US 6,358,978 B1Granted

Substituted benzimidazoles

AssigneeAventis Pharma Deutschland GmbH

InventorsOlaf Ritzeler, Hans Ulrich Stilz, Bernhard Neises, William Jerome Bock, Jr., Armin Walser, Gary A. Flynn, Jörg Habermann, Gerhard Jähne

Life of this patent

Estimating the term…

Abstract

Compounds of formula I are suitable for the production of pharmaceuticals for the prophylaxis and therapy of disorders in whose course an increased activity of NFκB is involved.

Claims28

Dependent claims

A compound of formula I

or a stereoisomeric form of the compound of formula I or a physiologically tolerable salt of the compound of formula I, where one of the substituents R1, R2, R3, and R4 is a radical of formula II
in which:
D is —C(O)—, —S(O)—, or —S(O )2—;
R8 is hydrogen or (C1-C4)-alkyl;
R9 is
(1) alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, or aspartic acid;
(2) 2-aminoadipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid, 2-amino-3-phenylaminoethyl-propionic acid, 2-amino-3-phenylamino-propionic acid, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine, 2-aminoheptanoic acid, pipecolic acid, hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine, allo-isoleucine, allo-threonine, allo-hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homophenylalanine, homocysteine, homocysteic acid, homotryptophan, cysteic acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine, phosphinothricin, 4-fluorophenylalanine, 3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, 4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluorotryptophan, 5-methoxytryptophan, methionine sulfone, methionine sulfoxide, or —NH—NR11—CON(R11)2, wherein R11 is as defined below:
(3) aryl, in which aryl is unsubstituted or substituted, selected from naphthyl, biphenylyl, anthryl, and fluorenyl;
(4) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted, selected from pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1,3,4-oxadiazole, 1,2,3,5-oxathiadiazole-2-oxides, triazolones, oxadiazolones, isoxazolones, oxadiazolidinediones, triazoles which are substituted by F, CN, CF3, or COO—(C1-C4)-alkyl, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, carboline, and benzo-fused, cyclopenta-, cyclohexa-, or cyclohepta-fused derivatives of these heteroaryls;
(5) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(5)(1) aryl, in which aryl is unsubstituted or substituted;
(5)(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(5)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(5)(4) —O—R11;
(5)(5) ═O;
(5)(6) halogen;
(5)(7) —CN;
(5)(8) —CF3;
(5)(9) —S(O)x—R11, in which x is the integer 0, 1, or 2;
(5)(10) —C(O)—O—R11;
(5)(11) —C(O)—N(R11)2;
(5)(12) —N(R11)2;
(5)(13) (C3-C6)-cycloalkyl;
(5)(14) a radical of formula
or
(5)(15) a radical of formula
in which
R11 is
(a) hydrogen;
(b) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted:
(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(4) halogen;
(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(6) —O—(C1-C6)-alkyl;
or
(7) —COOH;
(c) aryl, in which aryl is unsubstituted or substituted;
(d) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
or
(e) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
and
in the case of (R11)2, R11 independently of one another has the meaning of (a) to (e);
Z is
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroarl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(4) —(C1-C6)-alkyl, in which alkyl is mono- or disubstituted independently of one another by
(4)(1) aryl, in which aryl is unsubstituted or substituted;
(4)(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(4)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(4)(4) halogen;
(4)(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono- , di-, or trisubstituted independently of one another by halogen or by —COOH;
(4)(6) —O—(C1-C6)-alkyl;
or
(4)(7) —COOH;
or
(5) —C(O)—R10, in which
R10 is
(1) —O—R11;
or
(2) —N(R11)2;
in which R11 is as defined above;
or
R8 and R9, together with the nitrogen and carbon to which they are each bonded, form a heterocyclic ring of formula IIa
in which:
D, Z, and R10 are as defined in formula II;
A is nitrogen or —CH2—;
B is oxygen, sulfur, nitrogen, or —CH2;
X is oxygen, sulfur, nitrogen, or —CH2;
Y is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
X and Y together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, A, X, Y, B, and the carbon contains no more than one oxygen, X is not oxygen, sulfur, or nitrogen if A is a nitrogen atom;
contains no more than one sulfur;
contains 1, 2, 3, or 4 nitrogens;
and where oxygen and sulfur do not occur at the same time;
where the ring system formed by N, A, X, Y, B, and the carbon is unsubstituted or mono-, di-, or trisubstituted independently of one another by (C1-C8)-alkyl, in which alkyl is straight-chain or branched and is unsubstituted or mono- or disubstituted by
(1)(1) —OH;
(1)(2) (C1-C8)-alkoxy, in which alkoxy is straight-chain or branched;
(1)(3) halogen;
(1)(4) —NO2;
(1)(5) —NH2;
(1)(6) —CF3;
(1)(7) —OH;
(1)(8) methylenedioxy;
(1)(9) —C(O)—CH3;
(1)(10) —CH(O);
(1)(11) —CN;
(1)(12) —COOH;
(1)(13) —C(O)—NH2;
(1)(14) (C1-C4)-alkoxycarbonyl, in which alkoxycarbonyl is straight-chain or branched;
(1)(15) phenyl;
(1)(16) phenoxy;
(1)(17) benzyl;
(1)(18) benzyloxy;
or
(1)(19) tetrazolyl;
or
R9 and Z together with the carbons to which they each are bonded form a heterocyclic ring of formula IIc
in which:
D, R8, and R11 are as defined in formula II;
T is oxygen, sulfur, nitrogen, or —CH2—;
W is oxygen, sulfur, nitrogen, or —CH2—;
V is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
T and V together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
or
V and W together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, T, V, W, and the two carbons contains no more than one oxygen, no more than one sulfur, and 1, 2, 3, or 4 nitrogens;
where oxygen and sulfur do not occur at the same time;
and where the ring system formed by N, T, V, W, and the two carbons is unsubstituted or mono-, di-, or trisubstituted independently of one another by the substituents defined above under (1)(1) to (1)(19);
and
the other substituents R1, R2, R3, and R4 are chosen independently of one another, and are
(1) hydrogen;
(2) halogen;
(3) (C1-C4)-alkyl;
(4) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstitued or substituted;
(5) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
or
(6) (C1-C6)-alkyl;
(7) —CN;
(8) —NO2;
(9) —O—(C0-C4)-alkyl-aryl, in which alkyl is straight-chain or branched;
(10) —O—(C1-C4)-alkyl;
(11) —OR11;
(12) —N(R11)2;
(13) —S(O)xR11, in which x is the integer 0, 1, or 2;
or
(14) —CF3;
in which R11 is as defined above;
R5 is
(1) hydrogen;
(2) —OH;
or
(3) ═O;
and
R6 is
(1) aryl, in which aryl is unsubstituted or substituted, and is selected from phenyl, naphthyl, biphenylyl, anthryl, and fluorenyl, in which aryl is unsubstituted, monosubstituted, or polysubstituted independently of one another by (C1-C8)-alkyl, (C1-C8)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxytarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, and tetrazolyl;
or
(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted and is selected from pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1,3,4 oxadiazole, 1,2,3,5-oxathiadiazole-2-oxides, triazolones, oxadiazolones, isoxazolones, oxadiazolidinediones, triazoles which are substituted by F, CN, CF3, or COO—(C1-C4)-alkyl, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles, pyridine, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoitne, isoquinoline, quinoxaline, quinazoline, cinnoline, carboline, and benzo-fused, cyclopenta-, cyclohexa-, or cyclohepta-fused derivatives of these heteroaryls.

