Purine derivatives and their use in the treatment of disease

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

wherein

R 1 is selected from the group consisting of

wherein

R 18 on each occurrence independently represents fluoro or methyl;

m represents 0, 1, 2 or 3;

R 19 and R 20 independently represent hydrogen or fluoro;

R 21 represents fluoro;

R 22 on each occurrence independently represents fluoro, methoxy, hydroxymethyl or methoxycarbonyl;

q represents 0, 1 or 2 and r represents 0, 1, 2 or 3 provided that q+r is not 0;

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 independently represent hydrogen, C 1-3 alkyl or fluoro-C 1-3 alkyl; or R 3 and R 6 together form a methylene bridge; or R 3 and R 8 together form an ethylene bridge; or R 5 and R 6 together form an ethylene bridge;

n and p independently represent 0, 1 or 2;

R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 on each occurrence independently represent hydrogen, C 1-3 alkyl, fluoro-C 1-3 alkyl or hydroxy-C 1-3 alkyl; or R 11 and R 16 together form an ethylene bridge; or R 13 and R 14 together form an ethylene bridge; or R 14 and R 15 , together with the carbon atom to which they are attached, are linked to form a tetrahydropyranyl ring; and

Y represents O, CHR 23 , CR 24 R 25 or NR 26 ,

wherein

R 23 represents hydroxyl or fluoro-C 1-3 alkyl; or R 23 and R 13 , together with the carbon atoms to which they are attached, are linked to form a fused tetrahydrofuranyl ring;

R 24 and R 25 independently represent hydrogen or halogen; or R 24 and R 25 , together with the carbon atom to which they are attached, are linked to form a tetrahydropyranyl ring; and

R 26 represents C 1-3 alkyl or oxetanyl;

and

a compound, or a pharmaceutically acceptable salt thereof, selected from the following list of compounds:

8-(1H-Indol-4-yl)-6-(3-methyl-morpholin-4-yl)-2-[1,4]oxazepan-4-yl-9H-purine;

8-[8-(1H-Indol-4-yl)-6-(3-methyl-morpholin-4-yl)-9H-purin-2-yl]-8-aza-bicyclo[3.2.1] octan-3-ol;

8-[8-(1H-Indol-4-yl)-6-(3-methyl-morpholin-4-yl)-9H-purin-2-yl]-8-aza-bicyclo[3.2.1]octan-3-ol;

8-(1H-Indol-4-yl)-6-(3-methyl-morpholin-4-yl)-2-(4-methyl-piperazin-1-yl)-9H-purine;

8-(1H-Indol-4-yl)-6-(3-methyl-morpholin-4-yl)-2-(6-oxa-2-aza-spiro[3.5]non-2-yl)-9H-purine;

8-(1H-Indol-4-yl)-6-(3-methyl-morpholin-4-yl)-2-(4-oxetan-3-yl-piperazin-1-yl)-9H-purine;

8-(1H-Indol-4-yl)-6-(3-methyl-morpholin-4-yl)-2-(tetrahydro-furo[3,4-c]pyrrol-5-yl)-9H-purine;

2-(Hexahydro-furo[3,4-c]pyridin-5-yl)-8-(1H-indol-4-yl)-6-(3-methyl-morpholin-4-yl)-9H-piperidinpurine;

8-(1H-Indol-4-yl)-6-(3-methyl-morpholin-4-yl)-2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-9H-purine;

{4-[8-(1H-Indol-4-yl)-6-(3-methyl-morpholin-4-yl)-9H-purin-2-yl]-morpholin-2-yl}-methanol.

2. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 represents

3. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 represents

4. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 represents

5. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 independently represent hydrogen or methyl; or R 3 and R 6 together form a methylene bridge; or R 3 and R 8 together form an ethylene bridge; or R 5 and R 6 together form an ethylene bridge.

6. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y represents O.

7. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y represents CHR 23 or CR 24 R 25 .

