Carm1 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-11834455-B2
Application number	US-202016822478-A
Country	US
Kind code	B2
Filing date	Mar 18, 2020
Priority date	Mar 15, 2013
Publication date	Dec 5, 2023
Grant date	Dec 5, 2023

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-h):

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;
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;
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 two instances of G 8 , G 10 , G 11 , or G 12 are 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 atom 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(═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(═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 heteroaryl, or aryl unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —NO 2 , —N 3 , —SO 2 H, SO 3 H, —OH, —OR aa , —N(R bb ) 2 , —SH, —SR aa , —C(═O)R aa , —CO 2 H, —CHO, —CO 2 R aa , —OC(═O)R aa , —OCO 2 R aa , —C(═O)N(R bb ) 2 , —OC(═O)N(R bb ) 2 , C 1-4 alkyl, C 1-4 perhaloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl;
wherein:
each instance of R aa is, independently, C 1-4 alkyl; and
each instance of R bb is, independently, hydrogen or C 1-4 alkyl, or two R bb groups are joined to form a 3-6 membered heterocyclyl or 5-6 membered heteroaryl ring.

2. The compound or pharmaceutically acceptable salt of claim 1 , wherein:
X is O;
R 1 is optionally substituted C 1-4 aliphatic;
R 1a is hydrogen;
G 10 is C—R 10 ; and
G 11 is C—R 11 .

3. The compound of claim 1 , having the structure of Formula (I-1-A) or Formula (I-1-A′):

or a pharmaceutically acceptable salt thereof, wherein:
m is 0 or 1;
R 1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, or cyclopropyl;
R 1a is hydrogen;
R 2a , R 2b , and R 2d are hydrogen;
R 2c is hydrogen or halogen;
R 10 is hydrogen, optionally substituted alkyl, optionally substituted C 3-4 cycloalkyl, or halo;
each instance of R 13A is independently optionally substituted alkyl;
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)—;
x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
Q is N; Y is O; and W is CH or CR 13A ; or
Q is N, Y is S, and W is CH or CR 13A .

4. The compound or pharmaceutically acceptable salt of claim 3 , wherein:
R 2c is halogen;
L 1 is a bond or —N(R L )—;
Q is N; Y is O; and
W is CH or CR 13A .

5. The compound or pharmaceutically acceptable salt of claim 4 , wherein:
R 1 is methyl;
R 2c is chloro;
L 1 is a bond;
R 3 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
R 10 is methyl;
W is CR 13A ; and
each R 13A is methyl.

6. The compound of claim 1 , having the structure of Formula (I-1-A) or Formula (I-1-A′):

or a pharmaceutically acceptable salt thereof, wherein:
m is 1;
R 1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, or cyclopropyl;
R 1a is hydrogen;
R 2a , R 2b , and R 2d are hydrogen;

R 2c is hydrogen, chloro, or fluoro;
W is CH or CR 13A ;
Y is O or S;
R 10 is hydrogen, methyl, or chloro;
each R 13A is optionally substituted alkyl; and
R L and R 3 taken together form an optionally substituted heterocyclic ring, an optionally substituted heterocyclic ring which is fused to an optionally substituted aromatic ring, an optionally substituted heterocyclic ring which is fused to an optionally substituted heteroaromatic ring, an optionally substituted bicyclic heterocyclic ring system, an optionally substituted ortho-fused heterocyclic ring system, an optionally substituted spiro-fused heterocyclic ring system, or an optionally substituted bridged heterocyclic ring system.

7. The compound or pharmaceutically acceptable salt of claim 6 , wherein:
R 1 is methyl;
R 2c is chloro;
W is CR 13A ;
Y is O;
R 10 is methyl; and
each R 13A is methyl.

8. The compound of claim 1 , having the structure of Formula (I-1-Aa6) or Formula (I-1-Aa6′):

Assignees

• Epizyme Inc

Inventors

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

Classifications

• C07D487/10 Primary

  Spiro-condensed systems · CPC title

• C07D239/42

  One nitrogen atom (nitro radicals C07D239/30) · CPC title

• C07D401/04

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

• C07D403/04

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

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title