Fused thiazolopyrimidine derivatives as MNKS inhibitors

1. A compound of formula (I), or a pharmaceutically acceptable salt or ester thereof,

wherein:

R 1 is selected from:

CO—NR 12 R 13 , wherein R 12 and R 13 are each independently selected from H, alkyl, cycloalkyl and heterocycloalkyl, wherein said alkyl group is optionally substituted by one or more R 14 groups, and said heterocycloalkyl is optionally substituted by one or more R 10 groups; or R 12 and R 13 are linked, together with the nitrogen to which they are attached, to form a heterocycloalkyl group optionally containing one or more additional heteroatoms, and optionally substituted by one or more R 10 groups;

hydroxyalkyl;

H;

NH 2 ;

NH-alkyl, wherein said alkyl group is optionally substituted with one or more R 14 groups;

NH—CO-heterocycloalkyl;

heterocycloalkyl optionally substituted by one or more R 10 groups; and

alkoxy optionally substituted with one or more R 14 groups;

R 2 , R 3 , R 4 and R 5 are each independently selected from H, alkyl, hydroxyalkyl and (CH 2 ) n —R 12′ ;

or R 2 and R 3 are linked to form a cycloalkyl or heterocycloalkyl group each of which may be optionally further substituted with one or more R 10 groups;

or R 4 and R 5 are linked to form a cycloalkyl or heterocycloalkyl group each of which may be optionally further substituted with one or more R 10 groups;

or one of R 2 and R 3 is absent, one of R 4 and R 5 is absent, and the dashed line is a double bond;

Z 1 , Z 2 , Z 3 and Z 4 are all C;

R 6 , R 7 , R 8 and R 9 are each independently selected from H, CN, NO 2 , OH, alkoxy, NHCO-alkyl, halo and haloalkyl; or

Z 1 , Z 3 and Z 4 are all C, Z 2 is N, R 7 is absent and R 6 , R 8 and R 9 are as defined above; or

Z 2 , Z 3 and Z 4 are all C, Z 1 is N, R 6 is absent and R 7 , R 8 and R 9 are as defined above;

n is an integer from 1 to 10;

each R 12′ is independently selected from NH 2 , NHR 10 , NR 10 R 11 and heterocycloalkyl, wherein said heterocycloalkyl is optionally further substituted by one or more R 10 groups;

each R 10 and R 11 is independently alkyl; and

each R 14 is independently selected from OH, alkoxy, haloalkyl, NH 2 , NHR 10 , NR 10 R 11 , heteroaryl and heterocycloalkyl, wherein said heterocycloalkyl is optionally further substituted by one or more R 10 groups.

2. A compound according to claim 1 wherein Z 1 , Z 2 , Z 3 and Z 4 are all C.

3. A compound according to claim 1 wherein R 2 , R 3 , R 4 and R 5 are each independently selected from H, alkyl, and (CH 2 ) n —R 12′ .

4. A compound according to claim 1 wherein:

R 2 , R 3 , R 4 and R 5 are all H; or

R 2 and R 3 are both H, and R 4 and R 5 are both Me; or

R 2 and R 3 are both H, and R 4 and R 4 are linked to form a cycloalkyl or heterocycloalkyl group.

5. A compound according to claim 1 wherein R 6 , R 7 , R 8 and R 9 are each independently selected from H and halo.

6. A compound according to claim 1 wherein:

Z 1 , Z 2 , Z 3 and Z 4 are all C;

R 6 , R 7 , R 8 and R 9 are all H; or

R 6 , R 8 and R 9 are all H and R 7 is selected from fluoro, chloro, bromo, and CF 3 ; and

R 2 , R 3 , R 4 and R 5 are each independently selected from H, alkyl, and (CH 2 ) n —R 12′ .

7. A compound according to claim 1 wherein:

R 2 , R 3 , R 4 and R 5 are each independently selected from H, hydroxyalkyl, alkyl, and (CH 2 ) n —R 12′ , where n is 1 or 2 and R 12′ is selected from NH 2 , NMe, NMe 2 , pyrrolidin-1-yl, piperidin-1-yl and 4-methylpiperazin-1-yl.

8. A compound according to claim 1 wherein R 1 is CO—NR 12 R 13 .

9. A compound according to claim 1 where R 1 is CO—NR 12 R 13 wherein:

one of R 12 and R 13 is H and the other is selected from:

tetrahydropyran-4-yl;

piperdin-4-yl;

cyclopropyl;

tetrahydrofuran-4-yl;

N-methylpiperidin-4-yl;

alkyl optionally substituted by one or more groups selected from NHMe, NH 2 , NMe 2 , piperidin-4-yl, N-methylpiperidin-4-yl, tetrahydrofuranyl, OH, CF 3 , OMe and pyrrolidin-1-yl; or

R 12 and R 13 are linked, together with the nitrogen to which they are attached, to form a piperazinyl or morpholinyl group optionally substituted by one or more R 10 groups.

