PRMT5 inhibitors for treating adenomas

Abstract

The present invention relates to novel protein arginine methyltransferase 5 (PRMT5) inhibitor compounds and methods for treating adenomatous polyposis coli (APC) loss-of-function driven adenoma diseases in a human in need thereof.

Description

PRD4277WOPCT1 METHODS FOR TREATING ADENOMAS USING PRMT5 INHIBITORS FIELD OF THE INVENTION

[0001] The present invention relates to novel protein arginine methyltransferase 5 (PRMT5) inhibitor compounds and methods for treating adenomatous polyposis coli (APC) loss-of-function driven adenoma diseases in a human in need thereof. BACKGROUND OF THE INVENTION

[0002] Protein arginine methyltransferase 5 (PRMT5) is an enzyme that symmetrically di-methylates arginine residues on both histone- and non-histone proteins in the nucleus and cytoplasm, respectively, using S-adenosyl methionine (SAM) as the methyl donating cofactor. PRMT5 arginine methylation is implicated in the regulation of multiple cellular processes such as cell growth, transcription, cell differentiation, RNA splicing and signal transduction. PRMT5 co-exists as a binary complex with MEP50 (Methylsome protein 50). Both elevated PRMT5-MEP50 protein level and cytoplasmic accumulation are implicated in cancer tumorigenesis and have recently been correlated with poor clinical outcome. Notably, PRMT5 is often upregulated and implicated in tumorigenesis in various cancers including colorectal cancer.

[0003] Familial adenomatous polyposis (FAP) is an inherited condition caused by a mutation in the adenomatous polyposis coli (APC) tumor suppressor gene that causes a loss-of-function. Most people with FAP inherit an APC loss-of-function mutation from a parent. Additionally, 25 to 30 percent of adenoma diseases are attributed to spontaneous APC loss-of-function mutation.

[0004] The acquisition of biallelelic mutations in the APC gene is a rate-limiting step in the development of most colorectal cancers and occurs in the earliest lesions. The APC gene encodes a 312-kDa protein that localizes to multiple subcellular compartments and performs diverse functions. Notably, APC participates in a cytoplasmic complex that promotes the destruction of the transcriptional licensing factor beta-catenin. APC mutations that abolish this function trigger constitutive activation of the canonical WNT signaling pathway, a characteristic found in almost all colorectal cancers. By negatively regulating canonical WNT signaling, APC counteracts proliferation, promotes differentiation, facilitates apoptosis and suppresses invasion and tumor progression. APC further antagonizes canonical WNT signaling by interacting with and counteracting 1PRD4277WOPCT1 beta-catenin in the nucleus. Additionally, APC suppresses tumor initiation and progression in the colorectal epithelium through functions that are independent of canonical WNT signaling. For example, APC regulates the mitotic spindle to facilitate proper chromosome segregation, localizes to the cell periphery and cell protrusions to establish cell polarity and appropriate directional migration, and inhibits DNA replication by interacting directly with DNA.

[0005] FAP causes extra tissue (polyps) to form generally in the large intestine (colon) and rectum but can also form in the upper gastrointestinal tract, gastric fundus, duodenum, periampullary region, thyroid gland, central nervous system, adrenal glands, liver, skin, bone or connective tissue. About 70% of all polyps are adenomatous and if untreated, can become cancerous. Likewise, attenuated familial adenomatous polyposis (AFAP) is a milder form of FAP in which generally fewer colon polyps are present and cancer develops at a later timepoint than FAP.

[0006] Colons are the most common organs that are affected by adenomatous polyps. Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer death globally. The adenoma-carcinoma sequence describes a four-step progression of gene alterations in colonic epithelium which starts with initial genetic changes in an early adenoma that accumulate as it transforms to in situ carcinoma and ultimately to invasive and metastatic tumor.

[0007] In short, there is a need for improved methods for treating APC loss-of-function driven adenoma diseases including colorectal cancer, FAP and AFAP. SUMMARY OF THE INVENTION

[0008] The present invention provides methods of treating or preventing adenomatous polyposis coli (APC) loss-of-function driven adenoma disease in a subject in need thereof comprising administering a therapeutically effective amount of a protein arginine methyltransferase 5 (PRMT5) inhibitor or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer, and a diastereomer thereof disclosed herein.

[0009] In some embodiments, the subject suffering from adenomatous polyposis coli (APC) loss-of-function driven adenoma disease has at least one of the following: (i) at least one APC loss-of-function mutation, (ii) an APC truncated protein, 2PRD4277WOPCT1 (iii) a diagnosis of familial adenomatous polyposis or attenuated familial adenomatous polyposis, (iv) an adenomatous polyp, or (v) identified at least one parent as having a diagnosis of familial adenomatous polyposis or attenuated familial adenomatous polyposis.

[0010] In one embodiment, the subject does not have a mutation in TP53 gene that leads to loss of function of p53 protein.

[0011] In one embodiment, the subject does not have a mutation in KRAS gene that leads to constitutive activation of KRAS protein.

[0012] In one embodiment, the subject has identified at least one parent as having a diagnosis of familial adenomatous polyposis or attenuated familial adenomatous polyposis and wherein the parent has (i) at least one APC loss-of-function mutation, (ii) an APC truncated protein, (iii) an adenomatous polyp, or (iv) a diagnosis of familial adenomatous polyposis or attenuated familial adenomatous polyposis.

[0013] In one embodiment, the subject has an adenomatous polyp present in at least one of the following: colon, rectum, gastric fundus, duodenum, periampullary, thyroid gland, central nervous system, adrenal glands, liver, skin, bone or connective tissue. In one embodiment, the subject has an adenomatous polyp present in the colon or rectum.

[0014] In one embodiment, the APC loss-of-function driven adenoma disease is an adenocarcinoma. In one embodiment, the adenocarcinoma is colorectal cancer. In one embodiment, the adenocarcinoma is present in at least one of the following: colon, rectum, or duodenum.

[0015] In some embodiments, a method of treating or preventing colorectal cancer (CRC) in a subject in need thereof comprising administering a therapeutically effective amount of a protein arginine methyltransferase 5 (PRMT5) inhibitor or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer, and a diastereomer thereof disclosed herein.

[0016] In one embodiment, the methods further include administering a therapeutically effective amount of at least one other therapeutic agent. In one embodiment, at least one other therapeutic agent is sulindac, erlotinib, sorafenib, regorafenib, bortezomib, gefitinib, imatinib, vemurafenib, or vismodegib.

[0017] In one embodiment, the PRMT5 inhibitor is a compound of Formula (A): 3PRD4277WOPCT1wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents 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-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5heach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents 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; R12represents 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 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; 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; R10aand R10beach independently represent hydrogen or C1-4alkyl; 4PRD4277WOPCT1 R10cand R10deach 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, R13and R14; R13represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O)pand 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; R14represents 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, R3dand R3eeach independently represent hydrogen, halo, -NR7aR7b, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, –OH, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; R4a, R4b, R4c, R4d, R4e, R4fand R4geach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; 5PRD4277WOPCT1 R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents N or CR6a; Q2represents N or CR6b; Q3represents N or CR6c; Q4represents N or CR6d; provided that maximum one of Q3and Q4represents N; Q8represents N or CR6g; Q9represents N or CR6h; Q10represents N or CR6i; Q11represents N or CR6j; Q5represents CR3d; Q6represents N; and Q7represents CR4f; or Q5represents CR3d; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents CR4e; and Q7represents CR4f; or Q5represents N; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents N; and Q7represents CR4f; or Q5represents N; Q6represents N; and Q7represents N; R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, R6iand R6jeach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0018] In one embodiment, the PRMT5 inhibitor is: Compound 2:, Compound 3:, 6PRD4277WOPCT1 Compound 4:, Compound 5:, Compound 6:, Compound 7:, Compound 9:, Compound 11:, 7PRD4277WOPCT1 Compound 12:, Compound 13:, Compound 14:, Compound 15:, Compound 16:, 8PRD4277WOPCT1 Compound 17:, Compound 18:, Compound 19:, Compound 20:, 9PRD4277WOPCT1, Compound 24:, Compound 25:, 10PRD4277WOPCT1 Compound 26:, Compound 28:, Compound 29:, Compound 30:, Compound 31:, 11PRD4277WOPCT1 Compound 32:, Compound 33:, Compound 34:, Compound 35:, Compound 36:, 12PRD4277WOPCT1 Compound 37:, Compound 38:, Compound 40:, Compound 41:, Compound 46:, 13PRD4277WOPCT1 Compound 47:, Compound 48:, Compound 49:, or Compound 50:or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0019] In one embodiment, the PRMT5 inhibitor is Compound 40: 14PRD4277WOPCT1or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0020] In one embodiment, the PRMT5 inhibitor is a compound of Formula (B): (I)(B), wherein R1represents hydrogen or CH3; R2represents hydrogen; Rarepresents hydrogen or –C(=O)-C1-4alkyl; Rbrepresents hydrogen or –C(=O)-C1-4alkyl; Y represents –O-, –CH2– or –CF2–; R7arepresents hydrogen; R7brepresents hydrogen, or C1-4alkyl optionally substituted with one or more halo atoms; X1represents a covalent bond or –O-; X2represents a covalent bond, -CH2-,-CF2-, -CH2CH2-, -CF2CH2-, or -CH2CF2-; provided that X2represents a covalent bond, -CH2- or -CF2-, when X1represents –O-; X3represents N or CH; or in case one of the dotted lines represents an additional bond, X3represents C; R8and R10each independently are selected from the group consisting of hydrogen; halo; and C1-6alkyl optionally substituted with one or more halo atoms; 15PRD4277WOPCT1 R9and R11each independently are selected from the group consisting of hydrogen; halo; -NH2; and C1-6alkyl optionally substituted with one –NR9aR9b; or R8and R9are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1a; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR5aR5b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1a, -O-Ar1a, Het2aand –O-Het2c; or R10and R11are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1b; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR6aR6b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1b, -O-Ar1b, Het2band –O-Het2d; Z represents -CH2-, -C(=O)-, or –CH(C1-4alkyl)-; and in case X3represents C, Z can also represent =CH-; the dotted lines attached to X3are optional bonds that may be present when X3represents a carbon atom, provided that maximum one of the dotted lines represents an optional bond; in case one of the dotted lines attached to X3represents an additional bond, X3represents C, and (i) R7ais absent or (ii) R8is absent or (iii) Z represents =CH-; R9aand R9beach independently are selected from the group consisting of hydrogen and C1-4alkyl; or R9aand R9bare linked together to form together with the common nitrogen 16PRD4277WOPCT1 atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl which optionally contains one oxygen atom; R5aand R5beach independently are selected from the group consisting of hydrogen and C1-4alkyl; Het1aand Het1bare attached to the remainder of the molecule of Formula (B) through any available ring carbon atom; Het1aand Het1beach independently represent a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two heteroatoms each independently selected from O, S, S(=O)p and N; Ar1aand Ar1beach independently represent phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo; cyano; and C1-4alkyl optionally substituted with one or more halo atoms; Het2aand Het2beach independently represent a 4-, 5-, 6- or 7-membered monocyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)pand N; or a fused 8-, 9-, 10- or 11-membered bicyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)pand N; said monocyclic heterocyclyl or said fused bicyclic heterocyclyl optionally being substituted with one or more substituents each independently selected from the group consisting of halo, cyano, and C1-4alkyl optionally substituted with one or more halo atoms; Het2cand Het2dare attached to the remainder of the molecule of Formula (B) through any available ring carbon atom; Het2cand Het2deach independently represent a 4-, 5-, 6- or 7-membered monocyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)p and N; or a fused 8-, 9-, 10- or 11-membered bicyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)pand N; said monocyclic heterocyclyl or said fused bicyclic heterocyclyl optionally being substituted with one or more substituents each independently selected from the group consisting of halo, cyano, and C1-4alkyl optionally substituted with one or more halo atoms; R6aand R6beach independently are selected from the group consisting of hydrogen and C1-4alkyl; p represents 1 or 2; 17PRD4277WOPCT1 Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3) and (a-4):R3a, R3b, R3cand R3deach independently are selected from the group consisting of hydrogen, halo, -NR12aR12b, C1-4alkyl, and –O-C1-4alkyl; R12aand R12beach independently are selected from the group consisting of hydrogen; C3-6cycloalkyl; C1- 4alkyl; and C1-4alkyl substituted with one phenyl which is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, –OC1-4alkyl, -OH, and C1-4alkyl optionally substituted with one or more halo atoms; R4a, R4b, R4c, R4d, R4eand R4feach independently are selected from the group consisting of hydrogen, halo, -NR13aR13b, and C1-4alkyl; R13aand R13beach independently are selected from the group consisting of hydrogen and C1-4alkyl; Q1represents N or CR14a; Q2represents N or CR14b; Q3represents N or CR14c; Q4represents N or CR14d; provided that maximum one of Q3and Q4represents N; Q8represents N or CR14g; Q9represents N or CR14h; Q5represents CR3d; Q6represents N; and Q7represents CR4f; or Q5represents CR3d; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents CR4e; and Q7represents CR4f; or Q5represents N; Q6represents CR4e; and Q7represents N; or 18PRD4277WOPCT1 Q5represents N; Q6represents N; and Q7represents CR4f; or Q5represents N; Q6represents N; and Q7represents N; R14a, R14b, R14c, R14d, R14e, R14f, R14g, and R14h, each independently are selected from the group consisting of hydrogen; halogen; C1-4alkyl; –NR15aR15b; and C1-4alkyl substituted with one or more halo atoms; R15aand R15beach independently are selected from the group consisting of hydrogen and C1-4alkyl; provided that R10and R11may not be linked together when R8and R9are linked together; and wherein at least one of R8, R9, R10and R11contains a nitrogen atom; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0021] In one embodiment, the PRMT5 inhibitor is: Compound 42:,; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0022] In one embodiment, the PRMT5 inhibitor is a compound of Formula (C): 19PRD4277WOPCT1 (I)(C), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents 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 R5ieach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents 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 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 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-CR5fR5h- or -CR5aR5b-CR5cR5d-CR5eR5g-CR5fR5h-; or 20PRD4277WOPCT1 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)(b-1) (b-2) (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; R10represents -(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, R13and R14; R13represents 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; R14represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; 21PRD4277WOPCT1 Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3):R3a, R3dand R3eeach independently represent hydrogen, halo, -NR7aR7b, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, –OH, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; R4a, R4d, R4e, R4fand R4geach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents N or CR6a; Q2represents N or CR6b; Q8represents N or CR6g; Q9represents N or CR6h; Q10represents N or CR6i; Q11represents N or CR6j; Q5represents CR3d; Q6represents N; and Q7represents CR4f; or Q5represents CR3d; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents CR4e; and Q7represents CR4f; or Q5represents N; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents N; and Q7represents CR4f; or Q5represents N; Q6represents N; and Q7represents N; R6a, R6b, R6g, R6h, R6iand R6jeach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0023] In one embodiment, the PRMT5 inhibitor is: 22PRD4277WOPCT1 Compound 8:, Compound 27:, or Compound 39:; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0024] In one embodiment, the PRMT5 inhibitor is a compound of Formula (D):wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; X represents hydrogen; Y represents –O-, –CH2– or –CF2–; 23PRD4277WOPCT1 Q1represents CR6a; Q2represents N or CR6b; R6aand R6beach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; R3arepresents hydrogen, halo, -NR7aR7b, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, –OH, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; R4arepresents hydrogen, halo, -NR8aR8b, or C1-4alkyl; L represents -CH2-, -O-CH2-, -CH2-O-, or -O-; R5represents Ar or Het; and in case L represents -O- or -O-CH2-, R5can 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.

[0025] In one embodiment, the PRMT5 inhibitor is Compound 1:24PRD4277WOPCT1 Compound 10:or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0026] In one embodiment, the PRMT5 inhibitor is selected from any one of Compounds 51 to 71 as described herein (see experimental part; including subnumbers such as Compound 68b), or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0027] In one embodiment, the PRMT5 inhibitor is any of the Compounds described herein, or a pharmaceutically acceptable addition salt, or a solvate thereof. In one embodiment, the PRMT5 inhibitor is any of the Compounds described herein. In one embodiment, the PRMT5 inhibitor is any of the exemplified Compounds, or a pharmaceutically acceptable addition salt, or a solvate thereof. In one embodiment, the PRMT5 inhibitor is any of the exemplified Compounds.

[0028] The present invention also relates to novel and inventive Compounds selected from Compounds 51 to 71 as described herein (see experimental part), and pharmaceutically acceptable addition salts, and solvates thereof.

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0030] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. 25PRD4277WOPCT1 BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 shows viability in wild-type (WT) and APC loss-of-function (APCLOF) colorectal stem cell-derived organoids following 7 days of treatment with a PRMT5 inhibitor at different doses, namely, Compound 40 (Figure 1A) or Compound 41 (Figure 1B). Notably, viability reflects values normalized to DMSO.

[0032] Figure 2 shows viability in wild-type, APCLOF, and progression organoid models having APCLOFin addition to KRAS mutation (KRASMUT), p53 loss-of function mutation (p53LOF) or both KRASMUT / p53LOFfollowing 7 days of treatment with a PRMT5 inhibitor at different doses, namely Compound 40 (Figure 2A) or Compound 41 (Figure 2B). Curves represent an average of n=2 biological replicates. Notably, viability reflects values normalized to DMSO.

[0033] Figure 3 reflects results from Study A obtained in an Apcmin / + / DSS mouse model following treatment with either vehicle (20% 2-hydroxypropyl-beta-cyclodextrin (HP-CD)) or 10 mg / kg PRMT5 inhibitor Compound 40. Figure 3A shows the total number of macroscopic colonic polyp identified per colon following treatment with vehicle or Compound 40. Figure 3B shows the percentage of tumor area in the total colon area following treatment with vehicle or Compound 40. Figure 3C shows the percentage of body weight change in mice following treatment with vehicle or Compound 40.

[0034] Figure 4 reflects results from Study B obtained in an Apcmin / + / DSS mouse model following treatment with either vehicle (20% HP-CD), 5 mg / kg or 10 mg / kg PRMT5 inhibitor Compound 40. Figure 4A shows exemplary colon samples that were used to enumerate the baseline number of macroscopic colonic polyp identified per colon at week 3 post-DSS treatment. Figure 4B shows the baseline number of macroscopic colonic polyp identified per colon at week 3 post-DSS treatment. Figure 4C shows the number of macroscopic colonic polyp identified per colon at the 3-week endpoint following treatment with vehicle or Compound 40. Figure 4D shows the total tumor area of colon detected at the 3 week endpoint following treatment with vehicle or Compound 40. Figure 4E shows the percentage of body weight change in mice following treatment with vehicle or Compound 40. 26PRD4277WOPCT1 DETAILED DESCRIPTION OF THE INVENTION

[0035] As used herein, the terms "including", "containing" and “comprising” are used in their open, non-limiting sense.

[0036] The term “about” as used herein when immediately preceding a numerical value means a range of plus or minus 10% of that value, for example, “about 50” means 45 to 55, “about 25,000” means 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation.

