EP2007772A1 - Thiazolyl-dihydroquinazolines - Google Patents

Abstract

The invention relates to compounds of general formula (I), wherein the groups A, R<SUP>1</SUP>, R<SUP>2</SUP>, R<SUP>a</SUP> and R<SUP>b</SUP> are defined as in the claims and the description, and to the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, optionally the pharmacologically acceptable acid addition salts, solvates and hydrates thereof. The invention also relates to methods for producing said thiazolyl-dihydroquinazolines and to their use as drugs.

Description

 THIAZOLYL-dihydro-quinazolines

The present invention relates to novel thiazolyl-dihydro-quinazolines of the general formula (I)

where the radicals A, R ¹ , R ² , R ^a and R ^{b have} the meanings mentioned in the claims and the description, their tautomers, racemates, enantiomers, diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts, solvates and hydrates, and processes for the preparation of these thiazolyl-dihydro-quinazolines and their use as medicaments.

BACKGROUND OF THE INVENTION

Phosphatidylinositol 3-kinases (PI3 kinases) are a subfamily of lipid kinases that catalyze the transfer of a phosphate moiety to the 3 'position of the inositol ring of phosphoinositides.

They are involved in numerous cellular processes such as cell growth and differentiation processes, the control of cytoskeletal changes, and the regulation of intracellular transport events (Vanhaesebroeck et al., Annu Rev Biochem., 2001: 70: 535-602). PI3-kinases can be used in many tumors, such as breast cancer, ovarian or pancreatic carcinoma, tumor types such as colon, breast or lung carcinomas, but especially in autoimmune diseases such as Crohn's disease or rheumatoid arthritis, or in the cardiovascular system such for example, in the development of cardiac hypertrophy (Oudit et al., Circulation, 2003 Oct. 28; 108 (17): 2147-52). PI3-kinase modulators may provide a potential for anti-inflammatory therapy with relatively minor side effects (Ward and Finan, Curr Opin Pharmacol., 2003 Aug; 3 (4): 426-34).

PI3-kinase inhibitors for the treatment of inflammatory diseases are known in the literature. Thus, WO 03/072557 discloses 5-phenylthiazole derivatives, WO 04/029055 shows anellated azolpyrimidines and WO 04/007491 azolidinone-vinyl-linked benzene derivatives. Furthermore, the two documents WO 04/052373 and WO 04/056820 disclose benzoxazine and benzoxazin-3-one derivatives.

The object of the present invention is to provide novel compounds which, owing to their pharmaceutical activity, can be used as a PI3-kinase modulator for therapeutic use in the treatment of inflammatory or allergic diseases. Examples of these are inflammatory and allergic respiratory disorders, inflammatory and allergic skin diseases, inflammatory eye diseases, diseases of the nasal mucosa, inflammatory or allergic conditions, in which autoimmune reactions are involved or called kidney inflammations.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly, it has been found that the abovementioned object is achieved by compounds of the formula (I) in which A and the radicals R ¹ , R ² , R ^a and R ^{b have} the meanings mentioned below.

In particular, it has been found that compounds of the formula (I) act as inhibitors of PI3-kinase, in particular as inhibitors of PI3-kinase gamma. Thus, the compounds according to the invention can be used, for example, for the treatment of respiratory diseases. The present invention therefore relates to compounds of the general formula (I),

wherein

A is N or CH;

R ^{a is} hydrogen or an optionally substituted radical selected from

A group consisting of C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₁ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkenyl, C ₁ -C ₆ -haloalkyl, C ₆ -C ₄ -ar /! , Ce-Cu-aryl-CRCS alkyl, C ₅ -C ₀ - heteroaryl, C ₃ -C ₈ -cycloalkyl alkyl-Ci-C _4, C ₃ -C ₈ cycloalkenyl-Ci-C ₄ alkyl -, C ₅ -C ₀ - _{heteroaryl-Ci-C4} alkyl-, spiro, C ₃ -C ₈ -heterocycloalkyl and C ₃ -C ₈ alkyl heterocycloalkyl dC _4,

R ^{b is} hydrogen, OH or NH ₂ or an optionally substituted radical selected from the group consisting of C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₈ -

Cycloalkenyl, C _r C ₆ haloalkyl, C ₆ -C ₄ aryl, C ₆ -C ₄ aryl-Ci-C ₅ alkyl, C ₅ -C ₀ - heteroaryl, C ₃ -C ₈ cycloalkyl-C _r -alkyl- C _4, C ₃ -C ₈ cycloalkenyl alkyl-C _r C _4, C ₅ -C ₀ - alkyl- heteroaryl Ci-C _4, spiro, C ₃ -C ₈ heterocycloalkyl, CONH ₂ , C ₆ -C ₄ -aryl-NH-, Cs-Cs-heterocycloalkyl-NH- and OC _r C ₃ -alkyl, R ¹ is hydrogen or an optionally substituted radical selected from the group consisting of -C ₈ alkyl, QrCβ cycloalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl and Ce-Cu-aryl-CRCS alkyl-; or

R ² is hydrogen or an optionally substituted radical selected from the group consisting of C _r C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl, C ₃ -C ₈ - cycloalkenyl, C _r C ₆ - haloalkyl, C ₆ -C ₄ aryl, C ₆ -C ₄ -alkyl- aryl-Ci-C _5, C ₅ -C ₀ - heteroaryl, alkyl C ₃ -C ₈ cycloalkyl-C _4, C ₃ -C ₈ cycloalkenyl-C _r C ₄ alkyl, C ₅ -C ₀ - heteroaryl-Ci-Cβ-alkyl, C ₉ -C ₃ spiro, C ₃ -C ₈ -heterocycloalkyl, C ₃ - C ₈ -

HeterocycloalkylCrC ₆ -alkyl- and Ce-C _m -aryl-C 1 -C ₆ -alkyl-;

or

R ¹ and R ² together form an optionally substituted five-, six- or seven-membered ring consisting of carbon atoms and optionally 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen.

or

R ¹ and R ² together form an optionally substituted nine- to thirteen-membered spirocyclic ring,

or

R ^{2 is} a radical selected from the group consisting of the general

Formulas (A1) to (A18)

where X and Y may be linked to the same or different atoms of G, and X is a bond or an optionally substituted radical selected from the group consisting of -C ₇ -alkylene, C ₃ -C ₇ -alkenylene and C ₃ -C ₇ alkynylene, or

X together with R ¹ , R ³ or R ^{4 can form} a C 1 -C ₇ -alkylene bridge;

Y is a bond or optionally substituted C 1 -C ₄ -alkylene;

Q is an optionally substituted radical selected from the group consisting of C ₁ -C ₇ -alkylene, C ₃ -C ₇ -alkenylene and C ₃ -C ₇ -alkynylene, or Q together with R ¹ , R ³ or R ^{4 is} a C ₁ -C ₇ -alkylene Bridge can form;

R ³ , R ⁴ , R ^{5 are} identical or different, hydrogen or an optionally substituted

Radical selected from the group consisting of -C ₈ alkyl, C ₃ -C ₈ - cycloalkyl, C ₂ -C ₆ -haloalkyl, Ci-C ₄ alkyl-C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ cycloalkyl

C _r C ₄ alkyl, NR ⁷ R ^8, NR ⁷ R ⁸ -C _r C ₄ alkyl, C _r C ₄ alkoxy, Ci-C ₄ -alkoxy-C _r C ₄ - alkyl, C ₆ -C ₄ aryl and C ₅ -C ₀ -heteroaryl;

or in each case two of the substituents

R ³ , R ⁴ , R ⁵ together form an optionally substituted five-, six- or seven-membered ring consisting of carbon atoms and optionally 1-2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen;

G is a saturated, partially saturated or unsaturated ring system of 3-10 C atoms, wherein optionally up to 6 C atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;

R ^{6 is} identical or different, hydrogen or an optionally substituted radical selected from the group consisting of = O, C ₁ -C ₈ -alkyl, C ₂ -C ₆ -alkenyl C ₃ -C ₈ -cycloalkyl, C ₂ -C ₆ -haloalkyl, C ₆ -C ₄ aryl, C ₅ -C ₀ heteroaryl and C ₃ -C ₈ - heterocycloalkyl, or a radical selected from the group consisting of NR ⁷ R ^8, OR ^7, -CO-CrC ₃ - alkyl-NR ⁷ R ⁸ -O-Ci-C ₃ alkyl-NR ⁷ R ^8, CONR ⁷ R ^8, NR ⁷ COR ⁸ , -CO-C _r C ₃ -alkyl-NR ⁷ (CO) OR ⁸ , -O (CO) NR ⁷ R ⁸ , NR ⁷ (CO) NR ⁸ R ⁹ , NR ⁷ (CO) OR ⁸ , (CO) OR ⁷ , -O (CO) R ⁷ , COR ⁷ , (SO) R ⁷ , (SO ₂ ) R ⁷ , (SO ₂ ) NR ⁷ R ⁸ , NR ⁷ (SO ₂ ) R ⁸ , NR ⁷ (SO ₂ ) NR ⁸ R ⁹ , CN, -C _r C ₃ alkyl-C ₆ -C ₄ -aryl, -N H-CO-N HC _r C ₃ alkyl and halogen;

n 1, 2 or 3

R ^7, R ^8, R ⁹ are identical or different, represent hydrogen or an optionally substituted radical selected from the group consisting of C-ι-C ₈ alkyl, C ₃ -C ₈ -

Cycloalkyl, C _r C ₆ -haloalkyl, C ₁ -C ₄ -alkyl-C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl-C _r C ₃ -alkyl-, C ₆ -C ₄ -aryl, Ci -C ₄ alkyl-C ₆ -Ci4-aryl, C ₆ alkyl -Ci4-aryl-Ci-C _4, C ₃ -C ₈ -heterocycloalkyl, Ci-C ₅ alkyl-C ₃ -C ₈ - heterocycloalkyl, C ₃ -C ₈ -heterocycloalkyl-C _r C ₄ -alkyl, C _r C ₄ -alkyl (CO) - and C _r C ₄ -alkyl-O (CO) -;

or in each case two of the substituents

R ⁷ , R ⁸ , R ⁹ together form an optionally substituted five-, six- or seven-membered ring consisting of carbon atoms and optionally 1-2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen;

optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts, solvates and hydrates, with the proviso that the following compounds are excluded: a) 8-phenyl-4, 5-dihydro-thiazolo [4,5-h] quinazolin-2-yl) urea b) 1-methyl-3- (8-phenyl-4,5-dihydro-thiazolo [4,5-h] quinazoline-2 -yl) -urea c) 1, 1-Dimethyl-3- (8-phenyl-4,5-dihydro-thiazolo [4,5-h] quinazolin-2-yl) urea d) 1- (2-dimethylamino ethyl) -3- (8-phenyl-4,5-dihydro-thiazolo [4,5-h] quinazolin-

2-yl) -urea e) 4-Methyl-piperazine-1-carboxylic acid (8-phenyl-4,5-dihydro-thiazolo [4,5-h] quinazolin-2-yl) -amide f) piperidine-1-carboxylic acid (8-phenyl-4,5-dihydro-thiazolo [4,5-h] quinazolin-2-yl) -amide g) pyrrolidine-1-carboxylic acid (8-phenyl-4, 5-dihydro-thiazolo [4,5-h] quinazolin-2-yl) -amide h) 1-Methyl-3- (8-o-tolyl-4,5-dihydro-thiazolo [4,5-h] quinazoline -2-yl) -urea i) (8-o-tolyl-4,5-dihydro-thiazolo [4,5-h] quinazolin-2-yl) -urea j) 1, 1-dimethyl-3- (8 o-tolyl-4,5-dihydro-thiazolo [4,5-h] quinazolin-2-yl) urea and k) [8- (2-methoxy-phenyl) -4,5-dihydro-thiazolo [4 , 5-h] quinazolin-2-yl] urea and I) morpholine-4-carboxylic acid (8-phenyl-4,5-dihydro-thiazolo [4,5-h] quinazolin-2-yl) amides

Preference is given to compounds of the formula (I) in which

X, Y, Q and G may have the meaning given, and

AN, R ^a is hydrogen or a radical selected from the group consisting of C-ι-C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₃ - C ₈ cycloalkenyl, C _r C ₆ - haloalkyl, C ₆ -C ₄ -Ar / !, Ce-Cu-aryl-CRCS alkyl, C ₅ -C ₀ heteroaryl, C ₃ -C ₈ - cycloalkyl-C _r C alkyl _4, C ₃ -C ₈ cycloalkenyl-C _r C ₄ alkyl, C ₅ -C ₀ -heteroaryl-Ci-C ₄ - alkyl, spiro, C ₃ -C ₈ -heterocycloalkyl and C C ₃ -C ₈ -heterocycloalkyl-C ₁ -C ₄ -alkyl optionally containing one or more of the radicals, identically or differently, selected from the group consisting of C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C _6- alkynyl, C ₂ -C ₆ -alkynyl-NR ⁵ R ⁶ , C ₃ -C ₈ -cycloalkyl, d-Ce-haloalkyl, halogen, OH, C _r C ₄ -alkoxy, CN, NO ₂ , NR ¹⁰ R ¹¹ , OR ¹⁰ , COR ¹⁰ , COOR ¹⁰ , CONR ¹⁰ R ¹¹ , NR ¹⁰ COR ¹¹ , NR ¹⁰ (CO) NR ¹¹ R ¹² , 0 (CO) NR ¹⁰ R ¹¹ , NR ¹⁰ (CO) OR ¹¹ , SO ₂ R ¹⁰ , SOR ¹⁰ , SO ₂ NR ¹⁰ R ¹¹ , NR ¹⁰ SO ₂ NR ¹¹ R ¹² and NR ¹⁰ SO ₂ R ¹¹ , may be substituted; or R ^a is optionally substituted by a radical of the general formula (B)

wherein,

R ¹³ to R ^{16 are} identical or different, hydrogen or C 1 -C ₆ -alkyl, or two of the substituents

R ¹³ to R ¹⁶ together form an optionally substituted five-, six- or seven-membered ring consisting of carbon atoms and optionally 1-2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen;

R ¹⁰ , R ¹¹ , R ^{12 are} identical or different, hydrogen or a radical selected from the group consisting of C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₈ - Cycloalkyl and C _r C ₆

haloalkyl; or in each case two of the radicals R ¹⁰ , R ¹¹ , R ¹² together form a five-, six- or seven-membered ring consisting of carbon atoms and optionally 1-2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen;

R ^b is hydrogen, OH or NH _2, or an optionally substituted radical selected from the group consisting of Ci-C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ - cycloalkenyl, C _r C ₆ haloalkyl, C ₆ -C ₄ aryl, Ce-Cu-aryl-CRCS alkyl, C ₅ -C ₀ - heteroaryl, C ₃ -C ₈ cycloalkyl C _r C ₄ alkyl, C ₃ -C ₈ cycloalkenyl alkyl-C _r C _4, C ₅ -C ₀ - _{heteroaryl-Ci-C4} alkyl-, spiro, C ₃ -C ₈ heterocycloalkyl, CONH ₂ , C ₆ -C ₄ -aryl-NH-, QrCβ-heterocycloalkyl-NH- and OC _r C ₃ -alkyl, optionally with one or more of the radicals, identically or differently, selected from the group consisting of

Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C _r C ₆ haloalkyl, halogen, OH, OMe, CN, NH _2, NHMe and NMe _2, may be substituted;

R ^{1 is} hydrogen or a radical selected from the group consisting of C ₁ -C ₈ -alkyl, C ₃ -C ₈ -cycloalkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl and C ₆ -C ₄ -aryl-Ci C ₅ -alkyl, which may optionally have one or more of the radicals, identical or different, selected from the group consisting of halogen, COOH, NH ₂ , OH, CN, C ₁ -C 6 -alkyl, OMe, -NH (CO) -alkyl and - (CO) O-alkyl may be substituted,

R ² is hydrogen or a radical selected from the group consisting of -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl, C ₃ -C ₈ cycloalkenyl, C _r C ₆ haloalkyl, C ₆ - Ci ₄ -aryl,

Ce-Cu-aryl-CRCS alkyl, C ₅ -C, C ₀ -alkyl heteroaryl C ₃ -C ₈ cycloalkyl-C _4, C ₃ -C ₈ - alkyl cycloalkenyl CrC _4, Cs -Cio-heteroaryl-Ci-Cβ-alkyl, C ₉ -C ₃ spiro, C ₃ -C ₈ - heterocycloalkyl, C ₃ -C ₈ -heterocycloalkyl-C _r C ₆ alkyl, and Ce-Cu-aryl C 1 -C 4 -alkyl optionally having one or more of the radicals, identical or different, selected from the group consisting of halogen, NH ₂ , OH, CN, C 1 -C 6 -alkyl,

OMe, -NH (CO) alkyl, = 0, COOH and - (CO) O-alkyl may be substituted.

or

R ¹ and R ² together form a five-, six- or seven-membered ring consisting of carbon atoms and optionally 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, optionally with one or more of the radicals, the same or different selected from the group consisting of halogen, NH _2, OH, CN, d-Ce-alkyl, OMe, -NH (CO) - C _r C ₄ alkyl, and - (CO) O-CrC ₄ -

Alkyl may be substituted.

or

R ¹ and R ² together form an optionally substituted nine- to thirteen-membered spirocyclic ring,

or

R ^{2 is} a radical selected from the group consisting of the general

Formulas (A1) to (A18)

in which R ^3, R ^4, R ⁵ are identical or different, denote hydrogen or a radical selected from the group consisting of -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ haloalkyl, C ₄ alkyl d- -C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkyl-Ci-C ₄ alkyl, NR ⁷ R ⁸ , NR ⁷ R ⁸ -C _r C ₄ alkyl, C _r C ₄ alkoxy , Ci-C ₄ -alkoxy-C _r C ₄ alkyl, C ₆ -C ₄ aryl and C ₅ -C ₀ -

Heteroaryl, optionally substituted with one or more of the radicals, the same or different, selected from the group consisting of halogen, NH _2, OH, CN, NR ⁹ R ^10, -NH (CO) -C _r C ₄ alkyl and substituted MeO can be,

or in each case two of the substituents

R ³ , R ⁴ , R ⁵ together form a five-, six- or seven-membered ring consisting of carbon atoms and optionally 1-2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; which may optionally be substituted by one or more of the radicals, identically or differently, selected from the group consisting of halogen, NH ₂ , OH, CN, NR ⁹ R ¹⁰ , -NH (CO) -dC ₄ -alkyl and MeO,

R ^{6 is} identical or different, hydrogen or a radical selected from the group consisting of C _r C ₈ alkyl, C ₂ -C ₆ alkenyl C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ haloalkyl, C ₆ - Ci ₄ -aryl, C ₅ -C ₀ heteroaryl and C ₃ -C ₈ -heterocycloalkyl, optionally substituted by one or more of the radicals, the same or different, selected from the group consisting of, NH _2, NHMe, NMe ₂ OH , OMe, CN, -CRC ₃ -alkyl-C ₆ -C ₄ aryl, -NH-CO-NH-Ci-Cs-alkyl, C _r C ₆ alkyl, and - (CO) OC _r C ₆ alkyl substituted may be or a radical selected from the group consisting of = O, NR ⁷ R ⁸ , OR ⁷ , -CO-CrC ₃ - alkyl-NR ⁷ R ⁸ -O-Ci-C ₃ -alkyl-NR ⁷ R ⁸ , CONR ⁷ R ⁸ , NR ⁷ COR ⁸ , -CO-C _r C ₃ -alkyl-NR ⁷ (CO) OR ⁸ , -O (CO) NR ⁷ R ⁸ , NR ⁷ (CO) NR ⁸ R ⁹ , NR ⁷ (CO) OR ⁸ , (CO) OR ⁷ , -O (CO) R ⁷ , COR ⁷ , (SO) R ⁷ , (SO ₂ ) R ⁷ , (SO ₂ ) NR ⁷ R ⁸ , NR ⁷ (SO ₂ ) R ⁸ , NR ⁷ (SO ₂ ) NR ⁸ R ⁹ , CN and halogen;

n 1, 2 or 3 R ^7, R ^8, R ⁹ are identical or different, hydrogen or a radical selected from the group consisting of -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ haloalkyl, d- _C4 alkyl -C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ -cycloalkyl alkyl-C _3, C ₆ -C ₄ aryl, Ci-C ₄ - alkyl-C ₆ -C ₄ aryl, C ₆ -C ₄ aryl-Ci-C ₄ alkyl, C ₃ -C ₈ -heterocycloalkyl, C _r C ₅ - alkyl-CrCβ-heterocycloalkyl, C ₃ -C ₈ -heterocycloalkyl-Ci-C ₄ alkyl -, C _r C ₄ -

Alkyl (CO) - and CrC ₄ alkyl-O (CO) - optionally with one or more of the radicals, identical or different, selected from the group consisting of halogen, NH ₂ , OH, CN, OMe, NHMe, NMe ₂ dC ₆ alkyl and (CO) O may be Ci-C ₆ alkyl substituted

or in each case two of the substituents

R ⁷ , R ⁸ , R ⁹ together form a five, six or seven membered ring consisting of carbon atoms and optionally 1-2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; optionally with one or more of the radicals, identically or differently, selected from the group consisting of halogen, NH ₂ , OH, CN, OMe, NHMe, NMe ₂ C _r C ₆ alkyl and (CO) OC _r C ₆ alkyl , may be substituted.

mean.

Preference is furthermore given to compounds of the formula (I) in which

A, R ^a and R ¹ to R ^{16 may have} the meaning given, and

R ^{b is} hydrogen.

Preference is furthermore given to compounds of the formula (I) in which

R ¹ to R ^{16 may have} the meaning given and R ^a C ₆ -C ₄ -aryl or C _r C ₆ -alkyl wherein R ^{a is} optionally substituted by one or more of the radicals, identical or different, selected from the group consisting of d-Cβ-alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C _r C ₆ haloalkyl, halogen, OH, Ci-C ₄ alkoxy, CN, NO ₂ , NR ¹⁰ R ¹¹ , OR ¹⁰ , COR ¹⁰ , COOR ¹⁰ , CONR ¹⁰ R ¹¹ , NR ¹⁰ COR ¹¹ , NR ¹⁰ (CO) NR ¹¹ R ¹² , O (CO) NR ¹⁰ R ¹¹ , NR ¹⁰ (CO ) OR ¹¹ , SO ₂ R ¹⁰ , SOR ¹⁰ , SO ₂ NR ¹⁰ R ¹¹ , NR ¹⁰ SO ₂ NR ¹¹ R ¹² and NR ¹⁰ SO ₂ R ¹¹ , may be substituted; and

R ^{b is} hydrogen

mean.

Preference is furthermore given to compounds of the formula (I) in which A, R ^a and R ^{b can have} the meaning indicated and

R ¹ is hydrogen, C _r C ₅ alkyl or C ₃ -C ₈ cycloalkyl,

R ^{2 is} hydrogen, C _r C ₅ alkyl or C ₃ -C ₈ cycloalkyl, phenyl or

R ¹ and R ² together form an optionally substituted five- or six-membered ring consisting of carbon atoms and optionally 1 to 2 nitrogen atoms, or

R ¹ and R ² together form an optionally substituted nine- to thirteen-membered spirocyclic ring,

or

R ¹ , R ^{2 are} identical or different, a radical selected from the group consisting of the general formulas formulas (A1) -A (17), where

X can form a bond or an optionally substituted C 1 -C 3 -alkylene, or X together with R ¹ , R ³ or R ^{4 can form} a C 1 -C ₇ -alkylene bridge; Q is an optionally substituted C 1 -C ₃ -alkylene,

Q together with R ¹ , R ³ or R ^{4 can form} a C 1 -C ₇ -alkylene bridge;

R ^3, R ^4, R ⁵ are identical or different, represent hydrogen or an optionally substituted radical selected from the group consisting of -C ₄ -alkyl, Ci-C ₄ - alkoxy, C ₃ -C ₆ cycloalkyl, C ₃ -C ₈ -heterocycloalkyl, -C _r C ₃ alkyl C ₃ -C ₆ - cycloalkyl, phenyl and C ₅ -C -heteroaryl ₀

or in each case two of the substituents

R ³ , R ⁴ , R ⁵ together form an optionally substituted five- or six-membered ring consisting of carbon atoms and optionally 1-2 heteroatoms selected from the group consisting of oxygen and nitrogen; mean.

