Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
The invention relates to new bicyclic heterocyclic derivative compounds of formula (I): wherein R 1 , A, X 1 , X 2 , X 3 , X 4 , X 5 and R 2 are as defined herein, to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.
1. A method for the treatment of a disease state or condition selected from multiple myeloma, bladder carcinoma, hepatocellular carcinoma, oral squamous cell carcinoma, cervical carcinoma, and urothelial carcinoma, which method comprises administering to a subject in need thereof a compound of the formula (I):
wherein
represents a single or double bond, such that at least one bond within the 5 membered ring system is a double bond;
Ring A may be optionally substituted by 1, 2 or 3 R a groups;
R 4 and R 5 independently represent hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 1-6 alkanol, haloC 1-6 alkyl, —(CH 2 ) n —NR x R y , —(CH 2 ) s —COOR z , —(CH 2 ) n —O—(CH 2 ) m —OH, —(CH 2 ) n -aryl, —(CH 2 ) n —O-aryl, —(CH 2 ) n -heterocyclyl or —(CH 2 ) n —O-heterocyclyl wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, aryl and heterocyclyl groups may be optionally substituted by 1, 2 or 3 R a groups;
R x , R y and R z independently represent hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkanol, —COOC 1-6 alkyl, hydroxy, C 1-6 alkoxy, haloC 1-6 alkyl, —CO—(CH 2 ) n —C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or C 3-8 cycloalkenyl;
R 2 represents a —CONR 7 R 8 , or —COR x group;
R 7 and R 8 independently represent hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, aryl, heterocyclyl or R 7 and R 8 together with the nitrogen atom to which they are attached may form a nitrogen containing heterocyclyl ring, wherein said C 1-6 alkyl, aryl and heterocyclyl may be optionally substituted by 1, 2 or 3 R b groups;
R a represents halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, —OR x , —O—(CH 2 ) n —OR x , haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkanol, ═O, ═S, nitro, Si(R x ) 4 , —(CH 2 ) s —CN, —S—R x , —SO—R x , —SO 2 —R x , —COR x , —(CR x R y ) s —COOR z , —(CH 2 ) s —CONR x R Y , —(CH 2 ) s —NR x R y , —(CH 2 ) s —NR x COR y , —(CH 2 ) s —NR x SO 2 —R y , —(CH 2 ) s —NH—SO 2 —NR x R y , —OCONR x R y , —(CH 2 ) s —NR x CO 2 R y , —O—(CH 2 ) s —CR x R y —(CH 2 ) t —OR z or —(CH 2 ) s —SO 2 NR x R y groups;
R b represents an R a group or a —Y-carbocyclic or —Z-heterocyclyl group wherein said carbocyclic and heterocyclyl groups may be optionally substituted by one or more 1, 2 or 3 R a groups;
Y and Z independently represent a bond, —CO—(CH 2 ) s —, —COO—, —(CH 2 ) n —, —NR x —(CH 2 ) s —, —(CH 2 ) s —NR x —, —CONR x —, —NR x CO—, —SO 2 NR x —, —NR x SO 2 —, —NR x CONR y —, —NR x CSNR y —, —O—(CH 2 ) s —, —(CH 2 ) s —O—, —S—, —SO— or —(CH 2 ) s —SO 2 —;
m and n independently represent an integer from 1-4;
s and t independently represent an integer from 0-4;
or a pharmaceutically acceptable salt or solvate thereof.
2. A method as defined in claim 1 , wherein
R 4 and R 5 independently represent hydrogen, C 1-6 alkyl, C 1-6 alkanol, —(CH 2 ) n —NR x R y , —(CH 2 ) n -aryl or haloC 1-6 alkyl;
R x , R y and R z independently represent hydrogen, C 1-6 alkyl, C 1-6 alkanol, hydroxy, C 1-6 alkoxy, haloC 1-6 alkyl or —CO—(CH 2 ) n —C 1-6 alkoxy;
R a represents halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, —OR x , —O—(CH 2 ) n —OR x , haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkanol, ═O, ═S, nitro, —(CH 2 ) s —CN, —S—R x , —SO—R x , —SO 2 —R x , —COR x , —(CR x R y ) s —COOR z , —(CH 2 ) s —CONR x R y , —(CH 2 ) s —NR x R y , —(CH 2 ) s —NR x COR y , —(CH 2 ) s —NR x SO 2 —R y , —OCONR x R y , —(CH 2 ) s —NR x CO 2 R y , —O—(CH 2 ) s —CR x R y —(CH 2 ) t —OR z or —(CH 2 ) s —SO 2 NR x R y groups;
R b represents a —Y-carbocyclic or —Z-heterocyclyl group wherein said carbocyclic and heterocyclyl groups may be optionally substituted by 1, 2 or 3 R a groups; and
Y and Z independently represent a bond, CO, —(CH 2 ) n —, —NR x —(CH 2 ) n —, —O— or —O—(CH 2 ) s .
