Tetrahydroisoquinoline derived PRMT5-inhibitors

1. A compound of formula I:

wherein:

n is 1 or 2;

p is 0 or 1;

R 1 is optionally one or more halo or methyl groups;

R 2a and R 2b are independently selected from the group consisting of:

(i) F;

(ii) H;

(iii) Me; and

(iv) CH 2 OH;

R 2c and R 2d are independently selected from the group consisting of:

(i) F;

(ii) H;

(iii) Me; and

(iv) CH 2 OH;

R 3a and R 3b are independently selected from H and Me;

R 4 is either H or Me;

R 5 is either H or Me;

R 6a and R 6b are independently selected from H and Me;

A is either

(i) optionally substituted phenyl;

(ii) optionally substituted naphthyl; or

(iii) optionally substituted C 5-12 heteroaryl;

wherein when A is substituted, the substituents are independently selected from one of the following groups:

wherein when A is substituted, the substituents are independently selected from one of the following groups: C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-6 cycloalkyl, C 5-6 heteroaryl, C 5-6 heteroaryl methyl, C 4-6 heterocyclyl, C 4-6 heterocyclyl methyl, phenyl, benzyl, halo, amido, amidomethyl, acylamido, acylamidomethyl, C 1-4 alkyl ester, C 1-4 alkyl ester methyl, C 1-4 alkyl carbamoyl, C 1-4 alkyl carbamoyl methyl, C 1-4 alkylacyl, C 1-4 alkylacyl methyl, phenylcarbonyl, carboxy, carboxymethyl, ether, amino, aminomethyl, sulfonamido, sulfonamino, sulfone, sulfoxide, nitrile and nitrilemethyl and when A is phenyl, the optional substituent may also be a fused C 5-6 N 1 -containing heterocyclic ring.

2. A compound according to claim 1 , wherein R 1 represents one to four Me or halo groups.

3. A compound according to claim 1 , wherein:

(a) R 2a , R 2b , R 2c and R 2d are all H; or

(b) R 2a , R 2b , R 2c and R 2d consists of three H and one Me or CH 2 OH group; or

(c) R 2a , R 2b , R 2c and R 2d consists of two H and two Me groups.

4. A compound according to claim 1 , wherein:

(a) R 3a is H and R 3b is Me; or

(b) R 3a and R 3b are both H; or

(c) R 3a and R 3b are both Me.

5. A compound according to claim 1 , wherein:

(a) R 6a is H and R 6b is Me; or

(b) R 6a and R 6b are both H; or

(c) R 6a and R 6b are both Me.

