EP2176266A2 - Substituted imidazo[1,2b]pyridazines as kinase inhibitors, the production thereof, and use of the same as medicaments - Google Patents

Abstract

The invention relates to novel inhibitors for kinases, methods for producing such inhibitors, intermediate products for producing the same, and uses thereof.

Description

 Substituted imidazo [1, 2b] pyridazines as kinase inhibitors, their preparation and use as drugs

The present invention relates to novel substituted imidazo [1, 2b] pyridazines, their preparation and use as a medicament for the treatment of various diseases.

The compounds described in this invention are suitable for the inhibition of kinases, preferably kinases of the protein kinase (PK) family and in particular for the inhibition of kinases of the PKC subfamily, in particular for the inhibition of PKC theta kinase. The present compounds are useful as kinase inhibitors for the treatment of a variety of diseases due to a malfunction of a kinase, including immunological and general inflammatory processes as well as oncological processes as well as diseases such as type II diabetes and asthma as well as transplants; preferably inflammatory processes and immune responses that have the clinical picture of acute dermatitis, contact dermatitis but also psoriasis.

From a single publication (Bioorg. Med. Chem. Lett. 2004, 14, 2249-2252.) Are known pyrimidine derivatives with an attached imidazo [1, 2b] pyridazine residue as kinase inhibitors. These compounds differ from the compounds of the invention by their structure, in particular the imidazo [1, 2b] pyridazine ring. The patent application WO 02/066481 (AstraZeneca) describes pyridazine-substituted pyrimidines as anti-proliferative substances. Further prior art is mentioned below.

There is still a great need for effective drugs for the treatment of immunological and cell proliferative diseases, especially in dermatological indications.

It has now been found that substituted imidazo [1, 2b] pyridazines of the general formula I in which

Formula I

in which

Q is aryl or heteroaryl, with the exception of pyrimidine;

A and B are the same or different and are selected from the group consisting of i) H, Hal, -OH, -NR ³ R ⁴ , -CN, or -NO ₂ , ii) optionally mono- or polysubstituted with Hal, -OH, C ³ C6-heterocycloalkyl,

-NR ³ R ⁴ , -SO ₂ NR ³ R ⁴ , -SO ₂ R ³ or - (CO) -NR ³ -L substituted C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1- C 6 -haloalkoxy, C 3 -C 6 -cycloalkyl or C 3 -C 6 -heterocycloalkyl, where the C 3 -C 6 -heterocycloalkyl in the ring optionally has one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) or - (SO ₂ ) - groups and / or one or more double bonds, and iii) -NR ³ (CO) -L, -NR ³ (CO) -NR ³ -L, - (CO) -R ⁶ , -O- (CH ₂ ) _P -R ⁶ , - (CO) - (NR ³ ) -L, -NR ³ (CS) -NR ³ R ⁴ , -NR ³ (SO ₂ ) -L, - (SO ₂ ) -NR ³ R ⁴ , -NR ³ (CO) NR ³ R ⁴ , - (CO) NR ³ R ⁴ , -CO ₂ R ⁷ , -NR ³ (SO ₂ ) R ⁴ or -O- (CH ₂ ) _P -aryl, where the substituents may be the same or different in the case of multiple substitution, A and B form, in addition to the above definition, together form a C5-C7-cycloalkyl or C5-C7-heterocycloalkyl ring fused with Q, the latter containing at least one oxygen or one nitrogen atom in the ring and optionally additionally one or more oxygen atoms in the ring. Nitrogen or sulfur atoms and / or one or more

- (CO) - or - (SO ₂ ) - groups and / or optionally contain one or more double bonds,

p is 0 to 4,

L optionally mono- or polysubstituted with hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -hydroxyalkoxy, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy,

Is C1-C6-alkoxyalkoxy, C3-C6-heterocycloalkyl, or -NR ³ R ^4, substituted C1-C6-alkyl, C1-C6-haloalkyl or C3-C6-cycloalkyl or C3-C6-heterocycloalkyl, wherein the C3 C6 heterocycloalkyl in the ring optionally one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or - (SO ₂ ) - groups and / or one or more

May contain double bonds;

R ¹ and R ^{2 are} identical or different and are selected from the group consisting of j) -H and jj) optionally mono- or polysubstituted with -HaI ₁ -OH, -CN, C ₁ -C 6 -alkyl, C ₁ -C 6-

Haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C2-C6 alkynyl, aryl, aryloxy, heteroaryl, -S-C1-C6 Alkyl, - (CO) -R ⁶ , -NR ³ R ⁴ , -NR ³ (CO) -L, -NR ³ COOR ⁷ , -COOR ⁷ , - NR ³ CONR ³ R ⁴ , -NR ³ SO ₂ R ⁴ , -SO ₂ NR ³ R ⁴ , -CONR ³ R ⁴ or -SO ₂ R ³ substituted

C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or Heteroaryl or - A -

with - (CH ₂ ) _r -R ⁸ radical, where r is a number 0-3 and R ^{8 is} a radical

stands

where in R ¹ or R ² optionally contained aryl, heteroaryl, C 3 -C 6

Cycloalkyl or C 3 -C 6 -heterocycloalkyl groups may be monosubstituted or polysubstituted by -HaI, -CN, -OH, -Cl-C 6 -alkyl, C 1 -C 6 -haloalkyl, -Cl-C 6 -alkoxy, C 1 -C 6 -haloalkoxy, -C 1 -C 6 -hydroxyalkyl, -C ³ -C 6 -cycloalkyl, -NO ₂ , -NH ₂ , -C 1 -C 6 -haloalkyl, -NR ³ R ⁴ , -CONR ³ R ⁴ , -NR ³ COR ⁴ , NR ³ SO ₂ R ⁴ , -COR ⁶ , CO ₂ R ⁷ , -SO ₂ NR ³ R ⁴ , -SR ³ , SOR ³ , -SO ₂ R ³ , -OR ³ , -O (CH ₂ ) _P R ⁶ , wherein the Substituents may be the same or different with multiple substitution;

where in R ¹ or R ^2, two or more aryl or heteroaryl groups may not be substituents of the same carbon atom;

in addition to the above definition, R ² can jointly form a C 3 -C 6 -heterocycloalkyl ring which contains at least one nitrogen atom in the ring and optionally additionally in the ring one or more nitrogen, oxygen or sulfur atoms and / or one or more - (CO) or - (SO ₂ ) - groups and / or optionally contain one or more double bonds, wherein the ring formed by R ¹ and R ² optionally mono- or polysubstituted with -CN, -HaI, -OH, C 1 -C 6 -alkyl, C 1 -C ⁶ -haloalkyl, C ³ -C ⁶ -cycloalkyl, C ¹ -C ⁶ -hydroxyalkyl, C ¹ -C ⁶ -alkoxyalkyl, C ¹ -C ⁶ -haloalkoxy, C ¹ -C ⁶ -haloalkoxyalkyl, -NR ³ R ⁴ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ and / or with optionally mono- or polysubstituted with -HaI, C 1 -C 6 -alkoxy, C 1 -C ⁶ -haloalkoxy or - (CO) -R ⁶ -substituted aryl or heteroaryl, the Substituents may be the same or different with multiple substitution;

R ³ and R ^{4 are the} same or different and are selected from the group consisting of j) -H, and jj) optionally mono- or polysubstituted with -HaI, -OH, -CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl , C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-

Hydroxyalkyl, C3-C6-cycloalkyl, C3-C6 heterocycloalkyl, C2-C6-alkynyl, aryl, aryloxy, heteroaryl, -NR ⁶ R ^7, -CONR ⁶ R ^7, - (CO) -R ⁶ or -COOR ⁷ substituted C1 -C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl or heteroaryl wherein the C3-C6 heterocycloalkyl in the ring optionally contain one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or -SO ₂ - groups and / or one or more double bonds and, wherein the substituents may be the same or different in the case of multiple substitution;

R ³ and R ^{4 can form, in} addition to the above definition, together a C ³ -C ⁶ -heterocycloalkyl ring which contains at least one nitrogen atom in the ring and optionally additionally in the ring one or more nitrogen, oxygen or sulfur atoms and / or one or more - ( CO) - or - (SO ₂ ) - groups and / or optionally one or more double bonds, wherein the ring formed by R 3 and R 4 optionally mono- or polysubstituted with -CN, -HaI, -OH, C 1 -C 6 -alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, C1-C6-hydroxyalkyl, C1-C6-haloalkoxy, C1-C6-haloalkoxyalkyl, C1-C6-alkoxyalkyl or with - NR ⁶ R ⁷ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ and / or with optionally mono- or polysubstituted with -HaI, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy or - (CO) - R ⁶ -substituted aryl or heteroaryl where the substituents may be the same or different when substituted several times; R ⁶ and R ^{7 are the} same or different and are selected from the group consisting of j) -H and jj) optionally mono- or polysubstituted with -HaI, -OH, -CN, substituted C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl , C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or heteroaryl, wherein the C3-C6-heterocyclalkyl in the ring optionally one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or -SO ₂ - groups and / or one or more double bonds may contain, and wherein the substituents with multiple substitution may be the same or different

and their isomers, diastereomers, enantiomers and salts, are effective compounds for the inhibition of (defined below) kinases and therefore can be used in a number of (defined below) diseases.

Alkyl is in each case a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl.

Alkoxy is in each case a straight-chain or branched alkoxy radical, such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy,

Isobutyloxy, sec. Butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy.

The alkenyl substituents are in each case straight-chain or branched, where the following are, for example, the following radicals: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl But-2-en-1-yl, but-2-en-2-yl, 2-methylprop-2-en-1-yl, 2-methylprop-1-en-1-yl, But -1-en-3-yl, but-3-en-1-yl, AIIyI.

Alkynyl is in each case to be understood as meaning a straight-chain or branched alkynyl radical which contains 2-6, preferably 2-4, C atoms. For example, be the The following radicals are mentioned: acetylenyl, propyn-1-yl, propyn-3-yl (propargyl), but-1-yn-1-yl, but-1-yn-4-yl, but-2-yn-1-yl , But-1-yn-3-yl, 3-methylbut-1-yn-3-yl.

C 1 -C 6 -haloalkyl represents a straight-chain or branched alkyl radical in which at least one hydrogen atom is substituted by a halogen atom (fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine), for example fluoromethyl, trichloromethyl, 1, 2-difluoroethyl, Perfluoropropyl, 3,3,3-trifluoropropyl, 1-fluoro-isopropyl, perfluorobutyl, etc. Very particular preference is given to perfluoromethyl and perfluoroethyl groups.

C 1 -C 6 -haloalkoxy represents a straight-chain or branched alkoxy radical in which at least one hydrogen atom is substituted by a halogen atom (fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine), for example fluoromethoxy, trichloromethoxy, 1,2-difluoroethoxy, Perfluoropropoxy, 3,3,3-trifluoropropoxy, 1-fluoro-isopropoxy, perfluorobutoxy, etc. Very particular preference is given to perfluoromethoxy and perfluoroethoxy groups.

C3 -C6 heterocycloalkyl represents a 3-6 carbon atom

Alkyl ring, wherein it contains the heterocycloalkyl in the ring at least one atom, identical or different, from the following group oxygen, sulfur or nitrogen and optionally by one or more - (CO) -, - (CS) - or -SO ₂ - groups in the ring may be interrupted and may optionally contain one or more double bonds in the ring and the ring itself may optionally be mono- or polysubstituted by identical or different substituents.

As heterocycloalkyl z. Oxiranyl, Oxethanyl, Dioxolanyl, Dithianyl, Dioxanyl, Aziridinyl, Azetidinyl, Tetrahydrofuranyl, Tetrahydropyranyl, Dihydrooxazolyl, Tetrahydrooxazolyl, Tetrahydrothiazolyl, Tetrahydroisoquinolinyl, Octahydroisoquinolinyl, Tetrahydroquinolinyl, Octahydroquinolinyl,

Tetrahydroimidazolonyl, pyrazolidinyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperidonyl, piperazinyl, piperazinonyl, N-methylpyrrolidinyl, 2-hydroxymethylpyrolidinyl, 3-hydroxypyrrolidinyl, N -methylpiperazinyl, N-benzylpiperazinyl, N-acetylpiperazinyl, N -methylsulphonylpiperazinyl, 4- Hydroxypiperidinyl, 4- Aminocarbonylpiperidinyl, 2-hydroxyethylpiperidinyl, 4-hydroxymethylpiperidinyl, imidazolidinyl, tetrahydroimidazolonyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, trithianyl, tetrahydrotriazine thionyl, triazine thionyl, quinuclidinyl, nortropinyl, pydridonyl.

Preferred heterocycloalkyl groups include: tetrahydropyranyl, pyrrolidinyl, piperidinyl, N-methyl-piperidinyl, piperazinonyl, N-methylpiperazinyl, morpholinyl, pyrridonyl.

Substituents on the heterocycloalkyl ring may be, for example: cyano, halogen, hydroxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -haloalkoxy, C ₁ -C ₆ -alkoxyalkyl, C ₁ -C ₆ -hydroxyalkyl, C ₃ - C ₆ -cycloalkyl, aryl or with optionally mono- or polysubstituted by identical or different halogen, hydroxy or C 1 -C ₆ -alkylthio-substituted C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl or a substituent from the group - (CO) -C _{r is} C ₆ -alkyl, - (CO) -O-C ₁ -C ₆ -alkyl, - (SO ₂ ) -CrC ₆ -alkyl, - (SO ₂ ) -phenyl, -NH ₂ , -N (C 1 -C ₆ -alkyl ) ₂ , -NHCd-Ce-alkyl) etc.

Cycloalkyl is to be understood as meaning monocyclic alkyl rings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but also bicyclic rings or tricyclic rings such as, for example, adamantanyl. The cycloalkyl may optionally also be benzo-fused, e.g. (Tetralin) yl etc.

Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Halogen is in each case fluorine, chlorine, bromine or iodine.

The aryl radical in Q and the aryl radical optionally contained in R ¹ and R ² comprises in each case 3 to 12 carbon atoms and may each be benzo-fused. Examples which may be mentioned are: cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl, tetralinyl, etc. The heteroaryl radical Q comprises in each case 5 to 16 ring atoms and may instead of the carbon contain one or more, identical or different heteroatoms, such as oxygen, nitrogen or sulfur in the ring, and may be mono-, bi- or tricyclic, and may additionally each be benzo-fused , Pyrimidine is not included in the term heteroaryl as group Q.

Examples which may be mentioned: thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc. and benzo derivatives thereof, such as. Benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, etc .; or pyridyl, pyridazinyl, pyrazinyl, triazinyl, etc. and benzo derivatives thereof, such as. Quinolyl, isoquinolyl, etc .; or oxepinyl, azocinyl, indolizinyl, indolyl, indolinyl, isoindolyl, indazolyl, benzimidazolyl, purinyl, etc. and benzo derivatives thereof; or quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, tetralinyl, etc.

Preferred heteroaryl radicals are, for example, 5-ring heteroaromatics, such as thienyl, furanyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl and benzo derivatives of 5-ring heteroaromatics and 6-membered heteroaromatic compounds, such as pyridinyl, triazinyl, and benzo derivatives of 5-ring heteroaromatics, such as quinolinyl , Isoquinolinyl.

The heteroaryl radical optionally contained in R ¹ or R ² comprises in each case 5 to 16 ring atoms and may contain, instead of the carbon, one or more, identical or different heteroatoms, such as oxygen, nitrogen or sulfur in the ring, and may be mono-, bi- or tricyclic , and may additionally be benzo-fused in each case.

As examples of the heteroaryl radical in R ¹ or R ² may be mentioned: thienyl, furanyl, Pyrroidinylyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc. and benzo derivatives thereof, such as. Benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, etc .; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and Benzoderivate thereof, such as. Quinolyl, isoquinolyl, etc .; or oxepinyl, azocinyl, indolizinyl, indolyl, indolinyl, isoindolyl, indazolyl, benzimidazolyl, purinyl, etc. and benzo derivatives thereof; or quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, tetralinyl, etc.

Preferred heteroaryl radicals in R ¹ or R ² are, for example, 5-ring heteroaromatics, such as thienyl, pyrazolyl, furanyl, oxazolyl, thiazolyl, triazolyl, imidazolyl and benzo derivatives thereof and 6-membered heteroaromatics, such as pyridinyl, pyrazinyl, triazinyl, quinolinyl, Isoquinolinyl and benzo derivatives thereof.

Particularly preferred heteroaryl radicals in R ¹ or R ² are thienyl, pyrazolyl, furanyl, oxazolyl, thiazolyl, triazolyl, imidazolyl, pyridinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl.

If several aryl or heteroaryl groups are present in R ¹ or R ² , two or more aryl or heteroaryl groups may not be substituents of the same carbon atom.

For example, a group

^C 6 ^H 5

- CH C ₆ H ₅ excluded as group R ¹ or R ² .

If in R ¹ or R ² aryl, heteroaryl, C ³ -C 6 cycloalkyl or C 3 -C 6

Heterocycloalkylgruppen be included, then these can be mono- or polysubstituted with -HaI, -CN, - OH, -C1-C6-alkyl, C1-C6-haloalkyl, -C1-C6-alkoxy, CI-C-6- Haloalkoxy, C 1 -C 6 -hydroxyalkyl, C ³ -C 6 -cycloalkyl, -NO ₂ , -NH ₂ , -C 1 -C 6 -haloalkyl, -NR ³ R ⁴ , -CONR ³ R ⁴ , -NR ³ COR ⁴ , NR ³ SO ₂ R ⁴ , -COR ⁶ , CO ₂ R ⁷ , -SO ₂ NR ³ R ⁴ , -SR ³ , SOR ³ , -SO ₂ R ³ , -OR ³ , -O (CH ₂ ) _P R ⁶ , the

Substituents with multiple substitution may be the same or different. In a preferred embodiment, the aryl groups contained in R ¹ or R ² , Heteroaryl, C3-C6-cycloalkyl or C3-C6-heterocycloalkyl groups a maximum of 3 of the above-mentioned Substutuenten.

Isomers are to be understood as meaning chemical compounds of the same empirical formula but of different chemical structure. One generally distinguishes constitutional isomers and stereoisomers.

Constitutional isomers have the same molecular formula, but differ in how their atoms or atomic groups are linked. These include functional isomers, positional isomers, tautomers or valence isomers.

