Bicyclic heterocyclic compounds as FGFR inhibitors

1. A compound of formula (Id):

wherein

J and L are independently selected from carbon and nitrogen;

R 5 represents hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, alkanol, C 1-6 alkanol, haloC 1-6 alkyl, —(CH 2 ) n —NR x R y , —(CH 2 ) s —COOR z , or —(CH 2 ) n —O—(CH 2 ) m —OH, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl groups may be optionally substituted by one or more 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 and R 6 independently represent halogen, hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, —C≡N, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, —NHSO 2 R w , —CH═N—OR w , an aryl or heterocyclyl group wherein said aryl and heterocyclyl groups may be optionally substituted by one or more R b groups, and said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl may be optionally substituted by one or more R b′ groups, provided that R 2 and R 6 do not both represent hydrogen;

R w represents hydrogen or C 1-6 alkyl;

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 , —(CH 2 ) n —O—C 1-6 alkyl, —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, —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;

q represents an integer from 0 to 3;

R b represents an R a group or a —Y-carbocyclyl or —Z-heterocyclyl group wherein said carbocyclyl and heterocyclyl groups may be optionally substituted by one or more R a groups;

Y and Z independently represent a bond, —CO—(CH 2 ) s —, —COO—, —(CH 2 ) n —, —NR x —(CH 2 ) n —, —(CH 2 ) n —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 —;

R b′ represents an R a′ group or a —Y-carbocyclyl or —Z-heterocyclyl group wherein said carbocyclyl and heterocyclyl groups may be optionally substituted by one or more R a 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, —(CH 2 ) n —O—C 1-6 alkyl, —O—(CH 2 ) n —OR x , haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkanol, ═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;

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,

with the proviso that the compound of formula (Id) is not:

N-{2-fluoro-4-[6-(1-trityl-1H-4-pyrazolyl)imidazo[1,2-a]pyridine-3-yl]phenyl}-N′-isopropyl urea; or

N-{2-fluoro-4-[6-(1H-4-pyrazolyl)imidazo[1,2-a]pyridin-3-yl]phenyl}-N′-isopropylurea.

2. A compound as defined in claim 1 , wherein

R 5 represents hydrogen, C 1-6 alkyl, C 1-6 alkanol, —(CH 2 ) n —NR x R y , 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 2 represents an aryl or heterocyclyl group optionally substituted by one or more 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, —(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-aryl or —Z-heterocyclyl group wherein said aryl and heterocyclyl groups may be optionally substituted by one or more R a groups;

Y and Z independently represent a bond, CO, —(CH 2 ) n —, —NR x —(CH 2 ) n —, —O— or —O—(CH 2 ) s —;

aryl represents a carbocyclic ring; and

heterocyclyl represents a heterocyclic ring,

or a pharmaceutically acceptable salt or solvate thereof.

3. A compound as defined in claim 1 wherein A represents a phenyl or pyridyl group optionally substituted by one or more R a groups, or a pharmaceutically acceptable salt or solvate thereof.

4. A compound as defined in claim 1 wherein A represents phenyl or pyridyl substituted by the —NHCONHR 5 group at the 5-position and further optionally substituted by a single R a group at the 3-position, or a pharmaceutically acceptable salt or solvate thereof.

5. A compound as defined in claim 1 wherein R 5 represents —CH 2 CF 3 or —CH 2 CH 3 , or a pharmaceutically acceptable salt or solvate thereof.

6. A compound as defined in claim 1 wherein R 2 represents an aryl or heterocyclyl group optionally substituted by one or more R a groups, or a pharmaceutically acceptable salt or solvate thereof.

7. A compound as defined in claim 1 wherein R 2 represents an aryl group optionally substituted by a halogen, —Z-heterocyclyl group or —(CR x R y ) s —COOR z wherein said heterocyclyl group may be optionally substituted by a C 1-6 alkyl or —(CR x R y ) s —COOR z group, or R 2 represents a heterocyclyl group optionally substituted by a ═O, ═S, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-8 cycloalkyl, —(CH 2 ) s —NR x R y , —OR x , —(CH 2 ) n —O—C 1-6 alkyl, —COR x , —(CR x R y ) s —COOR z , —S—R X , —SO 2 —R x , —(CH 2 ) s —NR x R y , —(CH 2 ) s —SO 2 NR x R y or C 1-6 alkanol groups, or a pharmaceutically acceptable salt or solvate thereof.

8. A compound as defined in claim 1 wherein R 2 represents oxazole, oxadiazole, triazole, tetrazole, thiadiazole or oxathiadiazole optionally substituted by one or more methyl, ethyl or —S-methyl groups, or a pharmaceutically acceptable salt or solvate thereof.

