# US 10,118,918 B2 · PRMT5 inhibitors and uses thereof

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- Number: US 10,118,918 B2
- Document ID: US10118918B2
- Status: Granted
- Kind: B2
- Application number: 14/654,161
- Filed: 2013-12-20
- Published: 2015-12-17
- Granted: 2018-11-06
- Earliest claimed: 2012-12-21
- Assignees: Epizyme, Inc.
- Applicants: Epizyme, Inc.
- Inventors: Kenneth W. Duncan; Richard Chesworth; Paula Ann Boriack-Sjodin; Michael John Munchhof
- Web page: https://patentgrep.com/patent/US10118918B2

## CPC

- C07D 413/12: linked by a chain containing hetero atoms as chain links
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/06: Antianaemics
- A61P 35/00: Antineoplastic agents
- C07D 209/44: Iso-indoles; Hydrogenated iso-indoles
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 407/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Described herein are compounds of formula (A), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5-mediated disorders are also described.

## Claims

### Claim 1

A compound of Formula (A):
or a pharmaceutically acceptable salt thereof;
wherein:
R12 is hydrogen, and —R13 is halogen; or
R12 is hydrogen, and R13 is —OR1;
R1 is hydrogen, Rz, or —C(O)Rz, wherein Rz is optionally substituted C1-6 alkyl;
Lz is —C(O)N(R)— or —XA—C(R2A)(R3A)C(═O)N(R)—, wherein XA is —CR4AR5A—, and each instance of R2A, R3A, R4A, and R5A is hydrogen;
R is hydrogen or optionally substituted C1-6 aliphatic;
Ring Z is a monocyclic or bicyclic aromatic ring having 0-4 heteroatoms selected from nitrogen, wherein Ring Z is substituted with 0, 1, 2, 3, 4, or 5 Ry groups, as valency permits;
each Ry is independently selected from the group consisting of halo, —CN, —NO2, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, —N(RB)2, —SRA, —C(═O)RA, —C(O)ORA, —C(O)SRA, —C(O)N(RB)2, —C(O)N(RB)N(RB)2, —OC(O)RA, —OC(O)N(RB)2, —NRBC(O)RA, —NRBC(O)N(RB)2, —NRBC(O)N(RB)N(RB)2, —NRBC(O)ORA, —SC(O)RA, —C(═NRB)RA, —C(═NNRB)RA, —C(═NORA)RA, —C(═NRB)N(RB)2, —NRBC(═NRB)RB, —C(═S)RA, —C(═S)N(RB)2, —NRBC(═S)RA, —S(O)RA, —OS(O)2RA, —SO2RA, —NRBSO2RA, and —SO2N(RB)2;
each RA is independently selected from the group consisting of hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
each RB is independently selected from the group consisting of hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two RB groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring;
R21, R22, R23, and R24 are each independently hydrogen, halo, or optionally substituted aliphatic;
each Rx is independently selected from the group consisting of halo, —CN, optionally substituted aliphatic, and —OR′;
R′ is hydrogen or optionally substituted aliphatic;
n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and
x is 1, and y is 1; or
x is 0, and y is 2, 3, or 4; or
x is 1, and y is 3.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is of Formula (A-3-iv):
or a pharmaceutically acceptable salt thereof, wherein R12 is hydrogen.

### Claim 3 (depends on 1)

The compound of claim 1, wherein Ring Z is of the formula:
X1, X2, X3, and X4 are independently selected from the group consisting of N, CH, and CRy, provided that at least one of X2, X3, and X4 is not N;
L1 is a bond, —O—, or —N(R)—;
R is hydrogen or optionally substituted C1-6 aliphatic; and
CyD is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 3- to 8-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

### Claim 4 (depends on 3)

The compound of claim 3, wherein:
X1, X2, X3, and X4 are independently selected from the group consisting of CH and CRy; or
X1 is N, and each of X2, X3, and X4 are independently selected from the group consisting of CH and CRy; or
X2 is N, and each of X1, X3, and X4 are independently selected from the group consisting of CH and CRy; or
X3 is N, and each of X1, X2, and X4 are independently selected from the group consisting of CH and CRy; or
X4 is N, and each of X1, X2, and X3 are independently selected from the group consisting of CH and CRy; or
each of X1 and X2 is N, and each of X3 and X4 is independently CH or CRy; or
each of X1 and X3 is N, and each of X2 and X4 is independently CH or CRy; or
each of X1 and X4 is N, and each of X2 and X3 is independently CH or CRy; or
each of X2 and X4 is N, and each of X1 and X3 is independently CH or CRy; or
each of X2 and X3 is N, and each of X1 and X4 is independently CH or CRy; or
each of X3 and X4 is N, and each of X1 and X2 is independently CH or CRy.

### Claim 5 (depends on 3)

The compound of claim 3, wherein L1 is —O—, or —N(R)—; R is hydrogen or optionally substituted C1-6 aliphatic; and CyD is an optionally substituted 3- to 8-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

### Claim 6 (depends on 3)

The compound of claim 3, wherein the compound is of Formula (VD-c):
or a pharmaceutically acceptable salt thereof, wherein LD is —C(O)N(R)—.

### Claim 7 (depends on 1)

The compound of claim 1, wherein Lz is —C(O)N(R)—.

### Claim 8 (depends on 1)

The compound of claim 1, wherein Lz is —XA—C(R2A)(R3A)C(═O)N(R)—.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R1 is hydrogen.

### Claim 10 (depends on 1)

The compound of claim 1, wherein n is 0.

### Claim 11 (depends on 1)

The compound of claim 1, wherein Ring Z is a monocyclic aromatic ring having 0-4 heteroatoms selected from nitrogen and wherein Ring Z is substituted with 1 or 2 Ry groups, as valency permits;
Ry is independently selected from the group consisting of optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, and —N(RB)2;
each RA is independently selected from the group consisting of optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and
each RB is independently selected from the group consisting of hydrogen, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two RB groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring.

### Claim 12 (depends on 1)

The compound of claim 1, wherein Ring Z is selected from the group consisting of:

### Claim 13 (depends on 1)

The compound of claim 1 selected from the group consisting of:
and pharmaceutically acceptable salts thereof.

### Claim 14 (depends on 1)

The compound of claim 1 selected from the group consisting of:
and pharmaceutically acceptable salts thereof.

### Claim 15 (depends on 1)

The compound of claim 1 selected from the group consisting of:
and pharmaceutically acceptable salts thereof.

### Claim 16 (depends on 1)

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

### Claim 17 (depends on 1)

A kit or packaged pharmaceutical comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and instructions for use thereof.

### Claim 18 (depends on 13)

A pharmaceutical composition comprising a compound of claim 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 19 (depends on 13)

A kit or packaged pharmaceutical comprising a compound of claim 13, or a pharmaceutically acceptable salt thereof, and instructions for use thereof.

### Claim 20 (depends on 14)

A pharmaceutical composition comprising a compound of claim 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 21 (depends on 14)

A kit or packaged pharmaceutical comprising a compound of claim 14, or a pharmaceutically acceptable salt thereof, and instructions for use thereof.

### Claim 22 (depends on 15)

A pharmaceutical composition comprising a compound of claim 15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 23 (depends on 15)

A kit or packaged pharmaceutical comprising a compound of claim 15, or a pharmaceutically acceptable salt thereof, and instructions for use thereof.