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

A compound of Formula (I)

• wherein
• R1 represents hydrogen or —C(═O)—C1-4alkyl;
• R2 represents hydrogen or —C(═O)—C1-4alkyl;
• Y represents —O—, —CH2— or —CF2—;
• Z represents —CH2—, —X—CR5aR5b—, —CR5c═CR5d—, —CR5eR5g—CR5fR5h—, or —C≡C—;
• and when Y represents —CH2— or —CF2—, then Z can also represent —O— or —CR5aR5b—X;
• R5aR5b, R5c, R5d, R5e, R5f, R5g, and R5h each independently represent hydrogen or C1-4alkyl;
• X represents —O—, —S—, or —NR11—;
• R11 represents hydrogen, C1-4alkyl, or C1-4alkyl substituted with one substituent selected from the group consisting of —OH, —O—C1-4alkyl, R12, —NH2, —NH—C1-4alkyl, and —N(C1-4alkyl)2;
• R12 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 a 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 a 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, —NH2, —NH—C1-4alkyl, —N(C1-4alkyl)2, —NHR10d, —NR10cR10d, cyano, —CF3, —C(═O)—NH2, —C(═O)—NH—C1-4alkyl, —C(═O)—C1-4alkyl, C1-4alkyloxy, —C(═O)—O—C1-4alkyl, C3-6cycloalkyl, —O—C3-6cycloalkyl, —NH—C3-6cycloalkyl, —N(C3-6cycloalkyl)2, C2-6alkenyl, C1-4alkyl substituted with one C1-4alkyloxy, and C1-4alkyl optionally substituted with one —NR10aR10b;
• R10a and R10b each independently represent hydrogen or C1-4alkyl;
• R10c and R10d each independently represent C3-6cycloalkyl;
• R13;
• R14;
• C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C1-4alkyl;
• C1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C1-4alkyl;
• or C1-4alkyl substituted with one substituent selected from the group consisting of C3-6cycloalkyl, R13 and R14;
• R13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(═O)p and N;
• or a 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(═O)p and N;
• said 4- to 7-membered monocyclic aromatic ring or 6- to 11-membered bicyclic fused aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C1-4alkyl;
• p represents 1 or 2;
• R14 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), (a-3), (a-4) and (a-5):
• R3a, R3b, R3c, R3d and R3e each independently represent hydrogen, halo, —NR7aR7b, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, —OH, or —O—C1-4alkyl;
• R7a represents hydrogen;
• R7b represents hydrogen, C3-6Cycloalkyl, or C1-4alkyl;
• R4a, R4b, R4c, R4d, R4e, R4f and R4g each independently represent hydrogen, halo, —NR8aR8b, or C1-4alkyl;
• R8a and R8b each independently represent hydrogen or C1-4alkyl;
• Q1 represents N or CR6a;
• Q2 represents N or CR6b;
• Q3 represents N or CR6c;
• Q4 represents N or CR6d;
• provided that maximum one of Q3 and Q4 represents N;
• Q8 represents N or CR6g;
• Q9 represents N or CR6h;
• Q10 represents N or CR6i;
• Q11 represents N or CR6j;
• Q5 represents CR3d;
• Q6 represents N;
• and Q7 represents CR4f;
• or
• Q5 represents CR3d;
• Q6 represents CR4e;
• and Q7 represents N;
• or
• Q5 represents N;
• Q6 represents CR4e;
• and Q7 represents CR4f;
• or
• Q5 represents N;
• Q6 represents CR4e;
• and Q7 represents N;
• or
• Q5 represents N;
• Q6 represents N;
• and Q7 represents CR4f;
• or
• Q5 represents N;
• Q6 represents N;
• and Q7 represents N;
• R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, R6i and R6j each independently represent hydrogen, halogen, C1-4alkyl, —NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms;
• R9a and R9b each independently represent hydrogen or C1s-4alkyl;
• or a pharmaceutically acceptable addition salt or a solvate thereof.