Particular preference is given to compounds of the formula (I) in which A, R ^a and R ^{b can have} the meaning indicated and

R ¹ H, Me

R ^{2 is} hydrogen or a radical of the general formulas (A18), where

X is a bond or an optionally substituted radical selected from the group consisting of C ₁ -C ₇ -alkylene, C ₃ -C ₇ -alkenylene and C ₃ -C ₇ -alkynylene, or X together with R ¹ denotes a C ₁ -C ₇ -alkylene Bridge can form;

Y is a bond or methylene, ethylene;

X and Y may be linked to the same or different atoms of G, and G is a saturated, partially saturated or unsaturated ring system of 3-10 C atoms, wherein optionally up to 6 C atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;

R ^{6 is} identical or different, hydrogen or an optionally substituted radical selected from the group consisting of = 0, C ₁ -C ₄ -alkyl, C ₂ -C ₆ -alkenyl, C ₃ -C ₆ -cycloalkyl, C ₆ -C ₄ -aryl, C ₅ -C ₆ -heterocycloalkyl, and C ₅ -C ₆ -heteroaryl or a radical selected from the group consisting of NR ⁷ R ⁸ , OR ⁷ , -O-CrC ₃ -alkyl-NR ⁷ R ⁸ , CONR ⁷ R ⁸ , CO-C _r C ₃ -alkyl-NR ⁷ R ⁸ NR ⁷ COR ⁸ , NR ⁷ (CO) OR ⁸ , -CO-CrC ₃ -alkyl-NR ⁷ (CO) OR ⁸ , NR ⁷ (CO) NR ⁸ R ⁹ , NR ⁷ (CO) OR ⁸ , (CO) OR ⁷ , COR ⁷ , (SO ₂ ) R ⁷ , -d-C ₃ -alkyl-C ₆ -C ₄ -aryl, -NH-CO-NH- d-Cs-alkyl and CN,

n 1 or 2

R ⁷ , R ⁸ , R ^{9 are} identical or different, hydrogen or an optionally substituted radical selected from the group consisting of C ₁ -C ₅ -alkyl, C ₁ -C ₄ -alkyl, C ₆ -C ₄ -aryl, C ₃ -C ₆ - Heterocycloalkyl, C ₁ -C ₅ -alkyl-C ₃ -C ₈ -heterocycloalkyl- and C ₃ -C ₆ -cycloalkyl,

or in each case two of the substituents

R ⁷ , R ⁸ , R ⁹ together form an optionally substituted five- or six-membered ring consisting of carbon atoms and optionally 1-2 heteroatoms selected from the group consisting of oxygen and nitrogen;

mean,

Another object of the invention are compounds of formula (I) for use as medicaments. Another object of the invention is the use of the compounds of formula (I) for the manufacture of a medicament for the treatment of diseases in whose pathology an activity of PI3-kinases is involved, in which therapeutically effective doses of the compounds of formula (I) have a therapeutic benefit can unfold. Another object of the invention is the use of the compounds of formula (I), for the manufacture of a medicament for the treatment of inflammatory and allergic diseases of the respiratory tract. Another object of the invention is the use of the compounds of formula (I) for the manufacture of a medicament for the treatment of a disease selected from the group consisting of chronic bronchitis, acute bronchitis, bronchitis due to bacterial or viral infection or fungi or helminths, allergic bronchitis, toxic bronchitis, chronic obstructive bronchitis (COPD), asthma (intrinsic or allergic), pediatric asthma, bronchiectasis, allergic alveolitis, allergic or non-allergic rhinitis, chronic sinusitis, cystic fibrosis or cystic fibrosis, alpha-1-antitrypsin Deficiency, cough, pulmonary emphysema, interstitial lung disease, alveolitis, hyperreactive airways, nasal polyps, pulmonary edema, pneumonitis due to differential causes such as radiation-induced or by aspiration or infectious, collagenoses such as lupus erythematosus, systemic scleroderma, sarcoidosis and M. boeck.

Another object of the invention is the use of the compounds of formula (I), for the manufacture of a medicament for the treatment of inflammatory and allergic diseases of the skin. Another object of the invention is the use of the compounds of formula (I) for the manufacture of a medicament for the treatment of a disease selected from the group consisting of psoriasis, contact dermatitis, atopic dermatitis, alopecia areata (circular hair loss), erythema exudative multiforme (Stevens-Johnson syndrome), dermatitis herpetiformis, scleroderma, vitiligo, hives (urticaria), lupus erythematosus, follicular and areal pyoderma, endogenous and exogenous acne, acne rosacea, and other inflammatory and allergic or proliferative skin diseases.

Another object of the invention is the use of the compounds of formula (I) for the manufacture of a medicament for the treatment of inflammation of the eye. Another object of the invention is the use of the compounds of formula (I) for the manufacture of a medicament for the treatment of a disease which is selected from the group consisting of conjunctivitis of various species such as fungal or bacterial infections, allergic conjunctivitis, irritable conjunctivitis, drug-induced conjunctivitis, keratitis and uveitis. Another object of the invention is the use of the compounds of formula (I) for the manufacture of a medicament for the treatment of diseases of the nasal mucosa. Another object of the invention is the use of the compounds of formula (I) for the manufacture of a medicament for the treatment of a disease selected from the group consisting of allergic rhinitis, allergic sinusitis and nasal polyps.

Another object of the invention is the use of the compounds of formula (I), for the manufacture of a medicament for the treatment of inflammatory or allergic disease states, in which autoimmune reactions are involved.

Another object of the invention is the use of the compounds of formula (I) for the manufacture of a medicament for the treatment of a disease selected from the group consisting of Crohn's disease, ulcerative colitis, systemic lupus erythematosus, chronic hepatitis, multiple sclerosis, rheumatoid Arthritis, psoriatic arthritis, osteoarthritis, rheumatoid spondylitis.

Another object of the invention is the use of the compounds of formula (I), for the manufacture of a medicament for the treatment of renal inflammation. Another object of the invention is the use of the compounds of formula (I) for the manufacture of a medicament for the treatment of a disease selected from the group consisting of glomerulonephritis, interstitial nephritis and idiopathic nephrotic syndrome.

Of particular importance according to the invention is a pharmaceutical formulation comprising a compound of the formula (I). Preference is given to an inhalable pharmaceutical formulation comprising a compound of the formula (I).

Also preferred is an orally administrable pharmaceutical formulation comprising a compound of the formula (I).

Used terms and definitions

Alkyl groups and alkyl groups which are part of other groups are branched and unbranched alkyl groups having 1 to 10 carbon atoms, preferably 1 6, more preferably 1 to 4 carbon atoms, for example methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. Unless otherwise stated, of the above designations, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl include all of the possible isomeric forms. For example, the term propyl includes the two isomeric radicals n-propyl and iso-propyl, the term butyl n-butyl, iso-butyl, sec. Butyl and tert. Butyl, called pentyl, iso-pentyl, neopentyl, etc.

Unless otherwise defined, one or more hydrogen atoms in the abovementioned alkyl groups may optionally be replaced by other radicals. For example, these alkyl groups may be substituted by the halogen atoms fluorine, chlorine, bromine or iodine. The substituents are preferably fluorine or chlorine. Optionally, all hydrogen atoms of the alkyl group may also be replaced.

Unless otherwise stated, the alkyl bridge used is branched and unbranched 2-membered alkyl groups having 4 to 7 carbon atoms, for example, n-butylene, isobutylene, sec. Butylene and tert-butylene, pentylene, isopentylene, neopentylene, etc Designates bridges. Particularly preferred are n-butylene or n-pentylene bridges. In the abovementioned alkyl bridges, optionally 1 to 2 C atoms may be replaced by one or more heteroatoms selected from the group consisting of oxygen or sulfur.

The term "C _1-6 -alkylene" (including those which are part of other radicals) are to be understood as meaning branched and unbranched alkylene groups having 1 to 6 carbon atoms and branched and unbranched alkylene groups having 1 to 10 by the term "C _1-4 -alkylene" 4 carbon atoms understood. Preferred are alkylene groups having 1 to 4 carbon atoms. For example: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1, 1-dimethylethylene, 1, 2-dimethylethylene, pentylene, 1, 1-dimethylpropylene, 2,2, -dimethylpropylene, 1, 2-dimethylpropylene, 1, 3

Dimethylpropylene or hexylene. Unless otherwise stated, the definitions propylene, butylene, pentylene and hexylene include all conceivable isomeric forms of the respective radicals of the same carbon number. For example, propyl also includes 1-methylethylene and butylene includes 1-methylpropylene, 1, 1-dimethylethylene, 1, 2-dimethylethylene.

Alkenyl groups (including those which are part of other groups) are branched and unbranched alkenyl groups having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms. considered lenstoffatomen, more preferably 2-3 carbon atoms, as far as they have at least one double bond. Examples which may be mentioned are: ethenyl, propenyl, butenyl, pentenyl, etc. Unless stated otherwise, all the possible isomeric forms are included in the abovementioned designations propenyl, butenyl, etc. For example, the term butylene includes n-butenyl, 1-methylpropenyl, 2-methylpropenyl, 1,1-dimethylethenyl, 1,2-dimethylethenyl, etc.

Unless otherwise stated, one or more hydrogen atoms in the abovementioned alkenyl groups may optionally be replaced by other radicals. For example, these alkenyl groups may be substituted by the halogen atoms fluorine, chlorine, bromine or iodine. Preferably, the substituents are fluorine and chlorine. If appropriate, all hydrogen atoms of the alkenyl group may also be replaced.

The term "C ₂ - ₆ alkenylene" (including those which are part of other groups) are meant branched and unbranched alkenylene groups with 2 to 6 carbon atoms understood and the term "C _2-4 alkenylene" refers to branched and unbranched alkylene understood lengruppen having 2 to 4 carbon atoms. Alkenylene groups having 2 to 4 carbon atoms are preferred. Examples include: ethenylene, propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene, 1, 1-dimethylethenylene, 1, 2-dimethylethenylene, pentenylene, 1, 1-dimethylpropenylene, 2,2-dimethylpropenylene, 1, 2-dimethylpropenylene, 1, 3-dimethylpropenylene or hexenylene. Unless otherwise stated, the definitions propenylene, butenylene, pentenylene and hexenylene include all conceivable isomeric forms of the respective radicals of equal carbon number. For example, propenyl also includes 1-methylethenylene and butenylene includes 1-methylpropenylene, 1, 1-dimethylethenylene, 1, 2-dimethylethenylene.

Alkynyl groups (even if they are part of other groups) are branched and unbranched alkynyl groups having 2 to 10 carbon atoms, provided they have at least one triple bond, for example ethynyl, propargyl, butynyl, pentynyl, hexynyl etc., preferably ethynyl or propynyl. Preferred are alkynyl groups having 2 to 4 carbon atoms. Examples include: ethynyl, propynyl, butynyl, pentynyl, or hexynyl. Unless otherwise stated, the definitions of propynyl, butynyl, pentynyl and hexynyl include all conceivable isomeric forms of the respective radicals. For example, propynyl includes 1-propynyl and 2-propynyl, butynyl includes 1-, 2- and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl, etc.

Unless otherwise stated, one or more hydrogen atoms in the abovementioned alkynyl groups may optionally be replaced by other radicals. For example, these alkyl groups may be substituted by the halogen atoms fluorine, chlorine, bromine or iodine. Preferably, the substituents are fluorine and chlorine. Optionally, all hydrogen atoms of the alkynyl group may also be replaced.

The term "C ₂ - ₆ alkynylene" (including those which are part of other groups) advertising the branched and unbranched alkynylene groups with 2 to 6 carbon atoms and by the term "C _2-4 alkynylene" are meant branched and unbranched Alkylengrup- understood pen with 2 to 4 carbon atoms. Alkynylene groups having 2 to 4 carbon atoms are preferred. Examples include: ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1, 1-dimethylethynylene, 1, 2-dimethylethynylene, pentynylene, 1, 1-dimethylpropynylene, 2,2-dimethylpropynylene, 1, 2 Dimethylpropynylene, 1, 3-dimethylpropynylene or hexynylene. Unless otherwise stated, the definitions propynylene, butynylene, pentynylene and hexynylene include all conceivable isomeric forms of the respective radicals of the same carbon number. For example, propynyl also includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 1, 1-dimethylethynylene, 1, 2-dimethylethynylene.

Cycloalkyl radicals (including those which are part of other radicals) are saturated cycloalkyl radicals having 3-8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cyclooctyl, preferably cyclopropyl, cyclopentyl or cyclohexyl, where each the cycloalkyl radicals mentioned above may optionally bear one or more substituents or may be fused to a benzene ring. In addition, the cycloalkyl radicals can form, in addition to monocyclic, bicyclic, bridged or spirocyclic ring systems.

Cycloalkenyl (including those which are part of other radicals) are cyclic alkyl groups having 5 to 8, preferably 5 or 6, carbon atoms which contain one or two double bonds. For example: cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, Cyclooctenyl or cyclooctadienyl. In addition, the cycloalkenyl radicals can form, in addition to monocyclic radicals, bicyclic, bridged or spirocyclic ring systems.

As cycloalkynyl (including those which are part of other radicals) are meant cyclic alkyl groups having 5 to 8, preferably 5 or 6, carbon atoms which contain one or two triple bonds. Examples include: cyclopentynyl, cyclopentadinyl, cyclohexynyl, cyclohexadinyl, cycloheptinyl, cycloheptadiynyl, cyclooctynyl or cyclooctadinyl. In addition, the cycloalkynyl radicals can also form bicyclic, bridged or spirocyclic ring systems in addition to monocyclic compounds.

As haloalkyl (including those which are part of other radicals) are branched and unbranched alkyl groups having 1 to 6 carbon atoms, in which one or more hydrogen atoms by a halogen atom selected from the group fluorine, chlorine or bromine, preferably fluorine and chlorine, are exchanged. The term "C _1-4 -haloalkyl" means correspondingly branched and unbranched alkyl groups having 1 to 4 carbon atoms, in which one or more hydrogen atoms have been exchanged analogously as described above. Ci is preferred _-4 -haloalkyl. For example: CH ₂ F, CHF ₂ , CF ₃ .

The term aryl represents an aromatic ring system having 6 to 14 carbon atoms, preferably 6 or 10 carbon atoms, for example phenyl or naphthyl, preferably phenyl, which, unless otherwise specified, may carry, for example, one or more substituents. Further, any of the above-mentioned aryl systems may be optionally fused to a heterocycloalkyl group or a cycloalkyl group. Examples are: 2,3-dihydro-benzo [1,4] dioxin, benzo [1,3] dioxole, 1,2,3,4-tetrahydro-naphthalene and 3,4-dihydro-1H-quinoline. 2-one.

As heterocycloalkyl radicals are, unless otherwise described in the definitions, 5-, 6- or 7-membered, saturated or unsaturated, mono- or bicyclic heterocycles in which up to four carbon atoms by one or more hetero atoms selected from the group oxygen , Nitrogen or sulfur may be substituted, for example tetrahydrofuran, tetrahydrofuranone, γ-butylrolactone, α-pyran, γ-pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, thiolane, dithiolane, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, Imidazoline, imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, razin, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepane, oxazine, tetrahydrooxazinyl, isothiazole, pyrazolidine, preferably pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrahydro-oxazinyl, called the heterocycle optionally, preferably by fluorine or methyl, may be substituted. The ring may be linked to the molecule via a carbon atom or, if present, via a nitrogen atom.

Unless otherwise stated, a heterocyclic ring may be provided with a keto group. As an example for this are called.

Examples of 5-10-membered bicyclic heterorings are pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyridine,

As heteroaryl 5-10-membered mono- or bicyclic heteroaryl rings in which up to three carbon atoms may be replaced by one or more hetero atoms selected from the group oxygen, nitrogen or sulfur, which contain so many conjugated double bonds, that an aromatic system is formed. Each of the above heterocycles may optionally be further fused to a benzene ring. Preferred examples of fused heteroaryl radicals are: benzimidazole, indole and pyrimidopyrimidine. Furthermore, each of the above-mentioned heterocycles may be optionally fused to a heterocycloalkyl group or a cycloalkyl group.

Unless otherwise specified, the heteroaryl rings may, for example, carry one or more substituents, preferably halogen or methyl. The ring may be linked to the molecule via a carbon atom or, if present, via a nitrogen atom. As examples of five- or six-membered heterocyclic aromatic compounds, there are mentioned:

Examples of 5-10 membered bicyclic heteroaryl rings include pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine.

The term heterocyclic spiro rings ("spiro") is understood to mean 5-10-membered, spirocyclic rings which may optionally contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, in which case the ring can be attached via a carbon atom or if present, be linked to the molecule via a nitrogen atom. Unless otherwise stated, a spirocyclic ring may be provided with a keto group. As examples are mentioned:

Unless otherwise specified, the term "optionally substituted" in the context of the invention means the named group which is optionally substituted by a lower-molecular radical. Low-molecular radicals are understood to be chemically meaningful groups consisting of 1-200 atoms. Preferably, such groups have no negative effect on the pharmacological activity of the compounds. For example, the groups may include:

Straight or branched carbon chains, optionally interrupted by heteroatoms, optionally substituted by rings, heteroatoms or other common functional groups.

Aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms, which in turn may be substituted with functional groups.

A plurality of aromatic or nonaromatic ring systems consisting of carbon atoms and optionally heteroatoms, which may be linked by one or more carbon chains, optionally interrupted by heteroatoms, optionally substituted by heteroatoms or other common functional groups.

"= O" means an oxygen atom linked via a double bond.

The halogen is generally fluorine, chlorine, bromine or iodine.

The compounds according to the invention may be in the form of the individual optical isomers, mixtures of the individual enantiomers, diastereomers or racemates, in the form of tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids - for example acid addition salts with hydrohalic acids, for example or hydrobromic acid, or organic acids such as oxalic, fumaric, diglycolic or methanesulfonic acid.

If in the structural formula of a substituent a one-sided open hyphen "-" is used, this hyphen is to be understood as a connection point to the remainder of the molecule. The substituent takes the place of the corresponding radicals R ² , R ⁶ , etc. Unless the unilaterally open hyphen is used in the structural formula of a substituent, the point of attachment to the rest of the molecule clearly results from the structural formula itself.

The substituent R ^a may be hydrogen or an optionally substituted radical selected from the group consisting of -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ - cycloalkyl, C ₃ -C C ₈ -C 10 -cycloalkenyl, C ₁ -C ₆ -haloalkyl, C ₆ -C ₄ -ar / C ₁ -C ₆ -acyl-C ₁ -C ₆ -alkyl-, C ₅ -C 10 -heteroaryl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₄ - alkyl-, C ₃ -C ₈ alkyl cycloalkenyl-Ci-C _4, C ₅ -C ₀ - alkyl- heteroaryl Ci-C _4, spiro, C ₃ -C ₈ -heterocycloalkyl and C ₃ -C ₈ Heterocycloalkyl-C ₁ -C ₄ -alkyl-, preferably phenyl, wherein R ^{a is} preferably substituted by one or more, preferably one or two, radicals selected from the group consisting of C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ alkynyl, C ₃ - Cβ cycloalkyl, C _r C ₆ haloalkyl, halogen, OH, C _r C ₄ alkoxy, CN, NO _2, NR ¹⁰ R ^11, OR ^10, COR ^10, COOR ¹⁰ , CONR ¹⁰ R ¹¹ , NR ¹⁰ COR ¹¹ , NR ¹⁰ (CO) NR ¹¹ R ¹² , 0 (CO) NR ¹⁰ R ¹¹ , NR ¹⁰ (CO) OR ¹¹ , SO ₂ R ¹⁰ , SOR ¹⁰ , SO ₂ NR ¹⁰ R ¹¹ , NR ¹⁰ SO ₂ NR ¹¹ R ¹² and NR ¹⁰ SO ₂ R ¹¹ , b preferably dC ₆ -haloalkyl, halogen and CONR10R ¹¹ , particularly preferably CF ₃ , F, Cl, Br and CONHCH ₃ , may be substituted.

More preferably R ^{a represents} phenyl substituted by one or more of the radicals selected from the group consisting of CF ₃ , F, Cl, Br and CONHCH ₃ . Also particularly preferably, R ^{a is} butyl.

The substituents R ¹⁰ , R ¹¹ , R ^12, identical or different, may be hydrogen or a radical selected from the group consisting of the group consisting of C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl , C ₃ -C ₈ cycloalkyl and C _r C ₆ haloalkyl; or in each case two of the radicals

R ¹⁰ , R ¹¹ , R ¹² together form a five-, six- or seven-membered ring consisting of carbon atoms and optionally 1-2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen.

The substituent R ^b may be hydrogen, OH or NH _2, or an optionally substituted radical selected from the group consisting of Ci-C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₈ cycloalkenyl, C _r C ₆ - haloalkyl, C ₆ -C ₄ aryl, C ₆ -C ₄ aryl-Ci-C ₅ alkyl, C ₅ -C ₀ -heteroaryl, C ₃ -C ₈ -cycloalkyl-C _r C ₄ -alkyl-, C ₃ -C ₈ -cycloalkenyl-C _r C ₄ -alkyl-, C ₅ -C 10 -heteroaryl-C ₁ -C ₄ -alkyl-, spiro, C ₃ -C ₈ - Heterocycloalkyl, CONH _2, C ₆ -C ₄ aryl-NH-, d-Cβ-heterocycloalkyl NH and OC _r C ₃ alkyl, preferably unsubstituted or substituted with one or more of the radicals, the same or different, selected from the group consisting of d-Cβ-alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C _r C ₆ haloalkyl, halogen, OH, OMe, CN, NH ₂ , NHMe and NMe ₂ may be substituted.

Preferably, R ^{b is} hydrogen OH or NH ₂ or a radical selected from the group consisting of C _r C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₆ -C ₄ -aryl, haloalkyl, C ₅ -C 10 -heteroaryl and C ₆ -C ₄ -aryl-NH- which is optionally substituted by one or more of the radicals, identical or different, selected from the group consisting of d-ce Alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C _r C ₆ haloalkyl, halo, OH, OMe, CN, NH ₂ , NHMe, NMe ₂ can. Particularly preferably, R ^{b is} hydrogen.

The substituent R ¹ may represent hydrogen or an optionally substituted radical selected from the group consisting of -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ - alkynyl, and Cβ-C _M -Aryl-Ci-Cs-alkyl- mean. Preferably, R ^{1 is} hydrogen, C ₁ -C ₅ -alkyl or C ₃ -C ₈ -cycloalkyl. Particularly preferably, the substituent R ^{1 is} hydrogen or a radical selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, cyclobutyl and piperidine, particularly preferably R ^{1 is} hydrogen or methyl. The substituent R ¹ may preferably be substituted by one or more of the radicals, identically or differently, selected from the group consisting of halogen, COOH, NH ₂ , OH, CN, C 1 -C 6 -alkyl, OMe, -NH (CO) alkyl and (CO) OC _r C ₄ alkyl substituted.

The substituent R ² may represent hydrogen or an optionally substituted radical selected from the group consisting of -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl, C ₃ -C ₈ cycloalkenyl, C _r C ₆ - haloalkyl, C ₆ -C ₄ aryl, Ce-Cu-aryl-Ci-Cs-alkyl, C ₅ -C ₀ - alkyl heteroaryl, C ₃ -C ₈ cycloalkyl-C _r C _4, C ₃ - C ₈ cycloalkenyl-C _r C ₄ alkyl, C ₅ -C ₀ - heteroaryl-Ci-C ₆ alkyl, C ₃ -C ₉ spiro, C ₃ -C ₈ -heterocycloalkyl, C ₃ -C ₈ -heterocycloalkyl-d- C ₆ alkyl and C _Ce-M aryl-Ci-Cβ-alkyl; mean. Preferably, R ^{2 is} hydrogen or a radical selected from the group consisting of C ₁ -C ₅ -alkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₄ -alkyl, C ₆ -C ₄ -aryl-C ₁ -C ₅ -alkyl, C ₃ -C ₈ -heterocycloalkyl-Ci-C ₆ alkyl and C ₅ -C ₀ - heteroaryl-CrC ₆ alkyl. More preferably, R ^{2 is} hydrogen or a radical selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, C ₃ -Ce- cycloalkyl and phenyl, particularly preferably hydrogen or methyl. The substituent R ² may preferably be substituted by one or more of the radicals, identical or different, selected from the group consisting of halogen, NH ₂ , OH, CN, C 1 -C 6 -alkyl, OMe, -NH (CO) alkyl and (CO) OC _r C ₄ alkyl substituted.