139 more elements

A compound of formula I

or a stereoisomeric form of the compound of formula I or a physiologically tolerable salt of the compound of formula I, where one of the substituents R1, R2, R3, and R4 is a radical of formula II
in which:
D is —C(O)—, —S(O)—, or —S(O)2—;
R8 is hydrogen or (C1-C4)-alkyl;
R9 is
(1) alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, or aspartic acid;
(2) 2-aminoadipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid, 2-amino-3-phenylaminoethyl-propionic acid, 2-amino-3-phenylamino-propionic acid, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine, 2-aminoheptanoic acid, pipecolic acid, hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine, allo-isoleucine, allo-threonine, allo-hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homophenylalanine, homocysteine, homacysteic acid, homotryptophan, cysteic acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine, phosphinothricin, 4-fluorophenylalanine, 3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, 4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluorotryptophan, 5-methoxytryptophan, methionine sulfone, methionine sulfoxide, or —NH—NR11—CON(R11)2, wherein R11 is as defined below;
(3) aryl, in which aryl is unsubstituted or substituted, selected from naphthyl, biphenylyl, anthryl, and fluorenyl;
(4) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted, selected from pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1,3,4-oxadiazole, 1,2,3,5-oxathiadiazole-2-oxides, triazolones, oxadiazolones, isoxazolones, oxadiazolidinediones, triazoles which are substituted by F, CN, CF3, or COO—(C1-C4)-alkyl, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, carboline, and benzo-fused, cyclopenta-, cyclohexa-, or cyclohepta-fused derivatives of these heteroaryls;
(5) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(5)(1) aryl, in which aryl is unsubstituted or substituted;
(5)(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(5)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(5)(4) —O—R11;
(5)(5) ═O;
(5)(6) halogen;
(5)(7) —CN;
(5)(8) —CF3;
(5)(9) —S(O)x—R11, in which x is the integer 0, 1, or 2;
(5)(10) —C(O)—O—R11;
(5)(11) —C(O)—N(R11)2;
(5)(12) —N(R11)2;
(5)(13) (C3-C6)-cycloalkyl;
(5)(14) a radical of formula
or
(5)(15) a radical of formula
in which
R11 is
(a) hydrogen;
(b) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(4) halogen;
(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(6) —O—(C1-C6)-alkyl;
or
(7) —COOH;
(c) aryl, in which aryl is unsubstituted or substituted;
(d) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
or
(e) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
and
in the case of (R11)2, R11 independently of one another has the meaning of (a) to (e);
Z is
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(4) —(C1-C6)-alkyl, in which alkyl is mono- or disubstituted independently of one another by
(4)(1) aryl, in which aryl is unsubstituted or substituted;
(4)(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(4)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(4)(4) halogen;
(4)(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(4)(6) —O—(C1-C6)-alkyl;
or
(4)(7) —COOH;
or
(5) —C(O)—R10, in which
R10 is
(1) —O—R11;
or
(2) —N(R11)2;
in which R11 is as defined above;
or
R8 and R9, together with the nitrogen and carbon to which they are each bonded, form a heterocyclic ring of formula IIa
in which:
D, Z, and R10 are as defined in formula II;
A is nitrogen or —CH2—;
B is oxygen, sulfur, nitrogen, or —CH2;
X is oxygen, sulfur, nitrogen, or —CH2;
Y is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
X and Y together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, A, X, Y, B, and the carbon contains no more than one oxygen, X is not oxygen, sulfur, or nitrogen if A is a nitrogen atom;
contains no more than one sulfur;
contains 1, 2, 3, or 4 nitrogens;
and where oxygen and sulfur do not occur at the same time;
where the ring system formed by N, A, X, Y, B, and the carbon is unsubstituted or mono-, di-, or trisubstituted independently of one another by (C1-C8)-alkyl, in which alkyl is straight-chain or branched and is unsubstituted or mono- or disubstituted by
(1)(1) —OH;
(1)(2) (C1-C8)-alkoxy, in which alkoxy is straight-chain or branched;
(1)(3) halogen;
(1)(4) —NO2;
(1)(5) —NH2;
(1)(6) —CF3;
(1)(7) —OH;
(1)(8) methylenedioxy;
(1)(9) —C(O)—CH3;
(1)(10) —CH(O);
(1)(11) —CN;
(1)(12) —COOH;
(1)(13) —C(O)—NH2;
(1)(14) (C1-C4)-alkoxycarbonyl, in which alkoxycarbonyl is straight-chain or branched;
(1)(15) phenyl;
(1)(16) phenoxy;
(1)(17) benzyl;
(1)(18) benzyloxy;
or
(1)(19) tetrazolyl;
or
R9 and Z together with the carbons to which they each are bonded form a heterocyclic ring of formula IIc
in which:
D, R8, and R11 are as defined in formula II;
T is oxygen, sulfur, nitrogen, or —CH2—;
W is oxygen, sulfur, nitrogen, or —CH2—;
V is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
T and V together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
or
V and W together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, T, V, W, and the two carbons contains no more than one oxygen, no more than one sulfur, and 1, 2, 3, or 4 nitrogens;
where oxygen and sulfur do not occur at the same time;
and where the ring system formed by N, T, V, W, and the two carbons is unsubstituted or mono-, di-, or trisubstituted independently of one another by the substituents defined above under (1)(1) to (1)(19);
and
the other substituents R1, R2, R3, and R4 are chosen independently of one another, and are
(1) hydrogen;
(4) halogen;
(5) (C1-C4-alkyl;
(4) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(5) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
or
(6) (C1-C6)-alkyl;
(7) —CN;
(8) —NO2;
(9) —O—(C0-C4)-alkyl-aryl, in which alkyl is straight-chain or branched;
(10) —O—(C1-C4)-alkyl;
(11) —OR11;
(12) —N(R11)2;
—S(O)xR11, in which x is the integer 0, 1, or 2;
or
(14) —CF3;
in which R11 is as defined above;
R5 is
(1) hydrogen;
(2) —OH;
or
(3) ═O;
and
R6 is
(1) phenyl, optionally mono- or disubstituted independently of one another by —CN, —NO2, —O—(C1-C4)-alkyl, —N(R11)2, —NH—C(O)—R11, —S(O)xR11, in which x is the integer 0, 1, or 2, or —C(O)—R11, in which R11 is as defined above;
or
(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted and is selected from pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1,3,4 oxadiazole, 1,2,3,5-oxathiadiazole-2-oxides, triazolones, oxadiazolones, isoxazolones, oxadiazolidinediones, triazoles which are substituted by F, CN, CF3, or COO—(C1-C4)-alkyl, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles, pyridine, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, carboline, and benzo-fused, cyclopenta-, cyclohexa-, or cyclohepta-fused derivatives of these heteroaryls.

139 more elements

A method for treating disorders in whose course an increased activity of NFκB is involved, comprising administering to a patient in need thereof an effective amount of at least one compound of formula I

or a stereoisomeric form of the compound of formula I or a physiologically tolerable salt of the compound of formula I, where at least one of the substituents R1, R2, R3, and R4 is a radical of formula II
in which:
D is —C(O)—, —S(O)—, or —S(O)2—;
R8 is hydrogen or (C1-C4)alkyl;
R9 is
(1) glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lyslne, histidine, arginine, glutamic acid, aspartic acid, 2-aminoadipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid, 2-amino-3-phenylaminoethyl-propionic acid, 2-amino-3-phenylamino-propionic acid, phenylglycine, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine, 2-(2-thienyl)glycine, 2-aminoheptanoic acid, pipecolic acid, hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine, allo-isoleucine, allo-threonine, allo-hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homophenylalanine, homocysteine, homocysteic acid, homotryptophan, cysteic acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine, phosphinothricin, 4-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, 3-fluorophenylalanine, 3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, 4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluorotryptophan, 5-methoxytryptophan, methionine sulfone, methionine sulfoxide, or —NH—NR11—CON(R11)2, wherein R11 is as defined below;
(2) aryl, in which aryl is unsubstituted or substituted:
(3) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(4) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(5) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(5)(1) aryl, in which aryl is unsubstituted or substituted;
(5)(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(5)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(5)(4) —O—R11;
(5)(5) ═O;
(5)(6) halogen;
(5)(7) —CN;
(5)(8) —CF3;
(5)(9) —S(O)x—R11, in which x is the integer zero, 1, or 2;
(5)(10) —C(O)—O—R11;
(5)(11) —C(O)—N(R11)2;
(5)(12) —N(R11)2;
(5)(13) (C3-C8)-cycloalkyl;
(5)(14) a radical of formula
or
(5)(15) a radical of formula
in which
R11 is
(a) hydrogen;
(b) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4) halogen;
(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2 and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(6) —O—(C1-C5)-alkyl;
or
(7) —COOH;
(c) aryl, in which aryl is unsubstituted or substituted;
(d) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
or
(e) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
and
in the case of (R11)2, R11 independently of one another has the meaning of (a) to (e);
Z is
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4) —(C1-C6)-alkyl, in which alkyl is substituted or unsubstituted independently of one another by
(4)(1) aryl, in which aryl is unsubstituted or substituted;
(4)(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(4)(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4)(4) halogen;
(4)(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(4)(6) —O—(C1-C6)-alkyl;
or
(4)(7) —COOH;
or
(5) —C(O)—R10, in which
R10 is
(1) —O—R11;
or
(2) —N(R11)2;
in which R11 is as defined above;
or
R8 and R9, together with the nitrogen and carbon to which they are each bonded, form a heterocyclic ring of formula IIa
in which:
D, Z, and R10 are as defined in formula II;
A is nitrogen or —CH2—;
B is oxygen, sulfur, nitrogen, or —CH2;
X is oxygen, sulfur, nitrogen, or —CH2;
Y is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
X and Y together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, A, X, Y, B, and the carbon contains no more than one oxygen, X is not oxygen, sulfur, or nitrogen if A is a nitrogen atom;
contains no more than one sulfur;
contains 1, 2, 3, or 4 nitrogens;
and where oxygen and sulfur do not occur at the same time;
where the ring system formed by N, A, X, Y, B, and the carbon is unsubstituted or mono-, di, or trisubstituted independently of one another by (C1-C8)-alkyl, in which alkyl is unsubstituted or mono- or disubstituted by
(1)(1) —OH;
(1)(2) (C1-C8)-alkoxy, in which alkoxy is straight-chain or branched;
(1)(3) halogen;
(1)(4) —NO2;
(1)(5) —NH2;
(1)(6) —CF3;
(1)(7) —OH;
(1)(8) methylenedioxy;
(1)(9) —C(O)—CH3;
(1)(10) —CH(O);
(1)(11) —CN;
(1)(12) —COOH;
(1)(13) —C(O)—NH2;
(1)(14) (C1-C4)-alkoxycarbonyl, in which alkoxycarbonyl is straight-chain or branched;
(1)(15) phenyl;
(1)(16) phenoxy;
(1)(17) benzyl;
(1)(18) benzyloxy;
or
(1)(19) tetrazolyl;
or
R9 and Z together with the carbons to which they each are bonded form a heterocyclic ring of formula IIc
in which:
D, R8, and R11 are as defined in formula II;
T is oxygen, sulfur, nitrogen, or —CH2—;
W is oxygen, sulfur, nitrogen, or —CH2—;
V is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
T and V together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
or
V and W together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, T, V, W, and the two carbons contains no more than one oxygen, no more than one sulfur, and 1, 2, 3, or 4 nitrogens;
where oxygen and sulfur do not occur at the same time;
and where the ring system formed by N, T, V, W, and the two carbons is unsubstituted or mono, di-, or trisubstituted independently of one another by the substituents defined above under (1)(1) to (1)(19);
and
the other substituents R1, R2, R3, and R4 are chosen independently of one another, and are
(1) hydrogen;
(2) halogen;
(3) (C1-C4)-alkyl;
(4) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(5) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(6) (C1-C6)-alkyl;
(7) —CN;
(8) —NO2;
(9) —O—(C0-C4)-alkyl-aryl, in which alkyl is straight-chain or branched;
(10) —O—(C1-C4)-alkyl;
(11) —OR11;
(12) —N(R11)2;
(13) —S(O)xR11, in which x is the integer 0, 1, or 2;
or
(14) —CF3;
in which R11 is as defined above;
R5 is
(1) hydrogen;
(2) —OH;
or
(3) ═O;
and
R6 is
(1) aryl, in which aryl is unsubstituted or substituted, and is selected from phenyl, naphthyl, biphenylyl, anthryl, and fluorenyl, in which aryl is unsubstituted, monosubstituted, or polysubstituted independently of one another by (C1-C8)-alkyl, (C1-C8)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, and tetrazolyl;
or
(2) heteroaryl having 5 to 14 ring members, unsubstituted or mono-, di-, or trisubstituted;
or
(3) a heterocycle having 5 to 12 ring members, unsubstituted or mono-, di-, or trisubstituted.

