Kinase inhibitors

1. A compound of

formula III,

or a salt or protected derivative of said compound of formula III, wherein Z 2 represents a structural fragment of formula V:

wherein

R 2 and R 3 , together with the C-atoms to which they are attached, form a fused phenyl or pyridyl ring, which latter two rings are optionally substituted by one or more substituents selected from C 1-3 alkyl, C 1-3 haloalkyl, cyano and halo,

or one of R 2 and R 3 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 2 and R 3 together combine to form C 3-5 alkylene or C 3-5 alkenylene, which latter two groups are optionally substituted by one or more substituents selected from C 1-3 alkyl, C 1-3 haloalkyl, cyano and halo;

X 1 represents N or CH;

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

X 2 represents CR Z or N;

X 3 represents CR 5b or N;

R Z represents H, halo, cyano, hydroxy, C 1-3 alkyl or C 1-3 alkoxy, which latter two groups are optionally substituted by one or more halo atoms;

R 4 represents

-Q 1 -[C(R 6c )(R 6d )—(CH 2 ) 0-1 CH 2 —Z] 1-12 —CH 2 (CH 2 ) 0-1 CH 2 —R 6a ,

-Q 2 -C(R 6c )(R 6d )—[C 1-5 alkylene]-R 6a , which C 1-5 alkylene group is optionally substituted by oxo and/or by one or more R 6e ,

-Q 3 -[C 1-4 alkylene] 0-1 -Het x1 , which C 1-4 alkylene group is optionally substituted by oxo and/or by one or more R 6e and which Het x1 group is optionally substituted by one or more substituents selected from halo, hydroxy, oxo, C 3-6 cycloalkyl, C 1-3 alkoxy and —[C(O)] 0-1 —C 1-4 alkyl, the C 1-4 alkyl part of which latter group is optionally substituted by one or more R 6e ,

-Q 22 -[C 1-4 alkylene] 0-1 -phenyl, which C 1-4 alkylene group is optionally substituted by oxo and/or by one or more R 6e , and which phenyl group is substituted by [C(O)] 0-1 —C 1-4 alkyl, the C 1-4 alkyl part of which latter group is optionally substituted by one or more R 6e , and which phenyl group is optionally further substituted by one or more substituents selected from halo, hydroxy, oxo, C 3-6 cycloalkyl and C 1-3 alkoxy,

—S(O) p R 6b ,

—[C 1-4 alkylene] 0-1 -CO 2 H,

Het x2 which Het x2 group is optionally substituted by one or more substituents selected from halo, hydroxy, oxo, C 1-3 alkyl and C 1-3 alkoxy,

—COR 6b ,

—CH 2 OH,

—CH 2 OP(O)(OH) 2 or

-Q 4 -P(O)(OR 9 )(R 7 );

Z represents, independently upon each occurrence, O, C(O)N(R 8 ) or N(R 8 )C(O);

R 5a and R 5b independently represent C 1-3 alkoxy or C 1-3 alkyl, which latter two groups are optionally substituted by one or more halo atoms, or R 5a and R 5b independently represent —N(R e )(R f ), C 2-3 alkynyl, H, cyano, —C(O)NH 2 , hydroxy, halo or —S(O) 0-2 —C 1-3 alkyl;

R 6a represents OR 7a , —S(O) 0-2 R 7aa , N(R 7b )R 7c or CO 2 H;

R 6b represents C 1-8 alkyl, C 3-8 cycloalkyl, phenyl, Het 1 or Het 2 , which latter five groups are optionally substituted by one or more substituents selected from halo, hydroxy, —OP(O)(OH) 2 , C 1-3 alkyl, C 1-3 alkoxy, —C 1-3 alkylene-R 6e and CO 2 H,

or R 6b represents —C 1-4 alkylene-Het 3 , which Het 3 group is optionally substituted by one or more substituents selected from halo, hydroxy, oxo, C 3-6 cycloalkyl, C 1-3 alkoxy and —[C(O)] 0-1 —C 1-3 alkyl, which C 1-3 alkyl group is optionally substituted by one or more R 6e ,

or, when p is 1 or 2, R 6b may alternatively represent OH,

or, when p is 2, R 6b may alternatively represent —N(R 7b )R 7c or —N(R 7b )—C(O)—R 7c ;

R 6e represents, independently upon each occurrence, halo, hydroxy, —OP(O)(OH) 2 , C 1-3 alkoxy, —N(R g )(R h ) or —CO 2 H;

