# US 12,595,262 B2 · PRMT5 inhibitors

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- Number: US 12,595,262 B2
- Document ID: US12595262B2
- Status: Granted
- Kind: B2
- Application number: 17/787,113
- Filed: 2020-12-14
- Published: 2023-04-06
- Granted: 2026-04-07
- Earliest claimed: 2019-12-17
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme LLC
- Inventors: Michelle Machacek; Michael D. Altman; Chunhui Huang; Michael H. Reutershan; David L. Sloman; David J. Witter; Craig R. Gibeau
- Web page: https://patentgrep.com/patent/US12595262B2

## CPC

- A61K 31/4725: containing further heterocyclic rings
- C07D 487/04: Ortho-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/06: Antianaemics
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/14: containing three or more hetero rings
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention provides a compound selected from: compounds A, B, C, D and the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are PRMT5 inhibitors. Also provided are methods of making compounds disclosed herein, pharmaceutical compositions comprising compounds disclosed herein, and methods of using these compounds to treat cancer, sickle cell, and hereditary persistence of foetal hemoglobin (HPFH) mutations.

## Claims

### Claim 1

A compound selected from:
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound of claim 1 selected from:
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

A compound of claim 1, which is:
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

A compound of claim 1, which is:
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

A compound of claim 1, which is:
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

A compound of claim 1, which is:
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound of claim 1, which is: 1-{4-[(4-{[(3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl]carbonyl}-5-fluoropyridin-2-yl)amino]piperidin-1-yl}ethanone or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The compound of claim 1, which is: (6-(2,2-difluorocyclopropyl)imidazo[1,2-a]pyrimidin-2-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone, or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The compound of claim 1, which is: (6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone, or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The compound of claim 1, which is: (6-bromo-7-ethylimidazo[1,2-a]pyrimidin-2-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone, or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 12 (depends on 1)

The method for treating cancer comprising administering to a patient in need thereof a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

The method for treating sickle cell disease comprising administering to a patient in need thereof a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

The method for treating hereditary persistence of foetal hemoglobin (HPFH) mutations comprising administering to a patient in need thereof a compound of claim 1, or a pharmaceutically acceptable salt thereof.