The substituents R ¹ and R ² may together form an optionally substituted, five-, six- or seven-membered ring consisting of carbon atoms and optionally 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, preferably nitrogen. The group NR ¹ R ² particularly preferably represents an optionally substituted pyrrolidinyl or morpholine radical. The ring formed from the substituents R ¹ and R ² may preferably with one or more of the radicals, the same or different, selected from the group consisting of heterocycloalkyl, halogen, NH _2, OH, CN, C _r C ₆ alkyl, OMe, -NH (CO) alkyl and - (CO) O-C 1 -C ₄ -alkyl.

The substituents R ¹ and R ² may together form an optionally substituted nine- to thirteen-membered spirocyclic ring, preferably

, which is preferably substituted by a

Residue selected from the group consisting of methyl, ethyl, OH, = O and phenyl.

The substituent R may further be a group selected from the group consisting of the general formulas (A1) to (A18)

preferably (A1), (A2), (A3), (A6), (A8), (A10), (A1 1), (A17) and (A18).

X and Y may be linked to the same or different G atoms.

X can be a bond or an optionally substituted radical selected from the group consisting of -C ₇ -alkylene, C ₃ -C ₇ -alkenylene and C ₃ -C ₇ -alkynylene, preferably a bond, methylene and ethylene radical. X may together with R ¹ , R ³ or R ^{4 form} a C 1 -C ₇ -alkylene bridge, preferably a 5- or θ-membered heterocycle with R ¹ , R ³ or R ⁴ , more preferably a piperidinone or pyrrolidines - Ring with R ³ or R ^{4 may} optionally be substituted. The substituent R1 and X together preferably form a pyrrolidine or piperidine radical.

Y may be a bond or optionally substituted C 1 -C ₄ -alkylene, preferably a bond, methylene or ethylene.

Q is an optionally substituted radical selected from the group consisting of -C ₇ -alkylene, C ₃ -C ₇ -alkenylene and C ₃ -C ₇ alkynylene; preferably optionally substituted CrC ₃ alkylene, particularly preferably ethyl and propyl mean. Q may together with R ¹ , R ³ or R ^{4 form} a C 1 -C ₇ -alkylene bridge. R1 and Q preferably form a pyrrolidine or piperidine radical.

The substituents R ³ , R ⁴ , R ⁵ may be identical or different, hydrogen or an optionally substituted radical selected from the group consisting of Ci-Cβ-alkyl, C ₃ - Cs-cycloalkyl, C ₂ -C ₆ haloalkyl, Ci C ₄ alkyl C ₃ C ₈ cycloalkyl, C ₃ C ₈ cycloalkyl C _r C ₄ alkyl, NR ⁷ R ⁸ , NR ⁷ R ⁸ C _r C ₄ alkyl, C _r C ₄ alkoxy, Ci-C ₄ -alkoxy-C _r C ₄ alkyl, C ₆ -C ₄ aryl and C ₅ -Cio-heteroaryl; preferably hydrogen or an optionally substituted radical selected from the group consisting of dC ₄ alkyl, dC ₄ alkoxy and C ₃ -C ₆ - cycloalkyl, more preferably hydrogen, methyl, methoxy, ethoxy, propyloxy, butylene loxy, cyclopropyl and Cyclopentyl mean.

In each case two of the substituents R ³ , R ⁴ , R ⁵ may together form an optionally substituted five-, six- or seven-membered ring, preferably 5- or 6-membered ring, consisting of carbon atoms and optionally 1-2 heteroatoms, selected from the group consisting of oxygen, sulfur and nitrogen; preferably from oxygen or nitrogen. The radical NR ³ R ⁴ preferably denotes pyrrolidine, piperidine or morpholine.

The substituents R ³ , R ⁴ , R ⁵ or the ring formed therefrom can preferably be reacted with one or more of the radicals, identical or different, selected from the group be standing of halogen, NH _2, OH, CN, NR ⁹ R ^10, -NH (CO) -C _r C ₄ alkyl and MeO.

A may be N or CH, preferably N.

G may be a saturated, partially saturated or unsaturated ring system of 3-10 C atoms, wherein optionally up to 4 C atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; mean. G may preferably be a saturated, partially saturated or unsaturated ring system of 3-8 C atoms, more preferably of 5-6 C atoms, wherein optionally up to 6 C atoms, more preferably up to 4 C atoms are selected by heteroatoms from the group consisting of nitrogen, oxygen and sulfur, mean. G is preferably a ring system consisting of one or two 5-6 membered rings, more preferably selected from the group consisting of furan, cyclohexyl, cyclopropyl, phenyl, pyrrolidine, piperidine, tetrahydroquinoline, tetrahydroisoquinoline, indole, dihydroisoindole, piperazine, pyrrole , Pyrazole, pyridine, imidazolidine, imidazole, thiophene, thiazole, triazole, oxazole, oxadiazole, tetrazole, morpholine, benzimidazole, benzopyrrole, benzodioxole, and dihydrobenzo [1, 4] dioxines, particularly preferably furan, cyclohexyl, Cyclopropyl, phenyl, pyrrolidine, piperidine, tetrahydroquinoline, tetrahydroisoquinoline, dihydroisindole, pyrrole, pyrazole, pyridine, imidazolidine, imidazole, thiophene, thiazole, oxazole, oxadiazole, tetrazole, morpholine, benzimidazole, benzodioxole, and dihydrobenzo [1 , 4] dioxine.

The substituent R ⁶ may be the same or different, is hydrogen or an optionally substituted radical selected from the group consisting of, -C ₈ alkyl, C ₂ -C ₆ - alkenyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ haloalkyl, C ₆ -C ₄ aryl, C ₅ -C ₀ heteroaryl, C ₃ -C ₈ -

Heterocycloalkyl, preferably hydrogen or an optionally substituted radical selected from the group consisting of dC ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ -C ₄ aryl, C ₅ - C ₆ heterocycloalkyl, and C ₅ -C ₆ heteroaryl, more preferably hydrogen or an optionally substituted radical selected from the group consisting of CrC ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₅ -C ₆ heterocycloalkyl, C ₅ -C ₆ heteroaryl and phenyl. or a radical selected from the group consisting of = O, NR ⁷ R ⁸ , OR ⁷ , -CO-CrC ₃ -alkyl- NR ⁷ R ⁸ -O-Ci-C ₃ -alkyl-NR ⁷ R ⁸ , CONR ⁷ R ⁸ , NR ⁷ COR ⁸ , NR ⁷ (CO) OR ⁸ , -CO-C _r C ₃ -alkyl-NR ⁷ (CO) OR ⁸ , -O (CO) NR ⁷ R ⁸ , NR ⁷ (CO) NR ⁸ R ⁹ , NR ⁷ (CO) OR ⁸ , (CO) OR ⁷ , -O (CO) R ⁷ , COR ⁷ , (SO) R ⁷ , (SO ₂ ) R ⁷ , (SO ₂ ) NR ⁷ R ⁸ , NR ⁷ (SO ₂ ) R ⁸ , NR ⁷ (SO ₂ ) NR ⁸ R ⁹ , CN and halogen; preferably a radical selected from the group consisting of = O, NR ⁷ R ⁸ , OR ⁷ , -CO- C _r C ₃ -alkyl-NR ⁷ R ⁸ CONR ⁷ R ⁸ , NR ⁷ (CO) OR ⁸ , NR ⁷ COR ⁸ , -CO-C _r C ₃ -alkyl-NR ⁷ (CO) OR ⁸ , NR ⁷ (CO) NR ⁸ R ⁹ NR ⁷ (CO) OR ⁸ , (CO) OR ⁷ , COR ⁷ , (SO ₂ ) R ⁷ and CN, more preferably = O, OMe, -NMe-CO-NH-d-Cs-alkyl, -NH-CO-C _r C ₄ -alkyl, -NH-COO-C _r C ₄ -alkyl, -COO- C _r C ₄ alkyl and C _r C ₄ alkyl.

More preferably, the substituent R ^{6 may be} hydrogen or a radical selected from the group consisting of = O, OH, CN, CF ₃ , NH ₂ OCF ₃ NHCOMe, NHCO-butyl, NHCO-cyclopentyl, NHCOCyclopropyl, NHCO-morpholine, NHCO-NHMe , NHCO-NH-propyl, NHCO-NMeMe, NHCO-NMePropyl, NHCOPropyl, NHCO-pyrrolidine, NHSO ₂ -Me, CONH ₂ CONH, COOH, CONHMe, CONHPropyl, CONMe ₂ CONMe-butyl, CONMe, CONH-cyclohexyl, CONH-cyclopropyl, COO-butyl, SO ₂ Me, NHSO ₂ -NMeMe, NMe ₂ , NMeCOMe, NMeCOOButyl, NMeMe, phenyl, methyl, ethyl, propyl, butyl, methoxy, phenyl, oxazolidine, morpholine, imidazole, imidazolidine, pyrazole, piperazine, piperidine, Pyrimidine, pyrrolidine, pyrrolidine-CO-, cyclopropyl, cyclopentyl and cyclohexyl.

The substituent R ⁶ can preferably have one or more of the radicals, identical or different, selected from the group consisting of 0O, NH ₂ , NHMe, NMe ₂ OH, OMe, CN, -Ci-C ₃ -alkyl-C ₆ -C ₄ -aryl, -NH-CO-N HC _r C ₃ alkyl and - (CO) OC _r C ₄ alkyl substituted.

n is 1, 2 or 3, preferably 1 or 2, more preferably 1.

The substituents R ⁷ , R ⁸ , R ⁹ may be identical or different, hydrogen or an optionally substituted radical selected from the group consisting of C 1 -C ₈ -alkyl, C ₃ -C 6 -cycloalkyl, C _r C ₆ haloalkyl, Ci-C ₄ alkyl-C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ cycloalkyl-C _r C ₃ - alkyl, C ₆ -C ₄ aryl, Ci-C ₄ alkyl C ₆ -C ₄ -aryl, C ₆ -C ₄ -aryl-C ₁ -C ₄ -alkyl, C ₃ -C ₈ -heterocycloalkyl, C ₁ -C ₅ -alkyl-C ₃ -C ₈ -heterocycloalkyl, C ₃ - C ₈ heterocycloalkyl-CrC ₄ alkyl, C _r C ₄ alkyl (CO) - and C _r C ₄ alkyl-O (CO) -; preferably C _r C ₄ alkyl, C _r C ₂ haloalkyl, C _r C alkyl ₄ -cycloalkyl-C ₃ -C _8, C ₃ -C ₈ cycloalkyl-alkyl- C _r C _3, phenyl, C -C ₄ alkyl-C ₆ -C ₄ -aryl, C ₃ -C ₈ -heterocycloalkyl, C ₁ -C ₅ -alkyl-C ₃ -C ₈ -heterocycloalkyl, C _r C ₄ -alkyl (CO) - and C _r C ₄ - alkyl-O (CO) -, most preferably C _r C ₅ alkyl, _{Ci-C4-alkyl-C6-Ci 4} -aryl, C ₃ -C ₆ - heterocycloalkyl and -C ₅ alkyl-C ₃ -C ₈ -heterocycloalkyl-, mean or in each case two of the substituents R ⁷ , R ⁸ , R ⁹ together form an optionally substituted five-, six- or seven-membered ring consisting of carbon atoms and optionally 1-2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; preferably an optionally substituted five- or six-membered ring consisting of carbon atoms and optionally 1-2 heteroatoms selected from the group consisting of oxygen and nitrogen; especially preferably nitrogen, The substituents R ⁷ , R ⁸ , R ⁹ or the ring system formed therefrom can preferably with one or more of the radicals, identically or differently, selected from the group consisting of halogen, NH ₂ , OH, CN, OMe, NHMe , NMe ₂ d-Ce-alkyl and (CO) OC _r C ₆ alkyl substituted.

PRODUCTION METHOD

The compounds of the general formula (I) can be prepared by the following synthesis schemes (Schemes 1-5), where the substituents of the general formula (I) have the abovementioned meanings. These methods are to be understood as an explanation of the invention without limiting the same to their subject matter.

Scheme 1:

By deprotonation of the intermediate compound (IV) with a suitable base selected, for example, but not limited to the group of sodium methylate, sodium ethylate, lithium hexamethylsilazide sodium hydride with a suitable acylating reagent (V) are converted into the intermediate compound (VI). Rb has the meanings given above. Rz is a suitable leaving group selected, for example, but not limited to the group halogen, S-alkyl, S-aryl, O-alkylsulfonyl, O-arylsulfonyl, O-alkyl, imizazole, O-hetaryl, O-acyl, O-aryl where O-aryl may optionally be substituted by suitable electron-withdrawing groups (eg nitro). By reaction with a suitable amidine (VII) or one of its salts, the intermediate (VIII) is obtained. Ra has the meanings given above. The compound thus obtained is then removed by cleavage of the acetyl group (eg by acidic or basic Saponification or reaction with hydrazine hydrate) into the free aminothiazole (IX). The conversion to the ureas of the general formula (I) or (Ia) is then carried out using one of the following methods: Direct reaction with a suitable isocyanate (XIII) leads directly to compounds of the formula (Ia). Reaction with a suitable reagent (XIV) leads to compounds of the formula (I) where Rx is a suitable leaving group selected, for example, but not limited to the group halogen, S-alkyl, S-aryl, O-alkylsulfonyl, O-arylsulfonyl, O-alkyl, imizazole, O-hetaryl, O-acyl, O-aryl, where O-aryl may optionally be substituted by suitable electron-withdrawing groups (eg nitro). Another possibility is the reaction of the aminothiazole (IX) with a reagent of the general formula (X) to form an activated intermediate compound (XI). Rx and Ry are the same or suitable leaving groups selected, for example, but not limited to the group halogen, S-alkyl, S-aryl, O-alkylsulfonyl, O-arylsulfonyl, O-alkyl, imizazole, O-hetaryl, O-acyl , O-aryl, where O-aryl may optionally be substituted by suitable electron-withdrawing groups (eg nitro). Depending on the nature of the leaving group and the temperature, the intermediate (XI) may be in equilibrium with the isocyanate (XII) which may be formed by elimination of the leaving group Ry (XI). The further reaction of the intermediate compound (XI), (XII) or a mixture of both with suitable amines of the general formula (XV) leads to the desired compounds of the general formula (I). R ¹ and R ² have the meanings given above.

Scheme 2:

By reacting the intermediate compound (XI) with a reagent of the general formula (XVI), the intermediate compound (XVII) is obtained. PG1 is a suitable nitrogen protecting group selected, for example, but not limited to the group alkyl carbonyl (carbamates), phthalic acid, benzyl (optionally substituted, for example, p-methoxybenzyl). The reagent (XVI) can be used as one of the two possible enantiomers or as a racemate. After cleavage of the protective group PG1, the intermediate compound (XVIII) can be obtained. Reaction of this intermediate compound with reagents of the type (XIX), (XX), (XXI), (XXII), (XXIII) or (XXIV) gives the compounds (Ib), (Ic), (Id), (Ie), (If) or (Ig). R ⁵ and R ⁶ have the meanings described above. Rx and Rv are suitable leaving groups selected, for example, but not limited to the group halogen, S-alkyl, S-aryl, O-alkylsulfonyl, O-arylsulfonyl, O-alkyl, imizazole, O-hetaryl, O-acyl, O- Aryl, where O-aryl may optionally be substituted by suitable electron-withdrawing groups (eg nitro). Alternatively, the compounds of general formula (Ig) can be prepared analogously to the procedure described in Scheme 1 by reacting intermediate compound (XVIII) with the previously described, reagent of formula (X) and subsequent reaction of the resulting intermediate (XXV) with suitable amines of the formula (XXV). R ³ and R ⁴ also have the meanings described above.

Scheme 3:

By reacting the intermediate compound (XI) with the amino acid (XXVI), the carboxylic acid (XXVII) can be obtained which, after suitable activation by methods known from the literature, can be reacted with amines of the formula (XXV) described above. In this case, compounds of the general formula (Ih) are obtained. R ³ and R ⁴ have the meanings described above.

Scheme 4:

By reacting the intermediate compound (XI) with a reagent of the formula (XXVIII), compounds of the general formula (XXIX) are obtained. PG1 is a suitable nitrogen protecting group selected, for example, but not limited to the group alkylcarbonyl (carbamates), phthalic acid, benzyl (optionally substituted eg p-). Methoxybenzyl). After cleavage of the protective group PG1, the intermediate compound (XXX) can be obtained. Compounds of the general formula (Ii) and (Ij) can be obtained by reacting the intermediate compound (XXX) with the previously described reagents of the formula (XXIII) or (XXIV). Alternatively, the compounds of the general formula (Ij) can also be reacted analogously to the procedure described in Scheme 1 by reacting the intermediate compound (XXX) with the previously described reagent of the formula (X) and then reacting the resulting intermediate compound (XXXI) suitable amines of the formula (XXV). R ³ and R ⁴ also have the meanings described above. R ⁵ and R ⁶ have the meanings described above.

Scheme 5:

By reaction of the intermediate compound (XI) with the amino acid (XXXII), the carboxylic acid (XXXIII) can be obtained which, after suitable activation by methods known from the literature, can be reacted with amines of the formula (XXV) described above. In this case, compounds of the general formula (Ik), as well as by-products of the general formula (XXXIV) are obtained. The latter can be separated from the desired products by chromatographic methods. R ³ and R ⁴ have the meanings described above. The novel compounds of the general formula (I) can be prepared analogously to the following examples. The examples described below are to be understood as illustrative of the invention without, however, limiting it.

Synthesis of reagents:

2-chloro-3-fluorobenzamidine (VII.1):

320 ml (0.32 mmol) of a 1 molar solution of lithium hexamethyldisilazide (LiHMDS) in hexane are introduced into 800 ml of diethyl ether and treated at room temperature with 25.0 g (0.161) of 2-chloro-3-fluoro-benzonitrile. It is stirred for 2 h at room temperature and after cooling to 0 ° C with 280 ml of 3 normal hydrochloric acid. The precipitate is filtered off with suction, washed with water and dried. Yield: 16.5 g (49% of theory).

3-Isopropylbenzylamine hydrochloride (XV.1):

3-isopropyl-benzonitrile:

5.15 g (25.87 mmol) of m-bromo-isopropylbenzene and 2.69 g (30.04 mmol) of copper cyanide are stirred in 2.50 ml of pyridine at 180 ° C. for 24 hours. Then 15 ml of water, 15 ml of toluene and 15 ml of conc. Ammonia solution added, then extracted. The organic phase is dried and evaporated to dryness. Yield: 5.00 g (100% of theory)

3-Isopropylbenzylamine hydrochloride (XV.1):

5.00 g (34.43 mmol) of 3-isopropylbenzonitrile and 5.00 g of Raney nickel are hydrogenated in 500 ml of ammonia ammonia solution for 8 hours at room temperature and a pressure of 50 psi. After filtering off the catalyst is evaporated, the residue precipitated as the hydrochloride. Yield: 2.90 g (45% of theory)

Synthesis of the reagent (XV.2)

1- (2-Chloro-ethyl) -3- (3-cyano-phenyl) -urea:

65.00 g (550 mmol) of 3-amino-benzonitrile are dissolved in 450 ml of dioxane, 56 ml (660 mmol) of 1-chloro-2-isocyanato-ethane dissolved in 60 ml of dioxane are added dropwise. The reaction mixture is stirred at 60 ° C. for 3 hours and at room temperature for 16 hours. The precipitate is then filtered off with suction, washed with diethyl ether and dried. Yield: 110.00 g (90% of theory) mp: 138 ° -139 ° C

3- (2-oxo-imidazolidin-1-yl) benzonitrile:

1 10.00 g (490 mmol) of 1- (2-chloro-ethyl) -3- (3-cyano-phenyl) -urea are dissolved in 2000 ml of ethanol at 50 ° C. and a solution of 42.00 g (640 g) is added mmol) potassium hydroxide in 390 ml ethanol added within 1, 5 hours. The reaction mixture is stirred for 16 hours at room temperature, then precipitated precipitate is filtered off with suction, washed with water and dried. Yield: 68.00 g (75% of theory) mp: 149 ° -150 ° C

1- (3-Aminomethyl-phenyl) -imidazolidin-2-one hydrochloride (XV.2): 40.00 g (210 mmol) of 3- (2-oxo-imidazolidin-1-yl) -benzonitrile are suspended in 1500 ml of methanol, 53 ml of 37% hydrochloric acid are added. It is hydrogenated for 20 hours at room temperature and a pressure of 7 bar with 4.00 g of palladium / carbon. The catalyst is filtered off, the filtrate is concentrated and the resulting precipitate is filtered off with suction, washed with acetone and dried. Yield: 42.00 g (88% of theory) mp: 238 ° -239 ° C

Synthesis of the reagent (XV.3)

(3-Amino-benzyl) -carbamic acid tert-butyl ester:

9.35 g (76.49 mmol) of 3-aminomethyl-phenylamine are dissolved in 200 ml of dichloromethane and 100 ml of tetrahydrofuran, and a solution of 17.03 g (78.02 mmol) of Boc anhydride in 200 ml of dichloromethane is added dropwise. It is stirred for 2.5 hours at room temperature, then evaporated. The residue is precipitated as the hydrochloride. Yield: 17.48 g (88% of theory)

Tert-Butyl 3- (4-chloro-butyrylamino) -benzyl] -carbamate:

1.00 g (4.46 mmol) of (3-aminobenzyl) -carbamic acid tert-butyl ester are liberated as base, then initially charged in 40 ml of chloroform, 1.20 ml (8.66 mmol) of triethylamine and 0.50 ml (4.46 mmol) of 4-chlorobutyryl chloride. The reaction mixture is stirred for 16 hours at room temperature, then extracted with chloroform and water and sodium carbonate solution. The organic phase is dried and evaporated to dryness. Yield: 1.20 g (95% of theory)

[3- (2-Oxo-pyrrolidin-1-yl) -benzyl] -carbamic acid tert-butyl ester:

1.20 g (3.67 mmol) of tert-butyl 3- (4-chloro-butyrylamino) benzyl] -carbamate and 0.950 g (8.47 mmol) of potassium tert-butoxide are dissolved in 40 ml of tetrahydrofuran at 0 ° C submitted, stirred for 3 hours at room temperature. The reaction mixture is then added to water and extracted with dichloromethane. The organic phase is dried and evaporated to dryness. The residue is purified by chromatography. Yield: 0.500 g (47% of theory)

1- (3-aminomethyl-phenyl) -pyrrolidin-2-one hydrochloride (XV.3):

500 mg (1.72 mmol) of [3- (2-oxopyrrolidin-1-yl) -benzyl] -carbamic acid tert-butyl ester are initially charged in 2 ml of dichloromethane, 4.00 ml (8 mmol) of 2 molar ethereal hydrochloric acid added. It is stirred for 16 hours at room temperature, then evaporated. The residue is crystallized with acetone / ethanol and diethyl ether. Yield: 220 mg (56% of theory)

Synthesis of the reagent (XV.4)

[3- (tert-Butoxycarbonylamino-methyl) -phenyl] -carbamic acid 2-chloro-ethyl ester:

900 mg (3.48 mmol) of tert-butyl 3-aminobenzylcarbamate are liberated as the base, then taken up in 40 ml of tetrahydrofuran, 1.1 ml (8 mmol) of triethylamine and Added 75 ml (6.82 mmol) of 2-chloroethyl chloroformate. The reaction mixture is stirred at room temperature for 16 hours, then extracted with dichloromethane and water. The organic phase is separated off via phase separation cartridge and evaporated to dryness. Yield: 1.20 g (100% of theory)

[3- (2-Oxo-oxazolidin-3-yl) -benzyl] -carbamic acid tert-butyl ester:

1, 20 g (3.65 mmol) of [3- (tert-butoxycarbonylamino-methyl) -phenyl] -carbaminsäure 2-chloro ethyl ester and 0.850 g (7.58 mmol) of potassium tert-butoxide are at 0 ° C in 30 ml Tetrahy- drofuran presented, stirred for 3 hours at room temperature. The reaction mixture is then added to water and extracted with dichloromethane. The organic phase is dried and evaporated to dryness. The residue is purified by chromatography. Yield: 0.250 g (23% of theory)