[0037] The term “administer” or “administered” or “administering” refers to the administration of PRMT5 inhibitor or a pharmaceutical composition thereof to a subject by any method known to those skilled in the art in view of the present disclosure, such as by intramuscular, subcutaneous, oral, intravenous, cutaneous, intramucosal (e.g., gut), intranasal or intraperitoneal route of administration. In particular aspects, a pharmaceutical composition of the invention is administered to a subject orally.

[0038] The terms “adenomatous polyp” and “adenoma” as used herein, are used interchangeably and describe a growth of tissue (polyp) that consists of benign neoplastic tissue derived from epithelium of glandular origin, glandular characteristics, or both. Notably, adenoma cells do not necessarily need to be part of a gland but may possess secretory properties. Further, adenomas carry the potential to become malignant.

[0039] The term “adenocarcinoma” as used herein, refers to a malignant adenoma. The phrase “wild-type function” with respect to a particular protein refers to the protein activity that would be expected by such protein produced by a gene having a wild-type sequence.

[0040] The phrase “loss-of-function” refers to the lack of one or more functions of a particular protein that would be expected from such protein having an amino acid sequence that is produced by the wild-type gene. For example, the phrase “APC loss-of- function (APCLOF)” refers to an APC protein that lacks one or more functions of an APC protein having an amino acid sequence that is produced by the wild-type APC gene. Likewise, the phrase “p53 loss-of-function (p53LOF)” refers to a p53 protein that lacks one or more functions of a p53 protein having an amino acid sequence that is produced by the wild-type p53 gene.

[0041] The phrase “APC loss-of-function driven adenoma disease” as used herein, refers to any condition that includes formation of adenomatous polyps by cells having an APC loss-of-function mutation. 27PRD4277WOPCT1

[0042] The term “patient” or “subject” is used interchangeably, and refers to an animal, preferably a mammal (e.g., human, cat, dog, primate) who is or has been the object of treatment, observation or experiment. The term “mammal” as used herein, encompasses any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) such as monkeys or apes, humans, etc., more particularly a human.

[0043] The term “parent” as used herein, means an individual that is a genetic source of the patient’s genotype.

[0044] The phrase “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a patient that is being sought by a researcher, veterinarian, medicinal doctor or other clinician, which includes alleviation or reversal of the symptoms of the disease or disorder being treated.

[0045] The term “treatment”, as used herein, is intended to refer to all processes wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms.

[0046] As used herein, the term “PRMT5 inhibitor” refers to a compound that results in a reduction in the enzymatic activity of protein arginine methyltransferase 5 (PRMT5).

[0047] In one embodiment, PRMT5 is isoform A having the amino acid sequence as shown in GenBank Accession No. NP006100.

[0048] In one embodiment, the PRMT5 is isoform B having the amino acid sequence as shown in GenBank Accession No. NP001034708.

[0049] PRMT5 inhibitors include, but are not limited to, compounds of Formula (A), Formula (B), Formula (C), Formula (D), Formula (V), Formula (W), Formula (X), Formula (Y), Formula (Z), GSK-3326595, PF-06939999, PRT543, PRT811, LLY283, CT300, CT-x034, or Compounds 51 to 71. For ease of reference, the chemical structure of GSK-332695, PF-06939999, and LLY283 is reproduced below:28PRD4277WOPCT1.

[0050] When describing PRMT5 inhibitors of Formula (A), Formula (B), Formula (C), or Formula (D), or Compounds 51 to 71, used in methods of the present invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise.

[0051] When any variable occurs more than one time in any constituent or in any formula, its definition in each occurrence is independent of its definition at every other occurrence.

[0052] Whenever the term “substituted” is used with regard to PRMT5 inhibitors or Compounds, it is meant, unless otherwise is indicated or is clear from the context, to indicate that one or more hydrogens, in particular from 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using “substituted” are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e., a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.

[0053] When two or more substituents are present on a moiety they may, unless otherwise is indicated or is clear from the context, replace hydrogens on the same atom or they may replace hydrogen atoms on different atoms in the moiety. 29PRD4277WOPCT1

[0054] The prefix “C-y” (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, a C1-4alkyl group contains from 1 to 4 carbon atoms, a C1-3alkyl group contains from 1 to 3 carbon atoms and so on.

[0055] The term “halo” as a group or part of a group is generic for fluoro, chloro, bromo, iodo unless otherwise is indicated or is clear from the context.

[0056] The term "C1-4alkyl" as a group or part of a group refers to a hydrocarbyl radical of Formula CnH2n+1wherein n is a number ranging from 1 to 4. C1-4alkyl groups comprise from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. C1-4alkyl groups may be linear or branched and may be substituted as indicated herein. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. C1-4alkyl includes all linear, or branched alkyl groups with between 1 and 4 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, 2-methyl-ethyl, butyl and its isomers (e.g., n- butyl, isobutyl and tert-butyl), and the like.

[0057] The skilled person will realize that the term “C1-4alkoxy” or “C1-4alkyloxy” as a group or part of a group refers to a radical having the Formula –ORcwherein Rcis C1-4alkyl. Non-limiting examples of suitable C1-4alkyloxy include methyloxy (also methoxy), ethyloxy (also ethoxy), propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec- butyloxy and tert-butyloxy.

[0058] The term “C2-4alkenyl” as used herein as a group or part of a group represents a straight or branched chain hydrocarbon group containing from 2 to 4 carbon atoms and containing a carbon-carbon double bond such as, but not limited to, ethenyl, propenyl, butenyl, 1-propen-2-yl, and the like.

[0059] The term “C2-6alkenyl” as used herein as a group or part of a group represents a straight or branched chain hydrocarbon group containing from 2 to 6 carbon atoms and containing a carbon-carbon double bond such as, but not limited to, ethenyl, propenyl, butenyl, pentenyl, 1-propen-2-yl, hexenyl and the like.

[0060] The term “C3-6cycloalkyl” as used herein as a group or part of a group represents cyclic saturated hydrocarbon radicals having from 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0061] Some of the PRMT5 inhibitory compounds described herein may also exist in their tautomeric form. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For 30PRD4277WOPCT1 example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerisations. Valence tautomers include interconversions by reorganisation of some of the bonding electrons. Such forms in so far as they may exist, although not explicitly indicated in the any of the formulas detailed herein, are intended to be included within the scope of the compounds of the Formulas described herein.

[0062] As used herein, any chemical formula with bonds shown only as solid lines and not as solid wedged or hashed wedged bonds, or otherwise indicated as having a particular configuration (e.g., R, S) around one or more atoms, contemplates each possible stereoisomer, or mixture of two or more stereoisomers. Where the stereochemistry of any particular chiral atom is not specified in the structures shown herein, then all stereoisomers are contemplated and included as the compounds of the Formula specified, either as a pure stereoisomer or as a mixture of two or more stereoisomers.

[0063] The phrase “compound(s) of Formula” as used herein with respect to compounds of PRMT5 inhibitors defined by the structural formulas described herein (e.g., Formula (A), Formula (B), Formula (C) and Formula D), is meant to include the stereoisomers thereof (including enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible) and the tautomeric forms thereof. However where stereochemistry, is specified by bonds which are shown as solid wedged or hashed wedged bonds, or are otherwise indicated as having a particular configuration (e.g., R, S), then that stereoisomer is so specified and defined. It follows that a single compound may, where possible, exist in both stereoisomeric and tautomeric form. Additionally, an amorphous form, hydrates, solvates, polymorphs and pseudopolymorphs of such compounds of this invention, and mixtures thereof, are also envisaged as parts of this invention.

[0064] The skilled person will understand that in some embodiments, the term “PRMT5 inhibitor” might also refer to a pharmaceutically acceptable salt, solvate, polymorph, enantiomer, or a diastereomer thereof, even if not explicitly referred to.

[0065] The terms “stereoisomers”, “stereoisomeric forms” or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably.

[0066] Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture. 31PRD4277WOPCT1

[0067] Atropisomers (or atropoisomers) are stereoisomers which have a particular spatial configuration, resulting from a restricted rotation about a single bond, due to large steric hindrance.

[0068] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e., they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration. Substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration; for example if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration.

[0069] The meaning of all those terms, i.e., enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person.

[0070] The absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is specified by either R or S. Resolved stereoisomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. For instance, resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.

[0071] When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e., associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other stereoisomers. Thus, when a compound is for instance specified as (R), this means that the compound is substantially free of the (S) isomer; when a compound is for instance specified as E, this means that the compound is substantially free of the Z isomer; when a compound is for instance specified as cis, this means that the compound is substantially free of the trans isomer.

[0072] For therapeutic use, salts of the compounds and solvates thereof, are those wherein the counterion is pharmaceutically acceptable.

[0073] Pharmaceutically-acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g., in vacuo, by freeze- 32PRD4277WOPCT1 drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.

[0074] The pharmaceutically acceptable addition salts as mentioned hereinabove or hereinafter are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds described herein and solvates thereof, are able to form.

[0075] Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e., ethanedioic), malonic, succinic (i.e., butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p- toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

[0076] The compounds and solvates thereof containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.

[0077] Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g., the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g., primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.

[0078] The term solvate comprises the hydrates and solvent addition forms which the PRMT5 inhibitory compounds are able to form, as well as pharmaceutically acceptable addition salts thereof. Examples of such forms are e.g., hydrates, alcoholates and the like. 33PRD4277WOPCT1

[0079] The PRMT5 inhibitory compounds may be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, that can be separated from one another following art-known resolution procedures. A manner of separating the enantiomeric forms of the PRMT5 inhibitory compounds, and pharmaceutically acceptable addition salts, and solvates thereof, involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

[0080] The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature).

[0081] All isotopes and isotopic mixtures of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as2H,3H,11C,13C,14C ,13N,15O,17O,18O,32P,33P,35S,18F,36Cl,122I,123I,125I,131I,75Br,76Br,77Br and82Br. Preferably, the radioactive isotope is selected from the group of2H,3H,11C and18F. More preferably, the radioactive isotope is2H. In particular, deuterated compounds are intended to be included within the scope of the present invention.

[0082] Certain isotopically-labelled compounds of the present invention (e.g., those labelled with3H and14C) are useful in compound and for substrate tissue distribution assays. Tritiated (3H) and carbon-l4 (14C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as15O,13N,11C and18F are useful 34PRD4277WOPCT1 for positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0083] In one embodiment, the PRMT5 inhibitor is a compound of Formula (A):(A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents 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-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5heach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents 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; R12represents 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 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; 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, 35PRD4277WOPCT1 -NH-C3-6cycloalkyl, -N(C3-6cycloalkyl)2, C2-6alkenyl, C1-4alkyl substituted with one C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; R10aand R10beach independently represent hydrogen or C1-4alkyl; R10cand R10deach 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, R13and R14; R13represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O)pand 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; R14represents 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, R3dand R3eeach independently represent hydrogen, halo, -NR7aR7b, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, –OH, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; 36PRD4277WOPCT1 R4a, R4b, R4c, R4d, R4e, R4fand R4geach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents N or CR6a; Q2represents N or CR6b; Q3represents N or CR6c; Q4represents N or CR6d; provided that maximum one of Q3and Q4represents N; Q8represents N or CR6g; Q9represents N or CR6h; Q10represents N or CR6i; Q11represents N or CR6j; Q5represents CR3d; Q6represents N; and Q7represents CR4f; or Q5represents CR3d; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents CR4e; and Q7represents CR4f; or Q5represents N; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents N; and Q7represents CR4f; or Q5represents N; Q6represents N; and Q7represents N; R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, R6iand R6jeach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0084] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents 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-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5heach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents hydrogen or C1-4alkyl; 37PRD4277WOPCT1 Ar represents 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; 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; R10aand R10beach independently represent hydrogen or C1-4alkyl; R10cand R10deach independently represent C3-6cycloalkyl; 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, and R14; R14represents 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, R3dand R3eeach independently represent hydrogen, halo, -NR7aR7b, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, –OH, or –O-C1-4alkyl; 38PRD4277WOPCT1 R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; R4a, R4b, R4c, R4d, R4e, R4fand R4geach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents N or CR6a; Q2represents N or CR6b; Q3represents N or CR6c; Q4represents N or CR6d; provided that maximum one of Q3and Q4represents N; Q8represents N or CR6g; Q9represents N or CR6h; Q10represents N or CR6i; Q11represents N or CR6j; Q5represents CR3d; Q6represents N; and Q7represents CR4f; or Q5represents CR3d; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents CR4e; and Q7represents CR4f; or Q5represents N; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents N; and Q7represents CR4f; or Q5represents N; Q6represents N; and Q7represents N; R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, R6iand R6jeach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0085] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; Y represents –CH2– or –CF2–; Z represents –CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, -C^C-, –O-, or -CR5aR5b-X-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5heach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; 39PRD4277WOPCT1 R11represents 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; R12represents 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; R10aand R10beach independently represent hydrogen or C1-4alkyl; R10cand R10deach 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, R13and R14; R13represents 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)pand N; 40PRD4277WOPCT1 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; R14represents 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, R3dand R3eeach independently represent hydrogen, halo, -NR7aR7b, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, –OH, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; R4a, R4b, R4c, R4d, R4e, R4fand R4geach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents N or CR6a; Q2represents N or CR6b; Q3represents N or CR6c; Q4represents N or CR6d; provided that maximum one of Q3and Q4represents N; Q8represents N or CR6g; Q9represents N or CR6h; Q10represents N or CR6i; Q11represents N or CR6j; 41PRD4277WOPCT1 Q5represents CR3d; Q6represents N; and Q7represents CR4f; or Q5represents CR3d; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents CR4e; and Q7represents CR4f; or Q5represents N; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents N; and Q7represents CR4f; or Q5represents N; Q6represents N; and Q7represents N; R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, R6iand R6jeach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0086] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents 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-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5heach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents 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; R12represents 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 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; 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, 42PRD4277WOPCT1 -NH-C3-6cycloalkyl, -N(C3-6cycloalkyl)2, C2-6alkenyl, C1-4alkyl substituted with one C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; R10aand R10beach independently represent hydrogen or C1-4alkyl; R10cand R10deach 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, R13and R14; R13represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O)pand 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; R14represents 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, R3dand R3eeach independently represent hydrogen, halo, -NR7aR7b, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, –OH, or –O-C1-4alkyl; 43PRD4277WOPCT1 R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; R4a, R4b, R4c, R4d, R4e, R4fand R4geach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents CR6a; Q2represents CR6b; Q3represents N or CR6c; Q4represents N or CR6d; provided that maximum one of Q3and Q4represents N; Q8represents N or CR6g; Q9represents N or CR6h; Q10represents N or CR6i; Q11represents N or CR6j; Q5represents CR3d; Q6represents N; and Q7represents CR4f; or Q5represents CR3d; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents CR4e; and Q7represents CR4f; or Q5represents N; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents N; and Q7represents CR4f; or Q5represents N; Q6represents N; and Q7represents N; R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, R6iand R6jeach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0087] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents 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-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5heach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; 44PRD4277WOPCT1 R11represents 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; R12represents 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 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; 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, C2-6alkenyl, C1-4alkyl substituted with one C1-4alkyloxy, and C1-4alkyl optionally substituted with one – NR10aR10b; R10aand R10beach independently represent hydrogen or C1-4alkyl; R10cand R10deach independently represent C3-6cycloalkyl; 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, R13and R14; R13represents 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)pand 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; R14represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; 45PRD4277WOPCT1 Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3):R3a, R3band R3ceach independently represent hydrogen, halo, -NR7aR7b, C1-4alkyl, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; R4a, R4band R4ceach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents N or CR6a; Q2represents N or CR6b; Q3represents N or CR6c; Q4represents N or CR6d; provided that maximum one of Q3and Q4represents N; R6a, R6b, R6c, R6d, R6eand R6feach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0088] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents 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-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5heach independently represent hydrogen or C1-4alkyl; 46PRD4277WOPCT1 X represents –O-, -S-, or –NR11-; R11represents 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; R12represents 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 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; 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, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; R10aand R10beach independently represent hydrogen or C1-4alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3):R3a, R3band R3ceach independently represent hydrogen, halo, -NR7aR7b, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; R4a, R4band R4ceach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents N or CR6a; 47PRD4277WOPCT1 Q2represents N or CR6b; Q3represents N or CR6c; Q4represents N or CR6d; provided that maximum one of Q3and Q4represents N; R6a, R6b, R6c, R6d, R6eand R6feach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0089] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents 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-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5heach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents 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; R12represents 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 least1 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; 48PRD4277WOPCT1 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; R10aand R10beach independently represent hydrogen or C1-4alkyl; R10cand R10deach 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, R13and R14; R13represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O)pand 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)pand 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; R14represents 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): 49PRD4277WOPCT1R3a, R3b, R3c, R3dand R3eeach independently represent hydrogen, halo, -NR7aR7b, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, –OH, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; R4a, R4b, R4c, R4d, R4e, R4fand R4geach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents N or CR6a; Q2represents N or CR6b; Q3represents N or CR6c; Q4represents N or CR6d; provided that maximum one of Q3and Q4represents N; Q8represents N or CR6g; Q9represents N or CR6h; Q10represents N or CR6i; Q11represents N or CR6j; Q5represents CR3d; Q6represents N; and Q7represents CR4f; or Q5represents CR3d; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents CR4e; and Q7represents CR4f; or Q5represents N; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents N; and Q7represents CR4f; or Q5represents N; Q6represents N; and Q7represents N; R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, R6iand R6jeach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; 50PRD4277WOPCT1 R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0090] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen; R2represents hydrogen; 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-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5heach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents 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; R12represents 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 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; 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; R10aand R10beach independently represent hydrogen or C1-4alkyl; R10cand R10deach 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 51PRD4277WOPCT1 and –O-C1-4alkyl; or C1-4alkyl substituted with one substituent selected from the group consisting of C3-6cycloalkyl, R13and R14; R13represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O)pand 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; R14represents 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, R3dand R3eeach independently represent hydrogen, halo, -NR7aR7b, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, –OH, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; R4a, R4b, R4c, R4d, R4e, R4fand R4geach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents N or CR6a; Q2represents N or CR6b; Q3represents N or CR6c; 52PRD4277WOPCT1 Q4represents N or CR6d; provided that maximum one of Q3and Q4represents N; Q8represents N or CR6g; Q9represents N or CR6h; Q10represents N or CR6i; Q11represents N or CR6j; Q5represents CR3d; Q6represents N; and Q7represents CR4f; or Q5represents CR3d; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents CR4e; and Q7represents CR4f; or Q5represents N; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents N; and Q7represents CR4f; or Q5represents N; Q6represents N; and Q7represents N; R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, R6iand R6jeach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0091] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen; R2represents hydrogen; 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-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5heach independently represent hydrogen or C1- 4alkyl; X represents –O-, -S-, or –NR11-; R11represents 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; R12represents 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 optionally 1 or 2 ring carbon atoms are replaced by a nitrogen 53PRD4277WOPCT1 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, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; R10aand R10beach independently represent hydrogen or C1-4alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3); R3a, R3band R3ceach independently represent hydrogen, halo, -NR7aR7b, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; R4a, R4band R4ceach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents N or CR6a; Q2represents N or CR6b; Q3represents N or CR6c; Q4represents N or CR6d; provided that maximum one of Q3and Q4represents N; R6a, R6b, R6c, R6d, R6eand R6feach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0092] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents 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-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5heach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; 54PRD4277WOPCT1 R11represents 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; R12represents 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 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; 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; R10aand R10beach independently represent hydrogen or C1-4alkyl; R10cand R10deach 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, R13and R14; R13represents 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)pand 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; R14represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; 55PRD4277WOPCT1 Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R3arepresents hydrogen, halo, -NR7aR7b, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, –OH, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; R4arepresents hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents N or CR6a; Q2represents N or CR6b; in particular Q1and Q2represent CH; R6aand R6b, each independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1- 4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0093] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents 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-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5heach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents 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; R12represents 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 optionally 1 or 2 ring carbon atoms are replaced by a nitrogen 56PRD4277WOPCT1 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, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; R10aand R10beach independently represent hydrogen or C1-4alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R3arepresents hydrogen, halo, -NR7aR7b, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; R4arepresents hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents N or CR6a; Q2represents N or CR6b; in particular Q1and Q2represent CH; R6aand R6beach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0094] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; Y represents –O- or –CH2–; Z represents –CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C^C-; and when Y represents –CH2-, then Z can also represent -CR5aR5b-X-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5heach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents hydrogen or C1-4alkyl; Ar represents 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 57PRD4277WOPCT1 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, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, –NHR10d, cyano, -CF3, -C(=O)-NH2, -C(=O)-NH-C1-4alkyl, C1-4alkyloxy, -C(=O)-O-C1-4alkyl, C3-6cycloalkyl, C2-6alkenyl, C1-4alkyl substituted with one C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; R10aand R10brepresent C1-4alkyl; R10drepresents C3-6cycloalkyl; R14; C1-4alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one substituent selected from the group consisting of C3-6cycloalkyl, and R14; R14represents 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); R3a, R3b, R3cand R3deach independently represent hydrogen, halo, -NR7aR7b, C2-4alkenyl, C3-6cycloalkyl, –OH, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; R4a, R4b, R4c, R4d, R4eand R4feach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen; Q1represents CR6a; Q2represents CR6b; Q8represents CR6g; Q9represents CR6h; Q5represents CR3d; Q6represents N; and Q7represents CR4f; or Q5represents CR3d; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents CR4e; and Q7represents CR4f; or Q5represents N; Q6represents CR4e; and Q7represents N; R6a, R6b, R6c, R6d, R6e, R6f, R6gand R6heach independently represent hydrogen, halogen, or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof. 58PRD4277WOPCT1

