# US 11,078,205 B2 · Selective inhibitors of protein arginine methlytransferase 5 (PRMT5)

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- Number: US 11,078,205 B2
- Document ID: US11078205B2
- Status: Granted
- Kind: B2
- Application number: 16/744,771
- Filed: 2020-01-16
- Published: 2020-05-14
- Granted: 2021-08-03
- Earliest claimed: 2017-08-09
- Assignees: Prelude Therapeutics Incorporated
- Applicants: Prelude Therapeutics, Incorporated
- Inventors: Hong Lin; Juan Luengo; Rupa Shetty; Michael Hawkins
- Web page: https://patentgrep.com/patent/US11078205B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/7064: containing condensed or non-condensed pyrimidines
- A61P 35/02: specific for leukemia
- 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
- C07H 19/14: Pyrrolo-pyrimidine radicals
- 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
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

The disclosure is directed to compounds of Formula I Pharmaceutical compositions comprising compounds of Formula I, as well as methods of their use and preparation, are also described.

## Claims

### Claim 1

A compound of Formula I:
or a pharmaceutically acceptable salt or solvate thereof;
wherein
R1 is —C0-C6alk-C1-C6alkyl, —C0-C6alk-C1-C6haloalkyl, —C1-C6alk-O—C1-C6alkyl, —C1-C6alk-S—C1-C6alkyl, —C1-C6alk-S—C1-C6alk-CO2H, —C1-Chalk-aryl, —C1-C6alk-O-aryl, —C1-C6alk-NH-aryl, —C1-C6alk-S-aryl, —C0-C6alk-heteroaryl, —C1-C6alk-O-heteroaryl, —C1-C6alk-S-heteroaryl, —C1-C6alk-NH-heteroaryl, or —C(O)NH-aryl;
R2 is —C1-C6alkyl, —C1-C6haloalkyl, —C2-C6alkenyl, or —C2-C6alkynyl;
R3 is H, halo, NH2, or —C1-C6alkyl;
R4 is H, halo, —C1-C6alkyl, —C1-C6alk-O—C1-C6alkyl, —NR6R6′, —NHCONR6R6′, —NHC(S)NR6R6′, —NH—O—R6, or —NH—NR6R6′;
R5 is H, halo, —C1-C6alkyl, —C1-C6haloalkyl, —C2-C6alkenyl, —C2-C6alkynyl, or —C1-C6alk-OH; and
R6 and R6′ are each independently H, C1-C6alkyl, or —C1-C6alk-OC1-C6alkyl;
or R6 and R6′, together with the atom to which they are attached, form a C3-C6heterocycloalkyl ring.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is —C1-C6alk-O-heteroaryl.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is —C1-C6alk-S-heteroaryl.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is —C1-C6alk-NH-heteroaryl.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is —C1-C6alk-heteroaryl.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is —C1-C6alk-O-aryl.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is —C1-C6alk-aryl.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is —C(O)NH-aryl.

### Claim 9 (depends on 1)

The compound of claim 1 wherein R2 is —C1-C6alkyl.

### Claim 10 (depends on 1)

The compound of claim 1 wherein R2 is —C1-C6haloalkyl.

### Claim 11 (depends on 1)

The compound of claim 1 wherein R2 is —C2-C6alkenyl.

### Claim 12 (depends on 1)

The compound of claim 1 wherein R2 is —C2-C6alkynyl.

### Claim 13 (depends on 1)

The compound of claim 1 wherein R3 is H.

### Claim 14 (depends on 1)

The compound of claim 1 wherein R4 is H.

### Claim 15 (depends on 1)

The compound of claim 1 wherein R4 is —C1-C6alkyl.

### Claim 16 (depends on 1)

The compound of claim 1 wherein R4 is chloro, fluoro, bromo, or iodo.

### Claim 17 (depends on 1)

The compound of claim 1 wherein R4 is —NR6R6′, wherein R6 and R6′ are both H.

### Claim 18 (depends on 1)

The compound of claim 1 wherein R4 is —NHCONR6R6′, wherein R6 and R6′ are both —C1-C6alkyl.

### Claim 19 (depends on 1)

The compound of claim 1 wherein R4 is —NH—O—R6, wherein R6 is —C1-C6alkyl.

### Claim 20 (depends on 1)

The compound of claim 1 wherein R4 is —NH—NR6R6′, wherein R6 and R6′ are both —C1-C6alkyl or wherein R6 is —C1-C6alkyl and R6′ is preferably H.

### Claim 21 (depends on 1)

The compound of claim 1 wherein R5 is H.

### Claim 22 (depends on 1)

The compound of claim 1 wherein R5 is halo.

### Claim 23 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 24 (depends on 1)

A method of inhibiting a protein arginine methyltransferase 5 (PRMT5) enzyme, comprising: contacting the PRMT5 enzyme with an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 1)

A method of treating a disease in a subject comprising administering to the subject, a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the disease is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, leukemia acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CIVIL), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer, hemoglobinopathies, b-thalassemia, or sickle cell disease (SCD).

### Claim 26 (depends on 25)

The method of claim 25, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more other agents.