JP5680824B2 - Substituted imidazo [1,2b] pyridazines as kinase inhibitors, their preparation and use as pharmaceuticals - Google Patents

Description

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

  The compounds according to the invention are suitable for inhibiting kinases, preferably the kinases of the protein kinase (PK) family, in this connection in particular the kinases of the PKC subfamily, more particularly the PKC theta (θ) Suitable for inhibiting kinases.

  The compounds of the present invention are used not only for diseases caused by kinase dysfunction, including immunological and general inflammatory processes and carcinogenic processes, but also for the treatment of diseases such as type II diabetes and asthma, and for transplantation. Suitable as kinase inhibitors; preferably suitable as kinase inhibitors for the treatment of acute dermatitis, contact dermatitis and even inflammatory processes and clinical responses that show clinical signs of psoriasis.

  One publication (Bioorg. Med. Chem. Lett. 2004, 14, 2249-2252) discloses pyrimidine derivatives having bound imidazo [1,2b] pyridazine residues as kinase inhibitors. These compounds differ from the compounds of the present invention in terms of their structure, particularly the structure of the imidazo [1,2b] pyridazine ring. Patent application WO 02/066481 (AstraZeneca) describes pyridazine substituted pyrimidines as antiproliferative substances. Other prior art will be described later.

  There is a continuing need for effective drugs for the treatment of immunological and cell proliferative disorders, particularly for the treatment of dermatological signs.

Substituted imidazo [1,2b] pyridazine of general formula I

[Q is aryl or heteroaryl excluding pyrimidine;
A and B are the same or different, and
i) -H, -Hal, -OH, -NR 3 R 4, -CN or -NO _2,
ii) optionally mono - or poly _{-Hal -, - OH-, C 3} ~C 6 heterocycloalkyl ^{-, - NR 3 R 4 -} , - SO 2 NR 3 R 4 -, - SO 2 R 3 - or - (CO) -NR ³ may be substituted with -L-, C ₁ ~C ₆ 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, wherein said C ₃ -C ₆ heterocycloalkyl is one or more nitrogen, oxygen and / or sulfur atoms in the ring and / or 1 or May comprise a plurality of — (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 in the case of polysubstitution may be the same or different;

A and B in addition to the above definitions, taken together may form a Q fusion C ₅ -C ₇ cycloalkyl or C ₅ -C ₇ heterocycloalkyl ring, in the latter case at least in the ring One oxygen or one nitrogen atom and optionally further one or more oxygen, nitrogen or sulfur atoms and / or one or more — (CO) — or — (SO ₂ ) in the ring. ) -Group and / or may comprise one or more double bonds;
p is 0-4;

L mono desired - or poly - hydroxy -, 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 -, C ₁ -C ₆ alkoxyalkoxy -, C ₃ -C ₆ heterocycloalkyl - or -NR ³ R ⁴ - may be substituted by, C ₁ -C ₆ Alkyl, C ₁ -C ₆ haloalkyl or C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl, wherein said C ₃ -C ₆ heterocycloalkyl is one or more nitrogen, oxygen in the ring And / or may comprise sulfur atoms, and / or one or more — (CO) — or — (SO ₂ ) — groups, and / or one or more double bonds;

R ¹ and R ² are the same or different, and
j) -H, and
jj) optionally mono - or poly -Hal -, - OH -, - CN-, C 1 ~C 6 alkyl -, C ₁ -C ₆ haloalkyl -, C ₁ -C ₆ alkoxy -, C ₁ -C ₆ halo 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 -, - 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 — may be substituted, C ₁ to C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₂ ~ ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ heterocycloalkyl, selected from the group consisting of aryl or heteroaryl, or

である）を有し、
ここで前記Ｒ¹又はＲ²中に任意に存在するアリール、ヘテロアリール、Ｃ₃〜Ｃ₆シクロアルキル又はＣ₃〜Ｃ₆ヘテロシクロアルキル基は、−Hal、−ＣＮ、−ＯＨ、−Ｃ₁〜Ｃ₆アルキル、−Ｃ₁〜Ｃ₆ハロアルキル、−Ｃ₁〜Ｃ₆アルコキシ、Ｃ₁〜Ｃ₆ハロアルコキシ、−Ｃ₁〜Ｃ₆ヒドロキシアルキル、−Ｃ₃〜Ｃ₆シクロアルキル、−ＮＯ₂、−ＮＨ₂、−Ｃ₁〜Ｃ₆ハロアルキル−、−ＮＲ³Ｒ⁴、−ＣＯＮＲ³Ｒ⁴、−ＮＲ³ＣＯＲ⁴、−ＮＲ³ＳＯ₂Ｒ⁴、−ＣＯＲ⁶、−ＣＯ₂Ｒ⁷、−ＳＯ₂ＮＲ³Ｒ⁴、−ＳＲ³、−ＳＯＲ³、−ＳＯ₂Ｒ³−、ＯＲ³、−Ｏ（ＣＨ₂）_pＲ⁶により単置換もしくは多置換されることがあり；ここで多置換の場合の置換基は同一であっても異なってもよく； - (CH _{2) r} R ⁸ group (wherein r is a number from 0 to 3, and R ⁸ is group

Is)
Here, the aryl, heteroaryl, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl group optionally present in R ¹ or R ² is —Hal, —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 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 by R ⁶ may be monosubstituted or polysubstituted; multi wherein The substituents in the case of substitution may be the same or different;

Provided that two or more aryl or heteroaryl groups cannot be substituents on the same carbon atom in R ¹ or R ² ;
In addition to the above definitions, R ¹ and R ² can be taken together to form a C ₃ -C ₆ heterocycloalkyl ring, wherein the C ₃ -C ₆ heterocycloalkyl ring is at least one nitrogen in the ring. And optionally further comprising one or more nitrogen, oxygen or sulfur atoms, and / or one or more — (CO) — or — (SO ₂ ) — groups in the ring, and / or Or may comprise one or more double bonds; wherein the ring formed by R ¹ and R ² is optionally —CN, —Hal, —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 - by (CO) -R ⁶ or -COOR ^7, and / or mono - substituted with (CO) -R ⁶ - or poly -Hal-, C ₁ ~C ₆ alkoxy, C ₁ -C ₆ haloalkoxy - or May be mono- or polysubstituted by aryl or heteroaryl; the substituents in the case of polysubstitution may be the same or different;

R ³ and R ⁴ are the same or different, and j) -H, and jj) optionally mono - or poly -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 ^{-, - NR 6 R 7 -} , - CONR 6 R 7 -, - (CO) -R 6 - or -COOR ⁷ - substituted with, 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 heteroar- Lumpur,
Wherein the C ₃ -C ₆ heterocycloalkyl is one or more nitrogen, oxygen and / or sulfur atoms and / or one or more — (CO) — or —SO in the ring. ₂ -groups and / or may contain one or more double bonds, and the substituents in the case of polysubstitution may be the same or different;

In addition to the above definitions, the R ³ and R ⁴ groups can be taken together to form a C ₃ -C ₆ heterocycloalkyl ring, wherein the C ₃ -C ₆ heterocycloalkyl ring is at least one in the ring. Optionally comprising one or more nitrogen atoms, oxygen atoms or sulfur atoms, and / or one or more — (CO) — or — (SO ₂ ) — groups in the ring. Or may comprise one or more double bonds;

R ³ and the ring formed by R ⁴ is optionally _{-CN, -Hal, -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 haloalkoxy, C ₁ -C ₆ haloalkoxyalkyl, by C ₁ -C ₆ ^{alkoxyalkyl, -NR 6 R 7, -CONR 6} R 7, - (CO) -R 6 or - Simple by COOR ⁷ and / or by aryl or heteroaryl substituted by mono- or poly-Hal-, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy- or-(CO) -R ⁶ May be substituted or polysubstituted; the substituents in the case of polysubstitution may be the same or different;

R ⁶ and R ⁷ are the same or different and j) —H, and jj) C ₁ -C ₆ alkyl, C, optionally substituted with mono- or poly-Hal-, —OH—, —CN—, C _{From 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 heterocycloalkyl, aryl or heteroaryl Wherein the C ₃ -C ₆ heterocycloalkyl is one or more nitrogen, oxygen and / or sulfur atoms and / or one or more — (CO) — or —SO _{2 in the} ring. -Groups and / or may contain one or more double bonds, and the substituents in the case of polysubstitution may be the same or different]
And its isomers, diastereomers, enantiomers and salts are compounds that are effective in inhibiting kinases (specified below) and can therefore be used in a number of diseases (specified below). .

  Alkyl in each case represents a straight-chain or branched alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl and decyl. means.

  Alkoxy is in each case a linear or branched alkyl group such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy , Nonyloxy or decyloxy.

  Alkenyl substituents are in each case linear or branched alkenyl, for example meaning the following groups: 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, allyl.

  Alkynyl means in each case a straight-chain or branched alkynyl group comprising 2 to 6, preferably 2 to 4 C atoms. Examples of suitable groups are: ethynyl, propyn-1-yl, propyn-3-yl (propargyl), but-1-in-1-yl, but-1-in-4-yl, but 2-In-1-yl, but-1-in-3-yl, 3-methylbut-1-in-3-yl.

C ₁ -C ₆ haloalkyl is a linear or branched alkyl group in which at least one hydrogen atom is replaced 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-fluoroisopropyl, perfluorobutyl and the like. Perfluoromethyl and perfluoroethyl groups are very particularly preferred.

C ₁ -C ₆ haloalkoxy is a linear or branched alkoxy group in which at least one hydrogen atom is replaced by a halogen atom (fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine), for example fluoro It means methoxy, trichloromethoxy, 1,2-difluoroethoxy, perfluoropropoxy, 3,3,3-trifluoropropoxy, 1-fluoroisopropoxy, perfluorobutoxy and the like. Perfluoromethoxy and perfluoroethoxy groups are very particularly preferred.

