Fused thiazolopyrimidine derivatives as MNKs inhibitors
The present invention relates to compounds of formulae I and H, or pharmaceutically acceptable salts or esters thereof. Further aspects of the invention relate to pharmaceutical compositions and therapeutic uses of said compounds in the treatment of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, inappropriate cellular inflammatory responses, or neurodegenerative disorders, preferably tauopathies, even more preferably. Alzheimer's disease.
1. 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 alkyl optionally substituted by one or more groups selected from NR 10 R 11 and a heterocycloalkyl group selected from piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyranyl, wherein said heterocycloalkyl group 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 8 and R 9 are each independently selected from H, CN, NO 2 , OH, alkoxy, NHCO-alkyl, halo and haloalkyl;
R 7 is halo; 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; and
each R 10 and R 11 is independently alkyl.
2. A compound according to claim 1 wherein
Z 1 , Z 2 , Z 3 and Z 4 are all C; and
R 6 , R 8 and R 9 are all H and R 7 is halo.
3. A compound according to claim 1 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.
4. A compound according to claim 1 wherein R b is alkyl.
5. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
6. A method of treating a proliferative 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 .
7. 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 .
8. 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 .
9. A combination comprising a compound according to claim 1 and a further therapeutic agent.
10. A compound according to claim 1 , wherein Rh is isopropyl.
11. A compound of formula (II), or a pharmaceutically acceptable salt 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 alkyl optionally substituted by one or more groups selected from NR 10 R 11 and a heterocycloalkyl group selected from piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyranyl, wherein said heterocycloalkyl group is optionally substituted by one or more R 10 groups:
wherein Z 2 , Z 3 and Z 4 are all C, Z 1 is N and R 6 is absent;
R 7 , R 8 and R 9 are each independently selected from H, CN, NO 2 , OH, alkoxy, NHCO-alkyl, halo and haloalkyl; and
each R 10 and R 11 is independently alkyl.
12. A pharmaceutical composition comprising a compound according to claim 11 and a pharmaceutically acceptable carrier, diluent or excipient.
13. A method of treating a proliferative 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 11 .
14. 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 11 .
15. 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 11 .
16. A combination comprising a compound according to claim 11 and a further therapeutic agent.