Heterocyclic inhibitors of necroptosis

• US 8,658,689 B2
• Filed: 08/20/2012
• Issued: 02/25/2014
• Est. Priority Date: 08/15/2007
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated, President and Fellows of Harvard College (Harvard Corporation), Trustees of Boston University, Tufts University
• Original Assignee: Brigham and Women's Hospital Incorporated, President and Fellows of Harvard College (Harvard Corporation), Trustees of Boston University, Tufts University
• Inventors: Cuny, Gregory D., Teng, Xin, Yuan, Junying, Degterev, Alexei, Porco, John A. Jr.
• Primary Examiner(s): Otton, Alicia L
• Application Number:
  US13/589,867
• Publication Number:
  US 20120309795A1
• Time in Patent Office: 554 Days
• Field of Search: None
• US Class Current: 514/423
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: C07D 207/34 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/14 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 241/24 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 263/34 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/56 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 285/06 : 1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
• CPC Class Codes: C07D 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 307/84 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

The invention features a series of heterocyclic derivatives that inhibit tumor necrosis factor alpha (TNF-α) induced necroptosis. The heterocyclic compounds of the invention are described by Formulas (I) and (Ia)-(Ie) and are shown to inhibit TNF-α induced necroptosis in FADD-deficient variant of human Jurkat T cells. The invention further features pharmaceutical compositions featuring the compounds of the invention. The compounds and compositions of the invention may also be used to treat disorders where necroptosis is likely to play a substantial role.

Claims

1. A compound having a structure according to the following formula,

2. The compound of claim 1, wherein

R¹ is selected from methyl, ethyl, propyl, and butyl;

R² is selected from hydrogen, halogen and cyano; and

R³ is selected from hydrogen, (S)-methyl, (S)-ethyl, (S)-propyl, and (S)-butyl;

or any pharmaceutically acceptable salt thereof, or stereoisomer thereof.

3. The compound of claim 2, wherein

R¹ is selected from methyl and isopropyl;

R² is selected from hydrogen, chlorine, bromine and cyano;

R³ is selected from hydrogen and (S)-methyl; and

each X¹ and X² is independently chlorine or fluorine;

or any pharmaceutically acceptable salt thereof, or stereoisomer thereof.

4. The compound of claim 3, wherein R¹ is methyl, R² is cyano, R³ is (S)-methyl, X¹ is chlorine, and X² is fluorine;

or any pharmaceutically acceptable salt thereof, or stereoisomer thereof.

7. A pharmaceutical composition comprising the compound of claim 1, or any pharmaceutically acceptable salt thereof, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

5. A compound selected from the group consisting of:

6. The compound of claim 5, wherein said compound is

8. A pharmaceutical composition comprising the compound of claim 5, or any pharmaceutically acceptable salt thereof, or stereoisomer thereof, and a pharmaceutically acceptable excipient.