10. A compound of formula (II), or a pharmaceutically acceptable salt or ester thereof,

wherein:

R b is alkyl;

R 1a is selected from:

CO—NR 12a R 13a , wherein R 12a and R 13a are each independently selected from H, alkyl, cycloalkyl and mono or bicyclic heterocycloalkyl, wherein said alkyl group is optionally substituted by one or more (CH 2 ) m R 14a groups, and said heterocycloalkyl is optionally substituted by one or more groups selected from R 10 and (CH 2 ) m R 14a ; or R 12a and R 13a are linked, together with the nitrogen to which they are attached, to form a heterocycloalkyl group optionally containing one or more additional heteroatoms, and optionally substituted by one or more groups select from R 10 and (CH 2 ) m R 14a ;

hydroxyalkyl; and

COOH;

Z 1 , Z 2 , Z 3 and Z 4 are all C;

R 6 , R 7 , R 8 and R 9 are each independently selected from H, CN, NO 2 , OH, alkoxy, NHCO-alkyl, halo and haloalkyl; or

Z 1 , Z 3 and Z 4 are all C, Z 2 is N, R 7 is absent and R 6 , R 8 and R 9 are as defined above; or

Z 2 , Z 3 and Z 4 are all C, Z 1 is N, R 6 is absent and R 7 , R 8 and R 9 are as defined above;

m is an integer from 1 to 10;

each R 10 and R 11 is independently alkyl;

each R 14a is independently selected from CO 2 R 10 , COOH, OH, alkoxy, haloalkyl, NH 2 , NHR 10 , NR 10 R 11 , heteroaryl and heterocycloalkyl, wherein said heterocycloalkyl is optionally further substituted by one or more R 10 groups.

11. A compound according to claim 10 wherein

Z 1 , Z 2 , Z 3 and Z 4 are all C;

R 6 , R 7 , R 8 and R 9 are all H; or

R 6 , R 8 and R 9 are all H and R 7 is halo.

12. A compound according to claim 10 wherein Z 1 , Z 2 , Z 3 and Z 4 are all C, R 6 , R 8 and R 9 are all H, and R 7 is fluoro.

13. A compound according to claim 10 wherein R 1a is CO—NR 12a R 13a wherein:

one of R 12a and R 13a is H and the other is selected from:

alkyl optionally substituted by one or more (CH 2 ) m R 14a groups, wherein each R 14a is independently selected from NR 10 R 11 , COOH, OH and heterocycloalkyl; and

mono or bicyclic heterocycloalkyl optionally substituted by one or more groups selected from R 10 and (CH 2 ) m CO 2 R 10 ; or

R 12a and R 13a are linked, together with the nitrogen to which they are attached, to form a piperidinyl group optionally substituted by one or more groups selected from R 10 and (CH 2 ) m R 14a .

14. A compound of formula (II), or a pharmaceutically acceptable salt or ester thereof,

wherein:

R b is selected from alkyl, cycloalkyl and heterocycloalkyl, each of which may be optionally substituted by one or more groups selected from halo and alkoxy;

R 1a is a heterocycloalkyl group selected from, piperidinyl, quinuclidinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl and tetrahydropyranyl, each of which is optionally substituted by one or more R 10 groups;

Z 1 , Z 2 , Z 3 and Z 4 are all C;

R 6 , R 7 , R 8 and R 9 are each independently selected from H, CN, NO 2 , OH, alkoxy, NHCO-alkyl, halo and haloalkyl; or

Z 1 , Z 3 and Z 4 are all C, Z 2 is N, R 7 is absent and R 6 , R 8 and R 9 are as defined above; or

Z 2 , Z 3 and Z 4 are all C, Z 1 is N, R 6 is absent and R 7 , R 8 and R 9 are as defined above;

each R 10 is independently alkyl.

15. A compound which is selected from the following:

and pharmaceutically acceptable salts or esters thereof.

16. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

17. A method of treating a proliferatative disorder selected from a haematological tumour, a solid tumour and/or metastases thereof, comprising administering to a subject in need thereof a compound of claim 1 .

18. A method of treating a disease of uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, or a neurodegenerative disorder in a mammal, said method comprises administering to a mammal a therapeutically effective amount of a compound according to claim 1 .

19. A method of treating a mammal having a disease state alleviated by the inhibition of MNK, wherein the method comprises administering to a mammal a therapeutically effective amount of a compound according to claim 1 .

20. A combination comprising a compound according to claim 1 and a further therapeutic agent.