6-6 bicyclic aromatic ring substituted nucleoside analogues for use as PRMT5 inhibitors

1. A compound of Formula (I)

wherein

R 1 represents hydrogen or —C(═O)—C 1-4 alkyl;

R 2 represents hydrogen or —C(═O)—C 1-4 alkyl;

Y represents —CH 2 — or —CF 2 —;

Z represents —CH 2 —, —X—CR 5a R 5b —, —CR 5c ═CR 5d —, —CR 5e R 5g —CR 5f R 5h —, —C≡C—, —O—, or —CR 5a R 5b —X—;

R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , and R 5h each independently represent hydrogen or C 1-4 alkyl;

X represents —O—, —S—, or —NR 11 —;

R 11 represents hydrogen, C 1-4 alkyl, or C 1-4 alkyl substituted with one substituent selected from the group consisting of —OH, —O—C 1-4 alkyl, R 12 , —NH 2 , —NH—C 1-4 alkyl, and —N(C 1-4 alkyl) 2 ;

R 12 represents a 4-, 5-, 6- or 7-membered heterocyclic ring containing one nitrogen atom and optionally one oxygen atom; said 4-, 5-, 6- or 7-membered heterocyclic ring being attached to the remainder of the molecule via the ring nitrogen atom;

Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,

wherein at least 1 ring carbon atom of ring B is replaced by a nitrogen atom;

wherein optionally 1 additional ring carbon atom of ring A or ring B is replaced by a nitrogen atom; provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;

Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, —OH, —NH 2 , —NH—C 1-4 alkyl, —N(C 1-4 alkyl) 2 , —NHR 10d , —NR 10c R 10d , cyano, —CF 3 , —C(═O)—NH 2 , —C(═O)—NH—C 1-4 alkyl, —C(═O)—C 1-4 alkyl, C 1-4 alkyloxy, —C(═O)—O—C 1-4 alkyl, C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, —NH—C 3-6 cycloalkyl, —N(C 3-6 cycloalkyl) 2 , C 2-6 alkenyl, C 1-4 alkyl substituted with one C 1-4 alkyloxy, and C 1-4 alkyl optionally substituted with one —NR 10a R 10b ;

R 10a and R 10b each independently represent hydrogen or C 1-4 alkyl;

R 10c and R 10d each independently represent C 3-6 cycloalkyl; R 13 ; R 14 ; C 3-6 cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C 1-4 alkyl; C 1-4 alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C 1-4 alkyl; or C 1-4 alkyl substituted with one substituent selected from the group consisting of C 3-6 cycloalkyl, R 13 and R 14 ;

R 13 represents a monocyclic aromatic ring selected from the group consisting of pyrrolyl, pyridinyl and furanyl; or a bicyclic fused aromatic ring selected from the group consisting of indolyl and quinolinyl;

said monocyclic aromatic ring or bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C 1-4 alkyl;

R 14 represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;

Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), and (a-4):

wherein R 3a , R 3c , and R 3d each independently represent hydrogen, halo, —NR 7a R 7b ,

C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, —OH, or —O—C 1-4 alkyl;

R 7a represents hydrogen;

R 7b represents hydrogen, C 3-6 cycloalkyl, or C 1-4 alkyl;

R 4a , R 4c , R 4d , R 4e and R 4f each independently represent hydrogen, halo,

—NR 8a R 8b , or C 1-4 alkyl;

R 8a and R 8b each independently represent hydrogen or C 1-4 alkyl;

Q 1 represents N or CR 6a ;

Q 2 represents N or CR 6b ;

Q 8 represents N or CR 6g ;

Q 9 represents N or CR 6h ;

Q 5 represents CR 3d ; Q 6 represents N; and Q 7 represents CR 4f ; or

Q 5 represents CR 3d ; Q 6 represents CR 4e ; and Q 7 represents N; or

Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents CR 4f ; or

Q 5 represents N; Q 6 represents CR 4e ; and Q 7 represents N; or

Q 5 represents N; Q 6 represents N; and Q 7 represents CR 4f ; or

Q 5 represents N; Q 6 represents N; and Q 7 represents N;

R 6a , R 6b , R 6e , R 6f , R 6g , and R 6h each independently represent hydrogen, halogen, C 1-4 alkyl, —NR 9a R 9b , or C 1-4 alkyl substituted with one, two or three halo atoms;

R 9a and R 9b each independently represent hydrogen or C 1-4 alkyl;

or a pharmaceutically acceptable addition salt thereof.