C ₃ -C ₆ heterocycloalkyl, refers to an alkyl ring containing from 3 to 6 carbon atoms, wherein the heterocycloalkyl in the ring, oxygen, at least one identical or selected from oxygen, sulfur or nitrogen Comprising different atoms and the ring may be interrupted by one or more — (CO) —, — (CS) — or —SO ₂ — groups, and optionally one or more duplexes in the ring Bonds may be included, and the ring itself may optionally be mono- or polysubstituted as well or differently.

  Examples of heterocycloalkyl that may be mentioned are oxiranyl, oxetanyl, dioxolanyl, dithianyl, dioxanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydroisozoyl Quinolinyl, octahydroisoquinolinyl, tetrahydroquinolinyl, octahydroquinolinyl, tetrahydroimidazolonyl, pyrazolidinyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperidonyl, piperazinyl, piperazinyl, N-methylpyrrolidinyl, 2-hydroxy Methylpyrrolidinyl, 3-hydroxypyrrolidinyl, N-methylpiperazinyl, N-benzylpiperazinyl, N-acetylpiperazinyl, N-methyl Sulfonylpiperazinyl, 4-hydroxypiperidinyl, 4-aminocarbonylpiperidinyl, 2-hydroxyethylpiperidinyl, 4-hydroxymethylpiperidinyl, imidazolidinyl, tetrahydroimidazolonyl, morpholinyl, thiomorpholinyl, 1,1 -Dioxothiomorpholinyl, trithianyl, tetrahydrotriazinethionyl, triazinethionyl, quinuclidinyl, nortropinyl, pyridodonyl.

  Preferable heterocycloalkyl groups include tetrahydropyranyl, pyrrolidinyl, piperidinyl, N-methylpiperidinyl, piperazinyl, N-methylpiperazinyl, morpholinyl and pyridonyl.

Substituents on heterocycloalkyl ring, 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 optionally identically or differently by halogen, by hydroxyl or by C ₁ -C ₆ alkylthio, Substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or the following groups:-(CO) -C ₁ -C ₆ alkyl,-(CO) -O-C ₁ -C ₆ alkyl,- (SO) ₂ -C ₁ ~C ₆ alkyl, - (SO) ₂ - phenyl, -NH _2, selected from -N (C _{1 ~C 6} alkyl) ₂ and -NH (C _{1 ~C 6} alkyl) A substituent, etc. It is possible.

Cycloalkyl means not only monocyclic alkyl rings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but also bicyclic or tricyclic rings such as adamantanyl. Cycloalkyl may optionally be benzo-fused, such as (tetralin) yl.
Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Halogen means in each case fluorine, chlorine, bromine or iodine.
The aryl group in Q and the optionally present aryl group in R ¹ and R ² contain 3 to 12 carbon atoms in each case and may be benzofused in each case. Examples include cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl, tetralinyl and the like.

  The heteroaryl group Q contains in each case 5 to 16 ring atoms and may contain one or more identical or different heteroatoms, such as oxygen, nitrogen or sulfur atoms, in the ring instead of carbon atoms, It can be monocyclic, bicyclic or tricyclic and may be further benzofused in each case. The group Q in the definition of heteroaryl does not include pyrimidine.

  Examples include thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like, as well as their benzo derivatives 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 quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quino Sariniru, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenothiazinyl, phenol benzoxazinyl, xanthenyl, tetralinyl and the like.

  Preferred heteroaryl groups include, for example, 5-membered heteroaromatic rings such as thienyl, furanyl, oxazolyl, thiazolyl, imidazolyl and 5-membered heteroaromatic ring benzo derivatives, and 5-membered heteroaromatic rings such as pyridinyl, triazinyl. And 6-membered heteroaromatic benzo derivatives such as quinolinyl, isoquinolinyl.

The heteroaryl group optionally present in R ¹ or R ² contains in each case 5 to 16 ring atoms and one or more heteroatoms such as oxygen in the ring instead of carbon atoms. May contain nitrogen or sulfur atoms and may be monocyclic, bicyclic or tricyclic, and in each case may also be benzofused.

Examples of heteroaryl groups in R ¹ and R ² include thienyl, furanyl, pyroidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like and benzo derivatives thereof such as benzofuranyl, benzothienyl, Benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and benzo derivatives thereof such as quinolyl, isoquinolyl and the like; Indazolyl, benzimidazolyl, purinyl and the like and benzo derivatives thereof; or quinolinyl, isoquinolinyl, Nonolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, tetralinyl and the like can be mentioned.

Examples of preferred heteroaryl groups in R ¹ or R ² are 5-membered heteroaromatic rings such as thienyl, pyrazolyl, furanyl, oxazolyl, thiazolyl, triazolyl, imidazolyl and its benzo derivatives, and 6-membered heteroaromatic rings. For example pyridinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl and its benzo derivatives.

Particularly preferred heteroaryl groups in R ¹ or R ² are thienyl, pyrazolyl, furanyl, oxazolyl, thiazolyl, triazolyl, imidazolyl, pyridinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl.
When multiple aryl or heteroaryl groups are present in R ¹ or R ² , two or more aryl or heteroaryl groups must not be on the same carbon atom as a substituent.

が基Ｒ¹又はＲ²として好ましい。 For example, the following group:

Are preferred as the group R ¹ or R ² .

When aryl, heteroaryl, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl groups are present in R ¹ or R ² , they are —Hal, —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 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 or -SO ₂ NR ³ R ⁴ , —SR ³ , —SOR ³ , —SO ₂ R ³ , —OR ³ , —O (CH ₂ ) _p R ⁶ may be mono-substituted or poly-substituted. The groups can be the same or different. In a preferred embodiment, the aryl, heteroaryl, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl group present in R ¹ or R ² has at most three of the above substituents.

Isomers mean chemical compounds having the same molecular formula but different chemical structures. A distinction is generally made between structural isomers and stereoisomers.
Structural isomers have the same molecular formula but differ in the way their atoms or groups are bonded. Such isomers include functional isomers, positional isomers, interchangeable isomers or valence isomers.

Stereoisomers theoretically have the same structure (configuration) and therefore have the same molecular formula, but the configuration of atoms is different.
In general, structural isomers and conformational isomers are distinguished. Structural isomers are stereoisomers that can be converted into each other only by breaking bonds. They include enantiomers, diastereomers, and E / Z (cis / trans) isomers.

Enantiomers are stereoisomers related to each other like real images and mirror images, and do not have a plane of symmetry. All stereoisomers that are not enantiomers are called diastereomers. The E / Z (cis / trans) isomer at the double bond is a special example.
Conformational isomers are stereoisomers that can be converted into each other by the rotation of a single bond.
See also the IUPAC Rule E section (Pure Appl. Chem. 1976, 45, 11-30) regarding the classification of isomers by type.

The compounds of the general formula I also include possible interchangeable isomers; and also include E or Z isomers, or racemates and enantiomers if an asymmetric center is present. Double bond isomers can also be interpreted as such.
The compound of the present invention can also exist in the form of a solvate, particularly in the form of a hydrate, in which case the compound of the present invention contains a polar solvent, particularly water, as a constituent of the crystal lattice of the compound of the present invention. Become. The proportion of polar solvent, in particular water, can be a stoichiometric or non-stoichiometric proportion. The terms used for stoichiometric solvates (especially hydrates) are solvates such as hemi (semi)-, mono-, sesqui-, di-, tri-, tetra-, penta- and the like.

  Where acidic function is present, suitable salts are physiologically acceptable salts of organic and inorganic bases, such as readily soluble alkali metal and alkaline earth metal salts, and N-methylglucamine, dimethylglucamine, ethyl It is a salt of glucamine, lysine, 1,6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropanediol, Sovak base, 1-amino-2,3,4-butanetriol. .

  Where basic functions are present, physiologically acceptable salts of organic and inorganic acids are suitable, for example 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 in which R ¹ and R ² are the same or different and j) -H; and jj) optionally mono- or poly-Hal-, -OH-, -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 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 - in 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 Black alkyl, C ₃ -C ₆ are selected from the group consisting of heterocycloalkyl; wherein, C ₃ -C ₆ heterocycloalkyl, optionally, one or more nitrogen in the ring, oxygen and / or sulfur atom, And / or one or more — (CO) — or —SO ₂ — groups, and / or one or more double bonds; where the substituents in the case of polysubstitution are the same Q, A, B, R ³ , R ⁴ , R ⁶ , R ⁷ , p and L can be varied as defined above.

Further preferred compounds of the formula I are those in which R ¹ and R ² are the same or different and i) -H and ii) optionally mono- or poly-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 -, aryloxy _{-, - S-C 1 ~C} 6 alkyl ^{-, - (CO) -R 6} -, - NR 3 R 4 -, - NR 3 ( substituted by CO) L-or _{^{-NR 3 COOR 7, 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 Heteroshikuroa Selected from the group consisting of alkyl, aryl or heteroaryl; wherein the aryl or heteroaryl group defined in jj) above can be substituted as long as it does not contain alkyl, and the substituent in the case of polysubstitution May be the same or different; in this case, Q, A, B, R ³ , R ⁴ , R ⁶ , R ⁷ , p and L can be varied as defined above.

Further preferred compounds of the general formula I are phenyl, pyridyl, thiophenyl, furyl, imidazolyl, wherein Q is substituted with —OH—, —Hal—, —CN—, alkyl-, —OR ⁶ — or —NR ³ R ^4. Or pyrazolyl, wherein R ¹ and R ² are the same or different, and
j) -H, and jj) optionally mono- - or poly -Hal -, - OH -, - C 1 ~C 6 alkyl substituted with CN- -, 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 -, aryloxy _{-, - S-C 1 ~C} 6 alkyl ^{-, - (CO) -R 6} , -NR 3 R 4 -, - NR 3 (CO) -L- or -NR ³ COOR ⁷ - substituted by, 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, Selected from the group consisting of C ₃ -C ₆ heterocycloalkyl, aryl or heteroaryl Wherein said C ₃ -C ₆ heterocycloalkyl is optionally one or more nitrogen, oxygen and / or sulfur atoms and / or one or more — (CO) — or —SO ₂ — groups in the ring. And / or may contain one or more double bonds, and the aryl or heteroaryl groups defined in jj) may be substituted as long as they do not contain alkyl, and the substituents in the case of polysubstitution are the same Or different. In this case, R ³ , R ⁴ , R ⁶ , R ⁷ , p and L can be varied as defined above.