140 more elements

A method for treating disorders in whose course an increased activity of is involved, comprising administering to a patient in need thereof an effective amount of at least one compound of formula I

or a stereoisomeric form of the compound of formula I or a physiologically tolerable salt of the compound of formula I, where at least one of the substituents R1, R2, R3, and R4 is a radical of formula II
in which:
D is —C(O)—, —S(O)—, or —S(O)2—;
R8 is hydrogen or (C1-C4)-alkyl;
R9 is
(1) glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, aspartic acid, 2-aminoadipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid, 2-amino-3-phenylaminoethyl-propionic acid, 2-amino-3-phenylamino-propionic acid, phenylglycine, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine, 2-(2-thienyl)glycine, 2-aminoheptanoic acid, pipecolic acid, hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine, allo-isoleucine, allo-threonine, allo-hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homophenylalanine, homocysteine, homocysteic acid, homotryptophan, cysteic acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine, phosphinothricin, 4-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, 3-fluorophenylalanine, 3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, 4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluorotryptophan, 5-methoxytryptophan, methionine sulfone, methionine sulfoxide, or —NH—NR11—CON(R11)2, wherein R11 is as defined below;
(2) aryl, in which aryl is unsubstituted or substituted;
(3) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(4) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(5) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(5)(1) aryl, in which aryl is unsubstituted or substituted;
(5)(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(5)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(5)(4) —O—R11;
(5)(5) ═O;
(5)(6) halogen;
(5)(7) —CN;
(5)(8) —CF3;
(5)(9) —S(O)x—R11, in which x is the integer zero, 1, or 2;
(5)(10) —C(O)—O—R11;
(5)(11) —C(O)—N(R11)2;
(5)(12) —N(R11)2;
(5)(13) (C3-C6)-cycloalkyl;
(5)(14) a radical of formula
or
(5)(15) a radical of formula
in which
R11 is
(a) hydrogen;
(b) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di, or trisubstituted independently of one another by
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4) halogen;
(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2 and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(6) —O—(C1-C6)alkyl;
or
(7) —COOH;
(c) aryl, in which aryl is unsubstituted or substituted;
(d) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
or
(e) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
and
in the case of (R11)2, R11 independently of one another has the meaning of (a) to (e);
Z is
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4) —(C1-C6)-alkyl, in which alkyl is substituted or unsubstituted independently of one another by
(4)(1) aryl, in which aryl is unsubstituted or substituted;
(4)(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(4)(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4)(4) halogen;
(4)(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(4)(6) —O—(C1-C6)-alkyl;
or
(4)(7) —COOH;
or
(5) —C(O)—R10, in which
R10 is
(1) —O—R11;
or
(2) —N(R11)2;
in which R11 is as defined above;
or
R8 and R9, together with the nitrogen and carbon to which they are each bonded, form a heterocyclic ring of formula IIa
in which:
D, Z, and R10 are as defined in formula II;
A is nitrogen or —CH2—;
B is oxygen, sulfur, nitrogen, or —CH2;
X is oxygen, sulfur, nitrogen, or —CH2;
Y is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
X and Y together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, A, X, Y, B, and the carbon contains no more than one oxygen, X is not oxygen, sulfur, or nitrogen if A is a nitrogen atom;
contains no more than one sulfur;
contains 1, 2, 3, or 4 nitrogens;
and where oxygen and sulfur do not occur at the same time;
where the ring system formed by N, A, X, Y, B, and the carbon is unsubstituted or mono-, di-, or trisubstituted independently of one another by (C1-C8)-alkyl, in which alkyl is unsubstituted or mono- or disubstituted by
(1)(1) —OH;
(1)(2) (C1-C8)-alkoxy, in which alkoxy is straight-chain or branched;
(1)(3) halogen;
(1)(4) —NO2;
(1)(5) —NH2;
(1)(6) —CF3;
(1)(7) —OH;
(1)(8) methylenedioxy;
(1)(9) —C(O)—CH3;
(1)(10) —CH(O);
(1)(11) —CN;
(1)(12) —COOH;
(1)(13) —C(O)—NH2;
(1)(14) (C1-C4)-alkoxycarbonyl, in which alkoxycarbonyl is straight-chain or branched;
(1)(15) phenyl;
(1)(16) phenoxy;
(1)(17) benzyl;
(1)(18) benzyloxy;
or
(1)(19) tetrazolyl;
or
R9 and Z together with the carbons to which they each are bonded form a heterocyclic ring of formula IIc
in which;
D, R8, and R11 are as defined in formula II;
T is oxygen, sulfur, nitrogen, or —CH2—;
W is oxygen, sulfur, nitrogen, or —CH2—;
V is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
T and V together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
or
V and W together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, T, V, W, and the two carbons contains no more than one oxygen, no more than one sulfur, and 1, 2, 3, or 4 nitrogens;
where oxygen and sulfur do not occur at the same time;
and where the ring system formed by N, T, V, W, and the two carbons is unsubstituted or mono-, di-, or trisubstituted independently of one another by the substituents defined above under (1)(1) to (1)(19);
and
the other substituents R1, R2, R3, and R4 are chosen independently of one another, and are
(1) hydrogen;
(2) halogen;
(3) (C1-C4)-alkyl;
(4) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(5) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(6) (C1-C6)-alkyl;
(7) —CN;
(8) —NO2;
(9) —O—(C0-C4)-alkyl-aryl, in which alkyl is straight-chain or branched;
(10) —O—(C1-C4)-alkyl;
(11) —OR11;
(12) —N(R11)2;
(13) —S(O)xR11, in which x is the integer 0, 1, or 2;
or
(14) —CF3;
in which R11 is as defined above;
R5 is
(1) hydrogen;
(2) —OH;
or
(3) ═O;
and
R6 is
(1) phenyl, optionally mono- or disubstituted independently of one another by —CN, —NO2, —O—(C1-C4)-alkyl, —N(R11)2, —NH—C(O)—R11, —S(O)xR11, in which x is the integer 0, 1, or 2, —C(O)—R11, in which R11 is as defined above, or —(C1-C4)-alkyl-NH2;
or
(2) heteroaryl having 5 to 14 ring members, unsubstituted or mono-, di-, or trisubstituted;
or
(3) a heterocycle having 5 to 12 ring members, unsubstituted or mono-, di-, or trisubstituted.

140 more elements

A method for treating rheumatoid arthritis, osteoarthritis, asthma, cardiac infarct, Alzheimer's disease, carcinomatous disorders, or atherosclerosis, comprising administering to a patient in need thereof an effective amount of at least one compound of formula I

