Kinase inhibitors

1. A compound of formula (I):

wherein:

Q represents thienyl, phenyl or pyridinyl, either of which may optionally bear 1 to 3 substituents independently selected from, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, NH 2 , N(H)—C 1-6 alkyl, N(C 1-6 alkyl) 2 , -L-P(O)R′R″, C 1-6 alkylene-5-10 membered heterocycle and C 0-3 alkylene-O—C 0-6 alkylene-5-10 membered heterocycle;

L is a direct bond or C 1-2 alkylene;

R′ represents C 1-4 alkyl;

R″ represents C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy or hydroxy;

or R′ and R″ together combine to form C 3-6 n-alkylene, wherein one CH 2 of said n-alkylene group is optionally replaced by O, N(H) or N(C 1-4 alkyl);

X represents CH or N,

Y represents NR 2 R 3 ;

R is

C 1-6 alkyl,

C 2-6 alkenyl,

C 1-6 hydroxyalkyl,

C 1-6 haloalkyl,

C 1-6 alkyl substituted by C 2-3 alkynyl, C 1-3 alkoxy or cyano,

C 0-2 alkylene-C 3-8 cycloalkyl optionally substituted with C 1-3 alkyl,

a 4-5 membered heterocycle optionally substituted with C 1-3 alkyl or Si(R 1a )(R 1b )(R 1c );

R 1a and R 1b independently represent C 1-4 alkyl or C 3-6 cycloalkyl, or R 1a and R 1b together combine to form C 2-6 alkylene;

R 1c represents C 1-2 alkyl;

R a and R b , together with the C-atoms to which they are attached, form a fused phenyl ring that is optionally substituted by one or more substituents selected from C 1-3 alkyl, C 1-3 haloalkyl, cyano and halo,

or one of R a and R b represents H, halo, cyano, C 1-3 alkyl or C 1-3 haloalkyl and the other independently represents halo, cyano, C 1-3 alkyl or C 1-3 haloalkyl

or R a and R b together represent C 3-5 n-alkylene, which alkylene group is optionally substituted by one or more methyl substituents and/or which alkylene group optionally contains one C—C double bond between two C-atoms of the n-alkylene chain;

R 1 is selected from hydrogen, OH, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 0-3 alkylene-C 3-6 cycloalkyl, C 0-3 alkylene-O—C 1-3 alkylene-C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 0-3 alkylene-SO 2 C 1-3 alkyl, C 0-3 alkylene-SO 2 NR 4 R 5 , and C 0-3 alkylene-NR 6 R 7 and C 0-3 alkylene-NCOR 6 R 7 ;

one of R 2 and R 3 represents —[C 2-4 alkylene-O] 1-12 —[C 2-4 alkylene]-R 2a and the other of R 2 and R 3 is selected from H, C 1-8 alkyl, C 0-6 alkylene aryl, C 0-6 alkylene heteroaryl, —[C 2-4 alkylene-O] 0-12 —[C 2-4 alkylene]-R 2a , C 0-6 alkylene-4-10 membered heterocycle, and C 0-3 alkylene-O—C 0-6 alkylene-4-10 membered heterocycle with the proviso that when the said heterocycle is linked through nitrogen there are at least two C-atoms in the alkylene chain that links that nitrogen atom to the essential O atom of the substituent, wherein independently each alkyl or alkylene group optionally bears 1 oxo substituent, and optionally one or two carbon atoms in the alkyl or alkylene chain may each be replaced by a heteroatom selected from O, N or S(O) p , such that when said alkyl or alkylene comprises an amine said amino group is a tertiary amine,

wherein each 4-10 membered heterocycle is optionally substituted by 1 or 2 groups independently selected from halo, OH, C 1-6 alkyl, C 1-4 haloalkyl, C 0-3 alkylene-O—C 0-6 alkyl, C 0-3 alkylene-O—C 1-3 haloalkyl, C 0-6 alkylene aryl, C 0-3 alkylene-O—C 0-3 alkylene aryl, C 0-6 alkylene heteroaryl, C 0-3 alkylene-O—C 0-3 alkylene heteroaryl, C(O)C 1-6 alkyl, SO 2 NR 8 R 9 , and C 0-3 alkylene-NR 8 R 9 , C 0-3 alkylene-NR 8 SO 2 R 9 and C 0-3 alkylene-NR 8 C(O)R 9 ;