9. A compound as defined in claim 1 wherein Y and Z independently represent a bond, CO, —CH 2 —, —(CH 2 ) 2 , —(CH 2 ) 3 or —O—, or a pharmaceutically acceptable salt or solvate thereof.

10. A compound as defined in claim 1 which is a compound selected from:

1-{3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea,

1-{3-[7-(5-Methyl-[1,3,4]-thiadiazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea,

1-{3-[7-(5-Methyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea,

1-{3-[7-(5-Methylsulfanyl-[1,3,4] oxadiazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea,

1-{3-[7-(2-Methyl-2H-tetrazol-5-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea,

1-{3-[7-(1,5-Dimethyl-1H-imidazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea,

1-{3-[7-(1-Methyl-1H-imidazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea,

1-{3-[7-(1,5-Dimethyl-1H-[1,2,3]triazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea,

1-[3-(7-[1,3,4]Thiadiazol-2-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea,

1-[3-(7-Prop-1-ynyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea,

1-{3-[7-(3-Methyl-[1,2,4]thiadiazol-5-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea,

1-(3-{7-[1-(2-Hydroxy-ethyl)-1H-pyrazol-4-yl]-imidazo[1,2-a]pyridin-3-yl}-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea,

1-(3-{7-[1-(2-Amino-ethyl)-1H-pyrazol-4-yl]-imidazo[1,2-a]pyridin-3-yl}-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea,

1-{5-[7-(5-Methyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-pyridin-3-yl}-3-(2,2,2-trifluoro-ethyl)-urea,

1-(2,2,2-Trifluoro-ethyl)-3-{3-[7-(1,2,5-trimethyl-1H-imidazol-4-yl)-imidazo[1,2,a]pyridine-3-yl]-phenyl}-urea,

1-{3-[7-(4-Methyl-imidazol-1-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea,

1-{3-[7-(6-Methyl-pyridazin-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea,

and

1-[3-(7-[1,2,4]Thiadiazol-5-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea,

or a pharmaceutically acceptable salt or solvate thereof.

11. A compound according to claim 10 wherein the compound is 1-{3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea or a pharmaceutically acceptable salt or solvate thereof, or 1-[3-(7-[1,3,4]Thiadiazol-2-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea or a pharmaceutically acceptable salt or solvate thereof.

12. A compound as defined in claim 7 wherein R 2 represents a 5-membered heterocyclyl group optionally substituted by a ═O, ═S, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-8 cycloalkyl, —(CH 2 ) s —NR x R y , —OR x , —(CH 2 ) n —O—C 1-6 alkyl, —COR x , —(CR x R y ) s —COOR z , —S—R X , —SO 2 —R x , —(CH 2 ) s —NR x R y , —(CH 2 ) s —SO 2 NR x R y or C 1-6 alkanol groups, or a pharmaceutically acceptable salt or solvate thereof.

13. A process for the preparation of a compound of formula (Id) as defined in claim 1 , which process comprises:

(i) the reaction of a compound of the formula:

or a protected form thereof, with an appropriately substituted isocyanate or an appropriately substituted amine in the presence of carbonyl diimidazole (CDI); or

(ii) reacting a compound of formula (V) and (VI):

wherein R 1 is —NHCONHR 5 ,

and thereafter removing any protecting group present;

and optionally thereafter converting one compound of the formula (Id) into another compound of the formula (Id).

14. A pharmaceutical composition comprising a compound of formula (Id) as defined in claim 1 , or a pharmaceutically acceptable salt or solvate thereof.

15. A method of inhibiting a FGFR kinase, which method comprises contacting the kinase with a compound of formula (Id) as defined in claim 1 , or a pharmaceutically acceptable salt or solvate thereof.

16. A compound as defined in claim 1 wherein R 5 is haloC 1-6 alkyl, or a pharmaceutically acceptable salt or solvate thereof.

17. A compound as defined in claim 3 wherein R 5 is haloC 1-6 alkyl, or a pharmaceutically acceptable salt or solvate thereof.

18. A compound as defined in claim 1 wherein R 6 is hydrogen and R 2 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, —C≡N, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, —NHSO 2 R w , —CH═N—OR w , or an aryl or heterocyclyl group, wherein said aryl and heterocyclyl groups may be optionally substituted by one or more R b groups, and said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl may be optionally substituted by one or more R b′ groups, or a pharmaceutically acceptable salt or solvate thereof.

19. A compound according to claim 1 wherein the compound is 1-{3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-5-isopropoxy-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea, or a pharmaceutically acceptable salt or solvate thereof.

20. A compound according to claim 1 wherein the compound is 1-{3-[7-(5-methyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea, or a pharmaceutically acceptable salt or solvate thereof.