[0095] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; Y represents –O-, or –CH2–; Z represents –CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C^C-; and when Y represents –CH2-, then Z can also represent –O- or -CR5aR5b-X-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5heach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents hydrogen or C1-4alkyl; Ar represents 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; 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, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; R10aand R10beach independently represent hydrogen or C1-4alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3); R3a, R3band R3ceach independently represent hydrogen, halo, -NR7aR7b, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; R4a, R4band R4ceach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents CR6a; Q2represents CR6b; Q3represents CR6c; Q4represents CR6d; R6a, R6b, R6c, R6d, R6eand R6feach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; 59PRD4277WOPCT1 R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0096] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; Y represents –O-, or –CH2–; Z represents –CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C^C-; and when Y represents –CH2-, then Z can also represent –O- or -CR5aR5b-X-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5heach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents hydrogen or C1-4alkyl; Ar represents 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; Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, - C(=O)-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; R10aand R10beach independently represent hydrogen or C1-4alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3); R3a, R3band R3crepresent -NR7aR7b; R7arepresents hydrogen; R7brepresents hydrogen; R4a, R4band R4ceach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents CR6a; Q2represents CR6b; Q3represents CR6c; Q4represents CR6d; R6a, R6b, R6c, R6d, R6eand R6feach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; 60PRD4277WOPCT1 R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0097] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; in particular R1and R2represent hydrogen; Y represents –O- or –CH2–; Z represents –CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C^C-; and when Y represents –CH2-, then Z can also represent -CR5aR5b-X-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5heach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents hydrogen or C1-4alkyl; Ar represents 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; Ar is optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2); R3aand R3ceach independently represent halo, -NR7aR7b, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen; R4a, and R4ceach independently represent hydrogen, halo, or C1-4alkyl; Q1represents CR6a; Q2represents CR6b; R6a, R6b, R6eand R6feach independently represent hydrogen, halogen, or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0098] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; in particular R1and R2represent hydrogen; Y represents –O- or –CH2–; 61PRD4277WOPCT1 Z represents –CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C^C-; and when Y represents –CH2-, then Z can also represent -CR5aR5b-X-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5heach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents hydrogen or C1-4alkyl; Ar represents 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; Ar is optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, –NHR10d, cyano, -CF3, -C(=O)-NH-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl; R10drepresents C1-4alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2); R3aand R3ceach independently represent hydrogen, halo, -NR7aR7b, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; R4a, and R4ceach independently represent hydrogen, halo, or C1-4alkyl; Q1represents CR6a; Q2represents CR6b; R6a, R6b, R6eand R6feach independently represent hydrogen, halogen, or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0099] In another embodiment, the PRMT5 inhibitor is a compound of Formula (A), or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein one or more of the following restrictions apply: (i) R1and R2represent hydrogen; (ii) Y represents –O- or –CH2–; in particular Y represents –O-; (iii) Z represents –CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, or -C^C-; and when Y represents –CH2-, then Z can also represent -CR5aR5b-X-; 62PRD4277WOPCT1 (iv) R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5hrepresent hydrogen; (v) X represents –O-; (vi) R11represents hydrogen or C1-4alkyl; (vii) Ar is optionally substituted with one, two or three substituents, in particular one substituent, each independently selected from the group consisting of halo, -OH, -NH2, - NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl; (viii) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2); (ix) R3aand R3ceach independently represent halo, -NR7aR7b, or –O-C1-4alkyl; (x) R7aand R7brepresent hydrogen; (xi) R4a, and R4ceach independently represent hydrogen, halo, or C1-4alkyl; (xii) Q1represents CR6a; (xiii) Q2represents CR6b; (xiv) R6a, R6b, R6eand R6feach independently represent hydrogen, halogen, or C1-4alkyl.

[0100] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen; R2represents hydrogen; Y represents –O- or –CH2–; Z represents -X-CR5aR5b- or -CR5eR5g-CR5fR5h-; and when Y represents –CH2-, then Z can also represent -CR5aR5b-X-; R5a, R5b, R5e, R5f, R5g, and R5hrepresent hydrogen; X represents –O-; Ar representswherein Ar is optionally substituted in the position indicated by α with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, and –NHR10d; and wherein Ar is optionally substituted in the position indicated by β with a substituent selected from the group consisting of halo and CF3; 63PRD4277WOPCT1 provided however that Ar is substituted in at least one of the positions indicated by α or β; R10drepresents C3-6cycloalkyl; C1-4alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-4); R3aand R3deach independently represent hydrogen, halo, -NR7aR7b, C1-4alkyl, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; R4a, R4dand R4feach independently represent hydrogen or halo; Q1represents CR6a; Q2represents CR6b; Q8represents CR6g; Q9represents CR6h; Q5represents CR3d; Q6represents N; and Q7represents CR4f; R6a, R6b, R6g, and R6hrepresent hydrogen; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0101] In another embodiment, the PRMT5 inhibitor is a compound of Formula (A), or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein one or more of the following restrictions apply: (i) R1and R2represent hydrogen; (ii) Y represents –O- or –CH2–; (iii) Z represents -X-CR5aR5b- or -CR5eR5g-CR5fR5h-; and when Y represents –CH2-, then Z can also represent -CR5aR5b-X-; (iv) R5a, R5b, R5e, R5f, R5g, and R5hrepresent hydrogen; (v) X represents –O-; (vi) Ar represents 64PRD4277WOPCT1wherein Ar is optionally substituted in the position indicated by α with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, and –NHR10d; and wherein Ar is optionally substituted in the position indicated by β with a substituent selected from the group consisting of halo and CF3; provided however that Ar is substituted in at least one of the positions indicated by α or β; (vii) R10drepresents C3-6cycloalkyl; C1-4alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent; (viii) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-4); (ix) R3aand R3deach independently represent hydrogen, halo, -NR7aR7b, C1-4alkyl, or –O-C1-4alkyl; (x) R7arepresents hydrogen; (xi) R7brepresents hydrogen or C1-4alkyl; (xii) R4a, R4dand R4feach independently represent hydrogen or halo; (xiii) Q1represents CR6a; (xiv) Q2represents CR6b; (xv) Q8represents CR6g; (xvi) Q9represents CR6h; (xvii) Q5represents CR3d; Q6represents N; and Q7represents CR4f; (xviii) R6a, R6b, R6g, and R6hrepresent hydrogen.

[0102] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen; R2represents hydrogen; Y represents –O- or –CH2–; Z represents -X-CR5aR5b- or -CR5eR5g-CR5fR5h-; and when Y represents –CH2-, then Z can also represent -CR5aR5b-X-; R5a, R5b, R5e, R5f, R5g, and R5hrepresent hydrogen; X represents –O-; Ar represents 65PRD4277WOPCT1wherein Ar is optionally substituted in the position indicated by α with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, and –NHR10d; and wherein Ar is optionally substituted in the position indicated by β with a substituent selected from the group consisting of halo and CF3; provided however that Ar is substituted in at least one of the positions indicated by α or β; R10drepresents C3-6cycloalkyl; C1-4alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R3arepresents hydrogen, halo, -NR7aR7b, C1-4alkyl, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; R4arepresents hydrogen or halo; Q1represents CR6a; Q2represents CR6b; R6aand R6brepresent hydrogen; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0103] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen; R2represents hydrogen; Y represents –O- or –CH2–; Z represents -X-CR5aR5b- or -CR5eR5g-CR5fR5h-; R5a, R5b, R5e, R5f, R5g, and R5hrepresent hydrogen; X represents –O-; Ar representswherein Ar is optionally substituted in the position indicated by α with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, and –NHR10d; and 66PRD4277WOPCT1 wherein Ar is optionally substituted in the position indicated by β with a substituent selected from the group consisting of halo and CF3; provided however that Ar is substituted in at least one of the positions indicated by α or β; R10drepresents C3-6cycloalkyl; C1-4alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R3arepresents hydrogen, halo, -NR7aR7b, C1-4alkyl, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; R4arepresents hydrogen or halo; Q1represents CR6a; Q2represents CR6b; R6aand R6brepresent hydrogen; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0104] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen; R2represents hydrogen; Y represents –O- or –CH2–; Z represents -X-CR5aR5b- or -CR5eR5g-CR5fR5h-; and when Y represents –CH2-, then Z can also represent -CR5aR5b-X-; R5a, R5b, R5e, R5f, R5g, and R5hrepresent hydrogen; X represents –O-; Ar representswherein Ar is substituted in the position indicated by α with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, and –NHR10d; R10drepresents C3-6cycloalkyl; or C1-4alkyl substituted with one substituent selected from the group consisting of C3-6cycloalkyl, and R14; 67PRD4277WOPCT1 R14represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; Het represents the bicyclic aromatic heterocyclic ring system (a-1); R3arepresents hydrogen, halo, -NR7aR7b, or C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; R4arepresents hydrogen; Q1represents CR6a; Q2represents CR6b; R6aand R6brepresent hydrogen; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0105] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen; R2represents hydrogen; Y represents –O- or –CH2–; Z represents -X-CR5aR5b- or -CR5eR5g-CR5fR5h-; and when Y represents –CH2-, then Z can also represent -CR5aR5b-X-; R5a, R5b, R5e, R5f, R5g, and R5hrepresent hydrogen; X represents –O-; Ar representswherein Ar is optionally substituted in the position indicated by α with -NH2; and wherein Ar is substituted in the position indicated by β with a substituent selected from the group consisting of halo and CF3; Het represents the bicyclic aromatic heterocyclic ring system (a-1); R3arepresents hydrogen, halo, -NR7aR7b, or C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; R4arepresents hydrogen; Q1represents CR6a; Q2represents CR6b; 68PRD4277WOPCT1 R6aand R6brepresent hydrogen; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0106] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen; R2represents hydrogen; Y represents –O- or –CH2–; Z represents -X-CR5aR5b- or -CR5eR5g-CR5fR5h-; and when Y represents –CH2-, then Z can also represent -CR5aR5b-X-; R5a, R5b, R5e, R5f, R5g, and R5hrepresent hydrogen; X represents –O-; Ar representswherein Ar is substituted in the position indicated by α with -NH2; and wherein Ar is substituted in the position indicated by β with a substituent selected from the group consisting of halo and CF3; Het represents the bicyclic aromatic heterocyclic ring system (a-1); R3arepresents hydrogen, halo, -NR7aR7b, or C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; R4arepresents hydrogen; Q1represents CR6a; Q2represents CR6b; R6aand R6brepresent hydrogen; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0107] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen; R2represents hydrogen; Y represents –O- or –CH2–; Z represents -X-CR5aR5b- or -CR5eR5g-CR5fR5h-; and when Y represents –CH2-, then Z can also represent -CR5aR5b-X-; R5a, R5b, R5e, R5f, R5g, and R5hrepresent hydrogen; 69PRD4277WOPCT1 X represents –O-; Ar representsHet represents the bicyclic aromatic heterocyclic ring system (a-1); R3arepresents hydrogen, halo, -NR7aR7b, or C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; R4arepresents hydrogen; Q1represents CR6a; Q2represents CR6b; R6aand R6brepresent hydrogen; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0108] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; in particular R1and R2represent hydrogen; Y represents -CH2- or –O-; Z represents -X-CR5aR5b- or –CH2CH2-; R5aand R5beach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents hydrogen; Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein 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; Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; R10aand R10beach independently represent hydrogen or C1-4alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); 70PRD4277WOPCT1 R3arepresents hydrogen, halo, -NR7aR7b, or–O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen; R4arepresents hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents CR6a; Q2represents CR6b; R6aand R6beach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0109] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen; R2represents hydrogen; Y represents –CH2–; Z represents -CR5eR5g-CR5fR5h-; R5e, R5f, R5g, and R5hrepresent 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, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, –NHR10d, –NR10cR10d; R10cand R10deach independently represent C3-6cycloalkyl; 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 C3-6cycloalkyl substituent; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); 71PRD4277WOPCT1 R3arepresents hydrogen, -NR7aR7b, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; R4arepresents hydrogen; Q1represents CR6a; Q2represents CR6b; R6aand R6brepresent hydrogen; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0110] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen; R2represents hydrogen; Y represents –CH2–; Z represents -CR5eR5g-CR5fR5h-; R5e, R5f, R5g, and R5hrepresent hydrogen; Ar representsAr is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, –NHR10d; R10drepresents C1-4alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R3arepresents hydrogen, -NR7aR7b, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; R4arepresents hydrogen; Q1represents CR6a; Q2represents CR6b; R6aand R6brepresent hydrogen; or a pharmaceutically acceptable addition salt, or a solvate thereof. 72PRD4277WOPCT1

[0111] In another embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein one or more of the following restrictions apply: (i) R1represents hydrogen; R2represents hydrogen; (ii) Y represents –CH2–; (iii) Z represents -CR5eR5g-CR5fR5h-; (iv) R5e, R5f, R5g, and R5hrepresent hydrogen; (v) Ar representsAr is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, –NHR10d; (vi) R10drepresents C1-4alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent; (vii) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); (viii) R3arepresents hydrogen, -NR7aR7b, or –O-C1-4alkyl; (ix) R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; (x) R4arepresents hydrogen; (xi) Q1represents CR6a; Q2represents CR6b; (xii) R6aand R6brepresent hydrogen.

[0112] In another embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein one or more of the following restrictions apply: (i) R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; in particular R1and R2represent hydrogen; 73PRD4277WOPCT1 (ii) Y represents -CH2- or –O-; (iii) Z represents -X-CR5aR5b- or –CH2CH2-; (iv) R5aand R5beach independently represent hydrogen or C1-4alkyl; (v) X represents –O-, -S-, or –NR11-; (vi) R11represents hydrogen; (vii) Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, - CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; (viii) R10aand R10beach independently represent hydrogen or C1-4alkyl; (ix) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); (x) R3arepresents hydrogen, halo, -NR7aR7b, or –O-C1-4alkyl; (xi) R7arepresents hydrogen; R7brepresents hydrogen; (xii) R4arepresents hydrogen, halo, -NR8aR8b, or C1-4alkyl; (xiii) R8aand R8beach independently represent hydrogen or C1-4alkyl; (xiv) Q1represents CR6a; (xv) Q2represents CR6b; (xvi) R6aand R6beach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; (xvii) R9aand R9beach independently represent hydrogen or C1-4alkyl.

[0113] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; in particular R1and R2represent hydrogen; Y represents –O-; Z represents -X-CR5aR5b-; R5aand R5beach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents hydrogen; 74PRD4277WOPCT1 Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein 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; Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; R10aand R10beach independently represent hydrogen or C1-4alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R3arepresents hydrogen, halo, -NR7aR7b, or–O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen; R4arepresents hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents CR6a; Q2represents CR6b; R6aand R6beach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0114] In another embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein one or more of the following restrictions apply: (i) R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; in particular R1and R2represent hydrogen; (ii) Y represents –O-; (iii) Z represents -X-CR5aR5b-; (iv) R5aand R5beach independently represent hydrogen or C1-4alkyl; (v) X represents –O-, -S-, or –NR11-; 75PRD4277WOPCT1 (vi) R11represents hydrogen; (vii) Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, - CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; (viii) R10aand R10beach independently represent hydrogen or C1-4alkyl; (ix) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); (x) R3arepresents hydrogen, halo, -NR7aR7b, or –O-C1-4alkyl; (xi) R7arepresents hydrogen; R7brepresents hydrogen; (xii) R4arepresents hydrogen, halo, -NR8aR8b, or C1-4alkyl; (xiii) R8aand R8beach independently represent hydrogen or C1-4alkyl; (xiv) Q1represents CR6a; (xv) Q2represents CR6b; (xvi) R6aand R6beach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; (xvii) R9aand R9beach independently represent hydrogen or C1-4alkyl.

