1-phenoxy-3-(alkylamino)-propan-2-ol derivatives as CARM1 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9718816-B2
Application number	US-201414775197-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Aug 1, 2017
Grant date	Aug 1, 2017

Abstract

Provided herein are compounds of Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein X, R 1 , R 2a , R 2b , R 2c , R 2d , are as defined herein, and Ring HET is an optionally substituted 6,5-bicyclic heteroaryl ring system comprising 2 to 5 nitrogen atoms, inclusive, wherein the point of attachment is provided on the 6-membered ring of the 6,5-bicyclic heteroaryl ring system, and wherein the 6-membered ring is further substituted with a group of formula -L 1 -R 3 , wherein L 1 and R 3 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;
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, 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 an optionally substituted 6,5-bicyclic heteroaryl ring system comprising 2 to 5 nitrogen atoms, inclusive, wherein the point of attachment is provided on the 6-membered ring of the 6,5-bicyclic heteroaryl ring system, and wherein the 6-membered ring is further substituted with a group of formula -L 1 -R 3 ;
L 1 is a bond, —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 )—, —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(═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; and
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.

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 the Ring HET is of the formula:

wherein:
G 1 is C—R 7 or N;
G 2 is or N;
G 3 and G 7 are each independently C or N;
G 4 is C—R 4 , N, or N—R 4N ;
G 5 is C—R 5 , N, or N—R 5N ;
G 6 is C—R 6 , N, or N—R 6N ;
provided at least two and not more than five instances of G 1 , G 2 , G 3 , G 4 , G 5 , G 6 , and G 7 is nitrogen;
each instance of R 4N , R 5N , and R 6N is independently hydrogen, —C(═O)R′, —C(═O)OR′, —C(═O)N(R′) 2 , —S(═O)R′, —S(═O) 2 R′, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
each instance of R 4 , R 5 , R 6 , and R 7 is independently hydrogen, halo, —CN, —NO 2 , —C(═O)R′, —C(═O)OR′, —C(═O)N(R′) 2 , —N(R′) 2 , —OR′, —SR′, —S(═O)R′, —S(═O) 2 R′, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
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.

5. The compound of claim 4 , wherein Ring HET is selected from the group consisting of:

6. The compound of claim 4 , wherein the compound is of Formula (I-j):

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 4 , wherein the compound is of Formula (I-q):

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 4 , wherein at least one instance of R 4N , R 5N , and R 6N is optionally substituted C 3 carbocyclyl or optionally substituted C 1-4 alkyl.

9. The compound of claim 4 , wherein at least one instance of R 4 , R 5 , R 6 , and R 7 is hydrogen, optionally substituted C 1-4 alkyl, optionally substituted C 3 carbocyclyl, —CN, —C(═O)R′, —C(═O)OR′, or —C(═O)N(R′) 2 .

10. The compound of claim 1 , 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)—, and x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

11. The compound of claim 1 , wherein R 3 is an optionally substituted monocyclic or bicyclic heterocyclyl, or an optionally substituted monocyclic or bicyclic heteroaryl.

12. The compound of claim 1 , wherein R 3 is selected from the group consisting of:

wherein:
each instance of independently represents a single or double bond;
n is 0, 1, 2, or 3;
each instance of R 3A is ind

Assignees

• Epizyme Inc

Inventors

• Chesworth Richard
• Moradei Oscar Miguel
• Shapiro Gideon
• Duncan Kenneth W
• Mitchell Lorna Helen
• Jin Lei
• Babine Robert E

Classifications

• C07D498/08

  Bridged systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title