Stereoisomers basically have the same structure (constitution) - and therefore also the same molecular formula - but differ by the spatial arrangement of the atoms.

In general, a distinction is made between configuration isomers and conformational isomers. Configuration isomers are stereoisomers that can only be converted into each other by bond breaking. These include enantiomers, diastereomers and E / Z (ice / trans) isomers.

Enantiomers are stereoisomers that behave in the same way as image and mirror image and have no plane of symmetry. All stereoisomers that are not enantiomers are called diastereomers. A special case is E / Z (ice / trans) isomers of double bonds.

Conformational isomers are stereoisomers that can be converted into each other by the rotation of single bonds.

For the differentiation of the isomeric species from each other, see also the IUPAC rules Section E (Pure Appl. Chem. 1976, 45, 11-30.).

The compounds of general formula I according to the invention also include the possible tautomeric forms and include the E or Z isomers or, if a chiral center is present, also the racemates and enantiomers. These are also to be understood as meaning double bond isomers. The compounds according to the invention can also be present in the form of solvates, in particular of hydrates, the compounds according to the invention accordingly containing polar solvents, in particular of water, as structural element of the crystal lattice of the compounds according to the invention. The proportion of polar solvent, in particular water, can be present in a stoichiometric or even unstoichiometric ratio. In the case of stoichiometric solvates, hydrates, we also speak of hemi, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates.

If an acidic function is present, suitable salts are the physiologically tolerated salts of organic and inorganic bases, such as, for example, the readily soluble alkali and alkaline earth salts and N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6-hexadiamine , Ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, 1-amino-2,3,4-butanetriol.

If a basic function is included, the physiologically acceptable salts of organic and inorganic acids are suitable, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, fumaric acid, maleic acid, malic acid and the like.

Preferred compounds of the general formula I are those compounds in which R ¹ and R ^{2 are} identical or different and are selected from the group consisting of j) -H and jj) optionally one or more times with -HaI, - OH, - CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -hydroxyalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -heterocycloalkyl, C 2 -C 6 -alkynyl, aryl , Aryloxy, heteroaryl, -S-C 1 -C ⁶ -alkyl, - (CO) -R ⁶ , -NR ³ R ⁴ , -NR ³ (CO) -L, or - NR ³ COOR ⁷ substituted C 1 -C ⁶ -alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, wherein the C3-C6-heterocycloalkyl in the Ring optionally one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or -SO ₂ - groups and / or one or more double bonds may contain, and wherein the substituents in multiple Substitution may be the same or different. Q, A, B, R ³ , R ⁴ , R ⁶ , R ⁷ , p and L can be varied as defined above.

Further preferred are those compounds of general formula I in which R ¹ and R ^{2 are the} same or different and are selected from the group consisting of j) -H and jj) optionally one or more times with -HaI, -OH, -CN , C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-hydroxyalkyl, C3-C-6-cycloalkyl, C3-C6-heterocycloalkyl, C2-C6-alkynyl, Aryloxy, -S-C 1 -C ⁶ -alkyl, - (CO) -R ⁶ , -NR ³ R ⁴ , -NR ³ (CO) -L, or -NR ³ COOR ⁷ substituted C 1 -C ⁶ -alkyl, C 1 -C ⁶ Haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, aryl or heteroaryl, wherein the C 3 -C 6 heterocycloalkyl in the ring may optionally contain one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or -SO ₂ - groups and / or one or more double bonds, wherein the defined in jj) Group aryl or heteroaryl may be substituted, if it is not alkyl, and wherein the substituents may be the same or different for multiple substitution. Q, A ₁ B, R ³ , R ⁴ , R ⁶ , R ⁷ , p and L can be varied as defined above.

Preference is furthermore given to those compounds of the general formula I in which Q is -OH, -HAl, -CN, alkyl, -OR ⁶ , or -NR ³ R ⁴ substituted phenyl, pyridyl, thiophenyl, furyl, imidazolyl, or pyrazolyl, wherein R ¹ and R ^{2 are the} same or different and are selected from the group consisting of j) -H and jj) optionally mono- or polysubstituted with -HaI, -OH, -CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl , C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C2-C6 alkynyl, aryloxy, -S-C1-C6 alkyl, - (CO ) -R ⁶ , -NR ³ R ⁴ , -NR ³ (CO) -L, or - NR ³ COOR ⁷ substituted C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy , C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -heterocycloalkyl, aryl or heteroaryl, where the C 3 -C 6 -heterocycloalkyl in the ring optionally contains one or more nitrogen, oxygen and / or Sulfur atoms and / or one or more - (CO) - or -SO ₂ - groups and / or one or more double bonds may contain, wherein the in jj) defined group aryl or heteroaryl substituted can be, unless it is alkyl.And wherein the substituents may be the same or different with multiple substitution. R ³ , R ⁴ , R ⁶ , R ⁷ , p and L can be varied as defined above.

Preference is furthermore given to those compounds of the general formula I in which R ¹ and R ^{2 are} identical or different and are selected from the group consisting of -H, C ¹ -C ⁴ -alkyl substituted by NR ³ R ⁴ , optionally additionally mono- or polysubstituted with - Hal, -OH, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, C 2 -C 6 alkynyl, aryl, aryloxy, heteroaryl, -S-C 1 -C ⁶ -alkyl, - (CO) -R ⁶ , -NR ³ (CO) -L, or - NR ³ COOR ⁷ substituted, optionally one or more times with -HaI, -OH, -CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -hydroxyalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -heterocycloalkyl , C 2 -C 6 -alkynyl, aryl, aryloxy, heteroaryl, -S-C 1 -C ⁶ -alkyl, - (CO) -R ⁶ , -NR ³ (CO) -L, -NR ³ R ⁴ , or -NR ³ COOR ^{7-substituted} C5-C6 cycloalkyl, C5-C6-heterocycloalkyl, wherein R ³ and R ⁴ optionally may be identical or different, C1-C6-alkyl, C1-C6 haloalkyl, wherein R ³ and R ⁴ together form a C3- C6-Het erocycloalkylring can form, which contains at least one nitrogen atom in the ring and optionally additionally in the ring one or more nitrogen, oxygen or sulfur atoms and / or one or more - (CO) - or - (SO ₂ ) - groups and / or optionally or more double bonds, and wherein R6 and R7, same or different, is -H, -OH, C1-C6-alkoxy, C1-C6-haloalkoxy, or C1-C3-alkyl.

Particular preference is given to compounds of the general formula I in which R ^{1 is} selected from the group consisting of -H and C ¹ -C ³ -alkyl, where R ^{2 is} selected from the group consisting of C ³ -C ⁴ -alkyl substituted by NR ³ R ⁴ , optionally additionally mono- or polysubstituted with -HaI, -OH, -CN, C1-C6-alkyl, C1-C6-

Haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-hydroxyalkyl, C3-C6-cycloalkyl, C3-C6 heterocycloalkyl, C2-C6-alkynyl, aryl, aryloxy, heteroaryl, -S-C1-C6- Alkyl, - (CO) -R ⁶ , -NR ³ (CO) -L, or -NR ³ COOR ⁷ , where R ³ and R ⁴ , identical or different, are optionally mono- or polysubstituted with -HaI, -OH, -CN, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-hydroxyalkyl, C3-C6-cycloalkyl, C 3 -C ⁶ heterocycloalkyl, C 2 -C ⁶ -alkynyl, aryl, aryloxy, heteroaryl, -NR ⁶ R ⁷ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ substituted C 1 -C ⁶ -alkyl, C 1 -C ⁶ Haloalkyl, wherein R ³ and R ^{4 may} together form a C ³ -C 6 -heterocycloalkyl ring which contains at least one nitrogen atom in the ring and optionally additionally in the ring one or more nitrogen, oxygen or sulfur atoms and / or one or more - ( CO) - or - (SO2) - groups and / or optionally one or more double bonds, and wherein R6 and R7, identical or different, -H, -OH, C1-C6-alkoxy, C1-C6-haloalkoxy, or C1-C3 is alkyl.

In a further preferred embodiment, R ¹ or R ^{2 is} a hydrogen atom.

Particular preference is given to the compounds mentioned in the examples:

• 2.0 - 2.21

• 3.0 - 3.80 • 4.0 - 4.11

• 5.0 - 5.389

• 6.0 - 6.2

• 7.0 - 7.1

• 8.0 - 8.1

Another object of the present invention is a compound of general formula IIa and their use for the preparation of a compound of formula I, in which

General formula IIa

Y is a halogen atom (preferably chlorine or bromine), R ¹ and R ^{2 are} identical or different and are selected from the group consisting of j) -H and jj) optionally mono- or polysubstituted with -HaI, -OH, -CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-hydroxyalkyl, C3-C6-cycloalkyl, C3-C6 heterocycloalkyl, C2-C6-alkynyl, aryl, aryloxy, heteroaryl, -S-C1-C6-alkyl, - (CO) -R ⁶ , -NR ³ R ⁴ , -NR ³ (CO) -L, or -

NR ³ COOR ⁷ substituted C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 Heteracycloalkyl, aryl or heteroaryl, where the C 3 -C 6 heterocycloalkyl in the ring optionally contains one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or -SO ₂ - groups and / or may contain one or more double bonds, and wherein the substituents may be the same or different in the case of multiple substitution;

R ¹ and R ^{2 in} addition to the above definition can together form a C 3 -C 6 heterocycloalkyl ring which contains at least one nitrogen atom in the ring and optionally additionally in the ring one or more nitrogen, oxygen or sulfur atoms and / or one or more - ( CO) - or - (SO ₂ ) - groups and / or optionally one or more double bonds, wherein the ring formed by R ¹ and R ² optionally singly or multiply with -CN, -HaI, -OH, C1-

C ⁶ alkyl, C ¹ -C ⁶ haloalkyl, C ³ -C ⁶ cycloalkyl, C ¹ -C ⁶ hydroxyalkyl, C ¹ -C ⁶ haloalkoxyalkyl, C ¹ -C ⁶ haloalkoxy, C ¹ -C ⁶ alkoxyalkyl, -NR ³ R ⁴ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ and / or substituted with optionally mono- or polysubstituted with -HaI, C 1 -C 6 -alkoxy, C 1 -C ⁶ -haloalkoxy or - (CO) -R ⁶ -substituted aryl or heteroaryl can be, with the

Substituents may be the same or different with multiple substitution; wherein three or more nitrogen atoms in the ring may not be directly bonded to each other; where in R ¹ or R ² optionally contained aryl, heteroaryl, C 3 -C 6

Cycloalkyl or C3-C6 heterocycloalkyl one or more times may be substituted with -HaI ₁ -CN, - OH, -C ₁ -C 6 -alkyl, C ₁ -C 6 -haloalkyl, -C ₁ -C 6 -alkoxy, C ₁ -C 6 -haloalkoxy, -C ₁ -C 6 -hydroxyalkyl, -C ₃ -C 8 -Cycloalkyl, -NO ₂ , -NH ₂ , -C 1 -C 6 -haloalkyl, -NR ³ R ⁴ , -CONR ³ R ⁴ , -NR ³ COR ⁴ , NR ³ SO ₂ R ⁴ , -COR ⁶ , CO ₂ R ⁷ , -SO ₂ NR ³ R ⁴ , -SR ³ , SOR ³ , -SO ₂ R ³ , -OR ³ , -O (CH ₂ ) _P R ⁶ , where the substituents in multiple

Substitution may be the same or different;

R ³ and R ^{4 are} identical or different and are selected from the group consisting of j) -H and jj) optionally mono- or polysubstituted with -HaI, -OH, -CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-hydroxyalkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, C2-C6-alkynyl, aryl, aryloxy,

Heteroaryl, -NR ⁶ R ⁷ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ substituted C 1 -C ⁶ -alkyl, C 1 -C ⁶ -haloalkyl, C 1 -C ⁶ -alkoxy, C 1 -C ⁶ -haloalkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -heterocycloalkyl, aryl or heteroaryl, where the C 3 -C 6 -heterocycloalkyl in the ring optionally contains one or more nitrogen, oxygen and / or sulfur Atoms and / or one or more - (CO) - or -SO ₂ - groups and / or may contain one or more double bonds, and, wherein the substituents may be the same or different with multiple substitution;

R ³ and R ^{4 can form, in} addition to the above definition, together a C ³ -C ⁶ -heterocycloalkyl ring which contains at least one nitrogen atom in the ring and optionally additionally in the ring one or more nitrogen, oxygen or sulfur atoms and / or one or more - ( CO) - or - (SO ₂ ) - groups and / or optionally one or more double bonds, wherein the ring formed by R3 and R4 optionally singly or multiply with -CN, -HaI, -OH, C1-

C ⁶ alkyl, C 1 -C ⁶ haloalkyl, C 3 -C ⁶ cycloalkyl, C 1 -C ⁶ hydroxyalkyl, C 1 -C ⁶ alkoxyalkyl C 1 -C ⁶ haloalkoxyalkyl, C 1 -C ⁶ haloalkyl or with -NR ⁶ R ⁷ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ and / or with optionally mono- or polysubstituted with -HaI, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy or - (CO) - R ⁶ -substituted aryl or heteroaryl can be, with the Substituents may be the same or different with multiple substitution;

R ⁶ and R ^{r are the} same or different and are selected from the group consisting of j) -H and jj) optionally mono- or polysubstituted with -HaI, -OH, -CN, substituted C 1 -C 6 -alkyl, C 1 -C 6 Haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy,

C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -ethylene-cycloalkyl,

Aryl or heteroaryl, wherein the C3-C6 heterocycloalkyl in the ring optionally one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or -SO ₂ - groups and / or one or may contain a plurality of double bonds, and wherein the substituents may be the same or different with multiple substitution

and their isomers, diastereomers, enantiomers and salts.

Another object of the present invention is a compound of general formula IIb and their use for the preparation of a compound according to formula 1, in which

General formula IIb

X is chloro, bromo, O-SO ₂ -CF ₃ or O-SO ₂ -C ₄ F ₉ ;

Q is aryl or heteroaryl, with the exception of pyrimidine;

A and B are the same or different and are selected from the group consisting of i) H, Hal, -OH, -NR ³ R ⁴ , -CN, or -NO ₂ , ii) optionally mono- or polysubstituted with Hal, -OH, C ³ -C6-heterocycloalkyl, -NR ³ R ⁴ , -SO ₂ NR ³ R ⁴ , -SO ₂ R ³ or - (CO) -NR ³ -L substituted C1-C6- Alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 3 -C 6 -cycloalkyl or C 3 -C 6 -heterocycloalkyl, where the C 3 -C 6 -heterocycloalkyl in the ring optionally contains one or more nitrogen, Oxygen and / or sulfur atoms and / or one or more - (CO) - or - (SO ₂ ) - groups and / or one or more double bonds may contain, and iii) -NR ³ (CO) -L, - NR ³ (CO) -NR ³ -L, - (CO) -R ⁶ , -O- (CH ₂ ) _P -R ⁶ , - (CO) - (NR ³ H, -NR ³ (CS) -NR ³ R ⁴ , -NR ³ (SO ₂ ) -L, - (SO ₂ J-NR ³ R ⁴ , -NR ³ (CO) NR ³ R ⁴ , - (CO) NR ³ R ⁴ , -CO ₂ R ⁷ , -NR ³ (SO ₂ ) NR ⁴ or -O- (CH ₂ ) _P -aryl, where the substituents may be the same or different in the case of multiple substitution,

A and B, in addition to the above definition, together form a C5-C7 cycloalkyl or C5-C7 heterocycloalkyl ring annulated with Q, the latter containing at least one oxygen or one nitrogen atom in the ring and optionally one or more additionally in the ring

May contain oxygen or nitrogen or sulfur atoms and / or one or more - (CO) - or - (SO ₂ ) - groups and / or optionally one or more double bonds,

p O is up to 4,

L optionally mono- or polysubstituted with hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl,

C 1 -C 6 -hydroxyalkoxy, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkoxyalkoxy, C ³ -C 6 -heterocycloalkyl, or -NR ³ R ⁴ , substituted C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl or C3-C6-cycloalkyl or C3-C6-heterocycloalkyl, wherein the C3-C6 heterocycloalkyl in the ring optionally one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or - (SO ₂ ) - may contain groups and / or one or more double bonds;

R ³ and R ^{4 are} identical or different and are selected from the group consisting of j) -H, and jj) optionally mono- or polysubstituted with -HaI, -OH, -CN, C 1 -C 6 - Alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-hydroxyalkyl, C3-C6-cycloalkyl, C3-C6 heterocycloalkyl, C2-C6-alkynyl, aryl, aryloxy, heteroaryl, NR ⁶ R ⁷ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ substituted C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6 Alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6

Heterocycloalkyl, aryl or heteroaryl, wherein the C3-C6 heterocycloalkyl in the ring optionally one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or -SO ₂ - groups and / or may contain one or more double bonds, and wherein wherein the substituents may be the same or different upon multiple substitution;

In addition to the above definition, R ³ and R ^{4 may} together form a C ³ -C ⁶ -heterocycloalkyl ring which contains at least one nitrogen atom in the ring and optionally additionally in the ring one or more nitrogen, oxygen or sulfur atoms and / or one or more

- (CO) - or - (SO ₂ ) - groups and / or optionally contain one or more double bonds, wherein the ring formed by R3 and R4 optionally singly or multiply with -CN, -HaI, -OH, C1-C6- Alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, C1-C6-hydroxyalkyl, C1-C6-alkoxyalkyl, C1-C6-haloalkoxyalkyl, C1-C6-haloalkoxy or with

-NR ⁶ R ⁷ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ and / or optionally with one or more times -HaI, C 1 -C ⁶ -alkoxy, C 1 -C ⁶ -haloalkoxy or - ( CO) - R ⁶ substituted aryl or heteroaryl may be substituted, wherein the substituents may be the same or different with multiple substitution;

R ⁶ and R ^{7 are the} same or different and are selected from the group consisting of j) -H and jj) optionally mono- or polysubstituted with -HaI, -OH, -CN, substituted C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl , C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl or heteroaryl, wherein the C3-C6 heterocycloalkyl in the ring may optionally contain one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or -SO ₂ - groups and / or one or more double bonds, and, wherein the substituents in multiple substitution may be the same or different

and their isomers, diastereomers, enantiomers and salts.

