Small molecule inhibitors of necroptosis

• US 9,586,880 B2
• Filed: 09/20/2013
• Issued: 03/07/2017
• Est. Priority Date: 12/23/2008
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Hsu, Emily P., Yuan, Junying
• Primary Examiner(s): Anderson, Rebecca
• Assistant Examiner(s): Cheng, Karen
• Application Number:
  US14/033,176
• Publication Number:
  US 20140024657A1
• Time in Patent Office: 1,264 Days
• US Class Current: 1/1
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• 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 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• 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: C07C 33/38 : Alcohols containing six-membered aromatic rings and other rings and having unsaturation outside the aromatic rings
• CPC Class Codes: C07C 35/37 : with a hydroxy group on a condensed system having three rings
• CPC Class Codes: C07D 209/08 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 211/78 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 211/90 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 215/08 : with acylated ring nitrogen atom
• CPC Class Codes: C07D 231/06 : having one double bond between ring members or between a ring member and a non-ring member
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/56 : Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 233/02 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 277/18 : Nitrogen atoms
• CPC Class Codes: C07D 277/46 : by carboxylic acids, or sulfur or nitrogen analogues thereof
• CPC Class Codes: C07D 307/52 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 333/20 : by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 498/08 : Bridged systems

Abstract

Compounds having the following structure (VI-A):

or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof, wherein R_E1, R_E2, R_E3, R_E4, Z_E2 and Z_E3 are as disclosed herein, are provided. Pharmaceutical compositions comprising the compounds, and methods for use of the compounds for treating disorders associated with necrosptosis are also provided.

Claims

1. A compound having the following structure:

2. The compound of claim 1, wherein said compound has a structure according to the following formula:

3. The compound of claim 2, wherein R_E3 is unsubstituted C_3-10 cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl;

or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

4. The compound of claim 3, wherein R_E3 is unsubstituted aryl or heteroaryl,

or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

5. The compound of claim 2, wherein R_E3 is substituted C_3-10 cycloalkyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl;

or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

6. The compound of claim 5, wherein R_E3 is substituted aryl or substituted heteroaryl,

or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

7. The compound of claim 6, wherein R_E3 is substituted phenyl,

or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

8. The compound of claim 7, wherein said substituted phenyl is substituted with at least one halogen,

or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

9. The compound of claim 7, wherein said substituted phenyl is substituted with 1, 2, 3, 4, or 5 substituents selected, independently, from the group consisting of:

C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, —

N₃, —

OR′

, —

NR′

C(═

O)R″

, —

C(═

O)NRR′

, —

NRR′

, —

OC(═

O)NR′

R″

, —

NRC(═

O)OR′

, —

OH, and —

NC, wherein each R or R′

is selected, independently, from H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl,

or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

10. The compound of claim 2, wherein the stereocenter marked by the asterisk has the (R)-configuration,

or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

11. The compound of claim 2, wherein the stereocenter marked by the asterisk has the (S)-configuration,

or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

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

13. The compound of claim 1, wherein said compound has a structure according to the following formula:

14. The compound of claim 13, wherein R_E3 is unsubstituted C_3-10 cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl;

or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

15. The compound of claim 14, wherein R_E3 is unsubstituted aryl or heteroaryl,

or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

16. The compound of claim 13, wherein R_E3 is substituted C_3-10 cycloalkyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl;

or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

17. The compound of claim 16, wherein R_E3 is substituted aryl or substituted heteroaryl,

or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

18. The compound of claim 17, wherein R_E3 is substituted phenyl,

or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

19. The compound of claim 18, wherein said substituted phenyl is substituted with at least one halogen,

or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

20. The compound of claim 18, wherein said substituted phenyl is substituted with 1, 2, 3, 4, or 5 substituents selected, independently, from the group consisting of:

C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, —

N₃, —

OR′

, —

NR′

C(═

O)R″

, —

C(═

O)NRR′

, —

NRR′

, —

OC(═

O)NR′

R″

, —

NRC(═

O)OR′

, —

OH, and —

NC, wherein each R or R′

is selected, independently, from H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl,

or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

21. The compound of claim 13, wherein the stereocenter marked by the asterisk has the (R)-configuration,

or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

22. The compound of claim 13, wherein the stereocenter marked by the asterisk has the (S)-configuration,

or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

23. A pharmaceutical composition comprising the compound of claim 2 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof, and a pharmaceutically acceptable excipient.

24. A pharmaceutical composition comprising the compound of claim 13 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof, and a pharmaceutically acceptable excipient.

25. A method of treating a condition in a subject, said method comprising administering the compound of claim 1 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof, to said subject in a dosage sufficient to decrease necroptosis.

26. The method of claim 25, wherein said condition is a neurodegenerative disease of the central or peripheral nervous system, the result of retinal neuronal cell death, the result of cell death of cardiac muscle, the result of cell death of cells of the immune system;

stroke, liver disease, pancreatic disease, the result of cell death associated with renal failure;

heart, mesenteric, retinal, hepatic or brain ischemic injury, ischemic injury during organ storage, head trauma, septic shock, coronary heart disease, cardiomyopathy, myocardial infarction, bone avascular necrosis, sickle cell disease, muscle wasting, gastrointestinal disease, tuberculosis, diabetes, alteration of blood vessels, muscular dystrophy, graft-versus-host disease, viral infection, Crohn'"'"'s disease, ulcerative colitis, asthma, or any condition in which alteration in cell proliferation, differentiation or intracellular signaling is a causative factor.

27. A method of treating a condition in a subject, said method comprising administering the compound of claim 2 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof, to said subject in a dosage sufficient to decrease necroptosis.

28. The method of claim 27, wherein said condition is a neurodegenerative disease of the central or peripheral nervous system, the result of retinal neuronal cell death, the result of cell death of cardiac muscle, the result of cell death of cells of the immune system;

stroke, liver disease, pancreatic disease, the result of cell death associated with renal failure;

heart, mesenteric, retinal, hepatic or brain ischemic injury, ischemic injury during organ storage, head trauma, septic shock, coronary heart disease, cardiomyopathy, myocardial infarction, bone avascular necrosis, sickle cell disease, muscle wasting, gastrointestinal disease, tuberculosis, diabetes, alteration of blood vessels, muscular dystrophy, graft-versus-host disease, viral infection, Crohn'"'"'s disease, ulcerative colitis, asthma, or any condition in which alteration in cell proliferation, differentiation or intracellular signaling is a causative factor.

29. A method of treating a condition in a subject, said method comprising administering the compound of claim 13 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof, to said subject in a dosage sufficient to decrease necroptosis.

30. The method of claim 29, wherein said condition is a neurodegenerative disease of the central or peripheral nervous system, the result of retinal neuronal cell death, the result of cell death of cardiac muscle, the result of cell death of cells of the immune system;

stroke, liver disease, pancreatic disease, the result of cell death associated with renal failure;

heart, mesenteric, retinal, hepatic or brain ischemic injury, ischemic injury during organ storage, head trauma, septic shock, coronary heart disease, cardiomyopathy, myocardial infarction, bone avascular necrosis, sickle cell disease, muscle wasting, gastrointestinal disease, tuberculosis, diabetes, alteration of blood vessels, muscular dystrophy, graft-versus-host disease, viral infection, Crohn'"'"'s disease, ulcerative colitis, asthma, or any condition in which alteration in cell proliferation, differentiation or intracellular signaling is a causative factor.