[0115] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; in particular R1and R2represent hydrogen; Y represents –CH2- or –O-; Z represents -X-CR5aR5b- or –CH2CH2- R5aand R5beach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents hydrogen;Ar represents ; in particular Ar represents ; Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, - 76PRD4277WOPCT1 CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; R10aand R10beach independently represent hydrogen or C1-4alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R3arepresents hydrogen, halo, -NR7aR7b, or–O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen; R4arepresents hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents CR6a; Q2represents CR6b; R6aand R6beach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0116] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; in particular R1and R2represent hydrogen; Y represents –O-; Z represents -X-CR5aR5b-; R5aand R5beach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents hydrogen;Ar represents ; in particular Ar represents ; Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, - CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; 77PRD4277WOPCT1 R10aand R10beach independently represent hydrogen or C1-4alkyl; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R3arepresents hydrogen, halo, -NR7aR7b, or–O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen; R4arepresents hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents CR6a; Q2represents CR6b; R6aand R6beach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0117] In another embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein one or more of the following restrictions apply: (i) R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; in particular R1and R2represent hydrogen; (ii) Y represents –O-; (iii) Z represents -X-CR5aR5b-; (iv) R5aand R5beach independently represent hydrogen or C1-4alkyl; (v) X represents –O-, -S-, or –NR11-; (vi) R11represents hydrogen;(vii) Ar represents ; in particular Ar represents ; (viii) Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, 78PRD4277WOPCT1 cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; (ix) R10aand R10beach independently represent hydrogen or C1-4alkyl; (x) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); (xi) R3arepresents hydrogen, halo, -NR7aR7b, or–O-C1-4alkyl; (xii) R7arepresents hydrogen; R7brepresents hydrogen; (xiii) R4arepresents hydrogen, halo, -NR8aR8b, or C1-4alkyl; (xiv) R8aand R8beach independently represent hydrogen or C1-4alkyl; (xv) Q1represents CR6a; (xvi) Q2represents CR6b; (xvii) R6aand R6beach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; (xviii) R9aand R9beach independently represent hydrogen or C1-4alkyl.

[0118] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; in particular R1and R2represent hydrogen; Y represents –O- or –CH2-; Z represents -X-CR5aR5b- or –CH2CH2-; R5aand R5brepresent hydrogen; X represents –O-; R11represents hydrogen;Ar represents ; Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, and -CF3; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R3arepresents -NR7aR7b; R7arepresents hydrogen; R7brepresents hydrogen; 79PRD4277WOPCT1 R4arepresents hydrogen; Q1represents CR6a; Q2represents CR6b; R6aand R6brepresent hydrogen; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0119] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; in particular R1and R2represent hydrogen; Y represents –O- or –CH2-; Z represents -X-CR5aR5b- or –CH2CH2-; R5aand R5brepresent hydrogen; X represents –O-; R11represents hydrogen;Ar represents ; Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, and -CF3; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R3arepresents -NR7aR7b; R7arepresents hydrogen; R7brepresents hydrogen; R4arepresents hydrogen; Q1represents CR6a; Q2represents CR6b; R6aand R6brepresent hydrogen; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0120] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; in particular R1and R2represent hydrogen; Y represents –O-; Z represents -X-CR5aR5b-; R5aand R5brepresent hydrogen; X represents –O-; R11represents hydrogen; 80PRD4277WOPCT1Ar represents ; Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, and -CF3; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R3arepresents -NR7aR7b; R7arepresents hydrogen; R7brepresents hydrogen; R4arepresents hydrogen; Q1represents CR6a; Q2represents CR6b; R6aand R6brepresent hydrogen; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0121] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; in particular R1and R2represent hydrogen; Y represents –O-; Z represents -X-CR5aR5b-; R5aand R5brepresent hydrogen; X represents –O-; R11represents hydrogen;Ar represents ; Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, and -CF3; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R3arepresents -NR7aR7b; R7arepresents hydrogen; R7brepresents hydrogen; R4arepresents hydrogen; 81PRD4277WOPCT1 Q1represents CR6a; Q2represents CR6b; R6aand R6brepresent hydrogen; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0122] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; in particular R1and R2represent hydrogen; Y represents –O- or –CH2-; Z represents -X-CR5aR5b- or –CH2CH2-; R5aand R5brepresent hydrogen; X represents –O-; R11represents hydrogen;Ar represents ; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R3arepresents -NR7aR7b; R7arepresents hydrogen; R7brepresents hydrogen; R4arepresents hydrogen; Q1represents CR6a; Q2represents CR6b; R6aand R6brepresent hydrogen; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0123] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; in particular R1and R2represent hydrogen; Y represents –O-; Z represents -X-CR5aR5b-; R5aand R5brepresent hydrogen; X represents –O-; R11represents hydrogen;Ar represents ; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); 82PRD4277WOPCT1 R3arepresents -NR7aR7b; R7arepresents hydrogen; R7brepresents hydrogen; R4arepresents hydrogen; Q1represents CR6a; Q2represents CR6b; R6aand R6brepresent hydrogen; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0124] In another embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein one or more of the following restrictions apply: (i) R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; in particular R1and R2represent hydrogen; (ii) Y represents –O-; (iii) Z represents -X-CR5aR5b-; (iv) R5aand R5brepresent hydrogen; (v) X represents –O-; (vi) R11represents hydrogen;(vii) Ar represents ; Ar is optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, and -CF3; in particular Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, and -CF3;more in particular Ar represents; even more in particular Arrepresents ; 83PRD4277WOPCT1 (ix) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); (x) R3arepresents -NR7aR7b; (xi) R7arepresents hydrogen; R7brepresents hydrogen; (xii) R4arepresents hydrogen; (xiii) Q1represents CR6a; (xiv) Q2represents CR6b; (xv) R6aand R6brepresent hydrogen.

[0125] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R1and R2represent hydrogen.

[0126] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R1represents–C(=O)-C1-4alkyl; R2represents–C(=O)-C1-4alkyl.

[0127] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R1and R2represent hydrogen; Het represents (a-1); Q1represents CH; Q2represents CH; and Ar representsoptionally substituted according to any of the other embodiments.

[0128] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R1and R2represent hydrogen; Het represents (a-1); Q1represents CH; Q2represents CH; and 84PRD4277WOPCT1 Ar representswherein Ar is substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, –NHR10d, –NR10cR10d; R10cand R10deach independently represent C1-4alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent.

[0129] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y represents –O-.

[0130] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y represents –CH2- or –CF2-; in particular wherein Y represents –CH2-.

[0131] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein maximum one of Q1and Q2represents N.

[0132] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Q1represents CR6a; and Q2represents CR6b; in particular wherein Q1represents CH; and Q2represents CH.

[0133] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents (a-1); Q1represents CR6a; and Q2represents CR6b; in particular wherein Q1represents CH; and Q2represents CH.

[0134] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Q5represents CR3d; Q6represents N; and Q7represents CR4f; or Q5represents CR3d; Q6represents CR4e; and Q7represents N; or 85PRD4277WOPCT1 Q5represents N; Q6represents CR4e; and Q7represents CR4f; or Q5represents N; Q6represents CR4e; and Q7represents N.

[0135] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-4).

[0136] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R1and R2represent hydrogen; and Y represents –O-.

[0137] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3).

[0138] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2).

[0139] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-4).

[0140] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a bicyclic aromatic heterocyclic ring system of Formula (a-1).

[0141] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R1and R2represent hydrogen; Y represents –O-; and Het represents a bicyclic aromatic heterocyclic ring system of Formula (a-1). 86PRD4277WOPCT1

[0142] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar represents an optionally substituted 10-membered bicyclic aromatic ring system consisting of two fused 6- membered rings, wherein 1 or 2 ring carbon atoms are replaced by a nitrogen atom; provided that the nitrogen atom does not replace one of the two fused carbon atoms.

[0143] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein 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; R10aand R10beach independently represent hydrogen or C1-4alkyl; R10cand R10deach 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, R13and R14. 87PRD4277WOPCT1

[0144] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein 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;

[0145] 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.In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is optionally substituted with one or two substituents according to any of the other embodiments.

[0146] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is optionally substituted with one substituent according to any of the other embodiments.

[0147] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3a, R3c, R3brepresent hydrogen; and R4a, R4c, R4brepresent hydrogen, halo, or C1-4alkyl; in particular R4a, R4c, R4brepresent halo, or C1-4alkyl.

[0148] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3a, R3c, R3b, R3dand R3erepresent hydrogen; and R4a, R4c, R4b, R4d, R4e, R4fand R4grepresent hydrogen, halo, or C1-4alkyl; in particular R4a, R4c, R4b, R4d, R4e, R4fand R4grepresent halo, or C1-4alkyl. 88PRD4277WOPCT1

[0149] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3a, R3c, R3brepresent hydrogen, halo, -NR7aR7b, or –O-C1-4alkyl; in particular R3a, R3c, R3brepresent halo, -NR7aR7b, or –O-C1-4alkyl; R4a, R4c, R4brepresent hydrogen.

[0150] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3a, R3c, R3b, R3dand R3erepresent hydrogen, halo, -NR7aR7b, or –O-C1-4alkyl; in particular R3a, R3c, R3b, R3dand R3erepresent halo, -NR7aR7b, or –O-C1-4alkyl; R4a, R4c, R4b, R4d, R4e, R4fand R4grepresent hydrogen.

[0151] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3a, R3c, R3brepresent hydrogen, when R4a, R4c, R4bare different from hydrogen.

[0152] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3a, R3c, R3b, R3d, R3erepresent hydrogen, when R4a, R4c, R4b, R4d, R4e, R4f, R4gare different from hydrogen.

[0153] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R4a, R4c, R4brepresent hydrogen, when R3a, R3c, R3bare different from hydrogen.

[0154] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R4a, R4c, R4b, R4d, R4e, R4f, R4grepresent hydrogen, when R3a, R3c, R3b, R3d, R3eare different from hydrogen.

[0155] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein 89PRD4277WOPCT1 Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,wherein at least1 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 according to any of the other embodiments.

[0156] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings,wherein at least1 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, C2-6alkenyl, C1-4alkyl substituted with one C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; in particular 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, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b.

[0157] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof 90PRD4277WOPCT1 as mentioned in any of the other embodiments, wherein Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings with the following structure,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 according to any of the other embodiments..

[0158] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is selected from the group consisting of:wherein each Ar is optionally substituted according to any of the other embodiments.

[0159] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof 91PRD4277WOPCT1 as mentioned in any of the other embodiments, wherein Ar is selected from the group consisting of:wherein each Ar is optionally substituted according to any of the other embodiments.

[0160] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is selected from the group consisting of:wherein each Ar is optionally substituted according to any of the other embodiments.

[0161] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is selected from the group consisting of: 92PRD4277WOPCT1wherein each Ar is optionally substituted according to any of the other embodiments.

[0162] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is selected from the group consisting of:wherein each Ar is optionally substituted according to any of the other embodiments.

[0163] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is 93PRD4277WOPCT1wherein Ar is optionally substituted according to any of the other embodiments.

[0164] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is other thanwherein Ar is optionally substituted according to any of the other embodiments.

[0165] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar representswherein Ar is substituted with one, two, three or four substituents each independently selected from the group consisting of halo, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, –NHR10d, –NR10cR10d.

[0166] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar representswherein Ar is substituted with one substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, –NHR10d, –NR10cR10d; and optionally substituted with a halo substituent; R10cand R10deach independently represent C1-4alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent.

[0167] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar represents 94PRD4277WOPCT1wherein Ar is substituted in the position indicated by α with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, –NHR10d, –NR10cR10d; and wherein Ar is optionally substituted in the position indicated by β with a halo substituent.

[0168] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar representswherein Ar is substituted in the position indicated by α with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, –NHR10d, –NR10cR10d; and wherein Ar is optionally substituted in the position indicated by β with a halo substituent; R10cand R10deach independently represent C1-4alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent.

[0169] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar representswherein Ar is substituted in the position indicated by β with a halo substituent; in particular chloro or bromo; more in particular bromo.

[0170] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents (a-1); Q1represents CR6a; Q2represents CR6b; and Ar representswherein Ar is substituted in the position indicated by β with a halo substituent; in particular chloro or bromo; more in particular bromo. 95PRD4277WOPCT1

[0171] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is substituted with one substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, –NHR10d, –NR10cR10d; and wherein Ar is optionally substituted with another substituent selected from the list of substituents on Ar in any of the other embodiments.

[0172] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar representsoptionally substituted according to any of the other embodiments.

[0173] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar representsoptionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, - CF3, -C(=O)-NH-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl; in particular optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -NH2, -NH-C1-4alkyl, cyano, -CF3, C1-4alkyloxy, and C1-4alkyl; more in particular optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, or -CF3; more in particular optionally substituted with one or two halo substituents; more in particular substituted with one or two halo substituents; even more in particular substituted with one halo substituent; most in particular substituted with one chloro substituent. 96PRD4277WOPCT1

[0174] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar representsoptionally substituted according to any of the other embodiments.

[0175] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar representsoptionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl; in particular optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -NH2, -NH-C1-4alkyl, cyano, -CF3, C1-4alkyloxy, and C1-4alkyl; more in particular optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, or -CF3; more in particular optionally substituted with one or two halo substituents; more in particular substituted with one or two halo substituents; even more in particular substituted with one halo substituent; most in particular substituted with one chloro substituent.

[0176] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents (a-1); and Ar representsoptionally substituted with one, two or three substituents each independently selected 97PRD4277WOPCT1 from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl; in particular optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, -NH2, -NH-C1-4alkyl, cyano, -CF3, C1-4alkyloxy, and C1-4alkyl; more in particular optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, or -CF3; more in particular optionally substituted with one or two halo substituents; more in particular substituted with one or two halo substituents; even more in particular substituted with one halo substituent; most in particular substituted with one chloro substituent.

[0177] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents (a-1); and ; ;more in particular Ar represents .

[0178] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein 98PRD4277WOPCT1Ar represents;in particular Ar represents or ;more in particular Ar represents .

[0179] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R5b, R5gand R5hrepresent hydrogen.

[0180] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Q1represents CR6a; and Q2represents CR6b.

[0181] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X represents –O-; Q1represents CR6a; and Q2represents CR6b.

[0182] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X represents –O-; Q1represents CH; and Q2represents CRH.

[0183] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R5b, R5gand R5hrepresent hydrogen; Y represents –CH2- or –CF2-; in particular Y represents –CH2-; and Het represents (a-1); 99PRD4277WOPCT1 Q1represents CR6a; and Q2represents CR6b; in particular wherein Q1represents CH; and Q2represents CH.

[0184] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R5b, R5gand R5hrepresent hydrogen; Y represents –O-; and Het represents (a-1); Q1represents CR6a; and Q2represents CR6b; in particular wherein Q1represents CH; and Q2represents CH.

[0185] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Q2represents CR6b.

[0186] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Z represents -X-CR5aR5b-.

[0187] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Z represents -O-CH2-.

[0188] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Z represents -X-CR5aR5b-; X represents –O-; and R5aand R5brepresent hydrogen.

[0189] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X represents –O- or –NR11-; in particular X represents –O-.

[0190] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R7aand R7brepresent hydrogen. 100PRD4277WOPCT1

[0191] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents (a-1); R3arepresents –NR7aR7b; and R7aand R7brepresent hydrogen.

[0192] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar represents 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; Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, - C(=O)-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; R3a, R3band R3crepresent –NR7aR7b; and R7aand R7brepresent hydrogen.

[0193] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar represents 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; Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, - C(=O)-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; R3a, R3c, R3b, R3dand R3erepresent –NR7aR7b; and R7aand R7brepresent hydrogen.

[0194] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3a, R3band R3crepresent other than halo.

[0195] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof 101PRD4277WOPCT1 as mentioned in any of the other embodiments, wherein R3a, R3c, R3b, R3dand R3erepresent other than halo.

[0196] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3a, R3band R3crepresent -NR7aR7b; R7arepresents hydrogen; R7brepresents hydrogen.

[0197] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3a, R3band R3crepresent –NH2.

[0198] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar represents 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; Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, - C(=O)-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; Het represents (a-1); R3arepresents –NR7aR7b; and R7aand R7brepresent hydrogen.

[0199] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar represents 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; Ar is substituted with one substituent selected from the group consisting of halo, -OH, - NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, -C(=O)-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b; Het represents (a-1); R3arepresents –NR7aR7b; and R7aand R7brepresent hydrogen. 102PRD4277WOPCT1

[0200] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar representsoptionally substituted with one substituent selected from the group consisting of halo, - OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, -CF3, -C(=O)-NH-C1-4alkyl, C1-4alkyloxy, and C1-4alkyl; in particular optionally substituted with one substituent selected from the group consisting of halo, -NH2, -NH-C1-4alkyl, cyano, -CF3, C1-4alkyloxy, and C1-4alkyl; more in particular optionally substituted with one substituent selected from the group consisting of halo, and -CF3; more in particular optionally substituted with one halo substituent; more in particular substituted with one halo substituent; even more in particular substituted with one chloro substituent.

[0201] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is selected from the group consisting of:wherein each Ar is optionally substituted according to any of the other embodiments; in particular wherein Ar is optionally substituted with one substituent as defined in any of the other embodiments.

[0202] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof 103PRD4277WOPCT1 as mentioned in any of the other embodiments, wherein Ar is selected from the group consisting of:wherein each Ar is optionally substituted according to any of the other embodiments; in particular wherein Ar is optionally substituted with one substituent as defined in any of the other embodiments.

[0203] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is selected from the group consisting of:wherein each Ar is optionally substituted according to any of the other embodiments; in particular wherein Ar is optionally substituted with one substituent as defined in any of the other embodiments.

[0204] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, 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 -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, –NHR10d, and –NR10cR10d; R10cand R10deach independently represent C3-6cycloalkyl; 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 104PRD4277WOPCT1 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, R13and R14; R13represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O)pand 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)pand 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; R14represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo.

[0205] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, 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 -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, –NHR10d, and –NR10cR10d; and wherein Ar is optionally substituted in another position with a halo substituent.

[0206] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is selected from the group consisting of:wherein each Ar is substituted in position α with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, –NHR10d, and –NR10cR10d; and wherein Ar is optionally substituted in another position with a halo substituent. 105PRD4277WOPCT1

[0207] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar represents a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein 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; wherein each Ar is optionally substituted according to any of the other embodiments; in particular wherein Ar is optionally substituted with one substituent as defined in any of the other embodiments.

[0208] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is optionally substituted with one substituent as defined in any of the other embodiments.

[0209] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein 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, C2-6alkenyl, C1-4alkyl substituted with one C1-4alkyloxy, and C1-4alkyl optionally substituted with one –NR10aR10b.

[0210] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinAr represents ; Ar is optionally substituted with one substituent selected from the group consisting of halo, -OH, -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, and -CF3; 106PRD4277WOPCT1more in particular Ar represents; even more in particular Arrepresents .

[0211] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, whereinAr represents ; Ar is substituted with one substituent selected from the group consisting of halo, -OH, - NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, cyano, and -CF3;more in particular Ar represents; even more in particular Arrepresents ; Het represents (a-1); R3arepresents –NR7aR7b; and R7aand R7brepresent hydrogen.

[0212] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (A) are restricted to compounds of Formula (A-a1): (I-a1)(A-a1). 107PRD4277WOPCT1

[0213] It will be clear that all variables in the structure of Formula (A-a1), may be defined as defined for the compounds of Formula (A) or any subgroup thereof as mentioned in any of the other embodiments.

[0214] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (A) are restricted to compounds of Formula (A-a1): (I-a1)(A-a1) wherein R3arepresents -NH2; and R4arepresents hydrogen.

[0215] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (A) are restricted to compounds of Formula (A-a1):wherein R3arepresents -NH2; R4arepresents hydrogen; and.