2. The compound according to claim 1 , wherein

Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, —OH, —NH 2 , —NH—C 1-4 alkyl, —N(C 1-4 alkyl) 2 , cyano, —CF 3 , —C(═O)—NH—C 1-4 alkyl, —C(═O)—C 1-4 alkyl, C 1-4 alkyloxy, and C 1-4 alkyl optionally substituted with one —NR 10a R 10b ;

Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2)

R 3a and R 3c each independently represent hydrogen, halo, —NR 7a R 7b , or —O—C 1-4 alkyl;

R 7b represents hydrogen or C 1-4 alkyl;

R 4a and R 4c each independently represent hydrogen, halo, —NR 8a R 8b , or C 1-4 alkyl;

Q 1 represents N or CR 6a ;

Q 2 represents N or CR 6b ;

R 6a , R 6b , R 6e and R 6f each independently represent hydrogen, halogen, C 1-4 alkyl, —NR 9a R 9b , or C 1-4 alkyl substituted with one, two or three halo atoms.

3. The compound according to claim 1 , wherein

R 1 represents hydrogen;

R 2 represents hydrogen;

Y represents —CH 2 —;

Z represents —X—CR 5a R 5b —, —CR 5e R 5g —CR 5f R 5h —, or —CR 5a R 5b —X—;

R 5a , R 5b , R 5e , R 5f , R 5g , and R 5h represent hydrogen;

X represents —O—;

Ar represents

wherein Ar is optionally substituted in the position indicated by α with a substituent selected from the group consisting of —NH 2 , —NH—C 1-4 alkyl, and —NHR 10d ; and

wherein Ar is optionally substituted in the position indicated by β with a substituent selected from the group consisting of halo and CF 3 ;

provided however that Ar is substituted in at least one of the positions indicated by α or β;

R 10d represents C 3-6 cycloalkyl; C 1-4 alkyl substituted with one, two or three halo substituents; or C 1-4 alkyl substituted with one C 3-6 cycloalkyl substituent;

Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-4);

R 3a and R 3d each independently represent hydrogen, halo, —NR 7a R 7b , C 1-4 alkyl, or —O—C 1-4 alkyl;

R 7a represents hydrogen;

R 7b represents hydrogen or C 1-4 alkyl;

R 4a , R 4d and R 4f each independently represent hydrogen or halo;

Q 1 represents CR 6a ;

Q 2 represents CR 6b ;

Q 8 represents CR 6g ;

Q 9 represents CR 6h ;

Q 5 represents CR 3d ; Q 6 represents N; and Q 7 represents CR 4f ;

R 6a , R 6b , R 6g , and R 6h represent hydrogen.

4. The compound according to claim 1 , wherein R 1 and R 2 represent hydrogen.

5. The compound according to claim 1 , wherein Het represents a bicyclic aromatic heterocyclic ring system of Formula (a-1).

6. The compound according to claim 5 , wherein

R 3a represents —NR 7a R 7b ; and R 7a and R 7b represent hydrogen.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to claim 1 .

8. The compound according to claim 1 , wherein

Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, —OH, —NH 2 , —NH—C 1-4 alkyl, —N(C 1-4 alkyl) 2 , —NHR 10d , —NR 10c R 10d , cyano, —CF 3 , —C(═O)—NH 2 , —C(═O)—NH—C 1-4 alkyl, —C(═O)—C 1-4 alkyl, C 1-4 alkyloxy, —C(═O)—O—C 1-4 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-4 alkyl substituted with one C 1-4 alkyloxy, and C 1-4 alkyl optionally substituted with one —NR 10a R 10b ;

R 10c and R 10d each independently represent C 3-6 cycloalkyl; C 3-6 cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C 1-4 alkyl; C 1-4 alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C 1-4 alkyl; or C 1-4 alkyl substituted with one substituent selected from the group consisting of C 3-6 cycloalkyl, R 13 and R 14 ;

Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2):

R 3a and R 3c each independently represent hydrogen, halo, —NR 7a R 7b , C 1-4 alkyl, or —O—C 1-4 alkyl;

R 7b represents hydrogen or C 1-4 alkyl;

R 4a and R 4c each independently represent hydrogen, halo, —NR 8a R 8b , or C 1-4 alkyl;

Q 1 represents N or CR 6a ;

Q 2 represents N or CR 6b ;

R 6a , R 6b , R 6e and R 6f each independently represent hydrogen, halogen,

C 1-4 alkyl, —NR 9a R 9b , or C 1-4 alkyl substituted with one, two or three halo atoms.

