CARM1 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9738651-B2
Application number	US-201414775766-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Aug 22, 2017
Grant date	Aug 22, 2017

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 (II) 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 and R 1a are each independently hydrogen or optionally substituted C 1-4 aliphatic, or R 1 and R 1a may be joined to form a substituted or unsubstituted heterocyclic, or substituted or unsubstituted heteroaryl ring;
each of R 2a , R 2b , 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, or 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;
Ring HET is a 6-membered monocyclic heteroaryl ring system of the Formula:

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, optionally substituted C 3-4 cycloalkyl, 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 )—, or 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(═N R 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.

2. The compound of claim 1 , wherein X is —O—.

3. The compound of claim 1 , wherein X is —S— or —CH 2 —.

4. The compound of claim 1 , wherein Ring HET is:

5. The compound of claim 1 , wherein Ring HET is:

6. The compound of claim 1 , wherein Ring HET is:

7. The compound of claim 1 , wherein R 1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, or cyclopropyl, and R 1a is hydrogen.

8. The compound of claim 1 , wherein R 2a , R 2b , and R 2d are hydrogen.

9. The compound of claim 1 , wherein at least one of R 2a , R 2b , R 2c , and R 2d is halogen.

10. The compound of claim 1 , wherein L 2 is a bond, —N(R L )—, —NR L C(O)O—, —NR L C(O)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)—, wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

11. The compound of claim 1 , wherein R 13 is selected from the group consisting of:

wherein
each 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, or 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 3B and R 13B are independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group.

12. The compound of claim 1 , wherein Ring HET comprises a group -L 1 -R 3 attached thereto.

13. The compound of claim 12 , wherein L 1 is a bond, —N(R L )—, —NR L C(O)O—, —NR L C(O)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)—, wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

14. The compound of claim 12 , wherein R 3 is selected from the group consisting of:

Assignees

• Epizyme Inc

Inventors

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

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

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

• A61P3/00

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

• C07D498/04

  Ortho-condensed systems · CPC title