R 7a to R 7c independently represent H or C 1-4 alkyl optionally substituted by one or more halo atoms or by —CO 2 H,

or R 7a represents P(O)(OH) 2 or Het 3 , which latter group is optionally substituted by one or more substituents selected from halo, hydroxy, oxo, C 3-6 cycloalkyl, C 1-3 alkoxy and —[C(O)] 0-1 —C 1-3 alkyl, which C 1-3 alkyl group is optionally substituted by one or more R 6e ,

or R 7b and/or R 7c represents —[C a alkylene]-[C b alkylene]-OR 7d ,

or R 7b and R 7c together with the N-atom to which they are attached, form a 4- to 7-membered heterocyclic group that is fully saturated, partially unsaturated or fully aromatic and which heterocyclic group contains one N atom (the atom to which R 7b and R 7c are attached) and, optionally, one or more further heteroatoms selected from O, S and N, and which heterocyclic group is optionally substituted by one or more substituents selected from halo, hydroxy, oxo, C 1-4 alkyl, C 1-4 alkoxy and C 1-4 hydroxyalkyl;

a and b independently represent an integer selected from 1, 2 and 3, wherein the sum of a and b is 2, 3 or 4;

R 7d represents H or C 1-4 alkyl optionally substituted by one or more halo atoms;

R 7aa represents —C(R 7d )(R 7e )—C 1-3 alkylene-OH or C 1-4 alkyl optionally substituted by one or more halo atoms or by —CO 2 H;

Q 1 , Q 2 , Q 22 and Q 3 independently represent —C(O)N(R 8 )—, —O— or —S(O) 2 N(R 8 )—, or Q 1 , Q 2 and Q 22 independently represent S(O) q ;

Q 4 represents a direct bond or C 1-3 alkylene;

n, m, p and q independently represent 0, 1 or 2;

R 6c , R 6d , R e , R f , R g , R h and R 8 independently represent H or methyl,

or R 6c and R 6d independently represent hydroxymethyl;

R 7 represents H, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 3-7 cycloalkyl or phenyl, which latter four groups are optionally substituted by one or more substituents selected from halo, OH, C 1-3 alkyl and C 1-3 alkoxy;

R 9 represents H or C 1-4 alkyl, which latter group is optionally substituted by one or more halo atoms or by phenyl, which phenyl group is optionally substituted by one or more substituents selected from halo, OH, C 1-3 alkyl and C 1-3 alkoxy;

Het x1 and Het x2 independently represent Het 1a or Het 3 ;

Het 1 and Het 1a represent, independently upon each occurrence, a 5- or 6-membered heterocyclic group that is fully aromatic, which group contains one or more heteroatoms selected from N, O and S; and

Het 2 and Het 3 represent, independently upon each occurrence, a 4- to 9-membered heterocyclic group that is fully saturated or partially unsaturated, and is monocyclic or is fused or bridged bicyclic, which group contains one or more heteroatoms selected from N, O and S, wherein said protected derivative is a compound in which:

(a) a H-atom of the NH 2 group of formula Ill is replaced by:

R′—C(O)—, wherein R′ is H, C 1-8 alkyl, phenyl or benzyl, which latter two groups are optionally substituted by one or more groups selected from halo, hydroxy, methyl and methoxy, or

R″—O—C(O)—, wherein R″ is tert-butyl, phenyl, benzyl or fluorenyl, which latter three groups are optionally substituted by one or more groups selected from halo, hydroxy, methyl and methoxy; and/or

(b) when R 4 represents —CO 2 H, said —CO 2 H group is protected as a C 1-8 alkyl ester.

2. A compound of

formula III, or a salt or protected derivative thereof, as claimed in claim 1 , wherein said compound or protected derivative is

methyl 4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoate or

methyl 4-((4-((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoate.

3. A compound of formula VIIa,

or a salt of said compound of formula VIIa, wherein

Q X represents —[C 1-4 alkylene] 0-1 —C(O)O—C 1-4 alkyl;

R 1A represents:

C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, which latter four groups are optionally substituted by one or more substituents selected from C 1-2 alkyl, halo, hydroxy, —OP(O)(OH) 2 and C 1-2 alkoxy,

H, halo, cyano,

phenyl or Het 1 , which latter two groups are optionally substituted with one or more substituents selected from C 1-2 alkyl and C 1-2 alkoxy,

or R 1A and R 1B together represent a structural fragment selected from the following:

wherein the wavy lines represent the points of attachment to the phenyl ring;

A represents O, S or N(R A2 );

