# US 11,993,614 B2 · Monocyclic and bicyclic ring system substituted carbanucleoside analogues for use as PRMT5 inhibitors

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- Number: US 11,993,614 B2
- Document ID: US11993614B2
- Status: Granted
- Kind: B2
- Application number: 17/378,417
- Filed: 2021-07-16
- Published: 2021-12-02
- Granted: 2024-05-28
- Earliest claimed: 2016-10-03
- Assignees: Janssen Pharmaceutica NV
- Applicants: Janssen Pharmaceutica NV
- Inventors: Tongfei Wu; Dirk Brehmer; Lijs Beke; An Boeckx; Gaston Stanislas Marcella Diels; Edward Charles Lawson; Lieven Meerpoel; Vineet Pande; Marcus Cornelius Bernardus Catharina Parade; Wim Bert Griet Schepens; Weimei Sun; Johannes Wilhelmus John F. Thuring; Marcel Viellevoye
- Web page: https://patentgrep.com/patent/US11993614B2

## CPC

- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/0095: {Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches (A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006)}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 9/2059: {Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin}
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 35/00: Antineoplastic agents
- C07D 487/04: Ortho-condensed systems
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to novel monocyclic and bicyclic ring system substituted carbanucleoside analogues of Formula (I), wherein the variables have the meaning defined in the claims. The compounds according to the present invention are useful as PRMT5 inhibitors. The invention further relates to pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

## Claims

### Claim 1

A method of inhibiting PRMT5 comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I):
wherein
R1 represents hydrogen or —C(═O)—C1-4alkyl;
R2 represents hydrogen or —C(═O)—C1-4alkyl;
Y represents —CH2— or —CF2—;
Z represents —CH2—, —CHR5i—, —X—CR5aR5b—, —CR5c═CR5d—, —CR5eR5g—CR5fR5h—, —CR5aR5b—X—, —C≡C—, —CR5cR5d—CR5eR5g—CR5fR5h—, or
—CR5aR5b—CR5cR5d—CR5eR5g—CR5fR5h—,
R5a, R5b, R5c, R5d, R5e, R5f, R5g, R5h, and R5i each independently represent hydrogen or C1-4alkyl;
X represents —O—, or —NR11—;
R11 represents hydrogen, C1-4alkyl, or C1-4alkyl substituted with one substituent selected from the group consisting of —OH, —O—C1-4alkyl, —NH2, —NH—C1-4alkyl, and N(C1-4alkyl)2;
Ar represents a monocyclic aromatic ring or a bicyclic ring system;
wherein the monocyclic aromatic ring is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazolyl, and imidazolyl;
wherein the bicyclic ring system is
(i) a 9-membered bicyclic aromatic ring system consisting of a 6-membered ring fused with a 5-membered ring, containing one, two or three heteroatoms each independently selected from O, S, and N,
said 9-membered bicyclic aromatic ring being attached to the remainder of the molecule via a ring carbon atom of the 5- or 6-membered ring, or a ring nitrogen atom of the 5-membered ring; or
(ii) a 10-membered bicyclic aromatic ring system consisting of two fused 6-membered rings, wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom;
provided that when the nitrogen atom replaces one of the two fused carbon atoms, a carbonyl group is present in said bicyclic aromatic ring system;
provided that in case Ar represents a 10-membered bicyclic aromatic ring system, Z can only represent —CR5cR5d—CR5eR5g—CR5iR5h— or CR5aR5b—CR5cR5d—CR5eR5g—CR5fR5h—; or
(iii) a fused bicyclic partially aromatic ring system which is attached with the aromatic ring to linker Z, wherein the fused bicyclic partially aromatic ring system is selected from (b-1), (b-2) and (b-3)
wherein ring A is a monocyclic aromatic ring is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazolyl and imidazolyl;
wherein ring B is a C5-6cycloalkyl or a 5- to 6-membered saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S and N;
Ar is optionally substituted on the carbon atoms with in total one, two, three or four substituents each independently selected from the group consisting of halo, oxo, —OH, —NH2, —NH—C1-4alkyl, —NHR10, cyano, —CF3, C1-4alkyloxy, C3-6cycloalkyl, —O—C3-6cycloalkyl, C2-6alkenyl, C1-4alkyl, and
C1-4alkyl substituted with one C1-4alkyloxy; and
where possible Ar is optionally substituted on one N-atom with one substituent selected from the group consisting of C1-4alkyl; C3-6cycloalkyl; C1-4alkyl substituted with one, two or three halo atoms; and C3-6cycloalkyl substituted with one, two or three halo atoms;
R10 represents —(C═O)—C1-4alkyl; C3-6cycloalkyl; R13; R14; C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C1-4alkyl; C1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C1-4alkyl; or C1-4alkyl substituted with one substituent selected from the group consisting of C3-6cycloalkyl, R13 and R14;
R13 represents a 4- to 7-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, S(═O)p and N; said 4- to 7-membered monocyclic aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C1-4alkyl;
p represents 1 or 2;
R14 represents phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo;
Het represents a bicyclic aromatic heterocyclic ring system that is (a-1):
R3a independently represent hydrogen, halo, —NR7aR7b, C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, —OH, or —O—C1-4alkyl;
R7a represents hydrogen;
R7b represents hydrogen, C3-6cycloalkyl, or C1-4alkyl;
R4a independently represent hydrogen, halo,
—NR8aR8b, or C1-4alkyl;
R8a and R8b each independently represent hydrogen or C1-4alkyl;
Q1 represents N or CR6a;
Q2 represents N or CR6b;
R6a, R6b each independently represent hydrogen, halogen, C1-4alkyl, —NR9aR9b, or C1-4alkyl substituted with one, two or three halo atoms;
R9a and R9b each independently represent hydrogen or C1-4alkyl;
or a pharmaceutically acceptable addition salt or a solvate thereof.