9. The compound according to claim 1 , wherein

R 1 represents hydrogen;

R 2 represents hydrogen;

Y represents —CH 2 —;

Z represents —X—CR 5a R 5b — or —CR 5e R 5g —CR 5f R 5h —;

R 5a , R 5b , R 5e , R 5f , R 5g , and R 5h represent hydrogen;

X represents —O—;

Ar represents

wherein Ar is optionally substituted in the position indicated by α with a substituent selected from the group consisting of —NH 2 , —NH—C 1-4 alkyl, and —NHR 10d ; and

wherein Ar is optionally substituted in the position indicated by β with a substituent selected from the group consisting of halo and CF 3 ;

provided however that Ar is substituted in at least one of the positions indicated by α or β;

R 10d represents C 3-6 cycloalkyl; C 1-4 alkyl substituted with one, two or three halo substituents; or C 1-4 alkyl substituted with one C 3-6 cycloalkyl substituent;

Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

R 3a represents hydrogen, halo, —NR 7a R 7b , C 1-4 alkyl, or —O—C 1-4 alkyl;

R 7a represents hydrogen;

R 7b represents hydrogen or C 1-4 alkyl;

R 4a represents hydrogen or halo;

Q 1 represents CR 6a ;

Q 2 represents CR 6b ;

R 6a and R 6b represent hydrogen.

10. The compound according to claim 1 , wherein

R 1 represents hydrogen;

R 2 represents hydrogen;

Y represents —CH 2 —;

Z represents —CR 5e R 5g —CR 5f R 5h —;

R 5e , R 5f , R 5g , and R 5h represent hydrogen;

Ar represents any one of the following 10-membered bicyclic aromatic ring systems:

Ar is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, —NH 2 , —NH—C 1-4 alkyl, —N(C 1-4 alkyl) 2 , —NHR 10d , —NR 10c R 10d ;

R 10c and R 10d each independently represent C 3-6 cycloalkyl; C 3-6 cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C 1-4 alkyl; C 1-4 alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C 1-4 alkyl; or C 1-4 alkyl substituted with one C 3-6 cycloalkyl substituent;

Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

R 1a represents hydrogen, —NR 7a R 7b , or —O—C 1-4 alkyl;

R 7a represents hydrogen;

R 7b represents hydrogen or C 1-4 alkyl;

R 4a represents hydrogen;

Q 1 represents CR 6a ;

Q 2 represents CR 6b ;

R 6a and R 6b represent hydrogen.

11. The compound according to claim 1 , wherein

Ar is selected from the group consisting of:

wherein each Ar is optionally substituted in position α with a substituent selected from the group consisting of —NH 2 , —NH—C 1-4 alkyl, —N(C 1-4 alkyl) 2 , —NHR 10d , and —NR 10c R 10d ;

and wherein Ar is optionally substituted in another position with a halo substituent.

12. The compound according to claim 1 , wherein

Y represents —CH 2 —; Z represents —X—CR 5a R 5b — or —CH 2 CH 2 —;

R 5a and R 5b represent hydrogen; X represents —O—;

R 11 represents hydrogen;

Ar represents

Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, —OH, —NH 2 , —NH—C 1-4 alkyl, —N(C 1-4 alkyl) 2 , cyano, and —CF 3 ;

Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1);

R 3a represents —NR 7a R 7b ;

R 7a represents hydrogen;

R 7b represents hydrogen;

R 4a represents hydrogen;

Q 1 represents CR 6a ; Q 2 represents CR 6b ; R 6a and R 6b represent hydrogen.

13. The compound according to claim 1 , wherein Ar represents

14. The compound according to claim 1 , wherein Y represents —CH 2 —.

15. The compound according to claim 14 wherein Z represents —CH 2 CH 2 —.

16. The compound according to claim 1 , wherein

R 5b , R 5g and R 5h represent hydrogen;

Y represents —CH 2 —;

Het represents (a-1);

Q 1 represents CH; and Q 2 represents CH.

17. The compound according to claim 1 , wherein the compound is

or a pharmaceutically acceptable addition salt thereof.

18. The compound according to claim 17 , wherein the compound is