PRMT5 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9765068-B2
Application number	US-201614995092-A
Country	US
Kind code	B2
Filing date	Jan 13, 2016
Priority date	Dec 21, 2012
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

Described herein are compounds of Formula (I), 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.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
represents a single or double bond;
R 1 is hydrogen, R z , or —C(O)R z , wherein R z is optionally substituted C 1-6 alkyl;
X is a bond, —O—, —N(R)—, —CR 4 R 5 —, —O—CR 4 R 5 , —N(R)—CR 4 R 5 —, —O—CR 4 R 5 —O—, —N(R)—CR 4 R 5 —O, —N(R)—CR 4 R 5 —N(R)—, —O—CR 4 R 5 —N(R)—, —CR 4 R 5 —O—, —CR 4 R 5 —N(R)—, —O—CR 4 R 5 —CR 6 R 7 —, —N(R)—CR 4 R 5 —CR 6 R 7 —, —CR 6 R 7 —CR 4 R 5 —O—, —CR 6 R 7 —CR 4 R 5 —N(R)—, or —CR 6 R 7 —CR 4 R 5 —;
each R is independently hydrogen or optionally substituted C 1-6 aliphatic;
R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(O)OR A , —C(O)SR A , —C(O)N(R B ) 2 , —C(O)N(R B )N(R B ) 2 , —OC(O)R A , —OC(O)N(R B ) 2 , —NR B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , —NR B C(O)OR A , —SC(O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(O)R A , —OS(O) 2 R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ; or R 2 and R 3 are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring;
R 4 and R 5 are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(O)OR A , —C(O)SR A , —C(O)N(R B ) 2 , —C(O)N(R B )N(R B ) 2 , —OC(O)R A , —OC(O)N(R B ) 2 , —NR B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , —NR B C(O)OR A , —SC(O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(O)R A , —OS(O) 2 R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ; or R 4 and R 5 are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring;
R 6 and R 7 are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(O)OR A , —C(O)SR A , —C(O)N(R B ) 2 , —C(O)N(R B )N(R B ) 2 , —OC(O)R A , —OC(O)N(R B ) 2 , —NR B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , —NR B C(O)OR A , —SC(O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(O)R A , —OS(O) 2 R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ; or R 6 and R 7 are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring;
each R A 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 R B 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 R B groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring;
R 8 , R 9 , R 10 , and R 11 are independently hydrogen, halo, or optionally substituted aliphatic;
Cy is a monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 0, 1, 2, 3, or 4 R y groups;
each R y is independently selected from the group consisting of halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(O)OR A , —C(O)SR A , —C(O)N(R B ) 2 , —C(O)N(R B )N(R B ) 2 , —OC(O)R A , —OC(O)N(R B ) 2 , —NR B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , —NR B C(O)OR A , —SC(O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(O)R A , —OS(O) 2 R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ; or an R y group may be optionally taken together with R 2 or R 3 to form an optionally substituted 5- to 6-membered carbocyclic or heterocyclic ring fused to Cy;
each R x is independently selected from the group consisting of halo, —CN, optionally substituted aliphatic, —OR′, and —N(R″) 2 ;
R′ is hydrogen or optionally substituted aliphatic;
each R″ is independently hydrogen or optionally substituted aliphatic, or two R″ are taken together with their intervening atoms to form an optionally substituted heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits;
wherein each instance of aliphatic is independently an alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl group.

2. The compound of claim 1 , wherein R 1 is hydrogen.

3. The compound of claim 1 , wherein n is 0.

4. The compound of claim 1 , wherein R 2 and R 3 are each hydrogen.

5. The compound of claim 1 , wherein R is hydrogen.

6. The compound of claim 1 , wherein Cy is phenyl substituted with 1 or 2 R y groups.

7. The compound of claim 1 , wherein Cy is a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is substituted with 1 or 2 R y groups.

8. The compound of claim 1 , wherein Cy is a bicyclic saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 1 or 2 R y groups.

9. The compound of claim 1 , wherein Cy is substituted with 1 or 2 R y groups, and at least one R y is halo, —CN, —OR A , —N(R B ) 2 , C 1-6 alkyl, —C(O)NHR B , —SO 2 R A , —N(R B )C(O)R A , —N(R B )SO 2 R A , —SO 2 N(R B ) 2 , —C(O)R A , an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

10. The compound of claim 1 , wherein the compound is selected from the group consisting of;

Assignees

• Epizyme Inc

Inventors

• Duncan Kenneth W
• Chesworth Richard
• Boriack-Sjodin Paula Ann
• Munchhof Michael John
• Jin Lei

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title