These compounds of general formulas IIa and IIb are advantageous intermediates and can be used in the synthesis of the compounds of general formula I listed above.

For the compounds of the formulas IIa and IIb, the statements made above for the compounds of the formula I, including the preferred embodiments of the radicals, are basically analogous. It is particularly preferred if Q is a phenyl which is optionally mono- or polysubstituted by -OH, -HAI, -CN, alkyl, -OR ⁶ , or -NR ³ R ⁴ , pyridyl, thiophenyl, furyl, imidazolyl or pyrazolyl. It is further preferred if X is -Cl or -Br.

Particular preference is given to the following intermediates according to the invention: 3-bromo-6-chloro-imidazo [1,2-b] pyridazine, imidazo [1,2-b] pyridazi-6-yl- (3-pyrrolidin-1-yl-propyl ) -amines, 6-chloro-3-phenyl-imidazo [1,2-b] pyridazines, 6-chloro-3- (3-chloro-phenyl) -imidazo [1,2-b3pyridazine, 6-chloro-3- (1-methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazine, 6-chloro-3-thiophen-3-yl-imidazo [1,2-b] pyridazine.

Very particular preference is given to the intermediates 1.0 to 1.28 described in the examples. Synthesis scheme:

I

General formula IIa

The invention accordingly also relates to a process for the preparation of a compound according to the invention with the following process stages:

A1) 3-amino-6-halogen-pyrazine is converted to 6-halo-imidazo [1,2-b] pyridazine II,

A2) the product from step A1 is converted to a 3-halo-6-halo-imidazo [1,2b] pyridazine III,

A3) the product from step A2 is converted by reaction with a compound

NHR ¹ R ^{2 converted} to the compound according to the general formula IIa,

A4) the product from stage A3 is converted to the compound according to general formula I,

or

B1) 3-amino-6-halogen-pyrazine is converted to 6-halo-imidazo [1,2-b] pyridazine II, B2) the product from stage B1 is converted to a 3-halo-6-halo-imidazo [1,2-b] pyridazine III,

B3) the product from stage B2 is converted into the compound according to general formula IIb,

B4) the product from step B3 is converted to the compound according to general formula I.

or

C1) 3-amino-6-halogen-pyrazine is converted to 6-halo-imidazo [1,2-b] pyridazine II,

C2) the product from step C1 is converted by reaction with a compound NHR ¹ R ² to an imidazo [1,2-b] pyridazin-6-yl) - (R ¹ ) - (R ² ) -amine IV,

C3) the product from stage C2 is converted into the compound according to general formula IIa,

C4) the product from stage C3 is converted to the compound according to general formula I.

The reactions mentioned are preferably carried out as follows:

A1) 3-amino-6-halogen-pyrazine is reacted with chloroactetaldehyde to give 6-halo-imidazo [1,2-b] pyridazine,

A2) the product from step A1 is reacted with Λ / -bromo-succinimide to give a 3-bromo-6-halo-imidazo [1,2-b] pyridazine, A3) the product from step A2 is converted to a (3-bromo-imidazo [1,2-b] pyridazin-6-yl) by reaction with a compound NHR ¹ R ² in a Buchwald-Hartwig cross-coupling reaction (R ¹ ) - (R ² ) -amine reacted,

A4) the product from stage A3 is reacted, for example, with a boronic acid which is optionally substituted by the radicals A and B, to give the compound according to the general formula I,

or

B1) 3-amino-6-halogeno-pyrazine is reacted with chloroactetaldehyde to give 6-halo-imidazo [1,2-b] pyridazine,

B2) the product from stage B1 is reacted with Λ / bromo-succinimide to give a 3-bromo-6-halo-imidazo [1,2-b] pyridazine,

B3) the product from stage B2 is reacted, for example, with a boronic acid, which is optionally substituted by the radicals A and B, to give the compound according to general formula II,

B4) the product from step B3 is converted by reaction with a compound

NHR ¹ R ² reacted in a Buchwald-Hartwig cross-coupling reaction to give the compound according to the general formula I.

or

C1) 3-amino-6-halogen-pyrazine is reacted with chloroactetaldehyde to give 6-halo-imidazo [1,2-b] pyridazine,

C2) the product of step C1 is converted to an imidazo [1,2-b] pyridazin-6-yl) (R ¹ MR ² ) amine by reaction with a compound NHR ¹ R ² in a Buchwald-Hartwig cross-coupling reaction .

C3) the product from step C2 is reacted with Λ / -bromo-succinimide to give a (3-bromo- imidazo [1,2-b] pyridazin-6-yl) - (R ¹ ) - (R ² ) -amine, C4) the product from step C3 is reacted, for example, with a boronic acid, which is optionally substituted by the radicals A and B, to give the compound according to the general formula I.

The compounds according to the invention are particularly preferably prepared by the synthesis route A1-A4.

To protect sensitive side groups, the synthetic routes mentioned can also be prepared using protective groups. The skilled person such protective group techniques are known, for example from TW Greene, PGM Wuts "Protective Groups in Organic Synthesis", 2 ^nd edition, John Wiley and Sons., 1991

The steps A1, B1 and C1 can, for example, by heating with, for example, chloroacetaldehyde, to 60 to 13O ⁰ C, in particular 100 to 130 ⁰ C, in n-butanol as a solvent and for a period of 1 hour to 10 days, especially 3 to 6 Days to be executed.

The amination (stages A3, B4 or C2) can be carried out, for example, by heating with the corresponding amine to 90-180 ^° C., in particular 90 ^° C., for a period of 1 hour to 24 hours, in particular 1 hour to 16 hours , The heating can be carried out by means of conventional heating or by means of microwave radiation by a suitable device. The use of an auxiliary base such as K ₂ CO ₃ or Et, ₃ N is not always necessary. The use of a solvent such as acetonitrile, EtOH, n-BuOH or NMP is not always required. For example, the so-called Buchwald-Hartwig cross-coupling reaction can be used for the amination. The Buchwald-Hartwig cross-coupling reaction can be carried out, for example, according to one of the references D. Zim, SL Buchwald, Org. Lett, 5: 2413-2415 (2003) or S. Urgaonkar, M. Nagarajan, JG Verkade, J. Org. Chem., 68: 452-459 (2003). The conversion to the 3-bromo intermediate (steps A2, B2 and C3) can be obtained by submitting the precursor compound in chloroform and adding the Λ / bromo- succinimide at -5 ° to 30 ⁰ C, especially at 0 to 10 ⁰ C, carried out , followed by a reaction over 1 hour to 2 days, in particular 5 to 15 hours, at 0 to 30 ⁰ C, in particular at 15 to 25 ⁰ C followed. However, the person skilled in the art is also aware of alternative synthesis routes for the preparation of the 3-halo intermediates according to the invention.

Steps A4, B3 or C4 can be prepared, for example, by presenting the precursor compound in dimethoxyethane and adding a boronic acid in the presence of a palladium (0) source, for example bis (dibenzylideneacetone) palladium (O), a ligand, for example tri-o-tolylphosphine and a base, for example sodium bicarbonate by means of heating under reflux for 5 to 40 hours, in particular 10 to 20 hours.

Unless the preparation of the starting compounds is described, they are known or can be prepared analogously to known compounds or processes described herein.

The isomer mixtures can be prepared by conventional methods such as crystallization, chromatography or salt formation in the isomers, such as. B. are separated into the enantiomers, diastereomers or E / Z isomers, provided that the isomers are not in equilibrium with each other.

The salts are usually prepared by adding a solution of the compound of the formula I with the equivalent amount or an excess of a base or acid, which may be in solution, and separating off the precipitate or working up the solution in a customary manner.

For exemplary synthetic details only, reference is made to the examples.

The invention furthermore also relates to intermediates according to the invention as defined in the claims. Compounds of the invention are useful as kinase inhibitors, particularly tyrosine and serine / threonine kinases. The compounds of the general formula I according to the invention are, inter alia, inhibitors of the protein kinase C family, such as, for example, PKC theta, delta, iota, alpha and zeta.

An inhibitor of a kinase can therefore be used, on the one hand, to study the functional mechanisms of the kinase, in particular the investigation of a disease which is based on a malfunction of the kinase. But also a due to the malfunction of the kinase disease can be treated or prevented with the kinase inhibitor.

The invention therefore furthermore relates to the use of a compound of the general formula I according to the invention for the preparation of a pharmaceutical composition, in particular for inhibiting a cellular kinase, preferably kinases of the protein kinase (PK) family and in particular for inhibiting kinases of the PKC subfamily, in particular for the inhibition of PKC theta kinase, or for the treatment or prophylaxis of a disease which is associated with the overexpression or mutation of a cellular kinase, in particular of such a cellular kinase.

In addition, it has been found that, surprisingly, the compounds according to the invention are also inhibitors of the kinases of the ALK family. ALK means "activin receptor-like kinase" or "activin-like kinase". The compounds according to the invention act on ALK1, ALK2, ALK4 and ALK5, in particular on ALK1 and ALK5. The compounds according to the invention are therefore also suitable for the treatment or the prophylaxis of diseases which is associated with the overexpression or mutation of a kinase of the ALK family, in particular ALK1 and ALK5.

In one embodiment of the invention, the disease is a disease selected from the group consisting of epidermal hyperproliferation such as psoriasis, Alzheimer's, autoinflammatory diseases, fibrosis, impaired wound healing, diabetic retinopathy, nephropathy, age-related macular degeneration, Crohn's disease, excessive immune response, contact dermatitis, atopic dermatitis, multiple sclerosis, ALS, diabetes, asthma.

In another embodiment of the invention, the disease is a disease selected from the group consisting of benign tumors, malignant tumors, leukemia such as myeloblastic leukemia, lymphoma, sarcoma, such as

Osteosarcoma or chondrosarcoma, neuroblastoma, Wilm's tumor, malignant neoplasms of the bladder, breast, lung, pancreas, prostate, kidney, neoplasms of epithelial origin, such as breast cancer or its metastases.

In a further embodiment of the invention, compounds according to the invention are used for modulation, in particular reduction, of an immune reaction, for example after transplantation in order to avoid organ rejection.

A pharmaceutical composition according to the invention can be prepared by mixing a physiologically effective dose of a compound according to the invention with at least one galenic excipient and preparing it into a desired administration form.

As a physiologically effective dose, for example, an amount of 1 to 1000 mg, in particular from 50 to 500 mg, per administration unit per day for a 75 kg human in question, where the dose given as a single dose to be administered or divided into 2 or more daily doses can be.

The galenic preparation of a pharmaceutical composition according to the invention can be carried out in the usual way. As counter-ions for ionic compounds, for example, come Na ^+, K ^+, Li ⁺ or Cyclohexylammon-ium, or Cl ^{", Br",} acetate, trifluoroacetate, propionate, lactate, oxalate, malonate, maleate, citrate, benzoate, salicylate, etc., in Question. Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, salve suspensions, emulsions, drops or solutions for injection (iV, ip, im, sc) or nebulization (aerosols), transdermal systems, as well as preparations with protracted release of active ingredient, in the preparation of which conventional auxiliaries such as excipients, disintegrants, binders, coating, swelling or lubricants, as well as preservatives, stabilizers, Wetting agents or emulsifiers; Salts for changing the osmotic pressure or buffers, flavorings,

Sweeteners and solubilizers, find use. Surfactant auxiliaries such as salts of bile acids or animal or plant phospholipids, but also mixtures thereof and liposomes or components thereof can also be used as carrier systems. As adjuvants may be magnesium carbonate, magnesium stearate, gum arabic, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycols and solvents such as sterile water and monohydric or polyhydric alcohols, for example glycerol. Preferred administration forms are for topical application (ointments, transdermal systems, patches, dressings), for oral administration (tablets, dragees, juices, powders) or for parenteral administration (suspension, injection).

A pharmaceutical composition according to the invention can be prepared by mixing at least one inhibitor used according to the invention in a defined dose with a pharmaceutically suitable and physiologically tolerated carrier and optionally further suitable active ingredients, additives or excipients with a defined inhibitor dose and preparing it to the desired dosage form. These pharmaceutical preparations are also the subject of the present invention.

Finally, the invention also relates to a method for the treatment or prophylaxis of a disease which is associated with the overexpression of a cellular kinase, a pharmaceutical composition comprising a physiologically effective dose is administered a compound according to any one of ^claims' 1 to 8 of a person comprising, which at the Disease is ill or threatens to fall ill. In the following, the invention will be explained in more detail by means of examples which merely represent exemplary embodiments.

Preparation of starting materials:

6-Chloro-imidazo [1,2-b] pyridazines (Example 1.0 OP 3055)

5.0 g (38.6 mmol) 3-amino-6-chloropyridazine were heated together with 4.7 ml (40 mmol) of chloroacetaldehyde (55% in water) in 15 mL of n-butanol for a period of 5 days at 120 ⁰ C. After completion of the reaction, the reaction mixture was added to saturated sodium bicarbonate solution and washed with three times

Extracted ethyl acetate. Subsequently, the combined organic phases were washed with sat. Washed sodium chloride solution, dried over sodium sulfate and the solvent i. Vak. away. In the final chromatographic purification on silica gel, 4.17 g (70%) of the desired product were isolated as an amorphous, white solid.

¹ H-NMR (CDCl ₃ , stored over molecular sieves): δ = 7.06 (d, 1H); 7.79 (d, 1H); 7.92, (d, 1H); 7.96 (d, 1H) ppm.

3-Bromo-6-chloro-imidazo [1,2-b] pyridazines (Example 1.1 OP 3056)

478 mg (3.11 mmol) of 6-chloro-imidazo [1,2-b] pyridazine were initially charged under argon in 10 ml of chloroform and, while cooling with ice, 664 mg (3.73 mmol) of Λ / bromine succinimide were added. After completion of the addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was then treated with water and ethyl acetate and, after addition of saturated

Sodium bicarbonate solution, the phases were separated. The aqueous phase was extracted three more times with ethyl acetate. Thereafter, the combined organic phases were washed with sat. Washed sodium chloride solution and dried over sodium sulfate. In the final removal of the solvent i. Vak. The desired product was isolated in quantitative yield in the form of an amorphous, white solid, which was used in subsequent reactions without further chromatographic purification.

¹ H-NMR (CDCl ₃ , stored over molecular sieves): δ = 7.12 (d, 1 H); 7.79 (s, 1H); 7.90, (d, 1H) ppm.

6-Chloro-3-iodo-imidazo [1,2-b] pyridazines (Example 1.2)

14 g of 6-chloro-imidazo [1,2-b] pyridazine (Example 1.0) were suspended in 364 mL of acetonitrile and 20.51 g of N-iodosuccinimide added. The reaction was stirred at RT for 19 hours. Another 4.31 g of N-iodo-succinimide were added and the reaction was stirred for 24 hours. The reaction was cooled and the precipitated solid was filtered off with suction, washed with acetonitrile and dried. 17.67 g of the desired product are obtained.

¹ H NMR (300 MHz, d ₆ -DMSO): δ = 7.40 (d, 1H); 7.95 (s, 1H); 8.19 (d, 1H) ppm. Preparation of the intermediates according to the invention:

Imidazo [1,2-b] pyridazin-6-yl- (3-pyrrolidin-1-yl-propyl) -amines (Example 1.3)

100 mg (0.65 mmol) of 6-chloro-imidazo [1,2-b] pyridazine were placed under argon in 9 ml of tetrahydrofuran and 3 ml of dimethylformamide. Successively, 83 mg (0.65 mmol, 1.0 eq.) Of 1- (3-aminopropyl) -pyrrolidine, 60 mg (0.065 mmol, 0.1 eq.) Of (dibenzylideneacetone) palladium (O), 41 mg (0.065 mmol, 0.1 eq.) Were added. rac. 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl and 125 mg (1.3 mmol, 2.0 eq) of sodium fe / f-butylate were added and then heated to 80 ° C for 4 h.

Subsequently, the reaction mixture was treated with water and ethyl acetate and after addition of saturated sodium bicarbonate solution, the phases were separated. The aqueous phase was extracted three more times with ethyl acetate. Thereafter, the combined organic phases were washed with sat. Washed sodium chloride solution and dried over sodium sulfate. In the final chromatographic purification on silica gel, 53 mg (39%) of the desired product were isolated as an amorphous white solid.

¹ H NMR (CDCl ₃ , stored over molecular sieves): δ = 1.77-1.89 (m, 6H); 2.54 (m, 4H); 2.66 (m, 2H); 3.43 (m, 2H); 6.18 (see br, 1H); 6.31 (d, 1H); 7.44 (d, 1H); 7.57, (d, 1H); 7.61 (d, 1H) ppm.

LC-MS (ACN / H ₂ O 0.01% HCOOH; 33x4.6x1.5μ ODSII ₁ gradient: 100% H ₂ O - »90% ACN in 4.5 min): t = 0.41 min; m / z = 246 [M + H] ⁺ 38%; 123 [M + H] ⁺⁺ 100%; 6-Chloro-3-phenyl-imidazo [1,2-b] pyridazines (Example 1.4)

500 mg (2.15 mmol) of 3-bromo-6-chloro-imidazo [1,2-b] pyridazine were placed under argon in 25 ml of dimethoxyethane. Successively, 290 mg (2.4 mmol, 1.1 eq.) Of phenylboronic acid, 250 mg (0.43 mmol, 0.2 eq.) Were added.

Bis (dibenzylideneacetone) palladium (0) and 130 mg (0.43 mmol, 0.2 eq.) Of tri-o-tolylphosphine and 2.2. Saturated sodium bicarbonate solution was added and the reaction mixture heated at reflux for 15 hours.

Subsequently, the reaction mixture was added with ethyl acetate and after addition of saturated sodium bicarbonate solution, the phases were separated. The aqueous phase was extracted three more times with ethyl acetate. Thereafter, the combined organic phases were washed with sat. Washed sodium chloride solution and dried over sodium sulfate. The final chromatographic purification on silica gel isolated 239 mg (48%) of the desired product.

¹ H-NMR (CDCl ₃ , stored over molecular sieves): δ = 7.02 (d, 1 H); 7.35 (m, 1H); 7.43 (m, 2H); 7.89 (d, 1H); 7.95 - 8.0 (m, 3H) ppm.