Further preferred compounds of the general formula I are those wherein R ¹ and R ² are the same or different and are —H, C ₁ -C ₄ alkyl substituted with —NR ³ R ⁴ , optionally additionally mono- or poly-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 , optionally mono- or poly-Hal-, -OH-, -CN-, C ₁ -C ₆ alkyl -, C ₁ ~C ₆ haloalkyl -, C ₁ ~ 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 which may be substituted by ^7, C ₅ -C ₆ cycloalkyl, is selected from the group consisting of C ₅ -C ₆ heterocycloalkyl; wherein

R ³ and R ⁴ can optionally be the same or different C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or R ³ and R ^{4 taken} together are a C ₃ -C ₆ heterocycloalkyl ring. Wherein said C ₃ -C ₆ heterocycloalkyl ring comprises at least one nitrogen atom in the ring and optionally additionally one or more nitrogen, oxygen or sulfur atoms and And / or may comprise one or more — (CO) — or — (SO ₂ ) — groups and / or optionally one or more double bonds, wherein R ⁶ and R ⁷ may be the same or different. , -H, -OH, are those wherein C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy or C ₁ -C ₃ alkyl.

Particularly preferred compounds of the general formula I are selected from the group consisting of R ¹ —H and C ₁ -C ₃ alkyl,
C ₃ -C ₄ alkyl, wherein R ² is substituted with —NR ³ R ⁴ , optionally additionally mono- or poly-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 - Selected from the group consisting of C ₃ -C ₄ alkyl, optionally substituted by NR ³ COOR ⁷ ;

R ³ and R ⁴ are identical or different, optionally mono- - or poly -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 ^{-, - NR 6 R 7 -} , - CONR 6 R 7, - (CO) -R 6 - or which may be substituted by -COOR ^7, C ₁ ~C ₆ alkyl, C ₁ Selected from the group consisting of ˜C ₆ haloalkyl, or

R ³ and R ⁴ may form a C ₃ -C ₆ heterocycloalkyl ring together, it said C ₃ -C ₆ heterocycloalkyl ring comprises at least one nitrogen atom in the ring and Optionally additionally 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 in the ring. Wherein R ⁶ and R ⁷ are the same or different and are —H, —OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy or C ₁ -C ₃ alkyl It is.
In a more preferred embodiment, R ¹ or R ² is a hydrogen atom.

The following compounds mentioned in the examples are particularly preferred:
・ 2.0 ~ 2.21
・ 3.0 to 3.80
・ 4.0〜4.11
・ 5.0〜5.389
・ 6.0 to 6.2
・ 7.0〜7.1
・ 8.0-8.1

一般式IIａ A further aspect of the invention is a compound of general formula IIa:

Formula IIa

[In the above formula,
Y is a halogen atom (preferably chlorine or bromine);
R ¹ and R ² are the same or different, and j) -H, and jj) optionally mono - or poly -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 R 4 -, - NR 3 (CO) ^{-L -, - NR 3 COOR 7} - which may be substituted by, 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 is selected from the group consisting of aryl or heteroaryl, said C ₃ -C ₆ heterocycloalkyl ring 1 or more nitrogen in the ring optionally oxygen and / or sulfur atoms and / or one or more, The — (CO) — or —SO ₂ — group, and / or one or more double bonds, and the substituents in the case of polysubstitution may be the same or different;

R ¹ and R ² in addition to the above definitions, taken together may form a C ₃ -C ₆ heterocycloalkyl ring, wherein the C ₃ -C ₆ heterocycloalkyl 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 nitrogen, oxygen or sulfur atoms, and / or one or more-(CO) - or - (SO ₂₎ - group, and / or can contain one or more double bonds, where the ring formed by R ¹ and R ^2, -CN, -Hal, -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 haloalkoxyalkyl, C ₁ -C ₆ haloalkoxy, C ₁ ~ C ₆ alkoxyalkyl, -NR ^{3 4, -CONR 6 R 7, -} (CO) by -R ⁶ or -COOR ^7, and / or mono- - or poly -Hal-, C ₁ ~C ₆ alkoxy -, C ₁ -C ₆ haloalkoxy - or - Aryl or heteroaryl, which may be substituted with (CO) -R ⁶ , may be mono- or polysubstituted, where the substituents in the case of polysubstitution may be the same or different; Provided that three or more nitrogen atoms of the ring must not be directly connected to each other;

Where aryl which may be present in R ¹ or R ^2, heteroaryl, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl group, -Hal, -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 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 may be monosubstituted or polysubstituted, where The substituents in this case may be the same or different;

R ³ and R ⁴ are the same or different, and j) -H, and jj) mono- - or poly -Hal -, - OH -, - CN @ -, C1 -C6 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 —, which may be substituted by 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 heteroali The C ₃ -C ₆ heterocycloalkyl ring is optionally selected from one or more nitrogen, oxygen or sulfur atoms and / or one or more — (CO) — or — SO ₂ — groups and / or can contain one or more double bonds, where the substituents in the case of polysubstitution may be the same or different;

In addition to the above definition, R ³ and R ⁴ may be taken together to form a C ₃ -C ₆ heterocycloalkyl ring, wherein the C ₃ -C ₆ heterocycloalkyl is 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 1 Or a plurality of double bonds, wherein the ring formed by R ³ and R ⁴ is —CN, —Hal, —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 haloalkyl or -NR ³ R ^4, -CONR ⁶ R ⁷ ,-(CO) -R ⁶ or The -COOR ^7, and / or mono- - or poly -Hal-, C ₁ ~C ₆ alkoxy -, C ₁ -C ₆ haloalkoxy - or - (CO) aryl or heteroaryl which may be substituted with -R ⁶ The aryl may be mono- or polysubstituted, where the substituents in the case of polysubstitution may be the same or different;

R ⁶ and R ⁷ are the same or different and j) —H and jj) C ₁ -C ₆ alkyl, C ₁ which may be substituted by mono- or poly-Hal-, —OH—, —CN—. -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 heterocycloalkyl, a group consisting of aryl or heteroaryl The C ₃ -C ₆ heterocycloalkyl is selected from the group consisting of one or more nitrogen atoms, oxygen atoms or sulfur atoms and / or one or more — (CO) — or — (SO ₂ ) — in the ring. And / or may contain one or more double bonds, where the substituents in the case of polysubstitution may be the same or different.)
And their isomers, diastereomers, enantiomers and salts thereof, and their use to prepare compounds of formula I.

A further aspect of the invention is a compound of general formula IIb:

[In the above formula,
X is chlorine, bromine, O—SO ₂ —CF ₃ or O—SO ₂ —C ₄ F ₉ ;
Q is aryl or heteroaryl, excluding pyrimidine;

A and B are the same or different, and
i) -H, -Hal, -OH, -NR 3 R 4, -CN or -NO _2,
ii) optionally mono - or poly _{-Hal -, - OH-, C 3} ~C 6 heterocycloalkyl ^{-, - NR 3 R 4 -} , - SO 2 NR 3 R 4 -, - SO 2 R 3 - or - (CO) -NR ³ which may be substituted by -L, C ₁ ~C ₆ 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 (wherein said C ₃ -C ₆ heteroalkyl is one or more nitrogen, oxygen or sulfur atoms in the ring and / or one or more — (CO) — or - (SO ₂₎ - may include 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 ,-( Selected from the group consisting of CO) NR ³ R ⁴ , —CO ₂ R ⁷ , NR ³ (SO ₂ ) R ⁴ or —O— (CH ₂ ) _p -aryl;
Where the substituents in the case of polysubstitution may be the same or different;

A and B in addition to the above definitions, taken together may form a Q fusion C ₅ -C ₇ cycloalkyl or C ₅ -C ₇ heterocycloalkyl ring, in the latter case at least in the ring One or more oxygen or nitrogen atoms and optionally further one or more oxygen, nitrogen or sulfur atoms and / or one or more — (CO) — or — (SO ₂ ) in the ring. -Groups and / or may comprise one or more double bonds;

p is 0-4;
L mono desired - or poly - 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 be substituted by _{-NR 3 R 4, C 1 ~C} 6 alkyl, C ₁ -C ₆ haloalkyl or C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl, wherein said C ₃ -C ₆ heterocycloalkyl is one or more nitrogen, oxygen and / or sulfur atoms in the ring, and / or May comprise one or more — (CO) — or — (SO ₂ ) — groups and / or one or more double bonds;

R ³ and R ⁴ are the same or different, and
j) -H, and
jj) optionally mono - or poly -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 -, - ^{NR 6 R 7 -, - CONR} 6 R 7 -, - (CO) -R 6 - or which may be substituted by -COOR ^7, 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, a group consisting of aryl or heteroaryl Selected from;

In addition to the above definitions, the R ³ and R ⁴ groups can be taken together to form a C ₃ -C ₆ heterocycloalkyl ring, wherein the C ₃ -C ₆ heterocycloalkyl ring is at least one in the ring. Optionally comprising one or more nitrogen atoms, oxygen atoms or sulfur atoms, and / or one or more — (CO) — or — (SO ₂ ) — groups in the ring. Or it may comprise one or more double bonds; where the ring formed by R ³ and R ⁴ is optionally —CN, —Hal, —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, by C ₁ -C ₆ haloalkoxy, -NR ⁶ R ⁷ , —CONR ⁶ R ⁷ ,-(CO) -R ⁶ or -COOR ⁷ and / or mono- or poly-Hal-, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy- or-(CO) -R ^6- May be mono- or polysubstituted by aryl or heteroaryl, which may be substituted; where the substituents in the case of polysubstitution may be the same or different;

R ⁶ and R ⁷ are the same or different, and j) —H, and jj) C ₁ -C ₆ alkyl, C, which may be substituted with mono- or poly-Hal-, —OH—, —CN—, 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 heterocyclo alkyl, aryl or heteroaryl, selected from the group consisting of, wherein the C ₃ -C ₆ heterocycloalkyl 1 or more nitrogen in the ring, oxygen and / or sulfur atoms, and / or one or more A — (CO) — or —SO ₂ — group and / or one or more double bonds, and the substituents in the case of polysubstitution may be the same or different.
And its isomers, diastereomers, enantiomers and salts, and their use for preparing compounds of general formula I.
The compounds of the general formulas IIa and IIb are advantageous intermediates, which can be used in the synthesis of the compounds of the general formula I described above.