or a stereoisomeric form of the compound of formula I or a physiologically tolerable salt of the compound of formula I, where at least one of the substituents R1, R2, R3, and R4 is a radical of formula II
in which;
D is —C(O)—, —S(O)—, or —S(O)2—;
R8 is hydrogen or (C1-C4)-alkyl;
R9 is
(1) glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, systeine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, aspartic acid, 2-aminoadipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid, 2-amino-3-phenylaminoethyl-propionic acid, 2-amino-3-phenylamino-propionic acid, phenylglycine, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine, 2-(2-thienyl)glycine, 2-aminoheptanoic acid, pipecolic acid, hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine, allo-isoleucine, allo-threonine, allo-hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homophenylalanine, homocysteine, homocysteic acid, homotryptophan, cysteic acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine, phosphinothricin, 4-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, 3-fluorophenylalanine, 3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, 4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluorotryptophan, 5-methoxytryptophan, methionine sulfone, methionine sulfoxide, or —NH—NR11—CON(R11)2, wherein R11 is as defined below;
(2) aryl, in which aryl is unsubstituted or substituted;
(3) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(4) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(5) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(5)(1) aryl, in which aryl is unsubstituted or substituted;
(5)(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(5)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(5)(4) —O—R11;
(5)(5) ═O;
(5)(6) halogen;
(5)(7) —CN;
(5)(8) —CF3;
(5)(9) —S(O)x—R11, in which x is the integer zero, 1, or 2;
(5)(10) —C(O)—O—R11;
(5)(11) —C(O)—N(R11)2;
(5)(12) —N(R11)2;
(5)(13) (C3-C6)-cycloalkyl;
(5)(14) a radical of formula
or
(5)(15) a radical of formula
in which
R11 is
(a) hydrogen;
(b) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4) halogen;
(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2 and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(6) —O—(C1-C6)-alkyl;
or
(7) —COOH;
(c) aryl, in which aryl is unsubstituted or substituted;
(d) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
or
(e) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
and
in the case of (R11)2, R11 independently of one another has the meaning of (a) to (e);
Z is
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted
(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4) (C1-C6)-alkyl, in which alkyl is substituted or unsubstituted independently of one another by
(4)(1) aryl, in which aryl is unsubstituted or substituted;
(4)(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(4)(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4)(4) halogen;
(4)(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(4)(6) —O—(C1-C6)-alkyl;
or
(4)(7) —COOH;
or
(5) —C(O)—R10, in which
R10 is
(1) —O—R11;
or
(2) —N(R11)2;
in which R11 is as defined above;
or
R8 and R9, together with the nitrogen and carbon to which they are each bonded, form a heterocyclic ring of formula IIa
in which:
D, Z, and R10 are as defined in formula II;
A is nitrogen or —CH2—;
B is oxygen, sulfur, nitrogen, or —CH2;
X is oxygen, sulfur, nitrogen, or —CH2;
Y is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
X and Y together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, A, X, Y, B, and the carbon contains no more than one oxygen, X is not oxygen, sulfur, or nitrogen if A is a nitrogen atom;
contains no more than one sulfur;
contains 1, 2, 3, or 4 nitrogens;
and where oxygen and sulfur do not occur at the same time;
where the ring system formed by N, A, X, Y, B, and the carbon is unsubstituted or mono-, di-, or trisubstituted independently of one another by (C1-C8)-alkyl, in which alkyl is unsubstituted or mono- or disubstituted by
(1)(1) —OH;
(1)(2) (C1-C8)-alkoxy, in which alkoxy is straight-chain or branched;
(1)(3) halogen;
(1)(4) —NO2;
(1)(5) —NH2;
(1)(6) —CF3;
(1)(7) —OH;
(1)(8) methylenedioxy;
(1)(9) —C(O)—CH3;
(1)(10) —CH(O);
(1)(11) —CN;
(1)(12) —COOH;
(1)(13) —C(O)—NH2;
(1)(14) (C1-C4)-alkoxycarbonyl, in which alkoxycarbonyl is straight-chain or branched;
(1)(15) phenyl;
(1)(16) phenoxy;
(1)(17) benzyl;
(1)(18) benzyloxy;
or
(1)(19) tetrazolyl;
or
R9 and Z together with the carbons to which they each are bonded form a heterocyclic ring of formula IIc
in which:
D, R8, and R11 are as defined in formula II;
T is oxygen, sulfur, nitrogen, or —CH2—;
W is oxygen, sulfur, nitrogen, or —CH2—;
V is absent or is oxygen, sulfur, nitrogen, or —CH2;
or
T and V together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
or
V and W together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, T, V, W, and the two carbons contains no more than one oxygen, no more than one sulfur, and 1, 2, 3, or 4 nitrogens;
where oxygen and sulfur do not occur at the same time;
and where the ring system formed by N, T, V, W, and the two carbons is unsubstituted or mono-, di-, or trisubstituted independently of one another by the substituents defined above under (1)(1) to (1)(19);
and
the other substituents R1, R2, R3, and R4 are chosen independently of one another, and are
(1) hydrogen;
(2) halogen;
(3) (C1-C4)-alkyl;
(4) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(5) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(6) (C1-C6)-alkyl;
(7) —CN;
(8) —NO2;
(9) —O—(C0-C4)-alkyl-aryl, in which alkyl is straight-chain or branched;
(10) —O—(C1-C4)-alkyl;
(11) —OR11;
(12) —N(R11)2;
(13) —S(O)xR11, in which x is the integer 0, 1, or 2;
or
(14) —CF3;
in which R11 is as defined above;
R5is
(1) hydrogen;
(2) —OH;
or
(3) ═O;
and
R6 is
(1) aryl, in which aryl is unsubstituted or substituted, and is selected from phenyl, naphthyl, biphenylyl, anthryl, and fluorenyl, in which aryl is unsubstituted, monosubstituted, or polysubstituted independently of one another by (C1-C8)-alkyl, (C1-C8)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, and tetrazolyl;
or
(2) heteroaryl having 5 to 14 ring members, unsubstituted or mono-, di-, or trisubstituted;
or
(3) a heterocycle having 5 to 12 ring members, unsubstituted or mono-, di-, or trisubstituted.

140 more elements

A method for treating rheumatoid arthritis, osteoarthritis, asthma, cardiac infaret, Alzheimer's disease, carcinomatous disorders, or atherosclerosis, comprising administering to a patient in need thereof an effective amount of at least one compound of formula I

or a stereoisomeric form of the compound of formula I or a physiologically tolerable salt of the compound of formula I, where at least one of the substituents R1, R2, R3, and R4 is a radical of formula II
in which:
D is —C(O)—, —S(O)—, or —S(O)2—;
R8 is hydrogen or (C1-C4)-alkyl;
R9 is
(1) glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, aspartic acid, 2-aminoadipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid, 2-amino-3-phenylaminoethyl-propionic acid, 2-amino-3-phenylamino-propionic acid, phenylglycine, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine, 2-(2-thienyl)glycine, 2-aminoheptanoic acid, pipecolic acid, hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine, allo-isoleucine, allo-threonine, allo-hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homophenylalanine, homocysteine, homocysteic acid, homotryptophan, cysteic acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine, phosphinothricin, 4-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, 3-fluorophenylalanine, 3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, 4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluorotryptophan, 5-methoxytryptophan, methionine sulfone, methionine sulfoxide, or —NH—NR11—CON(R11)2, wherein R11 is as defined below;
(2) aryl, in which aryl is unsubstituted or substituted;
(3) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(4) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted:
(5) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(5)(1) aryl, in which aryl is unsubstituted or substituted;
(5)(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(5)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(5)(4) —O—R11;
(5)(5) ═O;
(5)(6) halogen;
(5)(7) —CN;
(5)(8) —CF3;
(5)(9) —S(O)x—R11, in which x is the integer zero, 1, or 2;
(5)(10) —C(O)—O—R11;
(5)(11) —C(O)—N(R11)2;
(5)(12) —N(R11)2;
(5)(13) (C3-C6)-cycloalkyl;
(5)(14) a radical of formula
or
(5)(15) a radical of formula
in which
R11 is
(a) hydrogen;
(b) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4) halogen;
(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2 and alkyl is unsubstituted or mono, di-, or trisubstituted independently of one another by halogen or by —COOH;
(6) —O—(C1-C6)-alkyl;
or
(7) —COOH;
(c) aryl, in which aryl is unsubstituted or substituted;
(d) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
or
(e) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
and
in the case of (R11)2, R11 independently of one another has the meaning of (a) to (e);
Z is
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted:
(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4) —(C1-C6)-alkyl, in which alkyl is substituted or unsubstituted independently of one another by
(4)(1) aryl, in which aryl is unsubstituted or substituted;
(4)(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(4)(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4)(4) halogen;
(4)(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(4)(6) —O—(C1-C6)-alkyl;
or
(4)(7) —COOH;
or
(5) —C(O)—R10, in which
R10 is
(1) —O—R11;
or
(2) —N(R11)2;
which R11 is as defined above;
or
R8 and R9, together with the nitrogen and carbon to which they are each bonded, form a heterocyclic ring of formula IIa
in which:
D, Z, and R10 are as defined in formula II;
A is nitrogen or —CH2—;
B is oxygen, sulfur, nitrogen, or —CH2;
X is oxygen, sulfur, nitrogen, or —CH2;
Y is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
X and Y together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, A, X, Y, B, and the carbon contains no more than one oxygen, X is not oxygen, sulfur, or nitrogen if A is a nitrogen atom;
contains no more than one sulfur;
contains 1, 2, 3, or 4 nitrogens;
and where oxygen and sulfur do not occur at the same time;
where the ring system formed by N, A, X, Y, B, and the carbon is unsubstituted or mono-, di-, or trisubstituted independently of one another by (C1-C8)-alkyl, in which alkyl is unsubstituted or mono- or disubstituted by
(1)(1) —OH;
(1)(2) (C1-C8)-alkoxy, in which alkoxy is straight-chain or branched;
(1)(3) halogen;
(1)(4) —NO2;
(1)(5) —NH2;
(1)(6) —CF3;
(1)(7) —OH;
(1)(8) methylenedioxy;
(1)(9) —C(O)—CH3;
(1)(10) —CH(O);
(1)(11) —CN;
(1)(12) —COOH;
(1)(13) —C(O)—NH2;
(1)(14) (C1-C4)-alkoxycarbonyl, in which alkoxycarbonyl is straight-chain or branched;
(1)(15) phenyl;
(1)(16) phenoxy;
(1)(17) benzyl;
(1)(18) benzyloxy;
or
(1)(19) tetrazolyl;
or
R9 and Z together with the carbons to which they each are bonded form a heterocyclic ring of formula IIc
in which:
D, R8, and R11 are as defined in formula II;
T is oxygen, sulfur, nitrogen, or —CH2—;
W is oxygen, sulfur, nitrogen, or —CH2—;
V is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
T and V together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
or
V and W together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, T, V, W, and the two carbons contains no more than one oxygen, no more than one sulfur, and 1, 2, 3, or 4 nitrogens;
where oxygen and sulfur do not occur at the same time;
and where the ring system formed by N, T, V, W, and the two carbons is unsubstituted or mono-, di-, or trisubstituted independently of one another by the substituents defined above under (1)(1) to (1)(19);
and
the other substituents R1, R2, R3, and R4 are chosen independently of one another, and are
(1) hydrogen;
(2) halogen;
(3) (C1-C4)-alkyl;
(4) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted:
(5) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(6) (C1-C6)-alkyl;
(7) —CN;
(8) —NO2;
(9) —O—(C0-C4)-alkyl-aryl, in which alkyl is straight-chain or branched;
(10) —O—(C1-C4)-alkyl;
(11) —OR11;
(12) —N(R11)2;
(13) —S(O)xR11, in which x is the integer 0, 1, or 2;
or
(14) —CF3;
in which R11 is as defined above;
R5 is
(1) hydrogen;
(2) —OH;
or
(3) ═O;
and
R6 is
(1) phenyl, optionally mono- or disubstituted independently of one another by —CN, —NO2, —O—(C1-C4)-alkyl, —N(R11)2, —NH—C(O)—R11, —S(O)xR11, in which x is the integer 0, 1, or 2, —C(O)—R11, in which R11 is as defined above, or —(C1-C4)-alkyl-NH2;
or
(2) heteroaryl having 5 to 14 ring members, unsubstituted or mono-, di-, or trisubstituted;
or
(3) a heterocycle having 5 to 12 ring members, unsubstituted or mono-, di-, or trisubstituted.

