Spiroquinoxaline derivatives as inhibitors of non-apoptotic regulated cell-death

Patent metadata

Field	Value
Publication number	US-RE48992-E
Application number	US-201416670784-A
Country	US
Kind code	E1
Filing date	Jul 15, 2014
Priority date	Jul 15, 2013
Publication date	Mar 29, 2022
Grant date	Mar 29, 2022

Abstract

The present invention relates to compounds which are inhibitors of non-apoptotic regulated cell death, and to pharmaceutical compositions containing such compounds. Furthermore, the present invention relates to the use of such compounds and pharmaceutical compositions in therapy, in particular in the treatment of a condition, disorder or disease that is characterised by non-apoptotic regulated cell-death or where non-apoptotic regulated cell-death is likely to play or plays a substantial role. The compounds and pharmaceutical compositions described herein are also useful in the treatment of a condition, disorder or disease that is characterised by oxidative stress or where oxidative stress is likely to play or plays a substantial role; and/or a condition, disorder or disease that is characterised by activation of (1) one or more components of the necrosome; (2) death domain receptors; and/or (3) Toll-like receptors; and/or (4) players in ferroptotic/ferroptosis signalling, or where activation of any one of (1) to (3) and/or (4) is likely to play or plays a substantial role.

First claim

The invention claimed is:

1. A compound selected from the group consisting of a spiroquinoxaline derivative having the general formula (I)

and solvates, salts, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, isotopically labeled forms, prodrugs, and combinations thereof,
wherein
E is —N(R 6 )—;
L is selected from the group consisting of C 1-10 alkylene, C 2-10 alkenylene, C 2-10 alkynylene, 1,1-(CH 2 ) a -cyclopropylene-(CH 2 ) b —, wherein each of a and b is independently selected from an integer between 0 and 3, and —(CH 2 ) m —[Y—(CH 2 ) n ] o —, wherein m is an integer between 1 and 6, n is an integer between 0 and 3, o is an integer between 1 and 3, wherein if n is 0 then o is 1; Y is independently selected from O, S, and —N(R 7 )—; and each of the C 1-10 alkylene, C 2-10 alkenylene, C 2-10 alkynylene, 1,1-cyclopropylene, —(CH 2 ) m —, and —(CH 2 ) n — groups is optionally substituted with one or more independently selected R 30 ;
G is phenyl, optionally substituted with 1, 2, 3, 4 or 5 independently selected R 8 ;
ring A is a monocyclic 4- to 10-membered N-heterocycloalkylene or a monocyclic 4- to 10-membered O/S-heterocycloalkylene, wherein each of the N-heterocycloalkylene and O/S-heterocycloalkylene is optionally substituted with one or more independently selected R 9 ;
R 1 is H;
R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO 2 , —OR 11 , —N(R 12 )(R 13 ), —N(R 11 )(OR 11 ), —S(O) 0-2 R 11 , —S(O) 1-2 OR 11 , —OS(O) 1-2 R 11 , —OS(O) 1-2 OR 11 , —S(O) 1-2 N(R 12 )(R 13 ), —OS(O) 1-2 N(R 12 )(R 13 ), —N(R 11 )S(O) 1-2 R 11 , —NR 11 S(O) 1-2 OR 11 , —NR 11 S(O) 1-2 N(R 12 )(R 13 ), —C(═X)R 11 , —C(═X)XR 11 , —XC(═X)R 11 , and —XC(═X)XR 11 , wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ;
or R 2 and R 3 may join together with the atoms to which they are attached to form a ring which is optionally substituted with one or more independently selected R 30 ; R 3 and R 4 may join together with the atoms to which they are attached to form a ring which is optionally substituted with one or more independently selected R 30 ; and/or R 4 and R 5 may join together with the atoms to which they are attached to form a ring which is optionally substituted with one or more independently selected R 30 ;
R 6 is H;
R 7 is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —OR 11 , and —NHR 20 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ;
R 8 is, in each case, selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO 2 , —OR 11 , —N(R 12 )(R 13 ), —N(R 11 )(OR 11 ), —S(O) 0-2 R 11 , —S(O) 1-2 OR 11 , —OS(O) 1-2 R 11 , —OS(O) 1-2 OR 11 , —S(O) 1-2 N(R 12 )(R 13 ), —OS(O) 1-2 N(R 12 )(R 13 ), —N(R 11 )S(O) 1-2 R 11 , —NR 11 S(O) 1-2 OR 11 , —NR 11 S(O) 1-2 N(R 12 )(R 13 ), —C(═X)R 11 , —C(═X)XR 11 , —XC(═X)R 11 , and —XC(═X)XR 11 , wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ;
R 9 is, when substituting a hydrogen atom bound to a ring carbon atom, independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO 2 , —OR 11 , —N(R 12 )(R 13 ), —S(O) 0-2 R 11 , —S(O) 1-2 OR 11 , —OS(O) 1-2 R 11 , —OS(O) 1-2 OR 11 , —S(O) 1-2 N(R 12 )(R 13 ), —OS(O) 1-2 N(R 12 )(R 13 ), —N(R 11 )S(O) 1-2 R 11 , —NR 11 S(O) 1-2 OR 11 , —NR 11 S(O) 1-2 N(R 12 )(R 13 ), —C(═X)R 11 , —C(═X)XR 11 , —XC(═X)R 11 , and —XC(═X)XR 11 , wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 , and/or any two R 9 which are bound to the same carbon atom of ring A may join together to form ═X; or R 9 is, when substituting a hydrogen atom bound to a ring nitrogen atom, independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, —OR 11 , —N(R 12 )(R 13 ), —S(O) 1-2 R 11 , —S(O) 1-2 OR 11 , —S(O) 1-2 N(R 12 )(R 13 ), —N(R 11 )S(O) 1-2 R 11 , —NR 11 S(O) 1-2 OR 11 , —NR 11 S(O) 1-2 N(R 12 )(R 13 ), —C(═X)R 11 , —C(═X)XR 11 , —N(R 14 )C(═X)R 11 , and —N(R 14 )C(═X)XR 11 , wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ; or R 9 is, when bound to a ring sulfur atom of ring A, independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, —OR 11 , and ═O, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ;
X is independently selected from O, S, and N(R 14 );
R 11 is, in each case, selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ;
R 12 and R 13 are, in each case, independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R 12 and R 13 may join together with the nitrogen atom to which they are attached to form the group —N═CR 15 R 16 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ;
R 14 is independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and —OR 11 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ;
R 15 and R 16 are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and —NH y R 20 2−y , or R 15 and R 16 may join together with the atom to which they are attached to form a ring which is optionally substituted with one or more independently selected R 30 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ;
y is an integer from 0 to 2;
R 20 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 ; and
R 30 is a 1 st level substituent and is, in each case, independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO 2 , —OR 71 , —N(R 72 )(R 73 ), —S(O) 0-2 R 71 , —S(O) 1-2 OR 71 , —OS(O) 1-2 R 71 , —OS(O) 1-2 OR 71 , —S(O) 1-2 N(R 72 )(R 73 ), —OS(O) 1-2 N(R 72 )(R 73 ), —N(R 71 )S(O) 1-2 R 71 , —NR 71 S(O) 1-2 OR 71

Assignees

• Helmholtz Zentrum Muenchen Deutsches Forschungszentrum Gesundheit & Umwelt Gmbh

Inventors

• Conrad Marcus
• Schick Joel
• Proneth Bettina
• Sennhenn Peter

Classifications

• A61K31/499

  Spiro-condensed pyrazines or piperazines · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title