The explanations given above for the compounds of the formula I, including preferred embodiments of the groups, apply in theory as well to the compounds of the formulas IIa and IIb. Q may be substituted with mono- or poly-OH-, -Hal-, -CN-, alkyl-, -OR ⁶ -or -NR ³ R ⁴ , phenyl, pyridyl, thiophenyl, furyl, imidazolyl or pyrazolyl Is particularly preferred. More preferably, X is —Cl or —Br.

The following intermediates of the present invention are particularly preferred: 3-bromo-6-chloroimidazo [1,2-b] pyridazine, imidazo [1,2-b] pyridazin-6-yl- (3-pyrrolidin-1-yl Propyl) amine, 6-chloro-3-phenylimidazo [1,2-b] pyridazine, 6-chloro-3- (3-chlorophenyl) imidazo [1,2-b] pyridazine, 6-chloro-3- (1 -Methyl-1H-pyrazol-4-yl) imidazo [1,2-b] pyridazine, 6-chloro-3-thiophen-3-ylimidazo [1,2-b] pyridazine.
The intermediates 1.0 to 1.28 described in the examples are very particularly preferred.

Synthesis scheme

The invention therefore also relates to a process for the preparation of the compounds of the invention, which comprises the following process steps:
A1) converting 3-amino-6-halopyrazine to 6-haloimidazo [1,2-b] pyridazine II;
A2) converting the product from step A1 to 3-halo-6-haloimidazo [1,2-b] pyridazine III;
A3) The product from step A2 is converted to a compound of general formula IIa by reaction with compound NHR ¹ R ² ,
A4) converting the product from step A3 to a compound of general formula I;

B1) converting 3-amino-6-halopyrazine to 6-haloimidazo [1,2-b] pyridazine II;
B2) converting the product from step B1 to 3-halo-6-haloimidazo [1,2-b] pyridazine III;
B3) converting the product from B2 to a compound of general formula IIb
B4) converting the product from B3 to a compound of general formula I; or

C1) converting 3-amino-6-halopyrazine to 6-haloimidazo [1,2-b] pyridazine II;
C2) converting the product from step C1 to imidazo [1,2-b] pyridazin-6-yl)-(R ¹ )-(R ² ) -amine IV by reaction with compound NHR ¹ R ² ;
C3) converting the product from step C2 to a compound of general formula IIa;
C4) The product from step C3 is converted to a compound of general formula I.

Said reaction is preferably carried out as follows:
A1) reacting 3-amino-6-halopyrazine with chloroacetaldehyde to give 6-haloimidazo [1,2-b] pyridazine;
A2) The product from step A1 is reacted with N-bromosuccinimide to convert to 3-bromo-6-halomidazo [1,2-b] pyridazine;
A3) (3-Bromoimidazo [1,2-b] pyridazi-6-yl)-(R ¹ ) by reacting the product from step A2 with compound NHR ¹ R ² in a Buchwald-Hartwig cross-coupling reaction. )-(R ² ) -amine,
A4) reacting the product from step A3 with a boronic acid which may be substituted, for example by groups A and B, to give compounds of general formula I;

B1) reacting 3-amino-6-halopyrazine with chloroacetaldehyde to give 6-haloimidazo [1,2-b] pyridazine;
B2) reacting the product from step B1 with N-bromosuccinimide to give 3-bromo-6-haloimidazo [1,2-b] pyridazine;
B3) reacting the product from step B2 with a boronic acid which may be substituted, for example by groups A and B, to give compounds of general formula II
B4) The product from step B3 is reacted with compound NHR ¹ R ² in a Buchwald-Hartwig cross-coupling reaction to convert it to a compound of general formula I; or

C1) reacting 3-amino-6-halopyrazine with chloroacetaldehyde to give 6-haloimidazo [1,2-b] pyridazine;
C2) (Imidazo [1,2-b] pyridazi-6-yl)-(R ¹ )-(R) by reacting the product from step C1 with compound NHR ¹ R ² in a Buchwald-Hartwig cross-coupling reaction. ² )-converted to amine,
C3) reacting the product from step C2 with N-bromosuccinimide to give (3-bromoimidazo [1,2-b] pyridazin-6-yl)-(R ¹ )-(R ² ) -amine;
C4) reacting the product from step C3 with a boronic acid which may be substituted, for example by the groups A and B,
The compounds of general formula I are given.

The compounds of the invention are particularly preferably prepared by synthetic routes A1 to A4.
In order to protect sensitive side groups, the use of protecting groups in the synthetic pathway can also be provided. Techniques for such protecting groups are well known to those skilled in the art, for example from TW Greene, PGM, Wuts “Protective Groups in Organic Synthesis”, 2nd edition, John Wiley & Sons, 1991.

  Stages A1, B1 and C1 are, for example, by heating with chloroacetaldehyde at 60-130 ° C., in particular at 100-130 ° C., for 1 hour to 10 days, in particular for 3-6 days, in n-butanol as solvent. Can be implemented.

The amination (stages A3, B4 and C2 respectively) is carried out, for example, by heating with a suitable amine at 90 to 180 ° C., in particular 90 ° C., for 1 to 24 hours, in particular 1 to 16 hours. be able to. Heating can be performed by conventional heating means or by microwave irradiation from a suitable apparatus. 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 necessary. For example, the so-called Buchwald-Hartwig cross-coupling reaction can be used for amination. The Buchwald-Hartwig cross-coupling reaction is described, for example, in the following 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 reaction to give the 3-bromo intermediate (stages A2, B2 and C3) introduced the precursor compound into chloroform and added N-bromosuccinimide at -5 ° C to 30 ° C, especially 0 ° C to 10 ° C. Thereafter, the reaction can be performed by reacting at 0 to 30 ° C., particularly 15 to 25 ° C. for 1 to 2 days, particularly 5 to 15 hours. However, other synthetic routes for preparing the 3-halo intermediates of the present invention are known to those skilled in the art.

  Stages A4, B3 and C4 introduce the precursor compound into dimethoxyethane, and a palladium (0) source, such as bis (dibenzylideneacetone) palladium (0), a ligand, such as tri-o-tolylphosphine, and a base Can be carried out, for example, by adding boronic acid in the presence of sodium hydrogen carbonate and heating at reflux for 5-40 hours, in particular 10-20 hours.

If the preparation of the starting compounds is not described, they are known or can be prepared analogously to known compounds or methods described herein.
Isomeric mixtures are fractionated into isomers, for example enantiomers, diastereomers or E / Z isomers, unless the isomers are in equilibrium with each other, eg by crystallization, chromatography or salt formation. can do.

The salts are prepared by adding an equal or excess amount of base or acid to the solution of the compound of formula I, where appropriate in solution, and removing the precipitate or processing the solution in the conventional manner.
See the Examples for typical details of synthesis.

The invention further relates to intermediates of the invention as described in the claims.
The compounds according to the invention are suitable as kinase inhibitors, in particular of tyrosine and serine / threonine kinases. The compounds of the invention of the general formula I are in particular inhibitors of the protein kinase C family, for example PKC theta (θ), delta (δ), iota (ι) and zeta (ζ).

Inhibitors of kinases can therefore be used on the one hand to investigate the mechanism of the function of the kinase, in particular for the study of diseases resulting from kinase dysfunction.
However, it is also possible to treat or prevent diseases resulting from kinase dysfunction using kinase inhibitors.

  The present invention thus specifically inhibits cellular kinases, preferably the kinases of the protein kinase (PK) family, in this context, in particular to inhibit the PKC subfamily, more particularly PKCθ kinases, and cells It relates to the use of the compounds of the invention of the general formula I for the preparation of a pharmaceutical composition for the treatment or prevention of diseases associated with overexpression or mutation of sex kinases, in particular cellular kinases as described above.

  Surprisingly, it has further been found that the compounds of the invention are also inhibitors of the ALK family of kinases. ALK means “activin receptor-like kinase” or “activin-like kinase”. In this context, the compounds of the invention act on ALK1, ALK2, ALK4 and ALK5, in particular ALK1 and ALK5. The compounds according to the invention are therefore also suitable for the treatment or prevention of diseases associated with overexpression or mutation of the ALK family, in particular ALK1 and ALK5 kinases.

  In one aspect of the invention, the disease is skin hyperproliferation such as psoriasis, Alzheimer's disease, autoinflammatory disease, fibrosis, wound healing disorder, diabetic retinopathy, nephropathy, age-related macular degeneration, clones It is a disease selected from the group consisting of disease, hyperimmune response, contact dermatitis, atopic dermatitis, multiple sclerosis, ALS, diabetes and asthma.

  In another aspect of the invention, the disease is benign tumor, malignant tumor, leukemia, eg myeloid leukemia, lymphoma, sarcoma, eg osteosarcoma or chondrosarcoma, neuroblastoma, Wilms tumor, bladder, breast, lung, pancreas A disease selected from the group consisting of prostate, renal malignant neoplasms, epithelial neoplasms such as breast cancer or metastases thereof.

In yet another aspect of the invention, the compounds of the invention are used to modulate the immune response, in particular to reduce the immune response, for example to prevent organ rejection after transplantation.
The pharmaceutical compositions of the invention can be prepared by mixing a physiologically effective amount of a compound of the invention with at least one pharmaceutical excipient and producing the desired dosage form.

  A suitable physiologically effective amount is, for example, an amount of 1-1000 mg per day, in particular 50-500 mg for a person weighing 75 kg, which can be administered at once as a single dose, or per day The dose can be divided into two or more doses.

