BMP inhibitors and methods of use thereof

• US 9,682,983 B2
• Filed: 03/13/2014
• Issued: 06/20/2017
• Est. Priority Date: 03/14/2013
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated
• Original Assignee: Brigham and Women's Hospital Incorporated, Dept of Health and Human Services National Institutes of Health
• Inventors: Alimardanov, Asaf, Grewal, Gurmit Singh, Lee, Arthur, McKew, John C., Mohedas, Agustin H., Xu, Xin, Yu, Paul B., Shen, Min, Cuny, Gregory D.
• Primary Examiner(s): Habte, Kahsay
• Application Number:
  US14/776,302
• Publication Number:
  US 20160046633A1
• Time in Patent Office: 1,195 Days
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
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• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/30 Oestrogens
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 519/00 : 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

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. These compounds may also be used to reduce circulating levels of ApoB-100 or LDL and treat or prevent acquired or congenital hypercholesterolemia or hyperlipoproteinemia; diseases, disorders, or syndromes associated with defects in lipid absorption or metabolism; or diseases, disorders, or syndromes caused by hyperlipidemia.

Claims

1. A compound having a structure of Formula I or a pharmaceutically acceptable salt, ester, or prodrug thereof,

2. The compound according to claim 1, wherein B is C—

R²⁵ when E is N, or K is C—

R²⁵ when M is N, or both, such that at least one of B and K is C—

R²⁵, wherein R²⁵ is selected from deuterium, fluorine, chlorine, methyl, ethyl, hydroxy, and methoxy.

3. The compound of claim 1, wherein Ar is a substituted or unsubstituted nitrogen-containing heteroaryl group selected from pyridine, pyrazine, pyrimidine, oxazole, thiazole, thiadiazole and substituted or unsubstituted:

4. The compound of claim 1, wherein when Ar is substituted, the substituent is selected from deuterium, halogen, hydroxy, cyano, lower alkyl, and lower alkoxy.

5. The compound of claim 1, wherein Ar is a substituted or unsubstituted six-membered ring.

6. The compound of claim 5, wherein:

L₁, if present, is disposed on the para-position of Ar relative to the bicyclic core bearing X, Y, and Z;

or

R⁴ is disposed on the para-position of Ar relative to the bicyclic core bearing X, Y, and Z if L₁ is absent.

7. The compound of claim 5, wherein when Ar is phenyl substituted with a non-protium substituent, either the substituent is halogen or cyano, or the substituent is positioned ortho to L₁ if L₁ is present or is positioned ortho to R⁴ if L₁ is absent, or both.

8. The compound of claim 1, wherein L₁ is absent.

9. The compound of claim 1, wherein L₁ has a structure

10. The compound of claim 1, wherein R⁴ is selected from

11. The compound according to claim 1, wherein

R⁴ is

12. The compound according to claim 1, wherein

R⁴ is

13. The compound according to claim 1, wherein A, G, and J are each CH.

14. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient or solvent.

15. A method of treating a disease or condition in a subject that would benefit from inhibition of Bone Morphogenetic Protein (BMP) signaling, comprising administering to the subject a compound of claim 1.

16. The method of claim 15, wherein the disease or condition is selected from pulmonary hypertension, hereditary hemorrhagic telangiectasia syndrome, cardiac valvular malformations, cardiac structural malformations, fibrodysplasia ossificans progressiva, juvenile familial polyposis syndrome, parathyroid disease, anemia, vascular calcification, atherosclerosis, valve calcification, renal osteodystrophy, ankylosing spondylitis, vascular inflammation, anemia of inflammation, inflammatory bowel disease, seronegative spondyloarthropathies, psoriasis, atherosclerosis, infections with viruses, bacteria, fungi, tuberculosis, and parasites, breast carcinoma, prostate carcinoma, renal cell carcinoma, bone metastasis, lung metastasis, osteosarcoma, and multiple myeloma.

17. A method of reducing circulating levels of ApoB-100 and/or LDL and/or total cholesterol in a subject and thereby reducing risk of primary or secondary cardiovascular events, comprising administering an effective amount of a compound of claim 1.

18. A method of treating hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia or hepatic steatosis in a subject, comprising administering an effective amount of a compound of claim 1.

19. The method of claim 18, wherein the hypercholesterolemia, hyperlipidemia, or hyperlipoproteinemia is autosomal dominant hypercholesterolemia (ADH), familial hypercholesterolemia (FH), polygenic hypercholesterolemia, familial combined hyperlipidemia (FCHL), hyperapobetalipoproteinemia, or small dense LDL syndrome (LDL phenotype B).