CARM1 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-10633389-B2
Application number	US-201816149519-A
Country	US
Kind code	B2
Filing date	Oct 2, 2018
Priority date	Mar 15, 2013
Publication date	Apr 28, 2020
Grant date	Apr 28, 2020

Abstract

Provided herein are compounds of Formula (I):

and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, wherein X, R 1 , R 1a , R 2a , R 2b , R 2c , R 2d , are as defined herein, and Ring HET is a 6-membered monocyclic heteroaryl ring system of Formula:

wherein L 2 , R 13 , G 8 , G 10 , G 11 , and G 12 are as defined herein. Compounds of the present invention are useful for inhibiting CARM1 activity. Methods of using the compounds for treating CARM1-mediated disorders are also described.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof;
wherein:
X is —O—, —S—, or —CH 2 —;
R 1 is hydrogen or optionally substituted C 1-4 aliphatic;
R 1a is hydrogen;
each of R 2a , R 2c , and R 2d is independently hydrogen, halogen, —CN, —NO 2 , —C(═O)R A2 , —C(═O)OR A2 , —C(═O)N(R A2 ) 2 , —OR A2 , —SR A2 , —N(R A2 ) 2 , —S(═O)R A2 , —S(═O) 2 R A2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, wherein each instance of R A2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R A2 groups attached to the same nitrogen atom are joined to form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring;
R 2b is halogen or —OR A2 ;
Ring HET is a 6-membered monocyclic heteroaryl ring system of the Formula:

wherein:
G 8 is C—R 8 or N;
G 10 is C—R 10 or N;
G 11 is C—R 11 or N;
G 12 is C—R 12 or N;
provided at least one instance of G 8 , G 10 , G 11 , or G 12 is N;
each instance of R 8 , R 10 , R 11 , and R 12 is independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , —C(═O)R′, —C(═O)OR′, —C(═O)N(R′) 2 , optionally substituted alkyl, and -L 1 -R 3 ;
each instance of R′ is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R′ groups attached to the same nitrogen are joined to form an optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring;
each instance of L 1 and L 2 is independently a bond, —O—, —N(R L )—, —S—, —C(O)—, —C(O)O—, —C(O)S—, —C(O)N(R L )—, —C(O)N(R L )N(R L )—, —OC(O)—, —OC(O)N(R L )—, —NR L C(O)—, —NR L C(O)N(R L )—, —NR L C(O)N(R L )N(R L )—, —NR L C(O)O—, —SC(O)—, —C(═NR L )—, —C(═NNR L )—, —C(═NOR L )—, —C(═NR L )N(R L )—, —NR L C(═NR L )—, —C(S)—, —C(S)N(R L )—, —NR L C(S)—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —SO 2 —, —N(R L )SO 2 —, —SO 2 N(R L )—, —N(R L )SO 2 N(R L )—, an optionally substituted C 1-10 saturated or unsaturated hydrocarbon chain, wherein one or more moieties selected from the group consisting of —O—, —N(R L )—, —S—, —C(O)—, —C(O)O—, —C(O)S—, —C(O)N(R L )—, —C(O)N(R L )N(R L )—, —OC(O)—, —OC(O)N(R L )—, —NR L C(O)—, —NR L C(O)N(R L )—, —NR L C(O)N(R L )N(R L )—, —NR L C(O)O—, —SC(O)—, —C(═NR L )—, —C(═NNR L )—, —C(═NOR L )—, —C(═NR L )N(R L )—, —NR L C(═NR L )—, —C(S)—, —C(S)N(R L )—, —NR L C(S)—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —SO 2 —, —N(R L )SO 2 —, —SO 2 N(R L )—, and —N(R L )SO 2 N(R L )— is optionally and independently present between two carbon atoms of the hydrocarbon chain, and optionally and independently present at one or both ends of the hydrocarbon chain;
each R L is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group, or R L and R 3 taken together form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, or R L and R 13 taken together form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring;
R 3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, provided when R 3 is hydrogen, then L 1 is not a bond; and
R 13 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, wherein, and unless otherwise specified,
heterocyclyl or heterocyclic refers to a radical of a 3-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur;
carbocyclyl or carbocyclic refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms and zero heteroatoms in the non-aromatic ring system; aryl refers to a radical of a monocyclic or polycyclic 4n+2 aromatic ring system having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system; and
heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is of Formula (I-a) or Formula (I-b):

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring HET is:

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, or cyclopropyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2a , R 2c , and R 2d are hydrogen.

6. The compound of claim 1 , wherein L 2 is a bond, —N(R 1 )—, —NR L C(O)O—, —NR L C(O)N(R L )—, —N(R L )—, —N(R L )SO 2 N(R L )—, —NR L —(CH 2 ) x —C(O)O—, —NR L —(CH 2 ) x —O—, —NR L C(O)N(R L )—, —NR L —(CH 2 ) x —, —(CH 2 ) x —NR L —, —NR L C(O)O(CH 2 ) x —, —NR L C(O)NR L (CH 2 ) x —, or —NR L (CH 2 ) x NR L C(O)—.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 13 is selected from the group consisting of:

each instance of independently represents a single or double bond;
m is 0, 1, 2, or 3;
each instance of R 13A is independently hydroxyl, substituted hydroxyl, thiol, substituted thiol, amino, substituted amino, carbonyl, sulfonyl, sulfinyl, —CN, —NO 2 , halogen, optionally substituted alkyl, or two R 13A groups are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring, or R 13A and R 13B group are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring; and
R 13B is hydrogen, optionally substituted alkyl, or a nitrogen protecting group.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring HET comprises a group -L 1 -R 3 is attached thereto.

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein L 1 is a bond, —N(R L )—, —NR L C(O)O—, —NR L C(O)N(R L )—, —N(R L )—, —N(R L )SO 2 N(R L )—, —NR L —(CH 2 ) x —C(O)O—, —NR L —(CH 2 ) x —O—, —NR L C(O)N(R L )—, —NR L —(CH 2 ) x —, —(CH 2 ) x —NR L —, —NR L C(O)O(CH 2 ) x —, —N

Assignees

• Epizyme Inc

Inventors

• Chesworth Richard
• Moradei Oscar Miguel
• Shapiro Gideon
• Jin Lei
• Babine Robert E

Classifications

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07D487/08

  Bridged systems · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D493/10

  Spiro-condensed systems · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title