The pharmaceutical composition of the present invention can be prepared by a method commonly used in the art. Examples of suitable counterions for ionic compounds are Na ⁺ , K ⁺ , Li ⁺ or cyclohexylammonium, or Cl ⁻ , Br ⁻ , acetic acid, trifluoroacetic acid, propionic acid, lactic acid, oxalic acid, malonic acid, malic acid. Citric acid, benzoic acid, salicylate ion, and the like. Examples of suitable solid or liquid pharmaceutical formulations are granules, powders, coated tablets, tablets, (micro) capsules, suppositories, syrups, solutions, ointments, suspensions, emulsions, drops or injectable solutions ( iv, ip, im, sc) or sprays (aerosols), transdermal systems; and conventional auxiliaries such as carriers, disintegrants, binders, coatings, wetting agents, lubricants or brighteners, preservatives, stable Agents, wetting or emulsifying agents; preparations with sustained release of the active ingredient, produced by using salts or buffers to alter osmotic pressure, flavoring agents, sweeteners and solubilizers.

  Carrier systems that can also be used are surfactant excipients such as salts of bile acids, or salts of animal or vegetable phospholipids, and mixtures thereof, as well as liposomes or components thereof. Excipients include magnesium carbonate, magnesium stearate, gum arabic, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and derivatives thereof; animal and vegetable oils such as fish liver oil , Sunflower oil, peanut oil or sesame oil, polyethylene glycol; solvents such as sterile water, mono- or polyhydric alcohols such as glycerol. Preferred dosage forms are for topical administration (ointments, transdermal systems, patches, bandages, oral administration (tablets, coated tablets, solutions, powders) or parenteral administration (suspensions, injections).

  The pharmaceutical composition of the present invention comprises at least one inhibitor used in accordance with the present invention at a particular dose mixed with a pharmaceutically suitable and physiologically acceptable carrier and, if appropriate, additional suitable By mixing with various active ingredients, additives or excipients and producing the desired dosage form. Those pharmaceutical products are likewise an aspect of the present invention.

Finally, the present invention provides a method for the treatment or prevention of diseases associated with overexpression of cellulose kinase, comprising a physiologically effective amount of a compound according to any one of claims 1-8. It also relates to a method of administration to a person suffering from or at risk of having a disease.
The invention will now be described in more detail by way of examples which are meant to be exemplary only.

Preparation of starting materials
6-Chloroimidazo [1,2-b] pyridazine (Example 1.0 OP 3055)

5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine was heated at 120 ° C. for 5 days with 4.7 ml (4.0 mmol) of chloroacetaldehyde (55% strength in water) in 15 ml of n-butanol. After the reaction is complete, the reaction mixture is added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and the solvent is distilled off in vacuo. In final purification by chromatography on silica gel, 4.17 g (70%) of the desired product was isolated in the form of an amorphous white solid.
¹ H-NMR (CDCl ₃ , stored on molecular sieve): δ = 7.06 (d, 1H); 7.79 (d, 1H); 7.92 (d, 1H); 7.96 (d, 1H) ppm.

3-Bromo-6-chloroimidazo [1,2-b] pyridazine (Example 1.1 OP 3056)

478 mg (3.11 mmol) of 6-chloroimidazo [1,2-b] pyridazine was introduced into 10 ml of chloroform under argon and 664 mg (3.73 mmol) of N-bromosuccinimide was added while cooling in ice. Added. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction mixture was then mixed with water and ethyl acetate, and the phases were separated after addition of saturated sodium bicarbonate solution. The aqueous phase was extracted 3 times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After final evaporation of the solvent in vacuo, the desired product was isolated in quantitative yield in the form of an amorphous white solid. It was used in the next reaction without further chromatographic purification.
¹ H-NMR (CDCl ₃ , stored on molecular sieve): δ = 7.12 (d, 1H); 7.79 (s, 1H); 7.90 (d, 1H) ppm.

6-Chloro-3-iodoimidazo [1,2-b] pyridazine (Example 1.2)

14 g of 6-chloroimidazo [1,2-b] pyridazine (Example 1.0) was suspended in 364 ml of acetonitrile and 20.51 g of N-iodosuccinimide was added. The mixture was stirred at RT for 19 hours. An additional 4.31 g of N-iodosuccinimide was added and the mixture 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 was 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 intermediates of the invention :
Imidazo [1,2-b] pyridazin-6-yl (3-pyrrolidin-1-ylpropyl) amine (Example 1.3)

  100 mg (0.65 mmol) of 6-chloroimidazo [1,2-b] pyridazine was introduced into 9 ml of tetrahydrofuran and 3 ml of dimethylformamide under argon. 83 mg (0.65 mmol, 1.0 equiv) 1- (3-aminopropyl) pyrrolidine, 60 mg (0.65 mmol, 0.1 equiv) (dibenzylideneacetone) palladium (0), 41 mg (0.065 mmol, 0.1 equiv) rac. , 2'-bis (diphenylphosphino) -1,1'-binaphthyl and 125 mg (1.3 mmol, 2.0 eq) sodium tert-butoxide were added in succession and then the mixture was heated at 80 ° C. for 4 hours.

  The reaction mixture was then mixed with water and ethyl acetate, and the phases were separated after addition of saturated sodium bicarbonate solution. The aqueous phase was extracted 3 times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. In final purification by chromatography on silica gel, 53 mg (39%) of the desired product was isolated in the form of an amorphous white solid.

¹ H-NMR (CDCl ₃ , stored on molecular sieve): δ = 1.77−1.89 (m, 6H); 2.54 (m, 4H); 2.66 (m, 2H); 3.43 (m, 2H); 6.18 (s, 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; 33 × 4.6 × 1.5μ ODSII, gradient: 100% H ₂ O → 90% ACN over 4.5 minutes): t = 0.41 min; m / z = 246 [M + H] ⁺ 38%; 123 [M + H] ⁺⁺ 100%.

6-Chloro-3-phenylimidazo [1,2-b] pyridazine (Example 1.4)

  500 mg (2.15 mmol) of 3-bromo-6-chloroimidazo [1,2-b] pyridazine was introduced into 25 ml of dimethoxyethane under argon. 290 mg (2.4 mmol, 1.1 eq) phenylboronic acid, 250 mg (0.43 mmol, 0.2 eq) bis (dibenzylideneacetone) palladium (0) and 130 mg (0.43 mmol, 0.2 eq) tri-o-tolylphosphine, 2.2 ml of saturated sodium bicarbonate solution was added sequentially and the reaction mixture was heated at reflux for 15 hours.

The reaction mixture was then mixed with ethyl acetate and a saturated sodium bicarbonate solution was added before the phases were separated. The aqueous phase was extracted 3 times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. In final purification by chromatography on silica gel, 239 mg (48%) of the desired product was isolated.
¹ H-NMR (CDCl ₃ , stored on molecular sieve): δ = 7.02 (d, 1H); 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-Bromoimidazo [1,2-b] pyridazin-6-ylamino) ethanol (Example 1.5)

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

¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 3.28−3.34 (m, 2H, shielded by solvent); 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 (EI +): m / z = 256; 258 (M + H) ⁺ . [Molecular weight = 257.09].

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

562 mg (2.0 mg) of 6-chloro-3-iodoimidazo [1,2-b] pyridazine and 2.35 ml (39.2 mmol) of ethanolamine were stirred at 90 ° C. for 16 hours. After cooling, the mixture was concentrated. The resulting residue was purified by chromatography (DCM / EtOH 9: 1). 224 mg of product was obtained.
¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 3.27-3.35 (m, 2H, shielded by solvent); 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 (ES +): m / z = 305 (M + H) ⁺ [molecular weight = 304.09].

In the same manner, the following compound was prepared.
Table 1:

6-Chloro-3-naphthalen-2-ylimidazo [1,2-b] pyridazine (Example 1.28)

3.5 g (12.52 mmol) 6-chloro-3-iodoimidazo [1,2-b] pyridazine (Example 1.2) and 2.37 g (13.78 mmol) 2-naphthylboronic acid (CAS No. 32316-92-0) ) To prepare 1.03 g of 6-chloro-3-naphthalen-2-ylimidazo [1,2-b] pyridazine in the same manner as in 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 final product of the invention :
Method A : (3-Phenylimidazo [1,2-b] pyridazin-6-yl)-(3-pyrrolidin-1-ylpropyl) amine (Example 2.0)

100 mg (0.435 mmol) of 6-chloro-3-phenylimidazo [1,2-b] pyridazine was dissolved in a mixture of 6 ml tetrahydrofuran and 2 ml dimethylformamide under argon. 56 mg (0.435 mmol, 1.0 eq) 1- (3-aminopropyl) pyrrolidine, 40 mg (0.07 mmol, 0.16 eq) bis (dibenzylideneacetone) palladium (0) (Pd ₂ dba ₃ ), 27 mg (0.0435 mmol, 0.1 eq) rac.2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (rac-BINAP) and 84 mg (0.87 mmol, 2 eq) sodium tert-butoxide (NaOtBu) And the reaction mixture was heated at 80 ° C. for 4 h.

  The reaction mixture was then mixed with ethyl acetate and the phases were separated after adding water. The aqueous phase was extracted 3 times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After multiple purification on silica gel in the final chromatographic fraction, 9 mg (6%) of the desired product was isolated in pure form.

¹ H-NMR (CDCl ₃ ; stored on molecular sieve): 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] ^< +>.
In the same manner, the following compound was prepared.
Table 2 :

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

35 mg (0.15 mmol) of 6-chloro-3- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-b] pyridazine in a mixture of 0.67 ml tetrahydrofuran and 0.33 ml dimethylformamide under argon Introduced in. Then 0.5 ml of a 0.45 M solution of pyridin-3-ylmethylamine (0.225 mmol) in toluene was added. A solution 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 a solution of 31.7 mg NaOtBu (0.3 mmol) in 0.91 ml THF. After the addition, the reaction mixture was shaken at 80 ° C. for 12 hours.