3- (3-Aminomethylphenyl) oxazolidin-2-one hydrochloride (XV.4):

380 mg (1.30 mmol) of [3- (2-oxo-oxazolidin-3-yl) -benzyl] -carbamic acid tert-butyl ester are initially charged in 2 ml of dichloromethane, and 4.00 ml (8 mmol) of 2 molar ethereal hydrochloric acid are added , It is stirred for 16 hours at room temperature, then evaporated. The residue is lyophilized. Yield: 300 mg (100% of theory)

Synthesis of the reagent (XV.5)

3-dimethylaminomethyl-benzonitrile:

5.00 g (37.37 mmol) of 3-cyanobenzaldehyde and 20.00 ml (40 mmol) of dimethylamine (2 molar solution in tetrahydrofuran) are introduced into 150 ml of tetrahydrofuran and cooled to 0 ° C. 12.40 g (81.73 mmol) of sodium triacetoxyborohydride are added, then stirred at 0 ° C for 2 hours and at room temperature for 2 hours. The reaction mixture is mixed with 25 ml of 15% potassium carbonate solution and stirred for 0.5 hours. After addition of ethyl acetate is extracted. The organic phase is washed with potassium carbonate solution, dried and evaporated to dryness. Yield: 7.00 g (94% of theory)

3-Dimethylaminomethylbenzylamine (XV.5):

7.00 g (34.95 mmol) of 3-dimethylaminomethylbenzonitrile are introduced into 100 ml of methanolic ammonia solution, hydrogenated with 1.40 g of Raney nickel at room temperature and a pressure of 3 bar. The catalyst is filtered off, the filtrate is evaporated. The residue is purified by chromatography. Yield: 2.40 g (42% of theory)

Synthesis of the reagent (XV.6)

7,8-Dihydro-6H-imidazo [1,5-c] pyrimidin-5-one:

50.00 g (450 mmol) of histamine are dissolved in 1500 ml of dimethylformamide, 73.87 g (450 mmol) of carbonyldiimidazole added. The reaction mixture is stirred for 5 hours at 70 ° C and 16 hours at room temperature. It is then evaporated, the residue from acetonitrile stirred hot. Yield: 53.73 g (87% of theory)

2-ethyl-5-oxo-5,6,7,8-tetrahydro-imidazo [1,5-c] pyrimidine-2-ium; bromide:

1.00 g (7 mmol) of 7,8-dihydro-6H-imidazo [1,5-c] pyrimidin-5-one and 1.70 ml (21 mmol) of ethyl bromide are dissolved in 12 ml of acetonitrile at 80 ° for 16 hours ° C stirred. After cooling, the suspension is filtered off with suction, washed and dried. Yield: 1.40 g (78% of theory)

2- (1-Ethyl-1H-imidazol-4-yl) ethylamine oxalate (XV.6):

1.16 g (5 mmol) of 2-ethyl-5-oxo-5,6,7,8-tetrahydro-imidazo [1,5-c] pyrimidine-2-ium; bromide are stirred in 7 ml (14 mmol) of 2 molar hydrochloric acid for 16 hours under reflux. It is then evaporated, the residue is recrystallized from acetonitrile / ethanol. The resulting very hygroscopic crystals are neutralized and evaporated. The residue is precipitated as an oxalate and recrystallized from ethanol. Yield: 1.00 g (93% of theory) Synthesis of the reagent (XV.7)

5-oxo-2-propyl-5,6,7,8-tetrahydro-imidazo [1,5-c] pyrimidine-2-ium; bromide:

2.00 g (15 mmol) of 7,8-dihydro-6H-imidazo [1,5-c] pyrimidin-5-one and 6.83 mmol) (75 mmol) of propyl bromide are dissolved in 20 ml of acetonitrile at 85 ° for 72 hours C stirred. After cooling, the suspension is filtered off with suction, washed and dried. Yield: 3.48 g

2- (1-Propyl-1H-imidazol-4-yl) ethylamine (XV.7):

100 mg (0.384 mmol) of 5-oxo-2-propyl-5,6,7,8-tetrahydro-imidazo [1,5-c] pyrimidine-2-ium; Bromide are stirred in 192 ul (1, 15 mmol) θmolarer hydrochloric acid for 16 hours under reflux. Subsequently, the solution is lyophilized. Yield: 81, 30 mg (64% of theory)

Synthesis of the reagent (XV.8)

2- (4-ethylthiazol-2-yl) ethylamine hydrobromide (XV.8):

2.00 g (9.50 mmol) of tert. Butyl N (3-amino-3-thioxopropyl) carbamate and 1.58 g (10.45 mmol) of 1-bromo-2-butanone are stirred in 40 ml of ethanol for 16 hours under reflux. The reaction mixture is evaporated, the residue purified by chromatography. Yield: 2.00 g (89% of theory)

Synthesis of the reagent (XV.9)

[2- (2-hydroxy-butylcarbamoyl) -ethyl] -carbamic acid benzyl ester:

23.20 g (103.93 mmol) of 3-benzyloxycarbonylamino-propionic acid, 14.10 g (104.35 mmol) of 1-hydroxybenzotriazole, 18.80 ml (135.07 mmol) of triethylamine and 21.00 g (135.27 mmol) (ethyl 3- (3-dimethylamino) -propylcarbondiimide hydrochloride (EDAC) are initially charged in 150 ml of dichloromethane, cooled to 0 ° C. and stirred at this temperature for 0.75 hours, then 10.50 g (114 , 26 mmol) 1-amino-2-butanol was added, stirred for 2.5 hours at 0 ° -5 ° C. The reaction mixture was extracted with water and 1 molar sodium bicarbonate solution, the organic phase was dried and evaporated to dryness. evaporated. The residue is extracted again with dichloromethane and sodium carbonate solution. Yield: 12.30 g (40% of theory)

[2- (2-oxo-butylcarbamoyl) -ethyl] -carbamic acid benzyl ester:

2.20 ml (26.05 mmol) of oxalyl chloride are initially charged in 10 ml of dichloromethane, and the solution is cooled to -53 ° C. Slowly 2.45 ml (34.49 mmol) of dimethyl sulfoxide are added dropwise in 5 ml of dichloromethane, stirred for 0.25 hours, then a solution of 6.30 g (21, 40 mmol) of [2- (2-hydroxy-butylcarbamoyl) - ethyl] -carbamic acid benzyl ester in 30 ml of dichloromethane. It is stirred for 1, 5 hours at -60 ° C, then added dropwise 12.60 ml of triethylamine. The suspension is stirred for 1 hour at -50 ° C, then allowed to come to room temperature within 16 hours. The reaction mixture is diluted with dichloromethane, extracted with 1 molar hydrochloric acid, 1 molar sodium carbonate solution and water. The organic phase is dried and evaporated to dryness. Yield: 5.82 g (93% of theory)

[2- (5-ethyl-oxazol-2-yl) -ethyl] -carbamic acid benzyl ester:

23.07 g (49.60 mmol) of PS-triphenylphosphine are suspended in 200 ml of dichloromethane, 12.65 g (49.82 mmol) of iodine are added. It is stirred for 0.1 hours at room temperature, then added dropwise 13.80 ml (99.28 mmol) of triethylamine. 5.80 g (19.84 mmol) of [2- (2-oxo) butylcarbamoyl) ethyl] -carbamic acid benzyl ester are dissolved in 150 ml of diclormethane added. The reaction mixture is stirred at room temperature for 72 hours, then the precipitate is filtered off. The filtrate is extracted with water, the organic phase dried and evaporated to dryness. Yield: 3.35 g (31% of theory)

2- (5-ethyl-oxazol-2-yl) ethylamine (XV.9):

2.86 g (10.43 mmol) of [2- (5-ethyl-oxazol-2-yl) -ethyl] -carbamic acid benzyl ester are initially charged in 130 ml of methanol, 0.910 mg of palladium / carbon 10% are added, then 5 hours hydrogenated at room temperature and a pressure of 14 psi. The catalyst is then filtered off with suction, the solution is evaporated. Yield: 1.45 g (99% of theory)

Synthesis of the reagent (XV.10)

[Tert-butyl 3-oxo-3- (N'-propionyl-hydrazino) -propyl] -carbamate:

25.00 g (132 mmol) of 3-tert-butoxycarbonylamino-propionic acid, 1.15 g (130 mmol) of ethanoic acid hydrazide, 50.91 g (159 mmol) of O- (1H-benzotriazol-1-yl) -N, N, N ^{', N'} - tetramethyluronium tetrafluoroborate (TBTU) and 50 ml of diisopropylethylamine are stirred in 500 ml of tetrahydrofuran / dichloromethane for 24 hours at room temperature. It is then evaporated, the residue with ethyl acetate and 10% potassium bicarbonate extracted carbonate solution. The organic phase is dried and evaporated to dryness. The residue is crystallized from isopropyl ether. Yield: 3.20 g (9% of theory)

[2- (5-Ethyl- [1,4, 4] oxadiazol-2-yl) -ethyl] -carbamic acid tert-butyl ester:

11.49 g (24.70 mmol) of PS-triphenylphosphine are initially charged in 240 ml of dichloromethane, 6.27 g (24.70 mmol) of iodine are added. It is stirred for 0.1 hours at room temperature, then added dropwise 7.00 ml (50.50 mmol) of triethylamine. 3.20 g (12.34 mmol) of tert-butyl 3-oxo-3- (N'-propionyl-hydrazino) -propyl] -carbamate are dissolved in 150 ml of dichloromethane. The reaction mixture is stirred for 24 hours at room temperature, then the precipitate is filtered off. The filtrate was evaporated and purified by chromatography.

Yield: 2.95 g (99% of theory)

2- (5-ethyl- [1,4-oxadiazol-2-yl) ethylamine (XV.10):

2.95 g (12.23 mmol) of tert-butyl [2- (5-ethyl- [1,4] oxadiazol-2-yl) -ethyl] -carbamate and 10 ml of trifluoroacetic acid are dissolved in 100 ml of dichloromethane Stirred hours at room temperature. It is then evaporated, the residue is made basic and extracted with ethyl acetate. The organic phase is dried and evaporated to dryness. Yield: 0.410 g (24% of theory)

Synthesis of the reagent (XV.11)

[2- (2-Hydroxy-3-methylbutylcarbamoyl) ethyl] -carbamic acid benzyl ester:

46.00 g (206.07 mmol) of 3-benzyloxycarbonylamino-propionic acid, 51, 37 g (267.95 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 27.85 g (206.07 mmol) of Hy - droxybenzotriazole (HOBT) and 37.14 ml (267.95 mmol) of triethylamine are initially charged in 700 ml of dichloromethane, it is stirred for 0.5 hours at 0 °, then 23.70 g (229.73 mmol) 1 Amino-3-methyl-butan-2-ol added. The reaction mixture is stirred for 16 hours at room temperature. It is then extracted with potassium carbonate solution and dichloromethane. The organic phase is washed with 1 molar sodium hydroxide solution, dried and evaporated to dryness. The residue is stirred with diethyl ether, then recrystallized with acetonitrile. Yield: 32.40 g (51% of theory)

[2- (3-Methyl-2-oxo-butylcarbamoyl) -ethyl] -carbamic acid benzyl ester:

10.81 ml (126.08 mmol) of oxalyl chloride are initially charged in 300 ml of dichloromethane, cooled to -70 ° C. 11, 94 ml (168.1 1 mmol) of dimethyl sulfoxide are slowly added dropwise. It is stirred for 0.1 hours, then 32.40 g (105.07 mmol) of [2- (2-hydroxy-3-methyl) butylcarbamoyl) ethyl] -carbamic acid benzyl ester in 70 ml of dichloromethane. The mixture is stirred for 1 hour, then added dropwise 62.48 ml (450.72 mmol) of triethylamine. The reaction mixture is stirred for 1, 5 hours at -70 ° C, then allowed to come slowly to room temperature. It is diluted with dichloromethane and washed with 1 molar hydrochloric acid, sat. Sodium carbonate solution, water and sat. Washed sodium chloride solution. The organic phase is dried and evaporated to dryness. Yield: 30.80 g (96% of theory)

[2- (5-Isopropyl-oxazol-2-yl) -ethyl] -carbamic acid benzyl ester:

100.00 g (215 mmol) of PS-triphenylphosphine are suspended in 1000 ml of dichloromethane, 59.92 g (236.06 mmol) of iodine are added. It is stirred for 0.1 hours at room temperature, then added dropwise 65.32 ml (470.24 mmol) of triethylamine. 28.80 g (94.91 mmol) of [2- (3-methyl-2-oxo-butylcarbamoyl) -ethyl] -carbamic acid benzyl ester are dissolved in 200 ml of dichloromethane added. The reaction mixture is stirred for 16 hours at room temperature. If complete conversion has not yet been achieved, 0.1 eq of triphenylphosphine and 0.1 eq of iodine are added. It is stirred for 16 hours at room temperature, then the precipitate is filtered off. The filtrate is evaporated, the residue extracted with water and chloroform, the organic phase dried and evaporated to dryness. The residue is purified by chromatography. Yield: 12.50 g (46% of theory)

2- (5-Isopropyl-oxazol-2-yl) -ethylamine (XV.11):

6.50 g (22.54 mmol) of [2- (5-isopropyl-oxazol-2-yl) -ethyl] -carbaminsäure benzyl ester are placed in 130 ml of methanol, 3.50 g of palladium / carbon 10%, then 5 hours hydrogenated at room temperature and a pressure of 14 psi. The catalyst is then filtered off with suction, the solution is evaporated. The residue is extracted with dichloromethane and potassium carbonate solution, the organic phase is dried and evaporated to dryness. Yield: 3.20 g (92% of theory)

Synthesis of the reagent (XV.12)

[3- (N'-Isobutyryl-hydrazino) -3-oxo-propyl] -carbamic acid tert-butyl ester:

25.00 g (132 mmol) of 3-tert-butoxycarbonylamino-propionic acid, 13.50 g (132 mmol) of isobutyric acid hydrazide, 50.91 g (159 mmol) of O- (1H-benzotriazol-1-yl) -N , N, N ^{', N'} - tetramethyluronium tetrafluoroborate (TBTU) and 50 ml of diisopropylethylamine are stirred in 500 ml of tetrahydrofuran / dichloromethane for 24 hours at room temperature. It is then evaporated, the residue extracted with ethyl acetate and 10% potassium bicarbonate solution. The organic phase is dried and evaporated to dryness. The residue is crystallized from toluene / isopropyl ether. Yield: 16.55 g (46% of theory)

[2- (5-Isopropyl- [1,4,3] oxadiazol-2-yl) -ethyl] -carbamic acid tert-butyl ester:

20.00 g (43.00 mmol) of PS-triphenylphosphine are initially charged in 240 ml of dichloromethane, 10.88 g (42.87 mmol) of iodine are added. It is stirred for 0.1 hours at room temperature, then added dropwise 12.10 ml (87.29 mmol) of triethylamine. 5.83 g (21, 33 mmol) of [3- (N'-isobutyryl-hydrazino) -3-oxo-propyl] -carbamic acid tert-butyl ester are added dissolved in 150 ml of dichloromethane. The reaction mixture is stirred for 24 hours at room temperature, then the precipitate is filtered off. The filtrate is evaporated and purified by chromatography. Yield: 5.40 g (99% of theory)

2- (5-Isopropyl- [1,4,4] oxadiazol-2-yl) -ethylamine (XV.12):

4.00 g (15.67 mmol) of tert-butyl [2- (5-isopropyl- [1,4] oxadiazol-2-yl) -ethyl] -carbamate and 20 ml of trifluoroacetic acid are dissolved in 200 ml of dichloromethane Stirred hours at room temperature. It is then evaporated, the residue is made basic and extracted with ethyl acetate. The organic phase is dried and evaporated to dryness. Yield: 1, 440 g (59% of theory)

Synthesis of the reagent (XV.13)

Methyl 3-tert-butoxycarbonylamino-propionate:

9.90 g (70.93 mmol) of β-alanine methyl ester hydrochloride are initially charged in 200 ml of acetonitrile, and 10 ml (72.14 mmol) of triethylamine are added. It is stirred for 0.3 hours at room temperature, first 15.48 g (70.93 mmol) of Boc anhydride, then 1.65 g (7.09 mmol) zirconium (IV) chloride was added. The reaction mixture is stirred for 2 hours at room temperature, then evaporated. The residue is extracted with ethyl acetate and water. The organic phase is dried and evaporated to dryness. Yield: 12.50 g (87% of theory)

N-Hydroxy-propionamidine:

Potassium carbonate (8.00 g, 57.88 mmol) is dissolved in 25 ml of water, 80 ml of ethanol, 4.00 g (57.56 mmol) of hydroxylamine and 4.11 ml (57.56 mmol) of propionitrile are added. The reaction mixture is stirred for 18 hours at room temperature, then evaporated, evaporated with toluene. The residue is mixed with ethanol, filtered off with suction and the filtrate is evaporated to dryness. Yield: 3.70 g (73% of theory)

[2- (3-Ethyl- [1,2,4] oxadiazol-5-yl) -ethyl] -carbamic acid tert-butyl ester:

2.00 g (22.70 mmol) of N-hydroxy-propionamidine are introduced into 10 ml of dimethylformamide and molecular sieve. 0.999 g (24.97 mmol) of sodium hydride (60% in mineral oil) are added. The mixture is stirred at 50 ° C. for 0.1 hour, then 5.00 g (24.60 mmol) of methyl 3-tert-butoxycarbonylamino-propionate in Added 20 ml of dimethylformamide. The reaction mixture is stirred for 3 hours at 50.degree. After cooling, 15 ml of water are added, filtered off with suction through CeNt. The 2 phases of the filtrate are separated, the organic phase is evaporated. The residue is purified by chromatography. Yield: 2.05 g (37% of theory)

2- (3-Ethyl- [1,2,4] oxadiazol-5-yl) ethylamine hydrochloride (XV.13):

2.05 g (8.50 mmol) of tert-butyl [2- (3-ethyl- [1,2,4] oxadiazol-5-yl) -ethyl] -carbamate are initially introduced in 20 ml of dichloromethane, 40 ml of 1 added molar ethereal hydrochloric acid. The reaction mixture is stirred at room temperature for 16 hours and at 40 ^° C. for 4 hours. After further addition of 10 ml of ethereal hydrochloric acid are stirred for 72 hours at room temperature. The suspension is evaporated. Yield: 1.50 g (99% of theory)

Synthesis of the reagent (XV.14)

N-hydroxy-isobutyramidine:

6.00 g (43.41 mmol) of potassium carbonate are dissolved in 19 ml of water, 60 ml of ethanol, 3.00 g (43.17 mmol) of hydroxylamine and 3.95 ml (43.44 mmol) of isobutyronitrile are added. The reaction mixture is stirred for 18 hours at room temperature, then evaporated, evaporated with toluene. The residue is mixed with ethanol, filtered off with suction and the filtrate is evaporated to dryness. Yield: 3.70 g (84% of theory)

[2- (3-Isopropyl- [1,2,4] oxadiazol-5-yl) -ethyl] -carbamic acid tert-butyl ester:

2.20 g (21, 54 mmol) of N-hydroxy-isobutyramidine are introduced into 10 ml of dimethylformamide and molecular sieve. 0.948 g (23.69 mmol) of sodium hydride (60% in mineral oil) are added. The mixture is stirred at 50 ° C. for 0.1 hours, then 6.20 g (30.51 mmol) of 3-tert-butylbenzene are added.

Butoxycarbonylamino-propionic acid methyl ester added in 20 ml of dimethylformamide.

The reaction mixture is stirred for 3 hours at 50.degree. After cooling, 15 ml

Water was added, filtered off with suction through CeNt. The 2 phases of the filtrate are separated, the aqueous phase extracted with ethyl acetate, the combined organic phase evaporated.

The residue is purified by chromatography.

Yield: 0.900 g (16% of theory)

2- (3-Isopropyl- [1,2,4] oxadiazol-5-yl) -ethylamine hydrochloride (XV.14):

900 mg (3.53 mmol) of tert-butyl [2- (3-isopropyl- [1,2,4] oxadiazol-5-yl) -ethyl] -carbamate are introduced into 10 ml of dichloromethane, 20 ml of 1 molar ethereal hydrochloric acid added. The reaction mixture is stirred for 16 hours at room temperature. After further addition of 10 ml of ethereal hydrochloric acid, stirring is continued for 72 hours at room temperature and 4 hours at 40.degree. The suspension is evaporated. The residue is dissolved in acetone, treated with diethyl ether and filtered with suction. Yield: 530 mg (78% of theory)

Synthesis of the reagent (XV.15)

3-tert-Butoxycarbonylamino-propionic acid ethyl ester:

5.00 g (32.55 mmol) of β-alanine ethyl ester hydrochloride are initially charged in 100 ml of acetonitrile, and 4.75 ml (34.27 mmol) of triethylamine are added. It is stirred for 0.3 hours at room temperature, first 7.30 g (33.45 mmol) Boc anhydride, then 0.759 g (3.26 mmol) zirconium (IV) chloride was added. The reaction mixture is stirred for 2 hours at room temperature, then evaporated. The residue is extracted with ethyl acetate and water. The organic phase is dried and evaporated to dryness. Yield: 7.50 g (100% of theory) N-hydroxy-cyclopropane:

Potassium carbonate (6.00 g, 43.41 mmol) is dissolved in 19 ml of water, 60 ml of ethanol, 3.00 g (43.17 mmol) of hydroxylamine and 3.25 ml (43.25 mmol) of cyclopropyl cyanide are added. The reaction mixture is stirred for 18 hours at room temperature, then evaporated, evaporated with toluene. The residue is mixed with ethanol, filtered off with suction and the filtrate is evaporated to dryness. Yield: 3.47 g (80% of theory)

[2- (3-Cyclopropyl- [1,2,4] oxadiazol-5-yl) -ethyl] -carbamic acid tert-butyl ester:

3.10 g (30.96 mmol) of N-hydroxy-cyclopropanecarboxamidine are introduced into 10 ml of dimethylformamide and molecular sieve. Add 1.32 g (34.06 mmol) of sodium hydride (60% in mineral oil). It is stirred for 0.1 hours at 50 ° C, then 7.40 g (34.06 mmol) of 3-tert-Butoxycarbonylamino-propionic acid ethyl ester in 20 ml of dimethylformamide was added. The reaction mixture is stirred for 3 hours at 50.degree. After cooling, 15 ml of water are added, filtered off with suction through CeNt. The 2 phases of the filtrate are separated, the aqueous phase extracted with ethyl acetate, the combined organic phase evaporated. The residue is purified by chromatography. Yield: 4.00 g (51% of theory)

2- (3-Cyclopropyl- [1,2,4] oxadiazol-5-yl) -ethylamine hydrochloride (XV.15): 4.00 g (15.79 mmol) of tert-butyl [2- (3-cyclopropyl- [1,2,4] oxadiazol-5-yl) -ethyl] -carbamate are introduced into 40 ml of dichloromethane, 80 ml of 1 added molar ethereal hydrochloric acid. The reaction mixture is stirred at reflux for 3 hours and at room temperature for 72 hours, then evaporated. The residue is dissolved in acetone, treated with diethyl ether and filtered with suction. Yield: 1.30 g (43% of theory)

SYNTHESIS OF INTERCONNECTIONS

Synthesis of Intermediate Compound (IV)

1 12 g (1.0 mol) of 1, 3-cyclohexanedione are suspended in 700 ml of ice water and 51.6 ml_ (1.0 mol) of bromine are added dropwise at 0 ° C within 45 minutes. The suspension is left for 3.5 hours at max. 10 ° C stirred. It is then filtered off with suction and the solid is stirred in 800 ml of water, filtered off, washed with 3 L of water and dried. The resulting solid is recrystallized from ethanol. Yield: 37 g (mp. 159-160 ° C.)