140 more elements

Dependencies are inferred from the claim text.

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US 6,358,978 B1Granted

Substituted benzimidazoles

AssigneeAventis Pharma Deutschland GmbH

InventorsOlaf Ritzeler, Hans Ulrich Stilz, Bernhard Neises, William Jerome Bock, Jr., Armin Walser, Gary A. Flynn, Jörg Habermann, Gerhard Jähne

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Abstract

Compounds of formula I are suitable for the production of pharmaceuticals for the prophylaxis and therapy of disorders in whose course an increased activity of NFκB is involved.

Claims28

Dependent claims

A compound of formula I

or a stereoisomeric form of the compound of formula I or a physiologically tolerable salt of the compound of formula I, where one of the substituents R1, R2, R3, and R4 is a radical of formula II
in which:
D is —C(O)—, —S(O)—, or —S(O )2—;
R8 is hydrogen or (C1-C4)-alkyl;
R9 is
(1) alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, or aspartic acid;
(2) 2-aminoadipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid, 2-amino-3-phenylaminoethyl-propionic acid, 2-amino-3-phenylamino-propionic acid, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine, 2-aminoheptanoic acid, pipecolic acid, hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine, allo-isoleucine, allo-threonine, allo-hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homophenylalanine, homocysteine, homocysteic acid, homotryptophan, cysteic acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine, phosphinothricin, 4-fluorophenylalanine, 3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, 4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluorotryptophan, 5-methoxytryptophan, methionine sulfone, methionine sulfoxide, or —NH—NR11—CON(R11)2, wherein R11 is as defined below:
(3) aryl, in which aryl is unsubstituted or substituted, selected from naphthyl, biphenylyl, anthryl, and fluorenyl;
(4) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted, selected from pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1,3,4-oxadiazole, 1,2,3,5-oxathiadiazole-2-oxides, triazolones, oxadiazolones, isoxazolones, oxadiazolidinediones, triazoles which are substituted by F, CN, CF3, or COO—(C1-C4)-alkyl, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, carboline, and benzo-fused, cyclopenta-, cyclohexa-, or cyclohepta-fused derivatives of these heteroaryls;
(5) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(5)(1) aryl, in which aryl is unsubstituted or substituted;
(5)(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(5)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(5)(4) —O—R11;
(5)(5) ═O;
(5)(6) halogen;
(5)(7) —CN;
(5)(8) —CF3;
(5)(9) —S(O)x—R11, in which x is the integer 0, 1, or 2;
(5)(10) —C(O)—O—R11;
(5)(11) —C(O)—N(R11)2;
(5)(12) —N(R11)2;
(5)(13) (C3-C6)-cycloalkyl;
(5)(14) a radical of formula
or
(5)(15) a radical of formula
in which
R11 is
(a) hydrogen;
(b) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted:
(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(4) halogen;
(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(6) —O—(C1-C6)-alkyl;
or
(7) —COOH;
(c) aryl, in which aryl is unsubstituted or substituted;
(d) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
or
(e) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
and
in the case of (R11)2, R11 independently of one another has the meaning of (a) to (e);
Z is
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroarl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(4) —(C1-C6)-alkyl, in which alkyl is mono- or disubstituted independently of one another by
(4)(1) aryl, in which aryl is unsubstituted or substituted;
(4)(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(4)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(4)(4) halogen;
(4)(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono- , di-, or trisubstituted independently of one another by halogen or by —COOH;
(4)(6) —O—(C1-C6)-alkyl;
or
(4)(7) —COOH;
or
(5) —C(O)—R10, in which
R10 is
(1) —O—R11;
or
(2) —N(R11)2;
in which R11 is as defined above;
or
R8 and R9, together with the nitrogen and carbon to which they are each bonded, form a heterocyclic ring of formula IIa
in which:
D, Z, and R10 are as defined in formula II;
A is nitrogen or —CH2—;
B is oxygen, sulfur, nitrogen, or —CH2;
X is oxygen, sulfur, nitrogen, or —CH2;
Y is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
X and Y together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, A, X, Y, B, and the carbon contains no more than one oxygen, X is not oxygen, sulfur, or nitrogen if A is a nitrogen atom;
contains no more than one sulfur;
contains 1, 2, 3, or 4 nitrogens;
and where oxygen and sulfur do not occur at the same time;
where the ring system formed by N, A, X, Y, B, and the carbon is unsubstituted or mono-, di-, or trisubstituted independently of one another by (C1-C8)-alkyl, in which alkyl is straight-chain or branched and is unsubstituted or mono- or disubstituted by
(1)(1) —OH;
(1)(2) (C1-C8)-alkoxy, in which alkoxy is straight-chain or branched;
(1)(3) halogen;
(1)(4) —NO2;
(1)(5) —NH2;
(1)(6) —CF3;
(1)(7) —OH;
(1)(8) methylenedioxy;
(1)(9) —C(O)—CH3;
(1)(10) —CH(O);
(1)(11) —CN;
(1)(12) —COOH;
(1)(13) —C(O)—NH2;
(1)(14) (C1-C4)-alkoxycarbonyl, in which alkoxycarbonyl is straight-chain or branched;
(1)(15) phenyl;
(1)(16) phenoxy;
(1)(17) benzyl;
(1)(18) benzyloxy;
or
(1)(19) tetrazolyl;
or
R9 and Z together with the carbons to which they each are bonded form a heterocyclic ring of formula IIc
in which:
D, R8, and R11 are as defined in formula II;
T is oxygen, sulfur, nitrogen, or —CH2—;
W is oxygen, sulfur, nitrogen, or —CH2—;
V is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
T and V together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
or
V and W together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, T, V, W, and the two carbons contains no more than one oxygen, no more than one sulfur, and 1, 2, 3, or 4 nitrogens;
where oxygen and sulfur do not occur at the same time;
and where the ring system formed by N, T, V, W, and the two carbons is unsubstituted or mono-, di-, or trisubstituted independently of one another by the substituents defined above under (1)(1) to (1)(19);
and
the other substituents R1, R2, R3, and R4 are chosen independently of one another, and are
(1) hydrogen;
(2) halogen;
(3) (C1-C4)-alkyl;
(4) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstitued or substituted;
(5) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
or
(6) (C1-C6)-alkyl;
(7) —CN;
(8) —NO2;
(9) —O—(C0-C4)-alkyl-aryl, in which alkyl is straight-chain or branched;
(10) —O—(C1-C4)-alkyl;
(11) —OR11;
(12) —N(R11)2;
(13) —S(O)xR11, in which x is the integer 0, 1, or 2;
or
(14) —CF3;
in which R11 is as defined above;
R5 is
(1) hydrogen;
(2) —OH;
or
(3) ═O;
and
R6 is
(1) aryl, in which aryl is unsubstituted or substituted, and is selected from phenyl, naphthyl, biphenylyl, anthryl, and fluorenyl, in which aryl is unsubstituted, monosubstituted, or polysubstituted independently of one another by (C1-C8)-alkyl, (C1-C8)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxytarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, and tetrazolyl;
or
(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted and is selected from pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1,3,4 oxadiazole, 1,2,3,5-oxathiadiazole-2-oxides, triazolones, oxadiazolones, isoxazolones, oxadiazolidinediones, triazoles which are substituted by F, CN, CF3, or COO—(C1-C4)-alkyl, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles, pyridine, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoitne, isoquinoline, quinoxaline, quinazoline, cinnoline, carboline, and benzo-fused, cyclopenta-, cyclohexa-, or cyclohepta-fused derivatives of these heteroaryls.