The reaction mixture was then mixed with 1 ml water and 3 ml ethyl acetate. The organic phase was separated and the solvent was distilled off. The crude product thus obtained was purified by HPLC. 8.7 mg (19%) of the desired product was isolated.
HPLC-MS (analytical value) of the purified product
Detection: UV = 254 nm; Column: Purosher STAR RP18e, 125 × 4 mm, 5 μm (Merck KGaA, Darmstadt); Eluent: A: H ₂ O / 0.1% TFA, B: CH ₃ CN / 0.1% TFA, Gradient: 10 5% → 95% B over minutes; flow rate: 1 ml / min.
Product retention time = 3.85 min; product MS: m / z = 301 ([M + H]).

In the same manner, the following compound was prepared.
Table 3 :

Description of HPLC-MS analysis for the examples listed in Table 3:
HPLC-MS Method A: Detection: UV = 254 nm; Column: Purosher STAR RP18e, 125 × 4 mm, 5 μm (Merck KGaA, Darmstadt); Eluent: A: H ₂ O / 0.1% TFA, B: CH ₃ CN / 0.1 % TFA, gradient: 5% → 95% B over 10 minutes; flow rate: 1 ml / min.
HPLC-MS Method B: Detection: UV = 254 nm; Column: XBridge C18, RP18e, 150 × 4.8 mm, 5 μm (Waters); 5% → 95% acetonitrile (0.1% NH ₄ OH) / water (gradient over 10 minutes) 0.1% NH ₄ OH / NH ₄ HCO ₃ ); 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) 2- (3-bromoimidazo [1,2-b] pyridazin-6-ylamino) ethanol (Example 1.5), 69 mg (0.5 mmol) 4-hydroxybenzeneboronic acid and 76 mg (0.066 mmol) ) Tetrakis (triphenylphosphine) palladium (0) was mixed with 3.4 ml dimethyl glycol and 2 ml aqueous NaOH solution (190 mg NaOH stock solution in 10 ml water) under argon. The mixture was stirred at 90 ° C. for 19 hours. After cooling, the mixture was diluted with saturated NaCl solution and extracted twice with ethyl acetate. The combined organic phases were washed with saturated NaCl solution, filtered through a silicon filter (Whatman) and concentrated. The resulting crude product was recrystallized from methanol. 40 mg of the desired product was obtained.

¹ H-NMR (400 MHz, d ₆ -DMSO): δ = 3.30-3.31 (m, 2H, shielded by solvent); 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); 7.93 (d, 2H); 9.57 (br s, 1H) ppm.
MS (ES +): m / z = 271 ([M + H] ^< +>). [Molecular weight = 270.29].

In the same manner, the following compound was prepared.
Table 4 :

The following compounds were prepared similarly.
Table 5 :

Description of HPLC-MS analytical conditions for the examples listed in Table 5 Detection: UV = 200-350 nm (Waters Acquity HPLC) / MS 100-800 Dalton; 20 V (Micromass / Waters ZQ 4000); Column: XBridge (Waters), 2.1 × 50 mm, BEH 1.7 μm; eluent: A: H ₂ O / 0.05% HCOOH, B: CH ₃ CN / 0.05% HCOOH.
Gradient: 10% → 90% B over 1.7 minutes, 90% B over 0.2 minutes, 98% → 2% B over 0.6 minutes; flow rate: 1.3 ml / min.

[3- (2-Methoxypyridin-4-yl) imidazo [1,2-b] pyridazin-6-yl] piperidin-4-ylamine (Example 6.0)

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

  300 mg (1.15 mmol) 6-chloro-3- (2-methoxypyridin-4-yl) imidazo [1,2-b] pyridazine (Example 1.14) and 230 mg (1.15 mmol) 4-aminopiperidine-1- From Method A, 292 mg of 4- [3- (2-methoxypyridin-4-yl) imidazo [1,2-b] pyridazin-6-ylamino from carboxylic acid tert-butyl ester (CAS No. 87120-72-7) Piperidine-1-carboxylic acid tert-butyl ester was prepared.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.32-1.38 (m, 11H); 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) ⁺ [molecular weight = 424.51].

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

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

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) ⁺ [molecular weight = 324.39].
The following compounds were prepared similarly.

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

82 mg (0.21 mmol) of N-tert-butyl-3- [6- (2-hydroxyethylamino) imidazo [1,2-b] pyridazin-3-yl] benzenesulfonamide was dissolved in 1.7 ml of tris under argon. Mix with fluoroacetic acid and stir at 50 ° C. for 5 hours. After cooling, the mixture 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 Whatman filter paper and concentrated. The resulting residue was purified by chromatography (DCM / EtOH 6: 4). 47 mg of product was 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 ( 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 compounds were prepared similarly.

  The following example compounds were prepared in a similar manner to Example 1.5 from 4- (6-chloroimidazo [1,2-b] pyridazin-3-yl) phenol and the appropriate amine.

Biological Effects The following examples illustrate the biological effects of the compounds of the present invention.
One skilled in the art knows that there are a number of diseases whose cause is derived from dysfunction of one or more kinases. Kinase dysfunction is induced by a number of mechanisms, for example, kinases may be overexpressed, resulting in incomplete cellular activity, or mutated kinases may be overexpressed, resulting in incomplete cellular activity. May cause. Incomplete cell activity can be, for example, incomplete cell proliferation, in particular increased cell proliferation (cell overgrowth). The result of such dysfunction can be a disease characterized by, for example, kinase overexpression or mutation.

Suitable assays for testing the efficacy of the compounds of the present invention for their ability to modulate kinase activity are known. Assays for examining the efficacy of the compounds of the present invention that regulate cell proliferation are also known.
Accordingly, the following biological examples are merely illustrative of the use of the claimed compounds according to the invention by way of example and are not to be construed as limiting in any way.

Importance of IL-2 in T cell immune response The extent to which the test substance affects antibody-induced interleukin 2 (IL-2) secretion was examined in the following test method. IL-2 is a central cytokine produced and released by activated T cells. IL-2 synthesis in T cells is regulated by multiple kinases. The inhibitory effect of substances on kinases causes, in particular, inhibition of IL-2 synthesis and inhibition of T cell immune responses. Cytokine measurements were performed using an ELISA kit.

Test Method Description Peripheral blood mononuclear cells (PBMC) are isolated from heparinized human whole blood by gradient centrifugation using Histopaque 1077 (Sigma) at room temperature, erythrocytes are lysed under high osmotic pressure and 2 in PBS After washing twice, it was removed into cell culture medium (RPMI-1640 + 10% inactivated fetal bovine serum in Glutamax-I [Gibco]).

A 96-well culture plate (Costar) was preincubated with 100 μl of a 0.1 μg / ml antibody solution [Gibco] in PBS for 18 hours at 4 ° C. per well. The antibodies used were anti-CD3 and anti-CD28 monoclonal antibodies (PharMingen). After washing 3 times with PBS, the plate was loaded with 200 μl of cell suspension (40000 cells / well). In addition, the test substance was added to a concentration of 1 × 10 ⁻⁶ to 1 × 10 ⁻¹² M.

The culture was incubated at 37 ° C. for 20 hours in an incubator. Following this incubation, the phases were briefly shaken, centrifuged, and 250 μl of the supernatant was taken and then the supernatant was frozen at −20 ° C.
Interleukin-2 was measured using an ELISA kit (Bioscience) and the color change absorption was analyzed on a SpectraMax 340 PC (wavelength 450 nm). The active substance caused a decrease in absorption.

Table: Assay data

ALK1 Kinase Flash Plate Assay An ALK1 kinase flash plate assay was established and used to examine the activity of compounds.

ALK1 phosphorylates the serine / threonine residues of the biotinylated substrate bovine α-casein in the presence of [γ- ³³ P] ATP. The radioactive product is detected through binding to a flashplate coated with streptavidin. The biotin residue of biotinylated casein binds to streptavidin with high affinity. Radiobiotinylated casein resulting from the ALK1 kinase reaction generates a chemiluminescent signal after streptavidin-mediated binding to the scintillator-containing surface of the flashplate. This signal comes from the proximity of the radiolabel to the scintillator at the well surface of the flashplate. Substrates that are not phosphorylated do not generate any signal because they do not contain radioactive phosphate groups. Free [γ- ³³ P] ATP remaining unbound in solution (supernatant) is washed away from the wells of the flashplate and therefore does not contribute significantly to the background signal. Therefore, the measured signal is a measure of ALK1 kinase activity. Measurements are made on a Perkin-Elmer topcount device or Perkin-Elmer ViewLux device.

Material :
Enzyme: Purified human recombinant ALK1 kinase (GST fused to the intracellular region [His142-Gln503] of ALK1); prepared in-house; aliquot stored at -80 ° C; diluted enzyme treatment solution: 2.5 ng / μl ALK1 (assay Freshly in buffer) and keep on ice until use.
Substrate: biotinylated bovine α-casein. Non-biotinylated casein from Sigma is biotinylated by standard methods using biotin-N-hydroxysuccinimide (NHS) ester. Substrate treatment solution: 0.83 μM ATP, 1.67 μM biotinylated α-casein, 7.4 nCi [γ- ³³ P] ATP / μl in assay buffer.

Assay plate: 384 well plate, small volume, white, Greiner (# 784075).
Flash plate: Streptavidin-coated flash plate, Perkin Elmer (384 well, # SPM410A).
Assay buffer: 50 mM Tris-HCl pH 8.0, 1 mM MnCl ₂ , 1 mM DTT, 0.01% NP40, 0.5 × complete EDTA free.
Stop solution: 33.3 μM ATP, 33.3 mM EDTA, 0.07% Triton X-100 in PBS.
Saturated solution for flash plates: 100 μM ATP, 0.2% Triton X-100 in PBS.
Adhesive film for plates: Greiner (# 676080).

Assay Description Protocol for 5 μl assay (all steps performed at 20 ° C .; use CyBi-Well pipettor and multidrop microdispenser for injection):
1. 50nl or 250nl material in 100% DMSO.
2. Add 3 μl of substrate treatment solution using a CyBi-Well pipettor.
3. Add 2 μl of enzyme treatment solution using a multidrop micro dispenser. Incubate at room temperature (20 ° C) for 60 minutes.