MS (ES +): m / z = 230 (100%) ([M + H] ⁺ ; 232 (45%). 2- (3-Bromo-imidazo [1,2-b] pyridazine-6-ylamino) -ethanol (Example 1.5)

400 mg (1.72 mmol) of 3-bromo-6-chloro-imidazo [1,2-b] pyridazine and 2.0 ml (33.4 mmol) of ethanolamine were stirred at 90 ^° C. for 16 h. After cooling, the batch was concentrated. The residue obtained was purified by chromatography (DCM / EtOH 9: 1). This gave 282 mg of the product.

¹ H NMR (300 MHz; d ₆ -DMSO): δ = 3.28-3.34 (m, 2H, solvent-covered); 3.56-3.61 (m, 2H); 4.74 (t, 1H); 6.71 (d, 1H); 7.13 (t, 1H); 7.43 (s, 1H); 7.64 (d, 1H) ppm.

MS (El +): m / z = 256; 258 (M + H) ⁺ . [Mol. Weight = 257.09].

2- (3-iodo-imidazo [1,2-b] pyridazin-6-ylamino) -ethanol (Example 1.6)

562 mg (2.0 mmol) of 6-chloro-3-iodo-imidazo [1,2-b] pyridazine and 2.35 ml (39.2 mmol) of ethanolamine were stirred at 90 ^° C. for 16 h. After cooling, the batch was concentrated. The residue obtained was purified by chromatography (DCM / EtOH 9: 1). This gave 224 mg of the product.

¹ H NMR (300 MHz, d ₆ -DMSO): δ = 3.27-3.35 (m, 2H, solvent-covered); 3.58-3.63 (m, 2H); 4.72 (t, 1H); 6.67 (d, 1H); 7.06 (t, 1H); 7.42 (s, 1H); 7.59 (d, 1H) ppm.

MS (ESI +): m / z = 305 (M + H) ⁺ . [Mol. Weight = 304.09]. In an analogous manner are prepared:

Table 1 :

358 846

358 860

358 861

601 352 6

(Cl

263 (Cl

602 976 8

601 957 6

601 957 2

601 957 0

601 370 5

601 979 6

602 059

5

602 059

7

602 059 6

603 336 3 (Cl

6-Chloro-3-naphthalen-2-yl-imidazo [1,2-b] pyridazines (Example 1.28)

1, 03 g of 6-chloro-3-naphthalen-2-yl-imidazo [1,2-b] pyridazines were prepared from 3.5 g (12.52 mmol) of 6-chloro-3-iodo-imidazo [1, 2 -b] pyridazine (Example 1.2) and 2.37 g (13.78 mmol) of 2-naphthylboronic acid (CAS No. 32316-92-0) prepared analogously to Example 1.4.

¹ H NMR (400 MHz, d ₆ -DMSO): δ = 7.43 (d, 1H); 7.51-7.57 (m, 2H); 7.92-7.98 (m, 2H); 8.02 - 8.05 (m, 1H); 8.13-8.16 (m, 1H); 8.31 (d, 1H); 8.43 (s, 1H); 8.69 (s, 1H) ppm. Preparation of the end products according to the invention:

Method A: (3-Phenylimidazo [1,2-b] pyridazin-6-yl) - (3-pyrrolidin-1-yl-propyl) -amines (Example 2.0)

100 mg (0.435 mmol) of 6-chloro-3-phenyl-imidazo [1,2-b] pyridazine were dissolved under argon in a mixture of 6 ml of tetrahydrofuran and 2 ml of dimethylformamide. Successively, 56 mg (0.435 mmol, 1.0 eq.) Of 1- (3-aminopropyl) -pyrrolidine, 40 mg (0.07 mmol, 0.16 eq.) Of bis (dibenzylideneacetone) palladium (0) (Pd ₂ dba ₃ ), 27 mg (m.p. 0.0435 mmol, 0.1 eq.) Rac. 2,2'-bis (diphenylphosphino) -1, 1 '- binaphthyl (rac-BINAP), and 84 mg (. 0.87 mmol, eq 2) of sodium tert-butoxide (NaOfBu) were added and the reaction mixture for 4 hours at 80 ⁰ C heated.

Then, the reaction mixture was added with ethyl acetate, and after adding water, the phases were separated. The aqueous phase was extracted three more times with ethyl acetate. Thereafter, the combined organic phases were washed with sat. Washed sodium chloride solution and dried over sodium sulfate. In the final chromatographic separation 9 mg (6%) of the desired product were isolated in clean form after repeated purification on silica gel. ¹ H-NMR (CDCl ₃ , stored over molecular sieves): δ = 1.8 (m, 4H); 1.88 (m, 2H); 2.55 (m, 4H); 2.68 (t, 2H); 3.51 (m, 2H); 6.19 (s, br. 1H); 6.38 (d, 1H); 7.33 (m, 1H); 7.46 (m, 2H); 7.63 (d, 1H); 7.79 (s, 1H); 8.12 (d, 2H) ppm.

MS (ES +): m / z = 322 (100%) ([M + H] ⁺ .

The following are prepared analogously: TABLE 2

Method B: [3- (1-Methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazin-6-yl] -pyridin-3-ylmethyl-amine (Example 3.0)

35 mg (0.15 mmol) of 6-chloro-3- (1-methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazine were placed under argon in a mixture of 0.67 ml of tetrahydrofuran and 0.33 ml of dimethylformamide , Subsequently, 0.5 mL of a 0.45 M solution of pyridin-3-yl-methylamine (0.225 mmol) in toluene was added. After addition of solutions of 1.72 mg Pd ₂ dba ₃ (18.8 μmol) and 3.5 mg rac-BINAP (56.3 μmol) in 0.91 mL THF and 31.7 mg NaOfBu (0.3 mmol) in 0.91 mL THF, the reaction mixture was at 8O ⁰ for 12 h C shaken.

Subsequently, the reaction mixture was mixed with 1 ml of water and 3 ml of ethyl acetate. The organic phase was separated and freed from the solvent. The crude product thus obtained was purified by HPLC. 8.7 mg (19%) of the desired product were isolated.

HPLC-MS (analytical) of the purified product

Detection: UV = 254 nm; Column: Purospher STAR RP18e, 125x4mm, 5 μm (Merck KGaA, Darmstadt); Flux: A: H ₂ O / 0.1% TFA, B: CH ₃ CN / 0.1% TFA, gradient: 5 to 95% B in 10 min; Flow rate: 1 ml / min:

Retention time of the product = 3.85 min; MS of the product: m / z = 301 ([M + H] ⁺ )

In an analogous manner are prepared:

Table 3:

Description of HPLC-MS Analysis Conditions of the Examples Listed in Table 3:

HPLC-MS Method A: Detection: UV = 254 nm; Column: Purospher STAR RP18e, 125x4mm, 5 μm (Merck KGaA, Darmstadt); Flux: A: H ₂ O / 0.1% TFA, B: CH ₃ CN / 0.1% TFA, gradient: 5 to 95% B in 10 min; Flow rate: 1 ml / min:

HPLC-MS Method B: Detection: UV = 254 nm; Column XBridge C18, RP18e, 150x4.8mm, 5μm (Waters); Gradient 5-95% acetonitrile (0.1% NH ₄ OH) in water (0.1% NH ₄ OH / NH ₄ HCO ₃ ) (10 min); Flow rate 1.0 mL / min.

Method C: (4- [6- (2-Hydroxyethylamino) -imidazo [1,2-b] pyridazin-3-yl] -phenol (Example 4.0)

85 mg (0.33 mmol) of 2- (3-bromo-imidazo [1,2-b] pyridazinyl-6-ylamino) -ethanol (Example 1.5), 69 mg (0.5 mmol) of 4-hydroxybenzene boronic acid and 76 mg (0; 066 mmol) of tetrakis- (triphenylphosphine) -palladium (0) were dissolved under argon with 3.4 ml of dimethylglycol and 2 ml of an aqueous NaOH solution. (a stock solution of 190 mg NaOH in 10 mL water). The mixture was stirred at 90 ^° C. for 19 hours. After cooling, the batch was washed with sat. NaCl solution. diluted and extracted 2 x ethyl acetate. The combined organic phases were washed with sat. NaCl solution. washed, filtered through a silicone filter (Whatman) and concentrated. The resulting crude product was recrystallized from methanol. 40 mg of the desired product are obtained.

¹ H-NMR (400 MHz, d _e -DMSO): δ = 3.30-3.31 (m, 2H, solvent-covered); 3.61-3.62 (m, 2H); 4.74 (m, 1H); 6.66 (d, 1H); 6.81 (d, 2H); 6.94-6.96 (m, 1H); 7.64-7.67 (m, 2H); 7.93 (d, 2H); 9.57 (brs, 1H) ppm.

MS (ESI +): m / z = 271 ([M + Hf). [Mol. Weight = 270.29]. In an analogous manner are prepared:

Table 4

In an analogous manner are prepared:

Table 5:

- -

Description of the HPLC-MS analysis conditions of the examples listed in Table 5:

Detection: UV = 200-350 nm (Waters Acquity HPLC) / MS 100-800 Daltons; 20V (Micromass / Waters ZQ 4000); Column: X Bridge (Waters), 2.1 x 50 mm, BEH 1, 7 μm; Flux: A: H ₂ O / 0.05% HCOOH, B: CH ₃ CN / 0.05% HCOOH.

Gradient: 10-90% B in 1.7 minutes, 90% B for 0.2 minutes, 98-2% B in 0.6 minutes; Flow rate: 1, 3 ml / min.

[3- (2'-Methoxy-pyridin-4-yl) -imidazo [1,2-b] pyridazin-6-yl] -piperidin-4-yl-amine (Example 6.0)

Step A: 4- [3- (2-Methoxy-pyridin-4-yl) -imidazo [1,2-b] pyridazin-6-ylamino] -piperidine-1-carboxylic acid tert-butyl ester (Example 6.1)

292 mg of 4- [3- (2-methoxy-pyridin-4-yl) -imidazo [1,2-b] pyridazine-6-ylamino] -piperidine-1-carboxyloxylic acid tert-butyl ester were prepared from 300 mg (1 , 15 mmol) of 6-chloro-3- (2-methoxypyridin-4-yl) -imidazo [1,2-b] pyridazine (Example 1.14) and 230 mg (1.15 mmol) of 4-amino-piperidine- 1 -carboxylic acid tert-butyl ester (CAS no. 87120-72-7) prepared according to method A.

1 H NMR (300 MHz, d ₆ -DMSO): δ = 1, 32-1, 38 (m, 11 H); 2.02 - 2.08 (m, 2H); 2.92-3.00 (m, 2H); 3.72-3.92 (m, 6H); 6.73 (d, 1H); 7.17 - 7.19 (m, 1H); 7.64-7.66 (m, 1H); 7.76-7.79 (m, 2H); 8.11-8.16 (m, 2H) ppm.

MS (ES +): m / z = 425 (M + H) ⁺ [mol. Weight = 424.51].

Step B: [3- (2-Methoxy-pyridin-4-yl) -imidazo [1,2-b] pyridazin-6-yl] -piperidin-4-yl-amine (Example 6.0)

280 mg (0.66 mmol) 4- [3- (2-methoxy-pyridin-4-yl) -imidazo [1,2-b] pyridazine-6-ylamino] -piperidine-1-carboxylic acid tert-butyl ester were presented in 3 ml of THF and treated with 0.8 ml of HCl in dioxane (4M) and stirred at RT overnight. HCl (conc) was added and the mixture was heated to 70 ^° C. for 4 hours. The reaction was diluted with water, adjusted to pH 11 using Et ₃ N and extracted with ethyl acetate three times. The combined organic phases were filtered through a silicone filter (Whatman) and concentrated. The final chromatographic separation on silica gel isolated 92 mg of the desired product.

1 H NMR (300 MHz, d ₆ -DMSO): δ = 1.30-1.43 (m, 2H); 2.03 - 2.08 (m, 2H); 2.59 - 2.67 (m, 2H); 2.99 - 3.06 (m, 2H); 3.66-3.75 (m, 1H), 3.89 (s, 3H); 6.77 (d, 1H); 7.15 - 7.18 (m, 1H); 7.66-7.69 (m, 1H); 7.80 (d, 1H); 8.87 (s, 1H); 8.15 - 8.19 (m, 2H) ppm.

MS (ES +): m / z = 325 (M + H) ⁺ [mol. Weight = 324.39].

The following example was prepared analogously:

3- [6- (2-Hydroxyethylamino) -imidazo [1,2-b] pyridazin-3-yl] - benzenesulfonamides (Example 7.0)

82 mg (0.21 mmol) of N-tert-butyl-3- [6- (2-hydroxy-ethylamino) -imidazo [1,2-b] pyridazin-3-yl] -benzenesulfonamide were added under argon with 1, 7 ml of trifluoroacetic acid and stirred at 50 ⁰ C for 5 hours. After cooling, the reaction was concentrated in vacuo and the residue was taken up in ethyl acetate. The organic phase was washed with saturated NaHCO ₃ solution and saturated NaCl solution, filtered through a Whatman filter and concentrated. The residue obtained was purified by chromatography (DCM / EtOH 6: 4). 47 mg of the product were obtained.

1 H NMR (400 MHz, d ₆ -DMSO): δ = 3.36 - 3.40 (m, 2H); 3.61-3.65 (m, 2H); 4.77 (t, 1H); 6.78 (d, 1H); 7.17 (t, 1H); 7.35 (s, 2H); 7.59 - 7.63 (m, 1H); 7.70 - 7.76 (m, 2H); 7.95 (S, 1H); 8.25 (d, 1H); 8.87 (m, 1H) ppm.

The following example was prepared analogously:

The following examples were prepared from 4 -; (6-chloro-imidazo [1,2-b] pyridazin-3-yl) phenol and the corresponding amine analogously to Example 1.5:

Biological effects

The following examples describe the biological activity of the compounds according to the invention:

It will be clear to those skilled in the art that there are a number of diseases in which the cause of the disease is due to a malfunction of one or more kinases. Malfunctions of kinases can be triggered by a variety of mechanisms, e.g. a kinase can be overexpressed, resulting in defective cell activity, or a mutated kinase can be overexpressed, also resulting in defective cell activity. The defective cell activity may be, for example, an incorrect cell proliferation, especially an increased cell proliferation (cell hyperproliferation). The result of such malfunctions may be, for example, a disease characterized by overexpression or mutation of the kinase.

Suitable assays for testing the effectiveness of the compounds of the invention on the modulation capacity of the kinase activity are known. Furthermore, assays are known to investigate the effectiveness of the compounds of the invention in the modulation of cell proliferation. The following biological examples therefore merely serve to exemplify the uses according to the invention of the claimed compounds and are therefore in no way to be understood as limiting.

Importance of IL-2 in the T cell immune response In the following test system it was investigated to what extent test substance influence the antibody-induced interleukin 2 (IL-2) secretion. IL-2 is a central cytokine that is produced and released by activated T cells. The IL-2 synthesis in the T cells is regulated by several kinases. An inhibitory effect of substances on kinases leads i.a. to an inhibition of IL-2 synthesis and an inhibition of the T cell immune response. The cytokine determinations were carried out by means of ELISA kits.

Description of the test system

Peripheral blood mononuclear cells (PBMC) were isolated from heparinized human whole blood by gradient centrifugation with Histopaque 1077 (Sigma) at room temperature, the erythrocytes hypotonic lyzed and washed twice in PBS in cell culture medium (10% fetal inactivated calf serum in RPMI-1640 + glutamax-I [Gibco]).

The 96 well culture plates (Costar) were previously incubated with 100 μl of antibody solution in PBS 0.1 μg / ml in PBS [Gibco] per well for 18 hours at 4 ^° C. The antibodies used were anti-CD3 and anti-CD28 monoclonal antibodies

(Pharmingen). After washing three times with PBS, the plates were provided with 200 μl of the cell suspension (40,000 cells / well). In addition, the

Test substances in concentrations so that they were in the concentrations of 1x10 ^"6 - 1x10 ^'12 M. The cultures were incubated for 20 hours in the incubator at 37 ° C. After this incubation, the plates were shaken briefly centrifuged and 250μl supernatant removed, the supernatants were then frozen at -20 ⁰ C.

Interleukin-2 determination was carried out with an ELISA kit (Bioscience) and the absorbance of the color change was analyzed on the SpectraMax 340 PC (wavelength 450 nm). Effective substances caused a reduction in absorption.

Table 1: Assay data

ALK1 kinase flashplate assay

To test the efficacy of compounds, an ALK1 kinase flashplate assay was established and used.

ALK1 phosphorylates serine / threonine residues of the biotinylated substrate bovine α-casein in the presence of [γ- ³³ P] ATP. The detection of the radioactively labeled product takes place by binding to streptavidin-coated flashplates. The biotin residues of the biotinylated casein bind with high affinity the streptavidin. Radioactively labeled biotinylated casein produced by the ALK1 kinase reaction causes a chemiluminescent signal after streptavidin-mediated binding to the scintillator-containing surface of the flashplates. This signal is due to the proximity of the radioactive label to the scintillator in the whale surface of the flashplates. Unphosphorylated substrate does not cause signal because it contains no radiolabeled phosphate groups. Free [γ- ³³ P] ATP which remains unbound in the solution (supernatant) is washed from the wells of the flashplates and therefore does not contribute significantly to a background signal. The measured signals are therefore a measure of the ALK1 kinase activity. The measurement is performed in a Perkin-Elmer TopCount instrument or a Perkin-Elmer ViewLux instrument.

Material:

Enzyme: Purified human recombinant ALK1 kinase (GST fused to the intracellular domain of ALK1 [His142-Gln503]); self made; Aliquots are stored at -80 ° C; diluted enzyme working solution: 2.5 ng / μl ALK1 (in

Assay buffer) is freshly prepared and stored on ice until use.

Substrate: biotinylated bovine α-casein. Unbiotinylated casein from Sigma is prepared by standard methods using a biotin-Λ / -hydroxy-succinimide

(NHS) ester biotinylated.