139 more elements

A compound of formula I

or a stereoisomeric form of the compound of formula I or a physiologically tolerable salt of the compound of formula I, where one of the substituents R1, R2, R3, and R4 is a radical of formula II
in which:
D is —C(O)—, —S(O)—, or —S(O)2—;
R8 is hydrogen or (C1-C4)-alkyl;
R9 is
(1) alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, or aspartic acid;
(2) 2-aminoadipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid, 2-amino-3-phenylaminoethyl-propionic acid, 2-amino-3-phenylamino-propionic acid, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine, 2-aminoheptanoic acid, pipecolic acid, hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine, allo-isoleucine, allo-threonine, allo-hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homophenylalanine, homocysteine, homacysteic acid, homotryptophan, cysteic acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine, phosphinothricin, 4-fluorophenylalanine, 3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, 4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluorotryptophan, 5-methoxytryptophan, methionine sulfone, methionine sulfoxide, or —NH—NR11—CON(R11)2, wherein R11 is as defined below;
(3) aryl, in which aryl is unsubstituted or substituted, selected from naphthyl, biphenylyl, anthryl, and fluorenyl;
(4) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted, selected from pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1,3,4-oxadiazole, 1,2,3,5-oxathiadiazole-2-oxides, triazolones, oxadiazolones, isoxazolones, oxadiazolidinediones, triazoles which are substituted by F, CN, CF3, or COO—(C1-C4)-alkyl, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, carboline, and benzo-fused, cyclopenta-, cyclohexa-, or cyclohepta-fused derivatives of these heteroaryls;
(5) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(5)(1) aryl, in which aryl is unsubstituted or substituted;
(5)(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(5)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(5)(4) —O—R11;
(5)(5) ═O;
(5)(6) halogen;
(5)(7) —CN;
(5)(8) —CF3;
(5)(9) —S(O)x—R11, in which x is the integer 0, 1, or 2;
(5)(10) —C(O)—O—R11;
(5)(11) —C(O)—N(R11)2;
(5)(12) —N(R11)2;
(5)(13) (C3-C6)-cycloalkyl;
(5)(14) a radical of formula
or
(5)(15) a radical of formula
in which
R11 is
(a) hydrogen;
(b) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(4) halogen;
(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(6) —O—(C1-C6)-alkyl;
or
(7) —COOH;
(c) aryl, in which aryl is unsubstituted or substituted;
(d) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
or
(e) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
and
in the case of (R11)2, R11 independently of one another has the meaning of (a) to (e);
Z is
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(4) —(C1-C6)-alkyl, in which alkyl is mono- or disubstituted independently of one another by
(4)(1) aryl, in which aryl is unsubstituted or substituted;
(4)(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(4)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(4)(4) halogen;
(4)(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(4)(6) —O—(C1-C6)-alkyl;
or
(4)(7) —COOH;
or
(5) —C(O)—R10, in which
R10 is
(1) —O—R11;
or
(2) —N(R11)2;
in which R11 is as defined above;
or
R8 and R9, together with the nitrogen and carbon to which they are each bonded, form a heterocyclic ring of formula IIa
in which:
D, Z, and R10 are as defined in formula II;
A is nitrogen or —CH2—;
B is oxygen, sulfur, nitrogen, or —CH2;
X is oxygen, sulfur, nitrogen, or —CH2;
Y is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
X and Y together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, A, X, Y, B, and the carbon contains no more than one oxygen, X is not oxygen, sulfur, or nitrogen if A is a nitrogen atom;
contains no more than one sulfur;
contains 1, 2, 3, or 4 nitrogens;
and where oxygen and sulfur do not occur at the same time;
where the ring system formed by N, A, X, Y, B, and the carbon is unsubstituted or mono-, di-, or trisubstituted independently of one another by (C1-C8)-alkyl, in which alkyl is straight-chain or branched and is unsubstituted or mono- or disubstituted by
(1)(1) —OH;
(1)(2) (C1-C8)-alkoxy, in which alkoxy is straight-chain or branched;
(1)(3) halogen;
(1)(4) —NO2;
(1)(5) —NH2;
(1)(6) —CF3;
(1)(7) —OH;
(1)(8) methylenedioxy;
(1)(9) —C(O)—CH3;
(1)(10) —CH(O);
(1)(11) —CN;
(1)(12) —COOH;
(1)(13) —C(O)—NH2;
(1)(14) (C1-C4)-alkoxycarbonyl, in which alkoxycarbonyl is straight-chain or branched;
(1)(15) phenyl;
(1)(16) phenoxy;
(1)(17) benzyl;
(1)(18) benzyloxy;
or
(1)(19) tetrazolyl;
or
R9 and Z together with the carbons to which they each are bonded form a heterocyclic ring of formula IIc
in which:
D, R8, and R11 are as defined in formula II;
T is oxygen, sulfur, nitrogen, or —CH2—;
W is oxygen, sulfur, nitrogen, or —CH2—;
V is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
T and V together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
or
V and W together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, T, V, W, and the two carbons contains no more than one oxygen, no more than one sulfur, and 1, 2, 3, or 4 nitrogens;
where oxygen and sulfur do not occur at the same time;
and where the ring system formed by N, T, V, W, and the two carbons is unsubstituted or mono-, di-, or trisubstituted independently of one another by the substituents defined above under (1)(1) to (1)(19);
and
the other substituents R1, R2, R3, and R4 are chosen independently of one another, and are
(1) hydrogen;
(4) halogen;
(5) (C1-C4-alkyl;
(4) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(5) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
or
(6) (C1-C6)-alkyl;
(7) —CN;
(8) —NO2;
(9) —O—(C0-C4)-alkyl-aryl, in which alkyl is straight-chain or branched;
(10) —O—(C1-C4)-alkyl;
(11) —OR11;
(12) —N(R11)2;
—S(O)xR11, in which x is the integer 0, 1, or 2;
or
(14) —CF3;
in which R11 is as defined above;
R5 is
(1) hydrogen;
(2) —OH;
or
(3) ═O;
and
R6 is
(1) phenyl, optionally mono- or disubstituted independently of one another by —CN, —NO2, —O—(C1-C4)-alkyl, —N(R11)2, —NH—C(O)—R11, —S(O)xR11, in which x is the integer 0, 1, or 2, or —C(O)—R11, in which R11 is as defined above;
or
(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted and is selected from pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1,3,4 oxadiazole, 1,2,3,5-oxathiadiazole-2-oxides, triazolones, oxadiazolones, isoxazolones, oxadiazolidinediones, triazoles which are substituted by F, CN, CF3, or COO—(C1-C4)-alkyl, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles, pyridine, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, carboline, and benzo-fused, cyclopenta-, cyclohexa-, or cyclohepta-fused derivatives of these heteroaryls.

139 more elements

or a stereoisomeric form of the compound of formula I or a physiologically tolerable salt of the compound of formula I, where at least one of the substituents R1, R2, R3, and R4 is a radical of formula II
in which:
D is —C(O)—, —S(O)—, or —S(O)2—;
R8 is hydrogen or (C1-C4)alkyl;
R9 is
(1) glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lyslne, histidine, arginine, glutamic acid, aspartic acid, 2-aminoadipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid, 2-amino-3-phenylaminoethyl-propionic acid, 2-amino-3-phenylamino-propionic acid, phenylglycine, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine, 2-(2-thienyl)glycine, 2-aminoheptanoic acid, pipecolic acid, hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine, allo-isoleucine, allo-threonine, allo-hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homophenylalanine, homocysteine, homocysteic acid, homotryptophan, cysteic acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine, phosphinothricin, 4-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, 3-fluorophenylalanine, 3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, 4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluorotryptophan, 5-methoxytryptophan, methionine sulfone, methionine sulfoxide, or —NH—NR11—CON(R11)2, wherein R11 is as defined below;
(2) aryl, in which aryl is unsubstituted or substituted:
(3) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(4) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(5) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(5)(1) aryl, in which aryl is unsubstituted or substituted;
(5)(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(5)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(5)(4) —O—R11;
(5)(5) ═O;
(5)(6) halogen;
(5)(7) —CN;
(5)(8) —CF3;
(5)(9) —S(O)x—R11, in which x is the integer zero, 1, or 2;
(5)(10) —C(O)—O—R11;
(5)(11) —C(O)—N(R11)2;
(5)(12) —N(R11)2;
(5)(13) (C3-C8)-cycloalkyl;
(5)(14) a radical of formula
or
(5)(15) a radical of formula
in which
R11 is
(a) hydrogen;
(b) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4) halogen;
(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2 and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(6) —O—(C1-C5)-alkyl;
or
(7) —COOH;
(c) aryl, in which aryl is unsubstituted or substituted;
(d) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
or
(e) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
and
in the case of (R11)2, R11 independently of one another has the meaning of (a) to (e);
Z is
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4) —(C1-C6)-alkyl, in which alkyl is substituted or unsubstituted independently of one another by
(4)(1) aryl, in which aryl is unsubstituted or substituted;
(4)(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(4)(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4)(4) halogen;
(4)(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(4)(6) —O—(C1-C6)-alkyl;
or
(4)(7) —COOH;
or
(5) —C(O)—R10, in which
R10 is
(1) —O—R11;
or
(2) —N(R11)2;
in which R11 is as defined above;
or
R8 and R9, together with the nitrogen and carbon to which they are each bonded, form a heterocyclic ring of formula IIa
in which:
D, Z, and R10 are as defined in formula II;
A is nitrogen or —CH2—;
B is oxygen, sulfur, nitrogen, or —CH2;
X is oxygen, sulfur, nitrogen, or —CH2;
Y is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
X and Y together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, A, X, Y, B, and the carbon contains no more than one oxygen, X is not oxygen, sulfur, or nitrogen if A is a nitrogen atom;
contains no more than one sulfur;
contains 1, 2, 3, or 4 nitrogens;
and where oxygen and sulfur do not occur at the same time;
where the ring system formed by N, A, X, Y, B, and the carbon is unsubstituted or mono-, di, or trisubstituted independently of one another by (C1-C8)-alkyl, in which alkyl is unsubstituted or mono- or disubstituted by
(1)(1) —OH;
(1)(2) (C1-C8)-alkoxy, in which alkoxy is straight-chain or branched;
(1)(3) halogen;
(1)(4) —NO2;
(1)(5) —NH2;
(1)(6) —CF3;
(1)(7) —OH;
(1)(8) methylenedioxy;
(1)(9) —C(O)—CH3;
(1)(10) —CH(O);
(1)(11) —CN;
(1)(12) —COOH;
(1)(13) —C(O)—NH2;
(1)(14) (C1-C4)-alkoxycarbonyl, in which alkoxycarbonyl is straight-chain or branched;
(1)(15) phenyl;
(1)(16) phenoxy;
(1)(17) benzyl;
(1)(18) benzyloxy;
or
(1)(19) tetrazolyl;
or
R9 and Z together with the carbons to which they each are bonded form a heterocyclic ring of formula IIc
in which:
D, R8, and R11 are as defined in formula II;
T is oxygen, sulfur, nitrogen, or —CH2—;
W is oxygen, sulfur, nitrogen, or —CH2—;
V is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
T and V together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
or
V and W together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, T, V, W, and the two carbons contains no more than one oxygen, no more than one sulfur, and 1, 2, 3, or 4 nitrogens;
where oxygen and sulfur do not occur at the same time;
and where the ring system formed by N, T, V, W, and the two carbons is unsubstituted or mono, di-, or trisubstituted independently of one another by the substituents defined above under (1)(1) to (1)(19);
and
the other substituents R1, R2, R3, and R4 are chosen independently of one another, and are
(1) hydrogen;
(2) halogen;
(3) (C1-C4)-alkyl;
(4) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(5) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(6) (C1-C6)-alkyl;
(7) —CN;
(8) —NO2;
(9) —O—(C0-C4)-alkyl-aryl, in which alkyl is straight-chain or branched;
(10) —O—(C1-C4)-alkyl;
(11) —OR11;
(12) —N(R11)2;
(13) —S(O)xR11, in which x is the integer 0, 1, or 2;
or
(14) —CF3;
in which R11 is as defined above;
R5 is
(1) hydrogen;
(2) —OH;
or
(3) ═O;
and
R6 is
(1) aryl, in which aryl is unsubstituted or substituted, and is selected from phenyl, naphthyl, biphenylyl, anthryl, and fluorenyl, in which aryl is unsubstituted, monosubstituted, or polysubstituted independently of one another by (C1-C8)-alkyl, (C1-C8)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, and tetrazolyl;
or
(2) heteroaryl having 5 to 14 ring members, unsubstituted or mono-, di-, or trisubstituted;
or
(3) a heterocycle having 5 to 12 ring members, unsubstituted or mono-, di-, or trisubstituted.