4). Add 15 μl of stop solution using CyBi-Well pipettor.
5. Transfer 18 μl of assay mixture to flashplate ^** using a CyBi-Well pipettor. Incubate at room temperature for at least 3 hours or overnight at 4 ° C. to allow binding to streptavidin-coated flash plates.
6). Wash the flush plate with 50 μl PBS without Ca ⁺⁺ and Mg ⁺⁺ each time.

7). Seal the plate with adhesive film.
8). Measured at top count (60 seconds / well).
^** Saturation of the flash plate: Pre-incubate the flash plate with 50 μl of saturated solution for at least 1 hour. After discarding 18 μl of this solution, 18 μl of the assay mixture is transferred to a flash plate.

Final concentration calculated for a reaction volume of 5 μl: 5 ng ALK1 / well; 1 μM biotinylated α-casein; 0.5 μM ATP; 22 nCi / well [γ- ³³ P] ATP; 1 mM MnCl ₂ ; 1 mM DTT; 50 mM Tris- HCl, pH 8.0; 0.01% NP-40; 0.5 × complete EDTA free; 1% or 5% DMSO.
Standardize data (enzyme reaction without inhibitor = 0% inhibition; enzyme reaction in the presence of 10 mM EDTA = 100% inhibition) and IC50 values are calculated using a 4-parameter approximation method using in-house software .

ALK4 Kinase Flash Plate Assay An ALK4 kinase flash plate assay was established and used to examine the activity of compounds.

ALK4 phosphorylates the serine / threonine residues of the biotinylated substrate bovine α-casein in the presence of [γ- ³³ P] ATP. The radioactive product is detected through binding to a flashplate coated with streptavidin. The biotin residue of biotinylated casein binds to streptavidin with high affinity. Radiobiotinylated casein resulting from the ALK4 kinase reaction generates a chemiluminescent signal after streptavidin-mediated binding to the scintillator-containing surface of the flashplate.

This signal comes from the proximity of the radiolabel to the scintillator at the surface of the well of the flashplate. Substrates that are not phosphorylated do not generate any signal because they do not contain radioactive phosphate groups. Free [γ- ³³ P] ATP remaining unbound in solution (supernatant) is washed away from the wells of the flashplate and therefore does not contribute significantly to the background signal. Therefore, the measured signal is a measure of ALK1 kinase activity. Measurements are made on a Perkin-Elmer topcount device or Perkin-Elmer ViewLux device.

Material :
enzyme:
Commercial recombinant human ALK4 kinase (amino acids 150-505) fused to GST at the N-terminus expressed by recombinant baculovirus in Sf21 insect cells (Upstate Biotechnology, Dundee, Scotland; Cat # 14-614MG), Lot # 28232U; Store aliquots at −80 ° C .; Dilute enzyme treatment solution: 2.5 ng / μl ALK1 (in assay buffer) is freshly prepared and stored on ice until use.

Substrate:
Biotinylated bovine α-casein. Non-biotinylated casein from Sigma is biotinylated by standard methods using biotin-N-hydroxysuccinimide (NHS) ester. Substrate treatment solution: 0.83 μM ATP, 1.67 μM biotinylated α-casein, 7.4 nCi [γ- ³³ P] ATP / μl in assay buffer.

Assay plate:
384 well plate, small volume, white, Greiner (# 784075).
Flash plate:
Streptavidin-coated flashplate, Perkin Elmer (384 well, # SPM410A).
Assay buffer:
50 mM Tris-HCl pH 8.0, 1 mM MnCl ₂ , 1 mM DTT, 0.01% NP40, 0.5 × complete EDTA free.
Stop solution:
33.3 μM ATP, 33.3 mM EDTA, 0.07% Triton X-100 in PBS.
Saturated solution for flash plates: 100 μM ATP, 0.2% Triton X-100 in PBS.
Adhesive film for plates: Greiner (# 676080).

Assay Description Protocol for 5 μl assay (all steps performed at 20 ° C .; use CyBi-Well pipettor and multidrop microdispenser for injection):
1. 50nl or 250nl material in 100% DMSO.
2. Add 3 μl of substrate treatment solution using a CyBi-Well pipettor.
3. Add 2 μl of enzyme treatment solution using a multidrop micro dispenser. Incubate for 45 minutes at room temperature (20 ° C).

4). Add 15 μl of stop solution using CyBi-Well pipettor.
5. Transfer 18 μl of assay mixture to flashplate ^** using a CyBi-Well pipettor. Incubate at room temperature for at least 3 hours or overnight at 4 ° C. to allow binding to streptavidin-coated flash plates.
6). Wash the flush plate with 50 μl PBS each time without Ca ⁺⁺ and Mg ⁺⁺ .

7). Seal the plate with adhesive film.
8). Measured at top count (60 seconds / well).
^** Saturation of the flash plate: Pre-incubate the flash plate with 50 μl of saturated solution for at least 1 hour. After discarding 18 μl of this solution, 18 μl of the assay mixture is transferred to a flash plate.

Final concentration calculated for 5 μl 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 ; 1 mM DTT; HCl, pH 8.0; 0.01% NP-40; 0.5 × complete EDTA free; 1% or 5% DMSO.
Standardize the data (enzyme reaction without inhibitor = 0% inhibition; enzyme reaction in the presence of 10 mM EDTA = 100% inhibition) and IC ₅₀ values using a 4-parameter approximation method using in-house software Calculation.

ALK1 transactivation assay In this case, HepG2 cell cultures are transiently transfected by known techniques using the ALK1 plasmid (an expression vector for the human ALK1 receptor). At the same time, an ID1 reporter plasmid containing a 1.3 kB (-1370 to +86) ID1 promoter upstream of the luciferase gene is cotransfected. ID1 is a known target gene of ALK1 and is therefore transactivated by cotransfection with the ALK1 receptor. Its specific transactivation is quantified by RLU (relative light units) detected depending on luciferase. A commercially available luciferase detection kit comprising the substrate luciferin is used for this.

Material :
HepG2 cells (hepatocellular carcinoma), ATCC HB-8065
96-well culture plate 96 white (Packard # 6005680)
Polypropylene 96-well plate, PBS- for compound dilution in DMSO; PBS ++, DMSO
DMEM-Ham F12 medium (Biochem # F4815) containing 10% dialyzed FCS, 1% PenStrep and 200 mM glutamine
OPTI MEM (Gibco # 51985-026)
Fugene (Roche # 1814443 1mL)
steadyliteHTS (Perkin Elmer # 6016981)

Experimental procedure :
Day 1: Seeding of cells on 96-well plate
HepG2 cells are seeded on 96-well plates at a density of 7000 cells / well in DMEM / HamsF12 + 5% FCS (+ 1% P / S, + 1% Gln).

Day 2: Transfection of cells Per well:
200 ng DNA: 100 ng ID1-luc (pGL3basic, Promega) +5 ng ALK1 wt (pcDNA3.1) +95 ng pcDNA3.1 (empty vector, Invitrogen)
0.4 μl fugene
6 μl OptiMEM

Incubate Fugene and OptiMEM for 5 minutes at RT. This mixture is incubated with DNA for 15 minutes at RT.
The plate is then incubated for 1 hour at RT under shaking conditions. After 4 hours at 37 ° C., the supernatant is aspirated off and medium (100 μl / well) containing a small amount of serum (0.2% FCS) and test substance is added to the wells. Incubate the plate at 37 ° C. for an additional 18 hours.

Day 3: RLU measurement
100 μl of luciferase substrate (Steadylite HTS, Packard) is added per well and after 10 minutes the plate is measured in a luminometer (eg Viktor luminometer, Perkin Elmer). Luciferase activity is quantified by relative light units (RLU).

IC ₅₀ calculation:
ALK1wt-DMSO control (without ALK1) = 100%
Substance (+ ALK1 wt) -DMSO control (without ALK1) = x%
IC ₅₀ = 50% inhibition of ALK1 transactivation

DU-145 proliferation assay First, DU-145 cells were seeded in 96-well microtiter plates (CulturPlate-96, clear flat bottom) at a concentration of 200 cells per well (medium volume: 100 μl; negative in starvation medium) Control), and grown for 18 hours under culture conditions. Then 100 μl of medium was removed and 100 μl of substance solution (diluted solution in medium) was added. Cells were incubated for 72 hours under culture conditions. At the end of material treatment, add 5 μl Alamar Blue labeling solution (Biosource cat # DAL 1100, Lot # 143152SA; dissolved in medium) (to make 1:20 dilution) and culture cells It was further grown for 3 hours under the conditions. The growth rate was then analyzed by measurement at 528 nm and 590 nm in FLx800 (fluorescence measuring device from BIO-TEK) in each case.

Cell lines and cell cultures A human cell culture system was used: DU-145 (prostate cell line ATCC No. HTB-81). All cell lines were grown at 37 ° C., 5% CO ₂ and 95% humidity in 175 cm ² culture bottles and split 1: 5 to 1:65 at 80% density according to their respective division rates. For this, the cells were first washed with 10 ml PBS and wetted with 2 ml trypsin (Gibco). Excess trypsin was removed and cells were incubated at room temperature for 10 minutes. Complete detachment of the treated cells was confirmed under a microscope. The cells were then removed into the medium and transferred to a new culture bottle at an appropriate volume ratio.

DU-145 medium :
DMEM HAM's F-12 (Biochrom AG, cat # F4815) + 1% P / S + 1% glutamine + 10% FCS (Biochrom AG, Lot'0218G)
DU-145 starvation medium :
DMEM HAM's F-12 (Biochrom AG, cat # F4815) + 1% P / S + 1% glutamine

Alternative proliferation assay. DNA replicating cells were labeled with bromodeoxyuricin (BrdU) and used as a measure of eukaryotic cell proliferation. In this method, cells in the synthesis phase (S phase) incorporate the thymidine analog BrdU into the growing DNA strand instead of thymidine. The DNA thus replicated can be detected with the aid of an anti-BrdU antibody labeled with a modified nucleotide BrdU and subsequently labeled with a fluorophore. This method was used to examine the effect of substances on cell proliferation.

