US 9,802,956 B2 · Spiroquinoxaline derivatives as inhibitors of non-apoptotic regulated cell-death

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.

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(R6)—;
L is selected from the group consisting of C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, 1,1-(CH2)a-cyclopropylene-(CH2)b—, wherein each of a and b is independently selected from an integer between 0 and 3, and —(CH2)m—[Y—(CH2)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(R7)—;
and each of the C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, 1,1-cyclopropylene, —(CH2)m—, and —(CH2)n— groups is optionally substituted with one or more independently selected R30;
G is phenyl, optionally substituted with 1, 2, 3, 4 or 5 independently selected R8;
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 R9;
R1 is H;
R2, R3, R4, and R5 are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO2, —OR11, —N(R12)(R13), —N(R11)(OR11), —S(O)0-2R11, —S(O)1-2OR11, —OS(O)1-2R11, —OS(O)1-2OR11, —S(O)1-2N(R12)(R13), —OS(O)1-2N(R12)(R13), —N(R11)S(O)1-2R11, —NR11S(O)1-2OR11, —NR11S(O)1-2N(R12)(R13), —C(═X)R11, —C(═X)XR11, —XC(═X)R11, and —XC(═X)XR11, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
or R2 and R3 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 R30;
R3 and R4 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 R30;
and/or R4 and R5 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 R30;
R6 is H;
R7 is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —OR11, and —NHR20, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
R8 is, in each case, selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO2, —OR11, —N(R12)(R13), —N(R11)(OR11), —S(O)0-2R11, —S(O)1-2OR11, —OS(O)1-2R11, —OS(O)1-2OR11, —S(O)1-2N(R12)(R13), —OS(O)1-2N(R12)(R13), —N(R11)S(O)1-2R11, —NR11S(O)1-2OR11, —NR11S(O)1-2N(R12)(R13), —C(═X)R11, —C(═X)XR11, —XC(═X)R11, and —XC(═X)XR11, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
R9 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, —NO2, —OR11, —N(R12)(R13), —S(O)0-2R11, —S(O)1-2OR11, —OS(O)1-2R11, —OS(O)1-2OR11, —S(O)1-2N(R12)(R13), —OS(O)1-2N(R12)(R13), —N(R11)S(O)1-2R11, —NR11S(O)1-2OR11, —NR11S(O)1-2N(R12)(R13), —C(═X)R11, —C(═X)XR11, —XC(═X)R11, and —XC(═X)XR11, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R30, and/or any two R9 which are bound to the same carbon atom of ring A may join together to form ═X;
or R9 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, —OR11, —N(R12)(R13), —S(O)1-2R11, —S(O)1-2OR11, —S(O)1-2N(R12)(R13), —N(R11)S(O)1-2R11, —NR11S(O)1-2OR11, —NR11S(O)1-2N(R12)(R13), —C(═X)R11, —C(═X)XR11, —N(R14)C(═X)R11, and —N(R14)C(═X)XR11, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
or R9 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, —OR11, and ═O, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
X is independently selected from O, S, and N(R14);
R11 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 R30;
R12 and R13 are, in each case, independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R12 and R13 may join together with the nitrogen atom to which they are attached to form the group —N═CR15R16, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
R14 is independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and —OR11, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
R15 and R16 are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and —NHyR202−y, or R15 and R16 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 R30, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R30;
y is an integer from 0 to 2;
R20 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 R30;
and
R30 is a 1st level substituent and is, in each case, independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, —CN, azido, —NO2, —OR71, —N(R72)(R73), —S(O)0-2R71, —S(O)1-2OR71, —OS(O)1-2R71, —OS(O)1-2OR71, —S(O)1-2N(R72)(R73), —OS(O)1-2N(R72)(R73), —N(R71)S(O)1-2R71, —NR71S(O)1-2OR71, —NR71 S(O)1-2N(R72)(R73), —C(═X1)R71, —C(═X1)X1R71, —X1C(═X1)R71, and —X1C(═X1)X1R71, and/or any two R30 which are bound to the same carbon atom of a cycloalkyl or heterocyclyl group may join together to form ═X1, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups being a 1st level substituent is optionally substituted by one or more 2nd level substituents, wherein said 2nd level substituent is, in each case, independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, halogen, —CF3, —CN, azido, —NO2, —OR81, —N(R82)(R83), —S(O)0-2R81, —S(O)1-2OR81, —OS(O)1-2R81, —OS(O)1-2OR81, —S(O)1-2N(R82)(R83), —OS(O)1-2N(R82)(R83), —N(R81)S(O)1-2R81, —NR81S(O)1-2OR81, —NR81S(O)1-2N(R82)(R83), —C(═X2)R81, —C(═X2)X2R81, —X2C(═X2)R81, and —X2C(═X2)X2R81, and/or any two 2nd level substituents which are bound to the same carbon atom of a cycloalkyl or heterocyclyl group being a 1st level substituent may join together to form ═X2, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl groups being a 2nd level substituent is optionally substituted with one or more 3rd level substituents, wherein said 3rd level substituent is, in each case, independently selected from the group consisting of C1-3 alkyl, halogen, —CF3, —CN, azido, —NO2, —OH, —O(C1-3 alkyl), —OCF3, —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —NHS(O)2(C1-3 alkyl), —S(O)2NH2−z(C1-3 alkyl)z, —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2−z(C1-3 alkyl)z, —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz−2(C1-3 alkyl)z, and —N(C1-3 alkyl)C(═NH)NH2−z(C1-3 alkyl)z, wherein z is 0, 1, or 2 and C1-3 alkyl is methyl, ethyl, propyl or isopropyl, and/or any two 3rd level substituents which are bound to the same carbon atom of a 3- to 14-membered cycloalkyl or heterocyclyl group being a 2nd level substituent may join together to form ═O, ═S, ═NH, or ═N(C1-3 alkyl);
wherein
R71, R72, and R73 are independently selected from the group consisting of —H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl groups is optionally substituted with one, two or three substituents selected from the group consisting of C1-3 alkyl, halogen, —CF3, —CN, azido, —NO2, —OH, —O(C1-3 alkyl), —OCF3, ═O, —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —NHS(O)2(C1-3 alkyl), —S(O)2NH2−z(C1-3 alkyl)z, —C(═O)(C1-3 alkyl), —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2−z(C1-3 alkyl)z, —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz−2(C1-3 alkyl)z, and —N(C1-3 alkyl)C(═NH)NH2−z(C1-3 alkyl)z, wherein z is 0, 1, or 2 and C1-3 alkyl is methyl, ethyl, propyl or isopropyl;
R81, R82, and R83 are independently selected from the group consisting of —H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl, wherein each of the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl groups is optionally substituted with one, two or three substituents selected from the group consisting of C1-3 alkyl, halogen, —CF3, —CN, azido, —NO2, —OH, —O(C1-3 alkyl), —OCF3, ═O, —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —NHS(O)2(C1-3 alkyl), —S(O)2NH2−z(C1-3 alkyl)z, —C(═O)(C1-3 alkyl), —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2−z(C1-3 alkyl)z, —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz−2(C1-3 alkyl)z, and —N(C1-3 alkyl)C(═NH)NH2−z(C1-3 alkyl)z, wherein z is 0, 1, or 2 and C1-3 alkyl is methyl, ethyl, propyl or isopropyl;
and
X1 and X2 are independently selected from O, S, and N(R84), wherein R84 is —H or C1-3 alkyl, with the proviso that
(1) when R2 to R5 are each H, L is —CH2—, and
(i) G is unsubstituted phenyl, then ring A is not
wherein R9 is —S(O)2N(CH3)2, (cyclopropyl)sulfonyl, or (3-pyridinyl)sulfonyl, or R9 is —C(O)Z, wherein Z is methyl, tert-butyl, methoxymethyl, 2-methoxyethyl, —CH2NHC(O)CH3, 2-methoxyethylamino, morpholin-4-ylmethyl, 2-furanylmethylamino, (2-methyl-1H-imidazol-1-yl)methyl, 2-furanyl, 3-furanyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, 1-ethyl-1H-pyrazol-3-yl, or 1-ethyl-1H-pyrazol-5-yl;
(ii) G is unsubstituted phenyl, then ring A is not
wherein R9 is (1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl or —C(O)Z, wherein Z is 2-methoxyethylamino, methoxycarbonylmethylamino, (2-trifluoromethylphenyl)amino, 5-chloro-1H-indo1-2-yl, 4,5,6,7-tetrahydro-1H-indazol-3-yl, or 3-(2-thienyl)-1H-pyrazol-5-yl;
(iii) G is 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, or 4-methoxyphenyl, then ring A is not
(iv) G is 3-methoxyphenyl, then ring A is not
wherein R9 is (3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl;
(v) G is 4-fluorophenyl, then ring A is not
wherein R9 is —C(O)Z, wherein Z is 6-methoxy-1H-indol-2-yl or 3,4-dimethoxyphenyl;
or
(vi) G is 4-chlorophenyl, then ring A is not
wherein R9 is —C(O)Z, wherein Z is 1-methyl-2-(2-methyl-1H-imidazol-1-yl)ethyl;
(2) when ring A is
R2 and R5 are both H, L is —CH2—, and
(i) R3 and R4 are both H, then G is not 3-methylphenyl, 3-methoxyphenyl, 4-chlorophenyl, or 4-fluorophenyl;
or
(ii) R3 and R4 are both methyl, then G is not 4-fluorophenyl;
and
(3) when R2 and R5 are both H, L is —CH2.

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

Life of this patent

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

Life of this patent

Abstract

Claims12