Substrate working solution: 0.83 μM ATP, 1.67 μM biotinylated α-casein, 7.4 nCi

[γ- ³³ P] ATP / μl in assay buffer

Assay plates: 384-well plates, small volume, white, Greiner (# 784075) Flashplates: Streptavidin-coated flashplates, Perkin bucket (384-WeII #

SPM410A)

Assay Buffer: 50mM Tris / HCl pH 8.0, 1mM MnCl ₂ , 1mM DTT, 0.01% NP40, 0.5x

Complete EDTA-free

Stop solution: 33.3 μM ATP, 33.3 mM EDTA, 0.07% Triton X-100 in PBS Flashplate saturation solution: 100 μM ATP, 0.2% Triton X-100 in PBS Adhesive film for plates: Greiner (# 676080)

assay Description

Protocol for a 5 ul assay (all steps are carried out at 20 ⁰ C; pipetting a CyBi-well pipettor, and a Multidrop micro-dispenser is used):

1. 50 nl or 250 nl substance in 100% DMSO

2. Add 3 μl substrate working solution with a CyBi-WeII pipettor

3. Add 2 ul enzyme working solution with Multidrop Micro incubation for 60 min Dispenser (20 ⁰ C) at room temperature

4. Add 15 μl stop solution with a CyBi-well pipettor

5. Transfer 18 μl Assay Mixture into Flashplates ** with a CyBi-Well Pipettor Incubation for at least 3 h at room temperature or overnight at 4 ° C to allow binding to the streptavidin-coated flashplates. 6. Wash the flashplates three times with 50 μl PBS each without Ca ⁺⁺ and Mg ⁺⁺

7. Close the plates with adhesive film

8. Measurement in Topcount (60 sec / well)

** Saturation of flashplates: The flashplates are preincubated for at least 1 h with 50 μl of saturation solution. 18 μl of this solution are discarded before 18 μl of assay mixture are transferred to the flashplates

Final concentrations calculated for 5 μl reaction volume: 5 ng ALK1 / well; 1 μM biotinylated α-casein; 0.5 μM ATP; 22 nCi / well [γ- ³³ P] ATP; 1 mM MnCl ₂ ; 1mM DTT; 50 mM Tris-HCl, pH 8.0; 0.01% NP40; 0.5x Complete EDTA-free; 1% or 5% DMSO.

The data are normalized (enzyme reaction without inhibitor = 0% inhibition, enzyme reaction in the presence of 10 mM EDTA = 100% inhibition) and IC ₅₀ values are calculated with a 4-parameter fit using in-house software. ALK4 kinase flashplate assay

To test the efficacy of compounds, an ALK4 kinase flashplate assay was established and used.

ALK4 phosphorylated in the presence of [γ- ³³ P] ATP Serine / threonine residues of the biotinylated substrate α-casein from bovine. The detection of the radioactively labeled product takes place by binding to streptavidin-coated flashplates. The biotin residues of the biotinylated casein bind with high affinity to the streptavidin. Radioactively labeled biotinylated casein produced by the ALK4 kinase reaction causes a chemiluminescent signal after streptavidin-mediated binding to the scintillator-containing surface of the flashplates. This signal is due to the proximity of the radioactive label to the scintillator in the whale surface of the flashplates. Unphosphorylated substrate does not cause signal because it contains no radiolabeled phosphate groups. Free [γ- ³³ P] ATP which remains unbound in the solution (supernatant) is washed from the wells of the flashplates and therefore does not contribute significantly to a background signal. The measured signals are therefore a measure of ALK1 kinase activity. The measurement is performed in a Perkin-Elmer TopCount instrument or a Perkin-Elmer ViewLux instrument.

Material:

Enzyme: Commercially available recombinant human ALK4 kinase (amino acids 150-505) fused at the N-terminus to GST expressed by recombinant baculoviruses in Sf21 insect cells (Upstate Biotechnology, Dundee, Scotland; Cat # 14-614MG) Lot # 28232U ; Aliquots are stored at -80 ⁰ C; diluted enzyme working solution: 2.5 ng / μl ALK1 (in assay buffer), prepared fresh and stored on ice until use. Substrate: biotinylated bovine α-casein. Unbiotinylated casein from Sigma is prepared by standard methods using a biotin-ΛA-hydroxy-succinimide

(NHS) ester biotinylated.

Substrate working solution: 0.83 μM ATP, 1.67 μM biotinylated oc-casein, 7.4 nCi [γ- ³³ P] ATP / μl in assay buffer

Assay plates: 384-well plates, small volume, white, Greiner (# 784075)

Flashplates: Streptavidin-coated Flashplates, Perkin Elmer (384-WeII #

SPM410A)

Assay buffer: 50mM Tris / HCl pH 8.0, 1mM MnCl ₂ , 1mM DTT, 0.01% NP40, 0.5x Complete EDTA-free

Stop solution: 33.3 μM ATP, 33.3 mM EDTA, 0.07% Triton X-100 in PBS

Flashplate saturation solution: 100 μM ATP, 0.2% Triton X-100 in PBS

Adhesive film for plates: Greiner (# 676080)

assay Description

Protocol for a 5 ul assay (all steps are carried out at 20 ⁰ C; for pipetting a CyBi-well pipettor, and a Multidrop micro-dispenser is used):

1. 50 nl or 250 nl substance in 100% DMSO 2. Add 3 μl of substrate working solution with a CyBi-WeII pipettor

3. Add 2 ul enzyme working solution with Multidrop Micro incubation for 45 min Dispenser (20 ⁰ C) at room temperature

4. Add 15 μl stop solution with a CyBi-well pipettor

5. Transfer 18 μl Assay Mixture into Flashplates ** with a CyBi-Well Pipettor Incubation for at least 3 h at room temperature or overnight at 4 ° C to allow binding to the streptavidin-coated flashplates.

6. Wash the flashplates three times with 50 μl PBS each without Ca ⁺⁺ and Mg ⁺⁺

7. Close the plates with adhesive film

8. Measurement in Topcount (60 sec / well) ** Saturation of flashplates: The flashplates are preincubated for at least 1 h with 50 μl of saturation solution. 18 μl of this solution are discarded before 18 μl of assay mixture are transferred to the flashplates

Final concentrations calculated for 5 μl of reaction volume: 1 ng ALK1 / well; 1 μM biotinylated α-casein; 0.5 μM ATP; 22 nCi / well [γ- ³³ P] ATP; 1 mM MnCl ₂ ; 1mM DTT; 50 mM Tris-HCl, pH 8.0; 0.01% NP40; 0.5x Complete EDTA-free; 1% or 5% DMSO.

The data are normalized (enzyme reaction without inhibitor = 0% inhibition, enzyme reaction in the presence of 10 mM EDTA = 100% inhibition) and IC ₅₀ values are calculated with a 4-parameter fit using in-house software.

ALK1 transactivation assay

Here, HepG2 cell cultures are transiently transfected with an ALK1 plasmid (expression vector for the human ALK1 receptor) by known techniques. Simultaneously, an ID1 reporter plasmid cotransfecting 1.3 kb (-1370 to +86) of the ID1 promoter upstream of the luciferase gene is cotransfected. ID1 is a known target gene of ALK1 and is therefore transactivated by co-transfection with the ALK1 receptor. The specific transactivation is quantified by ("relative light units", RLU) which are detected as a function of the luciferase. For this purpose, a commercially available kit for detecting the luciferase containing the substrate luciferin was used.

Material:

HepG2 cells (hepatocellular carcinoma), ATCC HB-8065 96well Culture Plates 96 white (Packard # 6005680) 96well plate polypropylene for compound dilution in DMSO PBS-; PBS ++, DMSO DMEM Harrf s F12 (Biochrome # F4815) with 10% FCS after dialysis, 1% PenStrep and 200mM Glutamine OPTI MEM (Gibco # 51985-026) Fugene (Roche # 1814443 1mL) SteadyliteHTS (Perkin Elmer # 6016981)

Experimental implementation:

Day 1: Sow the cells on 96-well plates

HepG2 cells are seeded on 96-well plates with a density of 7000 cells / well in DMEM / HamsF12 + 5% FCS (+ 1% P / S, +1% GIn).

Day 2: Transfection of the cells

Per well: 200 ng DNA: 100 ng ID1-Iuc (in pGL3basic, Promega) + 5 ng ALKIwt (in pcDNA3.1) + 95 ng pcDNA3.1 (empty vector, Invitogen) 0.4 μl Fugene 6 μl OptiMEM

Fugene and OptiMEM are incubated at RT for 5 min. This mixture is with the

DNA incubated for 15 minutes at RT.

Thereafter, the plate is incubated for 1 hour at RT under shaking conditions.

After 4 hours at 37 ° C, the supernatant is aspirated and the wells with medium

(100 .mu.l / well), which contains little serum (0.2% FCS) and test substance. The plates are incubated for a further 18 hours at 37 ° C. Taα 3: RLU measurement

100 μl luciferase substrate (steadylite HTS, Packard) is added per well and the plates are measured after 10 minutes in a luminometer (e.g., Victor luminometer, Perkin Elmer). The luciferase activity is quantified by relative light units (RLU).

Calculation of the IC50:

ALKIwt - DMSO control (without ALK1) = 100%

Substance (+ ALK1 wl) -DMSO control (without ALK1) = x% IC50 = 50% inhibition of ALK1 transactivation

DU-145 proliferation assay

First, DU-145 cells were seeded in a 96-well microtiter plate (CulturPlate-96, flat bottom transparent) at a concentration of 200 cells per well

(Volume of culture medium: 100 μl, negative control in lean medium) and for

18 h increased under culture conditions. Subsequently, 100 μl of the

Removed culture medium and 100 .mu.l of substance solution (dilution in

Culture medium) was added. The cells are incubated for 72 h under culture conditions. After the end of the substance treatment, 5 μl of an Alamar Blue

Marking Solution (Biosource Cat # DAL 1100, Lot # 143152SA;

Culture medium) was added (to produce a 1:20 dilution) and the cells propagated for an additional 3 hours under culture conditions. Anschießend was the

Proliferation rate by measurement on FLxδOO (fluorescence meter from BIO-TEK) evaluated at 528 nm and 590 nm, respectively.

Cell lines and cell culture

Human cell culture lines were used: DU-145 (prostate cell line ATCC No. HTB-81). AII cell lines were propagated in 175 cm ² culture flasks at 37 ° C, 5% CO ₂ and 95% humidity and at 80% confluence in accordance with the respective division rates split 1: 65: 5 to. 1 For this, the cells were first washed with 10 ml of PBS and wetted with 2 ml of trypsin (Gibco). Excess trypsin was removed and the cells incubated for 10 min at room temperature. Complete detachment of the treated cells was checked under a microscope. Subsequently, the cells were taken up in the culture medium and transferred in appropriate volume ratio into new cell culture bottles.

DU-145 culture medium:

DMEM HAM's F-12 (Biochrom AG, cat # F4815) + 1% P / S + 1% glutamine +

10% FCS (from Biochrom AG ₁ lot'0218G)

DU-145 lean medium:

DMEM HAM's F-12 (Biochrom AG, cat # F4815) + 1% P / S + 1% glutamine Further proliferation assays

DNA replicating cells can be labeled using bromodeoxyuiridine (BrdU) and used as a measure of the proliferation of eukaryotic cells. In this method, cells in the synthesis phase (S-phase) incorporate the thymidine analogue BrdU instead of thymidine into the growing DNA chain. The replicated DNA is thus labeled with the modified nucleotide BrdU and can subsequently be detected using a fluorophore-labeled anti-BrdU antibody. The method was used to study the effect of substances on cell proliferation. First, HeLa cells were seeded in a 96-well microtiter plate at a concentration of 7500 cells per well (volume: 200 μl) and propagated for 18 hours under culture conditions. Subsequently, 100 .mu.l of the culture medium were removed and added to 100 .mu.l of substance solution (dilution in culture medium). The cells are incubated for 6 hours, 18 hours or 48 hours under culture conditions. After the end of the substance treatment, the BrdU labeling solution (dissolved in the culture medium) was added (10 μM BrdU final concentration) and the cells were propagated for a further 3 h under culture conditions. Anschießend the BrdU-containing supernatant was removed and the Cells washed with PBS. Thereafter, the cells were fixed with 4% formalin solution (dissolved in PBS, 0.1% Triton-X-100) for 18 h at 4 ° C and washed three times with 200 ul PBS. To access the incorporated BrdU for antibody labeling, the DNA of the cells was digested with nuclease (GE / Amersham). Detection of the BrdU was then performed using an anti-BrdU monoclonal antibody (GE / Amersham). For this purpose, the fixed cells were incubated with an antibody / nuclease solution (50 .mu.l / well) for 45 min at 37 ⁰ C and then washed three times with 200 ul PBS. The fluorescent labeling was carried out by a fluorophore-labeled secondary antibody which binds to the anti-BrdU antibody. The chromatin of the cell nuclei was stained with Hoechst 33342.

In each case 9 image sections per well were recorded in the different fluorescence channels with an automated microscope (Discovery-1, Molecular Devices) and the BrdU incorporation or the proliferation rate was evaluated by means of a high-content analysis (HCA) method.

Cell lines and cell culture

Human cell culture lines were used: HeLa (from cervical carcinoma), PC3 (from prostate carcinoma) and MCF-7 (from mama carcinoma). In addition, CHO cells (from the ovaries of Chinese hamsters) were cultured. All cell lines were propagated in 175 cm ² culture flasks at 37 ° C, 5% CO ₂ and 95% humidity and at 80% confluency Mger corresponding to the respective division rates split 1: 65: 5 to. 1 For this, the cells were first washed with 10 ml of PBS and wetted with 2 ml of trypsin (Gibco). Excess trypsin was removed and the cells incubated for 10 min at room temperature. Complete detachment of the treated cells was checked under a microscope. Subsequently, the cells were taken up in the associated culture medium and transferred in appropriate volume ratio into new cell culture bottles.

HeLa culture medium: Dulbecco's medium (Gibco), 2 mM glutamine (Gibco), 100 U / ml penicillin (Gibco), 100 μg / ml streptomycin (Gibco) and 10% (v / v) fetal calf serum (PAA) PC3 culture medium:

RPMI 1640 medium (Gibco), 2 mM glutamine (Gibco), 100 U / ml penicillin (Gibco),

100 μg / ml streptomycin (Gibco) and 10% (v / v) fetal calf serum (PAA)

MCF-7 culture medium:

RPMI 1640 medium (Gibco), 2 mM glutamine (Gibco), 100 U / ml penicillin (Gibco), 100 μg / ml streptomycin (Gibco) and 10% (v / v) fetal calf serum (PAA), 0.1 nM estradiol (Sigma ) and 0.2 U / ml insulin (Sigma)

CHO culture medium:

Ham's F12 Medium (PAA), 2 mM Glutamine (Gibco), 100 U / ml Penicillin (Gibco), 100 μg / ml Streptomycin (Gibco) and 3% (v / v) Fetal Calf Serum (PAA)

Further state of the art

Further prior art is formed by the following references as well as the literature cited in these documents:

Priorities of the present application:

The present patent application claims the priority of the German patent application DE 102005 042 742.1 (filing date: 2.9.2005) claims, it also claims all the advantages of the deposit of the US patent application 60 / 713,333 (filing date: 2.9.2005, provisional application).

The independent claims of the priority application are as follows:

1. Compound of formula I

formula

in which

Q is aryl or heteroaryl;

A and B are the same or different and are selected from the group consisting of i) H, Hal, -OH, -NR ³ R ⁴ , -CN, or -NO ₂ , ii) optionally mono- or polysubstituted with Hal, -OH, C ³ -C6-heterocycloalkyl, -NR ³ R ⁴ or - (CO) -NR ³ -

L is substituted C1-C6-alkyl, C1-C6-alkoxy, C3-C6-cycloalkyl or C3-C6-heterocycloalkyl, wherein the C3-C6-heterocycloalkyl in the ring optionally one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or - (SO ₂ ) - groups and / or one or more double bonds may contain, and iii) -NR ³ (CO) -L, -

NR ³ (CO) -NR ³ -L, - (CO) -R ⁶ , -O- (CH ₂ ) _P -R ⁶ , - (CO) - (NR ³ ) -L, -NR ³ (CS) - NR ³ R ⁴ , or are -O (CH ₂ ) _p -aryl, where the substituents may be the same or different in the case of multiple substitution, A and B in addition or alternatively to the above definition together form a C5-C7-cycloalkyl or C5-C7 heterocycloalkyl ring fused with Q, the latter containing at least one oxygen or one nitrogen atom in the ring and optionally additionally one or more oxygen in the ring - nitrogen or sulfur atoms and / or one or more - (CO) - or (SO2) - groups and / or optionally contain one or more double bonds,

p is 0 to 4,

L is optionally mono- or polysubstituted with C 1 -C 6 -alkyl, C 1 -C 6 -hydroxyalkoxy, C 1 -C 6 -alkoxyalkoxy, C ³ -C 6 -heterocycloalkyl, or -NR ³ R ⁴ , substituted

C1-C6-alkyl, or C3-C6-cycloalkyl or C3-C6-heterocycloalkyl, wherein the C3-C6 heterocycloalkyl in the ring optionally one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO ) - or - (SO ₂ ) - groups and / or may contain one or more double bonds;

R ¹ and R ^{2 are} identical or different and are selected from the group consisting of j) -H and jj) optionally mono- or polysubstituted with -HaI, -OH, -CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C ⁶ -hydroxyalkyl, C ³ -C ⁶ -cycloalkyl, C ³ -C ⁶ -heterocycloalkyl, C 2 -C ⁶ -alkynyl, aryl, aryloxy, heteroaryl, -S-C 1 -C ⁶ -alkyl, - (CO) -R ⁶ , -NR ³ R ⁴ , -NR ³ (CO) -L, or -NR ³ COOR ⁷ substituted C 1 -C 6 -alkyl,

C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -heterocycloalkyl, aryl or heteroaryl, where the C 3 -C 6 -heterocycloalkyl in the ring optionally contains one or more nitrogen, Oxygen and / or sulfur atoms and / or one or more - (CO) - or -SO ₂ - groups and / or one or more double bonds may contain, and, wherein the substituents may be the same or different with multiple substitution;

R ¹ and R ^{2 may} additionally or alternatively to the above definition together form a C ³ -C 6 -heterocycloalkyl ring which comprises at least one Contains nitrogen atom in the ring and optionally additionally in the ring one or more nitrogen, oxygen or sulfur atoms and / or one or more - (CO) - or - (SO ₂ ) - groups and / or optionally may contain one or more double bonds, wherein the ring formed by R ¹ and R ² optionally singly or multiply with -CN, -HaI, -

