DE10131128A1 - New 5-aminosulfonyl-2-phenylacetamido-thiazole derivatives, useful as antiviral medicaments effective against herpes viruses, especially herpes simplex - Google Patents

Abstract

Thiazole derivatives (I) are new. Thiazole derivatives of formula (I) and their salts are new. R1 = H, halo, alkyl, alkoxy, aminoalkyl or haloalkyl; R3 = alkoxy or cycloalkyl; or alkyl (optionally substituted by 1-3 3-6C cycloalkyl, alkoxy, halo, OH, NH2, trialkylsilyloxy, Het1, Het2 or aryl (optionally substituted by OH or alkoxy)); Het1 = C- or N-bonded 5-6 membered aromatic heterocycle containing 1-3 S, N and/or O heteroatoms; Het2 = C- or N-bonded 3-8 membered, saturated or unsaturated, non-aromatic heterocycle containing 1-3 S, N and/or O heteroatoms; R4 = H, acyl, 2-6C alkenyl or cycloalkyl; or alkyl (optionally substituted by 1-3 halo, OH, cycloalkyl, acyl, alkoxy, COOH, NHCOOtBu, OEt, -CH2CH2OEt, phenoxy, aryl or NR13R14), or alkyl substituted by optionally benzo-fused Het1, 2-(R16)-pyrrolidino, tetrahydrofuran-2-yl, benzo-1,4-dioxan-2-yl, 2-oxo-pyrrolidino or -OCOR17R18; R13, R14 = H, acyl, alkyl, CONH2, mono- or dialkylaminoalkyl, mono- or dialkylaminocarbonyl, aryl or alkoxycarbonyl; or NR13R14 = 5-6 membered saturated heterocyclyl, optionally containing a further O, S or NR15 heteroatom and optionally substituted by =O; R15 = H or 1-4C alkyl; R16 = H or alkyl; R17, R18 = H, or alkyl or aryl (both optionally substituted by 1-3 of OH, alkoxy or halo); R5, R7 = H, alkyl, halo, NH2, mono- or dialkylamino or alkanoylamino; R6 = phenyl (optionally substituted by 1-3 R'6); R'6 = halo, aryl (optionally substituted by 1-3 alkanoyl, alkoxy, alkyl, halo, alkoxycarbonyl, NO2, haloalkyl, haloalkoxy, NH2, alkylthio, OH, COOH, CONH2, mono- or dialkylaminocarbonyl, mono- or dialkanoylamino, alkoxycarbonylamino, alkylsulfoxy, alkylsulfonyl, trialkylsilyloxy, Het2 or CN), alkoxy (optionally substituted by 1-6 F, but not perfluorinated), alkoxycarbonyl, alkylthio, OH, COOH, alkyl (optionally substituted by tetrahydrofuran-2-yl), Het1 (optionally substituted by 1-3 of alkanoyl, alkoxy, alkyl, halo, alkoxycarbonyl, NO2, haloalkyl, haloalkoxy, NH2, alkylthio, OH, COOH, CONH2, mono- or dialkylaminocarbonyl, mono- or dialkanoylamino, alkoxycarbonylamino, alkylsulfoxy, alkylsulfonyl, Het2 (mono- or bicyclic) or CN), Het2 (mono- or bicyclic; and optionally substituted by 1-3 O, halo, OH, alkoxycarbonyl, alkoxycarbonylamino, alkyl, haloalkyl or hydroxyalkyl), 2-6C alkenyl, OR19, NR20R21, CONR22R23, carbazole, dibenzofuran, dibenzothiophene, xanthene or 9,10-dihydroacridine; R19 = phenyl (optionally substituted by NR24R25) or alkyl (optionally substituted by 1-3 OH or halo); R24, R25 = H, alkyl or acyl; R20, R21 = H, CONH2, mono- or dialkylaminocarbonyl, phenyl, acyl or alkyl (optionally substituted by alkoxy or acyl, or by phenyl or Het1 (both optionally substituted by 1-3 of halo or OH)); and R22, R23 = H or alkyl; provided that all alkyl moieties or acyl groups have 1-6C, cycloalkyl moieties 3-8C and aryl moieties 6-10C unless specified otherwise.

Description

The present invention relates to new compounds, namely secondary ones Thiazolylsulfonamides, process for their preparation and their use as Medicines, especially as antiviral medicines.

WO 00/01498 relates to thiazolylureas with anti-herpes virus properties.

WO 00/05114 relates to indolinyl ureas with anti-herpes virus properties.

From the publication C. Ziegler et al., J. Org. Chem. 25, 1960, 1454-1455 2- Aminothiazole-5-sulfonamides known. In addition, in the German Laid-open specification 21 01 640 N-thiazol-2-yl amides and ureas with a herbicidal Effect described.

WO 97/24343 and WO 99/42455 relate to phenylthiazole derivatives with anti-herpes Virus properties.

• - Halogen,
• - (C₆-C₁₀)-Aryl, das gegebenenfalls durch 1 bis 3 Substituenten, ausgewählt aus (C₁-C₆)-Alkanoyl, (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkyl, Halogen, (C₁-C₆)-Alkoxycarbonyl, Nitro, Halogen-(C₁-C₆)-alkyl, Halogen-(C₁-C₆)-alkoxy, Amino, (C₁-C₆)-Alkylthio, Hydroxy, Carboxyl, Carbamoyl, Mono- oder Di-(C₁-C₆)-alkylaminocarbonyl, Mono- oder Di-(C₁-C₆)-alkanoylamino, (C₁-C₆)-Alkoxycarbonylamino, (C₁-C₆)- Alkylsulfoxy, (C₁-C₆)-Alkylsulfonyl, Tri-(C₁-C₆)-alkylsilyloxy, einem gegebenenfalls über ein Stickstoffatom gebundenen 3- bis 8-gliedrigen gesättigten oder ungesättigten, nicht aromatischen, mono- oder bicyclischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O, und/oder Cyano substituiert sein kann,
• - (C₁-C₆)-Alkoxy,
• - (C₁-C₆)-Alkoxycarbonyl,
• - (C₁-C₆)-Alkylthio,
• - Hydroxy,
• - Carboxyl,
• - partiell fluoriertem (C₁-C₆)-Alkoxy mit bis zu 6 Fluoratomen,
• - (C₁-C₆)-Alkyl, das gegebenenfalls durch einen Rest der Formel
  
  
  
• - einem gegebenenfalls über ein Stickstoffatom gebundenen 5- bis 6- gliedrigen aromatischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O, der gegebenenfalls durch 1 bis 3 Substituenten, ausgewählt aus (C₁-C₆)-Alkanoyl, (C₁-C₆)-Alkoxy, (C₁- C₆)-Alkyl, Halogen, (C₁-C₆)-Alkoxycarbonyl, Nitro, Halogen-(C₁-C₆)- alkyl, Halogen-(C₁-C₆)-alkoxy, Amino, (C₁-C₆)-Alkylthio, Hydroxy, Carboxyl, Carbamoyl, Aminocarbonyl, Mono- oder Di-(C₁-C₆)- alkylaminocarbonyl, Mono- oder Di-(C₁-C₆)-alkanoylamino, (C₁-C₆)- Alkoxycarbonylamino, (C₁-C₆)-Alkylsulfoxy, (C₁-C₆)-Alkylsulfonyl, einem gegebenenfalls über ein Stickstoffatom gebundenen 3- bis 8- gliedrigen gesättigten oder ungesättigten, nicht aromatischen, mono- oder bicyclischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O, und/oder Cyano substituiert sein kann,
• - einem gegebenenfalls über ein Stickstoffatom gebundenen 3- bis 8- gliedrigen gesättigten oder ungesättigten, nicht aromatischen, mono- oder bicyclischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O, der gegebenenfalls durch 1 bis 3 Substituenten ausgewählt aus Oxo, Halogen, Hydroxy, (C₁-C₆)-Alkoxycarbonyl, (C₁-C₆)-Alkoxycarbonylamino, (C₁-C₆)-Alkyl, Halogen-(C₁-C₆)-alkyl und Hydroxy-(C₁-C₆)-alkyl substituiert sein kann,
• - (C₂-C₆)-Alkenyl

und Gruppen der Formeln

• - -OR¹⁹
• - -NR²⁰R²¹ oder -CO-NR²²R²³,
• - Carbazol, Dibenzofuran oder Dibenzothiophen,
• - Xanthen oder 9,10-Dihydroacridin

besteht,
worin
R¹⁹ Phenyl bedeutet, das seinerseits gegebenenfalls durch eine Gruppe der Formel -NR²⁴R²⁵ substituiert ist,
worin
R²⁴ und R²⁵ gleich oder verschieden sind und Wasserstoff, (C₁-C₆)- Alkyl oder (C₁-C₆)-Acyl bedeuten,
oder
R¹⁹ (C₁-C₆)-Alkyl bedeutet, das gegebenenfalls ein- bis dreifach durch Hydroxy und/oder Halogen substituiert ist,
R²⁰ und R²¹ gleich oder verschieden sind und Wasserstoff, Carbamoyl, Mono- oder Di-(C₁-C₆)-alkylaminocarbonyl, Phenyl, (C₁-C₆)-Acyl oder (C₁-C₆)-Alkyl bedeuten,
wobei zuvor genanntes (C₁-C₆)-Alkyl gegebenenfalls durch (C₁-C₆)- Alkoxy, (C₁-C₆)-Acyl, durch Phenyl oder durch einen 5- bis 6- gliedrigen aromatischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O substituiert ist,
wobei zuvor genanntes Phenyl und zuvor genannter aromatischer Heterocyclus gegebenenfalls ein- bis dreifach gleich oder verschieden durch Halogen und/oder Hydroxy substituiert sind, und
R²² und R²³ gleich oder verschieden sind und Wasserstoff oder (C₁- C₆)-Alkyl bedeuten,
und R⁷ die Bedeutung von R⁵ aufweisen kann und mit dieser gleich oder verschieden sein kann,
und deren Salze. The present invention relates to new compounds which are thiazolylamide derivatives of the general formula (I):


in which
R ^{1 is} hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, amino (C ₁ -C ₆ ) alkyl or halogen (C ₁ -C ₆ ) alkyl stands,
R ^{2 represents} hydrogen
R ^{3 represents} (C ₁ -C ₆ ) alkoxy or (C ₃ -C ₈ ) cycloalkyl, or
represents (C ₁ -C ₆ ) alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₆ ) alkoxy , Halogen, hydroxy, amino, tri- (C ₁ -C ₆ ) alkylsilyloxy,
a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, where a nitrogen-containing heterocycle can also be bonded via the nitrogen atom,
a 3- to 8-membered saturated or unsaturated, non-aromatic, heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, and
(C ₆ -C ₁₀ ) aryl, which in turn can be substituted by hydroxy or (C ₁ -C ₆ ) alkoxy,
consists,
R ^{4 represents} hydrogen, (C ₁ -C ₆ ) acyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₈ ) cycloalkyl, or
R ^{4 represents} (C ₁ -C ₆ ) alkyl, which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkoxy, carboxyl,


where R ^{4 'represents} hydrogen,
- (OCH ₂ CH ₂ ) _n OCH ₂ CH ₃ , in which n is 0 or 1, phenoxy, (C ₆ -C ₁₀ ) aryl and -NR ¹³ R ¹⁴ ,
wherein
R ¹³ and R ^{14 are} identical or different and are hydrogen, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkyl, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, (C ₆ -C ₁₀ ) aryl or (C ₁ -C ₆ ) alkoxycarbonyl, or
R ¹³ and R ¹⁴ together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may optionally contain a further hetero atom from the S or O series or a radical of the formula -NR ¹⁵ and can be substituted by oxo,
wherein
R ^{15 is} hydrogen or (C ₁ -C ₄ ) alkyl, or
R ^{4 represents} (C ₁ -C ₆ ) alkyl which is substituted by a 5- to 6-membered aromatic, optionally benzo-fused heterocycle with up to 3 heteroatoms from the series S, N and / or O, a nitrogen-containing heterocycle can also be bound via the nitrogen atom, or by residues of the formulas


wherein
R ¹⁶ denotes hydrogen or (C ₁ -C ₆ ) alkyl,
R ¹⁷ and R ^{18 are} identical or different and denote hydrogen, (C ₁ -C ₆ ) alkyl or (C ₆ -C ₁₀ ) aryl, the aforementioned (C ₁ -C ₆ ) alkyl and (C ₆ - C ₁₀ ) aryl may optionally be substituted by 1 to 3 substituents selected from the group consisting of hydroxy, (C ₁ -C ₆ ) alkoxy and halogen,
R ^{5 represents} hydrogen, (C ₁ -C ₆ ) alkyl, halogen, amino, mono- or di (C ₁ -C ₆ ) alkylamino or represents (C ₁ -C ₆ ) alkanoylamino,
R ^{6 represents} phenyl which may optionally be substituted with one to three substituents selected from the group consisting of

