Fused heterocyclic compounds as selective BMP inhibitors

Patent metadata

Field	Value
Publication number	US-10196392-B2
Application number	US-201715652100-A
Country	US
Kind code	B2
Filing date	Jul 17, 2017
Priority date	Sep 28, 2012
Publication date	Feb 5, 2019
Grant date	Feb 5, 2019

Abstract

The present invention provides small molecule inhibitors of BMP signaling. These compounds 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.

First claim

We claim:

1. A method of treating a disease state associated with modulating the BMP signaling pathway in a subject, comprising administering to a subject suffering from the disease state at least one compound having a structure represented by the following formula (I):

wherein:
X, Y, and Z are independently N or CH;
A is substituted or unsubstituted and selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
R is selected from H, CF 3 , halogen, CN, alkyl, aryl, heteroaryl, or NR 1 R 2 ;
M is substituted or unsubstituted and is selected from aryl or heteroaryl;
D is selected from a bond, O, CR 1 R 2 , NH, NR 1 or NR 1 R 2 ;
E is absent or selected from H, CF 3 , halogen, CN, alkyl, aryl, heteroaryl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloheteroalkyl, —(CH 2 ) x —C 3 -C 12 cycloalkyl, or —(CH 2 ) x —C 3 -C 12 cycloheteroalkyl;
R 1 is absent or selected from H, alkyl, aryl, or heteroaryl;
R 2 is selected from H, alkyl, aryl, heteroaryl, COR 1 , or, R 1 and R 2 can form a C 3 -C 12 cycloalkyl or C 3 -C 12 cycloheteroalkyl containing O, N or S; and
x is an integer from 2 to 500; or
a pharmaceutically acceptable salt thereof
and wherein the disease state is selected from anemia, iron deficiency anemia or anemia of chronic disease, fibrodysplasia ossificans progressiva (FOP), breast cancer, prostate cancer, bone cancer, lung cancer, renal cancer, inflammatory bowel disease, pathological bone function, ectopic bone formation, maladaptive bone formation, hypertension, ventricular hypertrophy, atherosclerosis, acute megakaryoblastic leukemia, heart disease, myocardial ischemic injury, vascular calcification, aortic valve calcification, ventricular hypertrophy, liver damage, liver disease, Duchenne muscular dystrophy, hereditary spastic paraplegias, retinopathy of prematurity, diabetic retinopathy, wet macular degeneration, diabetic nephropathy, or renal fibrosis.

2. The method of claim 1 , wherein X, Y and Z together help form:

3. The method of claim 1 , wherein X, Y and Z together help form:

4. The method of claim 1 , wherein

is:

wherein A 1 is independently O, S, CR 1 R 2 or NR 1 .

5. The method of claim 1 , wherein M is optionally substituted with one or more R, and is selected from C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, aryl, heteroaryl, C 3 -C 12 heterocycloalkyl, or C 3 -C 12 heterocycloalkenyl.

6. The method of claim 1 , wherein M is optionally substituted phenyl or pyridine.

7. The method of claim 1 , wherein M, D, and E together form:

8. The method of claim 1 , wherein A is chosen from the following:

9. The method of claim 1 , wherein the compound of formula I has the structure:

or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , wherein the disease state is anemia.

11. The method of claim 10 , wherein the anemia is iron deficiency anemia or anemia of chronic disease.

12. The method of claim 1 , wherein the disease state is fibrodysplasia ossificans progressiva (FOP).

13. The method of claim 1 , wherein the disease state is breast cancer, prostate cancer, bone cancer, lung cancer, or renal cell cancer.

14. The method of claim 1 , wherein the disease state is pathologic bone function, ectopic bone formation or maladaptive bone formation.

15. The method of claim 1 , wherein the disease state is acute megakaryoblastic leukemia.

Assignees

• Univ Vanderbilt

Inventors

• Hopkins Corey R
• Hong Charles C
• Lindsley Craig W
• Engers Darren W

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

• A61P9/12

  Antihypertensives · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title