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US 2020/0369707 A1Published application
Novel spirobicyclic analogues
AssigneeJanssen Pharmaceutica NV
InventorsJonas VERHOEVEN, Guido Alfons F. VERNIEST, Johannes Wilhelmus John F. THURING, Tongfei WU, Vineet PANDE, Lieven MEERPOEL, Dirk BREHMER, Weimei SUN, Scott E. DENMARK
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Abstract
The present invention relates to novel spirobicyclic analogues of Formula (I) wherein the variables have the meaning defined in the claims. The compounds according to the present invention are useful as PRMT5 inhibitors. The invention further relates to pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
Claims20
A compound of Formula (I)
- wherein
- R1 represents hydrogen or —C(═O)—C1-4alkyl;
- R2 represents hydrogen or —C(═O)—C1-4alkyl;
- X represents hydrogen;
- Y represents —O—, —CH2— or —CF2—;
- Q1 represents CR6a;
- Q2 represents N or CR6b;
- R6a and 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;
- R3a represents 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 represents hydrogen, halo, —NR8aR8b, or C1-4alkyl;
- L represents —CH2—, —O—CH2—, —CH2—O—, or —O—;
- R5 represents Ar or Het;
- and in case L represents —O— or —O—CH2—, R5 can also represent hydrogen;
- Ar represents phenyl optionally substituted with one or more halo substituents;
- Het represents a monocyclic or bicyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4), (a-5), (a-6) and (a-7):
- wherein said monocyclic or bicyclic aromatic ring system is optionally substituted with one or more substituents each independently selected from the group consisting of halo and —NH2;
- or a pharmaceutically acceptable addition salt or a solvate thereof.
17 more elements
(canceled)
An intermediate of Formula (XXX)
- wherein
- Y represents —O—, —CH2— or —CF2—;
- Ra represents hydrogen or a hydroxyl protecting group such as for example C1-4alkyl, t-butyldimethylsilyl, C1-4alkyl-O—C1-4alkyl, tetrahydropyranyl,
- allyl, t-butyldiphenylsilyl, benzyl, —C(═O)—C1-4alkyl, or —C(═O)-phenyl;
- Rb represents —OH, ═O, —CH2—OH, or ═CH2;
- wherein the bond towards Rb represents a single bond in case R represents —OH or —CH2—OH, or a double bond in case Rb represents ═O or ═CH2;
- Rc1 and Rc2 represent —C(═O)—C1-4alkyl, benzoyl optionally substituted with one or two substituents each independently selected from —CH3 and —OCH3, benzyl optionally substituted with one or two substituents each independently selected from —CH3 and —OCH3, or —CH2-napthyl optionally substituted with one or two substituents each independently selected from —CH3 and —OCH3;
- or Rc1 and Rc2 taken together represent —C(C1-4alkyl)2-;
- or a pharmaceutically acceptable addition salt or a solvate thereof.
6 more elements
Dependencies are inferred from the claim text.