140 more elements

A method for treating disorders in whose course an increased activity of is involved, comprising administering to a patient in need thereof an effective amount of at least one compound of formula I

or a stereoisomeric form of the compound of formula I or a physiologically tolerable salt of the compound of formula I, where at least one of the substituents R1, R2, R3, and R4 is a radical of formula II
in which:
D is —C(O)—, —S(O)—, or —S(O)2—;
R8 is hydrogen or (C1-C4)-alkyl;
R9 is
(1) glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, aspartic acid, 2-aminoadipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid, 2-amino-3-phenylaminoethyl-propionic acid, 2-amino-3-phenylamino-propionic acid, phenylglycine, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine, 2-(2-thienyl)glycine, 2-aminoheptanoic acid, pipecolic acid, hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine, allo-isoleucine, allo-threonine, allo-hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homophenylalanine, homocysteine, homocysteic acid, homotryptophan, cysteic acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine, phosphinothricin, 4-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, 3-fluorophenylalanine, 3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, 4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluorotryptophan, 5-methoxytryptophan, methionine sulfone, methionine sulfoxide, or —NH—NR11—CON(R11)2, wherein R11 is as defined below;
(2) aryl, in which aryl is unsubstituted or substituted;
(3) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(4) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(5) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(5)(1) aryl, in which aryl is unsubstituted or substituted;
(5)(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(5)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(5)(4) —O—R11;
(5)(5) ═O;
(5)(6) halogen;
(5)(7) —CN;
(5)(8) —CF3;
(5)(9) —S(O)x—R11, in which x is the integer zero, 1, or 2;
(5)(10) —C(O)—O—R11;
(5)(11) —C(O)—N(R11)2;
(5)(12) —N(R11)2;
(5)(13) (C3-C6)-cycloalkyl;
(5)(14) a radical of formula
or
(5)(15) a radical of formula
in which
R11 is
(a) hydrogen;
(b) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di, or trisubstituted independently of one another by
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4) halogen;
(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2 and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(6) —O—(C1-C6)alkyl;
or
(7) —COOH;
(c) aryl, in which aryl is unsubstituted or substituted;
(d) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
or
(e) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
and
in the case of (R11)2, R11 independently of one another has the meaning of (a) to (e);
Z is
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4) —(C1-C6)-alkyl, in which alkyl is substituted or unsubstituted independently of one another by
(4)(1) aryl, in which aryl is unsubstituted or substituted;
(4)(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(4)(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4)(4) halogen;
(4)(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(4)(6) —O—(C1-C6)-alkyl;
or
(4)(7) —COOH;
or
(5) —C(O)—R10, in which
R10 is
(1) —O—R11;
or
(2) —N(R11)2;
in which R11 is as defined above;
or
R8 and R9, together with the nitrogen and carbon to which they are each bonded, form a heterocyclic ring of formula IIa
in which:
D, Z, and R10 are as defined in formula II;
A is nitrogen or —CH2—;
B is oxygen, sulfur, nitrogen, or —CH2;
X is oxygen, sulfur, nitrogen, or —CH2;
Y is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
X and Y together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, A, X, Y, B, and the carbon contains no more than one oxygen, X is not oxygen, sulfur, or nitrogen if A is a nitrogen atom;
contains no more than one sulfur;
contains 1, 2, 3, or 4 nitrogens;
and where oxygen and sulfur do not occur at the same time;
where the ring system formed by N, A, X, Y, B, and the carbon is unsubstituted or mono-, di-, or trisubstituted independently of one another by (C1-C8)-alkyl, in which alkyl is unsubstituted or mono- or disubstituted by
(1)(1) —OH;
(1)(2) (C1-C8)-alkoxy, in which alkoxy is straight-chain or branched;
(1)(3) halogen;
(1)(4) —NO2;
(1)(5) —NH2;
(1)(6) —CF3;
(1)(7) —OH;
(1)(8) methylenedioxy;
(1)(9) —C(O)—CH3;
(1)(10) —CH(O);
(1)(11) —CN;
(1)(12) —COOH;
(1)(13) —C(O)—NH2;
(1)(14) (C1-C4)-alkoxycarbonyl, in which alkoxycarbonyl is straight-chain or branched;
(1)(15) phenyl;
(1)(16) phenoxy;
(1)(17) benzyl;
(1)(18) benzyloxy;
or
(1)(19) tetrazolyl;
or
R9 and Z together with the carbons to which they each are bonded form a heterocyclic ring of formula IIc
in which;
D, R8, and R11 are as defined in formula II;
T is oxygen, sulfur, nitrogen, or —CH2—;
W is oxygen, sulfur, nitrogen, or —CH2—;
V is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
T and V together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
or
V and W together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, T, V, W, and the two carbons contains no more than one oxygen, no more than one sulfur, and 1, 2, 3, or 4 nitrogens;
where oxygen and sulfur do not occur at the same time;
and where the ring system formed by N, T, V, W, and the two carbons is unsubstituted or mono-, di-, or trisubstituted independently of one another by the substituents defined above under (1)(1) to (1)(19);
and
the other substituents R1, R2, R3, and R4 are chosen independently of one another, and are
(1) hydrogen;
(2) halogen;
(3) (C1-C4)-alkyl;
(4) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(5) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(6) (C1-C6)-alkyl;
(7) —CN;
(8) —NO2;
(9) —O—(C0-C4)-alkyl-aryl, in which alkyl is straight-chain or branched;
(10) —O—(C1-C4)-alkyl;
(11) —OR11;
(12) —N(R11)2;
(13) —S(O)xR11, in which x is the integer 0, 1, or 2;
or
(14) —CF3;
in which R11 is as defined above;
R5 is
(1) hydrogen;
(2) —OH;
or
(3) ═O;
and
R6 is
(1) phenyl, optionally mono- or disubstituted independently of one another by —CN, —NO2, —O—(C1-C4)-alkyl, —N(R11)2, —NH—C(O)—R11, —S(O)xR11, in which x is the integer 0, 1, or 2, —C(O)—R11, in which R11 is as defined above, or —(C1-C4)-alkyl-NH2;
or
(2) heteroaryl having 5 to 14 ring members, unsubstituted or mono-, di-, or trisubstituted;
or
(3) a heterocycle having 5 to 12 ring members, unsubstituted or mono-, di-, or trisubstituted.