R 2a represents OR 2b or N(R 2c )R 2d ;

R 2b to R 2d independently represent H or C 1-4 alkyl optionally substituted by one or more halo atoms, or R 2c and R 2d together represent

C 3-6 n-alkylene,

C 4-5 n-alkylene interrupted between C2 and C3 by —O— or —N(R 2e )— or

C 6 n-alkylene interrupted between C2 and C3, or between C3 and C4, by —O— or —N(R 2e )—,

any of which n-alkylene groups are optionally substituted by one or more substituents selected from halo, hydroxy, oxo, C 1-4 alkyl and C 1-4 alkoxy;

R 2e represents H or C 1-6 alkyl optionally substituted by one or more substituents selected from halo and hydroxy;

R 4 is H or C 1-4 alkyl;

R 5 is H or C 1-4 alkyl,

R 6 is H or C 1-4 alkyl, C(O)C 1-3 alkyl and SO 2 C 1-3 alkyl;

R 7 is H or C 1-4 alkyl, C(O)C 1-3 alkyl and SO 2 C 1-3 alkyl;

R 8 is H or C 1-4 alkyl, and

R 9 is H or C 1-4 alkyl,

p is 0, 1 or 2

or a pharmaceutically acceptable salt thereof, including all stereoisomers and tautomers thereof.

2. A compound according to claim 1 of formula (Id1) or formula (Id2):

wherein R, R a , R b , R 1 , Q and Y are as defined in claim 1 .

3. A compound according to claim 1 of formula (If1) or formula (If2):

wherein R, R a , R b , R 1 , Q and Y are as defined in claim 1 .

4. A compound according to claim 1 of formula (Ig1) or formula (Ig2):

wherein R, R a , R b , R 1 , X, Q and Y are as defined in claim 1 .

5. A compound or salt according to claim 1 , wherein R represents:

C 1-6 n-alkyl,

C 3-6 branched alkyl,

C 2-6 alkenyl,

C 1-6 hydroxyalkyl,

C 1-6 haloalkyl,

C 1-6 alkyl substituted by C 1-3 alkoxy or cyano,

C 0-2 alkylene-C 3-8 cycloalkyl optionally substituted with C 1-3 alkyl, or

a 4-5 membered heterocycle optionally substituted with C 1-3 alkyl.

6. A compound according to claim 1 , wherein:

R 1 represents ethynyl or OCH 3 ;

R 2 represents —(CH 2 CH 2 O) 2-4 CH 3 ; and

R 3 is H.

7. A compound of formula (Ig2)

wherein:

R represents isopropyl, 1-methylcyclopropyl, propen-2-yl or tert-butyl;

Q represents phenyl substituted in the para position by methyl, methoxy or dimethylamino;

X represents CH or N;

R 1 represents ethynyl or OCH 3 ;

Y is NR 2 R 3 ; and

one of R 2 and R 3 represents —(CH 2 CH 2 O) 2-3 CH 3 and the other of R 2 and R 3 is H,

or a pharmaceutically acceptable salt thereof, including all stereoisomers and tautomers thereof.

8. A compound according to claim 1 , wherein:

Q represents phenyl substituted in the para position by methyl, methoxy or dimethylamino; and

R represents isopropyl or tert-butyl.