3. A method as defined in claim 1 wherein R 4 is H and R 5 is selected from —CH 2 CF 3 and —CH 2 CH 3 .
4. A method as defined in claim 1 wherein R 2 represents a —CONR 7 R 8 group.
5. A method as defined in claim 4 wherein R 7 and R 8 both represent hydrogen or C 1-6 alkyl; or one of R 7 and R 8 represents hydrogen and the other represents:
C 1-6 alkyl optionally substituted by an —OR x group or a —Z-heterocyclyl group optionally substituted by an R a group;
C 3-8 cycloalkyl; or
heterocyclyl optionally substituted by an R a group.
6. A method as defined in claim 4 wherein R 7 and R 8 together with the nitrogen atom to which they are attached form a nitrogen containing heterocyclyl ring optionally substituted by 1, 2 or 3 R b groups.
7. A method as defined in claim 1 wherein R 2 represents a —COR x group.
8. A method as defined in claim 1 wherein Y and Z independently represent a bond, CO, —CH 2 —, —(CH 2 ) 2 , —(CH 2 ) 3 or —O—.
9. A compound as defined in claim 8 wherein Z represents a bond or —CH 2 —.
10. A method as defined in claim 1 wherein the compound of formula (I) has the following ring system:
11. A method as defined in claim 10 wherein R 4 is H and R 5 is selected from —CH 2 CF 3 and —CH 2 CH 3 .
12. A method as defined in claim 1 wherein the cancer is multiple myeloma.
13. A method of inhibiting FGFR kinase, which method comprises contacting the kinase with a compound of the formula (I):
wherein
represents a single or double bond, such that at least one bond within the 5 membered ring system is a double bond;
Ring A may be optionally substituted by 1, 2 or 3 R a groups;
R 4 and R 5 independently represent hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 1-6 alkanol, haloC 1-6 alkyl, —(CH 2 ) n —NR x R y , —(CH 2 ) n —COOR z , —(CH 2 ) n —O—(CH 2 ) m —OH, —(CH 2 ) n -aryl, —(CH 2 ) n —O-aryl, —(CH 2 ) n -heterocyclyl or —(CH 2 ) n —O—heterocyclyl wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, aryl and heterocyclyl groups may be optionally substituted by 1, 2 or 3 R a groups;
R x , R y and R z independently represent hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkanol, —COOC 1-6 alkyl, hydroxy, C 1-6 alkoxy, haloC 1-6 alkyl, —CO—(CH 2 ) n —C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or C 3-8 cycloalkenyl;
R 2 represents a —CONR 7 R 8 , or —COR x group;
R 7 and R 8 independently represent hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, aryl, heterocyclyl or R 7 and R 8 together with the nitrogen atom to which they are attached may form a nitrogen containing heterocyclyl ring, wherein said C 1-6 alkyl, aryl and heterocyclyl may be optionally substituted by 1, 2 or 3 R b groups;
R a represents halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, —OR x , —O—(CH 2 ) n —OR x , haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkanol, ═O, ═S, nitro, Si(R x ) 4 , —(CH 2 ) s —CN, —S-Rx, —SO—R x , —SO 2 —R x , —COR x , —(CR x R y ) s —COOR z , —(CH 2 ) s —CONR x R y , —(CH 2 ) s —NR x R y , —(CH 2 ) s —NR x COR y , —(CH 2 ) s —NR x SO 2 —R y , —(CH 2 ) s —NH—SO 2 —NR x R y , —OCONR x R y , —(CH 2 ) s —NR x CO 2 R y , —O—(CH 2 ) s —CR x R y —(CH 2 ) t —OR z or —(CH 2 ) s —SO 2 NR x R y groups;
R b represents an R a group or a —Y-carbocyclic or —Z-heterocyclyl group wherein said carbocyclic and heterocyclyl groups may be optionally substituted by one or more 1, 2 or 3 R a groups;
Y and Z independently represent a bond, —CO—(CH 2 ) s —, —COO—, —(CH 2 ) n —, —NR x —(CH 2 ) s —, —(CH 2 ) s —NR x —, —CONR x —, —NR x CO—, —SO 2 NR x —, —NR x SO 2-5 —NR x CONR y —, —NR x CSNR y —, —O—(CH 2 ) s —, —(CH 2 ) s —O—, —S—, —SO— or —(CH 2 ) s —SO 2 —;
m and n independently represent an integer from 1-4;
s and t independently represent an integer from 0-4;
or a pharmaceutically acceptable salt or solvate thereof.
14. A method according to claim 13 wherein R 2 represents a —CONR 7 R 8 group.
15. A method according to claim 13 wherein the compound of formula (I) has the following ring system:
16. A method as defined in claim 7 wherein R 2 represents —COMe.
17. A method as defined in claim 13 wherein R 4 is H and R 5 is selected from —CH 2 CF 3 and —CH 2 CH 3 .
18. A method as defined in claim 17 wherein R 2 represents a —CONR 7 R 8 group.
19. A method as defined in claim 13 wherein R 7 and R 8 both represent hydrogen or C 1-6 alkyl; or one of R 7 and R 8 represents hydrogen and the other represents:
C 1-6 alkyl optionally substituted by an —OR x group or a —Z-heterocyclyl group optionally substituted by an R a group;
C 3-8 cycloalkyl; or
heterocyclyl optionally substituted by an R a group.
20. A method as defined in claim 10 wherein R 2 represents a —CONR 7 R 8 group.