[0216] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof 108PRD4277WOPCT1 as mentioned in any of the other embodiments, wherein the compounds of Formula (A) are restricted to compounds of Formula (A-a1):wherein R1and R2represent hydrogen; R3arepresents hydrogen, -NR7aR7b, or –OC1-4alkyl; R4arepresents hydrogen; and Ar representswherein Ar is substituted in the position indicated by α with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, –NHR10d, –NR10cR10d; and wherein Ar is optionally substituted in the position indicated by β with a halo substituent; R10cand R10deach independently represent C1-4alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent. In an embodiment, the PRMT5 inhibitor is a compound of Formula (A-a1)wherein R1and R2represent hydrogen; R3arepresents hydrogen, -NR7aR7b, or –OC1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; Z represents –CH2CH2-; 109PRD4277WOPCT1 Y represents –O-, –CH2– or –CF2–; in particular –CH2–; R4arepresents hydrogen; and Ar representswherein Ar is substituted in the position indicated by α with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, –NHR10d, –NR10cR10d; and wherein Ar is optionally substituted in the position indicated by β with a halo substituent; R10cand R10deach independently represent C1-4alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0217] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A-a1) (I-a1)(A-a1) wherein R1and R2represent hydrogen; R3arepresents hydrogen, -NR7aR7b, or –OC1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; Z represents -X-CR5aR5b- or –CH2CH2-; R5aand R5brepresent hydrogen; X represents –O-; Y represents –O-, –CH2– or –CF2–; in particular –CH2–; R4arepresents hydrogen; and Ar representswherein Ar is optionally substituted in the position indicated by α with a substituent 110PRD4277WOPCT1 selected from the group consisting of -NH2, -NH-C1-4alkyl, -N(C1-4alkyl)2, –NHR10d, – NR10cR10d; and wherein Ar is optionally substituted in the position indicated by β with a halo substituent; R10cand R10deach independently represent C1-4alkyl substituted with one, two or three halo substituents; or C1-4alkyl substituted with one C3-6cycloalkyl substituent; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0218] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A-a1) (I-a1)(A-a1) wherein R1and R2represent hydrogen; R3arepresents -NR7aR7b; R7arepresents hydrogen; R7brepresents hydrogen; Z represents -X-CR5aR5b- or –CH2CH2-; R5aand R5brepresent hydrogen; X represents –O-; Y represents –O- or –CH2–; R4arepresents hydrogen; and Ar representswherein Ar is optionally substituted in the position indicated by α with -NH2; and wherein Ar is substituted in the position indicated by β with a halo substituent, in particular Br; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0219] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof 111PRD4277WOPCT1 as mentioned in any of the other embodiments, wherein Z represents -X-CR5aR5b- or –CH2CH2-.

[0220] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Z represents -X-CR5aR5b- or –CH2CH2-; R5aand R5brepresent hydrogen; X represents –O-.

[0221] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Z represents -X-CR5aR5b- or –CH2CH2-; R5aand R5brepresent hydrogen; X represents –O-; Het represents (a-1).

[0222] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Z represents -X-CR5aR5b- or –CH2CH2-; R5aand R5brepresent hydrogen; X represents –O-; Het represents (a-1); R3arepresents-NR7aR7b; R7arepresents hydrogen; R7brepresents hydrogen.

[0223] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X represents –O-.

[0224] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Z represents -X-CR5aR5b- or –CH2CH2-; R5aand R5brepresent hydrogen; 112PRD4277WOPCT1 X represents –O-; Ar representswherein Ar is optionally substituted in the position indicated by α with a substituent selected from the group consisting of -NH2, -NH-C1-4alkyl, and –NHR10d; and wherein Ar is optionally substituted in the position indicated by β with a substituent selected from the group consisting of halo and CF3; provided however that Ar is substituted in at least one of the positions indicated by α or β; Het represents (a-1); R3arepresents-NR7aR7b; R7arepresents hydrogen; R7brepresents hydrogen.

[0225] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents (a-1); R3arepresents-NR7aR7b; R7arepresents hydrogen; R7brepresents hydrogen.

[0226] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3a, R3b, R3c, R3dand R3erepresent -NR7aR7b; R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl.

[0227] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein 113PRD4277WOPCT1 R3a, R3b, R3c, R3dand R3erepresent -NR7aR7b; R7arepresents hydrogen; R7brepresents hydrogen.

[0228] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R11represents 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; and R10cand R10deach independently represent C3-6cycloalkyl; 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, and R14.

[0229] In an embodiment, the PRMT5 inhibitor is a compound of Formula (A) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y represents –CH2-; and Z represents –CH2CH2-.

[0230] In the context of Formula (A), the following definitions apply, unless a context dictates otherwise.

[0231] In case Z is -X-CR5aR5b-, it is intended that X is attached to Ar.

[0232] In case Z is -CR5c=CR5d-, it is intended that the C-atom with the R5csubstituent is attached to Ar.

[0233] In case Z is -CR5eR5g-CR5fR5h-, it is intended that the C-atom with the R5eand R5gsubstituents is attached to Ar.

[0234] In case Z is -CR5aR5b-X-, it is intended that the C-atom with the R5aand R5bsubstituents is attached to Ar.

[0235] The skilled person will realize that the 4-, 5-, 6- or 7-membered heterocyclic ring being attached to the remainder of the molecule via a ring nitrogen atom (in the definition of R12) particularly is a saturated ring. Non-limiting examples of R12are 1-piperidinyl, 1-pyrrolidinyl, 1-morpholinyl, 1-azetidinyl, and the like. 114PRD4277WOPCT1

[0236] It will be clear for the skilled person that, unless otherwise is indicated or is clear from the context, a substituent on a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms (as in the definition of R13) (non-limiting examples are pyrrolyl, pyridinyl, furanyl, and the like), may replace any hydrogen atom on a ring carbon atom or where possible on a ring nitrogen atom (in which case a hydrogen on a nitrogen atom may be replaced by a substituent). It will be clear for the skilled person that the same is applicable to the 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms (as in the definition of R13) (non- limiting examples are indolyl, quinolinyl, and the like).

[0237] A 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms (as in the definition of R13), may be attached to the remainder of the molecule of Formula (A) through any available ring carbon or nitrogen atom as appropriate, if not otherwise specified. It will be clear for the skilled person that the same is applicable to the 6- to 11-membered bicyclic fused aromatic ring containing one, two or three heteroatoms (as in the definition of R13).

[0238] In case a nitrogen atom replaces one of the two fused carbon atoms in the Ar group, a carbonyl group is present in said bicyclic aromatic ring system as exemplified by the structure shown below:which is optionally substituted according to any of the embodiments. It will be clear this example is non-limiting.

[0239] Other, non-limiting, examples of the Ar group being 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, are shown below: 115PRD4277WOPCT1each of which are optionally substituted according to any of the embodiments.

[0240] The skilled person will understand that the 10 members of the 10-membered Ar group (the 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), are 10 carbon atoms, 9 carbon atoms and 1 nitrogen atom, or 8 carbon atoms and 2 nitrogen atoms. Ar is optionally substituted according to any of the embodiments.

[0241] Whenever substituents are represented by chemical structure, “---” represents the bond of attachment to the remainder of the molecule of Formula (A). Lines drawn from substituents into ring systems indicate that the bond may be attached to any of the suitable ring atoms.

[0242] For example covers any one of the following ring systems: ..