OH, C 1 -C ⁶ -alkyl, C ³ -C ⁶ -cycloalkyl, C ¹ -C ⁶ -hydroxyalkyl, C ¹ -C ⁶ -alkoxyalkyl, -NR ³ R ⁴ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ and / or may be substituted by optionally mono- or polysubstituted by -HaI, C 1 -C ⁶ -alkoxy or - (CO) -R ⁶ -substituted aryl or heteroaryl, where the substituents may be identical or different in the case of multiple substitution;

R ³ and R ^{4 are the} same or different and are selected from the group consisting of j) -H, and jj) optionally mono- or polysubstituted with -HaI, -OH, -CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy , C 1 -C ⁶ -hydroxyalkyl, C 3 -C ⁶ -cycloalkyl, C 3 -C ⁶ -heterocycloalkyl, C 2 -C ⁶ -alkynyl, aryl, aryloxy, heteroaryl, -NR ⁶ R ⁷ ,

-CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ substituted C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3- C6- heterocycloalkyl, aryl or heteroaryl, wherein the C3-C6 heterocycloalkyl in the ring optionally one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or -SO ₂ - groups and / or may contain one or more double bonds, and wherein wherein the substituents may be the same or different in the case of multiple substitution;

R ³ and R ^{4 may} additionally or alternatively to the above definition together form a C ³ -C ⁶ -heterocycloalkyl ring which comprises at least one

Contains nitrogen atom in the ring and optionally additionally in the ring one or more nitrogen, oxygen or sulfur atoms and / or one or more - (CO) - or - (SO ₂ ) - groups and / or optionally may contain one or more double bonds, wherein the ring formed by R3 and R4 optionally singly or multiply with -CN, -HaI, - OH, C 1 -C ⁶ -alkyl, C 3 -C ⁶ -cycloalkyl, C 1 -C ⁶ -hydroxyalkyl, C 1 -C ⁶ -alkoxyalkyl or with -NR ⁶ R ⁷ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ and / or with optionally mono- or polysubstituted with -HaI, C 1 -C ⁶ -alkoxy or - (CO) -R ⁶ -substituted aryl or heteroaryl, where the substituents may be identical or different in the case of multiple substitution;

R ⁶ and R ^{7 are the} same or different and are selected from the group consisting of j) -H and jj) optionally mono- or polysubstituted with -HaI, -OH, -CN, substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy , C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -heterocycloalkyl, aryl or heteroaryl, where the

C3-C6 heterocycloalkyl in the ring may optionally contain one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or -SO ₂ - groups and / or one or more double bonds, and , where the substituents may be the same or different with multiple substitution

and their isomers, diastereomers, enantiomers and salts,

2. A compound according to claim 1, wherein R ¹ and R ^{2 are the} same or different and are selected from the group consisting of j) -H and jj) optionally one or more times with -HaI, -OH, -CN, C1-C6- Alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -hydroxyalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -heterocycloalkyl, C 2 -C 6 -alkynyl, aryl, aryloxy,

Heteroaryl, -S-C 1 -C ⁶ -alkyl, - (CO) -R ⁶ , -NR ³ R ⁴ , -NR ³ (CO) -L, or -NR ³ COOR ⁷ substituted C 1 -C ⁶ -alkyl, C 1 -C ⁶ Alkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -heterocycloalkyl, where the C 3 -C 6 -heterocycloalkyl in the ring optionally has one or more nitrogen, oxygen and / or sulfur atoms Atoms and / or one or more - (CO) - or -SO ₂ - groups and / or one or more double bonds, where the substituents may be the same or different with multiple substitution, and wherein R ¹ and R ^{2 are} complementary or alternatively to the above definition, may together form a C3-C6 heterocycloalkyl ring which is at least contains a nitrogen atom in the ring and optionally additionally in the ring one or more nitrogen, oxygen or sulfur atoms and / or one or more - (CO) - or - (SO2) groups and / or optionally may contain one or more double bonds, wherein optionally the ring formed by R ¹ and R ² singly or multiply with -CN, -HaI, -OH, C1-C6-

Alkyl, C ³ -C ⁶ -cycloalkyl, C ¹ -C ⁶ -hydroxyalkyl, C ¹ -C ⁶ -alkoxyalkyl, -NR ³ R ⁴ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ and / or with an optional or polysubstituted by -HaI, C1-C6-alkoxy or - (CO) -R ⁶ substituted aryl or heteroaryl may be substituted, wherein the substituents may be the same or different with multiple substitution.

3. A compound according to claim 1 or 2, wherein R ¹ and R ^{2 are the} same or different and are selected from the group consisting of j) -H and jj) optionally one or more times with -HaI, -OH, -CN, C1- C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C2-C6 alkynyl, aryloxy, -S-C1-C6 alkyl, - (CO) -R ⁶ , -NR ³ R ⁴ , -NR ³ (CO) -L, or -NR ³ COOR ⁷ substituted C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3- C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or heteroaryl, wherein the C3-C6-heterocycloalkyl in the ring optionally one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or -SO ₂ - may contain groups and / or one or more double bonds, wherein the group defined in jj) may be substituted aryl or heteroaryl, unless it is alkyl, wherein the substituents may be the same or different with multiple substitution, and where R ¹ and R ^{2 are} complementary or alternative iv to the above definition together form a C3-C6 heterocycloalkyl ring containing at least one nitrogen atom in the ring and optionally additionally in the ring one or more nitrogen, oxygen or sulfur atoms and / or one or more - (CO) - or - (SO ₂ ) - groups and / or may optionally contain one or more double bonds, wherein the ring formed by R ¹ and R ² optionally mono- or polysubstituted with -CN, -HaI, -OH ₁ C1-C6-alkyl, C3-C6 -

Cycloalkyl, C ¹ -C ⁶ -hydroxyalkyl, C ¹ -C ⁶ -alkoxyalkyl, -NR ³ R ⁴ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ and / or with optionally mono- or polysubstituted with -HaI, C 1 -C ⁶ -alkoxy or - (CO) -R ⁶ substituted aryl or heteroaryl may be substituted, wherein the substituents in multiple Substitution may be the same or different.

4. A compound according to claim 3, wherein Q is -OH, -HaI, -CN, alkyl, -OR ⁶ , or -

NR ³ R ^{4 is} substituted phenyl, pyridyl, pyrimidinyl, thiophenyl, furyl, imidazolyl, or pyrazolyl.

5. A compound according to claim 4, wherein R ¹ and R ^{2 are the} same or different and are selected from the group consisting of -H, with NR ³ R ⁴ substituted C1-C4 alkyl, optionally additionally one or more times with -HaI, -OH , -CN, C1-C6-

Alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -hydroxyalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -heterocycloalkyl, C 2 -C 6 -alkynyl, aryl, aryloxy, heteroaryl, -S-C 1 -C 6 -alkyl, - (CO) -R ⁶ , -NR ³ (CO) -L, or -NR ³ COOR ⁷ substituted, wherein R ³ and R ⁴ optionally, same or different, may be C 1 -C ⁶ alkyl, wherein R ³ and R ⁴ together is a C3 -C6-heterocycloalkyl ring containing at least one nitrogen atom in the ring and optionally additionally in the ring one or more nitrogen, oxygen or sulfur atoms and / or one or more - (CO) - or - (SO2) - groups and / or optionally contain one or more double bonds, and wherein R6 and R7, same or different, is -H, -OH, C1-C6-alkoxy, or C1-C3 alkyl.

A compound according to any one of claims 4 wherein R ^{1 is} selected from the group consisting of -H and C ¹ -C ³ -alkyl, wherein R ^{2 is} selected from the group consisting of C ³ -C ⁴ -alkyl substituted with NR ³ R ⁴ , optionally additionally mono- or polysubstituted with -HaI, -OH, -CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -hydroxyalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -heterocycloalkyl, C 2 -C 6 -alkyl,

Alkynyl, aryl, aryloxy, heteroaryl, -S-C 1 -C ⁶ -alkyl, - (CO) -R ⁶ , -NR ³ (CO) -L, or - NR ³ COOR ⁷ , where R ³ and R ^{4 are the} same or different, optionally mono- or polysubstituted with -HaI, -OH, -CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -hydroxyalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -heterocycloalkyl, C 2 -C 6 -alkyl Alkynyl, aryl, aryloxy, heteroaryl, -NR ⁶ R ⁷ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ substituted C ¹ -C ⁶ -alkyl, wherein R ³ and R ^{4 may} together form a C ³ -C ⁶ -heterocycloalkyl ring which contains at least one nitrogen atom in the ring and optionally additionally in the ring one or more nitrogen, oxygen or sulfur atoms and / or a or more - (CO) - or - (SO ₂ ) - groups and / or optionally one or more

May contain double bonds, and wherein R6 and R7, the same or different, is -H, -OH, C1-C6-alkoxy, or C1-C3-alkyl.

7. A compound according to claim 1, namely:

(3-Phenylimidazo [1,2-b] pyridazin-6-yl) - (3-pyrrolidin-1-yl-propyl) -amine (3-morpholin-4-yl-propyl) - (3-phenyl- imidazo [1,2-b] pyridazin-6-yl) -amines

(3- (3-Chloro-phenyl) -imidazo [1,2-b] pyridazin-6-yl) - (3-pyrrolidin-1-yl-propyl) -amine

(S-CS-Chloro-phenyl-imidazolyl-β-pyrpyridazine-θ-yl-HS-morpholino-1-yl-propyl) -amine [3- (1-methyl-1H-pyrazol-4-yl) -imidazo [1, 2 -b] pyridazin-6-yl] -pyridin-3-yl-methyl-amine

(3-Phenylimidazo [1,2-b] pyridazin-6-yl) -pyridin-3-yl-methyl-amine (3-imidazol-1-yl-propyl) - (3-phenyl-imidazo [1, 2-b] pyridazin-6-yl) -amine (4-fluorobenzyl) - (3-phenyl-imidazo [1,2-b] pyridazin-6-yl) -amine CyclohexylmethyK3-phenyl-imidazo [1, 2 -b] pyridazin-6-yl) -amine

(2,4-Diflouro-benzyl) - (3-phenyl-imidazo [1,2-b] pyridazin-6-yl) -amine

[3- (5-Methyl-1H-pyrazol-4-yl) -propyl] - (3-phenyl-imidazo [1,2-b] pyridazine-6-yl) -amine

1- [2- (3-phenyl-imidazo [1,2-b] pyridazin-6-yl-amino) -ethyl] -imidazolidin-2-one

(2-morpholin-4-yl-ethyl)) - (3-phenyl-imidazo [1,2-b] pyridazin-6-yl) -amine N * 1, N * 1 * -diethyl-N * 4- ( 3-phenyl-imidazo [1,2-b] pyridazin-6-yl) -pentane-1,4-diamine N, N-diethyl-N ^' - (3-phenyl-imidazo [1,2-b] pyridazin-6-yl) -propane-1,3-diamine

(3-Phenylimidazo [1,2-b] pyridazin-6-yl) - (2-pyrrolidin-1-yl-ethyl) -amine

[S-CS-chlorophenyl-imidazofi] -blpyridazine-β-yl-pyridine-S-yl-methyl-amine

^ - (S-chlorophenyl-imidazoCl -blpyridazine-e-ylHS-innidazol-i-yl-propyl) -amine

S-CS-chloro-Phenyo-imidazoti ^ -blpyridazin-θ-YLH ^ flouro-benzyO-amines

S ^ S-Chloro-phΘnyO-imidazofi ^ - ^ pyridazine-β-yl-cyclohexylmethyl-amine 3- (3-chloro-phenyl) -imidazo [1,2-b] pyridazin-6-yl) - (2,4 -diflouro-benzyl) -amine

1- {2- [3- (3-phenyl) -imidazo [1,2-b] pyridazin-6-yl-amino] -thyl} -imidazolidine

2-one

N * 4 * - [3- (3-Chloro-phenyl) -imidazo [1,2-b] pyridazin-6-yl] -N * 1 *, N * 1 * -diethyl-pentane-1,4-diamine

N '- [3- (3-chloro-phenyl) -imidazo [1,2-b] pyridazin-6-yl] -N, N-diethyl-propane-1,3-diamine

[3- (3-Chloro-phenyl) -imidazo [1,2-b] pyridazinyl-6-yl] - (2-pyrrolidin-1-yl-ethyl) -amine (3-imidazol-1-yl-propyl) - [3- (1-methyl-1H-pyrazol-4-yl) -imidazo [1,2b] pyridazin-6-yl] -amine

(4-Fluoro-benzyl) - [3- (1-methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazine-6-yl] -amine

Cyclohexylmethyl- [3- (1-methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazin-6-yl] -amine

(2,4-difluoro-benzyl) - [3- (1-methyl-1H-pyrazol-4-yl) -imidazo [1,2b] pyridazin-6-yl] -amine

[3- (1-Methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazin-6-yl] - [5-methyl-1H-pyrazol-4-yl) -propyl] amines 1 - {2- [3- (1-Methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyrϊdazin-6-yl-amino] -ethyl} -imidazolidin-2-one

(3- (1-Methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazin-6-yl) - (2-morpholin-4-yl-ethyl) -amine N * 1, N * 1 * -diethyl-N * 4- [3- (1-methyl-1H-pyrazol-4-yl) -imidazo [1,2b] pyridazin-6-yl] -pentane-1, 4- diamine

N, N-diethyl-N '- [3- (1-methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazin-6-yl] -propane-1,3-diamine

[3- (1-Methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazin-6-yl] - (2-pyrrolidin-1-yl-ethyl) -amine

Pyridin-3-yl-methyl- (3-thiophen-3-yl-imidazo [1,2-b] pyridazin-6-yl) -amine (4-fluoro-benzyl) - (3-thiophen-3-yl) imidazo [1,2-b] pyridazin-6-yl) -amines cyclohexylmethyl- (3-thiophen-3-yl-imidazo [1,2-b] pyridazin-6-yl) -amines (2,4-difluoro- benzyl) - (3-thiophen-3-yl-imidazo [1,2-b] pyridazin-6-yl) -amine [3- (5-methyl-1H-pyrazol-4-yl) -propyl] - ( 3-thiophen-3-yl-imidazo [1,2b] pyridazin-6-yl) -amine

1 - [2- (3-thiophen-3-yl-imidazo [1,2-b] pyridazin-6-yl-amino) -ethyl] imidazolidin-2-one

(2-morpholin-4-yl-ethyl) - (3-thiophen-3-yl-imidazo [1,2-b] pyridazin-6-yl) -amines

N * 1, N * 1 * -diethyl-N * 4- [3-thiophen-3-yl-imidazo [1,2-b] pyridazin-6-yl] -pentane-1,4-diamine

N, N-diethyl-N ^' - (3-thiophen-3-yl-imidazo [1,2-b] pyridazin-6-yl] -propane-1,3-diamine (2-pyrrolidin-1-yl-ethyl ) - (3-thiophen-3-yl-imidazo [1,2-b] pyridazin-6-yl) -amines 8. A process for the preparation of a compound according to any one of claims 1 to 7, comprising the following process steps:

A1) 3-amino-6-halogen-pyrazine is reacted with chloroactetaldehyde to give 6-halo-imidazo [1,2-b] pyridazine,

A2) the product from step A1 is reacted with Λ / -bromo-succinimide to give a 3-bromo-6-halo-imidazo [1,2-b] pyridazine,

A3) the product from step A2 is converted to a (3-bromo-imidazo [1,2-b] pyridazin-6-yl) by reaction with a compound NHR ¹ R ² in a Buchwald-Hartwig cross-coupling reaction (R ¹ ) - (R ² ) -amine reacted,

A4) the product from stage A3 is reacted, for example, with a boronic acid which is optionally substituted by the radicals A and B, to give the compound according to the general formula I,

or

B1) 3-amino-6-halogen-pyrazine is reacted with chloroactetaldehyde to give 6-halo-imidazo [1,2-b] pyridazine,

B2) the product from stage B1 is reacted with Λ / bromo-succinimide to give a 3-bromo-6-halo-imidazo [1,2-b] pyridazine,

B3) the product from stage B2 is reacted, for example, with a boronic acid, which is optionally substituted by the radicals A and B, to give the compound according to general formula II,

B4) the product from step B3 is converted by reaction with a compound NHR ¹ R ² in a Buchwald-Hartwig cross-coupling reaction to the compound according to general formula I.

or C1) 3-amino-6-halogen-pyrazine is reacted with chloroactetaldehyde to give 6-halo-imidazo [1,2-b] pyridazine,

C2) the product from step C1 is converted to an imidazo [1,2-b] pyridazin-6-yl) - (R ¹ ) - (R ² ) by reaction with a compound NHR ¹ R ² in a Buchwald-Hartwig cross-coupling reaction. -amine implemented,

C3) the product from step C2 is reacted with Λ / -bromo-succinimide to give a (3-bromo- imidazo [1,2-b] pyridazin-6-yl) - (R ¹ ) - (R ² ) -amine,

C4) the product from step C3 is reacted, for example, with a boronic acid, which is optionally substituted by the radicals A and B, to give the compound according to the general formula I.

9. Use of a compound according to any one of claims 1 to 7 for the preparation of a pharmaceutical composition.

10. Use of a compound according to any one of claims 1 to 7 for the inhibition of a cellular kinase, in particular a kinase from the group of the protein kinase C family, such as PKC theta, delta, iota, alpha and zeta.

11. Use of a compound according to any one of claims 1 to 7 for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of a disease, which is associated with the overexpression or mutation of a cellular kinase, in particular a cellular kinase according to claim 10.

The use of claim 9, wherein the disease is a disease selected from the group consisting of epidermal hyperproliferation such as psoriasis, Alzheimer's, autoinflammatory diseases, Crohn's disease, excessive immune response, contact dermatitis, atopic dermatitis,

Multiple Sclerosis, ALS, Diabetes, Asthma "is. 13. Use according to claim 9 for the modulation, in particular reduction, of an immune reaction, for example after transplantation to avoid organ rejection.

14. A process for the preparation of a pharmaceutical composition, wherein a physiologically effective dose of a compound according to one of

Claims 1 to 7 mixed with at least one galenic adjuvant and prepared to a dosage form.

A process for the treatment or prophylaxis of a disease associated with the overexpression or mutation of a cellular kinase, in particular a disease according to claim 12, wherein a pharmaceutical composition comprising a physiologically effective dose of a compound according to any one of claims 1 to 7 is administered to a subject who is suffering from the disease or threatens to fall ill.

