ALK2 inhibitors and methods for inhibiting BMP signaling

Patent metadata

Field	Value
Publication number	US-11026947-B2
Application number	US-201816608489-A
Country	US
Kind code	B2
Filing date	Apr 26, 2018
Priority date	Apr 27, 2017
Publication date	Jun 8, 2021
Grant date	Jun 8, 2021

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 and/or prodrug 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, aryl oxy, 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 and/or prodrug 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 , 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 1c is selected from H, alkyl and amino; and
R 1g is H or halo.

4. The compound of claim 2 , 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 , 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 and/or prodrug thereof.

7. A compound having a formula selected from:

Assignees

• Brigham & Womens Hospital Inc
• 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

• A61P43/00

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

• A61P35/04

  specific for metastasis · CPC title

• A61K31/5377

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title