[0243] In one embodiment, the PRMT5 inhibitor is a compound of Formula (B): 116PRD4277WOPCT1 (I)(B), wherein R1represents hydrogen or CH3; R2represents hydrogen; Rarepresents hydrogen or –C(=O)-C1-4alkyl; Rbrepresents hydrogen or –C(=O)-C1-4alkyl; Y represents –O-, –CH2– or –CF2–; R7arepresents hydrogen; R7brepresents hydrogen, or C1-4alkyl optionally substituted with one or more halo atoms; X1represents a covalent bond or –O-; X2represents a covalent bond, -CH2-, -CF2-, -CH2CH2-, -CF2CH2-, or -CH2CF2-; provided that X2represents a covalent bond, -CH2- or -CF2-, when X1represents –O-; X3represents N or CH; or in case one of the dotted lines represents an additional bond, X3represents C; R8and R10each independently are selected from the group consisting of hydrogen; halo; and C1-6alkyl optionally substituted with one or more halo atoms; R9and R11each independently are selected from the group consisting of hydrogen; halo; -NH2; and C1-6alkyl optionally substituted with one –NR9aR9b; or R8and R9are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 4-, 117PRD4277WOPCT1 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1a; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR5aR5b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1a, -O-Ar1a, Het2aand –O-Het2c; or R10and R11are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1b; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR6aR6b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1b, -O-Ar1b, Het2band –O-Het2d; Z represents -CH2-, -C(=O)-, or –CH(C1-4alkyl)-; and in case X3represents C, Z can also represent =CH-; the dotted lines attached to X3are optional bonds that may be present when X3represents a carbon atom, provided that maximum one of the dotted lines represents an optional bond; in case one of the dotted lines attached to X3represents an additional bond, X3represents C, and (i) R7ais absent or (ii) R8is absent or (iii) Z represents =CH-; R9aand R9beach independently are selected from the group consisting of hydrogen and C1-4alkyl; or R9aand R9bare linked together to form together with the common nitrogen atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl which optionally contains one oxygen atom; R5aand R5beach independently are selected from the group consisting of hydrogen and C1-4alkyl; Het1aand Het1bare attached to the remainder of the molecule of Formula (B) through any available ring carbon atom; 118PRD4277WOPCT1 Het1aand Het1beach independently represent a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two heteroatoms each independently selected from O, S, S(=O)p and N; Ar1aand Ar1beach independently represent phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo; cyano; and C1-4alkyl optionally substituted with one or more halo atoms; Het2aand Het2beach independently represent a 4-, 5-, 6- or 7-membered monocyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)p and N; or a fused 8-, 9-, 10- or 11-membered bicyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)pand N; said monocyclic heterocyclyl or said fused bicyclic heterocyclyl optionally being substituted with one or more substituents each independently selected from the group consisting of halo, cyano, and C1-4alkyl optionally substituted with one or more halo atoms; Het2cand Het2dare attached to the remainder of the molecule of Formula (B) through any available ring carbon atom; Het2cand Het2deach independently represent a 4-, 5-, 6- or 7-membered monocyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)p and N; or a fused 8-, 9-, 10- or 11-membered bicyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)pand N; said monocyclic heterocyclyl or said fused bicyclic heterocyclyl optionally being substituted with one or more substituents each independently selected from the group consisting of halo, cyano, and C1-4alkyl optionally substituted with one or more halo atoms; R6aand R6beach independently are selected from the group consisting of hydrogen and C1-4alkyl; p represents 1 or 2; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3) and (a-4): 119PRD4277WOPCT1R3a, R3b, R3cand R3deach independently are selected from the group consisting of hydrogen, halo, -NR12aR12b, C1-4alkyl, and –O-C1-4alkyl; R12aand R12beach independently are selected from the group consisting of hydrogen; C3-6cycloalkyl; C1-4alkyl; and C1-4alkyl substituted with one phenyl which is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, –OC1-4alkyl, -OH, and C1-4alkyl optionally substituted with one or more halo atoms; R4a, R4b, R4c, R4d, R4eand R4feach independently are selected from the group consisting of hydrogen, halo, -NR13aR13b, and C1-4alkyl; R13aand R13beach independently are selected from the group consisting of hydrogen and C1-4alkyl; Q1represents N or CR14a; Q2represents N or CR14b; Q3represents N or CR14c; Q4represents N or CR14d; provided that maximum one of Q3and Q4represents N; Q8represents N or CR14g; Q9represents N or CR14h; Q5represents CR3d; Q6represents N; and Q7represents CR4f; or Q5represents CR3d; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents CR4e; and Q7represents CR4f; or Q5represents N; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents N; and Q7represents CR4f; or 120PRD4277WOPCT1 Q5represents N; Q6represents N; and Q7represents N; R14a, R14b, R14c, R14d, R14e, R14f, R14g, and R14h, each independently are selected from the group consisting of hydrogen; halogen; C1-4alkyl; –NR15aR15b; and C1-4alkyl substituted with one or more halo atoms; R15aand R15beach independently are selected from the group consisting of hydrogen and C1-4alkyl; provided that R10and R11may not be linked together when R8and R9are linked together; and wherein at least one of R8, R9, R10and R11contains a nitrogen atom; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0244] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B), wherein R1represents hydrogen or CH3; R2represents hydrogen; Rarepresents hydrogen or –C(=O)-C1-4alkyl; Rbrepresents hydrogen or –C(=O)-C1-4alkyl; Y represents –O-, –CH2– or –CF2–; R7arepresents hydrogen; R7brepresents hydrogen, or C1-4alkyl optionally substituted with one or more halo atoms; X1represents a covalent bond or –O-; X2represents a covalent bond, -CH2-, -CF2-, -CH2CH2-, -CF2CH2-, or -CH2CF2-; provided that X2represents a covalent bond, -CH2- or -CF2-, when X1represents –O-; X3represents N or CH; or in case one of the dotted lines represents an additional bond, X3represents C; R8and R10each independently are selected from the group consisting of hydrogen; halo; and C1-6alkyl optionally substituted with one or more halo atoms; R9and R11each independently are selected from the group consisting of hydrogen; halo; -NH2; and C1-6alkyl optionally substituted with one –NR9aR9b; or R8and R9are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring 121PRD4277WOPCT1 N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1a; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR5aR5b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1a, -O-Ar1a, Het2aand –O-Het2c; or R10and R11are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1b; C3- 6cycloalkyl; -C1-4alkyl-C(=O)-NR6aR6b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1b, -O-Ar1b, Het2band –O-Het2d; Z represents -CH2-, -C(=O)-, or –CH(C1-4alkyl)-; and in case X3represents C, Z can also represent =CH-; the dotted lines attached to X3are optional bonds that may be present when X3represents a carbon atom, provided that maximum one of the dotted lines represents an optional bond; in case one of the dotted lines attached to X3represents an additional bond, X3represents C, and (i) R7ais absent or (ii) R8is absent or (iii) Z represents =CH-; R9aand R9beach independently are selected from the group consisting of hydrogen and C1-4alkyl; or R9aand R9bare linked together to form together with the common nitrogen atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl which optionally contains one oxygen atom; R5aand R5beach independently are selected from the group consisting of hydrogen and C1-4alkyl; Het1aand Het1bare attached to the remainder of the molecule of Formula (B) through any available ring carbon atom; Het1aand Het1beach independently represent a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two heteroatoms each independently selected from O, S, S(=O)p and N; 122PRD4277WOPCT1 Ar1aand Ar1beach independently represent phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo; cyano; and C1-4alkyl optionally substituted with one or more halo atoms; Het2aand Het2beach independently represent a 4-, 5-, 6- or 7-membered monocyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)p and N; or a fused 8-, 9-, 10- or 11-membered bicyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)pand N; said monocyclic heterocyclyl or said fused bicyclic heterocyclyl optionally being substituted with one or more substituents each independently selected from the group consisting of halo, cyano, and C1-4alkyl optionally substituted with one or more halo atoms; Het2cand Het2dare attached to the remainder of the molecule of Formula (B) through any available ring carbon atom; Het2cand Het2deach independently represent a 4-, 5-, 6- or 7-membered monocyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)p and N; or a fused 8-, 9-, 10- or 11-membered bicyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)pand N; said monocyclic heterocyclyl or said fused bicyclic heterocyclyl optionally being substituted with one or more substituents each independently selected from the group consisting of halo, cyano, and C1-4alkyl optionally substituted with one or more halo atoms; R6aand R6beach independently are selected from the group consisting of hydrogen and C1-4alkyl; p represents 1 or 2; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3); R3a, R3band R3ceach independently are selected from the group consisting of hydrogen, halo, -NR12aR12b, C1-4alkyl, and –O-C1-4alkyl; R12aand R12beach independently are selected from the group consisting of hydrogen; C3- 6cycloalkyl; C1-4alkyl; and C1-4alkyl substituted with one phenyl which is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, –OC1-4alkyl, -OH, and C1-4alkyl optionally substituted with one or more halo atoms; 123PRD4277WOPCT1 R4a, R4band R4ceach independently are selected from the group consisting of hydrogen, halo, -NR13aR13b, and C1-4alkyl; R13aand R13beach independently are selected from the group consisting of hydrogen and C1-4alkyl; Q1represents N or CR14a; Q2represents N or CR14b; Q3represents N or CR14c; Q4represents N or CR14d; provided that maximum one of Q3and Q4represents N; R14a, R14b, R14c, R14d, R14eand R14feach independently are selected from the group consisting of hydrogen; halogen; C1-4alkyl; –NR15aR15b; and C1-4alkyl substituted with one or more halo atoms; R15aand R15beach independently are selected from the group consisting of hydrogen and C1-4alkyl; provided that R10and R11may not be linked together when R8and R9are linked together; and wherein at least one of R8, R9, R10and R11contains a nitrogen atom; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0245] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B), wherein R1represents hydrogen or CH3; R2represents hydrogen; Rarepresents hydrogen; Rbrepresents hydrogen; Y represents –O-, –CH2– or –CF2–; R7arepresents hydrogen; R7brepresents hydrogen, or C1-4alkyl optionally substituted with one or more halo atoms; X1represents a covalent bond or –O-; X2represents a covalent bond, -CH2-,-CF2-, -CH2CH2-, -CF2CH2-, or -CH2CF2-; provided that X2represents a covalent bond, -CH2- or -CF2-, when X1represents –O-; X3represents N or CH; or in case one of the dotted lines represents an additional bond, X3represents C; R8and R10each independently are selected from the group consisting of hydrogen; halo; and C1-6alkyl optionally substituted with one or more halo atoms; 124PRD4277WOPCT1 R9and R11each independently are selected from the group consisting of hydrogen; halo; -NH2; and C1-6alkyl optionally substituted with one –NR9aR9b; or R8and R9are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1a; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR5aR5b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1a, -O-Ar1a, Het2aand –O-Het2c; or R10and R11are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1b; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR6aR6b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1b, -O-Ar1b, Het2band –O-Het2d; Z represents -CH2-, -C(=O)-, or –CH(C1-4alkyl)-; and in case X3represents C, Z can also represent =CH-; the dotted lines attached to X3are optional bonds that may be present when X3represents a carbon atom, provided that maximum one of the dotted lines represents an optional bond; in case one of the dotted lines attached to X3represents an additional bond, X3represents C, and (i) R7ais absent or (ii) R8is absent or (iii) Z represents =CH-; R9aand R9beach independently are selected from the group consisting of hydrogen and C1-4alkyl; or R9aand R9bare linked together to form together with the common nitrogen 125PRD4277WOPCT1 atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl which optionally contains one oxygen atom; R5aand R5beach independently are selected from the group consisting of hydrogen and C1-4alkyl; Het1aand Het1bare attached to the remainder of the molecule of Formula (B) through any available ring carbon atom; Het1aand Het1beach independently represent a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two heteroatoms each independently selected from O, S, S(=O)p and N; Ar1aand Ar1beach independently represent phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo; cyano; and C1-4alkyl optionally substituted with one or more halo atoms; Het2aand Het2beach independently represent a 4-, 5-, 6- or 7-membered monocyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)pand N; or a fused 8-, 9-, 10- or 11-membered bicyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)pand N; said monocyclic heterocyclyl or said fused bicyclic heterocyclyl optionally being substituted with one or more substituents each independently selected from the group consisting of halo, cyano, and C1-4alkyl optionally substituted with one or more halo atoms; Het2cand Het2dare attached to the remainder of the molecule of Formula (B) through any available ring carbon atom; Het2cand Het2deach independently represent a 4-, 5-, 6- or 7-membered monocyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)p and N; or a fused 8-, 9-, 10- or 11-membered bicyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)pand N; said monocyclic heterocyclyl or said fused bicyclic heterocyclyl optionally being substituted with one or more substituents each independently selected from the group consisting of halo, cyano, and C1-4alkyl optionally substituted with one or more halo atoms; R6aand R6beach independently are selected from the group consisting of hydrogen and C1-4alkyl; p represents 1 or 2; 126PRD4277WOPCT1 Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3); R3a, R3band R3ceach independently are selected from the group consisting of hydrogen, halo, -NR12aR12b, C1-4alkyl, and –O-C1-4alkyl; R12aand R12beach independently are selected from the group consisting of hydrogen; C3-6cycloalkyl; C1-4alkyl; and C1-4alkyl substituted with one phenyl which is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, –OC1-4alkyl, -OH, and C1-4alkyl optionally substituted with one or more halo atoms; R4a, R4band R4ceach independently are selected from the group consisting of hydrogen, halo, -NR13aR13b, and C1-4alkyl; R13aand R13beach independently are selected from the group consisting of hydrogen and C1-4alkyl; Q1represents N or CR14a; Q2represents N or CR14b; Q3represents N or CR14c; Q4represents N or CR14d; provided that maximum one of Q3and Q4represents N; R14a, R14b, R14c, R14d, R14eand R14feach independently are selected from the group consisting of hydrogen; halogen; C1-4alkyl; –NR15aR15b; and C1-4alkyl substituted with one or more halo atoms; R15aand R15beach independently are selected from the group consisting of hydrogen and C1-4alkyl; provided that R10and R11may not be linked together when R8and R9are linked together; and wherein at least one of R8, R9, R10and R11contains a nitrogen atom; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0246] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B), wherein R1represents hydrogen or CH3; R2represents hydrogen; Rarepresents –C(=O)-C1-4alkyl; Rbrepresents –C(=O)-C1-4alkyl; Y represents –O-, –CH2– or –CF2–; R7arepresents hydrogen; 127PRD4277WOPCT1 R7brepresents hydrogen, or C1-4alkyl optionally substituted with one or more halo atoms; X1represents a covalent bond or –O-; X2represents a covalent bond, -CH2-, -CF2-, -CH2CH2-, -CF2CH2-, or -CH2CF2-; provided that X2represents a covalent bond, -CH2- or -CF2-, when X1represents –O-; X3represents N or CH; or in case one of the dotted lines represents an additional bond, X3represents C; R8and R10each independently are selected from the group consisting of hydrogen; halo; and C1-6alkyl optionally substituted with one or more halo atoms; R9and R11each independently are selected from the group consisting of hydrogen; halo; -NH2; and C1-6alkyl optionally substituted with one –NR9aR9b; or R8and R9are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1a; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR5aR5b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1a, -O-Ar1a, Het2aand –O-Het2c; or R10and R11are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1b; C3- 6cycloalkyl; -C1-4alkyl-C(=O)-NR6aR6b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1b, -O-Ar1b, Het2band –O-Het2d; 128PRD4277WOPCT1 Z represents -CH2-, -C(=O)-, or –CH(C1-4alkyl)-; and in case X3represents C, Z can also represent =CH-; the dotted lines attached to X3are optional bonds that may be present when X3represents a carbon atom, provided that maximum one of the dotted lines represents an optional bond; in case one of the dotted lines attached to X3represents an additional bond, X3represents C, and (i) R7ais absent or (ii) R8is absent or (iii) Z represents =CH-; R9aand R9beach independently are selected from the group consisting of hydrogen and C1-4alkyl; or R9aand R9bare linked together to form together with the common nitrogen atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl which optionally contains one oxygen atom; R5aand R5beach independently are selected from the group consisting of hydrogen and C1-4alkyl; Het1aand Het1bare attached to the remainder of the molecule of Formula (B) through any available ring carbon atom; Het1aand Het1beach independently represent a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two heteroatoms each independently selected from O, S, S(=O)pand N; Ar1aand Ar1beach independently represent phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo; cyano; and C1-4alkyl optionally substituted with one or more halo atoms; Het2aand Het2beach independently represent a 4-, 5-, 6- or 7-membered monocyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)pand N; or a fused 8-, 9-, 10- or 11-membered bicyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)p and N; said monocyclic heterocyclyl or said fused bicyclic heterocyclyl optionally being substituted with one or more substituents each independently selected from the group consisting of halo, cyano, and C1-4alkyl optionally substituted with one or more halo atoms; Het2cand Het2dare attached to the remainder of the molecule of Formula (B) through any available ring carbon atom; Het2cand Het2deach independently represent a 4-, 5-, 6- or 7-membered monocyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each 129PRD4277WOPCT1 independently selected from O, S, S(=O)pand N; or a fused 8-, 9-, 10- or 11-membered bicyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)p and N; said monocyclic heterocyclyl or said fused bicyclic heterocyclyl optionally being substituted with one or more substituents each independently selected from the group consisting of halo, cyano, and C1-4alkyl optionally substituted with one or more halo atoms; R6aand R6beach independently are selected from the group consisting of hydrogen and C1-4alkyl; p represents 1 or 2; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3); R3a, R3band R3ceach independently are selected from the group consisting of hydrogen, halo, -NR12aR12b, C1-4alkyl, and –O-C1-4alkyl; R12aand R12beach independently are selected from the group consisting of hydrogen; C3-6cycloalkyl; C1-4alkyl; and C1-4alkyl substituted with one phenyl which is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, –OC1-4alkyl, -OH, and C1-4alkyl optionally substituted with one or more halo atoms; R4a, R4band R4ceach independently are selected from the group consisting of hydrogen, halo, -NR13aR13b, and C1-4alkyl; R13aand R13beach independently are selected from the group consisting of hydrogen and C1-4alkyl; Q1represents N or CR14a; Q2represents N or CR14b; Q3represents N or CR14c; Q4represents N or CR14d; provided that maximum one of Q3and Q4represents N; R14a, R14b, R14c, R14d, R14eand R14feach independently are selected from the group consisting of hydrogen; halogen; C1-4alkyl; –NR15aR15b; and C1-4alkyl substituted with one or more halo atoms; R15aand R15beach independently are selected from the group consisting of hydrogen and C1-4alkyl; provided that R10and R11may not be linked together when R8and R9are linked together; 130PRD4277WOPCT1 and wherein at least one of R8, R9, R10and R11contains a nitrogen atom; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0247] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B), wherein R1represents hydrogen or CH3; in particular hydrogen; R2represents hydrogen; Rarepresents hydrogen or –C(=O)-C1-4alkyl; Rbrepresents hydrogen or –C(=O)-C1-4alkyl; Y represents –O- or –CH2–; R7arepresents hydrogen; R7brepresents hydrogen, or C1-4alkyl optionally substituted with one or more halo atoms; X1represents a covalent bond or –O-; X2represents a covalent bond, -CH2-, -CF2CH2-, or -CH2CF2-; provided that X2represents a covalent bond or -CH2-, when X1represents –O-; X3represents N; or in case one of the dotted lines represents an additional bond, X3represents C; R8and R10each independently are selected from the group consisting of hydrogen; halo; and C1-6alkyl optionally substituted with one or more halo atoms; R9and R11each independently are selected from the group consisting of hydrogen; halo; -NH2; and C1-6alkyl optionally substituted with one –NR9aR9b; or R8and R9are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1a; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR5aR5b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1a, -O-Ar1a, and Het2a; or R10and R11are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more halo substituents; and wherein said 4-, 5-, 6- or 7-membered saturated 131PRD4277WOPCT1 heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; and C1-4alkyl substituted with one Ar1b; Z represents -CH2- or -C(=O)-; and in case X3represents C, Z can also represent =CH-; the dotted lines attached to X3are optional bonds that may be present when X3represents a carbon atom, provided that maximum one of the dotted lines represents an optional bond; in case one of the dotted lines attached to X3represents an additional bond, X3represents C, and (i) R7ais absent or (ii) R8is absent or (iii) Z represents =CH-; R9aand R9beach independently are selected from the group consisting of hydrogen and C1-4alkyl; or R9aand R9bare linked together to form together with the common nitrogen atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl which optionally contains one oxygen atom; R5aand R5beach independently are selected from the group consisting of hydrogen and C1-4alkyl; Het1ais attached to the remainder of the molecule of Formula (B) through any available ring carbon atom; Het1arepresents a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two heteroatoms each independently selected from O; Ar1aand Ar1beach independently represent phenyl optionally substituted with one or more halo substituents; Het2arepresents a 4-, 5-, 6- or 7-membered monocyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)p and N; or a fused 8-, 9-, 10- or 11-membered bicyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)p and N; said monocyclic heterocyclyl or said fused bicyclic heterocyclyl optionally being substituted with one or more C1-4alkyl substituents; p represents 1 or 2; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3); R3a, R3band R3ceach independently are selected from the group consisting of hydrogen, halo, and -NR12aR12b; 132PRD4277WOPCT1 R12aand R12beach independently are selected from the group consisting of hydrogen; C3-6cycloalkyl; C1-4alkyl; and C1-4alkyl substituted with one phenyl which is optionally substituted with one or more halo substituents; R4a, R4band R4ceach independently are selected from the group consisting of hydrogen and C1-4alkyl; Q1represents CR14a; Q2represents N or CR14b; Q3represents CR14c; Q4represents N; R14a, R14b, R14c, R14eand R14feach independently are selected from the group consisting of hydrogen and halogen; provided that R10and R11may not be linked together when R8and R9are linked together; and wherein at least one of R8, R9, R10and R11contains a nitrogen atom; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0248] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B), wherein R1represents hydrogen or CH3; in particular hydrogen; R2represents hydrogen; Rarepresents hydrogen or –C(=O)-C1-4alkyl; Rbrepresents hydrogen or –C(=O)-C1-4alkyl; Y represents –O- or –CH2–; R7arepresents hydrogen; R7brepresents hydrogen, or C1-4alkyl optionally substituted with one or more halo atoms; X1represents a covalent bond or –O-; X2represents a covalent bond, -CH2-,-CF2CH2-, or -CH2CF2-; provided that X2represents a covalent bond or -CH2-, when X1represents –O-; X3represents N; or in case one of the dotted lines represents an additional bond, X3represents C; R8and R10each independently are selected from the group consisting of hydrogen; halo; and C1-6alkyl optionally substituted with one or more halo atoms; R9and R11each independently are selected from the group consisting of hydrogen; halo; -NH2; and C1-6alkyl optionally substituted with one –NR9aR9b; or R8and R9are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or 133PRD4277WOPCT1 two N-atoms; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1a; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR5aR5b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1a, -O-Ar1a, and Het2a; or R10and R11are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more halo substituents; and wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; and C1-4alkyl substituted with one Ar1b; Z represents -CH2- or -C(=O)-; and in case X3represents C, Z can also represent =CH-; the dotted lines attached to X3are optional bonds that may be present when X3represents a carbon atom, provided that maximum one of the dotted lines represents an optional bond; in case one of the dotted lines attached to X3represents an additional bond, X3represents C, and (i) R7ais absent or (ii) R8is absent or (iii) Z represents =CH-; R9aand R9beach independently are selected from the group consisting of hydrogen and C1-4alkyl; or R9aand R9bare linked together to form together with the common nitrogen atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl which optionally contains one oxygen atom; R5aand R5beach independently are selected from the group consisting of hydrogen and C1-4alkyl; Het1ais attached to the remainder of the molecule of Formula (B) through any available ring carbon atom; Het1arepresents a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two heteroatoms each independently selected from O; Ar1aand Ar1beach independently represent phenyl optionally substituted with one or more halo substituents; Het2arepresents a 4-, 5-, 6- or 7-membered monocyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, 134PRD4277WOPCT1 S(=O)pand N; or a fused 8-, 9-, 10- or 11-membered bicyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)p and N; said monocyclic heterocyclyl or said fused bicyclic heterocyclyl optionally being substituted with one or more C1-4alkyl substituents; p represents 1 or 2; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3) and (a-4); R3a, R3b, R3cand R3deach independently are selected from the group consisting of hydrogen, halo, and -NR12aR12b; R12aand R12beach independently are selected from the group consisting of hydrogen; C3-6cycloalkyl; C1-4alkyl; and C1-4alkyl substituted with one phenyl which is optionally substituted with one or more halo substituents; R4a, R4b, R4cand R4deach independently are selected from the group consisting of hydrogen and C1-4alkyl; R4frepresent hydrogen; Q1represents CR14a; Q2represents N or CR14b; Q3represents CR14c; Q4represents N; Q8represents CR14g; Q9represents CR14h; Q5represents CR3d; Q6represents N; and Q7represents CR4f; R14a, R14b, R14c, R14eand R14feach independently are selected from the group consisting of hydrogen and halogen; R14gand R14hrepresent hydrogen; provided that R10and R11may not be linked together when R8and R9are linked together; and wherein at least one of R8, R9, R10and R11contains a nitrogen atom; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0249] In another embodiment, the PRMT5 inhibitor is a compound of Formula (B), or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein one or more of the following restrictions apply: (i) R1represents hydrogen; 135PRD4277WOPCT1 (ii) Y represents –O- or –CH2–; (iii) X2represents a covalent bond, -CH2-, -CF2CH2-, or -CH2CF2-; provided that X2represents a covalent bond or -CH2-, when X1represents –O-; (iv) X3represents N; or in case one of the dotted lines represents an additional bond, X3represents C; (v) R8and R10each independently are selected from the group consisting of hydrogen; halo; and C1-6alkyl optionally substituted with one or more halo atoms; R9and R11each independently are selected from the group consisting of hydrogen; halo; -NH2; and C1-6alkyl optionally substituted with one –NR9aR9b; or R8and R9are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1a; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR5aR5b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1a, -O-Ar1a, and Het2a; or R10and R11are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more halo substituents; and wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; and C1-4alkyl substituted with one Ar1b; (vi) Z represents -CH2- or -C(=O)-; and in case X3represents C, Z can also represent =CH-; the dotted lines attached to X3are optional bonds that may be present when X3represents a carbon atom, provided that maximum one of the dotted lines represents an optional bond; in case one of the dotted lines attached to X3represents an additional bond, X3represents C, and (i) R7ais absent or (ii) R8is absent or (iii) Z represents =CH-; (vii) Het1ais attached to the remainder of the molecule of Formula (B) through any available ring carbon atom; 136PRD4277WOPCT1 Het1arepresents a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two heteroatoms each independently selected from O; (viii) Ar1aand Ar1beach independently represent phenyl optionally substituted with one or more halo substituents; (ix) Het2arepresents a 4-, 5-, 6- or 7-membered monocyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)pand N; or a fused 8-, 9-, 10- or 11-membered bicyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)p and N; said monocyclic heterocyclyl or said fused bicyclic heterocyclyl optionally being substituted with one or more C1-4alkyl substituents; (x) R3a, R3band R3ceach independently are selected from the group consisting of hydrogen, halo, and -NR12aR12b; (xi) R12aand R12beach independently are selected from the group consisting of hydrogen; C3-6cycloalkyl; C1-4alkyl; and C1-4alkyl substituted with one phenyl which is optionally substituted with one or more halo substituents; (xii) R4a, R4band R4ceach independently are selected from the group consisting of hydrogen and C1-4alkyl; (xiii) Q1represents CR14a; (xiv) Q2represents N or CR14b; (xv) Q3represents CR14c; (xvi) Q4represents N; (xvii) R14a, R14b, R14c, R14eand R14feach independently are selected from the group consisting of hydrogen and halogen. In an embodiment, the PRMT5 inhibitor is a compound of Formula (B), wherein R1represents hydrogen; R2represents hydrogen; Rarepresents hydrogen or –C(=O)-C1-4alkyl; Rbrepresents hydrogen or –C(=O)-C1-4alkyl; Y represents –O- or –CH2–; R7arepresents hydrogen; R7brepresents hydrogen; X1represents a covalent bond or –O-; X2represents a covalent bond or -CH2-; 137PRD4277WOPCT1 X3represents N; or in case one of the dotted lines represents an additional bond, X3represents C; R8and R10each independently are selected from the group consisting of hydrogen and halo; R9and R11each independently are selected from the group consisting of hydrogen and halo; or R8and R9are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one N- atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one ring N-atom with C1-6alkyl; or R10and R11are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one N-atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one ring N-atom with C1-6alkyl; provided that R10and R11, or R8and R9are linked together; Z represents -CH2-; and in case X3represents C, Z can also represent =CH-; the dotted lines attached to X3are optional bonds that may be present when X3represents a carbon atom, provided that maximum one of the dotted lines represents an optional bond; in case one of the dotted lines attached to X3represents an additional bond, X3represents C, and (i) R7ais absent or (ii) R8is absent or (iii) Z represents =CH-; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2); R3aand R3crepresent NH2; R4aand R4crepresent hydrogen; Q1represents CR14a; Q2represents CR14b; R14a, R14b, R14eand R14feach independently are selected from the group consisting of hydrogen and halogen; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0250] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof 138PRD4277WOPCT1 as mentioned in any of the other embodiments, wherein the compounds of Formula (B) are restricted to the compounds of Formula (B-1): (I-1)(B-1), wherein all variables are defined as for compounds of Formula (B) or any subgroup thereof as mentioned in any of the other embodiments.

[0251] In an embodiment, PRMT5 inhibitor is a compound of Formula (B-1) (I-1)(B-1), wherein R1represents hydrogen; R2represents hydrogen; Rarepresents hydrogen or –C(=O)-C1-4alkyl; Rbrepresents hydrogen or –C(=O)-C1-4alkyl; Y represents –O- or –CH2–; R7arepresents hydrogen; R7brepresents hydrogen; X1represents a covalent bond or –O-; X2represents a covalent bond or -CH2-; X3represents N; or in case one of the dotted lines represents an additional bond, X3represents C; R10represents hydrogen or halo; 139PRD4277WOPCT1 R11represents hydrogen or halo; R8and R9are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one N- atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one ring N-atom with C1-6alkyl; Z represents -CH2-; and in case X3represents C, Z can also represent =CH-; the dotted lines attached to X3are optional bonds that may be present when X3represents a carbon atom, provided that maximum one of the dotted lines represents an optional bond; in case one of the dotted lines attached to X3represents an additional bond, X3represents C, and (i) R7ais absent or (iii) Z represents =CH-; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1); R3arepresents NH2; R4arepresents hydrogen; Q1represents CR14a; Q2represents CR14b; R14aand R14beach independently are selected from the group consisting of hydrogen and halogen; in particular R14arepresents hydrogen; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0252] In another embodiment, the PRMT5 inhibitor is a compound of Formula (B), or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein one or more of the following restrictions apply: (i) R1represents hydrogen; (ii) Y represents –O- or –CH2–; (iii) R7brepresents hydrogen; (iv) X2represents a covalent bond or -CH2-; (v) X3represents N; or in case one of the dotted lines represents an additional bond, X3represents C; (vi) R8and R10each independently are selected from the group consisting of hydrogen and halo; R9and R11each independently are selected from the group consisting of hydrogen and halo; 140PRD4277WOPCT1 or R8and R9are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one N- atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one ring N-atom with C1-6alkyl; or R10and R11are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one N-atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one ring N-atom with C1-6alkyl; (vii) Z represents -CH2-; and in case X3represents C, Z can also represent =CH-; the dotted lines attached to X3are optional bonds that may be present when X3represents a carbon atom, provided that maximum one of the dotted lines represents an optional bond; in case one of the dotted lines attached to X3represents an additional bond, X3represents C, and (i) R7ais absent or (ii) R8is absent or (iii) Z represents =CH-; (viii) Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2); (ix) R3aand R3crepresent NH2; (x) R4aand R4crepresent hydrogen; (xi) Q1represents CR14a; (xii) Q2represents CR14b; (xiii) R14a, R14b, R14eand R14feach independently are selected from the group consisting of hydrogen and halogen.

