino or N-methyl-N-(3-direthylaminopropyl)amino;

or a pharmaceutically acceptable salt thereof;

with the proviso that said compound is not N-(5-{[3-(dimethylamino)benzoyl]amino}-2-methylphenyl)quinoxaline-6-carboxamide.

13. A compound of formula (I) selected from:

N-(5-{[3-(1-cyano-1-methylethyl)-5-(3-hydroxyprop-1-yn-1-yl)benzoyl]amino}-2-methylphenyl)quinoxaline-6-carboxamide;

N-(5-{[3-(1-cyano-1-methylethyl)benzoyl]amino}-2-methylphenyl)quinoxaline-6-carboxamide;

N-[5-({3-(1-cyano-1-methylethyl)-5-[3-(4-methylpiperazin-1-yl)prop-1-yn-1-yl]benzoyl}amino)-2-methylphenyl]quinoxaline-6-carboxamide;

N-(5-{[3-(benzyloxy)-5-(1-cyano-1-methylethyl)benzoyl]amino}-2-methylphenyl) quinoxaline-6-carboxamide;

N-{5-[(3-tert-butylbenzoyl)amino]-2-methylphenyl}quinoxaline-6-carboxamide;

N-(5-{[3-(1-cyano-1-methylethyl)-5-propylbenzoyl]amino}-2-methylphenyl)quinoxaline-6-carboxamide;

N-(5-{[3-(1-cyano-1-methylethyl)-5-(2-pyrrolidin-1-ylethoxy)benzoyl]amino}-2-methylphenyl)quinoxaline-6-carboxamide;

N-(5-{[3-(1-cyano-1-methylethyl)-5-methylbenzoyl]amino}-2-methylphenyl)quinoxaline-6-carboxamide;

N-{5-[(3,5-di-tert-butylbenzoyl)amino]-2-methylphenyl}quinoxaline-6-carboxamide; and

N-(5-{[3-(1-cyanocyclobutyl)benzoyl]amino}-2-methylphenyl)quinoxaline-6-carboxamide;

or a pharmaceutically acceptable salt thereof.