8. A compound, or a pharmaceutically acceptable salt thereof, according to claim 1 which is selected from:

2,6-Bis-((R)-3-methyl-morpholin-4-yl)-8-pyridin-2-yl-9H-purine;

2-((S)-3-Methyl-morpholin-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-8-(1H-pyrazol-3-yl)-9H-purine;

8-(1H-Indol-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-2-[1,4]oxazepan-4-yl-9H-purine;

8-[4-(1H-Imidazol-2-yl)-phenyl]-2,6-bis-((R)-3-methyl-morpholin-4-yl)-9H-purine;

8-(6-Fluoro-1H-indol-4-yl)-2-((S)-3-methyl-morpholin-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-9H-purine;

{4-[2,6-Bis-((R)-3-methyl-morpholin-4-yl)-9H-purin-8-yl]-1H-indol-6-yl}-methanol;

2-((S)-3-Methyl-morpholin-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-8-pyridin-2-yl-9H-purine;

2,6-Bis-((S)-3-methyl-morpholin-4-yl)-8-pyridin-2-yl-9H-purine;

2,6-Di-morpholin-4-yl-8-pyridin-2-yl-9H-purine;

2,6-Bis-((S)-3-methyl-morpholin-4-yl)-8-(1H-pyrazol-3-yl)-9H-purine;

2,6-Bis-((R)-3-methyl-morpholin-4-yl)-8-(1H-pyrazol-3-yl)-9H-purine;

8-[8-(1H-Indol-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-9H-purin-2-yl]-8-aza-bicyclo[3.2.1]octan-3-ol;

8-[8-(1H-Indol-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-9H-purin-2-yl]-8-aza-bicyclo[3.2.1]octan-3-ol;

8-(1H-Indol-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-2-(4-methyl-piperazin-1-yl)-9H-purine;

8-(1H-Indol-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-2-(6-oxa-2-aza-spiro[3.5]non-2-yl)-9H-purine;

8-(1H-Indol-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-2-(4-oxetan-3-yl-piperazin-1-yl)-9H-purine;

8-(1H-Indol-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-2-(tetrahydro-furo[3,4-c]pyrrol-5-yl)-9H-purine;

2-(Hexahydro-furo[3,4-c]pyridin-5-yl)-8-(1H-indol-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-9H-purine;

8-(1H-Indol-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-9H-purine;

{(S)-4-[8-(1H-Indol-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-9H-purin-2-yl]-morpholin-2-yl}-methanol;

{(R)-4-[8-(1H-Indol-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-9H-purin-2-yl]-morpholin-2-yl}-methanol;

5-[2,6-Bis-((S)-3-methyl-morpholin-4-yl)-9H-purin-8-yl]-pyridin-2-ylamine;

5-[2,6-Bis-((R)-3-methyl-morpholin-4-yl)-9H-purin-8-yl]-pyridin-2-ylamine;

5-[2,6-Bis-((R)-3-methyl-morpholin-4-yl)-9H-purin-8-yl]-pyrimidin-2-yl-amine;

8-[4-(1H-Imidazol-2-yl)-phenyl]-2,6-bis-((S)-3-methyl-morpholin-4-yl)-9H-purine;

8-(6-Methoxy-1H-indol-4-yl)-2-((S)-3-methyl-morpholin-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-9H-purine;

4-[2,6-Bis-((R)-3-methyl-morpholin-4-yl)-9H-purin-8-yl]-1H-indole-6-carboxylic acid methyl ester; and

pharmaceutically acceptable salts thereof.

9. A compound according to claim 1 which is 2,6-Bis-((R)-3-methyl-morpholin-4-yl)-8-pyridin-2-yl-9H-purine having the following formula

or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 1 which is 8-(6-Fluoro-1H-indol-4-yl)-2-((S)-3-methyl-morpholin-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-9H-purine having the following formula

or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 1 which is 2-((S)-3-Methyl-morpholin-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-8-pyridin-2-yl-9H-purine having the following formula

or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 1 which is 2,6-Bis-((S)-3-methyl-morpholin-4-yl)-8-(1H-pyrazol-3-yl)-9H-purine having the following formula

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound according claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, diluent or carrier.

14. A method for the treatment of a disease or disorder modulated by the inhibition of the mTor enzyme, comprising administration of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof wherein the disease or disorder is cancer, a neurodegenerative disorder or an ophthalmological disease.

15. A combination product comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and another therapeutic agent.