[0253] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Raand Rbrepresent hydrogen.

[0254] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Rarepresents–C(=O)-C1-4alkyl; Rbrepresents–C(=O)-C1-4alkyl.

[0255] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof 141PRD4277WOPCT1 as mentioned in any of the other embodiments, wherein the compounds of Formula (B) are restricted to the compounds of Formula (B-1) (I-1)(B-1), wherein R8and R9are always linked together.

[0256] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (B) are restricted to the compounds of Formula (B-1), wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), and wherein R8and R9are always linked together.

[0257] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (B) are restricted to the compounds of Formula (B-2): (I-2)(B-2), wherein all variables are defined as for compounds of Formula (B) or any subgroup thereof as mentioned in any of the other embodiments.

[0258] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof 142PRD4277WOPCT1 as mentioned in any of the other embodiments, wherein the compounds of Formula (B) are restricted to the compounds of Formula (B-2) (I-2)(B-2), wherein R8and R9are always linked together.

[0259] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R8and R9are always linked together.

[0260] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (B) are restricted to the compounds of Formula (B-3) (I-3)(B-3), wherein all variables are defined as for compounds of Formula (B) or any subgroup thereof as mentioned in any of the other embodiments.

[0261] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof 143PRD4277WOPCT1 as mentioned in any of the other embodiments, wherein the compounds of Formula (B) are restricted to the compounds of Formula (B-3a) (I-3a)(B-3a), wherein all variables are defined as for compounds of Formula (B) or any subgroup thereof as mentioned in any of the other embodiments.

[0262] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (B) are restricted to the compounds of Formula (B-3a) (I-3a)(B-3a), wherein R8and R9are always linked together.

[0263] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (B) are restricted to the compounds of Formula (B-3) 144PRD4277WOPCT1 (I-3)(B-3), and wherein at least one of the dotted lines represents an additional bond.

[0264] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (B) are restricted to the compounds of Formula (B-3a) (I-3a)(B-3a), wherein R8and R9are always linked together, and wherein at least one of the dotted lines represents an additional bond.

[0265] All variables in the structures of Formula (B-1), (I-2), (I-3) or (I-3a), may be defined as defined for the compounds of Formula (B) or any subgroup thereof as mentioned in any of the other embodiments.

[0266] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein at least one of the dotted lines, where possible, represent an additional bond. 145PRD4277WOPCT1

[0267] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X3represents N.

[0268] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X3represents C or CH.

[0269] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R10and R11, or R8and R9are linked together.

[0270] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), and wherein R8and R9are always linked together.

[0271] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), and wherein R10and R11, or R8and R9are linked together.

[0272] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R8and R10each independently are selected from the group consisting of hydrogen; halo; and C1-6alkyl optionally substituted with one or more halo atoms; R9and R11each independently are selected from the group consisting of hydrogen; halo; -NH2; and C1-6alkyl optionally substituted with one –NR9aR9b; or R8and R9are linked together to form together with the common carbon atom to which they are attached a 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 5-, 6- or 7- 146PRD4277WOPCT1 membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1a; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR5aR5b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1a, -O-Ar1a, Het2aand –O-Het2c; or R10and R11are linked together to form together with the common carbon atom to which they are attached a 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N- atoms with a substituent selected from the group consisting of C1-6alkyl; Het1b; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR6aR6b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1b, -O-Ar1b, Het2band –O-Het2d.

[0273] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X2is other than a covalent bond; R8and R10each independently are selected from the group consisting of hydrogen; halo; and C1-6alkyl optionally substituted with one or more halo atoms; R9and R11each independently are selected from the group consisting of hydrogen; halo; -NH2; and C1-6alkyl optionally substituted with one –NR9aR9b; or R8and R9are linked together to form together with the common carbon atom to which they are attached a 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 5-, 6- or 7- membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1a; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR5aR5b; C1-4alkyl substituted with one or more halo atoms; and C1- 147PRD4277WOPCT14alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1a, -O-Ar1a, Het2aand –O-Het2c; or R10and R11are linked together to form together with the common carbon atom to which they are attached a 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N- atoms with a substituent selected from the group consisting of C1-6alkyl; Het1b; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR6aR6b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1b, -O-Ar1b, Het2band –O-Het2d.

[0274] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X1is a covalent bond; X2is other than a covalent bond; R8and R10each independently are selected from the group consisting of hydrogen; halo; and C1-6alkyl optionally substituted with one or more halo atoms; R9and R11each independently are selected from the group consisting of hydrogen; halo; -NH2; and C1-6alkyl optionally substituted with one –NR9aR9b; or R8and R9are linked together to form together with the common carbon atom to which they are attached a 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 5-, 6- or 7- membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1a; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR5aR5b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1a, -O-Ar1a, Het2aand –O-Het2c; 148PRD4277WOPCT1 or R10and R11are linked together to form together with the common carbon atom to which they are attached a 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N- atoms with a substituent selected from the group consisting of C1-6alkyl; Het1b; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR6aR6b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1b, -O-Ar1b, Het2band –O-Het2d.

[0275] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X1is a covalent bond; X2is other than a covalent bond; R8and R10each independently are selected from the group consisting of hydrogen; halo; and C1-6alkyl optionally substituted with one or more halo atoms; R9and R11each independently are selected from the group consisting of hydrogen; halo; -NH2; and C1-6alkyl optionally substituted with one –NR9aR9b; or R8and R9are linked together to form together with the common carbon atom to which they are attached a 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 5-, 6- or 7- membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1a; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR5aR5b; C1-4alkyl substituted with one or more halo atoms; and C1- 4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1a, -O-Ar1a, Het2aand –O-Het2c; or R10and R11are linked together to form together with the common carbon atom to which they are attached a 5-, 6- or 7-membered saturated heterocyclyl, containing one or 149PRD4277WOPCT1 two N-atoms and optionally one oxygen atom; wherein said 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N- atoms with a substituent selected from the group consisting of C1-6alkyl; Het1b; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR6aR6b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1b, -O-Ar1b, Het2band –O-Het2d; Het represents (a-1).

[0276] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X1is a covalent bond; X2is other than a covalent bond; R8and R9are linked together to form together with the common carbon atom to which they are attached a 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 5-, 6- or 7- membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1a; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR5aR5b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1a, -O-Ar1a, Het2aand –O-Het2c; R10is selected from the group consisting of hydrogen; halo; and C1-6alkyl optionally substituted with one or more halo atoms; R11is selected from the group consisting of hydrogen; halo; -NH2; and C1-6alkyl optionally substituted with one –NR9aR9b; Het represents (a-1). 150PRD4277WOPCT1

[0277] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X1represents a covalent bond.

[0278] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein all 4-, 5-, 6- or 7-membered saturated heterocyclyls are restricted to 5-, 6- or 7-membered saturated heterocyclyls, each of which may be optionally substituted according to any of the other embodiments; X1represents a covalent bond; and Het represents (a-1).

[0279] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y represents –CH2- or –CF2-; in particular wherein Y represents –CH2-.

[0280] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein maximum one of Q1and Q2represents N.

[0281] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Q1represents CR14a; and Q2represents CR14b; in particular wherein Q1represents CH; and Q2represents CH.

[0282] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents (a-1); Q1represents CR14a; and Q2represents CR14b; in particular wherein Q1represents CH; and Q2represents CH.

[0283] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R1and R2represent hydrogen; and Y represents –O-.

[0284] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof 151PRD4277WOPCT1 as mentioned in any of the other embodiments, wherein Raand Rbrepresent hydrogen; and Y represents –O-.

[0285] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Raand Rbrepresent hydrogen; R1and R2represent hydrogen; and Y represents –O-.

[0286] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2).

[0287] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a bicyclic aromatic heterocyclic ring system of Formula (a-1).

[0288] In an embodiment, the present invention relates to any one of the compounds of Formula (B-1), (I-2), (I-3) or (I-3a), wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2), in particular wherein Het represents a bicyclic aromatic heterocyclic ring system of Formula (a-1).

[0289] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3) and (a-4); R3a, R3b, R3cand R3deach independently are selected from the group consisting of hydrogen, halo, and -NR12aR12b; R12aand R12beach independently are selected from the group consisting of hydrogen; C3-6cycloalkyl; C1-4alkyl; and C1-4alkyl substituted with one phenyl which is optionally substituted with one or more halo substituents; R4a, R4b, R4cand R4deach independently are selected from the group consisting of hydrogen and C1-4alkyl; R4frepresent hydrogen; Q1represents CR14a; 152PRD4277WOPCT1 Q2represents N or CR14b; Q3represents CR14c; Q4represents N; Q8represents CR14g; Q9represents CR14h; Q5represents CR3d; Q6represents N; and Q7represents CR4f; R14a, R14b, R14c, R14eand R14feach independently are selected from the group consisting of hydrogen and halogen; R14gand R14hrepresent hydrogen.

[0290] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R1and R2represent hydrogen.

[0291] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R1and R2represent hydrogen; Y represents –O-; and Het represents a bicyclic aromatic heterocyclic ring system of Formula (a-1).

[0292] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Raand Rbrepresent hydrogen; Y represents –O-; and Het represents a bicyclic aromatic heterocyclic ring system of Formula (a-1).

[0293] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Raand Rbrepresent hydrogen; R1and R2represent hydrogen; Y represents –O-; and Het represents a bicyclic aromatic heterocyclic ring system of Formula (a-1).

[0294] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3a, R3c, R3brepresent hydrogen; and R4a, R4c, R4brepresent hydrogen, halo, or C1-4alkyl; in particular R4a, R4c, R4brepresent halo, or C1-4alkyl. 153PRD4277WOPCT1

[0295] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3a, R3c, R3brepresent hydrogen, halo, -NR12aR12b, or –O-C1-4alkyl; in particular R3a, R3c, R3brepresent halo, -NR12aR12b, or –O-C1-4alkyl; R4a, R4c, R4brepresent hydrogen.

[0296] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3a, R3c, R3brepresent hydrogen, when R4a, R4c, R4bare different from hydrogen.

[0297] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R4a, R4c, R4brepresent hydrogen, when R3a, R3c, R3bare different from hydrogen.

[0298] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R7aand R7brepresent hydrogen.

[0299] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents (a-1); R3arepresents –NR12aR12b; and R12aand R12brepresent hydrogen.

[0300] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3a, R3band R3crepresent other than halo.

[0301] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3a, R3band R3crepresent –NH2.

[0302] In an embodiment, the PRMT5 inhibitor is a compound of Formula (B) or a pharmaceutically acceptable addition salt, or a solvate thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het2a,Het2b, Het2cand Het2dare aromatic. 154PRD4277WOPCT1

[0303] In the context of Formula (B), the following definitions apply, unless a context dictates otherwise.

[0304] The expression "at least one" in particular means "one, two or three", more in particular "one or two", even more in particular "one".

[0305] Het2aand Het2bmay be attached to the remainder of the molecule of formula (B) through any available ring carbon or heteroatom as appropriate, if not otherwise specified. Thus, for example, when the heterocyclyl is imidazolyl, it may be 1- imidazolyl, 2-imidazolyl, 4-imidazolyl and the like.

[0306] It will be clear for the skilled person that, unless otherwise is indicated or is clear from the context, a substituent on a 4-, 5-, 6- or 7-membered monocyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)p and N (as in the definition of Het2a, Het2b, Het2cand Het2d), may replace any hydrogen atom on a ring carbon atom or where possible on a ring nitrogen atom (in which case a hydrogen on a nitrogen atom may be replaced by a substituent).

[0307] The term “C1-6alkyl” as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms such as the groups defined for C1-4alkyl and n-pentyl, n-hexyl, 2-methylbutyl and the like.

[0308] In case Z is =CH-, it is intended that the double bond is attached to X3being C.

[0309] Whenever substituents are represented by chemical structure, " --- " represents the bond of attachment to the remainder of the molecule of Formula (B). Lines drawn from substituents into ring systems indicate that the bond may be attached to any of the suitable ring atoms.

[0310] Non-limiting examples of Het1aand Het1bare carbon- linked oxetanyl (e.g., 3- oxetanyl), piperidinyl, tetrahydrofuranyl, pyrrolidinyl, thiolanyl, piperazinyl, tetrahydropyranyl and the like.

[0311] Non-limiting examples of Het2cand Het2dare carbon- linked oxetanyl (e.g., 3- oxetanyl), piperidinyl, tetrahydrofuranyl, pyrrolidinyl, thiolanyl, piperazinyl, tetrahydropyranyl, pyridinyl, furanyl, pyrizazinyl, thiazolyl, benzimidazolyl and the like; each of which may optionally be substituted, where possible, on carbon and / or nitrogen atoms according to any of the embodiments. 155PRD4277WOPCT1

[0312] Non-limiting examples of Het2aand Het2bare carbon- or nitrogen- linked oxetanyl, piperidinyl, tetrahydrofuranyl, pyrrolidinyl, thiolanyl, piperazinyl, tetrahydropyranyl, pyridinyl, furanyl, pyrizazinyl, thiazolyl, benzimidazolyl and the like; each of which may optionally be substituted, where possible, on carbon and / or nitrogen atoms according to any of the embodiments.

[0313] Non-limiting examples of R8and R9, or R10and R11, taken together to form a 4-, 5-, 6-or 7-membered saturated heterocyclyl, are piperidinyl, azetidinyl, pyrrolidinyl, morpholinyl, hexahydro-1H-azepinyl; each of which may optionally be substituted, where possible, on carbon and / or nitrogen atoms according to any of the embodiments.

[0314] In one embodiment, the PRMT5 inhibitor is a compound of Formula (C): (I)(C), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents 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 R5ieach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents 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 156PRD4277WOPCT1 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 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- CR5fR5h- or -CR5aR5b-CR5cR5d-CR5eR5g-CR5fR5h-; or 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)(b-1) (b-2) (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; R10represents -(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 157PRD4277WOPCT1 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, R13and R14; R13represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O)pand 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; R14represents 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-3):R3a, R3dand R3eeach independently represent hydrogen, halo, -NR7aR7b, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, –OH, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; R4a, R4d, R4e, R4fand R4geach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents N or CR6a; Q2represents N or CR6b; Q8represents N or CR6g; Q9represents N or CR6h; Q10represents N or CR6i; Q11represents N or CR6j; Q5represents CR3d; Q6represents N; and Q7represents CR4f; or Q5represents CR3d; Q6represents CR4e; and Q7represents N; or 158PRD4277WOPCT1 Q5represents N; Q6represents CR4e; and Q7represents CR4f; or Q5represents N; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents N; and Q7represents CR4f; or Q5represents N; Q6represents N; and Q7represents N; R6a, R6b, R6g, R6h, R6iand R6jeach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0315] In an embodiment, the PRMT5 inhibitor is a compound of Formula (C), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; Y represents –CH2– or –CF2–; Z represents –CH2-, -CHR5i-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, -CR5cR5d-CR5eR5g-CR5fR5h-, or -CR5aR5b-CR5cR5d-CR5eR5g-CR5fR5h-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, R5h, and R5ieach independently represent hydrogen or C1-4alkyl; X represents –O-; R11represents 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; 159PRD4277WOPCT1 provided that in case Ar represents a 10-membered bicyclic aromatic ring system, Z can only represent -CR5cR5d-CR5eR5g-CR5fR5h- 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)(b-1) (b-2) (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; R10represents -(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, R13and R14; R13represents 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; 160PRD4277WOPCT1 R14represents 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 (a-1); R3arepresents halo, -NR7aR7b, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; R4arepresents hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents CR6a; Q2represents CR6b; R6aand R6beach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0316] In an embodiment, the PRMT5 inhibitor is a compound of Formula (C), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; Y represents –CH2– or –CF2–; Z represents –CH2-, -CHR5i-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, -CR5cR5d-CR5eR5g-CR5fR5h-, or -CR5aR5b-CR5cR5d-CR5eR5g-CR5fR5h-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, R5h, and R5ieach independently represent hydrogen or C1-4alkyl; R11represents 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 161PRD4277WOPCT1 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-CR5fR5h- 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)(b-1) (b-2) (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; R10represents -(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; 162PRD4277WOPCT1 or C1-4alkyl substituted with one substituent selected from the group consisting of C3-6cycloalkyl, R13and R14; R13represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O)pand 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; R14represents 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 (a-1); R3arepresents halo, -NR7aR7b, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; R4arepresents hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents CR6a; Q2represents CR6b; R6aand R6beach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0317] In an embodiment, the PRMT5 inhibitor is a compound of Formula (C), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; Y represents –CH2– or –CF2–; Z represents –CH2-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, -CR5aR5b-X-, or -C^C-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5heach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents 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 selected from pyridinyl and imidazolyl; or 163PRD4277WOPCT1 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; 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, -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; R10represents -(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, R13and R14; R13represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O)pand 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; R14represents 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-3); R3a, R3dand R3eeach independently represent hydrogen, halo, -NR7aR7b, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, –OH, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; 164PRD4277WOPCT1 R4a, R4d, R4e, R4fand R4geach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents N or CR6a; Q2represents N or CR6b; Q8represents N or CR6g; Q9represents N or CR6h; Q10represents N or CR6i; Q11represents N or CR6j; Q5represents CR3d; Q6represents N; and Q7represents CR4f; or Q5represents CR3d; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents CR4e; and Q7represents CR4f; or Q5represents N; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents N; and Q7represents CR4f; or Q5represents N; Q6represents N; and Q7represents N; R6a, R6b, R6g, R6h, R6iand R6jeach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0318] In an embodiment, the PRMT5 inhibitor is a compound of Formula (C), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents 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 R5ieach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents 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; 165PRD4277WOPCT1 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-CR5fR5h- 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)(b-1) (b-2) (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 166PRD4277WOPCT1 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; R10represents -(C=O)-C1-4alkyl; C3-6cycloalkyl; 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, and R14; R14represents 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-3):;R3a, R3dand R3eeach independently represent hydrogen, halo, -NR7aR7b, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, –OH, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; R4a, R4d, R4e, R4fand R4geach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents N or CR6a; Q2represents N or CR6b; Q8represents N or CR6g; Q9represents N or CR6h; Q10represents N or CR6i; Q11represents N or CR6j; Q5represents CR3d; Q6represents N; and Q7represents CR4f; or 167PRD4277WOPCT1 Q5represents CR3d; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents CR4e; and Q7represents CR4f; or Q5represents N; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents N; and Q7represents CR4f; or Q5represents N; Q6represents N; and Q7represents N; R6a, R6b, R6g, R6h, R6iand R6jeach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl;