15.5 g (0.2 mol) of thiourea are initially introduced at room temperature in 200 ml of ethanol. To this suspension, 37.1 g (0.2 mol) of the intermediate described above are added in portions, then rinsed with 60 ml_ ethanol. The gradually resulting solution is stirred under reflux for 2 hours and then evaporated. The residue is extracted with water and diethyl ether, and the aqueous phase is basified with sodium carbonate solution. The resulting solid is filtered off with suction, washed with water, then stirred with methanol and evaporated to dryness. Yield: 22 g (mp. 265-268 ° C) 230 ml (2.4 mol) of acetic anhydride are initially charged at room temperature, 22 g (0.13 mol) of the intermediate described above are added and the mixture is stirred under reflux for 3 hours. The suspension partially goes into solution. After cooling by means of ice / salt bath, the solid is filtered off with suction, boiled twice in 150 ml of acetone, filtered off with suction and dried. Yield: 25 g (mp .: 268-272 ° C.) of the intermediate compound (IV)

Synthesis of the Intermediate Compound (VI.1)

20 g (0.37 mol) of sodium methylate are suspended in 50 ml of dimethylformamide, and a suspension of 21 g of the intermediate compound (IV) in 100 ml of dimethylformamide is added dropwise. It is stirred for 15 minutes, then cooled to 0 ° C. A mixture of 29.9 mL (0.37 mol) of ethyl formate (Va) and 60 mL of benzene is added dropwise and the reaction mixture is diluted with a further 100 mL of benzene. Gradually, a precipitate falls out and stirring is continued at 0 ° C for 3.5 hours. The suspension is hydrolyzed with 370 ml of 1 molar hydrochloric acid, the precipitated solid is filtered off with suction. The two phases of the mother liquor are separated, the aqueous phase extracted with dichloromethane. The resulting organic phase is dried and evaporated to dryness. The solid and the residue from the extraction are recrystallized from acetonitrile. Yield: 20 g of the intermediate compound (VI.1)

Synthesis of the Intermediate Compound (VIII.1)

4.00 g (16.79 mmol) of the intermediate compound (VI.1) are introduced into 10 ml of pyridine, 3.95 g (20 mmol) of 2-bromo-benzamidine added. The reaction mixture is stirred at 160 ° C for 4 hours. After cooling, it is precipitated with ethanol and water. Precipitated precipitate is filtered off with suction and dried. Yield: 3.50 g (52% of theory) of the intermediate compound (VIII.1)

Analogously, the intermediates (VIII.2) to (VIII.6) can be obtained by reacting the intermediate (VI.1) with the appropriate amidines (VII.2 - VII.6).

Synthesis of the Intermediate Compound (IX.1)

3.50 g (9 mmol) of the intermediate compound (VIII.1) are concentrated in 10 ml. Hydrochloric acid and 10 ml of water for 2 hours under reflux. Then precipitated precipitate is filtered off with suction and dried. Yield: 2.40 g (77% of theory) of the intermediate compound (IX.1)

Similarly, the intermediates (IX.2) to (IX.6) can be obtained by saponification of the intermediates (VIII.2) to (VIII.6).

Synthesis of the Intermediate Compound (Xl.1)

2.40 g (7 mmol) of the intermediate compound (IX.1) and 0.73 ml (6.72 mmol) of ethyl chlorothiol formate are stirred in 2 ml of pyridine at 60 ° C. for 4 hours. Then the reaction mixture is extracted with water and dichloromethane, the organic phase is treated with activated charcoal, dried and evaporated to dryness. The residue is purified by chromatography. Yield: 1.50 g (50% of theory) of the intermediate compound (X.1) Similarly, the intermediates (XI.2) to (Xl.6) can be obtained by reacting the intermediates (IX.2) to (IX.6) with Ethylchlorothiolformiat (X.1).

Synthesis of the Intermediate Compound (XVII.1)

2.42 g (6 mmol of the intermediate compound (XI.2), 1, 12 g (6 mmol) of (3S) - (+) - 3- (tert-butoxycarbonylamino) pyrrolidine, 2.05 ml (12 mmol) of diisopropylethylamine and 10 μl of triethylamine are stirred in 30 ml of ethanol for 3 hours at 80 ° C. Thereafter, the mixture is stirred with dichloromethane, water and sodium carbonate, the organic phase is separated off via phase separation cartridge and evaporated to dryness The residue is stirred with diethyl ether and filtered with suction. 2.54 g (80% of theory) of the intermediate (XVII.1)

Analogously, the intermediate compound (XVII.2) can be obtained.

Synthesis of Intermediate Compound (XVIII.1)

2.60 g (4.92 mmol) of the intermediate compound (XVII.1) are stirred in 30 ml of 2 molar ethereal hydrochloric acid for 3 hours at room temperature. The reaction mixture is evaporated to dryness. Yield: 2.60 g (100% of theory) of the intermediate (XVIII.1)

Analogously, the intermediate compound (XVIII.2) can be obtained.

Synthesis of the Intermediate Compound (XXVII.1)

3.00 g (7.45 mmol of the intermediate compound (XI.2), 1.41 g (7.50 mmol) of 3-aminomethylbenzoic acid hydrochloride and 5.13 ml (30 mmol) of triethylamine are dissolved in 25 ml of tetrahydrofuran Stirred for 7 hours at 80 ° C. Diethyl ether is added to the resulting suspension, the precipitate is filtered off with suction, stirred with dilute sodium bicarbonate solution and filtered with suction, yield: 3.30 g (90% of theory) of the intermediate compound ( XXVII.1)

Synthesis of the Intermediate Compound (XXV.1)

)

800 mg (1.73 mmol) of intermediate compound (XVIII.1) and 195.49 μl (1.80 mmol) of ethylchlorothiolate are stirred in 5 ml of pyridine at 60 ° C. for 48 hours. The reaction mixture is then evaporated, the residue extracted with water and dichloromethane. The organic phase is dried and evaporated to dryness. The product is crystallized with diethyl ether.

Yield: 510 mg (57% of theory) of the intermediate compound (XXV.1) HPLC-MS: Method A, RT = 2.82 min, MH + = 515/517

Synthesis of the Intermediate Compound (XXIX.1)

2.25 g (5.79 mmol) of the intermediate compound (XI.2), 1.50 g (6.75 mmol) of (3-aminomethylphenyl) -carbamic acid-tert-butyl ester and 3.74 ml (27 mmol) of triethylamine are stirred in 20 ml of ethanol at 80 ° C for 16 hours. The reaction mixture is then evaporated, the residue extracted with water and dichloromethane. The organic phase is dried and evaporated to dryness. The residue is crystallized from ethanol and diethyl ether. Yield: 2.63 g (81% of theory) of the intermediate compound (XXIX.1)

Synthesis of Intermediate Compound (XXX.1) = Example 5

2.63 g (4.67 mmol) of the intermediate compound (XXIX.1) are suspended in 20 ml of ethereal hydrochloric acid, then stirred at room temperature for 16 hours. The precipitate is then filtered off with suction and dried. Yield: 2.50 g (100% of theory) of the intermediate (XXX.1) Synthesis of the Intermediate Compound (XXXIII.1)

2.00 g (5.14 mmol) of the intermediate compound (XI.2), 600 mg (6.74 mmol) of β-alanine and 0.80 ml (5.77 mmol) of triethylamine are dissolved in 10 ml of ethanol for 16 hours at 80 ° C stirred. Precipitated precipitate is filtered off, the mother liquor is evaporated. The residue is crystallized with dimethylformamide, water and trifluoroacetic acid. Yield: 1.00 g (45% of theory) of the intermediate compound (XXXIII.1)

Synthesis of the Intermediate Compound (XXXI.1)

600 mg (1.20 mmol) of the intermediate compound (XXX.1) and 135.76 μl (1.25 mmol) of ethylchlorothiolate are stirred in 12 ml of pyridine for 16 hours at room temperature. Since no complete reaction is still added 0.2 eq Ethylchlorothiolformat, stirred at 60 ° C for 3 hours. Then the reaction mixture is extracted with water and dichloromethane. The organic phase is dried and evaporated to dryness. The residue is crystallized with diethyl ether. Yield: 540 mg (82% of theory) of the intermediate compound (XXXI.1)

SYNTHESIS OF THE COMPOUNDS OF FORMULA (I)

Methods A and B:

Waters ZMD, Alliance 2690/2695 HPLC, Waters 2700 Autosampler, Waters 996/2996 diode radar detector (wavelength range 210-400 nm). Stationary phase (column temperature: constant at 25 ° C):

Method A: XTerra® column, MS Ci ₈ 2.5 μm, 4.6 mm x 30 mm.

Method B: Merck Chromolith ™ SpeedROD RP-18e column, 4.6 mm x 50 mm.

Mobile phase: L1: water with 0.10% TFA; L2: acetonitrile with 0.10% TFA

Flow rates: Method A: 1, 00 mLI / min

Method B: 2.00 mL / imin Time (min)% L1% L2

0.0 95 5

0.1 95 5

3.1 2 98

4.5 2 98

5.0 95 5

Methods C and D:

Waters ZMD, Alliance 2790/2795 HPLC, Waters 2700 Autosampler, Waters 996/2996 diode radar detector (wavelength range 210-500 nm).

Stationary phase (column temperature: constant at 40 ° C):

Column X-Terra MS C18 4.6x50mm, 3.5μm.

Mobile phase: L1: water with 0.10% TFA; L2: acetonitrile with 0.10% TFA flow rates: 1.00 mL / min

Time (min)% L1% L2

0.0 95 5

0.1 95 5

5.1 2 98

6.5 2 98

7.0 95 5

The symbol X in the structural formula of the substituent used in Table A is to be understood as the point of attachment to the rest of the molecule. The substituent takes the place of the radicals R ^a and R ^b according to the column arrangement.

Examples

Synthesis of Example 17: 70 mg (0.156 mmol of the intermediate compound (XI.1), 40.82 mg (0.172 mmol) of 2- (4-ethylthiazol-2-yl) -ethylamine hydrobromide and 0.10 ml (0.721 mmol) of triethylamine are dissolved in 1 ml of ethanol was stirred for 16 hours at 80 ° C. The reaction mixture was concentrated by evaporation, the residue was purified by chromatography and corresponding fractions were lyophilised. Yield: 73.7 mg (87% of theory)

Analogously, Examples 1, 6-16, 18-153 and 264 can also be obtained by reacting the appropriate intermediates (XM) - (XI-6) with the appropriate amines (either known from the literature or described under "Synthesis of the Reagents") ,

Synthesis of Example 154:

20.15 mg (0.050 mmol) of the intermediate (XI.2) and 22.77 mg (0.225 mmol) of triethylamine are introduced into 1 ml of ethanol, 9.62 mg (0.075 mmol) (1-methyl-piperidin-4-yl ) -methylamine in 1 ml of ethanol. The reaction mixture is stirred for 16 hours at 70.degree. It is then evaporated, the residue purified by chromatography (LCMS). Corresponding fractions are lyophilized. Yield: 24.80 mg (85% of theory)

Analogously, Examples 155-223 can also be obtained by reacting the appropriate intermediates (XM) - (Xl.6) with the appropriate amines (either known from the literature or described under "Synthesis of the Reagents").

Synthesis of Example 225:

60 mg (0.129 mmol) of the intermediate compound (XVIIM) and 100 μl (0.573 mmol) of diisopropylethylamine are introduced into 1 ml of dimethylformamide, 22.96 μl (0.200 mmol) of 4-morpholine-carbonyl chloride are added. It is stirred for 16 hours at room temperature, then purified by chromatography (HPLC). Corresponding fractions are lyophilized. Yield: 47 mg (67% of theory) Analogously, Examples 224, and 226-237 can also be obtained by reacting the intermediate (XVIII.1) with the respectively suitable carboxylic acid chlorides, sulfonyl chlorides, carbamoyl chlorides, sulfamoyl chlorides or chloroformates. Furthermore, analogously to Examples 279 and 280, starting from intermediate compound (XXX.1).

Synthesis of Example 238:

19.62 μl (0.180 mmol) of isovaleric acid are initially introduced in 5 ml of dichloromethane, 100 μl (0.585 mmol) of diisopropylethylamine and 64.87 mg (0.200 mmol) of O- (1H-benzotriazol-1-yl) -N, N, N ^{', N'} -tetramethyluroniumtetrafluorborat (TBTU) were added. It is stirred for 0.5 hours at room temperature, then 80 mg (0.173 mmol) of the intermediate compound (XVIII.1) was added. The reaction mixture is stirred for 16 hours at room temperature, then stirred with dichloromethane, water and potassium carbonate. The organic phase is separated off via phase separation cartridge and evaporated to dryness. The residue is crystallized with diethyl ether. Yield: 51 mg (58% of theory)

Analogously, Example 239 can be obtained by reacting the intermediate (XVIII.1) with the appropriate carboxylic acid.

Synthesis of Example 241:

80 mg (0.173 mmol) of the intermediate compound (XVIII.2) and 150 μl (0.860 mmol) of diisopropylethylamine are initially charged in 1.50 ml of dimethylformamide, 26.19 μl (0.200 mmol) of isobutyryl chloride are added with cooling. It is stirred for 16 hours at room temperature, then purified by chromatography (HPLC). Corresponding fractions are lyophilized. Yield: 58 mg (68% of theory)

Examples 240 and 242-249 can likewise be obtained by reacting the intermediate compound (XVIII.2) with the respectively suitable carboxylic acid chlorides, sulfonyl chlorides, carbamoyl chlorides, sulfamoyl chlorides or chloroformates. Synthesis of Example 250:

19.62 μl (0.180 mmol) of isovaleric acid are initially introduced in 5 ml of dichloromethane, 100 μl (0.585 mmol) of diisopropylethylamine and 64.87 mg (0.200 mmol) of O- (1H-benzotriazol-1-yl) -N, N, N ^{', N'} -tetramethyluroniumtetrafluorborat (TBTU) were added. It is stirred for 0.5 hours at room temperature, then 80 mg (0.173 mmol) of the intermediate compound (XVIII.2) was added. The reaction mixture is stirred for 16 hours at room temperature, then stirred with dichloromethane, water and potassium carbonate. The organic phase is separated off via phase separation cartridge and evaporated to dryness. The residue is crystallized with diethyl ether. Yield: 62 mg (70% of theory) mp: 203 ° -204 ° C

Similarly, Example 251 can be obtained by reacting the intermediate compound (XVIII.2) with the appropriate carboxylic acid.

Synthesis of Example 252:

100 mg (0.203 mmol) of the intermediate compound (XXVII.1) are initially charged in 4 ml of dichloromethane, 100 μl (0.585 mmol) of diisopropylethylamine and 75 mg (0.231 mmol) of O- (1H-benzotriazol-1-yl) -N, N , N ^{', N'} -tetramethyluroniumtetrafluorborat (TBTU) were added. It is stirred for 0.5 hours at room temperature, then added 24.84 .mu.l (0.250 mmol) of isobutylamine. The reaction mixture is stirred for 16 hours at room temperature, then stirred with dichloromethane, water and potassium carbonate. The organic phase is separated off via phase separation cartridge and evaporated to dryness. The residue is purified by chromatography (HPLC), corresponding fractions are lyophilized. Yield: 53 mg (48% of theory)

Analogously, Examples 253-259 can be obtained by reacting the intermediate compound (XXVII.1) with the appropriate amines.

Synthesis of Example 260: 75 mg (0.146 mmol) of intermediate compound (XXV.1), 30 ml (0.350 mmol) of isopropylamine, 51, 29 μl (0.300 mmol) of diisopropylethylamine and 10 μl of triethylamine are stirred in 1 ml of ethanol at 80 ° C. for 3 hours. The reaction mixture is then stirred with dichloromethane and water, and the organic phase is separated off via phase separation cartridge and evaporated. The residue is crystallized with diethyl ether. Yield: 53 mg (71% of theory) mp: 198-199 ° C. HPLC-MS: Method A, RT = 2.54 min, MH + = 512

Analogously, Examples 261-263 and 265 can also be obtained by reacting the intermediate compound (XXV.1) with the appropriate amines.

Synthesis of Example 266:

10 mg (0.100 mmol) cyclopropylacetic acid are placed in 1 ml dimethylformamide, 37 mg (0.113 mmol) O- (1 H-benzotriazol-1-yl) -N, N, N ^{', N'} -tetramethyluroniumtetrafluorborat (TBTU) and 90 ml (0.516 mmol) of diisopropylethylamine was added. It is stirred for 0.5 hours at room temperature, then with 60 mg (0.141 mmol) of the intermediate compound (XVI-11.1). The reaction mixture is stirred at room temperature for 24 hours, then extracted with potassium carbonate solution and dichloromethane. The organic phase is dried and evaporated to dryness. The residue is purified by chromatography (HPLC). Corresponding fractions are lyophilized. Yield: 35.5 mg (70% of theory) HPLC-MS: Method A, RT = 2.65 min, MH + = 509

Analogously, the examples 267-273 can be obtained by reacting the intermediate of the intermediate (XVIII.1) with the respectively suitable carboxylic acids.

Synthesis of Example 274:

14.43 mg (0.240 mmol) of acetic acid, 92.59 mg (0.288 mmol) O- (1 H-benzotriazol-1-yl) - N, N, N ^{', N'} -tetramethyluroniumtetrafluorborat (TBTU) and 213, 90 .mu.l (1, 25 mmol) of diisopropylethylamine are placed in 2 ml of dimethylformamide, stirred for 0.5 hours at room temperature. 120 mg (0.240 mmol) of the intermediate (XXX.1) are added, Stirred for 16 hours at room temperature. Subsequently, the reaction mixture is purified by chromatography (HPLC). Corresponding fractions are lyophilized. Yield: 77 mg (63% of theory)

Analogously, the examples 275-278 can be obtained by reacting the intermediate compound (XXX.1) with the respectively suitable carboxylic acids.

Synthesis of Example 281:

70 mg (0.163 mmol) of the intermediate compound (XXXIII.1), 62.74 mg (0.195 mmol) O- (1 H- benzotriazol-1-yl) -N, N, N ^{', N'} -tetramethyluroniumtetrafluorborat (TBTU) and 144.96 μl of diisopropylethylamine are suspended in 2 ml of dimethylformamide, stirred at room temperature for 0.5 hours. 10.59 mg (0.179 mmol) of isopropylamine are added, stirred for 16 hours at room temperature. Subsequently, the reaction mixture is purified by chromatography (HPLC). Corresponding fractions are lyophilized. Yield: 22 mg (29% of theory)

Analogously, the examples 282-293 can also be obtained by reacting the intermediate compound (XXXIII.1) with the appropriate amines.

Synthesis of Example 294:

80 mg (0.145 mmol) of the intermediate compound (XXXI.1) and 200 μl (0.400 mmol) of 2 molar dimethylamine solution in tetrahydrofuran are stirred in 1 ml of ethanol at 80 ° C. for 3 hours. It is then evaporated, the residue extracted with water and dichloromethane. The organic phase is dried and evaporated to dryness. The product is crystallized with diethyl ether. Yield: 50 mg (64% of theory)

Analogously, Examples 295-299 can also be obtained by reacting the intermediate compound (XXXI.1) with the appropriate amines. Synthesis of Example 3

20 mg (0.032 mmol) of example compound 133 are stirred for 16 hours at room temperature in 20 ml of ethereal hydrochloric acid. The precipitate is then filtered off with suction and dried.

Yield: 10 mg (56% of theory) MP: 240 ° C

In an analogous manner, examples 2 and 4 can be obtained from example compounds 132 and 135, respectively.

In an analogous manner, the following compounds are prepared:

Table A

Biological test

The exemplified compounds of formula (I) are characterized by an affinity for PI3 kinase, ie in the test by an IC ₅₀ value of less than 800 nmol / liter.

In order to determine the inhibitory activity of the compounds on the PI3Kγ, an in vitro kinase assay was used. The expression and purification of Gp ₁ Y ₂ -HiS and p101-GST / p 1 10γ from Sf9 cells (spodoptera frugiperda 9) has been previously described (Maier et al., J. Biol. Chem. 1999 (274) 29311-29317 ). Alternatively, the following method of determining activity was used:

10 μl of the compound to be tested were placed on 96 well PVDF filter plates (0.45 μM) and incubated for 20 min with 30 μl lipid vesicles (PIP ₂ (0.7 μg / well), phosphatidylethanolamine (7.5 μg / well), phosphatidylserine (7.5 μg / well ), Sphingomyelin (0.7 μg / well) and phosphatidylcholine (3.2 μg / well)), which contained 1-3 ng PI3Kγ and 20-60 ng Gp ₁ Y ₂ -His. By adding 10 μl of reaction buffer (40 mM Hepes, pH 7.5, 100 mM NaCl, 1 mM EGTA, 1 mM β-glycerophosphate, 1 mM DTT, 7 mM MgCl ₂ and 0.1% BSA, 1 μM ATP and 0.2 μCi [γ- ³³ P] -ATP), the reaction was started and incubated for 120 min at room temperature. The reaction solution was sucked through the filters by applying a vacuum and washed with 200 μl of PBS. After drying the plates at 50 ° C., the radioactivity remaining in the plates was determined after addition of 50 μl of scintillation fluid using a Top-Count measuring device.

INDICATIONS

As has been found, the compounds of formula (I) are characterized by a variety of therapeutic applications. Particularly noteworthy are those applications for which the compounds of the formula (I) according to the invention can preferably be used as PI3-kinase modulator due to their pharmaceutical activity.

Generally speaking, these are diseases whose pathology involves activity of PI3 kinases, especially inflammatory and allergic diseases. In particular, there are inflammatory and allergic respiratory diseases, inflammatory diseases of the gastrointestinal tract, inflammatory diseases of the musculoskeletal system, inflammatory and allergic skin diseases, inflammatory ocular diseases, diseases of the nasal mucosa, inflammatory or allergic disease states in which autoimmune reactions are involved or called kidney inflammations. The treatment can be symptomatic, adaptive, curative or preventive.

Preferred respiratory diseases mentioned here would be chronic and / or obstructive respiratory diseases. The compounds of the formula (I) according to the invention can, on the basis of their pharmacological properties, a reduction in the

• tissue destruction

• respiratory tract inflammation • bronchial hyperreactivity

• Lung remodeling process as a result of inflammation

• cause the worsening of the disease (progression). The compounds according to the invention are particularly preferred for the preparation of a medicament for the treatment of chronic bronchitis, acute bronchitis, Bronchitis due to bacterial or viral infection or fungi or helminths, allergic bronchitis, toxic bronchitis, chronic obstructive pulmonary disease (COPD), asthma (intrinsic or allergic), pediatric asthma, bronchiectasis, allergic alveolitis, allergic or non-allergic rhinitis, chronic sinusitis, cystic Fibrosis or cystic fibrosis, alpha-1-antitrypsin deficiency, cough, pulmonary emphysema, interstitial lung diseases such as pulmonary fibrosis, asbestosis and silicosis and alveolitis; hyperreactive airways, nasal polyps, pulmonary edema such as toxic pulmonary edema and ARDS / IRDS, pneumonitis due to different causes such as radiation-induced or by aspiration or infectious, collagenoses such as lupus erythematodes, systemic scleroderma, sarcoidosis or M. boeck.

Also suitable are the compounds of formula (I) for the treatment of skin diseases, e.g. Psoriasis, contact dermatitis, atopic dermatitis, alopecia areaa (circular hair loss), erythema multiforme (Stevens-Johnson syndrome), dermatitis herpetiformis, scleroderma, vitiligo, hives (urticaria), lupus erythematosus, follicular and areal pyoderma, endogenous and exogenous acne, acne rosacea, and other inflammatory or allergic or proliferative skin diseases.

Furthermore, the compounds of formula (I) are useful for therapeutic use in inflammatory or allergic conditions involving autoimmune reactions, e.g. inflammatory bowel disease, e.g. Crohn's disease or ulcerative colitis; Diseases of the arthritis type, such as rheumatoid or psoriatic arthritis, osteoarthritis, rheumatoid spondylitis and other arthritic conditions or multiple sclerosis.

Also to be mentioned are the following general inflammatory or allergic diseases which can be treated by medicaments containing compounds of the formula (I):

• inflammation of the eye, such as Conjunctivitis (conjunctivitis) of various types, e.g. due to infections with fungi or bacteria, allergic conjunctivitis,

Irritant conjunctivitis, drug-induced conjunctivitis, keratitis, uveitis

• diseases of the nasal mucosa, such as allergic rhinitis / sinusitis or nasal polyps • Inflammatory or allergic conditions, such as systemic lupus erythematosus, chronic hepatitis, nephritis, such as glomerulonephritis, interstitial nephritis or idiopathic nephrotic syndrome.

As other diseases which may be treated with the medicament containing the compounds of formula (I) there are toxic or septic shock syndromes, atherosclerosis, otitis media, otitis media, cardiac hypertrophy, heart failure, stroke, ischemia - Reperfusion damage or neurodegenerative diseases such as Parkinson's disease or Alzheimer's called.