16. Intermediate product according to formula IIa

General formula IIa

in which

Y is replaced by -H or -HaI,

R ¹ and R ^{2 are} identical or different and are selected from the group consisting of j) -H and jj) optionally mono- or polysubstituted with -HaI, -OH, -CN ₁ C ₁ -C 6 -alkyl, C ₁ -C 6 -alkoxy, C1-C6-hydroxyalkyl, C3-C6-cycloalkyl, C3-C6 heterocycloalkyl, C2-C6-alkynyl, aryl, aryloxy, heteroaryl, -S-C1-C6-alkyl, - (CO) -R ⁶ , -NR ³ R ⁴ , -NR ³ (CO) -L, or -NR ³ COOR ⁷ substituted C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6 Alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -heterocycloalkyl, aryl or heteroaryl, where the C 3 -C 6 -heterocycloalkyl in the ring optionally has one or more nitrogen, oxygen and / or sulfur atoms and / or one or more (CO) - or -SO ₂ - may contain groups and / or one or more double bonds, and, wherein the substituents may be the same or different with multiple substitution;

R ¹ and R ^{2 may} additionally or alternatively to the above definition together form a C ³ -C 6 -heterocycloalkyl ring which comprises at least one

Contains nitrogen atom in the ring and optionally additionally in the ring one or more nitrogen, oxygen or sulfur atoms and / or one or more - (CO) - or - (SO ₂ ) - groups and / or optionally may contain one or more double bonds, wherein the ring formed by R ¹ and R ² optionally singly or multiply with -CN, -HaI, -

OH, C 1 -C ⁶ -alkyl, C ³ -C ⁶ -cycloalkyl, C ¹ -C ⁶ -hydroxyalkyl, C ¹ -C ⁶ -alkoxyalkyl, -NR ³ R ⁴ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ and / or may be substituted by optionally mono- or polysubstituted by -HaI, C 1 -C ⁶ -alkoxy or - (CO) -R ⁶ -substituted aryl or heteroaryl, where the substituents may be identical or different in the case of multiple substitution;

R ³ and R ^{4 are} identical or different and are selected from the group consisting of j) -H, jj) optionally mono- or polysubstituted with -HaI, -OH, -CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C ⁶ -hydroxyalkyl, C 3 -C ⁶ -cycloalkyl, C 3 -C ⁶ -heterocycloalkyl, C 2 -C ⁶ -alkynyl, aryl, aryloxy, heteroaryl, -NR ⁶ R ⁷ ,

-CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ substituted C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3- C6- heterocycloalkyl, aryl or heteroaryl, wherein the C3-C6 heterocycloalkyl in the ring optionally one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or -SO ₂ - groups and / or may contain one or more double bonds, and wherein wherein the substituents may be the same or different with multiple substitution;

R ³ and R ^{4 may} additionally or alternatively to the above definition together form a C ³ -C ⁶ -heterocycloalkyl ring which comprises at least one

Contains nitrogen atom in the ring and optionally additionally in the ring one or more nitrogen, oxygen or sulfur atoms and / or one or more - (CO) - or - (SO ₂ ) - groups and / or optionally may contain one or more double bonds, wherein the ring formed by R3 and R4 optionally singly or multiply with -CN, -HaI, -

OH, C 1 -C ⁶ -alkyl, C 3 -C ⁶ -cycloalkyl, C 1 -C ⁶ -hydroxyalkyl, C 1 -C ⁶ -alkoxyalkyl or with -NR ⁶ R ⁷ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ and / or with optionally mono- or polysubstituted with -HaI, C 1 -C ⁶ -alkoxy or - (CO) -R ⁶ -substituted aryl or heteroaryl, where the substituents may be identical or different in the case of multiple substitution;

R ⁶ and R ^{7 are} identical or different and are selected from the group consisting of j) -H, jj) optionally mono- or polysubstituted with -HaI, -OH, -CN, substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy , C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or heteroaryl, where the C3-C6-

Heterocycloalkyl in the ring may optionally contain one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or -SO ₂ - groups and / or one or more double bonds, and, wherein the substituents may be the same or different when substituted several times

and their isomers, diastereomers, enantiomers and salts. 17. Intermediate product according to the general formula IIb

General formula IIb

Q is aryl or heteroaryl;

A and B are the same or different and are selected from the group consisting of i) H, Hal, -OH, -NR ³ R ⁴ , -CN, or -NO ₂ , ü) optionally mono- or polysubstituted with Hal, -OH, C ³ -C6-heterocycloalkyl, -NR ³ R ⁴ or - (CO) -NR ³ -L substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C ³ -C 6 -cycloalkyl or C ³ -C ⁴ -cycloalkyl

C6-heterocycloalkyl, wherein said C 3 -C 6 heterocycloalkyl ring optionally containing one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or - (SO ₂₎ - groups and / or may contain one or more double bonds and iii) -NR ³ (CO) -L, - NR ³ (CO) -NR ³ -L, - (CO) -R ^6, -O- (CH _{2) P} -R ⁶ , - (CO) - (NR ³ ) -L, -NR ³ (CS) -

NR ³ R ⁴ , or are -O (CH ₂ ) _p -aryl, where the substituents may be the same or different in the case of multiple substitution,

A and B in addition or alternatively to the above definition together form a C5-C7-cycloalkyl or C5-C7 heterocycloalkyl ring fused with Q, the latter containing at least one oxygen or one nitrogen atom in the ring and optionally additionally one or more oxygen in the ring Nitrogen or sulfur atoms and / or one or more - (CO) - or - (SO ₂ ) - groups and / or may contain one or more double bonds,

p is 0 to 4, L optionally mono- or polysubstituted with C 1 -C 6 -alkyl, C 1 -C 6 -hydroxyalkoxy, C 1 -

C6-alkoxyalkoxy, C3-C6-heterocycloalkyl, or where the C3-C6 heterocycloalkyl, optionally in the ring with a -NR ³ R ^4, substituted C1-C6 alkyl or C3-C6-cycloalkyl or C3-C6-heterocycloalkyl or more Nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or

- (SO ₂ ) - may contain groups and / or one or more double bonds;

X is chloro, bromo, O-SO ₂ -CF ₃ or O-SO ₂ -C ₄ F ₉ ;

R ³ and R ^{4 are} identical or different and are selected from the group consisting of j) -H, jj) optionally mono- or polysubstituted with -HaI, -OH, -CN, C 1 -C 6 -alkyl,

C 1 -C ⁶ alkoxy, C 1 -C ⁶ hydroxyalkyl, C 3 -C ⁶ cycloalkyl, C 3 -C ⁶ heterocycloalkyl, C 2 -C ⁶ alkynyl, aryl, aryloxy, heteroaryl, -NR ⁶ R ⁷ , -CONR ⁶ R ⁷ , - (CO ) -R ⁶ or -COOR ⁷ substituted C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or heteroaryl, wherein the C 3 -C 6 heterocycloalkyl in the ring may optionally contain one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or -SO ₂ - groups and / or one or more double bonds, and, wherein the substituents may be the same or different with multiple substitution;

R ³ and R ⁴ additionally or alternatively to the above definition together form a C ³ -C ⁶ -heterocycloalkyl ring which contains at least one nitrogen atom in the ring and optionally additionally in the ring one or more nitrogen, oxygen or sulfur atoms and / or one or more - (CO) - or - (SO ₂₎ - groups and / or optionally one or more double bonds may contain, said by R3 and R4 formed ring is optionally mono- or polysubstituted by -CN, -Hal, - OH, C1-C6 alkyl, C3-C6-cycloalkyl, C1-C6-hydroxyalkyl, C1-C6-alkoxyalkyl or with -NR ⁶ R ^7, -CONR ⁶ R ^7, - (CO) -R ⁶ or -COOR ⁷ and / or optionally a - or more times with -HaI, C1-C6-alkoxy or - (CO) -R ⁶ substituted aryl or heteroaryl may be substituted, wherein the substituents may be the same or different with multiple substitution;

R ⁶ and R ^{7 are} identical or different and are selected from the group consisting of j) -H, jj) optionally mono- or polysubstituted with -HaI, -OH, -CN, substituted

C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -heterocycloalkyl, aryl or heteroaryl, where the C 3 -C 6 -heterocycloalkyl in the ring is optional may contain one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or -SO ₂ - groups and / or one or more double bonds, and, wherein the substituents with multiple substitution same or may be different

and their isomers, diastereomers, enantiomers and salts.

Claims

claims:

1. Compound of formula I

Formula I

in which

Q is aryl or heteroaryl, with the exception of pyrimidine;

A and B are identical or different and are selected from the group consisting of i) H, Hal -OH, -NR ³ R ^4, -CN, or -NO _2, ii) optionally mono- or polysubstituted by Hal, OH, C3 -C6-heterocycloalkyl, -NR ³ R ⁴ , -SO ₂ NR ³ R ⁴ , -SO ₂ R ³ or - (CO) -NR ³ -L substituted C1-C6-alkyl, C1-C6-haloalkyl, C1-C6 Alkoxy, C 1 -C 6 -haloalkoxy, C 3 -C 6 -cycloalkyl or C 3 -C 6 -heterocycloalkyl, where the C 3 -C 6 -heterocycloalkyl in the ring optionally contains one or more nitrogen,

Oxygen and / or sulfur atoms and / or one or more - (CO) - or - (SO ₂ ) - groups and / or one or more double bonds may contain, and iii) -NR ³ (CO) -L, - NR ³ (CO) -NR ³ -L, - (CO) -R ^6, -O- (CH _{2) p} -R ^6, - (CO) - (NR ³⁾ -L, -NR ³ (CS) - NR ³ R ⁴ , -NR ³ (SO ₂ ) -L, - (SO ₂ ) -NR ³ R ⁴ ,

-NR ³ (CO) NR ³ R ⁴ , - (CO) NR ³ R ⁴ , -CO ₂ R ⁷ , -NR ³ (SO ₂ ) R ⁴ or -O- (CH ₂ ) _p -aryl, wherein the Substituents with multiple substitution may be the same or different, A and B form, in addition to the above definition, together form a C5-C7-cycloalkyl or C5-C7-heterocycloalkyl ring fused with Q, the latter containing at least one oxygen or one nitrogen atom in the ring and optionally additionally one or more oxygen atoms in the ring. Nitrogen or sulfur atoms and / or one or more

- (CO) - or - (SO ₂ ) - groups and / or optionally contain one or more double bonds,

p is 0 to 4,

L optionally mono- or polysubstituted with hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -hydroxyalkoxy, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkoxy

Is alkoxyalkoxy, C3-C6-heterocycloalkyl, or -NR ³ R ^4, substituted C1-C6-alkyl, C1-C6-haloalkyl or C3-C6-cycloalkyl or C3-C6 heterocycloalkyl, wherein the C3-C6 heterocycloalkyl ring optionally one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or - (SO ₂ ) - groups and / or one or more

May contain double bonds;

R ¹ and R ^{2 are} identical or different and are selected from the group consisting of j) -H and jj) optionally mono- or polysubstituted with -HaI, -OH, -CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkyl,

Haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C2-C6 alkynyl, aryl, aryloxy, heteroaryl, -S-C1-C6 Alkyl, - (CO) -R ⁶ , -NR ³ R ⁴ , -NR ³ (CO) -L, -NR ³ COOR ⁷ , -COOR ⁷ , - NR ³ CONR ³ R ⁴ , -NR ³ SO ₂ NO ⁴ , -SO ₂ NR ³ R ⁴ , -CONR ³ R ⁴ or -SO ₂ R ³ substituted

C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or Heteroaryl or with ~ (CH ₂ ) _r -R ⁸ radical, where r is a number 0-3 and R ^{8 is} a radical

where aryl, heteroaryl, C 3 -C 6 -cycloalkyl or C 3 -C 6 -heterocycloalkyl groups optionally present in R ¹ or R ² may be monosubstituted or polysubstituted by -HaI, -CN, -OH, -Cl-C 6 -alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkyl, C 3 -C 6 cycloalkyl, -NO ₂ , -NH ₂ , -NR ³ R ⁴ , -CONR ³ R ⁴ , -NR ³ COR ⁴ , NR ³ SO ₂ R ⁴ , -COR ⁶ , CO ₂ R ⁷ , -SO ₂ NR ³ R ⁴ , -SR ³ , SOR ³ , -SO ₂ R ³ , -OR ³ , -O (CH ₂ ) _P R ⁶ , where the substituents may be the same or different when substituted several times;

where in R ¹ or R ^2, two or more aryl or heteroaryl groups may not be substituents of the same carbon atom;

In addition to the above definition, R ¹ and R ^{2 may} together form a C 3 -C 6 -heterocycloalkyl ring which contains at least one nitrogen atom in the ring and optionally additionally one or more in the ring

May contain groups and / or optionally one or more double bonds, where the ring formed by R ¹ and R ² optionally mono- or - nitrogen, oxygen or sulfur atoms and / or one or more - (CO) - or - (SO ₂₎ several times with -CN, -HaI, -OH, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, C1-C6-hydroxyalkyl, C1-

C ⁶ -alkoxyalkyl, C ¹ -C ⁶ -haloalkoxyalkyl, C ¹ -C ⁶ -haloalkoxy, -NR ³ R ⁴ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ and / or with optionally one or more times with -Hal, C1-C6-alkoxy, C1-C6-haloalkoxy or - (CO) -R ⁶ substituted aryl or heteroaryl may be substituted, wherein the substituents in case of multiple substitution may be the same or different;

R ³ and R ^{4 are} identical or different and are selected consisting of j) -H from the group and jj) optionally mono- or polysubstituted by -Hal, -OH, -CN, C1 -C6- Alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-hydroxyalkyl, C3-C6-cycloalkyl, C3-C6 heterocycloalkyl, C2-C6-alkynyl, aryl, aryloxy, heteroaryl, NR ⁶ R ⁷ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ substituted C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6 Alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6

Heterocycloalkyl, aryl or heteroaryl, wherein the C3-C6 heterocycloalkyl in the ring optionally one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or -SO ₂ - groups and / or may contain one or more double bonds, and wherein wherein the substituents may be the same or different upon multiple substitution;

In addition to the above definition, R ³ and R ^{4 may} together form a C ³ -C ⁶ -heterocycloalkyl ring which contains at least one nitrogen atom in the ring and optionally additionally in the ring one or more nitrogen, oxygen or sulfur atoms and / or one or more

- (CO) - or - (SO2) - groups and / or optionally contain one or more double bonds, wherein the ring formed by R3 and R4 optionally mono- or polysubstituted with -CN, -HaI, -OH, C1-C6-alkyl , C1-C6-haloalkyl, C3-C6-cycloalkyl, C1-C6-hydroxyalkyl, C1-C6-alkoxyalkyl, C1-C6-haloalkoxyalkyl, C1-C6-haloalkoxy or with

-NR ⁶ R ⁷ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ and / or optionally with one or more times -HaI, C 1 -C ⁶ -alkoxy, C 1 -C ⁶ -haloalkoxy or - ( CO) - R ⁶ substituted aryl or heteroaryl may be substituted, wherein the substituents may be the same or different with multiple substitution;

R ⁶ and R ^{7 are the} same or different and are selected from the group consisting of j) -H and jj) optionally mono- or polysubstituted with -HaI, -OH, -CN, substituted C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl , C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl or heteroaryl, wherein the C3-C6 heterocycloalkyl in the ring may optionally contain one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or -SO ₂ - groups and / or one or more double bonds, and, wherein the substituents in multiple substitution may be the same or different

and their isomers, diastereomers, enantiomers and salts,

2. A compound according to claim 1, wherein R ¹ and R ^{2 are the} same or different and are selected from the group consisting of j) -H and jj) optionally one or more times with -HaI, -OH, -CN, C1-C6- Alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-hydroxyalkyl, C3-C6-cycloalkyl, C3-C6

Heterocycloalkyl, C 2 -C 6 -alkynyl, aryl, aryloxy, heteroaryl, -S-C 1 -C ⁶ -alkyl, - (CO) -R ⁶ , -NR ³ R ⁴ , -NR ³ (CO) -L, or -NR ³ COOR ^{7 is} substituted C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl wherein the C3-C6 heterocycloalkyl in the ring optionally contain one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO) - or -SO ₂ - groups and / or one or more double bonds where R ¹ and R ^{2 may, in} addition to the above definition, together form a C ³ -C 6 heterocycloalkyl ring containing at least one nitrogen atom in the ring and optionally additionally in or on the ring may contain a plurality of nitrogen, oxygen or sulfur atoms and / or one or more - (CO) - or - (SO ₂ ) - groups and / or optionally one or more double bonds, where in the case of the ring formed by R ¹ and R ² , optionally singly or multiply with -CN, -HaI, -OH, C 1 -C 6 -

Alkyl, C 1 -C ⁶ -haloalkyl, C ³ -C ⁶ -cycloalkyl, C ¹ -C ⁶ -hydroxyalkyl, C ¹ -C ⁶ -alkoxyalkyl, C ¹ -C ⁶ -haloalkoxyalkyl, C ¹ -C ⁶ -haloalkoxy, -NR ³ R ⁴ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ and / or with optionally mono- or polysubstituted with -HaI, C 1 -C 6 -alkoxy, C 1 -C ⁶ -haloalkoxy or - (CO) -R ⁶ -substituted aryl or Heteroaryl may be substituted, wherein the substituents may be the same or different with multiple substitution.

