ALK2 inhibitors and methods for inhibiting BMP signaling

Patent metadata

Field	Value
Publication number	US-11654147-B2
Application number	US-202117340589-A
Country	US
Kind code	B2
Filing date	Jun 7, 2021
Priority date	Apr 27, 2017
Publication date	May 23, 2023
Grant date	May 23, 2023

Abstract

The present invention provides small-molecule inhibitors of BMP signaling and compositions and methods for inhibiting BMP signaling. These compounds and compositions may be used to modulate cell growth, differentiation, proliferation, and apoptosis, and thus may be useful for treating diseases or conditions associated with BMP signaling, including inflammation, cardiovascular disease, hematological disease, cancer, and bone disorders, as well as for modulating cellular differentiation and/or proliferation. These compounds and compositions may also be used to treat subjects with Sjögren's syndrome, or diffuse intrinsic pontine glioma (DIPG).

First claim

The invention claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein
A 1 is NR 4a or CR 4b R 5 ;
B 1 is N or CR 2 ;
Z 1 is N or CR 3 ;
R 1 is selected from cycloalkyl, aryl, heteroaryl, and heterocyclyl;
R 2 is H, CN, NO 2 , alkyl, or amino;
R 3 is selected from H, CN, NO 2 , alkyl, alkoxy, heterocyclyloxy, heteroaryloxy, aryloxy, cycloalkyloxy, carbonyl, amino, amido, sulfonyl, sulfonamido, cycloalkyl, aryl, heterocyclyl, and heteroaryl;
R 4a is selected from alkyl, alkenyl, alkynyl, carbonyl, O − , alkoxycarbonyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl;
R 4b is selected from halo, CN, NO 2 , hydroxy, alkyl, alkenyl, alkynyl, alkoxy, heterocyclyloxy, heteroaryloxy, aryloxy, cycloalkyloxy, amino, amido, carbonyl, alkoxycarbonyl, carboxy, sulfonyl, sulfonamido, thio, cycloalkyl, aryl, heterocyclyl, and heteroaryl;
R 5 is selected from H, halo, hydroxy and alkyl, or R 4b and R 5 together with A 1 form a ring selected from cycloalkyl and heterocyclyl;
each R 6 is independently selected from H, halo, CN, NO 2 , hydroxy, alkyl, alkenyl, alkynyl, alkoxy, heterocyclyloxy, heteroaryloxy, aryloxy, cycloalkyloxy, amino, amido, carbonyl, alkoxycarbonyl, carboxy, sulfonyl, sulfonamido, thio, cycloalkyl, aryl, heterocyclyl, and heteroaryl and oxo;
n is 0 or 1;
m is 0 or 1; and
x is 0, 1, 2, 3, or 4.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
A 1 is NR 4a or CR 4b R 5 ;
B 1 is N or CR 2 ;
Z 1 is N or CR 3 ;
R 1 is selected from aryl, heteroaryl, and heterocyclyl;
R 2 is H or amino;
R 3 is H or heterocyclyloxy;
R 4a is selected from alkyl, O − , aryl, heterocyclyl, and heteroaryl;
R 4b is selected from alkyl, alkoxy, amino, aryl, heterocyclyl, and heteroaryl;
R 5 is selected from H and alkyl, or
R 4b and R 5 together with A 1 form a ring selected from cycloalkyl and heterocyclyl;
each R 6 is independently selected from H, halo, alkyl and oxo;
n is 0 or 1;
m is 0 or 1; and
x is 0, 1, 2, 3, or 4.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, aryl, 5-6 membered heteroaryl,

wherein:
each E is independently selected from N and CR 1d ;
each G is independently selected from N and CR 1e ;
K 1 is N or CH;
K 2 is NH or S;
M is N or CR 1a ;
R 1a is selected from H, halo, alkyl, haloalkyl, and amido;
R 1b is selected from H, halo, CN, alkyl, haloalkyl, hydroxy, alkoxy, and haloalkoxy;
R 1c is selected from H, halo, CN, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino and amido, or
R 1b and R 1c together with the carbon atoms to which they are attached form a heterocyclyl;
R 1d is selected from H, CN, alkyl, haloalkyl, hydroxy, amido and sulfonamido;
R 1e is selected from H, alkyl and amino; and
R 1g is H or halo.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 4a is selected from alkyl, O, heterocyclyl, and heteroaryl;
R 4b is selected from alkyl, alkoxy, amino, amido, heterocyclyl, and heteroaryl;
R 5 is selected from H and alkyl, or
R 4b and R 5 together with A 1 form a heterocyclyl; and
each R 6 is independently selected from H, halo, and alkyl; and
x is 0 or 1.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, aryl, 5-6 membered heteroaryl,

wherein:
each E is independently selected from N and CR 1d ;
each G is independently selected from N and CR 1e ;
K 1 is N or CH;
K 2 is NH or S;
M is CR 1a ;
R 1a is selected from H and amido;
R 1b is selected from H, halo, alkyl, and alkoxy;
R 1c is selected from H, alkyl, and alkoxy, or
R 1b and R 1c together with the carbon atoms to which they are attached form a heterocyclyl;
R 1d is selected from H, alkyl, hydroxy, amido and sulfonamido;
R 1e is selected from H, alkyl and amino;
R 1f is H; and
R 1g is H.

6. A compound having a formula selected from:

or a pharmaceutically acceptable salt thereof.

7. A compound having a formula selected from:

Assignees

• Brigham & Womens Hospital Inc
• Us Health
• Us Health

Inventors

• Yu Paul B
• Huang Wenwei
• Sanderson Philip Edward
• Jiang Jian-Kang
• Shamim Khalida
• Zheng Wei
• Huang Xiuli
• Tawa Gregory
• Lee Arthur
• Alimardanov Asaf
• Huang Junfeng

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P19/02 Primary

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• C07F9/6561

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title