COMBINATIONS

The compounds of the formula (I) can be used alone or in combination with other active compounds of the formula (I). Optionally, the compounds of formula (I) may also be used in combination with W, wherein W represents a pharmacologically active agent and is, for example, selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR Inhibitors, dopamine agonists, H1 antihistamines, PAF

Antagonists and PI3 kinase inhibitors, preferably PI3-δ kinase inhibitors. Furthermore, two- or three-fold combinations of W with the compounds of formula (I) can be combined. Exemplary combinations of W would be:

W represents a betamimetic, combined with an active ingredient selected from the group consisting of anticholinergics, corticosteroids, PDE4 inhibitors, EGFR

Inhibitors and LTD4 antagonists,

W represents an anticholinergic agent combined with an active ingredient selected from the group consisting of betamimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors and LTD4 antagonists, -W represents a corticosteroid combined with an active agent selected from the group consisting of a PDE4 inhibitor, EGFR inhibitors and LTD4 antagonists

W represents a PDE4 inhibitor combined with an active agent selected from the group consisting of an EGFR inhibitor and LTD4 antagonist W represents an EGFR inhibitor combined with a LTD4 antagonist.

Preferred betamimetics for this purpose are compounds selected from the group consisting of albuterol, arformoterol, bambuterol, bitolertrol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharines, isoprenaline, levosalbutamol, mabuterol, meluadrine , Metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, salmetrol, soterenol, sulphonterol, terbutaline, tiaramide, toluubuterol, zinterol, CHF-1035, HOKU-81, KUL-1248 and (4- {6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethyl-amino] -hexyloxy} -butyl) -benzyl-sulfonamide

5- [2- (5,6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl] -8-hydroxy-1H-quinolin-2-one

4-hydroxy-7- [2 - {[2 - {[3- (2-phenylethoxy) propyl] sulphonyl} ethyl] amino} ethyl] -2 (3H) -benzothiazolone-1 - (2-fluoro-4 -hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol 1 - [3- (4-methoxybenzylamino) -4-hydroxyphenyl] -2- [4- (1 - benzimidazolyl) -2-methyl-2-butylamino] ethanol

1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino] ethanol - 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol

- 1 - [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol

- 1 - [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -1, 2,4-triazole-3 -yl] -2-methyl-2-butylamino} ethanol

5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1,4-benzoxazine-3- (4H) -one 1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert .-butylamino) ethanol 6-hydroxy-8- {1-hydroxy-2- [2- (4-methoxyphenyl) -1, 1-dimethylethylamino] ethyl} -4 H -benzo [1,4] oxazine 3-one - 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazine -3-one

6-Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid) -1, 1-dimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazin-3-one 8- {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3- on

6-Hydroxy-8- {1-hydroxy-2- [2- (4-hydroxyphenyl) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one - 6-Hydroxy-8- {1-hydroxy-2- [2- (4-isopropyl-phenyl) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one

- 8- {2- [2- (4-ethylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one 8- {2- [2- (4-Ethoxy-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

- 4- (4- {2- [2-hydroxy-2- (6-hydroxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) ethylamino] -2 methyl-propyl} -phenoxy) -butyric acid

- 8- {2- [2- (3,4-Difluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -on - 1 - (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert-butylamino) ethanol optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate ,

Preferred anticholinergic compounds here are compounds which are selected from the group consisting of tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt Trospium salts, preferably the chloride salt, tolterodine. In the above-mentioned salts, the cations are the pharmacologically active ingredients. As anions, the aforementioned salts may preferably contain chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate , Benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate being preferred as counterions. From all Salts, the chlorides, bromides, iodide and methanesulfonate are particularly preferred. Further named compounds are:

2,2-diphenylpropionate-methobromide

2,2-Diphenylpropionic acid copinester methobromide - 2-fluoro-2,2-diphenylacetic acid-co-ester methobromide

2-fluoro-2,2-diphenylacetate methobromide

3,3 ', 4,4'-Tetrafluorbenzilsäuretropenolester methobromide

3,3 ', 4,4'-Tetrafluorbenzilsäurescopinester methobromide

4,4'-Difluorobenzilic acid-tropol ester-methobromide - 4,4'-difluorobenzilic acid-co-ester methobromide

3,3'-difluorobenzilate methobromide

3,3'-Difluorbenzilsäurescopinester methobromide

9-Hydroxy-fluorene-9-carboxylic acid tropol ester methobromide

9-Fluoro-fluorene-9-carboxylic acid tropol ester -methobromide - θ -hydroxy-fluorene-θ-carboxylic acid copoester -methobromide

9-fluoro-fluorene-9-carboxylic acid copoprene methobromide

9-methyl-fluorene-9-carbonsäuretropenolesterMethobromid

9-methyl-fluorene-9-carbonsäurescopinesterMethobromid

Benzylic acid cyclopropyltropine ester methobromide - 2,2-diphenylpropionic acid cyclopropyltropine ester methobromide

9-Hydroxy-xanthene-9-carboxylic acid cyclopropyltropine ester methobromide θ-methyl-fluorene-θ-carboxylic acid cyclopropyltropine ester methobromide θ-methyl-xanthene-θ-carboxylic acid cyclopropyltropine ester methobromide θ -hydroxy-fluorene-θ-carboxylic acid cyclopropyltropine ester methobromide - 4,4'-difluorobenzilate methyl ester cyclopropyltropinester methobromide

9-hydroxy-xanthene-9-carboxylic acid tropol ester methobromide

9-Hydroxy-xanthene-9-carboxylic acid copoprene methobromide

9-methyl-xanthene-9-carboxylic acid tropol ester methobromide

9-Methyl-xanthene-9-carboxylic acid copoprene methobromide - 9-ethyl-xanthene-9-carboxylic acid-tropol ester methobromide

9-Difluoromethyl-xanthene-9-carboxylic acid tropol ester methobromide

9-hydroxymethyl-xanthene-9-carboxylic acid copo-ester -methobromide Preferred corticosteroids here are compounds which are selected from the group consisting of prednisolone, prednisone, butixocortepionate, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, cronoside, rofleponide, dexamethasone, betamethasone, deflazacort, RPR -106541, NS-126, ST-26 and

6,9-Difluoro-17 - [(2-furanylcarbonyl) oxy] -11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionic acid (S) -fluoromethyl ester

6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionic acid (S) - (2-oxo-tetrahydrofuran-3S-yl) ester, - Etiprednol dichloroacetate optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their salts and derivatives, their solvates and / or hydrates. Any reference to steroids includes reference to their optional salts or derivatives, hydrates or solvates. Examples of possible salts and derivatives of the steroids may be: alkali metal salts, such as, for example, sodium or potassium salts, suberobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmates, pivalates or even furoates.

Preferred PDE4 inhibitors here are compounds selected from the group consisting of enprofylline, theophylline, roflumilast, A-riflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofylline, atizoram, D-4418, bay 198004, BY343, CP-325,366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-1 1294A, CI-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, and - N- (3,5-dichloro-1-oxopyridine) -yl-difluoromethoxy -S-cyclopropylmethoxybenzamide - (-) p - [(4aR ^* , 10bS ^* ) -9-ethoxy-1,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [s] [1, 6] naphthyridin-6-yl] -N, N-diisopropylbenzamide (R) - (+) - 1- (4-bromobenzyl) -4 - [(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone 3- ( Cyclopentyloxy-4-methoxyphenyl) -1- (4-N '- [N-2-cyano-S-methylisothioureido] benzyl) -2-pyrrolidone cis [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl ) cyclohexane-1-carboxylic acid] 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxy-p henyl) cyclohexane-1-one cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol] (R) - (+) - Ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate (S) - (-) - Ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine -2-ylidene] acetate

9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a] pyridine 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (tert -butyl) -9 / - / - pyrazolo [3,4-c] -1, 2,4-triazolo [4,3-a] pyridine optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate ,

Preferred LTD4 antagonists here are compounds selected from the group consisting of montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078 , VUF-K-8707, L-733321 and

- ¹ - (((R) - (3- (2- (6,7-Difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2-hydroxy-2-propyl) phenyl) thio) methylcyclopropane -acetic acid,

- 1 - (((1 (R) -3 (3- (2- (2,3-Dichlorothieno [3,2-b] pyridin-5-yl) - (E) -ethenyl) phenyl) -3- ( 2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropaneacetic acid [2 - [[2- (4-tert-butyl-2-thiazolyl) -5-benzofuranyl] oxymethyl] phenyl] acetic acid optionally in Form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate , Examples of salts or derivatives which the LTD4-antagonists are capable of forming include: alkali metal salts, such as, for example, sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isocyanate, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or also FUROATE. The EGFR inhibitors used are preferably compounds selected from the group consisting of cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and - 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino] -7-cyclopropylmethoxy-quinazoline

4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-diethylamino) -1-oxo-2-buten-1-yl] amino} -

7-cyclopropylmethoxy-quinazoline

4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline

4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] -amino} -7-cyclopentyloxy- quinazoline

- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-ol buten-1-ylamino-cyclopropylmethoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholine-4 -yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo-butyne] iy ^ ^ aminoj -cyclopropylmethoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-buten-1-yl-amino ^ -cyclopropylmethoxy-quinazoline

4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -

7-cyclopentyloxy-quinazoline - 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - {[4- (N, N-bis (2-methoxy-ethyl) -amino) -1-oxo 2-butene-i-y-amino-1-yl-cyclopropylmethoxy-quinazoline

- 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-ethyl-amino] -1-oxo-2-butene i yljamino ^ -cyclopropylmethoxy-quinazoline

- 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -1-oxo-2-butene 1 -ylamino ^ -cyclopropylmethoxy-quinazoline

4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methyl-amino] -1-oxo-2-butene-1 yl} amino) -7-cyclopropylmethoxy-quinazoline

4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} - 7 - ((R) -tetrahydrofuran-3-yloxy) -quinazoline 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -

7 - ((S) -tetrahydrofuran-3-yloxy) -quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-butene-1-yl-amino ^ -cyclopentyloxy-quinazoline - 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methylamino) -1-oxo-2-butene]

1 -yl] amino} -7-cyclopentyloxy-quinazoline

4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -

7 - [(R) - (tetrahydrofuran-2-yl) methoxy] -quinazoline

4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} - 7 - [(S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline

4 - [(3-ethynyl-phenyl) amino] -6,7-bis- (2-methoxy-ethoxy) -quinazoline

4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (morpholin-4-yl) -propyloxy] -6 - [(vinylcarbonyl) amino] quinazoline

4 - [(R) - (1-Phenyl-ethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine-3-cyano-4 - [(3-chloro 4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-ethoxy-quinoline

4 - {[3-Chloro-4- (3-fluoro-benzyloxy) -phenyl] -amino} -6- (5 - {[(2-methanesulfonyl-ethyl) -amino] -methyl} -furan-2-yl) -quinazoline

- 4 - [(R) - (1-phenylethyl) amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-one butene-1-yl] amino} -7-methoxy-quinazoline

4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-

[(Tetrahydrofuran-2-yl) methoxy] -quinazoline

4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N, N-bis (2-methoxy-ethyl) -amino] -1-oxo-2-buten-1-yl } amino) -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline - 4 - [(3-ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxomorpholine 4-yl) -1-oxo-2-buten-1-yl] amino} quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7- [(R) - (tetrahydrofuran-2-yl) methoxy] -quinazoline

4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -6-

[(S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline

4 - [(3-chloro-4-fluoro-phenyl) amino] -6- {2- [4- (2-oxo-morpholin-4-yl) piperidin-1-yl] -ethoxy} -

7-methoxy-quinazoline 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [1- (tert -butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (trans-4-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline-4 - [(3-chloro-4-fluoro -phenyl) amino] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(methoxymethyl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy] -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) amino] -6 - ((S) -tetrahydrofuran-3-yloxy) -7-hydroxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline-4 - [(3-chloro-4-fluoro -phenyl) amino] -6- {trans-4 - [(dimethylamino) sulfonylamino] -cyclohexan-i-yloxyJ-7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholin-4-yl) carbonylamino] -cyclohexan-i-yloxy-7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholin-4-yl) -sulfonylamino] -cyclohexane-1-ylxyJ-7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-acetylamino-ethoxy) -quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) -quinazoline-4 - [(3-chloro-4-fluoro -phenyl) amino] -6- {1 - [(piperidin-1-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-aminocarbonylmethyl-piperidin-4-yloxy) -7-methoxy-quinazoline 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(tetrahydropyran-4-yl) -carbonyl] -N-methyl-amino-1-cyclohexan-1-yloxy methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -carbonyl] -N-methyl-amino-1-cyclohexan-1-yloxy -methoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -sulfonyl] -N-methyl-amino} - cyclohexane-1-oxy) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (trans-4-ethanesulphonylamino-cyclohexan-1-yloxy) -

7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-ethoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxy-ethoxy) -quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-acetylamino-cyclohexan-1-ylxy) -7-methoxy-quinazoline

4 - [(3-Ethynylphenyl) amino] -6- [1- (tert -butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline

4 - [(3-Ethynyl-phenyl) -amino] -6- (tetrahydropyran-4-yloxy] -7-methoxy-quinazolin-4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis -4- {N - [(piperidin-1-yl) carbonyl] -N-methyl-amino-1-cyclohexan-1-yloxy) -methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4-methylpiperazin-1-yl) -carbonyl] -N-methyl-amino-cyclohexane i-yloxy ^ methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {cis-4 - [(morpholin-4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [2- (2-oxopyrrolidin-1-yl) -ethyl] -piperidin-4-yloxy} -

7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) amino] -6- {1 - [(morpholin-4-yl) carbonyl] piperidin-4-yloxy} -7-

(2-methoxyethoxy) quinazoline - 4 - [(3-ethynylphenyl) amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline

4 - [(3-ethynyl-phenyl) amino] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline

4 - [(3-Ethynylphenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methylpiperidin-4-yloxy) -7 (2-methoxy-ethoxy) -quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-isopropyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazolin-4 - [(3-chloro-4-fluoro-phenyl ) amino] -6- (cis-4-methylamino-cyclohexane-1-oxy) -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {cis-4- [N- (2-methoxy-acetyl) -N-methyl-amino] -cyclohexan-1-yloxy} -methoxy -quinazoline

4 - [(3-ethynylphenyl) amino] -6- (piperidin-4-yloxy) -7-methoxyquinazoline-4 - [(3-ethynyl-phenyl) -amino] -6- [1- (2- methoxy-acetyl) -piperidin-4-yloxy] -7-methoxy-quinazoline

4 - [(3-ethynylphenyl) amino] -6- {1 - [(morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(cis-2,6-dimethyl-morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7- methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methyl-morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(S, S) - (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) carbonyl] -piperidin-4-yloxy} -7-methoxyquinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(N-methyl-N-2-methoxyethyl- amino) carbonyl] - piperidin-4-yloxy} -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (1-ethyl-piperidin-4-yloxy) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methoxyethyl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline-4 - [(3 Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(3-methoxy-propyl-amino) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-acetyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4- {N - [(morpholin-4-yl) -carbonyl] -N-methyl-amino-1-cyclohexan-1-yloxy -methoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7-

[(S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate ,

Preferred dopamine agonists are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viozane, optionally in the form of their racemates, enantiomers , Diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

As H1 -Antihistaminika here are preferably compounds used, which are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, Cexchlorpheniramin, pheniramine, doxylamine , Chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclocine, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofluorate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p - Toluenesulfonate.

Preferred PAF antagonists here are compounds which are selected from the group consisting of: 4- (2-chlorophenyl) -9-methyl-2- [3 (4-morpholinyl) -3-propanone-1-yl] -6H-thieno [3,2-f] -

[1, 2,4] triazolo [4,3-a] [1,4] diazepine - 6- (2-chlorophenyl) -8,9-dihydro-1-methyl-8 - [(4-morpholinyl) carbonyl] 4H, 7H-cyclo-penta- [4,5] thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine optionally in the form of their racemates, Enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate ,

As PI3-kinase-δ-inhibitors preferably compounds are used, which are selected from the group consisting of:

IC87114, 2- (6-aminopurine-9-ylmethyl) -3- (2-chlorophenyl) -6,7-dimethoxy-3H-quinazolin-4-one; 2- (6-aminopurine-o-ylmethyl) -6-bromo-3- (2-chlorophenyl) -3H-quinazolin-4-one; 2- (6-aminopurine-o-ylmethyl) -3- (2-chlorophenyl) -7-fluoro-3H-quinazole in-4-one; 2- (6-aminopurine-9-ylmethyl) -6-chloro-3- (2-chlorophenyl) -3H-quinazolin-4-one; 2- (6-aminopurine-9-ylmethyl) -3- (2-chlorophenyl) -5-fluoro-3H-quinazolin-4-one; 2- (6-aminopurine-o-ylmethyl) -5-chloro-3- (2-chloro-phenyl) -3H-quinazolin-4-one; 2- (6-aminopurine-9-ylmethyl) -3- (2-chlorophenyl) -5-methyl-3H-quinazolin-4-one; 2- (6-aminopurine-9-ylmethyl) -8-chloro-3- (2-chlorophenyl) -3H-quinazolin-4-one; 2- (6-aminopurine-9-ylmethyl) -3-biphenyl-2-yl-5-chloro-3H-quinazolin-4-one; 5-chloro-2- (9H-purin-6-ylsulfanylmethyl) -3- o-tolyl-3H-quinazolin-4-one; 5-chloro-3- (2-fluorophenyl) -2- (9H-purin-6-yl-sulfanylmethyl) -3H-quinazolin-4-one; 2- (6-aminopurine-9-ylmethyl) -5-chloro-3- (2-fluorophenyl) -3H-quinazolin-4-one; 3-biphenyl-2-yl-5-chloro-2- (9H-purin-6-ylsulfanyl-methyl) -3H-quinazolin-4-one; 5-chloro-3- (2- methoxyphenyl) -2- (9H-purin-6-yl-sulfanylmethyl) -3H-quinazolin-4-one; 3- (2-chlorophenyl) -5-fluoro-2- (9H-purin-6-yl-sulfanyl-methyl) -3H-quinazolin-4-one; 3- (2-chlorophenyl) -6,7-dimethoxy-2- (9H-purin-6-yl-sulfanyl-methyl) -3H-quinazolin-4-one; 6-bromo-3- (2-chlorophenyl) -2- (9H-purin-6-yl-sulfanylmethyl) -3H-quinazolin-4-one; 3- (2-chlorophenyl) -8-trifluoromethyl-2- (9H-purin-6-ylsulfanyl-methyl) -3H-quinazolin-4-one; 3- (2-chlorophenyl) -2- (9H-purin-6-ylsulfanylmethyl) -3H-benzo [g] quinazolin-4-ones; 6-chloro-3- (2-chlorophenyl) -2- (9H-purin-6-yl-sulfanylmethyl) -3H-quinazolin-4-one; 8-chloro-3- (2-chlorophenyl) -2- (9H-purin-6-yl-sulfanylmethyl) -3H-quinazolin-4-one; 3- (2-chlorophenyl) -7-fluoro-2- (9H-purin-6-yl-sulfanylmethyl) -3H-quinazolin-4-one; 3- (2-chlorophenyl) -7-nitro-2- (9H-purin-6-yl-sulfanyl-methyl) -3H-quinazolin-4-one; 3- (2-chlorophenyl) -6-hydroxy-2- (9H-purin-6-ylsulphanylmethyl) -3H-quinazolin-4-ones; 5-chloro-3- (2-chlorophenyl) -2- (9H-purin-6-yl-sulfanylmethyl) -3H-quinazolin-4-one; 3- (2-chlorophenyl) -5-methyl-2- (9H-purin-6-ylsulphanylmethyl) -3H-quinazolin-4-ones; 3- (2-chlorophenyl) -6,7-difluoro-2- (9H-purin-6-ylsulphanylmethyl) -3H-quinazolin-4-ones; 3- (2-chlorophenyl) -6-fluoro-2- (9H-purin-6-ylsulphanylmethyl) -3H-quinazolin-4-ones; 2- (6-aminopurine-9-ylmethyl) -3- (2-isopropylphenyl) -5-methyl-3H-quinazolin-4-one; 2- (6-aminopurine-9-ylmethyl) -5-methyl-3-o-tolyl-3H-quinazolin-4-one; 3- (2-fluorophenyl) -5-methyl-2- (9H-pipn-6-yl-sulfanylmethyl) -3H-quinazolin-4-one; 2- (6-aminopurine-9-ylmethyl) -5-chloro 3-o-tolyl-3H-quinazolin-4-one; 2- (6-aminopurine-9-ylmethyl) -5-chloro-3- (2-methoxy-phenyl) -3H-quinazolin-4-one; 2- (2-amino-ΘH-piπn-θ-ylsulfanylmethyl) J-S-cyclopropyl-S-methyl-SH-quinazolin-4-one; 3-cyclopropylmethyl-5-methyl-2- (9H-purin-6-ylsulfanylmethyl) 3-H-quinazolin-4-one; 2- (6-aminopurine-6-ylmethyl-S-cyclopropylmethyl-S-methyl-SH-quinazolin-1-one; 2- (2-amino-9H-p-n-6-ylsulfanyl-methyl) 3-cyclopropylmethyl-5-methyl-3H-quinazolin-4-ones; 5-methyl-3-phenethyl-2- (9H-purin-6-ylsulfanylmethyl) -3H-quinazolin-4-one; 2- (2- amino-9H-pipn-6-ylsulfanylmethyl) -5-methyl-3-phenethyl-3H-quinazolin-4-one; 3-cyclopentyl-5-methyl-2- (9H-purin-6-ylsulfanylmethyl) -3H-quinazoline -4-one; 2- (6-aminopurine-9-ylmethyl) - S -cyclopentyl-δ-methyl-SH-quinazolinone -one; 3- (2-chloropyridin-3-yl) -5-methyl-2- (9H-purin-6-ylsulfanylmethyl) -3H-quinazolin-4-ones; 2- (6-aminopurine-9-ylmethyl) -3- (2-chloropyridin-3-yl) -5-methyl-3H-quinazoline 4-one; 3-methyl-4- [5-methyl-4-oxo-2- (9 H -purin-6-ylsulfanylmethyl) -4 H -quinazolin-3-yl] -benzoic acid; 3-cyclopropyl-5-methyl -2- (9H-purine-6-ylsulfanylmethyl) -3H-quinazolin-4-one; 2- (6 -aminopurine-9-ylmethyl) -3-cyclopropyl-5-methyl-3H-quinazolin-4-one; 5-methyl-3- (4-nitrobenzyl) -2- (9H-purin-6-ylsulfanylmethyl) -3H-quinazolin-4-one; 3-cyclohexyl-5-methyl-2- (9H-purin-6-ylsulfanylmethyl) -3H-quinazolin-4-ones; 2- (6-aminopurin-9-ylmethyl) -3-cyclohexyl-5-methyl-3H-quinazolin-4-one; 2- (2-amino-9H-puπn-6-ylsulfanylmethyl) -3-cyclo-hexyl-5-methyl-3H-quinazolin-4-one; 5-methyl-3- (E-2-phenylcyclopropyl) -2- (9H-purin-6-ylsulfanylmethyl) -3H-quinazolin-4-one; 3- (2-chlorophenyl) -5-fluoro-2 - [(9H-piπn-6-ylamino) methyl] -3H-quinazolin-4-one; 2 - [(2-amino-9H-pipn-6-ylamino) methyl] -3- (2-chlorophenyl) -5-fluoro-3H-quinazolin-4-one; 5-methyl-2 - [(9H-purin-6-ylamino) methyl] -3-o-tolyl-3H-quinazolin-4-one; 2 - [(2-amino-9H-purin-6-ylamino) methyl] -5-methyl-3-o-tolyl-3H-quinazolin-4-one; 2 - [(2-fluoro-9H-purin-6-ylamino) methyl] -5-methyl-3-o-tolyl-3H-quinazolin-4-one; (2-chlorophenyl) -dimethylamino- (9H-purin-6-ylsulfanylmethyl) -3H-quinazolin-4-ones; 5- (2-benzyloxyethoxy) -3- (2-chlorophenyl) -2- (9H-purin-6-ylsulfanylmethyl) -3H-quinazolin-4-one; 6-aminopurine-9-carboxylic acid 3- (2-chlorophenyl) -5-fluoro-4-oxo-3,4-dihydro-quinazolin-2-ylmethyl ester; N- [3- (2-chlorophenyl) -5-fluoro-4-oxo-3,4-dihydro-quinazolin-2-ylmethyl] -2- (9H-purin-6-ylsulfanyl) -acetamide; 2- [1- (2-fluoro-9H-pipn-6-ylamino) ethyl] -5-methyl-3-o-tolyl-3H-quinazolin-4-one; 5-methyl-2- [1- (9H -purin-6-ylamino) ethyl] -3-o-tolyl-3H-quinazolin-4-one; 2- (6-dimethylaminopurine-9-ylmethyl) -5-methyl-3-o-tolyl-3H-quinazolin-4-one; 5-methyl-2- (2-methyl-6-oxo-1,6-dihydro-puπn-7-ylmethyl) -3-o-tolyl-3H-quinazolin-4-one; 5-methyl-2- (2-methyl-6-oxo-1,6-dihydro-purin-9-ylmethyl) -3-o-tolyl-3H-quinazolin-4-one; 2- (amino-dimethylaminopurine-9-ylmethyl) -5-methyl-3-o-tolyl-3H-quinazolin-4-one; 2- (2-amino-9H-pipn-6-ylsulfanyl-methyl) -5-methyl-3-o-tolyl-3H-quinazolin-4-one; 2- (4-amino-1, 3,5-triazin-2-ylsulfanylmethyl) -5-methyl-3-o-tolyl-3H-quinazolin-4-ones; 5-methyl-2- (7-methyl-7H-pipn-6-ylsulfanyl-methyl) -3-o-tolyl-3H-quinazolin-4-one; 5-methyl-2- (2-oxo-1,2-dihydro-pymidin-4-ylsulfanylmethyl) -3-o-tolyl-3H-quinazolin-4-one; 5-methyl-2-purin-7-ylmethyl-3-o-tolyl-3H-quinazolin-4-one; 5-methyl-2-piπn-9-ylmethyl-3-o-tolyl-3H-quinazolin-4 one; 5-methyl-2- (9-methyl-9H-purin-6-ylsulfanylmethyl) -3-o-tolyl-3H-quinazolin-4-one; 2- (2,6-diamino-pymidin-4-ylsulfanylmethyl) -5-methyl-3-o-tolyl-3H-quinazolin-4-ones; 5-methyl-2- (5-methyl- [1,2,4] triazolo [1,5-a] pyrimidin-7-ylsulfanylmethyl) -3-o-tolyl-3H-quinazolin-4-one; 5-methyl-2- (2-methylsulfanyl-9H-purin-6-ylsulfanylmethyl) -3-o-tolyl-3H-quinazolin-4-one; 2- (2-hydroxy-9H-purin-6-ylsulfanylmethyl) -5-methyl-3-o-tolyl-3H-quinazolin-4-one; 5-methyl-2- (1-methyl-1H-imidazol-2-ylsulfanyl-methyl) -3-o-tolyl-3H-quinazolin-4-one; 5-methyl-3-O-tolyl-2- (H- [1,2,4] triazol-3-ylsulfanylmethyl) -3H-quinazolin-4-one; 2- (2-amino-6-chloro-purin-9-ylmethyl) -5-methyl-3-o-tolyl-3H-quinazolin-4-ones; 2- (6-aminopurine-7-ylmethyl) -5-methyl-3-o-tolyl-3H-quinazolin-4-one; 2- (7-amino-1,2,3-triazolo [4,5-d] pyrimidin-3-ylmethyl) -5-methyl-3-o-tolyl-3H-quinazolin-4-one; 2- (7-amino-1,2,3-triazolo [4,5-d] pyrimidin-1-ylmethyl) -5-methyl-3-o-tolyl-3H-quinazolin-4-one; 2- (6-amino-9H-pipn-2-ylsulfanylmethyl) -5-methyl-3-o-tolyl-3H-quinazolin-4-one; 2- (2-amino-6- ethylamino-pyrimidin-4-ylsulfanylmethyl) -5-methyl-3-o-tolyl-3H-quinazolin-4-one; 2- (3-amino-5-methylsulfanyl-1,2,4-triazol-1-ylmethyl) -5-methyl-3-o-tolyl-3-quinazolin-4-one; 2- (5-amino-3-methylsulfanyl-1,2,4-triazol-1-ylmethyl) -5-methyl-3-o-tolyl-3H-quinazolin-4-one; 5-methyl-2- (6-methylaminopurine-9-ylmethyl) -3-o-tolyl-3H-quinazolin-4-one; 2- (6-benzylaminopurine-9-ylmethyl) -5-methyl-3-o-tolyl-3 H-quinazole in-4-one; 2- (2,6-diaminopurine-9-ylmethyl) -5-methyl-3-o-tolyl-3H-quinazolin-4-one; 5-methyl-2- (9H-purin-6-ylsulfanylmethyl) -3-o-tolyl-3H-quinazolin-4-one; 3-isobutyl-5-methyl-2- (9H-purin-6-ylsulfanylmethyl) -3H-quinazolin-4-one; N- {2- [5-methyl-4-oxo-2- (9H-purin-6-ylsulfanylmethyl) -4H-quinazolin-3-yl] -phenyl-acetamide; 5-methyl-3- (E-2-methylcyclohexyl) -2- (9H-pipn-6-ylsulfanylmethyl) -3H-quinazolin-4-one; 2- [5-methyl-4-oxo-2- (9H-purin-6-ylsulfanyl-methyl) -4H-quinazolin-3-yl] -benzoic acid; 3- {2 - [(2-dimethylaminoethyl) methylamino] phenyl} -5-methyl-2- (9H-purin-6-ylsulfanylmethyl) -3H-quinazolin-4-one; 3- (2-chlorophenyl) -5-methoxy-2- (9H-pipn-6-ylsulfanylmethyl) -3H-quinazolin-4-one; 3- (2-chlorophenyl) -5- (2-morpholin-4-yl-ethylamino) -2- (9H-purin-6-ylsulphanylmethyl) -3H-quinazolin-4-one; 3-benzyl-5-methoxy-2- (9H-pipn-6-ylsulfanyl-methyl) -3H-quinazolin-4-one; 2- (6-aminopurine-9-ylmethyl) -3- (2-benzyloxyphenyl) -5-methyl-3H-quinazolin-4-one; 2- (6-aminopurine-9-ylmethyl) -3- (2-hydroxyphenyl) -5-methyl-3H-quinazolin-4-one; 2- (1- (2-amino-9H-pipn-6-ylamino) ethyl) -5-methyl-3-o-tolyl-3H-quinazolin-4-ones; 5-methyl-2- [1- (9H-puπn-6-ylamino) propyl] -3-o-tolyl-3H-quinazolin-4-one; 2- (1- (2-fluoro-9H-purin-6-ylamino) propyl) -5-methyl-3-o-tolyl-3H-quinazolin-4-one; 2- (1- (2-amino-9H-pipn-6-ylamino) propyl) -5-methyl-3-o-tolyl-3H-quinazolin-4-one; 2- (2-benzyloxy-1- (9H-piπn-6-ylamino) ethyl) -5-methyl-3-o-tolyl-3H-quinazolin-4-ones; 2- (6-aminopurine-9-ylmethyl) -5-methyl-3- {2- (2- (1-methylpyrrolidin-2-yl) -ethoxy) -phenyl} -3H-quinazolin-4-one; 2- (6-aminopurine-9-ylmethyl) -3- (2- (3-dimethylamino-propoxy) -phenyl) -5-methyl-3H-quinazolin-4-one; 2- (6-aminopurine-9-ylmethyl) -5-methyl-3- (2-prop-2-ynyloxyphenyl) -3H-quinazolin-4-one; 2- (2- (1- (6-aminopurine-9-ylmethyl) -5-methyl-4-oxo-4H-quinazole in-3-yl] -phenoxy} -acetamide; 5-chloro-3- (3, 5-d-isluoro-phenyl) -2- [1- (9H-purin-6-ylamino) -propyl] -3H-quinazolin-4-one; 3-phenyl-2- [1- (9H-purin-6-one ylamino) -propyl] -3H-quinazolin-4-one; 5-fluoro-3-phenyl-2- [1- (9H-pu-ri n-6-ylamino) -propyl] -3H-quinazoline-4 3- (2,6-difluorophenyl) -5-methyl-2- [1- (9H-purin-6-ylamino) -propyl] -3H-quinazolin-4-one; 6-fluoro-3 - phenyl 2- [1- (9H -purin-6-ylamino) -ethyl] -3H-quinazolin-4-one; 3- (3,5-difluoro-phenyl) -5-methyl-2- [1 - (9H-purin-6-ylamino) -ethyl] -3H-quinazolin-4-one; 5-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -ethyl] -3H-quinazoline 4-one; 3- (2,3-difluoro-phenyl) -5-methyl-2- [1- (9H-purin-6-ylamino) -ethyl] -3H-quinazolin-4-one; 5-methyl -3-phenyl-2- [1- (9H-purin-6-ylamino) - ethyl] -3H-quinazolin-4-one; 3- (3-chloro-phenyl) -5-methyl-2- [1- (9H -purin-6-ylamino) -ethyl] -3H-quinazolin-4-one; 5-methyl-3-phenyl-2 - [(9H-purin-6-ylamino) -methyl] -3H-quinazolin-4-one; 2 - [(2-amino-9H-purin-6-ylamino) -methyl] -3- (3,5-difluoro-phenyl) -5-methyl-3H-quinazolin-4-one; 3- {2 - [(2] -diethylamino-ethyl) -methyl-amino] -phenyl) -5-methyl-2 - [(9H-purine-6-ylamino) -methyl] -3H-quinazolin-4-one ; 5-chloro-3- (2-fluoro-phenyl) -2 - [(9H-purin-6-ylamino) -methyl] -3H-quinazolin-4-one; 5-chloro-2 - [(9H-purin-6-ylamino) -methyl] -3-o-tolyl-3H-quinazolin-4-one; 5-chloro-3- (2-chloro-phenyl) -2 - [(9H-purin-6-ylamino) -methyl] -3H-quinazolin-4-one; 6-fluoro-3- (3-fluoro-phenyl) -2- [1- (9H-purin-6-ylamino) -ethyl] -3H-quinazolin-4-one; 2- [1- (2-amino-9 H -purin-6-ylamino) -ethyl] -5-chloro-3- (3-fluoro-phenyl) -3H-quinazolin-4-one; and, pharmaceutically acceptable salts and solvates thereof.

FORMULATIONS

The compounds according to the invention can be administered orally, transdermally, by inhalation, parenterally or sublingually. The compounds of the invention are present as active ingredients in conventional dosage forms, for example in compositions consisting essentially of an inert pharmaceutical carrier and an effective dose of the active ingredient, such as tablets, dragees, capsules, wafers, powders, solutions, suspensions , Emulsions, syrups, suppositories, transdermal systems etc. An effective dose of the compounds of the invention is from 0.1 to 5000, preferably from 1 to 500, more preferably from 5 to 300 mg / dose when administered orally, intravenously, subcutaneously or intramuscularly Application between 0.001 and 50, preferably between 0.1 and 10 mg / dose. Suitable inhalable dosage forms are inhalable powders, propellant-containing metered dose inhalers or propellant-free inhalable solutions. In the context of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile, ready-to-use inhalable solutions. For inhalative application, the use of powders, ethanolic or aqueous solutions is preferred. According to the invention, suitable solutions for inhalation are those which contain from 0.01 to 1.0, preferably from 0.1 to 0.5% of active ingredient. It is likewise possible to use the compounds according to the invention as infusion solution, preferably in a physiological saline solution or nutrient salt solution. The compounds according to the invention can be used alone or in combination with other active compounds according to the invention, if appropriate also in combination with other pharmacologically active substances. Suitable application forms are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders. Corresponding tablets may, for example, be prepared by mixing the active substance (s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents for obtaining the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Coated tablets can accordingly be prepared by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example, koillite or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers. Similarly, the dragee sheath to achieve a depot effect of several layers may consist of the above mentioned in the tablets excipients can be used.

Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or sugar, as well as a taste-improving agent, e.g. Flavorings such as vanillin or orange extract. They may also contain suspending aids or thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.

Injection solutions are prepared in the usual manner, e.g. with the addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid prepared and filled into injection bottles or ampoules.

The capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules. Suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.

Inhalable powders which can be used according to the invention may contain the active substance according to the invention either alone or in admixture with suitable physiologically acceptable excipients. If the active compounds according to the invention are mixed with physiologically acceptable excipients, the following physiologically acceptable excipients can be used to prepare these inhalable powders according to the invention: monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, sucrose, maltose), oligosaccharides and polysaccharides ( eg dextranes), polyalcohols (eg sorbitol, mannitol, xylitol), salts (eg sodium chloride, calcium carbonate) or mixtures of these auxiliaries with one another. Preferably, mono- or disaccharides are used, wherein the use of lactose or glucose, in particular, but not exclusively in the form of their hydrates, is preferred. Lactose, most preferably lactose monohydrate, is used as adjuvant for the purposes of the invention. Within the scope of the inhalable powders according to the invention, the auxiliaries have a maximum average particle size of up to 250 μm, preferably between 10 and 150 μm, particularly preferably between 15 and 80 μm. If appropriate, it may seem appropriate to add finer excipient fractions having a mean particle size of 1 to 9 .mu.m to the abovementioned excipients. The latter finer excipients are also selected from the aforementioned group of usable excipients. Finally, for the preparation of the inhalable powders according to the invention micronized active compounds according to the invention, preferably having an average particle size of 0.5 to 10 .mu.m, more preferably from 1 to 5 .mu.m, mixed with the excipient mixture. Methods for producing the inhalable powders according to the invention by grinding and micronizing as well as by final mixing of the constituents are known from the prior art.

The inhalable powders according to the invention can be applied by means of inhalers known from the prior art. Propellant gas-containing inhalation aerosols according to the invention can dissolve active compounds according to the invention in propellant gas or contain them in dispersed form. The propellant gases which can be used for the preparation of the inhalation aerosols are known from the prior art. Suitable propellant gases are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The abovementioned propellant gases can be used alone or in mixtures thereof. Particularly preferred propellants are halogenated alkane derivatives selected from TG134a and TG227 and mixtures thereof.

The propellant-containing inhalation aerosols may also contain other ingredients such as cosolvents, stabilizers, surfactants, antioxidants, lubricants, and pH adjusters. All of these ingredients are known in the art.

The abovementioned propellant-containing inhalation aerosols can be administered by means of inhalers known in the art (MDIs = metered dose inhalers).

Furthermore, the application of the active compounds according to the invention in the form of propellant-free inhalable solutions and inhalable suspensions. Suitable solvents for this purpose are aqueous or alcoholic, preferably ethanolic solutions. The solvent may be water only or it may be a mixture of water and ethanol. The relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70% by volume, in particular up to 60% by volume and more preferably up to 30% by volume. The remaining volume percentages are filled up with water. The solutions or suspensions containing the active compound according to the invention are adjusted to a pH of from 2 to 7, preferably from 2 to 5, with suitable acids. To adjust this pH, acids selected from inorganic or organic acids can be used. Examples of particularly suitable inorganic acids are hydrochloric acid,

Bromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others. Preferred inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use the acids already with one of the Active ingredients form an acid addition salt. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. Optionally, it is also possible to use mixtures of the abovementioned acids, in particular in the case of acids which, in addition to their acidification properties, also possess other properties, for example as flavorings, antioxidants or complexing agents, for example citric acid or ascorbic acid. Hydrochloric acid is particularly preferably used according to the invention for adjusting the pH.

In these formulations, the addition of editic acid (EDTA) or one of the known salts thereof, sodium edetate, as stabilizer or complexing agent may optionally be dispensed with. Other embodiments include this compound (s). In such a preferred embodiment, the content based on sodium edetate is below 100 mg / 100 ml, preferably below 50 mg / 100 ml, particularly preferably below 20 mg / 100 ml. In general, those inhalation solutions are preferred in which the content of sodium edetate is 0 to 10 mg / 100 ml. Co-solvents and / or other auxiliaries can be added to the propellant-free inhalable solutions. Preferred co-solvents are those which contain hydroxyl groups or other polar groups, for example alcohols - in particular isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. By auxiliaries and additives is meant in this context any pharmacologically acceptable substance which is not an active ingredient but which can be formulated together with the active ingredient (s) in the pharmacologically suitable solvent in order to improve the qualitative properties of the active ingredient formulation. These substances preferably do not develop any appreciable or at least no undesirable pharmacological effect in the context of the intended therapy. The auxiliaries and additives include, for example, surfactants such as soybean lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone other stabilizers, complexing agents, antioxidants and / or preservatives that ensure or prolong the useful life of the finished drug formulation, flavorings, vitamins and / or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonants. Preferred excipients include antioxidants, such as ascorbic acid, if not already used to adjust the pH, vitamin A, vitamin E, tocopherols, and similar vitamins or provitamins found in the human organism. Preservatives may be used to protect the formulation from contamination by germs. Suitable preservatives are those known in the art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art. The abovementioned preservatives are preferably present in concentrations of up to 50 mg / 100 ml, more preferably between 5 and 20 mg / 100 ml.

Apart from the solvent, preferred formulations contain water and the active ingredient according to the invention only benzalkonium chloride and sodium edetate. In another preferred embodiment, sodium edetate is dispensed with.

A therapeutically effective daily dose is between 1 and 2000 mg, preferably 10-500 mg per adult

The following examples illustrate the present invention without, however, limiting its scope:

Pharmaceutical Formulation Examples

A) Tablets per tablet

Active ingredient 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg

Magnesium stearate 5 mq

500 mg

The finely ground active substance, lactose and part of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried. The granules, the remainder of the corn starch and the magnesium stearate are sieved and mixed together. The mixture is compressed into tablets of suitable shape and size. B) Tablets per tablet

Active ingredient 80 mg

Corn starch 190 mg

Lactose 55 mg

Microcrystalline cellulose 35 mg

Polyvinylpyrrolidone 15 mg

Sodium carboxymethyl starch 23 mg

Magnesium stearate 2 mg

400 mg

The finely ground active ingredient, a portion of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the remainder of the corn starch and water to a granulate which is dried and sieved. To this is added the sodium carboxymethyl starch and the magnesium stearate, mixed and pressed the mixture into tablets of suitable size.

C) dragées per dragee

Active ingredient 5 mg

Cornstarch 41, 5 mg

Lactose 30 mg

Polyvinylpyrrolidone 3 mg

Magnesium stearate 0.5 mg

80 mg

The active ingredient, corn starch, lactose and polyvinylpyrrolidone are mixed well and moistened with water. The moist mass is forced through a sieve of 1 mm mesh size, dried at about 45 ° C. and then the granules are passed through the same sieve. After admixing magnesium stearate, curved tablet cores having a diameter of 6 mm are pressed on a tableting machine. The coated dragee cores are coated in a known manner with a layer consisting essentially of sugar and talc. The finished dragees are polished with wax. D) Capsules per capsule

Active ingredient 50 mg corn starch 268.5 mg

Magnesium stearate 1, 5 mg

320 mg

Substance and cornstarch are mixed and moistened with water. The wet mass is sieved and dried. The dry granules are sieved and mixed with magnesium stearate. The final mixture is filled into hard gelatine capsules size 1.

E) Ampoule solution

Active ingredient 50 mg

Sodium chloride 50 mg

Aqua pro inj. 5 ml

The active ingredient is dissolved at its own pH or optionally at pH 5.5 to 6.5 in water and treated with sodium chloride as isotonic. The resulting solution is filtered pyrogen-free and the filtrate filled under aseptic conditions in ampoules, which are then sterilized and sealed. The vials contain 5 mg, 25 mg and 50 mg active ingredient.

F) Suppositories

Active ingredient 50 mg

Adeps solidus 1650 mg

1700 mg

The hard fat is melted. At 40 ° C., the ground active substance is dispersed homogeneously. It is cooled to 38 ° C and poured into slightly pre-cooled suppository molds G) oral suspension

Active ingredient 50 mg

Hydroxyethyl cellulose 50 mg

Sorbic acid 5 mg

Sorbitol (70%) 600 mg

Glycerol 200 mg

Aroma 15 mg

Water ad 5 ml

Distilled water is heated to 70 ° C. Herein dissolved hydroxyethyl-cellulose with stirring. After addition of sorbitol solution and glycerol is cooled to room temperature. At room temperature, sorbic acid, flavor and substance are added. To vent the suspension is evacuated with stirring. and 50 mg of active ingredient.

H) Metered aerosol (suspension)

Active ingredient 0.3% by weight

Sorbitan trioleate 0.6% by weight HFAl 34A: HFA227 2: 1 99.1% by weight

The suspension is filled in a conventional aerosol container with metering valve. Per actuation preferably 50 ul suspension are delivered. If desired, the active ingredient can also be metered in higher

I) Metered dose inhaler (solution)

Active ingredient 0.3% by weight

Ethanol abs. 20% by weight aqueous HCl 0.01 mo 1/1 2.0% by weight HFA134A 77.7% by weight

The preparation of the solution is carried out in a conventional manner by mixing the individual components. J) Inhalation powder

Active substance 80 μg

Lactose monohydrate ad 10 mg

The preparation of the inhalable powder is carried out in the usual manner by mixing the individual components.