3. A compound according to claim 1, wherein R ¹ and R ^{2 are the} same or different and are selected from the group consisting of j) -H and jj) optionally mono- or polysubstituted with -HaI, -OH, -CN, C1-C6- Alkyl, C1-C2-haloalkyl, C1-C6-alkoxy, C1-C2-haloalkoxy, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl, aryloxy, heteroaryl, -S-C1-C6-alkyl, - (CO ) -R ⁶ , - NR ³ R ⁴ , -NR ³ (CO) -L, -NR ³ COOR ⁷ , -COOR ⁷ , -NR ³ SO ₂ R ⁴ , -SO ₂ NR ³ R ⁴ , -CONR ³ R ⁴ or -SO ₂ R ³ substituted C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-

Alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, or

with - (CH ₂ ) R ⁸ radical, where R ^{8 is} a radical

stands

where aryl, heteroaryl, C 3 -C 6 -cycloalkyl or C 3 -C 6 -heterocycloalkyl groups optionally present in R ¹ or R ² may be monosubstituted or polysubstituted by -HaI, -CN, -OH, -Cl-C 6 -alkyl, -C1-C2-haloalkyl, -C1-C6-alkoxy, -C1-C2-haloalkoxy, -C1-C6-hydroxyalkyl, -C3-C6-cycloalkyl,

-NO ₂ , -NH ₂ , -C 1 -C 6 -haloalkyl, -NR ³ R ⁴ , -CONR ³ R ⁴ , -NR ³ COR ⁴ , NR ³ SO ₂ R ⁴ , -COR ⁶ , CO ₂ R ⁷ , - SO ₂ NR ³ R ⁴ , -SR ³ , SOR ³ , -SO ₂ R ³ , -OR ³ , -O (CH ₂ ) _P R ⁶ , where the substituents may be the same or different in the case of multiple substitution;

where R ¹ or R ² does not contain two or more aryl or heteroaryl groups

Substituenden of the same carbon atom may be;

A compound according to claim 1 or 2 wherein R ¹ and R ^{2 are the} same or different and are selected from the group consisting of j) -H and jj) optionally. or more than once with -HaI, -OH, -CN, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-hydroxyalkyl, C3-C6-cycloalkyl, C3- C6 heterocycloalkyl, C 2 -C 6 -alkynyl, aryloxy, -S-C 1 -C ⁶ -alkyl, - (CO) -R ⁶ , -NR ³ R ⁴ ,

NR ³ (CO) -L, or -NR ³ COOR ⁷ substituted C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-alkynyl , C3-C6-cycloalkyl, CS-CΘ-heterocycloalkyl, aryl or heteroaryl, wherein the C3-C6-heterocycloalkyl in the ring optionally one or more nitrogen, oxygen and / or sulfur atoms and / or one or more - (CO ) - or -SO2-

Groups and / or may contain one or more double bonds, wherein the group defined in jj) may be substituted aryl or heteroaryl, if it is not alkyl, where the substituents may be the same or different when substituted several times, and wherein R ¹ and R ^{2, in} addition to the above definition, jointly designate a C3-C6

Heterocycloalkylring can form which contains at least one nitrogen atom in the ring and optionally additionally in the ring one or more nitrogen, oxygen or sulfur atoms and / or one or more - (CO) - or - (SO ₂ ) - groups and / or optionally or more double bonds, wherein the ring formed by R ¹ and R ^{2 is} optionally mono- or polysubstituted with -CN, -HaI, -OH, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkyl, C ⁶ -hydroxyalkyl, C ¹ -C ⁶ -alkoxyalkyl, C ¹ -C ⁶ -haloalkoxyalkyl, C ¹ -C ⁶ -haloalkoxy, -NR ³ R ⁴ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ⁷ and / or with optionally mono- or polysubstituted by -HaI, C1-C6-alkoxy, C1-C6-haloalkoxy or - (CO) -R ⁶ substituted aryl or heteroaryl may be substituted, wherein the substituents may be the same or different with multiple substitution.

5. A compound according to claim 3 or 4, wherein Q is an optionally mono- or polysubstituted with -OH, -HAI, -CN, alkyl, -OR ⁶ , or -NR ³ R ⁴ -phenyl, pyridyl, thiophenyl, furyl, imidazolyl, or Pyrazolyl is.

6. A compound according to claim 5, wherein R ¹ and R ^{2 are the} same or different and are selected from the group consisting of -H, NR ³ R ⁴ substituted C1-C4 alkyl, optionally additionally one or more times with -HaI, -OH , -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, C 2 -C 6 alkynyl , Aryl,

Aryloxy, heteroaryl, -S-C 1 -C ⁶ -alkyl, - (CO) -R ⁶ , -NR ³ (CO) -L, or -NR ³ COOR ⁷ , where R ³ and R ^{4 are} optional, identical or different, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, where R ³ and R ^{4 can} together form a C ³ -C 6 -heterocycloalkyl ring which contains at least one nitrogen atom in the ring and, optionally, additionally in the ring one or more nitrogen,

Oxygen or sulfur atoms and / or one or more - (CO) - or - (SO ₂ ) - groups and / or optionally one or more double bonds, and wherein R ⁶ and R ⁷ , identical or different, -H, - OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or C1-C3 alkyl.

A compound according to any one of claims 1-4, wherein R ^{1 is} selected from the group consisting of -H and C ¹ -C ³ -alkyl, wherein R ^{2 is} selected from the group consisting of C ³ -C ⁴ alkyl substituted with NR ³ R ⁴ , optionally additionally mono- or polysubstituted with -HaI, -OH, -CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -hydroxyalkyl, C 3 -C 6 -

Cycloalkyl, C3-C6 heterocycloalkyl, C2-C6-alkynyl, aryl, aryloxy, heteroaryl, - S-C1-C6-alkyl, - (CO) -R ^6, -NR ³ (CO) -L, or -NR ³ COOR ⁷ , wherein R ³ and R ⁴ , identical or different, optionally mono- or polysubstituted with -HaI, -OH, -CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C 6 -hydroxyalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -heterocycloalkyl, C 2 -C 6 -alkynyl, aryl,

Aryloxy, heteroaryl, -NR ⁶ R ⁷ , -CONR ⁶ R ⁷ , - (CO) -R ⁶ or -COOR ^{7 are} substituted C 1 -C ⁶ -alkyl, C 1 -C ⁶ -haloalkyl, wherein R ³ and R ⁴ together are a C ³ -C6- form a heterocycloalkyl ring containing at least one nitrogen atom in the ring and optionally additionally in the ring one or more nitrogen, oxygen or sulfur atoms and / or one or more - (CO) - or

- (SO ₂ ) - groups and / or optionally one or more And wherein R6 and R7, the same or different, is -H, -OH, C1-C6-alkoxy, C1-C6-haloalkoxy, or C1-C3-alkyl.

A compound according to any one of claims 1-7, wherein R ¹ or R ² is -H.

9. A compound according to claim 1, namely:

(3-Phenylimidazo [1,2-b] pyridazin-6-yl) - (3-pyrrolidin-1-yl-propyl) -amine (3-morpholin-4-yl-propyl) - (3-phenyl- imidazo [1,2-b] pyridazin-6-yl) -amines (3- (3-chloro-phenyl) -imidazo [1,2-b] pyridazin-6-yl) - (3-pyrrolidin-1-yl -propyl) -amines (3- (3-chloro-phenyl) -imidazo [1,2-b] pyridazin-6-yl) - (3-morpholin-4-yl-propyl) -amines

[3- (1-Methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazin-6-yl] -pyridin-3-yl-methyl-amine

(3-Phenylimidazo [1,2-b] pyridazin-6-yl) -pyridin-3-yl-methyl-amine (3-imidazol-1-yl-propyl) - (3-phenyl-imidazo [1, 2-b] pyridazin-6-yl) -amine (4-fluoro-benzyl) - (3-phenyl-imidazo [1,2-b] pyridazin-6-yl) -amine cyclohexylmethyl-1-phenyl-imidazoCi ^ - blpyridazine-6-ylamines (2,4-difluoro-benzyl) - (3-phenyl-imidazo [1,2-b] pyridazin-6-yl) -amines

[3- (5-Methyl-1H-pyrazol-4-yl) -propyl] - (3-phenyl-imidazo [1,2-b] pyridazin-6-yl) -amine

1- [2- (3-phenyl-imidazo [1,2-b] pyridazin-6-yl-amino) -ethyl] -imidazolidin-2-one (2-morpholin-4-yl-ethyl)) - (3 -phenyl-imidazo [1,2-b] pyridazin-6-yl) -amine

N * 1, N * 1 * -Diethyl-N * 4- (3-phenylimidazo [1,2-b] pyridazin-6-yl) -pentane-1, 4-diamine N, N-diethyl-N ^' - (3-phenyl-imidazo [1,2-b] pyridazin-6-yl) -propane-1,3-diamine (3-phenyl-imidazo [1,2-b] pyridazin-6-yl) - (2 -pyrrolidin-1-yl-ethyl) -amines [3- (3-chloro-phenyl) -imidazo [1,2-b] pyridazin-6-yl] -pyridin-3-yl-methyl-amines [3- ( 3-chloro-phenyl) -imidazo [1,2-b] pyridazin-6-yl] - (3-imidazol-1-yl-propyl) -amine 3- (3-Chloro-phenyl) -imidazo [1,2-b] pyridazin-6-yl) - (4-fluoro-benzyl) -amine 3- (3-chloro-phenyl) -imidazo [1, 2] b] pyridazin-6-yl) -cyclohexylmethyl-amine 3- (3-chloro-phenyl) -imidazo [1,2-b] pyridazin-6-yl) - (2,4-difluoro-benzyl) -amine 1- {2- [3- (3-phenyl) -imidazo [1,2-b] pyridazin-6-yl-amino] -ethyl} -imidazolidin-2-one N * 4 * - [3- (3-Chloro) phenyl) -imidazo [1,2-b] pyridazin-6-yl] -N * 1 *, N * 1 * -diethyl-pentane-1,4-diamine

N'-tS-CS-chlorophenyl-imidazofi ^ -blpyridazine-θ-ylj-N, N-diethyl-propane-1-s-diamine

[3- (3-Chloro-phenyl) -imidazo [1,2-b] pyridazin-6-yl] - (2-pyrrolidin-1-yl-ethyl) -amine (3-imidazol-1-yl-propyl) - [3- (1-methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazine-6-yl] -amine

(4-Fluoro-benzyl) - [3- (1-methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazin-6-yl] -amines

Cyclohexylmethyl- [3- (1-methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazin-6-yl] -amines

(2,4-difluoro-benzyl) - [3- (1-methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazin-6-yl] -amines

[3- (1-Methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazin-6-yl] - [5-methyl-1H-pyrazol-4-yl) -propyl] -amines 1 - {2- [3- (1-methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazin-6-yl-amino] -ethyl} -imidazolidin-2-ones

(3- (1-Methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazin-6-yl) - (2-morpholin-4-yl-ethyl) -amine

N * 1, N * 1 * -diethyl-N * 4- [3- (1-methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazin-6-yl] -pentane- 1,4-diamine

N, N-diethyl-N '- [3- (1-methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazin-6-yl] -propane-1,3-diamine

[3- (1-Methyl-1H-pyrazol-4-yl) -imidazo [1,2-b] pyridazin-6-yl] - (2-pyrrolidin-1-ethyl-ethyl) -amine Pyridin-S-yl-methyl-thiophen-S-yl-imidazotiphenyl-pyridazine-γ-yl-amine (4-fluorobenzyl) - (3-thiophen-3-yl-imidazo [1,2-b] pyridazin-6-yl) -amines cyclohexylmethyl-3-thiophen-3-yl-imidazo [1,2-b] pyridazin-6-yl) -amine (2,4-difluoro-benzyl) - (3-thiophene) 3-ylimidazo [1,2-b] pyridazin-6-yl) -amine [3- (5-methyl-1H-pyrazol-4-yl) -propyl] - (3-thiophen-3-yl -imidazo [1,2-b] pyridazine-6-yl) -amine

1- [2- (3-thiophen-3-yl-imidazo [1,2-b] pyridazin-6-yl-amino) -ethyl] imidazolidin-2-one (2-morpholin-4-yl-ethyl) - (3-thioph8n-3-yl-imidazo [1,2-b] pyridazin-6-yl) -amine

N * 1, N * 1 * -diethyl-N ^* 4- [3-thiophen-3-yl-imidazo [1,2-b] pyridazin-6-yl] -pentane-1-A-diamine

N, N-diethyl-N '- (3-thiophen-3-yl-imidazo [1,2-b] pyridazin-6-yl] -propane-1,3-diamine

(2-Pyrrolidin-1-yl-ethyl) - (3-thiophen-3-yl-imidazo [1,2-b] pyridazin-6-yl) -amine

10. A compound according to claim 1, namely compound according to one of the examples:

• 2.0 - 2.21,

• 3.0 - 3.80,

• 4.0 - 4.11,

• 5.0 - 5.389,

• 6.0 - 6.2, • 7.0 - 7.1 or

• 8.0 - 8.1.

11. A process for preparing a compound according to any one of claims 1 to 10, comprising the following process steps:

A1) 3-amino-6-halogen-pyrazine is converted to 6-halo-imidazo [1,2-b] pyridazine II,

A2) the product from step A1 is converted to a 3-halo-6-halo-imidazo [1,2b] pyridazine III, A3) the product from step A2 is reacted by reaction with a compound NHR ¹ R ² to give the compound according to general formula IIa,

A4) the product from stage A3 is converted to the compound according to general formula I,

or

B1) 3-amino-6-halogeno-pyrazine is converted to 6-halo-imidazo [1,2-b] pyridazine II,

B2) the product from stage B1 is converted to a 3-halo-6-halo-imidazo [1,2b] pyridazine III,

B3) the product from stage B2 is converted into the compound according to general formula IIb,

B4) the product from step B3 is converted to the compound according to general formula I.

or

C1) 3-amino-6-halogen-pyrazine is converted to 6-halo-imidazo [1,2-b] pyridazine II,

C2) the product from step C1 is converted to an imidazo [1,2-b] pyridazin-6-yl) (R ¹ ) - (R ² ) -amine IV by reaction with a compound NHR ¹ R ² ,

C3) the product from stage C2 is converted into the compound according to general formula IIa,

C4) the product from stage C3 is converted to the compound according to general formula I.

12. The method according to claim 11, comprising the following process steps: A1) 3-amino-6-halogen-pyrazine is reacted with chloroactetaldehyde to give 6-halo-imidazo [1,2-b] pyridazine,

A2) the product from step A1 is reacted with Λ / -bromo-succinimide to give a 3-bromo-6-halo-imidazo [1,2-b] pyridazine,

A3) the product from step A2 is converted by reaction with a compound

NHR ¹ R ² reacted in a Buchwald-Hartwig cross-coupling reaction to give a (3-bromo-imidazo [1,2-b] pyridazin-6-yl) - (R ¹ ) - (R ² ) -amine,

A4) the product from stage A3 is reacted, for example, with a boronic acid which is optionally substituted by the radicals A and B, to give the compound according to the general formula I,

or

B1) 3-amino-6-halogen-pyrazine is reacted with chloroactetaldehyde to give 6-halo-imidazo [1,2-b] pyridazine,

B2) the product from stage B1 is reacted with Λ / bromo-succinimide to give a 3-bromo-6-halo-imidazo [1,2-b] pyridazine,

B3) the product from stage B2 is reacted, for example, with a boronic acid, which is optionally substituted by the radicals A and B, to give the compound according to general formula II,

B4) the product from step B3 is converted by reaction with a compound NHR ¹ R ² in a Buchwald-Hartwig cross-coupling reaction to the compound according to general formula I.

or

C1) 3-amino-6-halogen-pyrazine is reacted with chloroactetaldehyde to give 6-halo-imidazo [1,2-b] pyridazine, C2) the product from step C1 is converted to an imidazo [1,2-b] pyridazin-6-yl) - (R ¹ ) - (R ² ) by reaction with a compound NHR ¹ R ² in a Buchwald-Hartwig cross-coupling reaction. -amine implemented,

C3) the product from step C2 is reacted with Λ / -bromo-succinimide to give a (3-bromo- imidazo [1,2-b] pyridazin-6-yl) - (R ¹ ) - (R ² ) -amine,

C4) the product from step C3 is reacted, for example, with a boronic acid, which is optionally substituted by the radicals A and B, to give the compound according to the general formula I.

13. Use of a compound according to any one of claims 1 to 10 for the preparation of a pharmaceutical composition.

14. Use of a compound according to any one of claims 1 to 10 for the inhibition of a cellular kinase.

Use of a compound according to any one of claims 1 to 10 for inhibiting a cellular kinase according to claim 14, wherein the kinase belongs to the group of the protein kinase C family, such as PKC theta, delta, iota, alpha and zeta.

16. Use of a compound according to any one of claims 1 to 9 for the inhibition of a cellular kinase according to claim 15, wherein the kinase from the class of the ALK family, preferably ALK1, ALK2, ALK4 or ALK5 is.

17. Use of a compound according to any one of claims 1 to 10 for

Preparation of a pharmaceutical composition for the treatment or prophylaxis of a disease which is associated with the overexpression or mutation of a cellular kinase according to claim 14, in particular a cellular kinase according to claim 15 or a cellular kinase according to claim 16.

The use of claim 13, wherein the disease is a disease selected from the group consisting of benign tumors, malignant tumors, leukemia such as myeloblastic leukemia, lymphoma, sarcoma, such as osteosarcoma or chondrosarcoma, neuroblastoma, Wilm ^'s tumor, malignant neoplasms of the bladder, breast, lung, pancreas, prostate, kidney, neoplasms of epithelial origin, such as breast cancer or their metastases.

The use of claim 13, wherein the disease is a disease selected from the group consisting of epidermal hyperproliferation such as psoriasis, Alzheimer's, autoinflammatory diseases, fibrosis, impaired wound healing, diabetic retinopathy, nephropathy, age-related macular degeneration, Crohn's disease, overreaching immune response, contact dermatitis, atopic dermatitis, multiple sclerosis, ALS, diabetes,

Asthma can be.

20. Use according to claim 13 for the modulation, in particular reduction, of an immune reaction, for example after transplantation to avoid organ rejection.

21. A process for the preparation of a pharmaceutical composition, wherein a physiologically effective dose of a compound according to any one of claims 1 to 10 mixed with at least one galenic adjuvant and prepared into a dosage form.

22. A method for the treatment or prophylaxis of a disease associated with the overexpression of a cellular kinase, wherein a pharmaceutical composition containing a physiologically effective dose of a compound according to any one of claims 1 to 10 is administered to a person suffering from the disease or to to fall ill.

23. Intermediate according to formula IIa

general formula IIa

in which

Y is a halogen atom, and

R ¹ and R ^{2 has} the meaning given in claim 1.

24. Intermediate product according to the general formula IIb

general formula IIb

Q, A and B have the meaning given in claim 1 and

X is chlorine, bromine, O-SO ₂ -CF ₃ or O-SO ₂ -C ₄ F ₉ .