6. A compound according to claim 1 which is of:

7. A compound according to claim 1 , which is a racemate at the carbon atom to which OH is attached.

8. A compound according to claim 1 , which is a single enantiomer at the carbon atom to which OH is attached.

9. A compound according to claim 1 , wherein A is optionally substituted phenyl, wherein the substituents are selected from: C 1-4 alkyl, fluoro, chloro, bromo, acetyl, methoxy, ethoxy, —C(═O)Me, —C(═O)Et, —CH 2 C(═O)Me, phenyl, —CF 3 , —CF 2 H, —CN, —CH 2 CN, —OBn, —OPh, —OCF 3 , —OCF 2 H, —O—(C 6 H 4 )—CN, —COOH, —CH 2 COOH, —C(═O)OMe, —C(═O)NH 2 , —C(═O)NMeH, —C(═O)NMe 2 , —C(═O)N i PrH, —C(═O)-piperidinyl, —C(═O)-pyrrolidinyl, —C(═O)-morpholino (which may be bridged or substituted with one or two methyl groups), —C(═O)-azetidinyl, —CH 2 C(═O)NH 2 , —CH 2 C(═O)-azetidinyl, —CH 2 C(═O)NMeH, —CH 2 C(═O)N i PrH, —CH 2 C(═O)-pyrrolidinyl, —CH 2 C(═O)-morpholino, —CH 2 -morpholino, —CH 2 -methylpiperazinyl, —OCH 2 pyridinyl, —OCH 2 -methyloxadiazolyl, —CH 2 -imidazolyl, —O-tetrahydropyranyl, —CH 2 -tetraydropyanyl, —NH-methylpyrazinyl, —CH 2 -triazolyl, —NHSO 2 Ph, —NHSO 2 Me, —SO 2 NMePh, —SO 2 NMe 2 , —SO 2 NHEt, —SO 2 CF 3 , -γ-lactam, —CH 2 NHC(═O)Me, —CH 2 NHC(═O)OMe, —CH 2 NHC(═O)CF 3 , morpholino, —CH 2 NH 2 , —C(═O)Ph, —OCH 2 -isoxazolyl, —NH-pyrimidinyl, pyridizinyl, pyrimidinyl, pyridinyl, pyrazolyl, methylpyrazolyl, dimethylpyrazolyl, pyrazinyl, pyridazinyl, methyloxadiazolyl, oxadiazolyl, dimethyloxadiazolyl, isoxazolyl, dimethyltriazolyl, imidazolyl, benzimidazolyl and thiadiazolyl.

10. A compound according to claim 9 , wherein:

(a) in the ortho position of the phenyl group there is a halo, C 1-4 alkyl, methoxy or ethoxy substituent; or

(b) in the meta position of the phenyl group there is a C 1-4 alkyl or C 5-6 heteroaryl substituent; or

(c) in the para position of the phenyl group there is an amido or amidomethyl substituent; or

(d) the phenyl group bears a halo or methoxy substituent in the ortho position, and an amido or amidomethyl substituent in the para position of the phenyl group; or

(e) the phenyl group bears a halo or methoxy substituent in the ortho position, and an amido or amidomethyl substituent in the para position of the phenyl group; or

(f) in the meta position of the phenyl group there is an amino substituent.

11. A compound according to claim 1 , wherein A is:

(a) optionally substituted naphthyl; or

(b) optionally substituted C 5-12 heteroaryl selected from the group consisting of: pyridinyl, pyrimidinyl, pyrazinyl, isoxazolyl, oxazolyl, thiophenyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridonyl, imidazolyl, benzimidazolyl, imidazopyridinyl and quinolinyl.

12. A compound according to claim 1 , wherein A is selected from one of the following groups:

13. A compound according to claim 1 , wherein A is selected from one of the following groups:

14. A compound according to claim 13 , wherein A is selected from one of the following groups:

15. A compound according to claim 1 , wherein A is selected from one of the following groups:

16. A compound according to claim 1 , wherein A is selected from one of the following groups:

17. A compound according to claim 1 , wherein A is selected from

phenyl with a para-amido substituent;

phenyl with a para-amido substituent, and an ortho-ethoxy group;

pyridyl with para ether or amino group, where the ether or amino substituent is a C 5-6 heterocyclic group, with an optional ortho-ethoxy group; and

pyridyl with a meta ether group, where the pyridyl N is in the para position.

18. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

19. A method of inhibiting PRMT5 in a patient in need thereof, comprising administering to the patient a PRMT5 inhibiting effective amount of a composition according to claim 18 .

20. A method of inhibiting PRMT5 in a patient in need thereof comprising administering to the patient a PRMT5 inhibiting effective amount of a pharmaceutical composition according to claim 18 , wherein said inhibition of PRMT5 inhibits γ-globin gene expression during the treatment of hemoglobinopathies.

21. The method of claim 19 , wherein said inhibition of PRMT5 treats a cancer that overexpresses PRMT5.

22. The method of claim 21 , wherein said cancer is chosen from prostate cancer, lung cancer, melanoma cancer, breast cancer, colorectal cancer, gastric cancer, esophagus carcinoma, lung carcinoma, B-cell lymphoma and B-cell leukemia.