[0319] In an embodiment, the PRMT5 inhibitor is a compound of Formula (C), wherein R1represents hydrogen; R2represents hydrogen; Y represents –CH2–; Z represents –CH2-, -CHR5i-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, -CR5cR5d-CR5eR5g-CR5fR5h-, or -CR5aR5b-CR5cR5d-CR5eR5g-CR5fR5h-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, R5h, and R5ieach independently represent hydrogen or C1-4alkyl; X represents –O-; 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 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-CR5fR5h- or -CR5aR5b-CR5cR5d-CR5eR5g-CR5fR5h-; or 168PRD4277WOPCT1 (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) and (b-3), wherein ring A is pyridinyl; wherein ring B is a 5- to 6-membered saturated heterocyclyl containing one or two heteroatoms each independently selected from O 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, -NH2, - NH-C1-4alkyl, -CF3, C3-6cycloalkyl, and C1-4alkyl; and where possible Ar is optionally substituted on one N-atom with one C1-4alkyl; Het represents a bicyclic aromatic heterocyclic ring system (a-1); R3arepresents halo, -NR7aR7b, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; R4arepresents hydrogen; Q1represents CR6a; Q2represents N or CR6b; R6aand R6beach independently represent hydrogen or halogen; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0320] In an embodiment, the PRMT5 inhibitor is a compound of Formula (C), wherein R1represents hydrogen; R2represents hydrogen; Y represents –CH2–; Z represents –CH2-, -CHR5i-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, -CR5cR5d-CR5eR5g-CR5fR5h-, or -CR5aR5b-CR5cR5d-CR5eR5g-CR5fR5h-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, R5h, and R5ieach independently represent hydrogen or C1-4alkyl; X represents –O-; 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 169PRD4277WOPCT1 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 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-CR5fR5h- 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) and (b-3), wherein ring A is pyridinyl; wherein ring B is a 5- to 6-membered saturated heterocyclyl containing one or two heteroatoms each independently selected from O 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, -NH2, - NH-C1-4alkyl, -CF3, C3-6cycloalkyl, and C1-4alkyl; and where possible Ar is optionally substituted on one N-atom with one C1-4alkyl; Het represents a bicyclic aromatic heterocyclic ring system (a-1); R3arepresents halo, -NR7aR7b, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; R4arepresents hydrogen; Q1represents CR6a; Q2represents CR6b; R6aand R6beach independently represent hydrogen or halogen; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0321] In an embodiment, the PRMT5 inhibitor is a compound of Formula (C), wherein R1represents hydrogen; R2represents hydrogen; Y represents –CH2–; 170PRD4277WOPCT1 Z represents –CH2-, -CHR5i-, -X-CR5aR5b-, -CR5c=CR5d-, -CR5eR5g-CR5fR5h-, -CR5cR5d-CR5eR5g-CR5fR5h-, or -CR5aR5b-CR5cR5d-CR5eR5g-CR5fR5h-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, R5h, and R5ieach independently represent hydrogen or C1-4alkyl; X represents –O-; 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 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-CR5fR5h- 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) and (b-3), wherein ring A is pyridinyl; wherein ring B is a 5- to 6-membered saturated heterocyclyl containing one or two heteroatoms each independently selected from O 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, -NH2, - NH-C1-4alkyl, –NHR10, -CF3, C3-6cycloalkyl, and C1-4alkyl; and where possible Ar is optionally substituted on one N-atom with one C1-4alkyl; R10represents -(C=O)-C1-4alkyl; Het represents a bicyclic aromatic heterocyclic ring system (a-1); 171PRD4277WOPCT1 R3arepresents halo, -NR7aR7b, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen or C1-4alkyl; R4arepresents hydrogen; Q1represents CR6a; Q2represents CR6b; R6aand R6beach independently represent hydrogen or halogen; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0322] In an embodiment, the PRMT5 inhibitor is a compound of Formula (C), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents 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 R5ieach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents 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 selected from the group consisting of pyridinyl, pyrimidinyl, pyrazolyl, and imidazolyl; 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; R10represents -(C=O)-C1-4alkyl; C3-6cycloalkyl; 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 172PRD4277WOPCT1 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, and R14; R14represents 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-3); R3a, R3dand R3eeach independently represent hydrogen, halo, -NR7aR7b, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, –OH, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; R4a, R4d, R4e, R4fand R4geach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents N or CR6a; Q2represents N or CR6b; Q8represents N or CR6g; Q9represents N or CR6h; Q10represents N or CR6i; Q11represents N or CR6j; Q5represents CR3d; Q6represents N; and Q7represents CR4f; or Q5represents CR3d; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents CR4e; and Q7represents CR4f; or Q5represents N; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents N; and Q7represents CR4f; or Q5represents N; Q6represents N; and Q7represents N; R6a, R6b, R6g, R6h, R6iand R6jeach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

[0323] In an embodiment, the PRMT5 inhibitor is a compound of Formula (C), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; 173PRD4277WOPCT1 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 R5ieach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents hydrogen, C1-4alkyl, or C1-4alkyl substituted with one substituent selected from the group consisting of -OH, -O-C1-4alkyl,...

Claims

1. PRD4277WOPCT1 CLAIMS 1. A protein arginine methyltransferase 5 (PRMT5) inhibitor or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer, and a diastereomer thereof, for use in treating or preventing adenomatous polyposis coli (APC) loss-of-function driven adenoma disease in a subject.

2. The PRMT5 inhibitor for use of claim 1, wherein the adenomatous polyposis coli (APC) loss-of-function driven adenoma disease is selected from colorectal cancer, familial adenomatous polyposis (FAP) or attenuated familial adenomatous polyposis (AFAP).

3. The PRMT5 inhibitor for use of claim 1, wherein the subject displays at least one of the following: (i) at least one APC loss-of-function mutation; (ii) an APC truncated protein; (iii) a diagnosis of familial adenomatous polyposis or attenuated familial adenomatous polyposis; (iv) an adenomatous polyp; or (v) identified at least one parent as having a diagnosis of familial adenomatous polyposis or attenuated familial adenomatous polyposis.

5. The PRMT5 inhibitor for use of claim 1, wherein the subject has an adenomatous polyp present in at least one of the following: colon, rectum, gastric fundus, duodenum, periampullary, thyroid gland, central nervous system, adrenal glands, liver, skin, bone or connective tissue.

6. The PRMT5 inhibitor for use of claim 1, wherein the patient has an adenomatous polyp present in the colon or rectum.

7. The PRMT5 inhibitor for use of claim 1, further comprising administering a therapeutically effective amount of at least one other therapeutic agent. 374 PRD4277WOPCT1 8. The PRMT5 inhibitor for use of claim 7, wherein at least one other therapeutic agent is sulindac, erlotinib, sorafenib, regorafenib, bortezomib, gefitinib, imatinib, vemurafenib, or vismodegib.

9. The PRMT5 inhibitor for use of claim 1, wherein the PRMT5 inhibitor is a compound of Formula (A): wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents 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-; R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5heach independently represent hydrogen or C1-4alkyl; X represents –O-, -S-, or –NR11-; R11represents 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; R12represents 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 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; 375 PRD4277WOPCT1 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; R10aand R10beach independently represent hydrogen or C1-4alkyl; R10cand R10deach 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, R13and R14; R13represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(=O)pand 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; R14represents 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): 376 PRD4277WOPCT1 R3a, R3b, R3c, R3dand R3eeach independently represent hydrogen, halo, -NR7aR7b, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, –OH, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; R4a, R4b, R4c, R4d, R4e, R4fand R4geach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents N or CR6a; Q2represents N or CR6b; Q3represents N or CR6c; Q4represents N or CR6d; provided that maximum one of Q3and Q4represents N; Q8represents N or CR6g; Q9represents N or CR6h; Q10represents N or CR6i; Q11represents N or CR6j; Q5represents CR3d; Q6represents N; and Q7represents CR4f; or Q5represents CR3d; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents CR4e; and Q7represents CR4f; or Q5represents N; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents N; and Q7represents CR4f; or Q5represents N; Q6represents N; and Q7represents N; 377 PRD4277WOPCT1 R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, R6iand R6jeach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof; provided that the following compounds, and pharmaceutically acceptable addition salts, and solvates thereof are excluded: , , .

10. The PRMT5 inhibitor for use of claim 9, wherein the PRMT5 inhibitor is: Compound 2: , Compound 3: , 378 PRD4277WOPCT1 Compound 4: , Compound 5: , Compound 6: , Compound 7: , Compound 9: , Compound 11: , 379 PRD4277WOPCT1 Compound 12: , Compound 13: , Compound 14: , Compound 15: , Compound 16: , 380 PRD4277WOPCT1 Compound 17: , Compound 18: , Compound 19: , Compound 20: , 381 PRD4277WOPCT1 Compound 21: , Compound 22: , Compound 23: , Compound 24: , 382 PRD4277WOPCT1 Compound 25: , Compound 26: , Compound 28: , Compound 29: , Compound 30: , 383 PRD4277WOPCT1 Compound 31: , Compound 32: , Compound 33: , Compound 34: , Compound 35: , 384 PRD4277WOPCT1 Compound 36: , Compound 37: , Compound 38: , Compound 40: , Compound 41: , 385 PRD4277WOPCT1 Compound 46: , , Compound 49: , or Compound 50: PRD4277WOPCT1 or a pharmaceutically acceptable addition salt, or a solvate thereof.

11. The PRMT5 inhibitor for use of claim 9, wherein the PRMT5 inhibitor is Compound 40: or a pharmaceutically acceptable addition salt, or a solvate thereof.

12. The PRMT5 inhibitor for use of claim 1, wherein the PRMT5 inhibitor is a compound of Formula (B): (I) (B), wherein R1represents hydrogen or CH3; R2represents hydrogen; Rarepresents hydrogen or –C(=O)-C1-4alkyl; Rbrepresents hydrogen or –C(=O)-C1-4alkyl; Y represents –O-, –CH2– or –CF2–; R7arepresents hydrogen; R7brepresents hydrogen, or C1-4alkyl optionally substituted with one or more halo atoms; 387 PRD4277WOPCT1 X1represents a covalent bond or –O-; X2represents a covalent bond, -CH2-,-CF2-, -CH2CH2-, -CF2CH2-, or -CH2CF2-; provided that X2represents a covalent bond, -CH2- or -CF2-, when X1represents –O-; X3represents N or CH; or in case one of the dotted lines represents an additional bond, X3represents C; R8and R10each independently are selected from the group consisting of hydrogen; halo; and C1-6alkyl optionally substituted with one or more halo atoms; R9and R11each independently are selected from the group consisting of hydrogen; halo; -NH2; and C1-6alkyl optionally substituted with one –NR9aR9b; or R8and R9are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1a; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR5aR5b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1a, -O-Ar1a, Het2aand –O-Het2c; or R10and R11are linked together to form together with the common carbon atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two N-atoms and optionally one oxygen atom; wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or more ring carbon atoms with one or more substituents each independently selected from the group consisting of halo, and C1-6alkyl optionally substituted with one or more halo atoms; and wherein said 4-, 5-, 6- or 7-membered saturated heterocyclyl is optionally substituted on one or two ring N-atoms with a substituent selected from the group consisting of C1-6alkyl; Het1b; C3-6cycloalkyl; -C1-4alkyl-C(=O)-NR6aR6b; C1-4alkyl substituted with one or more halo atoms; and C1-4alkyl substituted with one substituent selected from the group consisting of –OC1-4alkyl, cyano, C3-6cycloalkyl, Ar1b, -O-Ar1b, Het2band –O-Het2d; 388 PRD4277WOPCT1 Z represents -CH2-, -C(=O)-, or –CH(C1-4alkyl)-; and in case X3represents C, Z can also represent =CH-; the dotted lines attached to X3are optional bonds that may be present when X3represents a carbon atom, provided that maximum one of the dotted lines represents an optional bond; in case one of the dotted lines attached to X3represents an additional bond, X3represents C, and (i) R7ais absent or (ii) R8is absent or (iii) Z represents =CH-; R9aand R9beach independently are selected from the group consisting of hydrogen and C1-4alkyl; or R9aand R9bare linked together to form together with the common nitrogen atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocyclyl which optionally contains one oxygen atom; R5aand R5beach independently are selected from the group consisting of hydrogen and C1-4alkyl; Het1aand Het1bare attached to the remainder of the molecule of Formula (B) through any available ring carbon atom; Het1aand Het1beach independently represent a 4-, 5-, 6- or 7-membered saturated heterocyclyl, containing one or two heteroatoms each independently selected from O, S, S(=O)pand N; Ar1aand Ar1beach independently represent phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo; cyano; and C1-4alkyl optionally substituted with one or more halo atoms; Het2aand Het2beach independently represent a 4-, 5-, 6- or 7-membered monocyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)p and N; or a fused 8-, 9-, 10- or 11-membered bicyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)p and N; said monocyclic heterocyclyl or said fused bicyclic heterocyclyl optionally being substituted with one or more substituents each independently selected from the group consisting of halo, cyano, and C1-4alkyl optionally substituted with one or more halo atoms; Het2cand Het2dare attached to the remainder of the molecule of Formula (B) through any available ring carbon atom; 389 PRD4277WOPCT1 Het2cand Het2deach independently represent a 4-, 5-, 6- or 7-membered monocyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)p and N; or a fused 8-, 9-, 10- or 11-membered bicyclic aromatic or non-aromatic heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)pand N; said monocyclic heterocyclyl or said fused bicyclic heterocyclyl optionally being substituted with one or more substituents each independently selected from the group consisting of halo, cyano, and C1-4alkyl optionally substituted with one or more halo atoms; R6aand R6beach independently are selected from the group consisting of hydrogen and C1-4alkyl; p represents 1 or 2; Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3) and (a-4): R3a, R3b, R3cand R3deach independently are selected from the group consisting of hydrogen, halo, -NR12aR12b, C1-4alkyl, and –O-C1-4alkyl; R12aand R12beach independently are selected from the group consisting of hydrogen; C3-6cycloalkyl; C1-4alkyl; and C1-4alkyl substituted with one phenyl which is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, –OC1-4alkyl, -OH, and C1-4alkyl optionally substituted with one or more halo atoms; R4a, R4b, R4c, R4d, R4eand R4feach independently are selected from the group consisting of hydrogen, halo, -NR13aR13b, and C1-4alkyl; 390 PRD4277WOPCT1 R13aand R13beach independently are selected from the group consisting of hydrogen and C1-4alkyl; Q1represents N or CR14a; Q2represents N or CR14b; Q3represents N or CR14c; Q4represents N or CR14d; provided that maximum one of Q3and Q4represents N; Q8represents N or CR14g; Q9represents N or CR14h; Q5represents CR3d; Q6represents N; and Q7represents CR4f; or Q5represents CR3d; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents CR4e; and Q7represents CR4f; or Q5represents N; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents N; and Q7represents CR4f; or Q5represents N; Q6represents N; and Q7represents N; R14a, R14b, R14c, R14d, R14e, R14f, R14g, and R14h, each independently are selected from the group consisting of hydrogen; halogen; C1-4alkyl; –NR15aR15b; and C1-4alkyl substituted with one or more halo atoms; R15aand R15beach independently are selected from the group consisting of hydrogen and C1-4alkyl; provided that R10and R11may not be linked together when R8and R9are linked together; and wherein at least one of R8, R9, R10and R11contains a nitrogen atom; or a pharmaceutically acceptable addition salt, or a solvate thereof.

13. The PRMT5 inhibitor for use of claim 12, wherein the PRMT5 inhibitor is: Compound 42: , 391 PRD4277WOPCT1 , ; or a pharmaceutically acceptable addition salt, or a solvate thereof.

14. The PRMT5 inhibitor for use of claim 1, wherein the PRMT5 inhibitor is a compound of Formula (C): (I) (C), wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents 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 R5ieach independently represent hydrogen or C1-4alkyl; 392 PRD4277WOPCT1 X represents –O-, -S-, or –NR11-; R11represents 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-CR5fR5h- 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) (b-1) (b-2) (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; 393 PRD4277WOPCT1 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; R10represents -(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, R13and R14; R13represents 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; R14represents 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-3): ;R3a, R3dand R3eeach independently represent hydrogen, halo, -NR7aR7b, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, –OH, or –O-C1-4alkyl; R7arepresents hydrogen; 394 PRD4277WOPCT1 R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; R4a, R4d, R4e, R4fand R4geach independently represent hydrogen, halo, -NR8aR8b, or C1-4alkyl; R8aand R8beach independently represent hydrogen or C1-4alkyl; Q1represents N or CR6a; Q2represents N or CR6b; Q8represents N or CR6g; Q9represents N or CR6h; Q10represents N or CR6i; Q11represents N or CR6j; Q5represents CR3d; Q6represents N; and Q7represents CR4f; or Q5represents CR3d; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents CR4e; and Q7represents CR4f; or Q5represents N; Q6represents CR4e; and Q7represents N; or Q5represents N; Q6represents N; and Q7represents CR4f; or Q5represents N; Q6represents N; and Q7represents N; R6a, R6b, R6g, R6h, R6iand R6jeach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; R9aand R9beach independently represent hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt, or a solvate thereof.

15. The PRMT5 inhibitor for use of claim 14, wherein the PRMT5 inhibitor is Compound 8: , 395 PRD4277WOPCT1 Compound 27: , or Compound 39: ; or a pharmaceutically acceptable addition salt, or a solvate thereof.

16. The PRMT5 inhibitor for use of claim 1, wherein the PRMT5 inhibitor is a compound of Formula (D): wherein R1represents hydrogen or –C(=O)-C1-4alkyl; R2represents hydrogen or –C(=O)-C1-4alkyl; X represents hydrogen; Y represents –O-, –CH2– or –CF2–; Q1represents CR6a; Q2represents N or CR6b; R6aand R6beach independently represent hydrogen, halogen, C1-4alkyl, –NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms; 396 PRD4277WOPCT1 R9aand R9beach independently represent hydrogen or C1-4alkyl; R3arepresents hydrogen, halo, -NR7aR7b, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, –OH, or –O-C1-4alkyl; R7arepresents hydrogen; R7brepresents hydrogen, C3-6cycloalkyl, or C1-4alkyl; R4arepresents hydrogen, halo, -NR8aR8b, or C1-4alkyl; L represents -CH2-, -O-CH2-, -CH2-O-, or -O-; R5represents Ar or Het; and in case L represents -O- or -O-CH2-, R5can 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. The PRMT5 inhibitor for use of claim 16, wherein the PRMT5 inhibitor is Compound 1: , or 397 PRD4277WOPCT1 Compound 10: or a pharmaceutically acceptable addition salt, or a solvate thereof.

18. The PRMT5 inhibitor for use of claim 1, wherein the PRMT5 inhibitor is: 398 PRD4277WOPCT1 or a pharmaceutically acceptable addition salt, or a solvate thereof.

19. A compound selected from the group consisting of: 401 PRD4277WOPCT1 or a pharmaceutically acceptable addition salt, or a solvate thereof. 405

Images