Monocyclic and bicyclic ring system substituted carbanucleoside analogues for use as PRMT5 inhibitors

A method of inhibiting PRMT5 comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I):

• wherein
• R1 represents hydrogen or —C(═O)—C1-4alkyl;
• R2 represents hydrogen or —C(═O)—C1-4alkyl;
• Y represents —CH2— or —CF2—;
• Z represents —CH2—, —CHR5i—, —X—CR5aR5b—, —CR5c═CR5d—, —CR5eR5g—CR5fR5h—, —CR5aR5b—X—, —C≡C—, —CR5cR5d—CR5eR5g—CR5fR5h—, or
• —CR5aR5b—CR5cR5d—CR5eR5g—CR5fR5h—,
• R5a, R5b, R5c, R5d, R5e, R5f, R5g, R5h, and R5i each independently represent hydrogen or C1-4alkyl;
• X represents —O—, or —NR11—;
• R11 represents hydrogen, C1-4alkyl, or C1-4alkyl substituted with one substituent selected from the group consisting of —OH, —O—C1-4alkyl, —NH2, —NH—C1-4alkyl, and N(C1-4alkyl)2;
• Ar represents a monocyclic aromatic ring or a bicyclic ring system;
• wherein the monocyclic aromatic ring is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazolyl, and imidazolyl;
• wherein the bicyclic ring system is
• (i) a 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused with a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S, and N,
• said 9-membered bicyclic aromatic ring being attached to the remainder of the molecule via a ring carbon atom of the 5- or 6-membered ring, or a ring nitrogen atom of the 5-membered ring;
• or
• (ii) a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are 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;
• provided that in case Ar represents a 10-membered bicyclic aromatic ring system, Z can only represent —CR5cR5d—CR5eR5g—CR5iR5h— or CR5aR5b—CR5cR5d—CR5eR5g—CR5fR5h—;
• or
• (iii) a fused bicyclic partially aromatic ring system which is attached with the aromatic ring to linker Z, wherein the fused bicyclic partially aromatic ring system is selected from (b-1), (b-2) and (b-3)
• wherein ring A is a monocyclic aromatic ring is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazolyl and imidazolyl;
• wherein ring B is a C5-6cycloalkyl or a 5- to 6-membered saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S and N;
• Ar is optionally substituted on the carbon atoms with in total one, two, three or four substituents each independently selected from the group consisting of halo, oxo, —OH, —NH2, —NH—C1-4alkyl, —NHR10, cyano, —CF3, C1-4alkyloxy, C3-6cycloalkyl, —O—C3-6cycloalkyl, C2-6alkenyl, C1-4alkyl, and
• C1-4alkyl substituted with one C1-4alkyloxy;
• and
• where possible Ar is optionally substituted on one N-atom with one substituent selected from the group consisting of C1-4alkyl;
• C3-6cycloalkyl;
• C1-4alkyl substituted with one, two or three halo atoms;
• and C3-6cycloalkyl substituted with one, two or three halo atoms;
• R10 represents —(C═O)—C1-4alkyl;
• 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;
• said 4- to 7-membered monocyclic 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 that is (a-1):
• R3a 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 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;
• R6a, R6b 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 C1-4alkyl;
• or a pharmaceutically acceptable addition salt or a solvate thereof.