140 more elements

or a stereoisomeric form of the compound of formula I or a physiologically tolerable salt of the compound of formula I, where at least one of the substituents R1, R2, R3, and R4 is a radical of formula II
in which;
D is —C(O)—, —S(O)—, or —S(O)2—;
R8 is hydrogen or (C1-C4)-alkyl;
R9 is
(1) glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, systeine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, aspartic acid, 2-aminoadipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid, 2-amino-3-phenylaminoethyl-propionic acid, 2-amino-3-phenylamino-propionic acid, phenylglycine, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine, 2-(2-thienyl)glycine, 2-aminoheptanoic acid, pipecolic acid, hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine, allo-isoleucine, allo-threonine, allo-hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homophenylalanine, homocysteine, homocysteic acid, homotryptophan, cysteic acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine, phosphinothricin, 4-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, 3-fluorophenylalanine, 3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, 4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluorotryptophan, 5-methoxytryptophan, methionine sulfone, methionine sulfoxide, or —NH—NR11—CON(R11)2, wherein R11 is as defined below;
(2) aryl, in which aryl is unsubstituted or substituted;
(3) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(4) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(5) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(5)(1) aryl, in which aryl is unsubstituted or substituted;
(5)(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(5)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(5)(4) —O—R11;
(5)(5) ═O;
(5)(6) halogen;
(5)(7) —CN;
(5)(8) —CF3;
(5)(9) —S(O)x—R11, in which x is the integer zero, 1, or 2;
(5)(10) —C(O)—O—R11;
(5)(11) —C(O)—N(R11)2;
(5)(12) —N(R11)2;
(5)(13) (C3-C6)-cycloalkyl;
(5)(14) a radical of formula
or
(5)(15) a radical of formula
in which
R11 is
(a) hydrogen;
(b) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4) halogen;
(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2 and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(6) —O—(C1-C6)-alkyl;
or
(7) —COOH;
(c) aryl, in which aryl is unsubstituted or substituted;
(d) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
or
(e) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
and
in the case of (R11)2, R11 independently of one another has the meaning of (a) to (e);
Z is
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted
(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4) (C1-C6)-alkyl, in which alkyl is substituted or unsubstituted independently of one another by
(4)(1) aryl, in which aryl is unsubstituted or substituted;
(4)(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(4)(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4)(4) halogen;
(4)(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(4)(6) —O—(C1-C6)-alkyl;
or
(4)(7) —COOH;
or
(5) —C(O)—R10, in which
R10 is
(1) —O—R11;
or
(2) —N(R11)2;
in which R11 is as defined above;
or
R8 and R9, together with the nitrogen and carbon to which they are each bonded, form a heterocyclic ring of formula IIa
in which:
D, Z, and R10 are as defined in formula II;
A is nitrogen or —CH2—;
B is oxygen, sulfur, nitrogen, or —CH2;
X is oxygen, sulfur, nitrogen, or —CH2;
Y is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
X and Y together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, A, X, Y, B, and the carbon contains no more than one oxygen, X is not oxygen, sulfur, or nitrogen if A is a nitrogen atom;
contains no more than one sulfur;
contains 1, 2, 3, or 4 nitrogens;
and where oxygen and sulfur do not occur at the same time;
where the ring system formed by N, A, X, Y, B, and the carbon is unsubstituted or mono-, di-, or trisubstituted independently of one another by (C1-C8)-alkyl, in which alkyl is unsubstituted or mono- or disubstituted by
(1)(1) —OH;
(1)(2) (C1-C8)-alkoxy, in which alkoxy is straight-chain or branched;
(1)(3) halogen;
(1)(4) —NO2;
(1)(5) —NH2;
(1)(6) —CF3;
(1)(7) —OH;
(1)(8) methylenedioxy;
(1)(9) —C(O)—CH3;
(1)(10) —CH(O);
(1)(11) —CN;
(1)(12) —COOH;
(1)(13) —C(O)—NH2;
(1)(14) (C1-C4)-alkoxycarbonyl, in which alkoxycarbonyl is straight-chain or branched;
(1)(15) phenyl;
(1)(16) phenoxy;
(1)(17) benzyl;
(1)(18) benzyloxy;
or
(1)(19) tetrazolyl;
or
R9 and Z together with the carbons to which they each are bonded form a heterocyclic ring of formula IIc
in which:
D, R8, and R11 are as defined in formula II;
T is oxygen, sulfur, nitrogen, or —CH2—;
W is oxygen, sulfur, nitrogen, or —CH2—;
V is absent or is oxygen, sulfur, nitrogen, or —CH2;
or
T and V together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
or
V and W together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, T, V, W, and the two carbons contains no more than one oxygen, no more than one sulfur, and 1, 2, 3, or 4 nitrogens;
where oxygen and sulfur do not occur at the same time;
and where the ring system formed by N, T, V, W, and the two carbons is unsubstituted or mono-, di-, or trisubstituted independently of one another by the substituents defined above under (1)(1) to (1)(19);
and
the other substituents R1, R2, R3, and R4 are chosen independently of one another, and are
(1) hydrogen;
(2) halogen;
(3) (C1-C4)-alkyl;
(4) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(5) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(6) (C1-C6)-alkyl;
(7) —CN;
(8) —NO2;
(9) —O—(C0-C4)-alkyl-aryl, in which alkyl is straight-chain or branched;
(10) —O—(C1-C4)-alkyl;
(11) —OR11;
(12) —N(R11)2;
(13) —S(O)xR11, in which x is the integer 0, 1, or 2;
or
(14) —CF3;
in which R11 is as defined above;
R5is
(1) hydrogen;
(2) —OH;
or
(3) ═O;
and
R6 is
(1) aryl, in which aryl is unsubstituted or substituted, and is selected from phenyl, naphthyl, biphenylyl, anthryl, and fluorenyl, in which aryl is unsubstituted, monosubstituted, or polysubstituted independently of one another by (C1-C8)-alkyl, (C1-C8)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, and tetrazolyl;
or
(2) heteroaryl having 5 to 14 ring members, unsubstituted or mono-, di-, or trisubstituted;
or
(3) a heterocycle having 5 to 12 ring members, unsubstituted or mono-, di-, or trisubstituted.

140 more elements

or a stereoisomeric form of the compound of formula I or a physiologically tolerable salt of the compound of formula I, where at least one of the substituents R1, R2, R3, and R4 is a radical of formula II
in which:
D is —C(O)—, —S(O)—, or —S(O)2—;
R8 is hydrogen or (C1-C4)-alkyl;
R9 is
(1) glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, aspartic acid, 2-aminoadipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid, 2-amino-3-phenylaminoethyl-propionic acid, 2-amino-3-phenylamino-propionic acid, phenylglycine, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine, 2-(2-thienyl)glycine, 2-aminoheptanoic acid, pipecolic acid, hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine, allo-isoleucine, allo-threonine, allo-hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homophenylalanine, homocysteine, homocysteic acid, homotryptophan, cysteic acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine, phosphinothricin, 4-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, 3-fluorophenylalanine, 3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, 4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluorotryptophan, 5-methoxytryptophan, methionine sulfone, methionine sulfoxide, or —NH—NR11—CON(R11)2, wherein R11 is as defined below;
(2) aryl, in which aryl is unsubstituted or substituted;
(3) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(4) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted:
(5) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(5)(1) aryl, in which aryl is unsubstituted or substituted;
(5)(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(5)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(5)(4) —O—R11;
(5)(5) ═O;
(5)(6) halogen;
(5)(7) —CN;
(5)(8) —CF3;
(5)(9) —S(O)x—R11, in which x is the integer zero, 1, or 2;
(5)(10) —C(O)—O—R11;
(5)(11) —C(O)—N(R11)2;
(5)(12) —N(R11)2;
(5)(13) (C3-C6)-cycloalkyl;
(5)(14) a radical of formula
or
(5)(15) a radical of formula
in which
R11 is
(a) hydrogen;
(b) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4) halogen;
(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2 and alkyl is unsubstituted or mono, di-, or trisubstituted independently of one another by halogen or by —COOH;
(6) —O—(C1-C6)-alkyl;
or
(7) —COOH;
(c) aryl, in which aryl is unsubstituted or substituted;
(d) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
or
(e) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
and
in the case of (R11)2, R11 independently of one another has the meaning of (a) to (e);
Z is
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted:
(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4) —(C1-C6)-alkyl, in which alkyl is substituted or unsubstituted independently of one another by
(4)(1) aryl, in which aryl is unsubstituted or substituted;
(4)(2) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted;
(4)(3) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(4)(4) halogen;
(4)(5) —N—(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(4)(6) —O—(C1-C6)-alkyl;
or
(4)(7) —COOH;
or
(5) —C(O)—R10, in which
R10 is
(1) —O—R11;
or
(2) —N(R11)2;
which R11 is as defined above;
or
R8 and R9, together with the nitrogen and carbon to which they are each bonded, form a heterocyclic ring of formula IIa
in which:
D, Z, and R10 are as defined in formula II;
A is nitrogen or —CH2—;
B is oxygen, sulfur, nitrogen, or —CH2;
X is oxygen, sulfur, nitrogen, or —CH2;
Y is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
X and Y together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, A, X, Y, B, and the carbon contains no more than one oxygen, X is not oxygen, sulfur, or nitrogen if A is a nitrogen atom;
contains no more than one sulfur;
contains 1, 2, 3, or 4 nitrogens;
and where oxygen and sulfur do not occur at the same time;
where the ring system formed by N, A, X, Y, B, and the carbon is unsubstituted or mono-, di-, or trisubstituted independently of one another by (C1-C8)-alkyl, in which alkyl is unsubstituted or mono- or disubstituted by
(1)(1) —OH;
(1)(2) (C1-C8)-alkoxy, in which alkoxy is straight-chain or branched;
(1)(3) halogen;
(1)(4) —NO2;
(1)(5) —NH2;
(1)(6) —CF3;
(1)(7) —OH;
(1)(8) methylenedioxy;
(1)(9) —C(O)—CH3;
(1)(10) —CH(O);
(1)(11) —CN;
(1)(12) —COOH;
(1)(13) —C(O)—NH2;
(1)(14) (C1-C4)-alkoxycarbonyl, in which alkoxycarbonyl is straight-chain or branched;
(1)(15) phenyl;
(1)(16) phenoxy;
(1)(17) benzyl;
(1)(18) benzyloxy;
or
(1)(19) tetrazolyl;
or
R9 and Z together with the carbons to which they each are bonded form a heterocyclic ring of formula IIc
in which:
D, R8, and R11 are as defined in formula II;
T is oxygen, sulfur, nitrogen, or —CH2—;
W is oxygen, sulfur, nitrogen, or —CH2—;
V is absent or is oxygen, sulfur, nitrogen, or —CH2—;
or
T and V together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
or
V and W together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, T, V, W, and the two carbons contains no more than one oxygen, no more than one sulfur, and 1, 2, 3, or 4 nitrogens;
where oxygen and sulfur do not occur at the same time;
and where the ring system formed by N, T, V, W, and the two carbons is unsubstituted or mono-, di-, or trisubstituted independently of one another by the substituents defined above under (1)(1) to (1)(19);
and
the other substituents R1, R2, R3, and R4 are chosen independently of one another, and are
(1) hydrogen;
(2) halogen;
(3) (C1-C4)-alkyl;
(4) heteroaryl having 5 to 14 ring members, in which heteroaryl is unsubstituted or substituted:
(5) a heterocycle having 5 to 12 ring members, in which heterocycle is unsubstituted or substituted;
(6) (C1-C6)-alkyl;
(7) —CN;
(8) —NO2;
(9) —O—(C0-C4)-alkyl-aryl, in which alkyl is straight-chain or branched;
(10) —O—(C1-C4)-alkyl;
(11) —OR11;
(12) —N(R11)2;
(13) —S(O)xR11, in which x is the integer 0, 1, or 2;
or
(14) —CF3;
in which R11 is as defined above;
R5 is
(1) hydrogen;
(2) —OH;
or
(3) ═O;
and
R6 is
(1) phenyl, optionally mono- or disubstituted independently of one another by —CN, —NO2, —O—(C1-C4)-alkyl, —N(R11)2, —NH—C(O)—R11, —S(O)xR11, in which x is the integer 0, 1, or 2, —C(O)—R11, in which R11 is as defined above, or —(C1-C4)-alkyl-NH2;
or
(2) heteroaryl having 5 to 14 ring members, unsubstituted or mono-, di-, or trisubstituted;
or
(3) a heterocycle having 5 to 12 ring members, unsubstituted or mono-, di-, or trisubstituted.

140 more elements

Dependencies are inferred from the claim text.