Arginine methyltransferase inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9724332-B2
Application number	US-201514808290-A
Country	US
Kind code	B2
Filing date	Jul 24, 2015
Priority date	Mar 14, 2013
Publication date	Aug 8, 2017
Grant date	Aug 8, 2017

Abstract

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described.

First claim

What is claimed is:

1. A method of therapeutically treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
X is N, Z is NR 4 , and Y is CR 5 ; or
X is NR 4 , Z is N, and Y is CR 5 ; or
X is CR 5 , Z is NR 4 , and Y is N; or
X is CR 5 , Z is N, and Y is NR 4 ;
R x is optionally substituted C 1-4 alkyl or optionally substituted C 3-4 cycloalkyl;
L 1 is a bond, —O—, —N(R B )—, —S—, —C(O)—, —C(O)O—, —C(O)S—, —C(O)N(R B )—, —C(O)N(R B )N(R B )—, —OC(O)—, —OC(O)N(R B )—, —NR B C(O)—, —NR B C(O)N(R B )—, —NR B C(O)N(R B )N(R B )—, —NR B C(O)O—, —SC(O)—, —C(═NR B )—, —C(═NNR B )—, —C(═NOR A )—, —C(═NR B )N(R B )—, —NR B C(═NR B )—, —C(S)—, —C(S)N(R B )_, —NR B C(S)—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —SO 2 —, —N(R B )SO 2 —, —SO 2 N(R B )—, or an optionally substituted C 1-6 saturated or unsaturated hydrocarbon chain, wherein one or more methylene units of the hydrocarbon chain is optionally and independently replaced with —O—, —N(R B )—, —S—, —C(O)—, —C(O)O—, —C(O)S—, —C(O)N(R B )—, —C(O)N(R B )N(R B )—, —OC(O)—, —OC(O)N(R B )—, —NR B C(O)—, —NR B C(O)N(R B )—, —NR B C(O)N(R B )N(R B )—, —NR B C(O)O—, —SC(O)—, —C(═NR B )—, —C(═NNR B )—, —C(═NOR A )—, —C(═NR B )N(R B )—, —NR B C(═NR B )—, —C(S)—, —C(S)N(R B )—, —NR B C(S)—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —SO 2 —, —N(R B )SO 2 —, or —SO 2 N(R B )—;
each R A is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom;
each R B is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and a nitrogen protecting group, or an R B and R W on the same nitrogen atom may be taken together with the intervening nitrogen to form an optionally substituted heterocyclic ring;
R W is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; provided that when L 1 is a bond, R W is not optionally substituted aryl or optionally substituted heteroaryl;
R 3 is hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl;
R 4 is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl, or optionally substituted C 1-4 alkyl-Cy;
Cy is optionally substituted C 3-7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
R 5 is hydrogen, halo, —CN, optionally substituted C 1-4 alkyl, or optionally substituted C 3-4 cycloalkyl;
wherein the cancer is selected from the group consisting of breast cancer, prostate cancer, lung cancer, colorectal cancer, bladder cancer, and leukemia.

2. The method of claim 1 , wherein the cancer is leukemia.

3. The method of claim 2 , wherein the leukemia is acute lymphocytic leukemia.

4. The method of claim 2 , wherein the leukemia is acute myelocytic leukemia.

5. The method of claim 2 , wherein the leukemia is chronic myelocytic leukemia.

6. The method of claim 2 , wherein the leukemia is chronic lymphocytic leukemia.

7. The method of claim 1 , wherein the compound inhibits PRMT1 at an IC 50 less than or equal to 10 μM.

8. The method of claim 1 , wherein the compound inhibits PRMT1 at an IC 50 less than or equal to 1 μM.

9. The method of claim 1 , wherein the compound inhibits PRMT1 at an IC 50 less than or equal to 0.1 μM.

10. The method of claim 1 , wherein the compound is of Formula (II):

or a pharmaceutically acceptable salt thereof.

11. The method of claim 1 , wherein the compound is of Formula (III):

or a pharmaceutically acceptable salt thereof.

12. The method of claim 1 , wherein L 1 is a bond, and R W is optionally substituted carbocyclyl.

13. The method of claim 1 , wherein L 1 is a bond, and R W is optionally substituted cyclohexyl.

14. The method of claim 1 , wherein L 1 is a bond, and R W is optionally substituted heterocyclyl.

15. The method of claim 1 , wherein R 3 is C 1-4 alkyl.

16. The method of claim 15 , wherein R 3 is methyl.

17. The method of claim 1 , wherein R 4 and R 5 are hydrogen.

18. The method of claim 1 , wherein R x is optionally substituted C 1-4 alkyl.

19. The method of claim 18 , wherein R x is methyl.

20. The method of claim 1 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

21. A method of therapeutically treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
X is N, Z is NR 4 , and Y is CR 5 ; or
X is NR 4 , Z is N, and Y is CR 5 ; or
X is CR 5 , Z is NR 4 , and Y is N; or
X is CR 5 , Z is N, and Y is NR 4 ;
R x is optionally substituted C 1-4 alkyl or optionally substituted C 3-4 cycloalkyl;
L 1 is a bond, —O—, —N(R B )—, —S—, —C(O)—, —C(O)O—, —C(O)S—, —C(O)N(R B )—, —C(O)N(R B )N(R B )—, —OC(O)—, —OC(O)N(R B )—, —NR B C(O)—, —NR B C(O)N(R B )—, —NR B C(O)N(R B )N(R B )—, —NR B C(O)O—, —SC(O)—, —C(═NR B )—, —C(═NNR B )—, —C(═NOR A )—, —C(═NR B )N(R B )—, —NR B C(═NR B )—, —C(S)—, —C(S)N(R B )—, —NR B C(S)—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —SO 2 —, —N(R B )SO 2 —, —SO 2 N(R B )—, or an optionally substituted C 1-6 saturated or unsaturated hydrocarbon chain, wherein one or more methylene units of the hydrocarbon chain is optionally and independently replaced with —O—, —N(R B )—, —S—, —C(O)—, —C(O)O—, —C(O)S—, —C(O)N(R B )—, —C(O)N(R B )N(R B )—, —OC(O)—, —OC(O)N(R B )—, —NR B C(O)—, —NR B C(O)N(R B )—, —NR B C(O)N(R B )N(R B )—, —NR B C(O)O—, —SC(O)—, —C(═NR B )—, —C(═NNR B )—, —C(═NOR A )—, —C(═NR B )N(R B )—, —NR B C(═NR B )—, —C(S)—, —C(S)N(R B )—, —NR B C(S)—, —

Assignees

• Epizyme Inc

Inventors

• Chesworth Richard
• Mitchell Lorna Helen
• Shapiro Gideon

Classifications

• C07D401/04

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

• C07D405/04

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

• C07D231/12

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title