9. A compound according to claim 1 , wherein R represents tert-butyl.

10. A compound according to claim 1 selected from the group comprising or consisting of:

3-ethynyl-5-((4-((4-(3-(3-isopropyl-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;

3-((4-((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)-pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;

3-((4-((4-(3-(3-(tert-butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-benzamide;

3-((4-((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)-pyridin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;

3-((4-((4-(3-(3-(tert-butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)ureido)-naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-methoxyethoxy)ethyl)benzamide;

3-((4-((4-(3-(3-(tert-butyl)-1-(2,3,5,6-tetradeutero-4-(trideuteromethyl)phenyl) -1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;

3-((4-((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)-pyrimidin-2-yl)amino)-5-ethynyl-N-(2,5,8,11-tetraoxatridecan-13-yl)benzamide;

3-((4-((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)-pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-methoxyethoxy)ethyl)benzamide;

3-((4-((4-(3-(3-(tert-butyl)-1-(4-(dimethylamino)phenyl)-1H-pyrazol-5-yl)ureido) -naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)-ethoxy)ethyl)benzamide;

3-((4-((4-(3-(3-(tert-butyl)-1-(4-(dimethylamino)phenyl)-1H-pyrazol-5-yl)ureido) -naphthalen -1-yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxy)-ethoxy)ethyl)benzamide;

3-((4-((4-(3-(3-(tert-butyl)-1-(4-(dimethylamino)phenyl)-1H-pyrazol-5-yl)ureido) -naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)-ethoxy)ethyl)benzamide;

3-((4-((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)-5,6,7,8-tetrahydronaphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;

3-((4-((4-(3-(3-(tert-butyl)-1-(2,4-dimethoxyphenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;

3-((4-((4-(3-(3-(tert-butyl)-1-(3-((dimethylphosphoryl)methyl)phenyl)-1H -pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;

3-((4-((4-(3-(3-(tert-butyl)-1-(3-((dimethylphosphoryl)methyl)phenyl)-1H -pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;

3-((4-((4-(3-(3-(tert-butyl)-1-(4-(dimethylamino)phenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;

3-((4-((4-(3-(3-(tert-butyl)-1-(4-methoxy-2-methylphenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide,

and pharmaceutically acceptable salts thereof.

11. A compound according to claim 1 that is 3-((4-((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound according to claim 1 , in combination with one or more pharmaceutically acceptable diluents or carriers.

13. A combination product comprising:

(A) a compound according to claim 1 ; and

(B) another therapeutic agent,

wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.

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

(a) reacting a compound of formula (II):

with a compound of formula (II):

wherein LG II represents a leaving group and one of Z 1 and Z 2 is a structural fragment of formula (IV):

wherein R and Q are as defined in claim 1 , and the other of Z 1 and Z 2 is a structural fragment of formula (V):

wherein R 1 , R a , R b , X and Y are as defined in claim 1 ;

(b) reacting a compound of formula (VI):

wherein R, R a , R b , Q and X are as defined in claim 1 and LG VI represent a leaving group, with a compound of formula (VII):

wherein R 1 and Y are as defined in claim 1 ;

(c) reacting a compound of formula (VIII):

with a compound of formula (III), wherein the compound of formula (III) and Z 1 and Z 2 are as defined above;

(d) reacting a compound of formula (IX):

wherein Z 1 is as defined above, with an azide-forming agent, which reaction is followed, without isolation, by thermal rearrangement of the intermediate acyl azide (of formula Z 1 —C(O)—N 3 ) to provide, in situ, a compound of formula (VIII), which compound is then reacted with a compound of formula (III), as defined above, to provide the compound of formula (I);

(e) reacting a compound of formula (X):

wherein R, R 1 , R a , R b , Q and X are as defined in claim 1 and R X represents H or C 1-4 alkyl, with a compound of formula (XI):

wherein R 2 and R 3 are as hereinbefore defined; or

(f) deprotecting a protected derivative of a compound of formula (I).

15. A method of treating inflammation, said method comprising administering to a subject an effective amount of:

a compound as defined in claim 1 , or pharmaceutically acceptable salt thereof, or

a pharmaceutical formulation comprising a compound as defined in claim 1 , or pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable diluents or carriers, or

a combination product comprising:

(A) compound as defined in claim 1 , and

(B) another therapeutic agent,

wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, and

wherein the inflammation is a component in a disease or condition selected from the group consisting of COPD, Crohn's disease and ulcerative colitis.