### Claim 2 (depends on 1)

The method according to claim 1 wherein the disease or condition is cancer.

### Claim 3 (depends on 1)

The method according to claim 1, wherein
Z represents —CH2—, —X—CR5aR5b—, —CR5c═CR5d—, —CR5eR5g—CR5fR5h—, —CR5aR5b—X—, or —C≡C—;
R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5h each independently represent hydrogen or C1-4alkyl;
Ar represents a monocyclic aromatic ring selected from pyridinyl and imidazolyl; or 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.

### Claim 4 (depends on 1)

The method according to claim 1, wherein
R1 represents hydrogen; R2 represents hydrogen;
Y represents —CH2—;
Z represents —CH2—, —CHR5i—, —X—CR5aR5b—, —CR5c═CR5d—, —CR5eR5g—CR5fR5h—, —CR5cR5d—CR5eR5g—CR5iR5h—, or —CR5aR5b—CR5cR5d—CR5eR5g—CR5iR5h—;
R5a, R5b, R5c, R5d, R5e, R5f, R5g, R5h, and R5i each 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—CR5iR5h— or —CR5aR5b—CR5cR5d—CR5eR5g—CR5fR5h—; or
(iii) a fused bicyclic partially aromatic ring system which is attached with the aromatic ring to linker Z, wherein the fused bicyclic partially aromatic ring system is selected from (b-1) 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;
R3a represents halo, —NR7aR7b, or —O—C1-4alkyl;
R7a represents hydrogen;
R7b represents hydrogen or C1-4alkyl;
R4a represents hydrogen;
Q1 represents CR6a;
Q2 represents N or CR6b;
R6a and R6b each independently represent hydrogen or halogen.

### Claim 5 (depends on 3)

The method according to claim 3, wherein
R1 represents hydrogen;
R2 represents hydrogen;
Y represents —CH2—;
Z represents —X—CR5aR5b, —CR5c═CR5d—, or —CR5eR5g—CR5fR5h—;
R5a, R5b, R5c, R5d, R5e, R5f, R5g, and R5h represent hydrogen;
X represents —O—;
Ar represents a monocyclic aromatic ring selected from pyridinyl and imidazolyl; or 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;
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, —NH2, —NH—C1-4alkyl, —CF3, C3-6cycloalkyl, and C1-4alkyl; and
where possible Ar is optionally substituted on one N-atom with one substituent selected from the group consisting of C1-4alkyl;
R3a represents halo, —NR7aR7b, or —O—C1-4alkyl;
R7a represents hydrogen;
R7b represents hydrogen, or C1-4alkyl;
R4a represents hydrogen;
Q1 represents CR6a;
Q2 represents CR6b;
R6a and R6b represent hydrogen, or halogen.

### Claim 6 (depends on 1)

The method according to claim 1, wherein
Ar represents a monocyclic aromatic ring selected from pyridinyl 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, —OH, —NH2, —NH—C1-4alkyl, —NHR10, cyano, —CF3, C1-4alkyloxy, C3-6cycloalkyl, —O—C3-6cycloalkyl, C2-6 alkenyl, C1-4alkyl, and C1-4alkyl substituted with one C1-4alkyloxy.

### Claim 7 (depends on 1)

The method according to claim 1, wherein
Ar represents 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.

### Claim 8 (depends on 7)

The method according to claim 7, wherein
Ar represents a monocyclic aromatic ring selected from pyridinyl and imidazolyl; or a 9-membered bicyclic aromatic ring system selected from the group consisting of
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.

### Claim 9 (depends on 1)

The method according to claim 1, wherein
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, —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.

### Claim 10 (depends on 1)

The method according to claim 1, wherein Ar represents the bicyclic ring system;
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.

### Claim 11 (depends on 1)

The method according to claim 1, wherein
Z represents —CH2—, —CHR5i—, —X—CR5aR5b—, —CR5c═CR5d—, —CR5eR5g—CR5fR5h—, —CR5cR5d—CR5eR5g—CR5iR5h—, or —CR5aR5b—CR5cR5d—CR5eR5g—CR5iR5h—;
R5a, R5b, R5c, R5d, R5e, R5f, R5g, R5h, and R5i each independently represent hydrogen or C1-4alkyl;
X represents —O—;
R3a represents halo, —NR7aR7b, or —O—C1-4alkyl;
Q1 represents CR6a; and
Q2 represents CR6b.

### Claim 12 (depends on 4)

The method according to claim 4, wherein Q2 represents CR6b.

### Claim 13 (depends on 1)

The method according to claim 1, wherein R1 and R2 represent hydrogen.

### Claim 14 (depends on 1)

The method according to claim 1, wherein Y represents —CH2—.

### Claim 15 (depends on 1)

The method according to claim 1, wherein R3a represents —NR7aR7b; and R7a and R7b represent hydrogen.

### Claim 16 (depends on 1)

The method according to claim 1, wherein inhibiting PRMT5 is useful for treating or preventing a disease or condition selected from a blood disorder, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection, and lung injuries.