• - halogen,
• - (C ₆ -C ₁₀ ) aryl, optionally with 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl , Halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) alkylthio , Hydroxy, carboxyl, carbamoyl, mono- or di- (C ₁ -C ₆ ) -alkylaminocarbonyl, mono- or di- (C ₁ -C ₆ ) -alkanoylamino, (C ₁ -C ₆ ) -alkoxycarbonylamino, (C ₁ -C ₆ ) - alkylsulfoxy, (C ₁ -C ₆ ) alkylsulfonyl, tri- (C ₁ -C ₆ ) alkylsilyloxy, a 3- to 8-membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle can be substituted with up to 3 heteroatoms from the series S, N and / or O, and / or cyano,
• - (C ₁ -C ₆ ) alkoxy,
• - (C ₁ -C ₆ ) alkoxycarbonyl,
• - (C ₁ -C ₆ ) alkylthio,
• - hydroxy,
• - carboxyl,
• partially fluorinated (C ₁ -C ₆ ) alkoxy with up to 6 fluorine atoms,
• - (C ₁ -C ₆ ) alkyl, optionally by a radical of the formula
  
  
  
• - A 5- to 6-membered aromatic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, optionally with 1 to 3 substituents, selected from (C ₁ -C ₆ ) alkanoyl , (C ₁ -C ₆ ) alkoxy, (C ₁ - C ₆ ) alkyl, halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen ( C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) alkylthio, hydroxy, carboxyl, carbamoyl, aminocarbonyl, mono- or di- (C ₁ -C ₆ ) alkylaminocarbonyl, mono- or di- ( C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ -C ₆ ) alkylsulfonyl, a 3- to 8- optionally bonded via a nitrogen atom membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle with up to 3 heteroatoms from the series S, N and / or O, and / or cyano,
• - A 3- to 8-membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, optionally selected from 1 to 3 substituents Oxo, halogen, hydroxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkyl and hydroxy- (C ₁ -C ₆ ) alkyl may be substituted,
• - (C ₂ -C ₆ ) alkenyl

and groups of formulas

• - -OR ¹⁹
• - -NR ²⁰ R ²¹ or -CO-NR ²² R ²³ ,
• - carbazole, dibenzofuran or dibenzothiophene,
• - xanthene or 9,10-dihydroacridine

consists,
wherein
R ¹⁹ denotes phenyl, which in turn is optionally substituted by a group of the formula -NR ²⁴ R ²⁵ ,
wherein
R ²⁴ and R ^{25 are} identical or different and are hydrogen, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) acyl,
or
R ¹⁹ denotes (C ₁ -C ₆ ) -alkyl which is optionally mono- to trisubstituted by hydroxy and / or halogen,
R ²⁰ and R ^{21 are the} same or different and are hydrogen, carbamoyl, mono- or di- (C ₁ -C ₆ ) alkylaminocarbonyl, phenyl, (C ₁ -C ₆ ) acyl or (C ₁ -C ₆ ) alkyl mean,
where the aforementioned (C ₁ -C ₆ ) alkyl optionally by (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) acyl, by phenyl or by a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O is substituted,
wherein the aforementioned phenyl and the aforementioned aromatic heterocycle are optionally substituted one to three times in the same or different manner by halogen and / or hydroxy, and
R ²² and R ^{23 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
and R ^{7 can have} the meaning of R ⁵ and can be the same or different with it,
and their salts.

Physiologically acceptable salts of the compounds according to the invention can for example salts of the substances according to the invention with mineral acids, carboxylic acids or be sulfonic acids. Z are particularly preferred. B. salts with Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, Ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, Acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, Maleic acid or benzoic acid.

Salts with customary bases can also be mentioned, such as for example alkali metal salts (e.g. sodium or potassium salts), alkaline earth salts (e.g. Calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as diethylamine, triethylamine, Ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methylpiperidine.

The compounds of the invention can, depending on the Substitution patterns in stereoisomeric forms that are either like image and mirror image (Enantiomers) or that do not behave like image and mirror image (diastereomers), exist. The invention relates to both the enantiomers or diastereomers or their respective mixtures. The racemic shapes can be just like that Separate diastereomers into the stereoisomerically uniform constituents in a known manner.

The scope of the invention also includes those compounds which are only in the Body to be converted to the actual active ingredients of formula (I) (so-called prodrugs).

(C ₁ -C ₆ ) -alkyl suitably represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms (C ₁ -C ₄ ) is preferred. Examples include:
Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. A straight-chain or branched alkyl radical having 1 to 3 carbon atoms ((C ₁ -C ₃ ) -alkyl) is particularly preferred.

Halogen (C ₁ -C ₆ ) alkyl suitably represents a (C ₁ -C ₆ ) alkyl group, which can be as defined above, and which preferably has 1 to 3 halogen atoms, namely F, Cl, Br and / or I. Chlorine or fluorine, as substituents, for example, trifluoromethyl, fluoromethyl, etc.

Hydroxy (C ₁ -C ₆ ) alkyl suitably represents a (C ₁ -C ₆ ) alkyl group which can be defined as above and which has 1 to 3 hydroxyl groups as substituents, for example hydroxymethyl etc.

Amino (C ₁ -C ₆ ) alkyl suitably represents a (C ₁ -C ₆ ) alkyl group which can be defined as above and which has 1 to 3 amino groups as substituents, for example aminomethyl etc.

In the context of the invention, (C ₂ -C ₆ ) alkenyl advantageously represents a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms. Examples include: ethenyl, n-prop-2-en-1-yl and n-but-2-en-1-yl. A straight-chain or branched alkenyl radical having 2 to 4 carbon atoms is preferred.

(C ₁ -C ₆ ) alkoxy expediently represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. A straight-chain or branched alkoxy radical having 1 to 4 carbon atoms (C ₁ -C ₄ ) is preferred. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy. A straight-chain or branched alkoxy radical having 1 to 3 carbon atoms (C ₁ -C ₃ ) is particularly preferred.

Halogen (C ₁ -C ₆ ) alkoxy expediently represents single or multiple halogen-substituted (C ₁ -C ₆ ) alkoxy. Regarding the (C ₁ -C ₆ ) alkoxy portion and the definition of halogen, reference is made to the above definition. For example, halogen (C ₁ -C ₆ ) alkoxy includes one or more partially chlorinated and / or fluorinated or perfluorinated (C ₁ -C ₆ ) alkoxy such as trifluoromethoxy, fluoromethoxy, chloromethoxy, pentafluoroethoxy, trifluoromethyl methoxy etc.

Partially fluorinated (C ₁ -C ₆ ) alkoxy having up to 6 fluorine atoms expediently represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms, which can be substituted by 1 to 6, preferably 1 to 4, more preferably 1 to 3, fluorine atoms , A straight-chain or branched alkoxy radical having 1 to 4 carbon atoms and 1 to 4 fluorine atoms is preferred. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy, each of which has one to four fluorine atoms. (1,3-Difluoroprop-2-yl) -oxy and 1,1,2,2-tetrafluoroethoxy are particularly preferred.

(C ₁ -C ₆ ) -Alkylthio expediently represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. A straight-chain or branched alkylthio radical having 1 to 4 carbon atoms (C ₁ -C ₄ ) is preferred. Examples include: methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio. A straight-chain or branched alkylthio radical having 1 to 3 carbon atoms (C ₁ -C ₃ ) -alkylthio is particularly preferred.

(C ₁ -C ₆ ) -alkoxycarbonyl advantageously represents a straight-chain or branched alkoxycarbonyl radical having 1 to 6 carbon atoms. A straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms (C ₁ -C ₄ ) is preferred. Examples include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl. A straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms (C ₁ -C ₄ ) is particularly preferred.

Mono- or di- (C ₁ -C ₆ ) -alkylaminocarbonyl expediently stands in the context of the invention for a carbamoyl group (H ₂ N-CO-) in which one or both hydrogen atoms are replaced by a (C ₁ -C ₆ ) alkyl group are replaced. With regard to the definition of the (C ₁ -C ₆ ) alkyl group, reference is made to the above explanation of (C ₁ -C ₆ ) alkyl. Examples include methylaminocarbonyl, dimethylaminocarbonyl, etc.

Mono- or di- (C ₁ -C ₆ ) acylamino in the context of the invention expediently represents an amino group (H ₂ N-) in which one or both hydrogen atoms are replaced by a (C ₁ -C ₆ ) acyl group. With regard to the definition of the (C ₁ -C ₆ ) acyl group, reference is made to the above explanation of (C ₁ -C ₆ ) acyl. Examples include (C ₁ -C ₆ ) alkanoyl, as mentioned in the definition of (C ₁ -C ₆ ) acyl.

(C ₁ -C ₆ ) Alkylsulfoxy expediently represents a (C ₁ -C ₆ ) alkyl-S (= O) group, reference being made to the above definition in relation to the (C ₁ -C ₆ ) alkyl group can.

(C ₁ -C ₆ ) -Alkylsulfonyl expediently represents a (C ₁ -C ₆ ) -alkyl-SO ₂ group, reference being made to the above definition in relation to the (C ₁ -C ₆ ) -alkyl group.

(C ₆ -C ₁₀ ) aryl generally represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

In the context of the invention, (C ₁ -C ₆ ) -acyl is expediently a straight-chain or branched acyl radical having 1 to 6 carbon atoms. Examples include: formyl, acetyl, ethanoyl, propanoyl, isopropanoyl, butanoyl, isobutanoyl and pentanoyl. A straight-chain or branched acyl radical having 1 to 4 carbon atoms is preferred. Acetyl and ethanoyl are particularly preferred.

(C ₃ -C ₈ ) Cycloalkyl in the context of the invention stands for cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. The following may preferably be mentioned: cyclopropyl, cyclopentyl and cyclohexyl. The meaning of (C ₃ -C ₆ ) cycloalkyl is appropriately for cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl.

Halogen generally stands for fluorine, chlorine, bromine and Iodine. Fluorine, chlorine and bromine are preferred. Fluorine and Chlorine.

In the context of the invention, (C ₁ -C ₆ ) alkanoyl represents formyl and (C ₁ -C ₅ ) alkylcarbonyl groups, (C ₁ -C ₅ ) alkyl can be a straight-chain or branched-chain alkyl group having 1 to 5 carbon atoms, for example Acetyl, propionyl, butyryl, pentanoyl.

A 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the Row S, O and / or N stands for example for pyridyl, pyrimidyl, thienyl, furyl, Pyrrolyl, thiazolyl, N-triazolyl, oxazolyl or imidazolyl. Preferred are pyridyl, Furyl, thiazolyl and N-triazolyl.

A 5- to 6-membered aromatic benzocondensed heterocycle with up to 3 Heteroatoms from the S, O and / or N series represent, for example, benzimidazolyl.

A 5- to 6-membered saturated heterocycle bonded via a nitrogen atom, which can be formed from two substituent groups together with the nitrogen atom to which they are bonded, and which may optionally be a further heteroatom from the series S or O or a radical of the formula For the purposes of the invention, NR ¹⁵ , in which R ^{15 is} as defined above, generally represents morpholinyl, piperidinyl, piperazinyl, methylpiperazinyl, thiomorpholinyl or pyrrolidinyl. Morpholinyl, piperidinyl, pyrrolidinyl and thiomorpholinyl are particularly preferred.

A 3- to 8-membered, optionally bonded via a nitrogen atom saturated or unsaturated, non-aromatic heterocycle with up to 3 Heteroatoms from the series S, N and / or O include z. B. the above 5- to 6-membered saturated heterocycles bonded via a nitrogen atom and 3-, 7- and 8-membered heterocycles, such as. B. aziridines (e.g. 1-azacyclopropan-1-yl), Azetidines (e.g. 1-azacyclobutan-1-yl) and azepines (e.g. 1-azepan-1-yl). The unsaturated representatives can contain 1 to 2 double bonds in the ring.

The side group of a naturally occurring α-amino acid with the meaning of R ¹⁰ includes, for example: hydrogen (glycine), methyl (alanine), propan-2-yl (valine), 2-methyl-propan-1-yl (leucine), 1-methyl-propan-1-yl (isoleucine), a propane-1,3-diyl group connected to the nitrogen atom of the amino group (proline), a 2-hydroxypropane-1,3-diyl group, the is connected to the nitrogen atom of the amino group (hydroxyproline), a group of the formula


a benzyl group (phenylalanine), a methylthioethyl group (methionine), hydroxymethyl (serine), p-hydroxybenzyl (tyrosine), 1-hydroxyethan-1-yl (threonine), mercaptomethyl (cysteine), carbamoylmethyl (asparagine), carbamoylethyl (glutamine ), Carboxymethyl (aspartic acid), carboxyethyl (glutamic acid), 4-aminobutan-1-yl (lysine), 3-guanidinopropan-1-yl (arginine), imidazol-4-ylmethyl (histidine), 3-ureidopropan-1-yl (Citrulline), mercaptoethyl (homocysteine), hydroxyethyl (homoserine), 4-amino-3-hydroxybutan-1-yl (hydroxylysine), 3-amino-propan-1-yl (ornithine), etc.

The general or preferred ranges listed above Residual definitions apply both to the end products of the formula (I) and accordingly for the starting materials or intermediate products required for the production.

Those in the respective combinations or preferred combinations of residues radical definitions specified in detail are independent of the respective specified combinations of the residues arbitrarily also by residue definitions other combinations replaced.

• - Halogen,
• - (C₆-C₁₀)-Aryl, das gegebenenfalls durch 1 bis 3 Substituenten, ausgewählt aus (C₁-C₆)Alkanoyl, (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkyl, Halogen, (C₁-C₆)Alkoxycarbonyl, Nitro, Halogen(C₁-C₆)alkyl, Halogen(C₁-C₆)alkoxy, Amino, (C₁-C₆)Alkylthio, Hydroxy, Carboxyl, Carbamoyl, Mono- oder Di(C₁-C₆)alkylaminocarbonyl, Mono- oder Di(C₁-C₆)alkanoylamino, (C₁-C₆)Alkoxycarbonylamino, (C₁-C₆)- Alkylsulfoxy, (C₁-C₆)Alkylsulfonyl, Tri(C₁-C₆)alkylsilyloxy, einem gegebenenfalls über ein Stickstoffatom gebundenen 3- bis 8-gliedrigen gesättigten oder ungesättigten, nicht aromatischen, mono- oder bicyclischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O, und/oder Cyano substituiert sein kann,
• - (C₁-C₆)-Alkoxy,
• - (C₁-C₆)-Alkoxycarbonyl,
• - (C₁-C₆)-Alkylthio,
• - Hydroxy,
• - Carboxyl,
• - partiell fluoriertem (C₁-C₆)-Alkoxy mit bis zu 6 Fluoratomen,
• - (C₁-C₆)-Alkyl, das gegebenenfalls durch einen Rest der Formel
  
  
  
• - einem gegebenenfalls über ein Stickstoffatom gebundenen 5- bis 6- gliedrigen aromatischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O, der gegebenenfalls durch 1 bis 3 Substituenten, ausgewählt aus (C₁-C₆)Alkanoyl, (C₁-C₆)-Alkoxy, (C₁-C₆)- Alkyl, Halogen, (C₁-C₆)Alkoxycarbonyl, Nitro, Halogen(C₁-C₆)alkyl, Halogen(C₁-C₆)alkoxy, Amino, (C₁-C₆)Alkylthio, Hydroxy, Carboxyl, Carbamoyl, Mono- oder Di(C₁-C₆)alkylaminocarbonyl, Mono- oder Di(C₁-C₆)alkanoylamino, (C₁-C₆)Alkoxycarbonylamino, (C₁-C₆)- Alkylsulfoxy, (C₁-C₆)Alkylsulfonyl, einem gegebenenfalls über ein Stickstoffatom gebundenen 3- bis 8-gliedrigen gesättigten oder ungesättigten, nicht aromatischen, mono- oder bicyclischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O, und/oder Cyano substituiert sein kann,
• - einem gegebenenfalls über ein Stickstoffatom gebundenen 3- bis 8- gliedrigen gesättigten oder ungesättigten, nicht aromatischen, mono- oder bicyclischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O, der gegebenenfalls durch 1 bis 3 Substituenten ausgewählt aus Oxo, Halogen, Hydroxy, (C₁-C₆)-Alkoxycarbonyl, (C₁-C₆)-Alkoxycarbonylamino, (C₁-C₆)-Alkyl, Halogen(C₁-C₆)alkyl und Hydroxy(C₁-C₆)-alkyl substituiert sein kann,
  und Gruppen der Formeln
• - -OR¹⁹
• - -NR²⁰R²¹ oder -CO-NR²²R²³

besteht,
worin R¹⁹ Phenyl bedeutet, das seinerseits gegebenenfalls durch eine Gruppe der Formel -NR²⁴R²⁵ substituiert ist,
worin
R²⁴ und R²⁵ gleich oder verschieden sind und Wasserstoff, (C₁-C₆)- Alkyl oder (C₁-C₆)-Acyl bedeuten,
oder
R¹⁹ (C₁-C₆)-Alkyl bedeutet, das gegebenenfalls ein- bis dreifach durch Hydroxy und/oder Halogen substituiert ist,
R²⁰ und R²¹ gleich oder verschieden sind und Wasserstoff, Carbamoyl, Mono- oder Di(C₁-C₆)alkylaminocarbonyl, Phenyl, (C₁-C₆)- Acyl oder (C₁-C₆)-Alkyl bedeuten,
wobei zuvor genanntes (C₁-C₆)-Alkyl gegebenenfalls durch (C₁-C₆)-Alkoxy, (C₁-C₆)-Acyl, durch Phenyl oder durch einen 5- bis 6-gliedrigen aromatischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O substituiert ist,
wobei zuvor genanntes Phenyl und zuvor genannter aromatischer Heterocyclus gegebenenfalls ein- bis dreifach gleich oder verschieden durch Halogen und/oder Hydroxy substituiert sind, und
R²² und R²³ gleich oder verschieden sind und Wasserstoff oder (C₁-C₆)-Alkyl bedeuten,
und R⁷ die Bedeutung von R⁵ aufweisen kann und mit dieser gleich oder verschieden sein kann,
und deren Salze. In a further embodiment, the invention relates to compounds of the general formula (I)
in which
R ^{1 represents} hydrogen, halogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy or halogen (C ₁ - C ₄ ) alkyl,
R ^{2 represents} hydrogen,
R ^{3 represents} (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl,
which is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, (C ₁ -C ₆ ) alkoxy and hydroxy,
R ^{4 represents} hydrogen, (C ₁ -C ₆ ) acyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₈ ) cycloalkyl, or
R ^{4 represents} (C ₁ -C ₆ ) alkyl, which can optionally be substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkoxy,
- (OCH ₂ CH ₂ ) _n OCH ₂ CH ₃ , in which n is 0 or 1, phenoxy, (C ₆ -C ₁₀ ) aryl and -NR ¹³ R ¹⁴ ,
wherein
R ¹³ and R ^{14 are the} same or different and are hydrogen, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkyl, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylamino- (C ₁ -C ₆ ) alkyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, (C ₆ - C ₁₀ ) aryl or (C ₁ -C ₆ ) alkoxycarbonyl, or
R ¹³ and R ¹⁴ together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which can optionally contain a further hetero atom from the S or O series or a radical of the formula -NR ¹⁵ and can be substituted by oxo,
wherein
R ^{15 is} hydrogen or (C ₁ -C ₄ ) alkyl, or
R ^{4 represents} (C ₁ -C ₆ ) alkyl which is substituted by a 5- to 6-membered aromatic, optionally benzo-fused heterocycle with up to 3 heteroatoms from the series S, N and / or O, a nitrogen-containing heterocycle can also be bound via the nitrogen atom, or by residues of the formulas


wherein
R ¹⁶ denotes hydrogen or (C ₁ -C ₆ ) alkyl,
R ¹⁷ and R ^{18 are the} same or different and are hydrogen, (C ₁ -C ₆ ) alkyl or (C ₆ -C ₁₀ ) aryl, the aforementioned (C ₁ -C ₆ ) alkyl and (C ₆ -C ₁₀ ) -aryl may optionally be substituted by 1 to 3 substituents selected from the group consisting of hydroxy, (C ₁ -C ₆ ) alkoxy and halogen,
R ^{5 represents} hydrogen, (C ₁ -C ₆ ) alkyl, halogen, amino, mono- or di (C ₁ -C ₆ ) alkylamino or represents (C ₁ -C ₆ ) alkanoylamino,
R ^{6 represents} phenyl which may optionally be substituted with one to three substituents selected from the group consisting of

• - halogen,
• - (C ₆ -C ₁₀ ) aryl which may be substituted by 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, Halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) alkylthio, hydroxy, carboxyl, carbamoyl, Mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, mono- or di (C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ -C ₆ ) alkylsulfonyl, tri (C ₁ -C ₆ ) alkylsilyloxy, a 3- to 8-membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, and / or cyano may be substituted,
• - (C ₁ -C ₆ ) alkoxy,
• - (C ₁ -C ₆ ) alkoxycarbonyl,
• - (C ₁ -C ₆ ) alkylthio,
• - hydroxy,
• - carboxyl,
• partially fluorinated (C ₁ -C ₆ ) alkoxy with up to 6 fluorine atoms,
• - (C ₁ -C ₆ ) alkyl, optionally by a radical of the formula
  
  
  
• a 5- to 6-membered aromatic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, optionally with 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) alkylthio, hydroxy, carboxyl, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, mono- or di (C ₁ -C ₆ ) alkanoylamino, (C ₁ - C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ -C ₆ ) alkylsulfonyl, a 3- to 8-membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle optionally bonded via a nitrogen atom with bis can be substituted to form 3 heteroatoms from the series S, N and / or O, and / or cyano,
• - A 3- to 8-membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, optionally selected from 1 to 3 substituents Oxo, halogen, hydroxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkyl and hydroxy (C ₁ -C ₆ ) alkyl may be substituted,
  and groups of formulas
• - -OR ¹⁹
• - -NR ²⁰ R ²¹ or -CO-NR ²² R ²³

consists,
in which R ^{19 is} phenyl, which in turn is optionally substituted by a group of the formula -NR ²⁴ R ²⁵ ,
wherein
R ²⁴ and R ^{25 are} identical or different and are hydrogen, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) acyl,
or
R ¹⁹ denotes (C ₁ -C ₆ ) -alkyl which is optionally mono- to trisubstituted by hydroxy and / or halogen,
R ²⁰ and R ^{21 are} identical or different and denote hydrogen, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, phenyl, (C ₁ -C ₆ ) acyl or (C ₁ -C ₆ ) alkyl,
wherein the aforementioned (C ₁ -C ₆ ) alkyl optionally by (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) acyl, by phenyl or by a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O is substituted,
wherein the aforementioned phenyl and the aforementioned aromatic heterocycle are optionally substituted one to three times in the same or different manner by halogen and / or hydroxy, and
R ²² and R ^{23 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
and R ^{7 can have} the meaning of R ⁵ and can be the same or different with it,
and their salts.

In a preferred embodiment, the invention relates to compounds of the general formula (I) in which R ^{1 is} hydrogen or (C ₁ -C ₆ ) -alkyl.

In a further preferred embodiment, the invention relates to compounds of the general formula (I) in which R ^{3 represents} methyl, ethyl or cyclopropyl.

In a further preferred embodiment, the invention relates to compounds of the general formula (I) in which R ^{4 is} hydrogen or (C ₁ -C ₆ ) -alkyl.

In a further preferred embodiment, the invention relates to compounds of the general formula (I) in which R ⁵ and R ^{7 are} hydrogen.

• - Halogen,
• - (C₆-C₁₀)-Aryl, das gegebenenfalls durch 1 bis 3 Substituenten, ausgewählt aus (C₁-C₆)Alkanoyl, (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkyl, Halogen, (C₁-C₆ )Alkoxycarbonyl, Nitro, Halogen(C₁-C₆)alkyl, Halogen(C₁-C₆)alkoxy, Amino, Hydroxy, Mono- oder Di(C₁-C₆)alkylamino, Mono- oder Di(C₁-C₆)- Alkanoylamino, (C₁-C₆)Alkoxycarbonylamino, und/oder Cyano substituiert sein kann, und
• - einem gegebenenfalls über ein Stickstoffatom gebundenen 5- bis 6-gliedrigen aromatischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O, der gegebenenfalls durch 1 bis 2 Halogenatome substituiert sein kann,

besteht. In a further preferred embodiment, the invention relates to compounds of the general formula (I), in which
R ^{6 represents} phenyl which may optionally be substituted with one to three substituents selected from the group consisting of

• - halogen,
• - (C ₆ -C ₁₀ ) aryl which may be substituted by 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, Halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, hydroxy, mono- or di (C ₁ -C ₆ ) alkylamino, Mono- or di (C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkoxycarbonylamino, and / or cyano can be substituted, and
• a 5- to 6-membered aromatic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, which can optionally be substituted by 1 or 2 halogen atoms,

consists.

In a further preferred embodiment, the invention relates to compounds which have the following formula:


wherein
R ¹ , R ³ , R ⁴ , R ⁵ and R ^{7 are} as defined in claim 1,
R ²⁶ and R ^{27 are the} same or different and are partial for hydrogen, halogen, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkylthio, hydroxy, carboxyl fluorinated (C ₁ -C ₆ ) alkoxy having up to 6 fluorine atoms, (C ₁ -C ₆ ) alkyl, a group of the formulas -OR ¹⁹ , -NR ²⁰ R ²¹ or -CO- NR ²² R ²³ , in which
R ¹⁹ denotes phenyl, which in turn is optionally substituted by a group of the formula -NR ²⁴ R ²⁵ ,
wherein
R ²⁴ and R ^{25 are} identical or different and are hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₆ ) -acyl, or
R ¹⁹ denotes (C ₁ -C ₆ ) -alkyl which is optionally mono- to trisubstituted by hydroxy and / or halogen,
R ²⁰ and R ^{21 are} identical or different and are hydrogen, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, phenyl, (C ₁ -C ₆ ) acyl or (C ₁ -C ₆ ) alkyl,
wherein the aforementioned (C ₁ -C ₆ ) alkyl optionally by (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) acyl, phenyl or by a 5- to 6-membered aromatic heterocycle with up to 3 Heteroatoms from the series S, N and / or O is substituted,
wherein the aforementioned phenyl and the aforementioned aromatic heterocycle are optionally substituted one to three times in the same or different manner by halogen and / or hydroxy, and
R ²² and R ^{23 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
R ^{28 represents} (C ₆ -C ₁₀ ) aryl, which is optionally substituted by 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ - C ₆ ) Alkyl, halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) -Alkyl thio, hydroxy, carboxyl, carbamoyl, mono- or di- (C ₁ -C ₆ ) -alkylaminocarbonyl, mono- or di- (C ₁ -C ₆ ) -alkanoylamino, (C ₁ -C ₆ ) -alkoxycarbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ -C ₆ ) alkylsulfonyl, tri- (C ₁ -C ₆ ) alkylsilyloxy, a 3- to 8-membered saturated or unsaturated, non-aromatic, optionally bonded via a nitrogen atom , mono- or bicyclic heterocycle with up to 3 heteroatoms from the series S, N and / or O, and / or cyano may be substituted, or
R ^{28 represents} a 5- to 6-membered aromatic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, which is optionally selected from 1 to 3 substituents selected from (C ₁ -C ₆ ) Alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ - C ₆ ) alkyl, Halogen-C ₁ -C ₆ ) -alkoxy, amino, (C ₁ -C ₆ ) -alkylthio, hydroxy, carboxyl, carbamoyl, mono- or di- (C ₁ -C ₆ ) -alkylaminocarbonyl, mono- or di- ( C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ -C ₆ ) alkylsulfonyl, a 3- to 8- optionally bonded via a nitrogen atom membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle with up to 3 heteroatoms from the series S, N and / or O, and / or cyano,
and their salts.

Z are particularly preferred. B. the compounds N- {5 - [(methylamino) sulfonyl] -4- methyl-1,3-thiazol-2-yl} -N-methyl-2- [4- (1H-pyrazol-1-yl) phenyl] acetamide, N- [5- (-Cyclopropylaminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2-pyridinyl) - phenyl] acetamide and N- [5- (methylaminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N- methyl-2- [4- (2-pyridinyl) phenyl] acetamide.

In a further preferred embodiment, the invention relates to compounds of the general formula (I) with the exception of 2- (5'-fluoro-2'-methyl-1,1'-biphenyl-4-yl) -N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazol-2-yl} - acetamide, N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1.3 -thiazol-2-yl} -2- [4'- (trifluoromethoxy) -1,1'-biphenyl-4-yl] acetamide, 2- (4-ethoxyphenyl) -N-methyl-N- {4-methyl- 5 - [(methylamino) sulfonyl] -1,3-thiazol-2-yl} acetamide, N- [2- (dimethylamino) ethyl] -2- (4-ethoxyphenyl) -N- {4-methyl-5- [ (methylamino) sulfonyl] -1,3-thiazol-2-yl} acetamide, 2- (1,1'-biphenyl-4-yl) -N- {4-methyl-5 - [(methylamino) sulfonyl] - 1,3-thiazol-2-yl} acetamide, 2- (1,1'-biphenyl-4-yl) -N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazole- 2-yl} acetamide, 2- (1,1'-biphenyl-4-yl) -N-cyclopropyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazol-2-yl } acetamide, 2- (1,1'-biphenyl-4-yl) - N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazol-2-yl} -N- (3rd -pyridinylmethyl) acetamide, 2- (1,1'-biphenyl-4-yl) -N- {4-m ethyl-5 - [(methylamino) sulfonyl] -1,3-thiazol-2-yl} -N- [3- (2-oxo-1-pyrrolidinyl) propyl] acetamide, 2- (1,1'- Biphenyl-4-yl) -N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazol-2-yl} -N- [2- (2-oxo-1-pyrrolidinyl) - ethyl] acetamide, 2- (1,1'-biphenyl-4-yl) -N- (5 - {[(2-ethoxyethyl) amino] sulfonyl} -4-methyl-1,3-thiazol-2-yl ) -N-methyl-acetamide, 2- (1,1'-biphenyl-4-yl) -N- (5 - {[(3-methoxypropyl) amino] sulfonyl} -4-methyl-1,3-thiazole -2-yl) -N-methyl-acetamide, 2- (1,1'-biphenyl-4-yl) -N- (5 - {[(3-ethoxypropyl) amino] sulfonyl} -4-methyl-1 , 3-thiazol-2-yl) -N-methyl-acetamide, 2- (1,1'-biphenyl-4-yl) -N- (3-ethoxypropyl) -N- (5 - {[(3-ethoxypropyl ) amino] sulfonyl} -4-methyl-1,3-thiazol-2-yl) acetamide, 2- (2'-fluoro-1,1'-biphenyl-4-yl) -N-methyl-N- {4 -methyl-5 - [(methylamino) sulfonyl] -1,3-thiazol-2-yl} - acetamide, N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazole -2-yl} -2- [2'- (trifluoromethoxy) -1,1'-biphenyl-4-yl] acetamide, 2- (2'-formyl-1,1'-biphenyl-4-yl) -N - methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazol-2-yl} -ac etamid, 2- (2'-amino-1,1'-biphenyl-4-yl) -N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazol-2- yl} acetamide, N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazol-2-yl} -2- (2'-nitro-1,1'-biphenyl -4-yl) acetamide, N- (3-ethoxypropyl) -N- (5- {[(3-ethoxypropyl) amino] sulfonyl} -4-methyl-1,3-thiazol-2-yl) -2 - (3'-methoxy-1,1'-biphenyl-4-yl) acetamide, N- (5 - {[(3-ethoxypropyl) amino] sulfonyl} -4-methyl-1,3-thiazol-2-yl ) -2- (3'-methoxy-1,1'-biphenyl-4-yl) -N-methylacetamide, N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3- thiazol-2-yl} -2- [3 '- (trifluoromethoxy) -1,1'-biphenyl-4-yl] acetamide, N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] - 1,3-thiazol-2-yl} -2- [4- (2-pyridinyl) phenyl] acetamide, N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazole -2-yl} -2- [4- (3-pyridinyl) phenyl] acetamide, N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazol-2-yl} -2- [4- (3-pyridinyl) phenyl] acetamide hydrochloride, N- (5 - {[(2-ethoxyethyl) amino] sulfonyl} -4-methyl-1,3-thiazol-2-yl) - 2- (4-ethoxyphenyl) -N-me thylacetamide, 2- (4-bromophenyl) -N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazol-2-yl} acetamide, 2- (1,1 '-Biphenyl-4-yl) -N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazol-2-yl} propanamide, tert-butyl 2 - ((1st , 1'-biphenyl-4-ylacetyl) {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazol-2-yl} amino) ethyl carbamate, 2- (1,1'-biphenyl-4 -yl) -N-ethyl-N- (4-methyl-5- {[(2,2,2-trifluoroethyl) amino] sulfonyl} -1,3-thiazol-2-yl) acetamide, 2- (1 , 1'-Biphenyl-4-yl) -N-methyl-N- (4-methyl-5 - {[(2,2,2-trifluoroethyl) amino] sulfonyl} -1,3-thiazol-2-yl) -acetamide, 2- (1,1'-biphenyl-4-yl) -N- (4-methyl-5 - {[(2,2,2-trifluoroethyl) amino] - sulfonyl} -1,3-thiazole- 2-yl) -N-propylacetamide, 2- [4- (3-amino-2-pyridinyl) phenyl] - N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3- thiazol-2-yl} acetamide, 2- [4- (2-amino-5-methyl-3-pyridinyl) phenyl] -N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] - 1,3-thiazol-2-yl} acetamide, 2- [4- (3-amino-2-pyridinyl) phenyl] -N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1 , 3-thiazol-2-yl} aceta mid hydrochloride, 2- [4- (5-cyano-3-pyridinyl) phenyl] -N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazol-2-yl } acetamide, N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazol-2-yl} -2- [4- (4-methyl-3-pyridinyl) phenyl] -acetamide, N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazol-2-yl} -2- [2 '- (trifluoromethyl) -1,1'-biphenyl -4- yl] acetamide, 2- (3'-fluoro-1,1'-biphenyl-4-yl) -N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1 , 3-thiazol-2-yl} acetamide, 2- (4-butoxyphenyl) -N- (5 - {[(2-ethoxyethyl) amino] sulfonyl} -4-methyl-1,3-thiazol-2-yl ) -N-methyl-acetamide, 2- (4-dibenzo [b, d] furan-4-ylphenyl) -N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3- thiazol-2-yl} acetamide, N ⁵ - (1,1'-biphenyl-4-ylacetyl) -N ² - (tert-butoxycarbonyl) -N ⁵ - {4-methyl-5 - [(methylamino) sulfonyl ] -1,3-thiazol-2-yl} ornithine, 4 - ((1,1'-biphenyl-4-yl-acetyl) {4-methyl-5 - [(methylamino) sulfonyl] -1.3 -thiazol-2-yl} amino) -2 - [(tert-butoxycarbonyl) amino] butanoic acid, 2- (1,1'-biphenyl-4-yl) -N-methyl-N- [4-methyl-5- ({[3- (4- morpholinyl) propyl] amino} sulfonyl) -1,3-thiazol-2-yl] acetamide, 2- (4-ethoxyphenyl) -N-methyl-N- [4-methyl-5 - ({[3- (4- morpholinyl) propyl] amino} sulfonyl) -1,3-thiazol-2-yl] acetamide, N- (5 - {[(2-aminoethyl) amino] sulfonyl} -4-methyl-1,3-thiazol-2- yl) -2- (1,1'-biphenyl-4-yl) -N-methyl-acetamide, N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazole- 2-yl} -2- {4- [3- (trifluoromethyl) -2-pyridinyl] phenyl} - acetamide, N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3- thiazol-2-yl} -2- [4- (5-pyrimidinyl) phenyl] acetamide, 2- (1,1'-biphenyl-4-yl) -N- (5 - {[(2-hydroxyethyl) - amino] sulfonyl} -4-methyl-1,3-thiazol-2-yl) -N-methylacetamide, 2- [4- (3-hydroxy-2-pyridinyl) phenyl] -N-methyl-N- {4- methyl-5 - [(methylamino) sulfonyl] -1,3-thiazol-2-yl} acetamide, 2- (1,1'-biphenyl-4-yl) -N- (5 - {[(2 - {[ tert-butyl (dimethyl) silyl] oxy} - ethyl) amino] sulfonyl} -4-methyl-1,3-thiazol-2-yl) -N-methylacetamide, N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazol-2-yl} -2- [4- (2-pyrazinyl) phenyl] acetamide, N-methyl-N- {4-methyl-5 - [(methylami no) sulfonyl] -1,3-thiazol-2-yl} -2- [4- (2-pyridinyl) phenyl] acetamide hydrochloride, N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl ] -1,3-thiazol-2-yl} -2- [4- (2-pyrimidinyl) phenyl] acetamide, N-methyl- N- {4-methyl-5 - [(methylamino) sulfonyl] -1, 3-thiazol-2-yl} -2- [4- (1H-pyrazol-1-yl) phenyl] acetamide, N-methyl-N- {4-methyl-5 - [(methylamino) sulfonyl] -1, 3-thiazol-2-yl} -2- [4- (1H-1,2,4-triazol-1-yl) phenyl] acetamide, 2- {4- [2- (methyl {4-methyl-5 - [(methylamino) sulfonyl] -1,3-thiazol-2-yl} amino) -2-oxoethyl] phenyl} -isonicotinamide, N- (5 - {[(2 - {[tert-butyl (dimethyl) silyl] oxy} ethyl) amino] -sulfonyl} -4-methyl-1,3-thiazol-2-yl) -N-methyl-2- [4- (2-pyridinyl) phenyl] acetamide and N- (5 - {[ (2-hydroxyethyl) amino] sulfonyl} -4-methyl-1,3-thiazol-2-yl) -N-methyl-2- [4- (2-pyridinyl) phenyl] acetamide.

• 1. Verbindungen der allgemeinen Formel (II)
  
  
  in welcher
  R¹, R³ und R⁴ die oben angegebene Bedeutung haben,
  mit Verbindungen der allgemeinen Formel (III)
  
  
  in welcher
  A für eine Abgangsgruppe, wie z. B. Halogen, vorzugsweise Chlor, oder Hydroxy steht, und R⁵, R⁶ und R⁷ die oben angegebene Bedeutung haben, in inerten Lösemitteln, gegebenenfalls in Anwesenheit einer Base und/oder eines Hilfsmittels zu Verbindungen der Formel (I) umsetzt,
• 2. Verbindungen der allgemeinen Formel (X)
  
  
  worin
  R¹, R³, R⁴, R⁵, R⁷, R²⁶ und R²⁷ die oben angegebene Bedeutung haben, und E Trifluormethansulfonat oder Halogen, vorzugsweise Brom oder Iod ist, mit Boronsäuren oder Stannanen der allgemeinen Formel (XI):
  
  R²⁸M (XI)
  
  worin
  R²⁸ die oben angegebene Bedeutung hat und M beispielsweise eine Tri(C₁-C₆)alkylstannylgruppe, wie eine Trimethylstannylgruppe oder eine Boronsäuregruppe sein kann, in inerten Lösemitteln in Gegenwart von Palladiumkatalysatoren, z. B. Tetrakis(triphenylphosphan)palladium (0), ggf. in Anwesenheit von Base, z. B. Kaliumphosphat bei Temperaturen von 50-140°C zu Verbindungen der Formel (XIV)
  
  
  

umsetzt, und

• 1. Verbindungen der allgemeinen Formel (XII)
  
  
  worin
  R¹, R³, R⁴, R⁵, R⁷, R²⁶ und R²⁷ die oben angegebene Bedeutung haben, und M die oben angegebene Bedeutung besitzt, mit Trifluormethansulfonaten oder Halogeniden der allgemeinen Formel (XIII):
  
  R²⁸E (XIII)
  
  worin
  R²⁸ die oben angegebene Bedeutung hat und E die oben angegebene Bedeutung besitzt, in inerten Lösemitteln in Gegenwart von Palladiumkatalysatoren, z. B. Tetrakis(triphenylphosphan)palladium (0), ggf. in Anwesenheit von Base, z. B. Kaliumphosphat bei Temperaturen von 50-140°C zu Verbindungen der Formel (XIV) umsetzt.

The invention further relates to processes for the preparation of the compounds of general formula (I), characterized in that

• 1. Compounds of the general formula (II)
  
  
  in which
  R ¹ , R ³ and R ^{4 have} the meaning given above,
  with compounds of the general formula (III)
  
  
  in which
  A for a leaving group, such as B. halogen, preferably chlorine, or hydroxy, and R ⁵ , R ⁶ and R ^{7 have} the meaning given above, in inert solvents, optionally in the presence of a base and / or an auxiliary, to give compounds of the formula (I),
• 2. Compounds of the general formula (X)
  
  
  wherein
  R ¹ , R ³ , R ⁴ , R ⁵ , R ⁷ , R ²⁶ and R ^{27 have} the meaning given above, and E is trifluoromethanesulfonate or halogen, preferably bromine or iodine, with boronic acids or stannanes of the general formula (XI):
  
  R ²⁸ M (XI)
  
  wherein
  R ^{28 has} the meaning given above and M for example a tri (C ₁ -C ₆ ) alkylstannyl group, such as a trimethylstannyl group or a boronic acid group, in inert solvents in the presence of palladium catalysts, e.g. B. tetrakis (triphenylphosphine) palladium (0), optionally in the presence of base, e.g. B. Potassium phosphate at temperatures of 50-140 ° C to compounds of formula (XIV)
  
  
  

implements, and

• 1. Compounds of the general formula (XII)
  
  
  wherein
  R ¹ , R ³ , R ⁴ , R ⁵ , R ⁷ , R ²⁶ and R ^{27 have} the meaning given above, and M has the meaning given above, with trifluoromethanesulfonates or halides of the general formula (XIII):
  
  R ²⁸ E (XIII)
  
  wherein
  R ^{28 has} the meaning given above and E has the meaning given above, in inert solvents in the presence of palladium catalysts, for. B. tetrakis (triphenylphosphine) palladium (0), optionally in the presence of base, e.g. B. Potassium phosphate at temperatures of 50-140 ° C to compounds of formula (XIV).

The process [A] according to the invention can be illustrated by way of example using the following formula schemes:

Here mean:
HOBt: 1-hydroxy-1H-benzotriazole
EDC: N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide × HCl
DMF: N, N-dimethylformamide

Process [A] according to the invention can also be explained by way of example using the following formula schemes:

The method [B] according to the invention can be explained by way of example using the following formula schemes:

Herein means:
DMF: N, N-dimethylformamide

The process [C] according to the invention can be illustrated by the following formula schemes:

Herein means:
DMF: N, N-dimethylformamide

Conventional organic solvents are suitable as solvents for processes [A], [B] and [C] Solvents that do not change under the reaction conditions. For this preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, Glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or Petroleum fractions, or halogenated hydrocarbons such as dichloromethane, Trichloromethane, carbon tetrachloride, dichlorethylene, trichlorethylene or chlorobenzene, or Ethyl acetate, dimethyl sulfoxide, dimethylformamide (DMF) or acetonitrile. Likewise it is possible to use mixtures of the solvents mentioned. DMF is preferred.

In general, inorganic or organic bases can be used as bases for process [A] according to the invention. These preferably include organic amines (trialkyl (C ₁ -C ₆ ) amines) such as triethylamine, or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7 -en (DBU), pyridine, diaminopyridine, N-methylmorpholine or N-methylpiperidine or morpholine. Triethylamine is preferred.

Known dehydration or Coupling reagents, such as, for example, carbodiimides, such as diisopropylcarbodiimide, Dicyclohexylcarbodiimide (DCC) or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (EDC), or carbonyl compounds such as carbonyldiimidazole (CDI) or Isobutyl chloroformate, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2- oxazolium-3-sulfonate, or phosphorus compounds such as Propanephosphonic anhydride, phosphoric acid diphenyl ester azide, Benzotriazolyl-N-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), or uronium compounds such as O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), or methanesulfonic acid chloride, optionally in the presence of auxiliaries such as N-hydroxysuccinimide or N-hydroxybenzotriazole.

In general, the base is used in an amount of 0.05 mol to 10 mol, preferably from 1 mol to 2 mol based on 1 mol of the compound of the formula (III).

The methods of the invention are generally in one Temperature range from -50 ° C to + 100 ° C, preferably from -30 ° C to + 60 ° C, performed.

The methods of the invention are generally at normal pressure carried out. However, it is also possible to use the process under positive pressure or under negative pressure to be carried out (e.g. in a range from 0.5 to 5 bar).

The compounds of the general formula (II) can be prepared, for example, by compounds of the general formula (VI)


in which
R ^{1 has} the meaning given above,
by reaction with the chlorosulfonic acid / SOCl _{2 system} in the compounds of the general formula (VII)


in which
R ^{1 has} the meaning given above,
transferred, then with amines of the general formula (V)

HNR ² R ³ (V)

in which
R ² and R ^{3 have} the meaning given above,
in inert solvents, the compounds of the general formula (VIII)


in which
R ¹ , R ² and R ^{3 have} the meaning given above,
produces, and in a last step a reaction with amines of the general formula (IX)

H ₂ NR ^{4 '} (IX)

in which
R ^{4 'has} the meaning of R ⁴ given above and is the same or different with it, but is not hydrogen,
in inert solvents and in the presence of a base.

The reaction with chlorosulfonic acid / SO ₂ Cl takes place first at room temperature and then below the reflux temperature of the respective ether.

The reaction is generally carried out at normal pressure. It is also possible to carry out the process at overpressure or underpressure (e.g. in a range from 0.5 to 5 bar).

As a solvent for the reaction with the amines of the general formula (V) alcohols such as methanol, ethanol, propanol and Isopropanol. Methanol is preferred.

The reaction with the amines of the general formula (V) initially takes place in Room temperature and then below the reflux temperature of the respective Ether.

The reaction is generally carried out at normal pressure. It is also possible to carry out the process at overpressure or underpressure (e.g. in a range from 0.5 to 5 bar).

The reaction with the compounds of the general formula (IX) takes place in ethers such as diethyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether. Methanol is preferred.

In general, inorganic or organic bases can be used as bases. These preferably include organic amines (tri (C ₁ -C ₆ ) alkylamines, such as triethylamine), or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec- 7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. Triethylamine is preferred.

In general, the base is used in an amount of 0.05 mol to 10 mol, preferably from 1 mol to 2 mol based on 1 mol of the compound of the formula (VIII).

Some of the compounds of the general formula (VI) are known or according to customary methods can be produced [cf. Hantzsch, Chem. Ber. 1927, 60, 2544].

The compounds of general formulas (VII) and (VIII) are new and can be as are produced as described above.

Amines of the general formulas (V) and (IX) are known.

Compounds of the general formulas (III) are known or can be subtracted Manufacture processes known from the literature.

Biphenylmethylcarboxylic acid or biphenylacetic acid derivatives of the formula (III) can be prepared in a manner known per se by transition metal-catalyzed, for example palladium-catalyzed, coupling reactions, such as, for example, B. the Suzuki or Stille clutch. The pyridylphenylmethylcarboxylic acid derivatives of the formula (III) are known from the literature (see, for example, BM Artico et al. In Eur. J. Med. Chem. (1992) 27, 219-228) or can be prepared by processes known per se. The following reaction schemes A, B, C and D exemplify the synthesis of biphenylacetic acid derivatives from the corresponding boronic acids and the synthesis of pyridylphenylacetic acid derivatives from the corresponding stannyl compounds:

Compounds of the formula (III) in which R ⁵ and R ^{7 are,} for example, fluorine can be prepared by the process shown in the following reaction scheme:

The fluorination with DAST (N, N-diethylaminosulfur trifluoride) takes place according to J. Fluor. Chem. 61, 1993, 117.

The invention further relates to the compounds of formula (I) claim 1 Use as a medicine.

The invention further relates to a pharmaceutical composition comprising a Compound of general formula (I) in admixture with at least one pharmaceutically acceptable carrier or excipient.

The invention further relates to the use of a compound of the general Formula (I) 1 for the manufacture of a medicament, in particular a medicament for Treatment and / or prevention of viral infections, such as herpes viruses, in particular Herpes simplex virus.

The compounds of the general formula (I) according to the invention do not show one predictable surprising spectrum of action. They have an antiviral effect to representatives of the group Herpes viridae, especially to herpes Simplex viruses (HSV). They are therefore for the treatment and prophylaxis of Diseases caused by herpes viruses, especially diseases caused by Herpes simplex viruses are caused.

The compounds of the general formula (I) according to the invention have Surprisingly, no influence on the carbonic anhydrase. You therefore point no undesirable effects on influencing carbonic anhydrase are connected such. B. hyperplasia or diuretic effect (urothelial hyperplasia induced by carbonic anhydrase inhibitors (CAIs) in animals and its relationship to urinary Na and pH, Durand-Cavagna G., Owen R.A., Gordon L.R., Peter C.P., Boussiquet-Leroux C., Fundam Appl Toxicol. 1992 Jan; 18 (1): 137-43).

In vitro activity Viruses and cells

HSV (HSV-1 Walki, HSV-1F or HSV-2G) was grown on Vero cells (ATCC CCL-81) under the following conditions: The cells were grown in M199 medium (5% fetal calf serum, 2 mM glutamine, 100 IU / ml penicillin, 100 µg / ml streptomycin) grown in cell culture flasks at 37 ° C and 5% CO ₂ . The cells were split 1: 4 twice a week. The medium was removed for the infection, the cells were washed with "Hank's solution", detached with 0.05% trypsin, 0.02% EDTA (Seromed L2143) and with a density of 4 × 10 ⁵ cells per ml under the above-mentioned conditions for 24 hours incubated. The medium was then removed and the virus solution with a mo i of <0.05 in a volume of 2 ml per 175 cm ² surface was added. After incubation for one hour under the conditions mentioned, the medium was made up to a volume of 50 ml per 175 cm ² bottle. 3 days after infection, the cultures showed clear signs of a cytopathic effect. The virus was released by freezing twice (-80 ° C) and thawing (37 ° C). The cell debris was separated by centrifugation (300 g, 10 min, 4 ° C) and the supernatant was frozen in aliquots at -80 ° C.

The virus titer was determined using a plaque assay. For this Vero cells were seeded in a density of 4 × 10 ⁵ cells per well in 24 well plates and after 24 hours incubation (37 ° C, 5% CO ₂ ) with dilutions of the virus stock from 10 ^-2 to 10 ^-12 (100 ul inoculum ) infected. The medium was removed 1 hour after infection and the cells were coated with 1 ml overlay medium (0.5% methyl cellulose, 0.225 sodium bicarbonate, 2 mM glutamine, 100 IU / ml penicillin, 100 µg / ml streptomycin, 5% fetal calf serum in MEM Overlay Eagle Medium with Earl's Salt) and incubate for 3 days. The cells were then fixed with 4% formalin for 1 hour, washed with water, stained with Giemsa (Merck) for 30 min and then washed and dried. The virus titer was determined with a plaque viewer. The virus stocks used for the experiments had a titer of 1 × 10 ⁶ / ml-1 × 10 ⁸ / ml.

The anti-HSV effect was demonstrated in a screening test system 96-well microtiter plates with the help of various cell lines neuronal, lymphoid and epithelial origin such as Vero (kidney cell line of the green Vervet monkey), MEF (murine embryonic fibroblasts), HELP (human embryonic Fibroblasts), NT2 (human neuronal cell line) or Jurkat (human lymphoid T- Cell line). The influence of substances on the spread of the cytopathogenic effect was compared to the reference substance acyclovir Sodium (Zovirax®), a clinically approved anti-herpes chemotherapy drug, certainly.

The substances (50 mM) dissolved in DMSO (dimethyl sulfoxide) are examined on microtiter plates (e.g. 96-well MTP) in final concentrations of 250-0.5 µM (micromolar) in duplicate determinations (4 substances / plate). In the case of potent substances, the dilutions are continued over several plates up to 0.5 pM (picomolar). Toxic and cytostatic effects are also included. After the corresponding substance dilutions (1: 2) on the microtiter plate in medium, a suspension of cells (1 × 10 ⁴ cells per well) such as, for example, Vero cells in M199 (Medium 199) with 5% fetal calf serum, 2 mM glutamine and optionally 100 IU / ml penicillin and 100 µg / ml streptomycin or MEF cells in EMEM (Eagle's Minimum Essential Medium) with 10% fetal calf serum, 2 mM glutamine and optionally 100 IU / ml penicillin and 100 µg / ml streptomycin, or HELF Cells in EMEM with 10% fetal calf serum, 2 mM glutamine and optionally 100 IU / ml penicillin and 100 µg / ml streptomycin, or NT2 and Jurkat cells in DMEM (4.5 mg / l glucose plus pyridoxine) with 10% fetal calf serum 2 mM glutamine, 1 mM sodium pyruvate, non-essential amino acids and optionally 100 IU / ml penicillin and 100 µg / ml streptomycin were added to each well and the cells in the relevant wells were infected with an appropriate amount of virus (HSV-1F or HSV- 2G with a mo i (multiplicity of infection) of 0.0025 for HELF, Vero and MEF cells and a mo i of 0.1 for NT2 and Jurkat cells). The plates are then incubated at 37 ° C in a CO ₂ incubator (5% CO ₂ ) for several days. After this time the cell lawn of z. B. Vero cells in the substance-free virus controls, starting from 25 infectious centers, completely lysed or destroyed by the cytophatogenic effect of the HSV viruses (100% CPE). The plates are first optically evaluated using a microscope and then analyzed using a fluorescent dye. For this purpose, the cell culture supernatant from all the wells of the MTP is suctioned off and filled with 200 μl PBS washing solution. The PBS is suctioned off again and all wells are filled with 200 μl fluorescent dye solution (fluorescein diacetate, 10 μg / ml in PBS). After an incubation period of 30-90 min, the test plates are measured in a fluorescence measuring device at an excitation wavelength of 485 nm and an emission wavelength of 538 nm.

The results are summarized for some compounds in Table 1 below. Table 1

IC ₅₀ here means the half-maximum fluorescence intensity in relation to the non-infected cell control (100% value). The IC ₅₀ value can also be related to a suitable active ingredient control (see assay description: infected cells in the presence of a substance with an anti-herpes effect of a suitable concentration, such as Zovirax 20 µM). This active ingredient control achieves fluorescence intensities of 85 to 95% in relation to cell control.

Derivatives according to the invention are preferred whose IC ₅₀ (HSV-1 F / Vero) in the in vitro screening test system described above is preferably less than 50 μM, more preferably less than 25 μM and very particularly preferably less than 10 μM.

• 1. Behandlung und Prophylaxe von Herpes-Infektionen, insbesondere Herpes Simplex-Infektionen bei Patienten mit Krankheitsbildern wie Herpes labialis, Herpes genitalis, und HSV bedingter Keratitis, Enzephalitis, Pneumonie, Hepatitis etc.
• 2. Behandlung und Prophylaxe von Herpes-Infektionen, insbesondere Herpes Simplex-Infektionen bei immunsupprimierten Patienten (z. B. AIDS- Patienten, Krebspatienten, Patienten mit genetisch bedingter Immundefiziens, Transplantationspatienten)
• 3. Behandlung und Prophylaxe von Herpes-Infektionen, insbesondere Herpes Simplex-Infektionen bei Neugeborenen und Kleinkindern
• 4. Behandlung und Prophylaxe von Herpes-Infektionen, insbesondere Herpes Simplex-Infektionen und Herpes-, insbesondere Herpes Simplex-positiven Patienten zur Unterdrückung der Rekurrenz (Suppressionstherapie)

The compounds according to the invention are therefore valuable active substances for the treatment and prophylaxis of diseases which are triggered by herpes viruses, in particular herpes simplex viruses. The following areas of indication can be mentioned, for example:

• 1. Treatment and prophylaxis of herpes infections, especially herpes simplex infections in patients with clinical pictures such as herpes labialis, genital herpes, and HSV-related keratitis, encephalitis, pneumonia, hepatitis etc.
• 2. Treatment and prophylaxis of herpes infections, especially herpes simplex infections in immunosuppressed patients (e.g. AIDS patients, cancer patients, patients with genetic immunodeficiencies, transplant patients)
• 3. Treatment and prophylaxis of herpes infections, especially herpes simplex infections in newborns and young children
• 4. Treatment and prophylaxis of herpes infections, in particular herpes simplex infections and herpes, in particular herpes simplex-positive patients to suppress recurrence (suppression therapy)

In vivo effect animals

6 week old female mice, strain BALB / cABom, were from one commercial breeders (Bomholtgard Breeding and Research Center Ltd.).

infection

The animals were anesthetized in a tight glass jar with diethyl ether (Merck). 50 μl of a dilution of the virus stock (infection dose 5 × 10 ⁴ Pfu) was introduced into the nose of the anesthetized animals using an Eppendorf pipette. This infection dose leads to death in 90-100% of the animals from a generalized infection with prominent respiratory and central nervous symptoms on average between 5 and 8 days.

Treatment and evaluation

6 hours after infection, the animals were dosed at 0.1-100 mg / kg Body mass 3 times a day at 7 a.m., 2 p.m. and 7 p.m. over a period of Treated 5 days. The substances were pre-dissolved in DMSO and in Tylose / PBS (Hoechst) resuspended (final concentration 1.5% DMSO, 0.5% tylose in PBS).

After the last application, the animals were observed and the Times of death determined.

A comparison of the survival curves yielded z. B. an ED ₅₀ of about 2 mg / kg for HSV-2 and for the compound of Example 11 an ED ₅₀ of about 0.5 mg / kg, where ED ₅₀ means that 50% of the animals survive at this dose.

The inhibition of carbonic anhydrase activity can be according to the publication "Synthesis and Physicochemical Properties of Thiadiazolol [3,2-a] pyrimidinesulfonamides and Thiadiazolol [3,2-a] triazinesulfonamides as Candidates for Topically Effective Carbonic Anhydrase Inhibitors ", A.R. Katritzky, K.C. Caster, T. H. Maren, C. W. Conroy, A. Bar-Ilan, Journal of Medicinal Chemistry 1987, 30, 2058-2062 can be measured on the basis of human raw material.

Carbonic anhydrase assay

A test protocol for measuring carbonic anhydrase enzyme activity at room temperature using the pH indicator method is as follows:
1 µL inhibitor (50 mM) solution in DMSO, final test concentration 100 mM to 1 nM or 1 µM water in control experiments are mixed with 0.5 to 2 EU human carbonic anhydrase I (180 U / mg) in 400 µl water and 200 for 2 minutes µl phenol red indicator solution (20 mg / liter) incubated. An enzyme unit (EU) is defined as the one that doubles the uncatalyzed rate. The reaction is initiated by adding 100 μl of 0.5 M bicarbonate buffer (0.3 M Na ₂ CO ₃ ; 0.2 M NaHCO ₃ ) and then passing CO ₂ through a needle (0.7 × 30 mm; 22 G × 1.25) in the assay solution at 10 ml gas volume / minute. The time until the color changes (pH 7.2) is measured with a stopwatch.

The percentage inhibition is calculated as follows:
(Time to change color without enzyme - Time to change color with enzyme and inhibitor) / Time to change color without enzyme - Time to change color with enzyme).

IC ₅₀ values (inhibitory concentration) represent the molar amount of inhibitor, which reduce the EU activity by 50% in the assay.

In the experiment, the compounds of Examples 1 and 2 and 3 and 4 showed no carbonic anhydrase activity, while a carbonic anhydrase activity of 1-3 μM (IC ₅₀ ) was detectable for the compound of Example 7.

Further results are summarized in the following Table 2: Table 2

The new active ingredients can be introduced into the usual formulations in a known manner are transferred, such as tablets, coated tablets, pills, granules, aerosols, syrups, Emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically acceptable carriers and solvents. Here, the therapeutically active compound in a concentration of about 0.5 to 90% by weight of the total mixture is present, d. H. in amounts that are sufficient are to achieve the specified dosage range.

The formulations are prepared, for example, by stretching the Active ingredients with solvents and / or carriers, optionally using of emulsifiers and / or dispersants, z. B. in the case of use of water as a diluent, optionally organic solvents Auxiliary solvents can be used.

The application is carried out in the usual way, preferably orally, parenterally or topically, especially perlingually or intravenously.

In the case of parenteral use, solutions of the active ingredients can be found below Use of suitable liquid carrier materials can be used.

In general, it has proven to be advantageous for intravenous administration Amounts of about 0.001 to 20 mg / kg, preferably about 0.01 to 10 mg / kg Body weight for effective results, and oral Application is about 0.01 to 30 mg / kg, preferably 0.1 to 20 mg / kg body weight.

Nevertheless, it may be necessary from the amounts mentioned deviate, depending on the body weight or the type of Application route, from individual behavior towards the drug, the Kind of its formulation and the time or interval at which the Administration takes place. So in some cases it may be sufficient with less than the aforementioned minimum quantity, while in other cases the mentioned upper limit must be exceeded. Larger in the case of application Quantities it may be advisable to take these in several single doses throughout the day to distribute.

It may make sense to use the compounds of the invention to combine other active substances, in particular antiviral active substances.

starting compounds Example I 2-chloro-4-methyl-1,3-thiazole-5-sulfonyl chloride

150 g (1.12 mol) of 2-chloro-4-methyl-1,3-thiazole are added dropwise at room temperature to a solution of 331 g (2.81 mmol) of thionyl chloride in 653 g (5.61 mmol) of chlorosulfonic acid. The solution is heated to reflux for 48 hours. The mixture is then poured into 3 l of ice water and extracted with 4 × 400 ml of dichloromethane. The combined organic phases are washed with 2.5 l of water, dried over sodium sulfate and concentrated. After the crude product has been distilled, 233.7 g of product are obtained in the form of an oil. (Bp 87-96 ° C, 0.7 mbar, GC 98.1%, yield 89.6%). Example II 2-chloro-N, 4-dimethyl-1,3-thiazole-5-sulfonamide

177 ml of a solution of methylamine in methanol (2 M, 0.354 mol) at 0 ° to a solution of 41 g (0.177 mol) of 2-chloro-4-methyl-1,3-thiazole-5-sulfonyl chloride in 360 ml of dichloromethane C. added. The mixture is stirred at 0 ° C. for 30 min, 1.8 l of water are added and the mixture is extracted 5 times with 400 ml of dichloromethane each time. The combined organic phases are dried over sodium sulfate and the solvent is distilled off. 39.93 g of an oil are obtained, which solidifies on standing (Rf = 0.43 (toluene / ethyl acetate = 2/1), yield 99.7%). Example III 2-chloro-N-cyclopropyl-4-methyl -1,3-thiazole-5-sulfonamide

177 ml of a solution of cyclopropylamine in methanol (2 M, 0.354 mol) at 0 ° to a solution of 41 g (0.177 mol) of 2-chloro-4-methyl-1,3-thiazole-5-sulfonyl chloride in 360 ml of dichloromethane C. added. The mixture is stirred at 0 ° C. for 30 min, 1.8 l of water are added and the mixture is extracted 5 times with 400 ml of dichloromethane each time. The combined organic phases are dried over sodium sulfate and the solvent is distilled off. 39.93 g of an oil are obtained which solidify on standing. The raw product is used in the next stage without further purification. Example IV N-Cyclopropyl-4-methyl-2- (methylamino) -1,3-thiazole-5-sulfonamide

144 g (0.57 mol) of 2-chloro-N-cyclopropyl-4-methyl-1,3-thiazole-5-sulfonamide are placed in 600 ml of acetonitrile at room temperature and 147 g (1.9 mol) of a 40% solution aqueous methylamine solution metered in at room temperature. The reaction mixture is stirred for 6 h at 50 ° C and then concentrated on a rotary evaporator. The residue is mixed with water, suction filtered and dried.
Yield: 78 g (55%), mp: 198 ° C. Example V [4- (2-pyridinyl) phenyl] acetic acid methyl ester

7.85 g (34.3 mmol) of methyl 4-bromophenylacetate are placed under argon in 95 ml of toluene and at room temperature with 7.97 g (61.7 mmol) of diisopropylethylamine, 9.50 g (37.7 mmol) of 2-trimethylstannylpyridine and 0.4 g (0.3 mmol) of tetrakis (triphenylphosphine) palladium (0) were added. The mixture is then heated under reflux for 18 h. After cooling, it is washed with 100 ml of 1N hydrochloric acid and saturated sodium bicarbonate solution. The organic phase was discarded. The acidic and basic water phases were neutralized, extracted with 100 ml of dichloromethane each time, and the combined organic phases were dried over magnesium sulfate and freed from the solvent in vacuo. Example VII is obtained as a colorless oil after silica gel chromatography (toluene / ethyl acetate gradient 5: 1-1: 1).
Yield: 1.6 g (19%)
¹ H NMR (400 MHz, d ⁶ -DMSO, δ / ppm): 3.64 (s, 3H), 3.76 (s, 2H), 7.33-7.40 (m, 1H), 7.39 (d, J = 8.2 Hz; 2H), 7.86-7.90 (m, 1H), 7.96 (d, J = 8.0 Hz; 1H), 8.05 (d, J = 8.2 Hz; 2H), 8.67 (d, J = 4.2 Hz, broad; 1H ). Example VIII [4- (2-pyridinyl) phenyl] acetic acid

700 mg (3.11 mol) of methyl [4- (2-pyridinyl) phenyl] acetate are placed in 5 ml of tetrahydrofuran, and 6.2 ml of a 1 M potassium hydroxide solution in water are added at room temperature. The mixture is then stirred at room temperature for 18 h, then the solvent is largely removed in vacuo, the residue is taken up in 10 ml of water and the pH is brought to about 5 using 2N hydrochloric acid. Extraction of the aqueous phase twice with 10 ml of dichloromethane each gave, after drying the combined organic phases over magnesium sulfate and removing the solvent in vacuo, the compound of Example VIII in the form of a solid.
Yield: 300 mg (46%)
¹ H-NMR (400 MHz, d ⁶ -DMSO, δ / ppm): 3.76 (s, 2H), 7.45-7.51 (m, 1H), 7.50 (d, J = 8.3 Hz; 2H), 8.00 (td, J ₁ = 7.7 Hz, J ₂ = 1.9 Hz; 1H), 8.07 (d, J = 7.9 Hz; 1H), 8.15 (d, J = 8.3 Hz; 2H), 8.78 (dt, J ₁ = 4.0 Hz , J ₂ = 0.9 Hz; 1H).

The following compounds are prepared analogously to the above-mentioned regulations: Preparation Examples Example 1 N- {5 - [(Cyclopropylamino) sulfonyl] -4-methyl-1,3-thiazol-2-yl} -N-methyl-2- [4- (1H-pyrazol-1-yl) phenyl] acetamide

1.0 g (4.95 mmol) 4-pyrazolylphenylacetic acid (Artico, M .; Silvestri, R .; Stefancich, G .; Avigliano, L .; Giulio, A. Di; et al .; Eur. J. Med. Chem. Chim. Ther .; 27; 3; 1992; 219-228) and 1.05 g (5.50 mmol) of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide are placed in 10 ml of acetonitrile at room temperature. 1.36 g (5.50 mmol) of N-cyclopropyl-4-methyl-2- (methylamino) -1,3-thiazole-5-sulfonamide and 0.67 g (4.95 mmol) of 1-hydroxy-1H- Benzotriazole (12-17% water, Fluka) are added and the mixture is stirred overnight at room temperature. The solvent is then distilled off and the residue is further purified by chromatography on silica gel with dichloromethane / methanol 96: 4 as the eluent. A yellow solid is obtained, which is recrystallized from methyl tert-butyl ether.
Yield: 0.53 g (22.4%, HPLC: 100%)
Mp .: 206 ° C
MS (ESI, m / z): 432 (100%), [M + H] ⁺ Example 2 N- {5 - [(Cyclopropylamino) sulfonyl] -4-methyl-1,3-thiazol-2-yl} - N-methyl-2- [4- (1H-pyrazol-1-yl) phenyl] acetamide hydrochloride

50 mg (0.12 mmol) N- {5 - [(cyclopropylamino) sulfonyl] -4-methyl-1,3-thiazol-2-yl} - N-methyl-2- [4- (1H-pyrazol-1 -yl) phenyl] acetamide are dissolved in 4 ml of acetone and 4.23 mg (0.12 mmol) of a 1 N hydrochloric acid solution are added. The mixture is stirred overnight, the solvent is distilled off and the residue is dried.
Yield: 41 mg (76%)
Mp: 207 ° C

Example 3 N- {5 - [(methylamino) sulfonyl] -4-methyl-1,3-thiazol-2-yl} -N-methyl-2- [4- (1H- pyrazol-1-yl) phenyl] acetamide Example 4 N- {5 - [(methylamino) sulfonyl] -4-methyl-1,3-thiazol-2-yl} -N-methyl-2- [4- (1H- pyrazol-1-yl) phenyl] acetamide hydrochloride Example 5 (comparative example) N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -2- [1,1'-biphenyl] -4-yl-N- methylacetamide

138.2 mg (0.65 mmol) of 4-biphenylacetic acid and 99.7 mg (0.65 mmol) of 1-hydroxy-1H-benzotriazole hydrate are placed in 5 ml of dimethylformamide at room temperature. 150 mg (0.72 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulfonamide and 138.7 mg (0.72 mmol) of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride added and the mixture stirred for 72 h at room temperature. The reaction mixture is then suctioned off and the residue is recrystallized from 2-propanol. A white solid is obtained.
Yield: 240 mg (83.0%)
Mp: 191 ° C
¹ H-NMR (300 MHz, d ⁶ -DMSO, δ / ppm): 2.47 (s, 3H; partly under DMSO signal), 3.71 (s, 3H), 4.20 (s, 2H), 7.32-7.70 (m, 11H).

The following compounds are prepared analogously to the above-mentioned regulations: Example 6 N- [5- (Methylaminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -2- [1,1'-biphenyl] -4- yl-N-methylacetamide

Mp 180 ° C. Example 7 (comparative example) N- {5- [aminosulfonyl] -4-methyl-1,3-thiazol-2-yl} -N-methyl-2- [4- (1H-pyrazol-1- yl) phenyl] acetamide

0.100 g (0.48 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulfonamide are dissolved in 10 ml of N, N-dimethylformamide and at room temperature with 0.110 g (0.53 mmol) [4- (1H-Pyrazol-1-yl) phenyl] acetic acid, 0.070 g (0.53 mmol) of 1-hydroxy-1H-benzotriazole and 0.070 g (0.53 mmol) of N, N'-diisopropylcarbodiimide were added. The solution is stirred at room temperature overnight. The mixture is then poured onto water and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried with sodium sulfate and concentrated. The crude product is finely cleaned on a preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient).
Yield: 0.11 g (59%)
MS (ESI): 783 (2 Mz + H), 392 (Mz + H).
¹ H-NMR (300 MHz, DMSO, δ / ppm): 2.48 (s, 3H), 3.72 (s, 3H), 4.20 (s, 2H), 6.55 (t, J = 2 Hz; 1H), 7.38 ( d, J = 7 Hz; 2H), 7.65 (s, 2H), 7.75 (d, J = 2 Hz; 1H), 7.82 (d, J = 7 Hz; 2H), 8.49 (d, J = 2 Hz; 1H). Example 8 (Comparative Example) N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -2- (2 ', 5'-difluoro-1,1'-biphenyl-4-yl ) -N-methylacetamide

1.00 g (4.0 mmol) (2 ', 5'-difluoro [1,1'-biphenyl] -4-yl) acetic acid and 0.54 g (4.0 mmol) 1-hydroxy-1H-benzotriazole Hydrate are placed in 15 ml of dimethylformamide at room temperature. 0.84 g (4.0 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulfonamide and 0.77 g (4.0 mmol) of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide Hydrochloride are added and the mixture is stirred at room temperature for 18 h. The dimethylformamide is largely removed in a high vacuum at 50 ° C., the residue is stirred 3 times with 50 ml of water each time, filtered off, stirred with 50 ml of isopropanol and filtered off again. After removal of the solvent in vacuo, the compound of Example 87 is obtained in the form of a pale yellow solid.
Yield: 0.83 g (47.3%)
Mp: 184 ° C
¹ H NMR (400 MHz, DMSO, δ / ppm): 2.49 (s, 3H), 3.71 (s, 3H), 4.24 (s, 2H), 7.22-7.46 (m, 3H), 7.38 (d, J = 8.2 Hz; 2H), 7.56 (d, J = 8.2 Hz; 2H), 7.65 (s, 2H).

Example 9 N- [5- (-cyclopropylaminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2- pyridinyl) phenyl] acetamide Example 10 N- [5- (methylaminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2- pyridinyl) phenyl] acetamide Example 11 (comparative example) N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2- [4- (2- pyridinyl) phenyl] acetamide

300 mg (1.41 mmol) of [4- (2-pyridinyl) phenyl] acetic acid and 190 mg (1.41 mmol) of 1-hydroxy-1H-benzotriazole hydrate are placed in 4 ml of dimethylformamide at room temperature. 307 mg (1.48 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulfonamide and 284 mg (1.48 mmol) of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride are added and the mixture was stirred at room temperature for 18 h. The solvent is then removed in vacuo, the residue is taken up in toluene and the solvent is removed again in vacuo. The residue is stirred with 15 ml of water and 3 ml of methanol, then filtered off and the filtrate extracted with 20 ml of dichloromethane. Solid matter and dichloromethane phase are combined and the solvent removed in vacuo. The compound of Example 38 is obtained in the form of a white solid.
Yield: 440 mg (74.0%)
Mp: 188-192 ° C
MS (ESI, m / z): 403 (100%, [M + H] ^+
1 H-NMR (400 MHz, d ⁶ -DMSO, δ / ppm): 2.38 (s, 3H; under DMSO signal), 3.64 (s, 3H), 4.15 (s, 2H), 7.28-7.26 (m, 1H ), 7.32 (d, J = 8 Hz; 2H), 7.58 (s, 2H), 7.82-7.96 (m, 2H), 7.98 (d, J = 8.0 Hz; 2H), 8.61 (m; 1H) ,

Claims (14)

1. Compound of the general formula (I)


in which
R ¹ represents hydrogen, halogen, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, amino (C ₁ - C ₆₎ alkyl or halo (C ₁ -C ₆₎ alkyl stands,
R ^{2 represents} hydrogen
R ^{3 represents} (C ₁ -C ₆ ) alkoxy or (C ₃ -C ₈ ) cycloalkyl, or
represents (C ₁ -C ₆ ) alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₆ ) alkoxy , Halogen, hydroxy, amino, tri- (C ₁ -C ₆ ) alkylsilyloxy,
a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, where a nitrogen-containing heterocycle can also be bonded via the nitrogen atom,
a 3- to 8-membered saturated or unsaturated, non-aromatic, heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, and (C ₆ -C ₁₀ ) -aryl, which in turn by Hydroxy or (C ₁ -C ₆ ) alkoxy may be substituted,
consists,
R ^{4 represents} hydrogen, (C ₁ -C ₆ ) acyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₈ ) cycloalkyl, or
R ^{4 represents} (C ₁ -C ₆ ) alkyl, which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkoxy, carboxyl,


wherein R ^{4 'is} hydrogen, - (OCH ₂ CH ₂ ) _n OCH ₂ CH ₃ , where n is 0 or 1, phenoxy, (C ₆ -C ₁₀ ) aryl and -NR ¹³ R ¹⁴ ,
wherein
R ¹³ and R ^{14 are} identical or different and are hydrogen, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkyl, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, (C ₆ -C ₁₀ ) aryl or (C ₁ -C ₆ ) alkoxycarbonyl, or
R ¹³ and R ¹⁴ together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may optionally contain a further hetero atom from the S or O series or a radical of the formula -NR ¹⁵ and may be substituted by oxo,
wherein
R ^{15 is} hydrogen or (C ₁ -C ₄ ) alkyl, or
R ^{4 represents} (C ₁ -C ₆ ) alkyl which is substituted by a 5- to 6-membered aromatic, optionally benzo-fused heterocycle with up to 3 heteroatoms from the series S, N and / or O, a nitrogen-containing heterocycle can also be bound via the nitrogen atom, or by residues of the formulas


wherein
R ¹⁶ denotes hydrogen or (C ₁ -C ₆ ) alkyl,
R ¹⁷ and R ^{18 are} identical or different and denote hydrogen, (C ₁ -C ₆ ) alkyl or (C ₆ -C ₁₀ ) aryl, the aforementioned (C ₁ -C ₆ ) alkyl and (C ₆ - C ₁₀ ) aryl may optionally be substituted by 1 to 3 substituents selected from the group consisting of hydroxy, (C ₁ -C ₆ ) alkoxy and halogen,
R ^{5 represents} hydrogen, (C ₁ -C ₆ ) alkyl, halogen, amino, mono- or di (C ₁ - C ₆ ) alkylamino or represents (C ₁ -C ₆ ) alkanoylamino,
R ^{6 represents} phenyl which may optionally be substituted with one to three substituents selected from the group consisting of
Halogen,
(C ₆ -C ₁₀ ) aryl optionally substituted by 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, halogen, (C ₁ -C ₆₎ alkoxycarbonyl, nitro, halo (C ₁ - C ₆₎ -lkyl, halo (C ₁ -C ₆₎ -lkoxy, amino, (C ₁ -C ₆₎ alkylthio, Hydroxy, carboxyl, carbamoyl, mono- or di- (C ₁ -C ₆ ) -alkylaminocarbonyl, mono- or di- (C ₁ -C ₆ ) -alkanoylamino, (C ₁ -C ₆ ) -alkoxycarbonylamino, (C ₁ - C ₆₎ alkylsulfoxy, (C ₁ -C ₆₎ - alkylsulfonyl, tri- (C ₁ -C ₆₎ alkylsilyloxy, a bound optionally via a nitrogen atom 3- to 8-membered saturated or unsaturated, nonaromatic, mono- or bicyclic heterocycle can be substituted with up to 3 heteroatoms from the series S, N and / or O, and / or cyano,
(C ₁ -C ₆ ) alkoxy,
(C ₁ -C ₆ ) alkoxycarbonyl,
(C ₁ -C ₆ ) alkylthio,
hydroxy,
carboxyl,
partially fluorinated (C ₁ -C ₆ ) alkoxy with up to 6 fluorine atoms,
(C ₁ -C ₆ ) alkyl, optionally by a radical of the formula


a 5- to 6-membered aromatic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, optionally with 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) alkylthio, hydroxy, carboxyl, carbamoyl, aminocarbonyl, mono- or di- (C ₁ - C ₆ ) alkylaminocarbonyl, mono- or di- (C ₁ -C ₁ ) -alkanoylamino, (C ₁ -C ₆ ) -alkoxycarbonylamino, (C ₁ -C ₆ ) -alkylsulfoxy, (C ₁ -C ₆ ) -alkylsulfonyl, a 3- to 8-membered group which may be bonded via a nitrogen atom saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle can be substituted with up to 3 heteroatoms from the series S, N and / or O, and / or cyano,
a 3- to 8-membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, optionally selected from 1 to 3 substituents from oxo , Halogen, hydroxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkyl and hydroxy- ( C ₁ -C ₆ ) alkyl can be substituted,
(C ₂ -C ₆ ) alkenyl
and groups of formulas
-OR ¹⁹ ,
-NR ²⁰ R ²¹ or -CO-NR ²² R ²³
Carbazole, dibenzofuran or dibenzothiophene,
Xanthene or 9,10-dihydroacridine
consists,
in which R ^{19 is} phenyl, which in turn is optionally substituted by a group of the formula -NR ²⁴ R ²⁵ ,
wherein
R ²⁴ and R ^{25 are} identical or different and are hydrogen, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) acyl,
or
R ¹⁹ denotes (C ₁ -C ₆ ) -alkyl which is optionally mono- to trisubstituted by hydroxy and / or halogen,
R ²⁰ and R ^{21 are the} same or different and are hydrogen, carbamoyl, mono- or di- (C ₁ -C ₆ ) alkylaminocarbonyl, phenyl, (C ₁ -C ₆ ) acyl or (C ₁ -C ₆ ) alkyl mean,
where the aforementioned (C ₁ -C ₆ ) alkyl optionally by (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) acyl, by phenyl or by a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O is substituted,
wherein the aforementioned phenyl and the aforementioned aromatic heterocycle are optionally substituted one to three times in the same or different manner by halogen and / or hydroxy, and
R ²² and R ^{23 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
and R ^{7 can have} the meaning of R ⁵ and can be the same or different with it,
and their salts. 2. Compounds of general formula (I) according to claim 1, wherein
R ^{1 is} hydrogen, halogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy or
Halogen (C ₁ -C ₄ ) alkyl,
R ^{2 represents} hydrogen,
R ^{3 represents} (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl,
which is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, (C ₁ -C ₆ ) alkoxy and hydroxy,
R ^{4 represents} hydrogen, (C ₁ -C ₆ ) acyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₈ ) cycloalkyl, or
R ^{4 represents} (C ₁ -C ₆ ) alkyl, which can optionally be substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkoxy, - (OCH ₂ CH ₂ ) _n CH ₂ CH ₃ , where n is 0 or 1, phenoxy, (C ₆ -C ₁₀ ) aryl and -NR ¹³ R ¹⁴ ,
wherein
R ¹³ and R ^{14 are} identical or different and are hydrogen, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkyl, carbamoyl, mono- or di (C ₁ - C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, (C ₆ -C ₁₀ ) aryl or (C ₁ -C ₆ ) alkoxycarbonyl, or
R ¹³ and R ¹⁴ together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may optionally contain a further hetero atom from the S or O series or a radical of the formula -NR ¹⁵ and can be substituted by oxo,
wherein
R ^{15 is} hydrogen or (C ₁ -C ₄ ) alkyl, or
R ^{4 represents} (C ₁ -C ₆ ) alkyl which is substituted by a 5- to 6-membered aromatic, optionally benzo-fused heterocycle with up to 3 heteroatoms from the series S, N and / or O, a nitrogen-containing heterocycle can also be bound via the nitrogen atom, or by residues of the formulas


wherein
R ¹⁶ denotes hydrogen or (C ₁ -C ₆ ) alkyl,
R ¹⁷ and R ^{18 are} identical or different and denote hydrogen, (C ₁ -C ₆ ) alkyl or (C ₆ -C ₁₀ ) aryl, the aforementioned (C ₁ -C ₆ ) alkyl and (C ₆ -C ₁₀ ) -aryl may optionally be substituted by 1 to 3 substituents selected from the group consisting of hydroxy, (C ₁ -C ₆ ) alkoxy and halogen,
R ^{5 represents} hydrogen, (C ₁ -C ₆ ) alkyl, halogen, amino, mono- or di (C ₁ -C ₆ ) alkylamino or represents (C ₁ -C ₆ ) alkanoylamino,
R ^{6 represents} phenyl which may optionally be substituted with one to three substituents selected from the group consisting of
Halogen,
(C ₆ -C ₁₀ ) aryl optionally substituted by 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, halogen , (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ - C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) alkylthio, hydroxy, carboxyl, carbamoyl, mono - or di (C ₁ -C ₆ ) alkylaminocarbonyl, mono- or di (C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ -C ₆ ) Alkylsulfonyl, tri (C ₁ -C ₆ ) alkylsilyloxy, a 3- to 8-membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, and / or cyano may be substituted,
(C ₁ -C ₆ ) alkoxy,
(C ₁ -C ₆ ) alkoxycarbonyl,
(C ₁ -C ₆ ) alkylthio,
hydroxy,
carboxyl,
partially fluorinated (C ₁ -C ₆ ) alkoxy with up to 6 fluorine atoms,
(C ₁ -C ₆ ) alkyl, optionally by a radical of the formula


is substituted,
a 5- to 6-membered aromatic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, optionally with 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) - alkoxy, amino, (C ₁ -C ₆ ) alkylthio, hydroxy, carboxyl, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, mono- or di (C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ -C ₆ ) alkylsulfonyl, a 3- to 8-membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle which is optionally bonded via a nitrogen atom up to 3 heteroatoms from the series S, N and / or O, and / or cyano can be substituted,
a 3- to 8-membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, which is optionally selected from 1 to 3 substituents from oxo , Halogen, hydroxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkyl and hydroxy (C ₁ - C ₆ ) alkyl may be substituted,
and groups of formulas
-OR ¹⁹ ,
-NR ²⁰ R ²¹ or -CO-NR ²² R ²³
consists,
in which R ^{19 is} phenyl, which in turn is optionally substituted by a group of the formula -NR ²⁴ R ²⁵ ,
wherein
R ²⁴ and R ²⁵ are identical or different and are hydrogen, (C ₁ - C ₆₎ alkyl or (C ₁ -C ₆₎ acyl,
or
R ¹⁹ denotes (C ₁ -C ₆ ) -alkyl which is optionally mono- to trisubstituted by hydroxy and / or halogen,
R ²⁰ and R ^{21 are} identical or different and are hydrogen, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, phenyl, (C ₁ -C ₆ ) acyl or (C ₁ -C ₆ ) alkyl,
wherein the aforementioned (C ₁ -C ₆ ) alkyl optionally by (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) acyl, by phenyl or by a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O is substituted,
wherein the aforementioned phenyl and the aforementioned aromatic heterocycle are optionally substituted one to three times in the same or different manner by halogen and / or hydroxy, and
R ²² and R ^{23 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
and R ^{7 can have} the meaning of R ⁵ and can be the same or different with it,
and their salts. 3. Compounds of general formula (I) according to claim 1, wherein R ^{1 is} hydrogen or C ₁ to C ₆ alkyl. 4. Compounds of general formula (I) according to claim 1, wherein R ^{3 is} methyl, ethyl or cyclopropyl. 5. Compounds of general formula (I) according to claim 1, wherein R ^{4 is} hydrogen or C ₁ to C ₆ alkyl. 5. Compounds of general formula (I) according to claim 1, wherein R ⁵ and R ^{7 are} hydrogen. 6. Compounds of general formula (I) according to claim 1, wherein
R ^{6 represents} phenyl which may optionally be substituted with one to three substituents selected from the group consisting of
Halogen,
(C ₆ -C ₁₀ ) aryl optionally substituted by 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, halogen , (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ - C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, hydroxy, mono- or di (C ₁ -C ₆ ) alkylamino, mono - Or di (C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkoxycarbonylamino, and / or cyano may be substituted, and
an optionally bound via a nitrogen atom 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, which can optionally be substituted by 1 or 2 halogen atoms,
consists. 7. Compounds according to claim 1, which have the following formula:


wherein
R ¹ , R ³ , R ⁴ , R ⁵ and R ^{7 are} as defined in claim 1,
R ²⁶ and R ²⁷ are identical or different and represent hydrogen, halogen, (C ₁ - C ₆₎ alkoxy, (C ₁ -C ₆₎ -alkoxycarbonyl, (C ₁ -C ₆₎ -alkylthio, hydroxyl, carboxyl, partially fluorinated (C ₁ -C ₆ ) alkoxy having up to 6 fluorine atoms, (C ₁ -C ₆ ) alkyl, a group of the formulas -OR ¹⁹ , -NR ²⁰ R ²¹ or -CO-NR ²² R ²³ , in which
R ¹⁹ denotes phenyl, which in turn is optionally substituted by a group of the formula -NR ²⁴ R ²⁵ ,
wherein
R ²⁴ and R ^{25 are} identical or different and are hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₆ ) -acyl, or
R ¹⁹ denotes (C ₁ -C ₆ ) -alkyl which is optionally mono- to trisubstituted by hydroxy and / or halogen,
R ²⁰ and R ^{21 are} identical or different and denote hydrogen, carbamoyl, mono- or di (C ₁ -C ₆ ) alkylaminocarbonyl, phenyl, (C ₁ -C ₆ ) acyl or (C ₁ -C ₆ ) alkyl,
where the aforementioned (C ₁ -C ₆ ) alkyl optionally by (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) acyl, phenyl or by a 5- to 6-membered aromatic heterocycle with up to 3 Heteroatoms from the series S, N and / or O is substituted,
wherein the aforementioned phenyl and the aforementioned aromatic heterocycle are optionally substituted one to three times in the same or different manner by halogen and / or hydroxy, and
R ²² and R ^{23 are} identical or different and are hydrogen or (C ₁ -C ₆ ) alkyl,
R ^{28 represents} (C ₆ -C ₁₀ ) aryl, which is optionally substituted by 1 to 3 substituents selected from (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ - C ₆ ) Alkyl, halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) -Alkyl thio, hydroxy, carboxyl, carbamoyl, mono- or di- (C ₁ -C ₆ ) -alkylaminocarbonyl, mono- or di- (C ₁ -C ₆ ) -alkanoylamino, (C ₁ -C ₆ ) -alkoxycarbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ -C ₆ ) alkylsulfonyl, tri- (C ₁ -C ₆ ) alkylsilyloxy, a 3- to 8-membered saturated or unsaturated, non-aromatic, optionally bonded via a nitrogen atom , mono- or bicyclic heterocycle with up to 3 heteroatoms from the series S, N and / or O, and / or cyano may be substituted, or
R ^{28 represents} a 5- to 6-membered aromatic heterocycle, optionally bonded via a nitrogen atom, with up to 3 heteroatoms from the series S, N and / or O, which is optionally selected from 1 to 3 substituents selected from (C ₁ -C ₆ ) Alkanoyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl, halogen, (C ₁ -C ₆ ) alkoxycarbonyl, nitro, halogen (C ₁ - C ₆ ) alkyl, Halogen-C ₁ -C ₆ ) -alkoxy, amino, (C ₁ -C ₆ ) -alkylthio, hydroxy, carboxyl, carbamoyl, mono- or di- (C ₁ -C ₆ ) -alkylaminocarbonyl, mono- or di- ( C ₁ -C ₆ ) alkanoylamino, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkylsulfoxy, (C ₁ -C ₆ ) alkylsulfonyl, a 3- to 8- optionally bonded via a nitrogen atom membered saturated or unsaturated, non-aromatic, mono- or bicyclic heterocycle with up to 3 heteroatoms from the series S, N and / or O, and / or cyano,
and their salts. 8. Compounds according to claim 1 for use as a medicament. 9. Pharmaceutical composition, which is a compound of general Formula (I) according to claim 1 in admixture with a pharmaceutical compatible carriers or excipients. 10. Use of a compound of general formula (I) according to claim 1 for the manufacture of a drug. 11. Use of a compound of general formula (I) according to claim 1 for the manufacture of a medicament for the treatment of viral infections. 12. Use of a compound of general formula (I) according to claim 1 for the manufacture of a medicament for the treatment of viral infections Herpes viruses. 13. Use of a compound of general formula (I) according to claim 1 for the manufacture of a medicament for the treatment of viral infections Herpes simplex virus.