Claims

claims 1. Compounds of the general formula (I) wherein A is N or CH, R ^{a is} hydrogen or an optionally substituted radical selected from Group consisting of C _r C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₃ -C _β cycloalkenyl, C _r C ₆ haloalkyl, C ₆ -C ₄ aryl, Ce-C ^ -aryl-Ci-Cs-alkyl, C ₅ -C ₀ - heteroaryl, C ₃ -C ₈ -cycloalkyl alkyl-Ci-C _4, C ₃ -C ₈ -Cycloalkenyl-C _r C ₄ alkyl, C ₅ -Ci ₀ - HeteroarylCrC ₄ -alkyl-, spiro, C ₃ -C ₈ -heterocycloalkyl and C ₃ -C ₈ -heterocycloalkyl- C _r C ₄ -alkyl-, R ^b is hydrogen, OH or NH _2, or an optionally substituted radical selected from the group consisting of d-Cβ-alkyl, C ₃ -C _β cycloalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkenyl, C _r Ce-haloalkyl, C ₆ -C ₄ aryl, C ₆ -C ₄ aryl-Ci-C ₅ alkyl, C ₅ -C ₀ heteroaryl, C ₃ -C ₈ - cycloalkyl-C _r C ₄ alkyl, C ₃ -C ₈ cycloalkenyl alkyl-C _r C _4, C ₅ -C ₀ -C ₄ -heteroaryl - alkyl-, spiro, C ₃ -C ₈ -heterocycloalkyl , CONH ₂ , C ₆ -C ₄ -aryl-NH-, C ₃ -C ₈ - Heterocycloalkyl-NH- and OC _r C ₃ -alkyl R ¹ is hydrogen or an optionally substituted radical selected from the group consisting of -C ₈ alkyl, QrCβ cycloalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl and Ce-Cu-aryl-CRCS alkyl-; or R ² is hydrogen or an optionally substituted radical selected from the group consisting of C _r C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl, C ₃ -C ₈ - cycloalkenyl, C _r C ₆ - haloalkyl, C ₆ -C ₄ aryl, C ₆ -C ₄ -alkyl- aryl-Ci-C _5, C ₅ -C ₀ - heteroaryl, alkyl C ₃ -C ₈ cycloalkyl-C _4, C ₃ -C ₈ cycloalkenyl-C _r C ₄ alkyl, C ₅ -C ₀ - heteroaryl-Ci-Cβ-alkyl, C ₉ -C ₃ spiro, C ₃ -C ₈ -heterocycloalkyl, C ₃ - C ₈ - HeterocycloalkylCrC ₆ -alkyl- and Ce-C _m -aryl-C 1 -C ₆ -alkyl-; or R ¹ and R ² together form an optionally substituted five-, six- or seven-membered ring consisting of carbon atoms and optionally 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. or R ¹ and R ² together form an optionally substituted nine- to thirteen-membered spirocyclic ring, or R ^{2 is} a radical selected from the group consisting of the general Formulas (A1) to (A18) in which X and Y may be linked to the same or different atoms of G, and X is a bond or an optionally substituted radical selected from the group consisting of C ₁ -C ₇ -alkylene, C ₃ -C ₇ -alkenylene and C ₃ -C ₇ -alkynylene, or X together with R ¹ , R ³ or R ^{4 is} a Ci -C ₇ -alkylene bridge can form; Y is a bond or optionally substituted C 1 -C ₄ -alkylene; Q is an optionally substituted radical selected from the group consisting of C _r C ₇ -alkylene, C ₃ -C ₇ -alkenylene and C ₃ -C ₇ alkynylene; Q together with R ¹ , R ³ or R ^{4 can form} a CrC ₇ -alkylene bridge; R ^3, R ^4, R ⁵ are identical or different, represent hydrogen or an optionally substituted radical selected from the group consisting of -C ₈ alkyl, C ₃ -C ₈ - cycloalkyl, C ₂ -C ₆ haloalkyl, _Ci-C4- Alkyl C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkyl C _r C ₄ alkyl, NR ⁷ R ⁸ , NR ⁷ R ⁸ -C _r C ₄ alkyl, C _r C ₄ alkoxy, Ci-C ₄ -alkoxy-C _r C ₄ - alkyl, C ₆ -C ₄ aryl and C ₅ -C ₀ -heteroaryl; or in each case two of the substituents R ³ , R ⁴ , R ⁵ together form an optionally substituted five-, six- or seven-membered ring consisting of carbon atoms and optionally 1-2 heteroatoms selected from the group consisting of Oxygen, sulfur and nitrogen; G is a saturated, partially saturated or unsaturated ring system of 3-10 C atoms, wherein optionally up to 6 C atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; R ^{6 is} identical or different, hydrogen or an optionally substituted radical selected from the group consisting of = 0, C ₁ -C ₈ -alkyl, C ₂ -C ₆ -alkenyl, C ₃ -C ₈ -cycloalkyl, C ₂ - C ₆ haloalkyl, C ₆ -C ₄ aryl, C ₅ -C ₀ heteroaryl, C ₃ -C ₈ -heterocycloalkyl, or a group selected from the group consisting of NR ⁷ R ^8, oR ^7, -CO- -C ₃ - alkyl-NR ⁷ R ⁸ -O-Ci-C ₃ alkyl-NR ⁷ R ^8, CONR ⁷ R ^8, NR ⁷ COR ^8, CO-C _r C ₃ alkyl NR ⁷ (CO) OR ⁸ , -O (CO) NR ⁷ R ⁸ , NR ⁷ (CO) NR ⁸ R ⁹ , NR ⁷ (CO) OR ⁸ , (CO) OR ⁷ , -O (CO) R ⁷ , COR ⁷ , (SO) R ⁷ , (SO ₂ ) R ⁷ , (SO ₂ ) NR ⁷ R ⁸ , NR ⁷ (SO ₂ ) R ⁸ , NR ⁷ (SO ₂ ) NR ⁸ R ⁹ , CN, -C _r C ₃ alkyl C ₆ -C ₄ aryl, -N H-CO-N HC _r C ₃ alkyl and halogen; n 1, 2 or 3 R ^7, R ^8, R ⁹ are identical or different, represent hydrogen or an optionally substituted radical selected from the group consisting of -C ₈ alkyl, C ₃ -C ₈ - cycloalkyl, C _r C ₆ haloalkyl, Ci-C ₄ - Alkyl-C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl-dC ₃ -alkyl, C ₆ -C ₄ -aryl, C ₁ -C ₄ -alkyl-C ₆ -C ₄ -aryl-, C ₆ -C ₄ -aryl-C 1 -C ₄ -alkyl, C ₃ -C ₈ -heterocycloalkyl, Ci-C ₅ alkyl-C ₃ -C ₈ heterocycloalkyl, C ₃ -C ₈ - heterocycloalkyl-C _r C ₄ alkyl, C _r C ₄ alkyl (CO) - and C _r C ₄ alkyl-O (CO) -; or in each case two of the substituents R ⁷ , R ⁸ , R ⁹ together form an optionally substituted five-, six- or seven-membered ring consisting of carbon atoms and optionally 1-2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts, solvates and hydrates, with the proviso that the following compounds are excluded: a) 8-phenyl-4,5-dihydro-thiazolo [4,5-h] quinazolin-2-yl) urea b) 1-methyl-3- (8-phenyl-4,5-dihydro-thiazolo [4 , 5-h] quinazolin-2-yl) urea c) 1,1-dimethyl-3- (8-phenyl-4,5-dihydro-thiazolo [4,5-h] quinazolin-2-yl) urea d) 1- (2-Dimethylamino-ethyl) -3- (8-phenyl-4,5-dihydro-thiazolo [4,5-h] quinazolin-2-yl) -urea e) 4-Methyl-piperazine-1 -carboxylic acid (8-phenyl-4,5-dihydro-thiazolo [4,5-h] quinazolin-2-yl) -amide f) piperidine-1-carboxylic acid (8-phenyl-4,5-dihydro-thiazolo [4,5-h] quinazolin-2-yl) -amide g) pyrrolidine-1-carboxylic acid (8-phenyl-4,5-dihydro-thiazolo [4,5-h] quinazoline) 2-yl) -amide h) 1-methyl-3- (8-o-tolyl-4,5-dihydro-thiazolo [4,5-h] quinazolin-2-yl) -urea i) (8-o- Tolyl-4,5-dihydro-thiazolo [4,5-h] quinazolin-2-yl) urea j) 1,1-Dimethyl-3- (8-o-tolyl-4,5-dihydro-thiazolo [4 , 5-h] quinazolin-2-yl) urea and k) [8- (2-methoxyphenyl) -4,5-dihydro-thiazolo [4,5-h] quinazolin-2-yl] urea and I) Morpholine-4-carboxylic acid (8-phenyl-4,5-dihydro-thiazolo [4,5-h] quinazolin-2-yl) amides 2. Compounds according to claim 1, wherein A, X, Y, Q and G may have the meaning given, and AT, R ^a is hydrogen or a radical selected from the group consisting of C-ι-C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, C _r C ₆ - haloalkyl, C ₆ -C ₄ -Ar / !, Ce-Cu-aryl-CRCS alkyl, C ₅ -C ₀ heteroaryl, C ₃ -C ₈ - cycloalkyl-C _r C ₄ alkyl, C ₃ -C ₈ cycloalkenyl-C _r C ₄ alkyl, C ₅ -C ₀ -heteroaryl-Ci-C ₄ - alkyl, spiro, C ₃ -C ₈ -heterocycloalkyl and C ₃ - C ₈ -heterocycloalkyl-C 1 -C ₄ -alkyl optionally having one or more of the radicals, identical or different, selected from the group consisting of C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ - alkynyl, C ₂ -C ₆ alkynyl-NR ⁵ R ^6, C ₃ -C ₈ cycloalkyl, d-Ce-haloalkyl, halogen, OH, C _r C ₄ alkoxy, CN, NO _2, NR ¹⁰ R ^11, OR ¹⁰ , COR ¹⁰ , COOR ¹⁰ , CONR ¹⁰ R ¹¹ , NR ¹⁰ COR ¹¹ , NR ¹⁰ (CO) NR ¹¹ R ¹² , 0 (CO) NR ¹⁰ R ¹¹ , NR ¹⁰ (CO) OR ¹¹ , SO ₂ R ¹⁰ , SOR ¹⁰ , SO ₂ NR ¹⁰ R ¹¹ , NR ¹⁰ SO ₂ NR ¹¹ R ¹² and NR ¹⁰ SO ₂ R ¹¹ , may be substituted; or R ^a is optionally substituted by a radical of the general formula (B) wherein, R ¹³ to R ^{16 are} identical or different, hydrogen or C 1 -C ₆ -alkyl, or two of the substituents R ¹³ to R ¹⁶ together form an optionally substituted five-, six- or seven-membered ring consisting of carbon atoms and optionally 1-2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; R ¹⁰ , R ¹¹ , R ^{12 are} identical or different, hydrogen or a radical selected from the group consisting of C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₈ - Cycloalkyl and C _r C ₆ haloalkyl; or in each case two of the radicals R ¹⁰ , R ¹¹ , R ¹² together form a five, six or seven membered ring consisting of carbon atoms and optionally 1-2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; R ^b is hydrogen, OH or NH _2, or an optionally substituted radical selected from the group consisting of Ci-C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkenyl, C _r Ce-haloalkyl, C ₆ -C ₄ -Ar / !, Ce-Cu-aryl-CRCS alkyl, C ₅ -C ₀ heteroaryl, C ₃ -C ₈ - Cycloalkyl dd alkyl, C ₃ -C ₈ cycloalkenyl alkyl-Ci-C _4, C ₅ -C ₀ -C ₄ -heteroaryl - alkyl-, spiro, C ₃ -C ₈ heterocycloalkyl, CONH _2, C ₆ -C ₄ -aryl-NH-, C ₃ -C ₈ -heterocycloalkyl-NH- and OC _r C ₃ -alkyl optionally having one or more of the radicals, identical or different, selected from the group consisting of d-Ce Alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₈ -cycloalkyl, C _r C ₆ -haloalkyl, halogen, OH, OMe, CN, NH ₂ , NHMe, NMe _2, may be substituted; R ^{1 is} hydrogen or a radical selected from the group consisting of C ₁ -C ₈ -alkyl, C ₃ -C ₈ -cycloalkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl and C ₆ -C ₄ -aryl-Ci C ₅ alkyl optionally having one or more of the same or different radicals selected from the group consisting of halogen, COOH, NH ₂ , OH, CN, C ₁ -C 6 alkyl, OMe, -NH (CO ) -Alkyl and - (CO) O-alkyl may be substituted, R ² is hydrogen or a radical selected from the group consisting of -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl, C ₃ -C ₈ cycloalkenyl, C _r C ₆ haloalkyl, C ₆ - Ci ₄ -aryl, C ₆ -C ₄ aryl-Ci-C ₅ alkyl, C ₅ -C ₀ heteroaryl, C ₃ -C ₈ cycloalkyl-alkyl- C _r C _4, C ₃ -C ₈ - Cycloalkenyl-CrC ₄ -alkyl, Cs-Cio-heteroaryl-C ₁ -C ₆ -alkyl, C ₉ -C ₃ -piro, C ₃ -C ₈ -heterocycloalkyl, C ₃ -C ₈ -heterocycloalkyl-C _r C ₆ -Alkyl and C ₆ -C ₄ -aryl-C ₁ -C ₆ -alkyl, which is optionally substituted by one or more of the radicals, identical or different, selected from the group consisting of halogen, NH ₂ , OH, CN, d- Cβ-Alky !, OMe, -NH (CO) -alkyl, = 0, COOH and - (CO) O-alkyl may be substituted. or R ¹ and R ² together form a five-, six- or seven-membered ring consisting of carbon atoms and optionally 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, optionally with one or more of the radicals, the same or different selected from the group consisting of halogen, NH _2, OH, CN, d-Ce-alkyl, OMe, -NH (CO) - C _r C ₄ alkyl, and - (CO) O-CrC ₄ - alkyl may be substituted. or R ¹ and R ² together form an optionally substituted nine- to thirteen-membered spirocyclic ring, or R ^{2 is} a radical selected from the group consisting of the general Formulas (A1) to (A18) in which R ^3, R ^4, R ⁵ are identical or different, denote hydrogen or a radical selected from the group consisting of -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ haloalkyl, C ₄ alkyl d- -C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkyl-Ci-C ₄ alkyl, NR ⁷ R ⁸ , NR ⁷ R ⁸ -C _r C ₄ alkyl, C _r C ₄ alkoxy , Ci-C ₄ -alkoxy-C _r C ₄ alkyl, C ₆ -C ₄ aryl and C ₅ -C ₀ - heteroaryl which is optionally substituted with one or more of the radicals, the same or different, selected from the group consisting made of halogen, NH _2, OH, CN, NR ⁹ R ^10, -NH may be substituted (CO) -C ₄ alkyl and C _r MeO, or in each case two of the substituents R ³ , R ⁴ , R ⁵ together form a five-, six- or seven-membered ring consisting of carbon atoms and optionally 1-2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; optionally with one or more of the radicals, identical or different, selected from the group consisting of halogen, NH ₂ , OH, CN, NR ⁹ R ¹⁰ , -NH (CO) -dC ₄ -alkyl and MeO may be substituted, R ^{6 is} identical or different, is hydrogen or a radical selected from the group consisting of C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl C ₃ -C ₈ -cycloalkyl, C ₂ -C ₆ -haloalkyl, C ₆ - Ci ₄ -aryl, C ₅ -C ₀ heteroaryl and C ₃ -C ₈ -heterocycloalkyl, optionally substituted by one or more of the radicals, the same or different, selected from the group consisting of, NH _2, NHMe, NMe ₂ OH, OMe, CN, -CrCs-alkyl-Ce-Cu-aryl, -NH-CO-NH-d-Cs-alkyl, C _r C ₆ -alkyl and - (CO) OC _r C ₆ -alkyl, or a radical selected from the group consisting of = O, NR ⁷ R ⁸ , OR ⁷ , -CO-CrC ₃ - alkyl-NR ⁷ R ⁸ -O-C ₁ -C ₃ -alkyl-NR ⁷ R ⁸ , CONR ⁷ R ⁸ , NR ⁷ COR ⁸ , -CO-C _r C ₃ -alkyl - NR ⁷ (CO) OR ⁸ , -O (CO) NR ⁷ R ⁸ , NR ⁷ (CO) NR ⁸ R ⁹ , NR ⁷ (CO) OR ⁸ , (CO) OR ⁷ , -O (CO) R ⁷ . COR ⁷ , (SO) R ⁷ , (SO ₂ ) R ⁷ , (SO ₂ ) NR ⁷ R ⁸ , NR ⁷ (SO ₂ ) R ⁸ , NR ⁷ (SO ₂ ) NR ⁸ R ⁹ , CN and halogen; n 1, 2 or 3 R ⁷ , R ⁸ , R ^{9 are} identical or different, hydrogen or a radical selected from the group consisting of C _r C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ haloalkyl, C _r C ₄ alkyl-C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ -cycloalkyl alkyl-C _3, C ₄ -C ₆ aryl, C _r C ₄ - alkyl-C ₆ -C ₄ aryl -, C ₆ -C ₄ -aryl-C ₁ -C ₄ -alkyl, C ₃ -C ₈ -heterocycloalkyl, C _r C ₅ - alkyl-QrCβ-heterocycloalkyl, C ₃ -C ₈ -heterocycloalkyl-C ₁ -C ₄ alkyl, CrC ₄ - Alkyl (CO) - and CrC ₄ alkyl-0 (C0) - optionally with one or more of the radicals, identical or different, selected from the group consisting of halogen, NH ₂ , OH, CN, OMe, NHMe, NMe ₂ C _r C ₆ alkyl and (CO) O Ci-C ₆ alkyl, may be substituted or in each case two of the substituents R ⁷ , R ⁸ , R ⁹ together form a five, six or seven membered ring consisting of carbon atoms and optionally 1-2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; optionally with one or more of the radicals, identically or differently, selected from the group consisting of halogen, NH ₂ , OH, CN, OMe, NHMe, NMe ₂ C _r C ₆ alkyl and (CO) OC _r C ₆ alkyl , may be substituted, mean. 3. Compounds according to claim 1 or 2, wherein A, R ^a and R ¹ to R ^{16 may have} the meaning given, and R ^{b is} hydrogen. 4. Compounds according to any one of claims 1 or 2, wherein A, R ¹ to R ^{16 may have} the meaning given, R ^a C ₆ -C ₄ aryl or C _r C ₆ alkyl wherein R ^a optionally substituted with one or more of the radicals, the same or different, selected from the group consisting of d-Cβ-alkyl, C ₂ -C ₆ alkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C _r C ₆ haloalkyl, halo- gen, OH, C _r C ₄ alkoxy, CN, NO _2, NR ¹⁰ R ^11, OR ^10, COR ¹⁰ , COOR ¹⁰ , CONR ¹⁰ R ¹¹ , NR ¹⁰ COR ¹¹ , NR ¹⁰ (CO) NR ¹¹ R ¹² , 0 (CO) NR ¹⁰ R ¹¹ , NR ¹⁰ (CO) OR ¹¹ , SO ₂ R ¹⁰ , SOR ¹⁰ , SO ₂ NR ¹⁰ R ¹¹ , NR ¹⁰ SO ₂ NR ¹¹ R ¹² and NR ¹⁰ SO ₂ R ¹¹ , may be substituted; and R ^{b is} hydrogen mean. 5. Compounds according to any one of claims 1 to 4, wherein A, R ^a and R ^{b may have} the meaning given, and R ¹ is hydrogen, C _r C ₅ alkyl or C ₃ -C ₈ cycloalkyl, R ^{2 is} hydrogen, C _r C ₅ alkyl or C ₃ -C ₈ cycloalkyl, phenyl or R ¹ and R ² together form an optionally substituted five- or six-membered ring consisting of carbon atoms and optionally 1 to 2 nitrogen atoms, or R ¹ and R ² together form an optionally substituted nine- to thirteen-membered spirocyclic ring, or R ¹ , R ^{2 are} identical or different, a radical selected from the group consisting of the general formulas formulas (A1) -A (17), where X is a bond or an optionally substituted CrC ₃ alkylene, or X together with R ¹ , R ³ or R ^{4 can form} a 5- or 6-membered heterocycle; Q is an optionally substituted C ¹ -C 3 -alkylene, Q together with R ¹ , R ³ or R ^{4 can form} a C 1 -C ₇ -alkylene bridge; R ³ , R ⁴ , R ^{5 are} identical or different, hydrogen or an optionally substituted Radical selected from the group consisting of -C ₄ -alkyl, Ci-C ₄ - alkoxy, C ₃ -C ₆ cycloalkyl, C ₃ -C ₈ -heterocycloalkyl, -dC ₃ alkyl C ₃ -C ₆ - Cycloalkyl, phenyl and C ₅ -Cio heteroaryl or in each case two of the substituents R ³ , R ⁴ , R ⁵ together form an optionally substituted five- or six-membered ring consisting of carbon atoms and optionally 1-2 heteroatoms selected from the group consisting of oxygen and nitrogen; mean. 6. Compounds according to any one of claims 1 to 4, wherein A, R ^a and R ^{b may have} the meaning given, and R ¹ H, Me R ^{2 is} hydrogen or a radical of the general formulas (A18), where X ¹ is a CrC form a bond or an optionally substituted radical selected from the group consisting of -C ₇ -alkylene, C ₃ -C ₇ -alkenylene and C ₃ -C ₇ -alkynylene, or X together with R ₇ -alkylene bridge can Y is a bond or methylene, ethylene; X and Y may be linked to the same or different atoms of G, and G is a saturated, partially saturated or unsaturated ring system of 3-10 C atoms, wherein optionally up to 6 C atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; R ^{6 is} identical or different, hydrogen or an optionally substituted radical selected from the group consisting of = 0, C ₁ -C ₄ -alkyl, C ₂ -C ₆ -alkenyl, C ₃ -C ₆ - Cycloalkyl, C ₆ -C ₄ -aryl, C ₅ -C ₆ -heterocycloalkyl, and C ₅ -C ₆ -heteroaryl or a radical selected from the group consisting of NR ⁷ R ⁸ , OR ⁷ , -O-CrC ₃ - alkyl-NR ⁷ R ⁸ , CONR ⁷ R ⁸ , CO-C _r C ₃ -alkyl-NR ⁷ R ⁸ NR ⁷ COR ⁸ , NR ⁷ (CO) OR ⁸ , -CO-CrC ₃ - alkyl-NR ⁷ (CO) OR ⁸ , NR ⁷ (CO) NR ⁸ R ⁹ , NR ⁷ (CO) OR ⁸ , (CO) OR ⁷ , COR ⁷ , (SO ₂ ) R ⁷ , -d- C ₃ - alkyl-C ₆ -C ₄ -aryl, -NH-CO-NH-C ₁ -C -alkyl and CN n 1 or 2 R ⁷ , R ⁸ , R ^{9 are} identical or different, hydrogen or an optionally substituted radical selected from the group consisting of C ₁ -C ₅ -alkyl, C ₁ -C ₄ -alkyl-C ₆ -C ₄ -aryl, C ₃ -C ₆ - Heterocycloalkyl, C ₁ -C ₅ -alkyl-C ₃ -C ₈ -heterocycloalkyl- and C ₃ -C ₆ -cycloalkyl, or in each case two of the substituents R ⁷ , R ⁸ , R ⁹ together form an optionally substituted five- or six-membered ring consisting of carbon atoms and optionally 1-2 heteroatoms selected from the group consisting of oxygen and nitrogen; mean, 7. Compounds according to any one of claims 1 to 6 for use as medicaments. 8. Use of the compounds according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment of diseases in whose pathology an activity of PI3-kinases is involved, in which therapeutically effective doses of the compounds of formula (I) can develop a therapeutic benefit. 9. Use according to claim 8, characterized in that it is inflammatory and allergic diseases of the respiratory tract. 10. Use according to claim 8 or 9, characterized in that it is a disease selected from the group consisting of chronic bronchitis, acute bronchitis, bronchitis due to bacterial or viral infection or fungi or helminths, allergic bronchitis, toxic bronchitis , chronic obstructive bronchitis (COPD), asthma (intrinsic or allergic), pe- diarrheal asthma, bronchiectasis, allergic alveolitis, allergic or non-allergic rhinitis, chronic sinusitis, cystic fibrosis or cystic fibrosis, alpha-1-antitrypsin deficiency, cough, pulmonary emphysema, interstitial lung disease, alveolitis, hyperreactive airways, nasal polyps, pulmonary edema, pneumonitis due to different causes such as radiation-induced or by aspiration or infectious, collagenoses such as lupus erythematosus, systemic scleroderma, sarcoidosis and M. boeck. 1 1. Use according to claim 8, characterized in that it is inflammatory and allergic diseases of the skin. 12. Use according to claim 8 or 11, characterized in that it is a disease selected from the group consisting of psoriasis, contact dermatitis, atopic dermatitis, alopecia areata (circular hair loss), erythema exsudativum multiforme ( Stevens-Johnson syndrome), dermatitis herpetiformis, scleroderma, vitiligo, hives (urticaria), lupus erythematosus, follicular and areal pyoderma, endogenous and exogenous acne, acne rosacea, and other inflammatory and allergic or proliferative skin diseases. 13. Use according to claim 8, characterized in that it is inflammation of the eye. Use according to claim 8 or 13, characterized in that it is a disease selected from the group consisting of conjunctivitis (conjunctivitis) of different species, e.g. by infections with fungi or bacteria, allergic conjunctivitis, irritant conjunctivitis, drug-induced conjunctivitis, keratitis and uveitis. 15. Use according to claim 8, characterized in that it is diseases of the nasal mucosa. 16. Use according to claim 8 or 15, characterized in that it is a disease selected from the group consisting of allergic rhinitis, allergic sinusitis and nasal polyps. 17. Use according to claim 8, characterized in that it is an inflammatory or allergic disease states in which autoimmune reactions are involved. 18. Use according to claim 8 or 17, characterized in that it is a disease selected from the group consisting of Crohn's disease, ulcerative colitis, systemic lupus erythematosus, chronic hepatitis, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, Osteoarthritis, rheumatoid spondylitis. 19. Use according to claim 8, characterized in that it is kidney inflammations. 20. Use according to claim 8 or 19, characterized in that it is a disease selected from the group consisting of glomerulonephritis, interstitial nephritis and idiopathic nephrotic syndrome. 21. Pharmaceutical formulation comprising a compound of the formula (I) according to one of claims 1 to 6. 22. An inhalable pharmaceutical formulation according to claim 21 comprising a compound of the formula (I) according to claims 1 to 6. 23. Orally administrable pharmaceutical formulation according to claim 21 comprising a compound of formula (I) according to one of claims 1 to 6. 24. Drug combinations which, in addition to one or more compounds of the formula (I) according to one of claims 1 to 6 as another active ingredient containing one or more compounds selected from the classes of betamimetics, anticholinergics, corticosteroids, other PDE4 inhibitors, LTD4 - Antagonists, EGFR inhibitors, dopamine agonists, H1 antihistamines, PAF antagonists and PI3 kinase inhibitors, or two- or three-fold combinations thereof.