Pyrropyrimidine compounds as MNKs inhibitors
The present invention relates to compounds of formulae I, or pharmaceutically acceptable salts or esters thereof, wherein: R 1 is selected from H and CO—NR 8 R 9 , wherein R 8 and R 9 are each independently selected from H, alkyl, cycloalkyl and mono or bicyclic heterocycloalkyl, wherein said alkyl group is optionally substituted by one or more R 12 groups, and said heterocycloalkyl is optionally substituted by R 10 or R 12 ; or R 8 and R 9 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 12 ; R 2 is selected from H and alkyl, wherein said alkyl group is optionally substituted by one or more R 12 groups; R 3 is selected from alkyl, cycloalkyl and heterocycloalkyl, each of which may be optionally substituted by halo, OH or alkoxy; Z 1 , Z 2 , Z 3 and Z 4 are all C; R 4 , R 5 , R 6 and R 7 are each independently selected from H, alkyl, 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 5 is absent and R 4 , R 6 and R 7 are as defined above; or Z 1 , Z 3 and Z 4 are all C, Z 1 is N, R 4 is absent and R 5 , R 6 and R 7 are as defined above; each R 10 and R11 is independently alkyl; each R 12 is independently selected from CO 2 R 10 , COOH, OH, alkoxy, haloalkyl, NH 2 , NHR 10 , NR 10 R 11 , heteroaryl and heterocycloalkyl; R 13 is H or halo. Further aspects 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 (I), or a pharmaceutically acceptable salt or ester thereof,
wherein:
R 1 is selected from:
H;
CO—NR 8 R 9 , wherein R 8 and R 9 are each independently selected from H, alkyl, cycloalkyl and mono or bicyclic heterocycloalkyl, wherein said alkyl group is optionally substituted by one or more R 12 groups, and said heterocycloalkyl is optionally substituted by one or more groups selected from R 10 and R 12 ; or R 8 and R 9 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 12 ;
R 2 is selected from H and alkyl, wherein said alkyl group is optionally substituted by one or more R 12 groups;
R 3 is selected from alkyl, cycloalkyl and heterocycloalkyl, each of which may be optionally substituted by one or more groups selected from halo, OH and alkoxy;
Z 1 , Z 2 , Z 3 and Z 4 are all C;
R 4 , R 5 , R 6 and R 7 are each independently selected from H, alkyl, 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 5 is absent and R 4 , R 6 and R 7 are as defined above; or
Z 2 , Z 3 and Z 4 are all C, Z 1 is N, R 4 is absent and R 5 , R 6 and R 7 are as defined above;
each R 10 and R 11 is independently alkyl;
each R 12 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;
R 13 is H or halo.
2. A compound according to claim 1 wherein:
Z 1 , Z 2 , Z 3 and Z 4 are all C; and
R 4 , R 5 , R 6 and R 7 are each independently selected from H, alkyl, alkoxy, and halo.
3. A compound according to claim 1 wherein
Z 1 , Z 2 , Z 3 and Z 4 are all C;
R 4 , R 5 , R 6 and R 7 are all H; or
R 4 , R 6 and R 7 are all H and R 5 is halo.
4. A compound according to claim 1 wherein Z 1 , Z 2 , Z 3 and Z 4 are all C, R 4 , R 6 and R 7 are all H, and R 5 is fluoro.
5. A compound according to claim 1 wherein R 3 is selected from alkyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuranyl and tetrahydropyranyl, each of which may be optionally substituted by one or more groups selected from fluoro, OH and methoxy.
6. A compound according to claim 1 wherein R 3 is alkyl.
7. A compound according to claim 1 wherein R 1 is H.
8. A compound according to claim 1 wherein R 1 is CO—NR 8 R 9 and one of R 8 and R 9 is H, and the other is alkyl optionally substituted by one or more groups selected from NR 10 R 11 and heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more R 10 groups.
9. A compound according to claim 1 wherein R 2 is selected from H, and alkyl, wherein said alkyl is optionally substituted by one or more groups selected from OH and alkoxy.
10. A compound according to claim 1 wherein R 2 is selected from H, methyl, ethyl, isopropyl, hydroxyethyl and methoxyethyl.
11. A compound which is selected from the following:
and pharmaceutically acceptable salts or esters thereof.
12. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
13. A method of treating a proliferative disorder selected from a hematological tumour, a solid tumour and/or metastases a neurodegenerative disorder or an inappropriate cellular inflammatory response, thereof, comprising administering to a subject in need thereof a compound of claim 1 .
14. A compound according to claim 1 , wherein the compound of formula (I) is
or a pharmaceutically acceptable salt or ester thereof.