R A1 represents H, C 1-4 alkyl or hydroxy;

R A2 represents H or C 1-4 alkyl;

R 1B is represents —NR X S(O) 2 R Y1 , —C(O)NR X R Y , H, halo, cyano, —C 1-4 alkylene-CN, —C 1-4 alkylene-OH, —NR X R X1 , —C(O)OR X , —S(O) 2 NR X R Y , —NR X C(O)R Y , —NR X2 S(O) 2 NR X R Y , —NR X P(O)R Y1 R Y2 , —NR X C(O)OR Y1 or Het 1 optionally substituted with one or more substituents selected from halo, hydroxy, C 1-2 alkyl and C 1-2 alkoxy;

R X and R X1 independently represent H or C 1-6 alkyl optionally substituted by one or more substituents selected from halo, hydroxy, —OP(O)(OH) 2 and C 1-2 alkoxy, or R X and R X1 together represent C 3-6 n-alkylene or C 4-5 n-alkylene interrupted between C2 and C3 by —O— or —N(R X2 )—, or R X1 represents Het 1 optionally substituted with one or more substituents selected from halo, hydroxy, C 1-2 alkyl and C 1-2 alkoxy;

R Y , R Y1 and R Y2 independently represent C 1-6 alkyl, C 3-7 cycloalkyl, phenyl, benzyl, Het 1 or Het 2 , which latter six groups are optionally substituted by one or more substituents selected from C 1-2 alkyl, halo, hydroxy, —OP(O)(OH) 2 , C 1-2 alkoxy, C(O)OH, C(O)O—(C 1-4 alkyl) and —N(R a )(R b ), and/or which Het 2 group is substituted with one or more oxo groups,

or R Y represents H,

or R X and R Y together represent C 3-6 n-alkylene or C 4-5 n-alkylene interrupted between C2 and C3 by —O—, —S(O) n — or —N(R X2 )—;

R a and R b independently represent H, methyl or —C(R c )(R d )—C 1-3 alkyl, the C 1-3 alkyl portion of which latter group is optionally substituted by one or more hydroxy substituents,

or R a and R b together represent C 3-6 n-alkylene or C 4-5 n-alkylene interrupted between C2 and C3 by —O—, —S(O) m — or —N(R X2 )—;

R c and R d independently represent H or methyl;

each R X2 independently represents H or C 1-4 alkyl;

R 1C and R 1E independently represent H, halo, cyano or methyl;

provided that at least one of R 1A , R 1B , R 1C and R 1E is other than H;

R 1D represents trimethylsilyl, C 2-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, phenyl, Het 1 or Het 2 , which latter seven groups are optionally substituted by one or more substituents selected from C 1-2 alkyl, halo, cyano, hydroxy, —OP(O)(OH) 2 and C 1-2 alkoxy;

R 2 and R 3 , together with the C-atoms to which they are attached, form a fused phenyl or pyridyl ring, which latter two rings are optionally substituted by one or more substituents selected from C 1-3 alkyl, C 1-3 haloalkyl, cyano and halo,

or one of R 2 and R 3 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 2 and R 3 together combine to form C 3-5 alkylene or C 3-5 alkenylene, which latter two groups are optionally substituted by one or more substituents selected from C 1-3 alkyl, C 1-3 haloalkyl, cyano and halo;

X 1 represents N or CH;

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

X 2 represents CR Z or N;

X 3 represents CR 5b or N;

R 5a and R 5b independently represent C 1-3 alkoxy or C 1-3 alkyl, which latter two groups are optionally substituted by one or more halo atoms, or R 5a and R 5b independently represent —N(R e )(R f ), C 2-3 alkynyl, H, cyano, —C(O)NH 2 , hydroxy, halo or —S(O) 0-2 —C 1-3 alkyl;

R Z represents H, halo, cyano, hydroxy, C 1-3 alkyl or C 1-3 alkoxy, which latter two groups are optionally substituted by one or more halo atoms;

R e and R f independently represent H or methyl;

Het 1 represents, independently upon each occurrence, a 5- or 6-membered heterocyclic group that is fully aromatic, which group contains one or more heteroatoms selected from N, O and S; and

Het 2 represents, independently upon each occurrence, a 4- to 9-membered heterocyclic group that is fully saturated or partially unsaturated, and is monocyclic or is fused or bridged bicyclic, which group contains one or more heteroatoms selected from N, O and S.

4. A compound of formula VIIa, or a salt thereof, as claimed in claim 3 , wherein said compound is methyl 4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)-phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoate.