KR20030088509A - Novel Arylsulphonamides as Antiviral Agents - Google Patents

Abstract

The present invention relates to novel arylsulfonamides of the general formula (I), to their preparation and to their use as antiviral agents, in particular against cytomegalovirus.

<Formula I>

Wherein the substituents R ¹ , R ² , R ³ , R ⁴ , A and X are as defined in claim 1.

Description

Novel Arylsulphonamides as Antiviral Agents

The present invention relates to novel compounds, their preparation and their use as medicaments, in particular as antiviral agents, in particular as antiviral agents for cytomegalovirus.

From International Publication WO 99/37291, compound 2,2-dimethyl-N- [4-[[[4- (4-phenyl-2H-1,2,3-triazol-2-yl) phenyl] -sul Phonyl] amino] phenyl] -propanamide is known to have antiviral activity.

The present invention relates to compounds of formula (I) and tautomers, stereoisomers, stereoisomer mixtures thereof and pharmacologically acceptable salts thereof.

Where

R ² and R ³ are the same or different and are hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) Alkoxy, or chemical formula or Wherein R ⁵ , R ⁶ and R ⁷ are the same or different and each is hydrogen or a portion thereof selected from the group consisting of hydroxyl, halogen, cyano, trifluoromethyl and trifluoromethoxy Group of (C ₁ -C ₆ ) -alkyl which may be substituted by two substituents,

A is attached to an adjacent phenyl ring via a C atom and represents a 5 or 6 membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of N, O and S,

R ¹ represents (C ₆ -C ₁₀ ) -aryl, in each case 5 to 10 membered heteroaryl or 5 to 10 membered heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of N, O and S Indicate,

R ¹ is hydroxyl, amino, mono- (C ₁ -C ₆ ) -alkylamino, di- (C ₁ -C ₆ ) -alkylamino, halogen, nitro, cyano, oxo, some of which are amino or hydroxide 5 having up to 2 heteroatoms selected from the group consisting of (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy, phenyl, N, O and S which may be substituted by a siloxane 5 or 6 membered heteroaryl having one or more heteroatoms selected from the group consisting of 6 membered heterocyclyl, N, O and S, —C (O) —OR ⁸ , —C (O) —NR ⁹ R ¹⁰ , To be substituted by up to 3 substituents selected from the group consisting of -NH-C (O) -R ¹¹ , -NH-C (O) -C (O) -R ¹² and -NH-SO ₂ -R ¹³ . Where R ⁸ , R ⁹ and R ¹⁰ are the same or different and each represents hydrogen or (C ₁ -C ₆ ) -alkyl, or

R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached contain (C ₁ -C ₄ ) -alkyl, amino, hydroxyl, containing additional nitrogen or oxygen heteroatoms, some of which are optionally substituted by hydroxyl or amino, 5 or 6 membered heterocycle which may be mono- or di-substituted by the same or different substituents from the group consisting of (C ₁ -C ₄ ) -alkoxy, oxo, carboxyl and (C ₁ -C ₄ ) -alkoxycarbonyl Form the

R ¹¹ and R ¹² are the same or different and each represents trifluoromethyl, (C ₁ -C ₆ ) -alkoxy, hydroxyl, or amino, (C ₁ -C ₆ ) -alkoxycarbonylamino, mono - (C ₁ -C ₆₎ - acylamino, hydroxyl, amidino, guanidino, (C ₁ -C ₆₎ - by the same or different substituents from alkoxycarbonyl, carboxyl and the group consisting of phenyl optionally Mono- or di-substituted (C ₁ -C ₆ ) -alkyl;

R ¹³ is (C ₁ -C ₆ ) -alkyl or (C which may in each case be substituted by halogen, amino, hydroxyl, (C ₁ -C ₄ ) -alkoxy or (C ₁ -C ₄ ) -alkyl ₆ -C ₁₀ ) -aryl),

R ⁴ is from the group consisting of amino, hydroxyl, halogen, (C ₁ -C ₆ ) -alkoxy, (C ₁ -C ₅ ) -alkanoyloxy, and a portion of which is composed of halogen, nitro, cyano, amino and hydroxyl Or (C ₁ -C ₆ ) -alkyl which may be substituted up to three times by the same or different substituents from the group consisting of mono- or di-substituted phenyl optionally by the same or different substituents of

Three times by the same or different substituents from the group consisting of amino, hydroxyl, halogen, (C ₁ -C ₆ ) -alkoxy, and some of which are amino, hydroxyl, halogen, and (C ₁ -C ₆ ) -alkoxy Or (C ₃ -C ₇ ) -cycloalkyl which may be substituted up to three times by the same or different substituents from the group consisting of (C ₁ -C ₆ ) -alkyl optionally substituted below,

(C ₆ -C ₁₀ ) -aryl optionally substituted with the same or different substituents from the group consisting of halogen, nitro, cyano, amino and hydroxyl,

X represents oxygen or sulfur,

The nitrogen-containing heterocycle may also be present as N-oxide.

In the context of the present invention, (C ₁ -C ₆ ) -alkyl refers to a straight or branched alkyl radical having 1 to 6 carbon atoms. The following radicals may be mentioned by way of example: methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl and n-hexyl.

In the context of the present invention, (C ₃ -C ₇ ) -cycloalkyl denotes a cycloalkyl group having 3 to 7 carbon atoms. The following radicals may be mentioned by way of example: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the context of the present invention, (C ₁ -C ₆ ) -alkoxy refers to a straight or branched alkoxy radical having 1 to 6 carbon atoms. The following radicals may be mentioned by way of example: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy. Preferred are methoxy and ethoxy.

In the context of the present invention, (C ₆ -C ₁₀₎ -aryl denotes an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

In the context of the present invention, aralkyl refers to (C ₆ -C ₁₀₎ -aryl, part of which is attached to (C ₁ -C ₄ ) -alkyl. Preferably benzyl.

In the context of the present invention, mono- (C ₁ -C ₆ ) -alkylamino refers to an amino group having straight, branched or cyclic alkyl substituents having 1 to 6 carbon atoms. The following radicals may be mentioned by way of example: methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino, t-butylamino, n-pentylamino, cyclopentylamino and n-hexylamino.

In the context of the present invention, di - (C ₁ -C ₆₎ - alkylamino represents an amino group having 1 to 6 two identical or different straight-chain, branched or cyclic alkyl substituent having a carbon atom in each case, . The following radicals may be mentioned by way of example: N, N -dimethylamino, N, N -diethylamino, N -ethyl- N -methylamino, N -methyl- N -n-propylamino, N -methyl- N -Cyclopropylamino, N -isopropyl- N -n-propylamino, N- t-butyl- N -methylamino, N -ethyl- N -n-pentylamino and N -n-hexyl- N -methylamino.

In the context of the present invention, (C ₁ -C ₆ ) -alkoxycarbonyl refers to straight or branched alkoxy ladaki having 1 to 6 carbon atoms, attached via a carbonyl group. Preferred are straight or branched alkoxycarbonyl radicals having 1 to 4 carbon atoms. The following radicals may be mentioned by way of example and by way of preference: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.

In the context of the present invention, (C ₁ -C ₆ ) -alkoxycarbonylamino refers to an amino group having 1 to 6 carbon atoms in the alkoxy radical and having a straight or branched alkoxycarbonyl substituent attached via a carbonyl group. Preferred are alkoxycarbonylamino radicals having 1 to 4 carbon atoms in the alkoxy radical. The following radicals may be mentioned by way of example and by way of preference: methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino and t-butoxycarbonylamino.

In the context of the present invention, mono- (C ₁ -C ₆ ) -acylamino refers to an amino group having 1 to 6 carbon atoms and having straight or branched alkanoyl substituents attached through a carbonyl group. Preferred are monoacylamino radicals having one or two carbon atoms. The following radicals may be mentioned by way of example and by way of preference: formamido, acetamido, propionamido, n-butyramido and pivalolamido.

In the context of the present invention, (C ₁ -C ₅ ) -alkanoyloxy preferably has 1 to 5 carbon atoms, having oxygen atoms doubled in the 1-position and attached to the 1-position via an additional oxygen atom. Linear or branched alkyl radicals having Preferred are straight-chain or branched alkanoyloxy radicals having 1 to 3 carbon atoms. The following radicals may be mentioned by way of example and by way of preference: acetoxy, propionoxy, n-butyoxy, i-butyoxy and pivaloyloxy.

In the context of the present invention, halogen generally refers to fluorine, chlorine, bromine and iodine. Preferred are fluorine, chlorine and bromine. Especially preferred are fluorine and chlorine.

In the context of the present invention, 5 to 10 membered heteroaryl refers to a 5 to 10 membered hetero-containing aromatic ring which may contain 1 to 4 heteroatoms selected from the group consisting of O, S and N, for example Pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolisenyl, indolyl, benzo [b] thienyl, benzo [b] furyl, indah Zolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl and the like.

In the context of the present invention, 5 to 10 or 5 or 6 membered saturated or partially unsaturated heterocyclyl having up to 3 heteroatoms from the group consisting of S, N and O may generally have one or more double bonds. And mono or bicyclic heterocycles attached via ring carbon atoms or ring nitrogen atoms. The following radicals may be mentioned by way of example: tetrahydrofur-2-yl, tetrahydrofur-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, Pyrrolin-1-yl, piperidin-1-yl, piperidin-3-yl, 1,2-dihydropyridin-1-yl, 1,4-dihydropyridin-1-yl, piperazine- 1-yl, morpholin-1-yl, azepin-1-yl, 1,4-diazepin-1-yl. Preferred are piperidinyl, morpholinyl and pyrrolidinyl.

1,2,4-oxadiazoles attached via the 3- or 5-position represent oxadiazoles attached to the phenylsulfonamide via ring carbon atoms in the 3- or 5-position.

In the context of the present invention, preferred salts are pharmacologically acceptable salts of the compounds according to the invention.

Pharmacologically acceptable salts of the compounds according to the invention may be acid addition salts of the compounds according to the invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are, for example, 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. Salt.

However, salts which may be mentioned include, for example, salts with conventional bases such as alkali metal salts (eg sodium salts or potassium salts), alkaline earth metal salts (eg calcium salts or magnesium salts) or ammonium salts; Ammonia, or for example diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, 1-ephenamine or methylpiperidine Salts derived from organic amines; Or salts derived from natural amino acids such as, for example, glycine, lysine, arginine or histidine.

The compounds according to the invention may exist in the form of stereoisomers which are one of the same phase and enantiomers (enantiomers), or non-identical phases and enantiomers (diastereomers). The present invention relates to both the enantiomers or diastereomers, and mixtures thereof, respectively. The racemic forms can be separated into stereoisomeric homogeneous components by methods known per se, such as diastereomers.

In addition, the present invention also encompasses prodrugs of the compounds according to the invention. According to the present invention, prodrugs may be partly less biologically or even inactive, but upon administration, in a corresponding biologically active form (e.g. metabolically, solublely or alternatively) under physiological conditions To derivatives of the compounds of formula (I).

In addition, the present invention provides that R ² and R ³ are the same or different, hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₆ ) -alkyl, (C _1- C ₆ ) -alkoxy, or or Wherein R ⁵ , R ⁶ and R ⁷ are the same or different and each is 1 or 2 wherein hydrogen or a portion thereof is selected from the group consisting of hydroxyl, halogen, cyano, trifluoromethyl and trifluoromethoxy Group of (C ₁ -C ₆ ) -alkyl which may be substituted by 4 substituents,

A is attached to an adjacent phenyl ring via a C atom and represents a 5 or 6 membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of N, O and S,

R ¹ is (C ₆ -C ₁₀ ) -aryl, in each case 5 to 10 membered heteroaryl or 5 to 10 membered heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of N, O and S; Indicate,

Wherein R ¹ is hydroxyl, amino, mono- (C ₁ -C ₆ ) -alkylamino, di- (C ₁ -C ₆ ) -alkylamino, halogen, nitro, cyano, oxo, some of which are amino or hydroxide (C ₁ -C ₆ ) -alkyl which may be substituted by hydroxy; 5 or 6 membered heteroaryl having one or more heteroatoms selected from the group consisting of (C ₁ -C ₆ ) -alkoxy, phenyl, N, O and S, —C (O) —OR ⁸ , —C (O) May be substituted by up to 3 substituents selected from the group consisting of —NR ⁹ R ¹⁰ and —NH—C (O) —R ¹¹ , wherein R ⁸ , R ⁹ and R ¹⁰ are the same or different, Each represents hydrogen or (C ₁ -C ₆ ) -alkyl,

R ¹¹ represents (C ₁ -C ₆ ) -alkyl optionally substituted or substituted by the same or different substituents from the group consisting of amino, hydroxyl, guanidino, carboxyl and phenyl),

R ⁴ is amino, hydroxyl, halogen, (C ₁ -C ₆₎ - alkoxy, and parts thereof, halogen, nitro, cyano, amino and hydroxyl by identical or different substituents from the group consisting of a lock chamber or optionally substituted Represent (C ₁ -C ₆ ) -alkyl which may be substituted up to three times by the same or different substituents from the group consisting of disubstituted phenyl,

Three times by the same or different substituents from the group consisting of amino, hydroxyl, halogen, (C ₁ -C ₆ ) -alkoxy, and some of which are amino, hydroxyl, halogen, and (C ₁ -C ₆ ) -alkoxy Or (C ₃ -C ₇ ) -cycloalkyl which may be substituted up to three times by the same or different substituents from the group consisting of (C ₁ -C ₆ ) -alkyl optionally substituted below,

(C ₆ -C ₁₀ ) -aryl optionally substituted with the same or different substituents from the group consisting of halogen, nitro, cyano, amino and hydroxyl,

X represents oxygen or sulfur,

To nitrogen-containing heterocycles, which may also exist as N-oxides, and tautomers, stereoisomers, stereoisomer mixtures thereof, and pharmacologically acceptable salts thereof.

Preferably the present invention preferably has the same or different R ² and R ³ , hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₆ ) -alkyl, ( C ₁ -C ₆ ) -alkoxy, or or Wherein R ⁵ , R ⁶ and R ⁷ are the same or different and each is 1 or 2 wherein hydrogen or a portion thereof is selected from the group consisting of hydroxyl, halogen, cyano, trifluoromethyl and trifluoromethoxy Group of (C ₁ -C ₆ ) -alkyl which may be substituted by 4 substituents,

A is attached to an adjacent phenyl ring via a C atom and represents a 5 or 6 membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of N, O and S,

R ¹ is (C ₆ -C ₁₀ ) -aryl, in each case 5 to 10 membered heteroaryl or 5 to 10 membered heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of N, O and S; Indicate,

Wherein R ¹ is hydroxyl, amino, mono- (C ₁ -C ₆ ) -alkylamino, di- (C ₁ -C ₆ ) -alkylamino, halogen, nitro, cyano, oxo, some of which are amino or hydroxide (C ₁ -C ₆ ) -alkyl which may be substituted by hydroxy; 5 or 6 membered heteroaryl having one or more heteroatoms selected from the group consisting of (C ₁ -C ₆ ) -alkoxy, phenyl, N, O and S, —C (O) —OR ⁸ , —C (O) May be substituted by up to 3 substituents selected from the group consisting of —NR ⁹ R ¹⁰ and —NH—C (O) —R ¹¹ , wherein R ⁸ , R ⁹ and R ¹⁰ are the same or different and each Represents hydrogen or (C ₁ -C ₆ ) -alkyl,

R ¹¹ represents (C ₁ -C ₆ ) -alkyl optionally substituted or substituted by the same or different substituents from the group consisting of amino, hydroxyl, guanidino, carboxyl and phenyl),

R ⁴ is amino, hydroxyl, halogen, (C ₁ -C ₆₎ - alkoxy, and parts thereof, halogen, nitro, cyano, amino and hydroxyl by identical or different substituents from the group consisting of a lock chamber or optionally substituted Represent (C ₁ -C ₆ ) -alkyl which may be substituted up to three times by the same or different substituents from the group consisting of disubstituted phenyl,

Three times by the same or different substituents from the group consisting of amino, hydroxyl, halogen, (C ₁ -C ₆ ) -alkoxy, and some of which are amino, hydroxyl, halogen, and (C ₁ -C ₆ ) -alkoxy Or (C ₃ -C ₇ ) -cycloalkyl which may be substituted up to three times by the same or different substituents from the group consisting of (C ₁ -C ₆ ) -alkyl optionally substituted below,

(C ₆ -C ₁₀ ) -aryl optionally substituted with the same or different substituents from the group consisting of halogen, nitro, cyano, amino and hydroxyl,

X represents oxygen,

To nitrogen-containing heterocycles, which may also exist as N-oxides, and tautomers, stereoisomers, stereoisomer mixtures thereof, and pharmacologically acceptable salts thereof.

In addition, the present invention preferably R ² and R ³ are the same or different, and represent hydrogen or halogen,

A radical of formula (A-II) wherein A is attached to an adjacent phenyl ring via one of the carbon atoms at position 3 or 5, or a radical of formula (A-II) attached to an adjacent phenyl ring via one of the carbon atoms at position 2 or 5; Indicates

R ¹ represents in each case 5 to 10 membered heteroaryl or 5 or 10 membered heterocyclyl having up to 3 heteroatoms selected from the group consisting of N, O and S, or represents phenyl,

Wherein R ¹ is (C ₁ -C ₄ ) -alkyl, hydroxyl, oxo, halogen, amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (some of which is optionally substituted with amino or hydroxyl; May be substituted by 1 to 3 substituents selected from the group consisting of C ₁ -C ₄ ) -alkylamino and —NH—C (O) —R ¹¹ , wherein R ¹¹ is amino, hydroxyl, guani (C ₁ -C ₆ ) -alkyl optionally substituted by the same or different substituents from the group consisting of dino and carboxy),

Which may be substituted with more than three times by identical or different substituents from the group consisting of alkoxy _{(C 1 -C 4) - -} R 4 is amino, hydroxyl, fluorine, chlorine and (C ₁ -C ₄₎ alkyl Or

Identical or different substituents from the group consisting of amino, hydroxyl, fluorine, chlorine, (C ₁ -C ₄ ) -alkoxy, and some of which are amino, hydroxyl, fluorine, chlorine, and (C ₁ -C ₄ ) -alkoxy (C ₃ -C ₅ ) -cycloalkyl which may be substituted up to three times by the same or different substituents from the group consisting of (C ₁ -C ₄ ) -alkyl optionally substituted up to three times by

X represents oxygen or sulfur,

To nitrogen-containing heterocycles, which may also exist as N-oxides, and tautomers, stereoisomers, stereoisomer mixtures thereof, and pharmacologically acceptable salts thereof.

In the above formulas,

Y represents oxygen or sulfur.

The present invention particularly preferably represents that R ² and R ³ are the same or different and represent hydrogen or halogen,

A radical of formula (A-II) wherein A is attached to an adjacent phenyl ring via one of the carbon atoms at position 3 or 5, or a radical of formula (A-II) attached to an adjacent phenyl ring via one of the carbon atoms at position 2 or 5; Indicates

R ¹ represents in each case 5 to 10 membered heteroaryl or 5 or 10 membered heterocyclyl having up to 3 heteroatoms selected from the group consisting of N, O and S, or represents phenyl,

Wherein R ¹ is (C ₁ -C ₄ ) -alkyl, hydroxyl, oxo, halogen, amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (some of which is optionally substituted with amino or hydroxyl; May be substituted by 1 to 3 substituents selected from the group consisting of C ₁ -C ₄ ) -alkylamino and —NH—C (O) —R ¹¹ , wherein R ¹¹ is amino, hydroxyl, guani (C ₁ -C ₆ ) -alkyl optionally substituted by the same or different substituents from the group consisting of dino and carboxy),

Which may be substituted with more than three times by identical or different substituents from the group consisting of alkoxy _{(C 1 -C 4) - -} R 4 is amino, hydroxyl, fluorine, chlorine and (C ₁ -C ₄₎ alkyl Or

Identical or different substituents from the group consisting of amino, hydroxyl, fluorine, chlorine, (C ₁ -C ₄ ) -alkoxy, and some of which are amino, hydroxyl, fluorine, chlorine, and (C ₁ -C ₄ ) -alkoxy (C ₃ -C ₅ ) -cycloalkyl which may be substituted up to three times by the same or different substituents from the group consisting of (C ₁ -C ₄ ) -alkyl optionally substituted up to three times by

A compound of formula (I) and their tautomers, stereoisomers, stereoisomer mixtures, and pharmacologically acceptable salts thereof, wherein X represents oxygen.

<Formula A-I>

<Formula A-II>

In the above formulas,

Y represents oxygen or sulfur.

The present invention particularly preferably represents that R ² and R ³ represent hydrogen,

A is a chemical formula Represents a radical of

R ¹ represents a radical selected from the group consisting of phenyl, pyridyl, pyrazinyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, oxazolyl, pyrazolyl, imidazolyl, pyrrolyl and indolyl ,

R ¹ may be substituted by 1 or 2 substituents selected from the group consisting of methyl, aminomethyl, hydroxyl, bromine, chlorine, fluorine, amino, dimethylamino and -NH-C (O) -R ¹¹ Wherein R ¹¹ represents (C ₁ -C ₆ ) -alkyl optionally substituted or substituted by the same or different substituents from the group consisting of amino, hydroxyl, guanidino and carboxyl,

R ⁴ represents tert-butyl optionally substituted up to three times by the same or different substituents from the group consisting of hydroxyl, fluorine and chlorine,

Some of which represent cyclopropyl or cyclobutyl substituted by methyl optionally substituted by hydroxyl, fluorine or chlorine,

X represents oxygen,

To nitrogen-containing heterocycles, which may also exist as N-oxides, and tautomers, stereoisomers, stereoisomer mixtures thereof, and pharmacologically acceptable salts thereof.

Especially preferably, in the present invention, R ² and R ³ represent hydrogen,

A is a chemical formula Represents a radical of

R ¹ represents a radical selected from the group consisting of phenyl, pyridyl, pyrazinyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, oxazolyl, pyrazolyl, imidazolyl, pyrrolyl and indolyl ,

R ¹ may be substituted by 1 or 2 substituents selected from the group consisting of methyl, aminomethyl, hydroxyl, bromine, chlorine, fluorine, amino, dimethylamino and -NH-C (O) -R ¹¹ Wherein R ¹¹ represents (C ₁ -C ₆ ) -alkyl optionally substituted or substituted by the same or different substituents from the group consisting of amino, hydroxyl, guanidino and carboxyl,

R ⁴ represents tert-butyl optionally substituted up to three times by the same or different substituents from the group consisting of hydroxyl, fluorine and chlorine,

Some of which represent cyclopropyl or cyclobutyl substituted by methyl optionally substituted by hydroxyl, fluorine or chlorine,

A compound of formula (I) wherein X represents oxygen.

In one preferred embodiment, the invention relates to compounds of formula la

Where

R ¹ , R ⁴ , A and X are as defined above,

R ² and R ³ are the same or different and are hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₆ ) -Represents alkoxy.

In another preferred embodiment, the present invention has the formula R ⁴ or A compound of formula (I) representing one of the radicals of

In another preferred embodiment, the invention relates to compounds of formula (I), in which A represents 1,2,4-oxadiazoles attached via the 3-position.

Very particularly preferred compounds of the invention are sulfonamides selected from the group of the formula:

Moreover, the present invention

[A] reacting nitro-aniline of formula A-1 with a compound of formula A-2 in the presence of a base in an inert solvent to obtain a compound of formula A-3,

[B] reducing the nitro-aromatic compound of formula A-3 to an aromatic amine of formula B-1 in an inert solvent, for example in the presence of a transition metal catalyst and hydrogen,

[C] In an inert solvent, reacting the compound of Formula B-1 with a sulfonic acid derivative of Formula C-1 in the presence of a base to obtain a compound of Formula C-2,

[D] In a polar protic solvent such as, for example, an alcohol, at an elevated temperature, preferably at a boiling point of the solvent, the nitrile of Formula C-2 is reacted with hydroxylamine in the presence of a base to give the following formula D-1 Gaining Ami Dogism,

[E] condensing agents such as, for example, benzotriazolyl-N-oxytris (dimethylamino) phosphonium hexafluorophosphate (PyBOP), or other activators known in peptide chemistry, and also acid chlorides, and bases In the presence of, for example, acylated amidoxime of formula (D-1) with a carboxylic acid of formula (E-1) in a polar aprotic solvent such as tetrahydrofuran, and the acylated amidoxime is crude Is isolated, and then cyclized at elevated temperature to obtain 1,2,4-oxadiazole, for example in a high-boiling polar solvent such as DMF.

Where

R ³ has the meaning given above.

Where

X and R ⁴ have one of the meanings given above,

Q represents a leaving group, for example halogen, preferably chlorine or bromine.

Where

X, R ³ and R ⁴ have one of the meanings given above.

Where

X, R ³ and R ⁴ have one of the meanings given above.

Where

R ² has the meaning given above,

Z represents a leaving group, for example halogen, preferably chlorine or bromine.

Where

X, R ² , R ³ and R ⁴ have one of the meanings given above.

Where

X, R ² , R ³ and R ⁴ have one of the meanings given above.

Where

R ¹ has the meaning given above.

The process according to the invention for preparing 1,2,4-oxadiazoles attached via the 3-position is exemplified by its typical method by the following scheme.

Moreover, the present invention

[F] The sulfonyl halide of the formula (F-1) is reacted with the aniline of the formula (B-1) in the presence of a base to obtain a sulfonamide of the formula (F-2), and then the group of R ^F-1 Cleaving from the compound of Formula F-2 in the presence of a hydroxyl anion to obtain a sulfonamide of Formula F-3,

[G] The amide-oxime of formula G-1 is condensed with the compound of formula F-3 to obtain a compound of formula G-2,

[H] Preparation of the compound of formula I, wherein the compound of formula G-2 is thermally cyclized to obtain 1,2,4-oxadiazole of formula H-1 attached through the 5-position It is about a method.

Where

R ² and Z have the meanings given above,

R ^F-1 represents a (C ₁ -C ₄ ) -alkyl, aralkyl or carboxylic acid protecting group.

Where

R ^F-1 , R ² , R ³ , R ⁴ and X have the meanings given above.

Where

R ¹ has the meaning given above.

Where

R ¹ , R ² , R ³ , R ⁴ and X have the meanings given above.

Where

R ¹ , R ² , R ³ , R ⁴ and X have the meanings given above.

The compounds according to the invention can be prepared according to the following schemes, for example.

Suitable solvents for all process steps are conventional inert solvents that do not change under reaction conditions. Preferred examples thereof include ethers such as diethyl ether, glycol monomethyl ether or glycol dimethyl ether, dioxane or tetrahydrofuran; Or alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, or tert-butanol; Or hydrocarbons such as benzene, toluene, xylene, cyclohexane or mineral oil fractions; Or halogenated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride; Or organic solvents such as dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mixtures of the aforementioned solvents and water, if appropriate. Especially preferred are methylene chloride, tetrahydrofuran, dioxane and dioxane / water, especially the solvents mentioned in the section "General Procedures".

Suitable bases are tri- (C ₁ -C ₆ ) -alkylamines, for example organic amines such as triethylamine, or heterocycles such as pyridine, methylpiperidine, piperidine or N-methylmorpholine. Preferred are triethylamine and pyridine.

The base is generally in each case about 0.1 to 5 moles, preferably 1 to 3 moles, based on 1 mole of the compound of Formulas A-1, B-1, C-2, D-1 and E-1 Used in molar amounts.

The reaction can be carried out at atmospheric pressure as well as at elevated or reduced pressure (for example from 0.5 to 3 bar). Generally the reaction is carried out at atmospheric pressure.

The reaction is carried out at a temperature of 0 ° C. to 150 ° C., preferably at a temperature of 0 ° C. to 30 ° C., and at atmospheric pressure. The conversion of compound G-2 to H-1 is carried out at elevated temperature, preferably at a temperature of at least 100 ° C.

The reaction is generally carried out using hydrogen, in an inert organic solvent such as dimethylformamide, alcohol, ether or acet ester, or mixtures thereof using a catalyst such as Raney-nickel, palladium, palladium on carbon, or platinum. , Or using an hydride or borane, or using an inorganic reducing agent such as, for example, tin (II) chloride, in an inert solvent, if appropriate in the presence of a catalyst. Preferred is palladium on carbon.

The reaction can be carried out at atmospheric or elevated pressure (eg 1 to 5 bar). In general, the reaction is carried out at atmospheric pressure. Hydrogenation is preferably carried out under elevated pressure, generally at 3 bar.

The reduction reaction is generally carried out at a temperature of 0 ° C to + 60 ° C, preferably at + 10 ° C to + 40 ° C.

Suitable solvents for acylation are conventional organic solvents that do not change under the reaction conditions. Preferred examples thereof include ethers such as diethyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether; Or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions; Or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene; Or ethyl acetate, or triethylamine, pyridine, dimethylformamide, acetonitrile or acetone. Mixtures of the aforementioned solvents can also be used. Preferred are dichloromethane, tetrahydrofurin and pyridine.

The acylation is carried out at atmospheric pressure in the solvents listed above, at temperatures of 0 ° C. to + 150 ° C., preferably at room temperature to + 100 ° C.

The compounds of the formulas A-1, A-2, C-1, E-1, F-1 and G-1 are known per se or can be prepared by methods known in the literature.

Further compounds of formula (I) in which A represents 1,3,4-oxadiazole are polymerized according to the "Split & Mix" method, for example using an IRORI system, as shown in Scheme 4 below. It can be prepared on a support.

Furthermore, the compounds of formula (I) are obtained by the process according to Scheme 5 below, which is carried out by mixing methods including, for example, solid phase synthesis and synthesis in solution.

In addition, according to the methods shown in Schemes 4 and 5, by cyclizing the hydrazide of the formula H-2 by the removal of water to obtain a compound of formula (I), X represents oxygen, A represents carbon at position 2 or 5 Further compounds of formula (I) according to the invention can be prepared which represent radicals of the formula (A-II) attached to adjacent phenyl rings via one of the atoms.

<Formula A-II>

Where

Y represents oxygen.

Where

X, R ¹ , R ² , R ³ and R ⁴ are as defined above,

FH represents hydrogen, an amino protecting group or a polymerization support.

According to the methods shown in Schemes 4 and 5, the hydrazide of formula H-3 is cyclized in the presence of a thio donor, preferably a Lawesson reagent, to obtain a compound of formula I wherein Y represents sulfur And then removing the —C (O) —R ^{4 ′} group and finally reacting with a compound of formula a, where X represents oxygen and A is attached to an adjacent phenyl ring via one of the carbon atoms at position 2 or 5 Compounds of formula I can be prepared which represent radicals of formula A-II.

<Formula A-II>

Where

Y represents sulfur.

Where

R ¹ , R ² and R ³ are as defined above,

FH represents hydrogen, an amino protecting group or a polymerization support,

R ^{4 ′} represents (C ₁ -C ₆ ) -alkoxy, (C ₁ -C ₆ ) -alkenoxy or aralkyloxy.

Wherein R ⁴ and Q are as defined above.

The compounds of formula (I) according to the invention exhibit a surprising range of activities that could not be predicted. They exhibit antiviral activity against representatives of the Herpes viridae group, in particular against human cytomegalovirus (HCMV). Thus, they are suitable for the treatment and prevention of disorders caused by herpes sera, in particular disorders caused by human cytomegalovirus.

Depending on their specific properties, the compounds of formula (I) can be used for the manufacture of a medicament suitable for the prevention or treatment of diseases, in particular viral disorders.

According to their properties, the compounds according to the invention are useful active compounds for the treatment and prevention of infections with human cytomegalovirus and disorders caused by such infections. Examples of indication areas that may be mentioned are:

1) Treatment and prevention of HCMV infection (retinitis, interstitial pneumonia, gastrointestinal infection) in AIDS patients.

2) Treatment and prevention of cytomegalovirus infection and life-threatening HCMV retinitis or encephalitis of the bone marrow, or organ transplant patients often suffering from gastrointestinal or systemic HCMV infection.

3) Treatment and prevention of HCMV infection in newborns and infants.

4) Treatment of acute HCMV infection in pregnant women.

5) Treatment of HCMV infection in immunosuppressed patients suffering from cancer and being treated for cancer.

The novel active compounds can be used on their own and also in combination with other antiviral active compounds such as, for example, gancyclovir or acyclovir, if necessary.

Description of Biological Tests:

In vitro Actions:

Anti-HCMV (anti-human cytomegalovirus) and anti-MCMV (anti-mouse cytomegalovirus) cytopathicity tests:

The test compound was used as a 50 mmol (mM) solution in dimethyl sulfoxide (DMSO). Ganciclovir, foscarnet and cidofovir were used as reference compounds. Add 2 μl of 50, 5, 0.5, and 0.05 mM DMSO stocks to 98 μ of each cell culture medium in rows 2 to H, respectively, and then repeat 1: 2 with 50 μl of medium in each case as two replicate measurements. Dilutions were made up to column 11 of the 96-well plate. The wells of rows 1 and 12 contained 50 μl of medium, respectively. Next, 150 μl suspension of 1 × 10 ⁴ cells (human lung fibroblasts [HELF]) (column 1 = cell control), or a mixture of HCMV infected and uninfected HELF cells (MOI = 0.001 to 0.002, ie uninfected cells) One to two infected cells per 1000) (columns 2 to 12) were pipetted into each well. Row 12 (no drug) was used as a virus control. Final test concentrations were 250-0.0005 μM. Plates were incubated for 6 days at 37 ° C./5% CO ₂ , ie until all cells in the virus control were infected (100% cytopathic effect [CPE]). The wells were then fixed and stained by addition of a mixture of formalin and Giemsa dye (30 min), washed twice with distilled water and dried at 50 ° C. in a drying chamber. Plates were then visually assessed using an overhead microscope (Technomara's plaque multiplier).

The following data were measured from the test plate:

CC ₅₀ (HELF) = drug concentration (μM), in which no visible cell proliferation inhibitory effect on cells is significant compared to untreated cell controls.

EC ₅₀ (HCMV) = drug concentration (μM) that inhibits CPE (cytopathogenic effect) by 50% compared to untreated virus control.

SI (selectivity) = CC ₅₀ (HELF) / EC ₅₀ (HCMV).

In comparison to the procedure described above for HCMV, anti-MCMV testing was performed with the following modifications: Cell-free virus suspension was mixed with concentrated cell suspension (3T3 mouse cells) and allowed to adsorb the virus for 15 minutes. After incubation, the suspension was diluted with medium to 1.3 × 10 ⁵ cells / ml (final multiple infectivity (MOI) = 0.05 to 0.1) and in each case 150 μl was dispersed in the wells. Infection time was 5 days.

Representative activity data for the compounds according to the invention are listed in Table 1.

In vivo Actions:

MCAV lethality test :

animal:

Two to three week old female immunocompetent mice (12-14 g) of Balb / C AnN or CD1 line were purchased from commercial propagators (Bomholtgaard, Iffa, Credo). Animals were not kept under sterile conditions.

Virus Cultures:

Smith-based mouse cytomegalovirus (MCMV) was repeatedly passed in vivo in female CD1 mice. After 21 days of intraperitoneal infection (2 × 10 ⁴ plaque forming units / 0.2 ml / mouse), the salivary glands were removed and dissolved 3 times in minimal essential medium (MEM) + 10% fetal calf serum (FCS) and ultraturax ( Homogenized using Ultraturrax). 10% DMSO v / v was added, 1 ml aliquots were prepared, and the virus suspension was stored at -140 ° C. Salivary gland isolates were serially diluted in 10 steps, stained with Gimsa stain, titers were measured in cell culture for NIH 3T3 cells, and lethal doses were measured in 2 to 3 week old Balb / C mice in vivo.

Viral Infection, Treatment and Evaluation of Test Animals:

Two to three week old female immunocompetent Balb / C mice (12-14 g) were infected intraperitoneally with 3 × 10 ⁵ PFU / 0.2 ml / mouse. Six hours after infection, mice were orally treated with the drug twice daily (8.00 and 16.00 hours) for five days. Dosage was 3, 10, 30 or 90 mg / kg body weight and volume administered was 10 ml / kg body weight. The drug was formulated in the form of a cellulose suspension at a concentration of 0.5% in 2% DMSO. Placebo treated control animals were killed 4 to 8 days after infection. Evaluation was performed by measuring survival of drug treated animals relative to placebo treated control animals after treatment with the drug.

HCMV Xenograft Gelfoam (R) Models:

animal:

Fox Chase SCID or Fox Chase SCID-NOD, 3-4 week old female immunodeficiency mice (16-18 g), was purchased from a commercial propagator (Bolmholtt, Jackson). Animals were kept in sterile conditions under sterile conditions (including collars and food).

Virus Cultures:

DavisSmith family human cytomegalovirus (HCMV) was cultured in vitro in human fetal foreskin fibroblasts (NHDF cells). Virus infected cells were collected 5-7 days after infection with NHDF cells (multiplicity of infection (MOI) = 0.01) and in the presence of minimal essential medium (MEM) + 10% fetal calf serum (FCS) in 10% DMSO- Store at 140 ° C. Virus infected cells were serially diluted in 10 steps, biostained with Neutral Red, and titers were measured on 24-well plates of congenital NHDF cells.

Preparation, Transplantation, Treatment and Evaluation of Sponges:

First, collagen sponges (dimensions 1 × 1 × 1 cm, Gelfoam (R); Peisel & Lorey, Order No. 407534; KT Chong et al., Abstracts of 39 ^th Interscience Conference on Antimicrobial Agents and Chemotherapy , 1999, p. 439) were wetted with phosphate buffered saline (PBS) and the air bubbles contained were removed by degassing and the sponges were then stored in MEM + 10% FCS. Three hours after infection, 1 × 10 ⁶ virus infected NHDF cells (HCMV-Davis M.0.I = 0.01) were removed and added dropwise to a wet sponge in 20 μl of MEM + 10% FCS. After 12-13 hours, the infected sponges were incubated with 5 ng / μl of basic fibroblast growth factor (bFGF) in 25 μl of PBS / 0.1% BSA / 1 mM DTT. For transplantation, immunodeficiency mice were anesthetized with Avertin, the hair on the back was removed using an electric razor, the epidermis opened 1-2 cm, alleviated, and a wet sponge was implanted under the back skin. . Surgical wounds were closed using tissue glue. 24 hours after transplantation, mice were orally treated with the drug twice daily (8.00 and 16.00 hours) over 8 days. Dosage was 10 or 30 mg / kg body weight and dose volume was 10 ml / kg body weight. The drug was formulated in the form of a cellulose suspension at a concentration of 0.5% in 2% DMSO. Ten days after implantation and 16 hours after the last dose of drug, animals were painlessly killed and the sponges removed. Virus infected cells were released from the sponge by digestion with collagenase (330 U / 1.5 ml) and stored at −140 ° C. in the presence of MEM + 10% fetal calf serum in 10% DMSO. Virus infected cells were serially diluted in 10 steps, biostained with neutral red, and titers were measured on 24-well plates of congenital NHDF cells. After treatment with the drug, the number of infectious virus particles was measured as compared to that in the placebo treated control.

The test described below was used to examine the potential side effects of the drugs according to the invention on the induction of cytochrome P450 enzymes.

Assessment of Induction of Cytochrome P450 Enzymes in Human Hepatocyte Cultures:

At a cell density of 2.5 × 10 ⁵ cells, primary human hepatocytes were incubated between two layers of collagen in 24-well microtiter plates for 8 days at 37 ° C. and 5% CO ₂ . The cell culture medium was changed daily.

48 hours after incubation, hepatocytes were treated with different concentrations of test drug for 5 days to compare with inducer rifampicin (50 μM) and phenobarbital (2 mM), and each test was performed twice. The final concentration of test drug was 0.1-10 μg / ml.

Using cell cultures, the inducible effects of test drugs on cytochrome (CYP) P450 enzymes 1A2, 2B6, 2C19 and 3A4 were evaluated using substrates 7-ethoxyresorupine (CYP1A2), [ ¹⁴ C] S-mefenitoin (CYP2B6 and 2C19) and [ ¹⁴ C] testosterone (CYP3A4) were added at 8 days. The induction potential of the test drug was measured using measured enzyme activity CYP1A2, 2B6, 2C19 and 3A4 of treated cells compared to untreated cells.

The novel active compounds can be converted into conventional formulations such as tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, in known manner using inert, non-toxic pharmaceutically suitable excipients and solvents. In this case, the therapeutically active compound should be present in each case at a concentration of approximately 0.5 to 90% by weight of the total mixture, ie in an amount sufficient to achieve the indicated dosage range.

The formulations may be prepared, for example, by thickening the active compound with a solvent and / or excipient, if appropriate, using an emulsifying and / or dispersing agent, where appropriate for example water as a diluent and organic as an auxiliary solvent. It is also possible to use a solvent.

Administration is carried out in a customary manner, preferably orally, parenterally or topically, in particular sublingually or intravenously.

For parenteral administration, suitable liquid carrier materials may be used as solutions of the active compounds.

In general, it is advantageous to administer about 0.001 to 10 mg, preferably about 0.01 to 5 mg, per kg of body weight to achieve an effective result for intravenous administration, and about 0.01 to about 1 kg of body weight for oral administration. It has been found advantageous to administer 25 mg, preferably 0.1 to 10 mg.

Notwithstanding the above, where appropriate, it may be necessary to deviate from the stated amounts depending on body weight, route of administration, individual response to the medicament, the mode of formulation of the medicament, and the time or interval of administration. Thus, in some cases, an amount less than the minimum amount mentioned above may be suitable, in other cases it should exceed the above mentioned upper limit. If a relatively large dose is administered, it may be advisable to divide it into several individual doses throughout the day.

Abbreviation:

Aloc-Cl allyl chloroformate

DCM dichloromethane

DICN, N'-diisopropylcarbodiimide

DIEA diisopropylethylamine

DMF dimethylformamide

eq.equivalent

sat.Saturated

HOAc acetic acid

HOBthydroxybenzotriazole

HONSuN-hydroxysuccinimide

MTP Microtiter Edition

PS-polystyrene resin

PyBOPbenzotriazolyl-N-oxy-tris (dimethylamino) phosphonium

Hexafluorophosphate

Rt stay time

RT room temperature

TBABH tetrabutylammonium borohydride

TFAtrifluoroacetic acid

THF tetrahydrofuran

TMOFtrimethyl orthoformate

General procedure for the reaction of a compound of formula [A-1] with a compound of formula [A-2] (GP 1):

1.0 equivalent of Compound [A-1] is dissolved in dioxane (0.2 M solution), 2.5 equivalents of pyridine are added, the solution is cooled to 5 ° C. and 1.1 equivalents of Compound [A-2] wherein Q is preferably chlorine. Was added dropwise as a 1.0 M solution. The mixture was further stirred at 5 ° C. for 30 minutes, then cooling was terminated and the mixture was stirred at room temperature for 16 hours. The mixture was poured into H ₂ 0 and the precipitated product was filtered off by suction, washed with H ₂ 0 and dried under high vacuum.

General procedure for the hydrogenation of compounds of formula [A-3] (GP 2):

0.14 mol of compound [A-3] was dissolved in 500 ml of DMF or ethanol under argon and a suspension of 6.0 g of 10% Pd-C was added. The mixture was then hydrogenated under 3 bar hydrogen pressure. After the reaction was complete (monitored by TLC or HPLC), the Pd-C catalyst was filtered off and the solvent was removed under reduced pressure. The crude product of formula [B-1] was further reacted without further purification.

General procedure for sulfonylation of a compound of formula [B-1] (GP 3):

Under argon 1.0 equivalent of compound [B-1] was dissolved in dioxane (0.2 M solution) and 2.5 equivalents of pyridine was added. The mixture is stirred at room temperature for 30 minutes, then 1.1 equivalents of compound of formula [C-1], wherein Z dissolved in dioxane (1.0 M solution) is preferably chlorine, are added and the mixture is stirred at room temperature for 16 hours. It was. The solution was then poured into H ₂ 0 and extracted three times with DCM. The organic phase was washed with saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ , filtered and the solvent removed under reduced pressure. The residue [C-2] was dried under high vacuum and then further reacted without further purification.

General procedure for the synthesis of compounds of formula [D-1] from compounds of formula [C-2] (GP 4):

The compound of formula [C-2] (1.0 equiv) was dissolved in ethanol (0.1 M solution), hydroxylamine hydrochloride (1.5 equiv) and triethylamine (1.6 equiv) were added to the solution, and the solution was then added. Heated under reflux for 4 hours and stirred for further 16 hours at room temperature. The solvent is removed under reduced pressure, the residue is taken up in ethyl acetate and extracted three times with water, the organic phase is dried over MgSO ₄ , filtered and the solvent is removed under reduced pressure. The residue [D-1] was dried under high vacuum.

General procedure for the reaction of a compound of Formula [D-1] with a compound [E-1] (GP 5):

First, 1.0 equivalent of the compound of the formula [D-1], 1.05 equivalent of the carboxylic acid [E-1] and 1.1 equivalent of PyBOP were added to THF (0.1 M solution), and 1.1 equivalent of N, N-diisopropylethylamine was added. To the suspension was added and the resulting solution was stirred at rt for 16 h. The mixture was then diluted with 10 ml of DCM and extracted once with 1 N HCl, NaHCO ₃ saturated solution and NaCl saturated solution each. The organic phase was dried over Na ₂ S0 ₄ , filtered and the solvent removed under reduced pressure. The crude product was further reacted immediately.

General procedure for the synthesis of 1,2,4-oxadiazoles from the crude product obtained in GP 5 (GP 6):

1.0 mmol of crude product obtained in GP 5 was dissolved in 10 ml of DMF and the solution was heated at 110 ° C. After the reaction was complete (monitored by TLC or HPLC, about 2-16 hours), the mixture was distilled off with DCM and extracted twice with H ₂ O. The combined aqueous phases were extracted twice with DCM, the organic phases were combined, dried over Na ₂ SO ₄ , filtered and the solvent removed under reduced pressure. The resulting compound of formula (I) was purified by silica gel chromatography (cyclohexane / ethyl acetate) or by preparative HPLC.

General Procedure for Synthesis with Polymeric Support:

General procedure for the synthesis of 1,3,4-oxadiazoles according to Scheme 4:

The reaction according to Scheme 4 is carried out using a "dividing and using four carbonyl chlorides, 24 carboxylic acids, and two meta- or para-isomers of phenylenediamine or sulfonyl chloride, known in the solid phase chemistry. Mixing on the polymerization support using an IRORI system according to the "mixing" method. At this time, the first two steps were carried out in the flask and the remaining steps were carried out in IRORI MiniKans (100 mg resin / can).

Synthesis of Starting Resin (I) and (II) on Polymeric Support According to Scheme 4:

Reductive amination of formyl resin (0.78 mmol / g from Nova Biochem):

In the flask, formyl resin (1.0 equiv) was suspended in TMOF / DMF (100 ml per 12.5 g of resin) and diamine (6.0 equiv) was added. The suspension was shaken at 40 ° C. for 16 hours and a solution of TBABH (4.0 equiv) and HOAc (16.0 equiv) in freshly prepared DMF was added. After 8 hours at room temperature, the solvent was filtered off and the reducing solution was added once more to the resin. After 16 hours more at room temperature, the solvent was filtered off by suction and the resin (I) was washed twice in each case with 200 ml of 50% concentration of HOAc, DMF, THF and DCM each and dried under high vacuum.

Sulfonylation of polymer bound phenylenediamine:

Resin (I) (1.0 equiv) was dissolved in THF and sulfonyl chloride (1.5 equiv) was added. The suspension was shaken for 16 hours at room temperature and the solvent was filtered off by suction. Resin (II) was then washed twice with 100 ml each of 50% concentrations of HOAc, DMF, THF and DCM in each case and dried under high vacuum.

Preparation of resins for IRORI systems:

Type II resin is distributed in 96 minicans (1 ml suspension / can) in each case as a suspension (DMF / DCM 2: 1 v / v 30 ml per 3.0 g of resin), washed three times with DCM in each case, and Was dried under reduced pressure.

Reaction Sequence (IRORI):

Acylation with Acid Chloride:

The can was sorted, dissolved in THF, 5.0 equivalents of DIEA and 5.0 equivalents of acid chloride were added, the cans simply evacuated and shaken for 3 hours at room temperature. The reaction solution was then separated off, the candles combined and washed twice with 50% concentration of HOAc, DMF, THF, DCM.

Hydrazide Synthesis:

The combined cans were taken up in a mixture of 2 N NaOH / MeOH / THF (5: 7: 15 v / v), simply evacuated and stirred at 50 ° C. for 5 hours. The cans were then washed twice with 50% concentration of HOAc, DMF, THF, DCM in each case and dried under reduced pressure. The cans were then dissolved in THF, 5 equivalents of DIC and 10 equivalents of HONSu were added and the cans shaken for 3 hours at room temperature. The can was filtered off, washed twice with THF, then dissolved in THF once more and 3 equivalents of hydrazine hydrate was added. After 3 hours more at room temperature, the can was filtered off by suction and washed twice with 50% concentration of HOAc, DMF, THF and DCM in each case.

Acylation with Carboxylic Acid / DIC / HOBt:

3 equivalents of DIC, 6 equivalents of DIEA and 6 equivalents of HOBt were added to carboxylic acid (3 equivalents) in THF. After 60 minutes of activation at room temperature, the solution was added to previously sorted cans and shaken for 16 hours at room temperature. The candles were then combined and washed twice with 50% concentrations of HOAc, DMF, THF, DCM in each case and dried under reduced pressure.

Cyclization of 1,3,4-oxadiazole:

The combined cans were taken up in DMF, DCI (10 equiv) was added, the cans simply evacuated and stirred at 110 ° C. for 48 hours. The cans were then washed twice with 50% concentration of HOAc, DMF, THF, DCM in each case and dried under reduced pressure.

Separation from Polymeric Support:

After sorting into IRORI separation blocks, the cans are cut, the resin is distributed into FlexChem blocks, and the product in each deep-well MTP using 1.0 ml of TFA / DCM (1: 1 v / v). Separation at room temperature for 45 minutes. The resin was washed with DCM and the solvent was evaporated.

General procedure for the synthesis of 1,3,4-thiadiazole according to Scheme 5:

The synthesis was carried out using a combination of solid phase synthesis and synthesis in solution.

Synthesis of Monosulfonylated Phenylenediamine:

Phenylenediamine (1.0 equiv) was dissolved in THF (0.4 M solution), 1.0 equiv sulfonyl chloride was added and the mixture was stirred at rt for 16 h. The mixture was then diluted with DCM, extracted twice with water, the aqueous phases were reextracted once with DCM, the organic phases combined, dried over Na ₂ SO ₄ and concentrated using a rotary evaporator. The crude product was further reacted without further purification.

Attachment to the polymeric support and synthesis of thiadiazoles:

Reductive amination of formyl resin (0.78 mmol / g from Nova Biochem):

In the flask, formyl resin (1.0 equiv) was suspended in TMOF / DMF (100 ml per 12.5 g of resin) and sulfonylated phenylenediamine (6.0 equiv) was added. The suspension was shaken at 40 ° C. for 16 hours and a solution of TBABH (4.0 equiv) and HOAc (16.0 equiv) in freshly prepared DMF was added. After 8 hours at room temperature, the solvent was filtered off and the reducing solution was added once more to the resin. After 16 hours more at room temperature, the solvent was filtered off by suction and the resin was washed twice in each case with 200 ml of 50% concentration of HOAc, DMF, THF and DCM each and dried under high vacuum.

Acylation of Resin :

The resin was suspended in THF in a syringe with PE frit (from MultiSyntech) and 3.0 equivalents of DIEA and 3.0 equivalents of carbonyl chloride were added. The suspension was shaken for 3 hours at room temperature, filtered off by suction and the resin washed twice with 50% concentration of HOAc, DMF, THF and DCM in each case.

Hydrazide Synthesis:

In a syringe with PE frit (from MultiSynthec) the resin was dissolved in a mixture of 2N NaOH / MeOH / THF 5: 7: 15 v / v) and stirred at 50 ° C. for 5 hours, followed by 50% concentration of HOAc, Wash twice with DMF, THF and DCM in each case. The resin was then dissolved in THF, 5 equivalents of DIC and 10 equivalents of HONSu were added and the mixture was stirred at room temperature for 3 hours. The resin was filtered off, washed twice with THF, then dissolved in THF once more and 3 equivalents of hydrazine hydrate was added. After 3 hours more at room temperature, the resin was filtered off by suction and washed twice with 50% concentration of HOAc, DMF, THF and DCM in each case.

Acylation of Hydrazide with Carboxylic Acid / DIC / HOBt:

3 equivalents of DIC, 6 equivalents of DIEA and 6 equivalents of HOBt were added to carboxylic acid (3 equivalents) in THF. After 6 minutes of activation at room temperature, the solution was added to the resin (1 ml per 100 mg of resin) and the mixture was shaken for 16 hours at room temperature. The resin was then filtered off by suction and washed twice with 50% concentrations of HOAc, DMF, THF and DCM in each case. LC-MS of the separated sample showed that the double bond of the allyloxycarbonyl group was hydrogenated by this reaction.

Thiadiazole Synthesis:

First, the resin was charged in dioxane (1 ml per 100 mg of resin), 5.0 equivalents of Laweson reagent was added, and the mixture was stirred at 90 ° C. for 3 hours. The resin was then filtered off by suction and washed twice with DMF, 50% concentration of HOAc, DMF, THF and DCM in each case.

Separation from the polymeric support, removal of carbonate protecting groups, and synthesis of amides:

The resin was treated with TFA / DCM (1: 1 v / v, 1 ml per 100 mg of resin), filtered off after 45 minutes and washed with DCM (equal volume). TFA and DCM were removed under reduced pressure, and the residue was taken up in ethanol / 2.5 N NaOH (1: 1 v / v, 0.5 M solution), stirred at 75 ° C. for 16 hours, diluted with DCM and extracted twice with water The aqueous phase was adjusted to pH 7 with 1 N HCl, extracted three times with DCM, all organic phases combined, washed twice with water, dried over Na ₂ SO ₄ and concentrated using a rotary evaporator. . The residue was taken up in THF, 1.05 equivalents of DIEA and 1.05 equivalents of acid chloride were added and the mixture was shaken at room temperature for 16 hours. The volatile components were then removed under reduced pressure and the product was separated by preparative HPLC.

Starting material:

Example I

1-Methyl-N- (3-nitrophenyl) -cyclopropanamide

The compound was prepared according to GP 1 from 80.0 g of 3-nitroaniline.

Yield: 107 g (81% of theory)

Example II

3-Fluoro-2,2-dimethyl-N- (3-aminophenyl) -propanamide

The compound was prepared according to GP 1 and GP 2 from 3-nitroaniline without purification of the intermediate.

Yield: 85% of theory (over 2 steps)

Example III

1-Methyl-N- (3-aminophenyl) -cyclopropanamide

The compound was prepared according to GP 2 from 107 g of compound from Example 1.

Yield: 80 g (87% of theory)

Example IV

3-fluoro-2,2-dimethyl-N- (3-{[(4-methylphenyl) sulfonyl] amino} phenyl) -propanamide

The compound was prepared according to GP 3 from 18.68 g of compound from Example II.

Yield: 19.96 g (78% of theory)

Example V

N- {3-[({4- [amino (hydroxyimino) methyl] phenyl} sulfonyl) amino] phenyl} -3-fluoro-2,2-dimethylpropanamide

The compound was prepared according to GP 4 from 10.0 g of compound from Example IV.

Yield: 10.5 g (97% of theory)

Example VI

N- (3-{[(4-cyanophenyl) sulfonyl] amino} phenyl) -1-methylcyclopropanecarboxamide

The compound was prepared according to GP 3 from 90 g of compound from Example III.

Yield: 150 g (crude) of crude product

HPLC: Rt = 2.87 min (HPLC Method / Instrument 9)

Example VII

N- {3-[({4- [amino (hydroxyimino) methyl] phenyl} sulfonyl) amino] phenyl} -1-methyl-cyclopropanecarboxamide

The compound was prepared according to GP 3 from 168 g of compound from Example VI (as crude product).

Yield: 118 g (57% of theory)

HPLC: Rt = 2.7 min (HPLC Method / Instrument 5)

MW 388.45; m / z found: 389

Example VIII

2-aminoacetyl-picolin

25.0 g (0.23 mol) of 6-aminopicoline were dissolved in 250 mL of acetic acid and 47.2 g (0.46 mol) of acetic anhydride were added with stirring and ice-cooling. First, the mixture was stirred for an additional 30 minutes with ice-cooling, after which the ice bath was removed and stirring was continued for 16 hours at room temperature. The clear solution was then concentrated under reduced pressure. The oily residue was crystallized in an ice bath and the crystals were dried under reduced pressure.

Example IX

2-Aminoacetyl-picolinic acid

31.0 g (0.21 mole) of 2-aminoacetylpicoline was dissolved in 310 mL of water and heated at 75 ° C., and 60.0 g (0.38 mole) of potassium permanganate in each case were added over a 3 hour cycle in which the purple disappeared again. . The mixture was stirred at 75 ° C. for an additional 5 hours, after which the reaction mixture was filtered. The aqueous phase was extracted four times with dichloromethane and then acidified to pH 4 with 1N hydrochloric acid. The precipitate was filtered off, washed with 0.1N hydrochloric acid and dried under reduced pressure.

Manufacturing Example:

In the preparation examples 1,2,4-oxadiazoles attached at the 3-position shown below were prepared from compounds of example V type according to GP 5 and GP 6.

Example 1

3-fluoro-2,2-dimethyl-N- {3-[({4- [5- (2-pyridinyl) -1,2,4-oxadiazol-3-yl] phenyl} -sulfonyl ) Amino] phenyl} propanamide

First, 5.93 g (45.92 mmol) of N, N-diisopropylethylamine, 5.65 g (45.92 mmol) of picolinic acid and 23.89 g (45.92 mmol) of PyBOP are charged to 70 mL of THF, and the mixture is stirred at room temperature for 30 minutes. 17.05 g (41.74 mmol) of amidoxime from Example V were then added and the solution was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 50 mL of DMF and the solution was stirred at 110 ° C. for 4 hours.

The mixture was then diluted with 300 mL of DMC and the organic phase was extracted three times with 200 mL of 2N H ₂ SO ₄ and once with saturated NaHCO ₃ solution. The organic phase was dried over Na ₂ S0 ₄ , filtered and the solvent removed under reduced pressure (crude product 43.5 g). The product was purified by silica gel chromatography using cyclohexane / ethyl acetate (6: 4 v / v), after purification, stirred with cyclohexane, the solid was filtered off with suction and dried under reduced pressure.

Example 2

N- (3-{[(4- {5- [3- (dimethylamino) phenyl] -1,2,4-oxadiazol-3-yl} phenyl) sulfonyl] -amino} phenyl) -1- Methylcyclopropanecarboxamide

Example 3

1-methyl-N- {3-[({4- [5- (2-pyridinyl) -1,2,4-oxadiazol-3-yl] phenyl} sulfonyl) -amino] phenyl} cyclopropane Carboxamide

First 20.0 g (51.59 mmol) of suitable amidoxime, 6.66 g (54.06 mmol) of picolinic acid and 29.47 g (56.66 mmol) of PyBOP were charged to 60 mL of THF and 7.32 g of N, N-diisopropylethylamine at room temperature. 56.66 mmol) was added to the suspension and the resulting clear solution was stirred at rt for 16 h. The mixture was then diluted with 250 mL of DCM and extracted once with 250 mL of 1N HCl, saturated NaHCO ₃ solution and saturated NaCl solution. The organic phase was dried over Na ₂ S0 ₄ , filtered and the solvent removed under reduced pressure. The crude product (25.41 g) was dissolved in 250 mL of DMF and the solution was stirred at 110 ° C. for 2.5 h. The mixture was then diluted with 250 mL of DCM and the organic phase was extracted twice with 250 mL of H ₂ O. The combined aqueous phases were extracted twice with 250 mL of DCM, the organic phases were combined, dried over Na ₂ SO ₄ , filtered and the solvent removed under reduced pressure (crude product 43.5 g). The product was purified by chromatography on silica gel 60 using cyclohexane / ethyl acetate 1: 1 v / v.

Example 4

N- {3-[({4- [5- (2-amino-1,3-thiazol-4-yl) -1,2,4-oxadiazol-3-yl] phenyl} sulfonyl)- Amino] phenyl} -1-methylcyclopropanecarboxamide

Example 5

1-methyl-N- {3-[({4- [5- (6-methyl-2-pyridinyl) -1,2,4-oxadiazol-3-yl] phenyl} -sulfonyl) amino] Phenyl} cyclopropanecarboxamide

Example 6

1-methyl-N- {3-[({4- [5- (3-methyl-1H-pyrazol-5-yl) -1,2,4-oxadiazol-3-yl] phenyl} -sul Phenyl) amino] phenyl} cyclopropanecarboxamide

Example 7

1-methyl-N- {3-[({4- [5- (1,3-thiazol-4-yl) -1,2,4-oxadiazol-3-yl] phenyl} sulfonyl)- Amino] phenyl} cyclopropanecarboxamide

Example 8

N- {3-[({4- [5- (1,5-dimethyl-1H-pyrazol-3-yl) -1,2,4-oxadiazol-3-yl] phenyl} -sulfonyl) Amino] phenyl} -1-methylcyclopropanecarboxamide

Example 9

1-methyl-N- {3-[({4- [5- (5-methyl-1H-pyrazol-3-yl) -1,2,4-oxadiazol-3-yl] phenyl} -sul Phenyl) amino] phenyl} cyclopropanecarboxamide

Example 10

N- {3-[({4- [5- (1-isoquinolinyl) -1,2,4-oxadiazol-3-yl] phenyl} sulfonyl) -amino] phenyl} -1-methyl Cyclopropanecarboxamide

Example 11

1-methyl-N- {3-[({4- [5- (2-methyl-1,3-thiazol-4-yl) -1,2,4-oxadiazol-3-yl] phenyl} -Sulfonyl) amino] phenyl} cyclopropanecarboxamide

Example 12

N- (3-{[(4- {5- [2- (aminomethyl) -1,3-thiazol-4-yl] -1,2,4-oxadiazol-3-yl} phenyl)- Sulfonyl] amino} phenyl) -1-methylcyclopropanecarboxamide

Example 13

3-fluoro-2,2-dimethyl-N- [4-({[3- (5-phenyl-1,2,4-oxadiazol-3-yl) phenyl] sulfonyl} -amino) phenyl] Propanamide

Further 1,2,4-oxadiazole derivatives attached via position 3 and prepared according to the process according to the invention are listed in Table 2:

TABLE 2

Additional 1,3,4-oxadiazole derivatives attached via position 5 and prepared according to the process according to the invention are listed in Table 3 below:

TABLE 3

Example 131

1-methyl-N- {4-[({3- [5- (2-pyridinyl) -1,3,4-thiadiazol-2-yl] phenyl} sulfonyl) amino] -phenyl} cyclopropane Carboxamide

Example 132

N- (3-{[(4- {5- [6- (acetylamino) -2-pyridinyl] -1,2,4-oxadiazol-3-yl} phenyl) sulfonyl] -amino} phenyl ) -1-methylcyclopropanecarboxamide

First 8.1 g (20.85 mmol) of amidoxime from Example VII were charged into 50 mL of THF, followed by 4.13 g (22.94 mmol) of 2-aminoacetylpicolinic acid (Example IX) and 16.28 g (31.28 mmol) of PyBOP. After that, 2.96 g (22.94 mmol) of N, N-diisopropylethylamine were added dropwise. The mixture was stirred at rt for 16 h, after which the reaction mixture was concentrated under reduced pressure, dissolved in dichloromethane and washed successively once each with 1N hydrochloric acid and saturated sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue (8.26 g) was dissolved in 75 mL of N, N-dimethylformamide and stirred at 115 ° C. for 4 hours. After cooling, 200 mL of ethyl acetate was added and the mixture was washed once with 1N hydrochloric acid, once with saturated sodium chloride solution, twice with saturated sodium bicarbonate solution and once with saturated sodium chloride solution. During washing, crystals formed in the organic phase. Thus, the organic phase was left for 30 minutes and the precipitated crystals were filtered off with suction and washed with methanol [1 fragment, yield: 5.04 g (23% of theory)]. The mother liquor was dried over sodium sulfate, filtered and concentrated using a rotary evaporator. Stirring with dichloromethane gave two additional fragments of the crystalline product [fragment 2, yield: 3.5 g (16% of theory); Fragment 3, yield: 1.1 g (5% of theory). The remaining mother liquor further contained a product which could be purified by chromatography [yield: 1.01 g (5% of theory)].

Example 133

N- (3-{[(4- {5- [6- (acetylamino) -2-pyridinyl] -1,2,4-oxadiazol-3-yl} phenyl) sulfonyl] -amino} phenyl ) -3-fluoro-2,2-dimethylpropanamide

First, 7.80 g (19.1 mmol) of amidoxime from Example V was charged to 100 mL of THF, followed by 3.78 g (21.0 mmol) of 2-aminoacetylpicolinic acid and 14.91 g (28.6 mmol) of PyBOP, and finally 2.71 g (21.0 mmol) of N, N-diisopropylethylamine were added dropwise. The mixture was stirred at 40 ° C. for 16 hours, after which the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate and washed successively twice with 1N hydrochloric acid and saturated sodium chloride solution, respectively. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by filtration through silica gel 60 using mobile phase ethyl acetate. The resulting product (9.9 g) was dissolved in 90 mL of N, N-dimethylformamide and stirred at 115 ° C. for 4 hours. After cooling, the solvent was removed under reduced pressure, 200 mL of ethyl acetate was added and the mixture was washed once with 1N hydrochloric acid, once with saturated sodium chloride solution, twice with saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase was dried over sodium sulphate and then the solvent was removed. During concentration, a precipitate formed, after which the suspension was diluted with dichloromethane and the precipitate was separated off and washed with dichloromethane.

Example 134

N- {3-[({4- [5- (6-amino-2-pyridinyl) -1,2,4-oxadiazol-3-yl] phenyl} sulfonyl) amino] -phenyl} -1 -Methylcyclopropanecarboxamide

15 g (28.16 mmol) of the compound from Example 132 were suspended in 370 mL of ethanol and 279 mL (281.7 mmol) of 1N aqueous sodium hydroxide solution were added. The mixture was stirred at 45 ° C. for 5 hours (suspension slightly dissolved), then the mixture was adjusted to pH 5 with 1N hydrochloric acid in an ice bath, the precipitated crystals were filtered off, washed with water and ethanol, and high vacuum Under drying at 80 ° C. for 16 h.

Example 135

N- {3-[({4- [5- (6-amino-2-pyridinyl) -1,2,4-oxadiazol-3-yl] phenyl} sulfonyl) amino] -phenyl} -3 -Fluoro-2,2-dimethylpropanamide

19.3 g (34.9 mmol) of the compound from Example 133 were dissolved in 290 mL of a mixture of water / conc. Hydrochloric acid (1: 1 v / v) and the suspension was stirred at 100 ° C. for 4 hours. The suspension is then filtered, the filter cake is stirred between saturated sodium bicarbonate solution and ethyl acetate, the organic phase is separated off and concentrated using a rotary evaporator and the crude product is chromatographed [silica gel 60, mobile phase toluene / acetone ( 8: 2 v / v)]. To remove adherent residual solvents, the clear fragments were combined (6.8 g), dissolved in 130 mL of 1N aqueous sodium hydroxide solution (turbid solution) at 0 ° C. and the solution acidified to pH 5 with 1N hydrochloric acid. The precipitate was filtered off, washed with water and dried under high vacuum.

Example 136

Ethyl ({6- [3- (4-{[(3-{[(1-methylcyclopropyl) carbonyl] amino} phenyl) amino] -sulfonyl} -phenyl) -1,2,4-oxadia Sol-5-yl] -2-pyridinyl} amino) (oxo) -acetate

Under argon, 400 mg (0.82 mmol) of the compound from Example 134 were dissolved in 12 mL of dichloromethane and 70 mg (0.09 mmol) of pyridine and 150 mg (1.1 mmol) of monoethyl oxalyl chloride were added with stirring. The solution was stirred for an additional 30 minutes at room temperature. The reaction mixture was then added to 25 mL of pH 7 buffer, the aqueous phase was extracted three times with dichloromethane, and the combined organic phases were washed twice each with saturated sodium chloride solution, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was separated off, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel 60 using mobile phase toluene / ethyl acetate (1: 1 v / v).

Example 137

({6- [3- (4-{[(3-{[(1-methylcyclopropyl) carbonyl] amino} phenyl) amino] sulfonyl} -phenyl) -1,2,4-oxadiazole- 5-yl] -2-pyridinyl} amino) (oxo) -acetic acid

152 mg (0.26 mmol) of the compound from Example 136 were dissolved in 7.5 mL of dioxane and 0.75 mL (0.75 mmol) of 1N aqueous sodium hydroxide solution were added. The mixture was stirred at rt for 16 h and then acidified carefully to pH 7 with 1N hydrochloric acid and the solvent was removed under reduced pressure. The crude product was purified by HPLC (CromSil C18, 250 x 30 mm, flow rate 50 mL / min, run time 35 min, detection at 254 nm, gradient 10% acetonitrile @ 3 min-> 90% acetonitrile @ 31 Min-> 90% acetonitrile @ 34 min-> 10% acetonitrile @ 34.01 min).

Example 138

1-methyl-N- [3-({[4- (5- {6-[(methylsulfonyl) amino] -2-pyridinyl} -1,2,4-oxadiazol-3-yl) phenyl ] Sulfonyl} amino) phenyl] cyclopropanecarboxamide

200 mg (0.38 mmol) of the compound from Example 134 were dissolved in 10 mL of THF, and 0.5 mL (6.18 mmol) of pyridine and 90 mg (0.75 mmol) of methanesulfonyl chloride were added under argon. The mixture is stirred at rt for 16 h, after which the solvent is removed under reduced pressure, the residue is dissolved in 5 mL of methanol and again concentrated under reduced pressure, and the crude product is purified by HPLC (Chromsil C18, 250 x 30 mm, flow rate). 50 mL / min, runtime 35 min, detection at 254 nm, gradient 10% acetonitrile @ 3 min-> 90% acetonitrile @ 31 min-> 90% acetonitrile @ 34 min-> 10% acetonitrile @ 34.01 min Purified).

Additional 1,2,4-oxadiazole derivatives attached via position 3 and prepared according to the process according to the invention are listed in Table 4:

TABLE 4

The compounds and tables listed in the preparation examples were characterized using the LC-MS and HPLC methods described below:

Method 1:

Column: Kromasil C18, LR temperature: 30 ° C., flow rate = 0.75 mL min ⁻¹ , mobile phase: A = 0.01 M HClO ₄ , B = CH ₃ CN, gradient: → 0.5 min 98% A → 4.5 min 10 % A → 6.5 min 10% A

Method 2:

Column: Chromasil C18, 60 x 2 mm, LR temperature: 30 ° C., flow rate = 0.75 mL min ⁻¹ , mobile phase: A = 0.01 MH ₃ PO ₄ , B = CH ₃ CN, gradient: → 0.5 min 90% A → 4.5 minutes 10% A → 6.5 minutes 10% A

Method 3:

Column: Chromasil C18, 60 x 2 mm, LR temperature: 30 ° C., flow rate = 0.75 mL min ⁻¹ , mobile phase: A = 0.005 M HClO ₄ , B = CH ₃ CN, gradient: → 0.5 min 98% A → 4.5 Minute 10% A → 6.5 minutes 10% A

Method 4:

Column: Symmetric C18, 2.1 x 150 mm, column oven: 50 ° C., flow rate = 0.6 mL min ⁻¹ , mobile phase: A = 0.6 g 30% concentration HCl / 1 water, B = CH ₃ CN, gradient: 0.0 min 90% A → 4.0 min 10% A → 9 min 10% A

Method 5:

LC-MS: MHZ-2Q, Instrument Micromass Quattro LCZ

Column: symmetrical C18, 50 mm x 2.1 mm, 3.5 μm, temperature: 40 ° C., flow rate = 0.5 mL min ⁻¹ , mobile phase: A = CH ₃ CN + 0.1% formic acid, mobile phase B = water + 0.1% formic acid, gradient: 0.0 min 10% A → 4 min 90% A → 6 min 90% A

Method 6:

LC-MS: MHZ-2P, Instrument Micromass Platform LCZ

Column: symmetrical C18, 50 mm x 2.1 mm, 3.5 μm, temperature: 40 ° C., flow rate = 0.5 mL min ⁻¹ , mobile phase: A = CH ₃ CN + 0.1% formic acid, mobile phase B = water + 0.1% formic acid, gradient: 0.0 min 10% A → 4 min 90% A → 6 min 90% A

Method 7:

LC-MS: MHZ-7Q, instrument micromass Cuaro LCZ

Column: symmetrical C18, 50 mm x 2.1 mm, 3.5 μm, temperature: 40 ° C., flow rate = 0.5 mL min ⁻¹ , mobile phase: A = CH ₃ CN + 0.1% formic acid, mobile phase B = water + 0.1% formic acid, gradient: 0.0 min 5% A → 1 min 5% A → 5 min 90% A → 6 min 90% A

Method 8:

Column: Symmetric C18, 2.1 x 150 mm, column oven: 50 ° C., flow rate = 0.9 mL min ⁻¹ , mobile phase: A = 0.3 g 30% concentration HCl / 1 water, B = CH ₃ CN, gradient: 0.0 min 90% A → 3.0 min 10% A → 6.0 min 10% A

Method 9:

HP1100, column: LiChroCart 75-5 LiChrospher 100 RP-18 5 μm, column oven: 40 ° C., flow rate = 2.5 mL min ⁻¹ , mobile phase: A = 0.05% TFA with water , B = CH ₃ CN with 0.05% TFA, slope: 0.0 min 90% A → 0.05 min 90% A → 5.0 min 5% A → 7.0 min 5% A → 7.05 min 90% A → 8.0 min 90% A

Claims (20)

The compounds of formula (I) and their tautomers, stereoisomers, stereoisomer mixtures and pharmacologically acceptable salts thereof. <Formula I> Where R ² and R ³ are the same or different and are hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) Alkoxy, or chemical formula or Wherein R ⁵ , R ⁶ and R ⁷ are the same or different and each is hydrogen or a portion thereof selected from the group consisting of hydroxyl, halogen, cyano, trifluoromethyl and trifluoromethoxy Group of (C ₁ -C ₆ ) -alkyl which may be substituted by two substituents, A is attached to an adjacent phenyl ring via a C atom and represents a 5 or 6 membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of N, O and S, R ¹ represents (C ₆ -C ₁₀ ) -aryl, in each case 5 to 10 membered heteroaryl or 5 to 10 membered heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of N, O and S Indicate, R ¹ is hydroxyl, amino, mono- (C ₁ -C ₆ ) -alkylamino, di- (C ₁ -C ₆ ) -alkylamino, halogen, nitro, cyano, oxo, some of which are amino or hydroxide (C ₁ -C ₆ ) -alkyl which may be substituted by hydroxy; Selected from the group consisting of 5 or 6 membered heterocyclyl, N, O and S having up to 2 heteroatoms selected from the group consisting of (C ₁ -C ₆ ) -alkoxy, phenyl, N, O and S 5 or 6 membered heteroaryl having one or more heteroatoms, -C (O) -OR ⁸ , -C (O) -NR ⁹ R ¹⁰ , -NH-C (O) -R ¹¹ , -NH-C (O ) -C (O) -R ¹² and -NH-SO ₂ -R ¹³ may be substituted by up to three substituents selected from the group wherein R ⁸ , R ⁹ and R ¹⁰ are the same or different Each represents hydrogen or (C ₁ -C ₆ ) -alkyl, or R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached contain (C ₁ -C ₄ ) -alkyl, amino, hydroxyl, containing additional nitrogen or oxygen heteroatoms, some of which are optionally substituted by hydroxyl or amino, 5 or 6 membered heterocycle which may be mono- or di-substituted by the same or different substituents from the group consisting of (C ₁ -C ₄ ) -alkoxy, oxo, carboxyl and (C ₁ -C ₄ ) -alkoxycarbonyl Form the R ¹¹ and R ¹² are the same or different and each represents trifluoromethyl, (C ₁ -C ₆ ) -alkoxy, hydroxyl, or amino, (C ₁ -C ₆ ) -alkoxycarbonylamino, mono - (C ₁ -C ₆₎ - acylamino, hydroxyl, amidino, guanidino, (C ₁ -C ₆₎ - by the same or different substituents from alkoxycarbonyl, carboxyl and the group consisting of phenyl optionally Mono- or di-substituted (C ₁ -C ₆ ) -alkyl; R ¹³ is (C ₁ -C ₆ ) -alkyl or (C which may in each case be substituted by halogen, amino, hydroxyl, (C ₁ -C ₄ ) -alkoxy or (C ₁ -C ₄ ) -alkyl ₆ -C ₁₀ ) -aryl), R ⁴ is amino, hydroxyl, halogen, (C ₁ -C ₆ ) -alkoxy, (C ₁ -C ₅ ) -alkanoyloxy, and a portion thereof consisting of halogen, nitro, cyano, amino and hydroxyl Or (C ₁ -C ₆ ) -alkyl which may be substituted up to three times by the same or different substituents from the group consisting of mono- or di-substituted phenyl, optionally by the same or different substituents from Three times by the same or different substituents from the group consisting of amino, hydroxyl, halogen, (C ₁ -C ₆ ) -alkoxy, and some of which are amino, hydroxyl, halogen, and (C ₁ -C ₆ ) -alkoxy Or (C ₃ -C ₇ ) -cycloalkyl which may be substituted up to three times by the same or different substituents from the group consisting of (C ₁ -C ₆ ) -alkyl optionally substituted below, (C ₆ -C ₁₀ ) -aryl optionally substituted with the same or different substituents from the group consisting of halogen, nitro, cyano, amino and hydroxyl, X represents oxygen or sulfur, The nitrogen-containing heterocycle may also be present as N-oxide. The method of claim 1, R ² and R ³ are the same or different and are hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) Alkoxy, or a chemical formula or Wherein R ⁵ , R ⁶ and R ⁷ are the same or different and each is 1 or 2 wherein hydrogen or a portion thereof is selected from the group consisting of hydroxyl, halogen, cyano, trifluoromethyl and trifluoromethoxy Group of (C ₁ -C ₆ ) -alkyl which may be substituted by 4 substituents, A is attached to an adjacent phenyl ring via a C atom and represents a 5 or 6 membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of N, O and S, R ¹ is (C ₆ -C ₁₀ ) -aryl, in each case 5 to 10 membered heteroaryl or 5 to 10 membered heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of N, O and S; Indicate, Wherein R ¹ is hydroxyl, amino, mono- (C ₁ -C ₆ ) -alkylamino, di- (C ₁ -C ₆ ) -alkylamino, halogen, nitro, cyano, oxo, some of which are amino or hydroxide (C ₁ -C ₆ ) -alkyl which may be substituted by hydroxy; 5 or 6 membered heteroaryl having one or more heteroatoms selected from the group consisting of (C ₁ -C ₆ ) -alkoxy, phenyl, N, O and S, —C (O) —OR ⁸ , —C (O) May be substituted by up to 3 substituents selected from the group consisting of —NR ⁹ R ¹⁰ and —NH—C (O) —R ¹¹ , wherein R ⁸ , R ⁹ and R ¹⁰ are the same or different, Each represents hydrogen or (C ₁ -C ₆ ) -alkyl, R ¹¹ represents (C ₁ -C ₆ ) -alkyl optionally substituted or substituted by the same or different substituents from the group consisting of amino, hydroxyl, guanidino, carboxyl and phenyl), Mono- or mono-substituted by the same or different substituents from the group consisting of amino, hydroxyl, halogen, (C ₁ -C ₆ ) -alkoxy, and R ⁴ , part of which is halogen, nitro, cyano, amino and hydroxyl, or Represent (C ₁ -C ₆ ) -alkyl which may be substituted up to three times by the same or different substituents from the group consisting of disubstituted phenyl, Up to three times with the same or different substituents from the group consisting of amino, hydroxyl, halogen, (C ₁ -C ₆ ) -alkoxy and parts thereof of amino, hydroxyl, halogen and (C ₁ -C ₆ ) -alkoxy Or (C ₃ -C ₇ ) -cycloalkyl which may be substituted up to three times by the same or different substituents from the group consisting of (C ₁ -C ₆ ) -alkyl optionally substituted with (C ₆ -C ₁₀ ) -aryl optionally substituted with the same or different substituents from the group consisting of halogen, nitro, cyano, amino and hydroxyl, X represents oxygen or sulfur, Compounds of formula (I) and tautomers, stereoisomers, stereoisomer mixtures thereof and pharmacologically acceptable salts thereof, wherein said nitrogen-containing heterocycle may also be present as N-oxide. The method of claim 1, R ² and R ³ are the same or different and are hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) Alkoxy, or a chemical formula or Wherein R ⁵ , R ⁶ and R ⁷ are the same or different and each is 1 or 2 wherein hydrogen or a portion thereof is selected from the group consisting of hydroxyl, halogen, cyano, trifluoromethyl and trifluoromethoxy Group of (C ₁ -C ₆ ) -alkyl which may be substituted by 4 substituents, A is attached to an adjacent phenyl ring via a C atom and represents a 5 or 6 membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of N, O and S, R ¹ is (C ₆ -C ₁₀ ) -aryl, in each case 5 to 10 membered heteroaryl or 5 to 10 membered heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of N, O and S; Indicate, Wherein R ¹ is hydroxyl, amino, mono- (C ₁ -C ₆ ) -alkylamino, di- (C ₁ -C ₆ ) -alkylamino, halogen, nitro, cyano, oxo, some of which are amino or hydroxide (C ₁ -C ₆ ) -alkyl which may be substituted by hydroxy; 5 or 6 membered heteroaryl having one or more heteroatoms selected from the group consisting of (C ₁ -C ₆ ) -alkoxy, phenyl, N, O and S, -C (O) -OR ⁸ , -C (O ) -NR ⁹ R ¹⁰ and -NH-C (O) -R ¹¹ may be substituted by up to 3 substituents selected from the group wherein R ⁸ , R ⁹ and R ¹⁰ are the same or different and Each represents hydrogen or (C ₁ -C ₆ ) -alkyl, R ¹¹ represents (C ₁ -C ₆ ) -alkyl optionally mono- or di-substituted by the same or different substituents from the group consisting of amino, hydroxyl, guanidino, carboxyl and phenyl), R ⁴ is amino, hydroxyl, halogen, (C ₁ -C ₆₎ - alkoxy, and parts thereof, halogen, nitro, cyano, amino and hydroxyl by identical or different substituents from the group consisting of a lock chamber or optionally substituted Represent (C ₁ -C ₆ ) -alkyl which may be substituted up to three times by the same or different substituents from the group consisting of disubstituted phenyl, Three times by the same or different substituents from the group consisting of amino, hydroxyl, halogen, (C ₁ -C ₆ ) -alkoxy, and some of which are amino, hydroxyl, halogen, and (C ₁ -C ₆ ) -alkoxy Or (C ₃ -C ₇ ) -cycloalkyl which may be substituted up to three times by the same or different substituents from the group consisting of (C ₁ -C ₆ ) -alkyl optionally substituted below, (C ₆ -C ₁₀ ) -aryl optionally substituted with the same or different substituents from the group consisting of halogen, nitro, cyano, amino and hydroxyl, X represents oxygen, Compounds of formula (I) and tautomers, stereoisomers, stereoisomer mixtures thereof and pharmacologically acceptable salts thereof, wherein said nitrogen-containing heterocycle may also be present as N-oxide. The method of claim 1, R ² and R ³ are the same or different and represent hydrogen or halogen, A radical of formula (A-II) wherein A is attached to an adjacent phenyl ring via one of the carbon atoms at position 3 or 5, or a radical of formula (A-II) attached to an adjacent phenyl ring via one of the carbon atoms at position 2 or 5; Indicates R ¹ represents in each case 5 to 10 membered heteroaryl or 5 or 10 membered heterocyclyl having up to 3 heteroatoms selected from the group consisting of N, O and S, or represents phenyl, Wherein R ¹ is (C ₁ -C ₄ ) -alkyl, hydroxyl, oxo, halogen, amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (some of which is optionally substituted with amino or hydroxyl; May be substituted by 1 to 3 substituents selected from the group consisting of C ₁ -C ₄ ) -alkylamino and —NH—C (O) —R ¹¹ , wherein R ¹¹ is amino, hydroxyl, guani (C ₁ -C ₆ ) -alkyl optionally substituted by the same or different substituents from the group consisting of dino and carboxy), Which may be substituted with more than three times by identical or different substituents from the group consisting of alkoxy _{(C 1 -C 4) - -} R 4 is amino, hydroxyl, fluorine, chlorine and (C ₁ -C ₄₎ alkyl Or Identical or different substituents from the group consisting of amino, hydroxyl, fluorine, chlorine, (C ₁ -C ₄ ) -alkoxy, and some of which are amino, hydroxyl, fluorine, chlorine, and (C ₁ -C ₄ ) -alkoxy (C ₃ -C ₅ ) -cycloalkyl which may be substituted up to three times by the same or different substituents from the group consisting of (C ₁ -C ₄ ) -alkyl optionally substituted up to three times by X represents oxygen or sulfur, Compounds of formula (I) and tautomers, stereoisomers, stereoisomer mixtures thereof and pharmacologically acceptable salts thereof, wherein said nitrogen-containing heterocycle may also be present as N-oxide. <Formula A-I> <Formula A-II> In the above formulas, Y represents oxygen or sulfur. The method of claim 1, R ² and R ³ are the same or different and represent hydrogen or halogen, A radical of formula (A-II) wherein A is attached to an adjacent phenyl ring via one of the carbon atoms at position 3 or 5, or a radical of formula (A-II) attached to an adjacent phenyl ring via one of the carbon atoms at position 2 or 5; Indicates R ¹ represents in each case 5 to 10 membered heteroaryl or 5 or 10 membered heterocyclyl having up to 3 heteroatoms selected from the group consisting of N, O and S, or represents phenyl, Wherein R ¹ is (C ₁ -C ₄ ) -alkyl, hydroxyl, oxo, halogen, amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (some of which is optionally substituted with amino or hydroxyl; May be substituted by 1 to 3 substituents selected from the group consisting of C ₁ -C ₄ ) -alkylamino and —NH—C (O) —R ¹¹ , wherein R ¹¹ is amino, hydroxyl, guani (C ₁ -C ₆ ) -alkyl optionally substituted by the same or different substituents from the group consisting of dino and carboxy), Which may be substituted with more than three times by identical or different substituents from the group consisting of alkoxy _{(C 1 -C 4) - -} R 4 is amino, hydroxyl, fluorine, chlorine and (C ₁ -C ₄₎ alkyl Or Identical or different substituents from the group consisting of amino, hydroxyl, fluorine, chlorine, (C ₁ -C ₄ ) -alkoxy, and some of which are amino, hydroxyl, fluorine, chlorine, and (C ₁ -C ₄ ) -alkoxy (C ₃ -C ₅ ) -cycloalkyl which may be substituted up to three times by the same or different substituents from the group consisting of (C ₁ -C ₄ ) -alkyl optionally substituted up to three times by A compound of formula (I) and their tautomers, stereoisomers, stereoisomer mixtures and pharmacologically acceptable salts thereof, wherein X represents oxygen. <Formula A-I> <Formula A-II> In the above formulas, Y represents oxygen or sulfur. The method of claim 1, R ² and R ³ represent hydrogen, A is a chemical formula Represents a radical of R ¹ represents a radical selected from the group consisting of phenyl, pyridyl, pyrazinyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, oxazolyl, pyrazolyl, imidazolyl, pyrrolyl and indolyl , R ¹ may be substituted by 1 or 2 substituents selected from the group consisting of methyl, aminomethyl, hydroxyl, bromine, chlorine, fluorine, amino, dimethylamino and -NH-C (O) -R ¹¹ Wherein R ¹¹ represents (C ₁ -C ₆ ) -alkyl optionally substituted or substituted by the same or different substituents from the group consisting of amino, hydroxyl, guanidino and carboxyl, R ⁴ represents tert-butyl optionally substituted up to three times by the same or different substituents from the group consisting of hydroxyl, fluorine and chlorine, Some of which represent cyclopropyl or cyclobutyl substituted by methyl optionally substituted by hydroxyl, fluorine or chlorine, X represents oxygen, Compounds of formula (I) and tautomers, stereoisomers, stereoisomer mixtures thereof and pharmacologically acceptable salts thereof, wherein said nitrogen-containing heterocycle may also be present as N-oxide. The method of claim 1, R ² and R ³ represent hydrogen, A represents a radical of the formula R ¹ represents a radical selected from the group consisting of phenyl, pyridyl, pyrazinyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, oxazolyl, pyrazolyl, imidazolyl, pyrrolyl and indolyl , R ¹ may be substituted by 1 or 2 substituents selected from the group consisting of methyl, aminomethyl, hydroxyl, bromine, chlorine, fluorine, amino, dimethylamino and -NH-C (O) -R ¹¹ Wherein R ¹¹ represents (C ₁ -C ₆ ) -alkyl optionally mono- or disubstituted by the same or different substituents from the group consisting of amino, hydroxyl, guanidino and carboxyl, R ⁴ represents tert-butyl optionally substituted up to three times by the same or different substituents from the group consisting of hydroxyl, fluorine and chlorine, Some of which represent cyclopropyl or cyclobutyl substituted by methyl optionally substituted by hydroxyl, fluorine or chlorine, A compound of formula I, wherein X represents oxygen. The compound of formula Ia according to claim 1. <Formula Ia> Where R ¹ , R ⁴ , A and X are as defined in claim 1, R ² and R ³ are the same or different and are hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₆ ) -Represents alkoxy. The compound of claim 1, wherein R ⁴ is or A compound of formula I, which represents one of the radicals of. The compound of formula I according to claim 1, wherein A represents 1,2,4-oxadiazole attached via the 3-position. The compound of claim 1 selected from the group of the following compounds. By reacting amidoxime of formula (D-1) with a carboxylic acid of formula (E-1) or by condensing sulfonamide of formula (F-3) with amidoxime of formula (G-1) And then cyclizing the compound of formula G-2 by removal of water to obtain a compound of formula I, wherein A is attached to an adjacent phenyl ring through one of the carbon atoms at positions 3 or 5 A process for preparing a compound of formula I according to claim 1 which represents a radical. <Formula A-I> Where Y represents oxygen. <Formula D-1> Where X, R ² , R ³ and R ⁴ are as defined in claim 1. <Formula E-1> Where R ¹ is as defined in claim 1. <Formula F-3> Where X, R ² , R ³ and R ⁴ are as defined in claim 1. <Formula G-1> Where R ¹ is as defined in claim 1. <Formula G-2> Where R ¹ , R ² , R ³ , R ⁴ and X are as defined in claim 1. The hydrazide of formula (H-2) is cyclized to remove water to give a compound of formula (I), wherein A is attached to an adjacent phenyl ring via one of the carbon atoms at position 2 or 5 to A process for preparing the compound of formula I according to claim 1. <Formula A-II> Where Y represents oxygen. <Formula H-2> Where X, R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1, FH represents hydrogen, an amino protecting group or a polymerization support. The hydrazide of formula H-3 is cyclized in the presence of a thio donor, preferably a Lawesson reagent, to give a compound of formula I wherein Y represents sulfur, followed by -C (O) -R ^{4 '} By removing the group and finally reacting with a compound of formula (a), X represents oxygen and A represents a radical of formula (A-II) wherein A is attached to an adjacent phenyl ring via one of the carbon atoms at position 2 or 5 A process for preparing a compound of formula I according to claim. <Formula A-II> Where Y represents sulfur. <Formula H-3> Where R ¹ , R ² and R ³ are as defined in claim 1, FH represents hydrogen, an amino protecting group or a polymerization support, R ^{4 ′} represents (C ₁ -C ₆ ) -alkoxy, (C ₁ -C ₆ ) -alkenoxy or aralkyloxy. <Formula a> Wherein R ⁴ and Q are as defined in claim 1. Use of a compound of formula (I) according to any one of claims 1 to 11 for the prevention or treatment of a disease. Use of a compound of formula (I) according to any one of claims 1 to 11 for the manufacture of a medicament. The use of a compound of formula I according to claim 16, wherein the medicament is for controlling a viral disorder. Use of a compound of formula I according to claim 16 or 17, wherein the medicament is for controlling cytomegalovirus infection. A medicament comprising the compound of formula I according to claim 1. A compound of formula la according to claim 1. <Formula Ia> Where R ¹ , R ² , R ³ , R ⁴ , A and X are as defined in claim 1.