  First, HeLa cells were seeded in 96-well microtiter plates at a concentration of 7500 cells / well (volume: 200 μl) and grown for 18 hours under culture conditions. Then 100 μl of medium was removed and 100 μl of substance solution (diluted solution in medium) was added. Cells were incubated for 6 hours, 18 hours or 48 hours under culture conditions. At the end of the substance treatment, BrdU labeling solution (dissolved in the medium) was added (final concentration of BrdU 10 μM) and the cells were grown under culture conditions for an additional 3 hours. BrdU containing supernatant was removed and cells were washed with PBS.

  The cells were then fixed with 4% strength formalin solution (PBS, dissolved in 0.1% Triton X-100) for 18 hours at 4 ° C., and the cells were washed 3 times with 200 μl PBS. Cellular DNA was digested with nuclease (GE / Amersham) to make the incorporated BrdU accessible to the antibody label. Subsequently, BrdU was detected using a monoclonal anti-BrdU antibody (GE / Amersham). For this, the fixed cells were incubated with antibody / nuclease solution (50 μl / well) for 45 minutes at 37 ° C. and then washed 3 times with 200 μl PBS. Fluorescence labeling was performed using a fluorophore-labeled second antibody that binds to the anti-BrdU antibody. Cellular chromatin was stained with Hoechst 33342.

  In each case, nine video sections per well were recorded in various fluorescent channels using automated microscopy (Discovery-1, Molecular Devices) and analyzed for BrdU incorporation and growth rate by high content analysis (HCA) method.

Cell lines and cell cultures Human cell culture systems were used: HeLa (derived from cervical cancer), PC3 (derived from prostate cancer) and MCF-7 (derived from breast cancer). In addition, CHO cells (derived from Chinese hamster ovary) were cultured.
All cell lines were grown in 175 cm ² culture bottles at 37 ° C., 5% CO ₂ and 95% humidity and split 1: 5 to 1:65 at 80% density according to their respective division rates. For this, the cells were first washed with 10 ml PBS and wetted with 2 ml trypsin (Gibco). Excess trypsin was removed and cells were incubated at room temperature for 10 minutes. Complete detachment of the treated cells was confirmed under a microscope. The cells were then removed into the medium and transferred to a new culture bottle at an appropriate volume ratio.

HeLa medium :
Dulbecco's medium (Gibco), 2 mM glutamine (Gibco), 100 U / ml penicillin (Gibco), 100 μg / ml streptomycin (Gibco) and 10% (v / v) fetal bovine serum (PAA).
PC3 medium :
RPMI 1640 medium (Gibco), 2 mM glutamine (Gibco), 100 U / ml penicillin, 100 μg / ml streptomycin (Gibco) and 10% fetal calf serum (PAA).

MCF-7 medium :
RPMI 1640 medium (Gibco), 2 mM glutamine (Gibco), 100 U / ml penicillin (Gibco), 100 μg / ml streptomycin (Gibco) and 10% fetal calf serum (PAA), 0.1 nM estradiol (Sigma) and 0.2 U / ml insulin (Sigma).
CHO medium :
Ham F12 medium (PAA), 2 mM glutamine (Gibco), 100 U / ml penicillin (Gibco), 100 μg / ml streptavidin (Gibco) and 3% fetal calf serum (PAA).

Additional Prior Art Additional prior art is formed by the following publications and the references cited in those publications.

Priority of this application:
This patent application claims the priority of German patent application DE 10 2005 042 742.1 (filing date: September 2, 2005), which is US patent application 60/713 333 (filing date: September 2, 2005). All the advantages of Japan, the preliminary application) are also claimed.
The independent claims of the priority application are as follows:

1. Compounds of formula I:

[Wherein Q is aryl or heteroaryl;
A and B are the same or different, and
i) H, Hal, -OH, -NR 3 R 4, -CN or -NO _2,
ii) optionally mono- - or poly _{-Hal -, - OH-, C 3} ~C 6 heterocycloalkyl -, - NR ³ R ⁴ - or - may be substituted by (CO) -NR ³ -L, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl, wherein said C ₃ -C ₆ heterocycloalkyl is in the ring Comprising 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. Yes, 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 —O— (CH ₂ ) _p -aryl,
Selected from the group consisting of
Where the substituents in the case of polysubstitution may be the same or different;

A and B may be combined to form a Q-fused C ₅ -C ₇ cycloalkyl or C ₅ -C ₇ heterocycloalkyl ring in addition to or in place of the above definitions, in the latter case Comprises at least one oxygen or one nitrogen atom in the ring, and optionally further one or more oxygen, nitrogen or sulfur atoms and / or one or more — (CO) — or in the ring - (SO ₂₎ - may comprise group, and / or one or more double bonds;
p is 0-4;

L mono desired - or poly -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 C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl, which may be substituted with-, wherein said C ₃ -C ₆ heterocycloalkyl is in the ring It may comprise 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. Often;

R ¹ and R ² are the same or different and j) -H, and
By jj) optionally mono- - or poly -Hal -, - 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 , 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, selected from the group consisting of aryl or heteroaryl, wherein said C ₃ -C ₆ heterocycloalkyl group , One or more nitrogen, oxygen and / or in the ring (CO) - - sulfur atom, and / or one or more of or -SO ₂ - group, and / or one or more may contain a double bond, and the substituent in the case of multiple substitution at the same May or may not be;

R ¹ and R ² may be combined to form a C ₃ -C ₆ heterocycloalkyl ring in addition to or instead of the above definition, wherein the C ₃ -C ₆ heterocycloalkyl ring is a ring At least one nitrogen atom in the ring and optionally further one or more nitrogen atoms, oxygen atoms or sulfur atoms, and / or one or more — (CO) — or — (SO ₂ ) in the ring. ) -Groups and / or may comprise one or more double bonds; wherein the ring formed by R ¹ and R ² is optionally -CN, -Hal, -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 by ^7, and / or mono - also Ku poly -Hal-, C ₁ ~C ₆ haloalkoxy - or - by (CO) aryl or heteroaryl which may be substituted by -R ^6, may be mono- or polysubstituted, wherein the multi The substituents in the case of substitution may be the same or different;

R ³ and R ⁴ are the same or different, and j) -H, and jj) optionally mono - or poly -Hal -, - 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 - which may be substituted by, 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,
Wherein the C ₃ -C ₆ heterocycloalkyl is one or more nitrogen, oxygen and / or sulfur atoms and / or one or more — (CO) — or —SO in the ring. ₂ -groups and / or may contain one or more double bonds, and the substituents in the case of polysubstitution may be the same or different;

In addition to the above definitions, the R ³ and R ⁴ groups can be taken together to form a C ₃ -C ₆ heterocycloalkyl ring, wherein the C ₃ -C ₆ heterocycloalkyl ring is at least one in the ring. Optionally comprising one or more nitrogen atoms, oxygen atoms or sulfur atoms, and / or one or more — (CO) — or — (SO ₂ ) — groups, and / or Or it may comprise one or more double bonds; where the ring formed by R ³ and R ⁴ is optionally —CN, —Hal, —OH, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ hydroxyalkyl, a C ₁ -C ₆ ^{alkoxyalkyl, -NR 6 R 7, -CONR 6} R 7, - by (CO) -R ⁶ or -COOR ^7, and / or mono- - or poly -Hal-, C ₁ C ₆ alkoxy - or - by (CO) aryl or heteroaryl which may be substituted by -R ^6, it may be mono- or polysubstituted; substituents in the case of polysubstituted here are the same May be different;

R ⁶ and R ⁷ are the same or different and j) -H, and jj) C ₁ -C ₆ alkyl, optionally substituted with mono- or poly-Hal-, -OH-, -CN- Selected from the group consisting of 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 Wherein said C ₃ -C ₆ heterocycloalkyl is one or more nitrogen, oxygen and / or sulfur atoms and / or one or more — (CO) — or —SO ₂ — groups in the ring, and / or Or may contain one or more double bonds, and the substituents in the case of polysubstitution may be the same or different.)
And its isomers, diastereomers, enantiomers and salts.

2. Identical or different R ¹ and R ^2, and j) -H, and jj) optionally mono - or poly -Hal -, - 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 , 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, is selected from the group consisting of C ₃ -C ₆ heterocycloalkyl; wherein said C ₃ -C ₆ heterocycloalkyl, optionally, 1 Moshiku in the ring More nitrogen, oxygen and / or sulfur atoms, and / or one or more - (CO) - or -SO ₂ - group, and / or can contain one or more double bonds, polysubstituted here The substituents in this case may be the same or different; and

Instead of R ¹ and R ² or as defined above in addition to the above definitions, together may form a C ₃ -C ₆ heterocycloalkyl ring, wherein the C ₃ -C ₆ heterocycloalkyl ring ring At least one nitrogen atom in it and optionally additionally one or more nitrogen, oxygen or sulfur atoms in the ring and / or one or more — (CO) — or — (SO ₂ ) — A ring, and / or optionally one or more double bonds, wherein the ring formed by R ¹ and R ² is optionally -CN, -Hal, -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 by ^7, and / or mono - or port -Hal-, C ₁ ~C ₆ alkoxy - or - by (CO) aryl or heteroaryl which may be substituted by -R ^6, may be substituted one or more times, in the case of polysubstituted here The compound according to claim 1, wherein the substituents may be the same or different.

3. Identical or different R ¹ and R ^2, and j) -H, and jj) optionally mono - or poly -Hal -, - 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-, aryloxy-, -S-C _1- C ₁ -C ₆ alkyl, optionally substituted with C ₆ alkyl-, — (CO) —R ⁶ —, —NR ³ R ⁴ —, —NR ³ (CO) L— or —NR ³ COOR ⁷ , 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, selected from the group consisting of aryl or heteroaryl, wherein in even 1 to ring in the case where the C ₃ -C ₆ heterocycloalkyl Ku is more nitrogen, oxygen and / or sulfur atoms, and / or one or more - (CO) - or -SO ₂ - can contain groups, and / or one or more double bonds, wherein

The aryl or heteroaryl groups defined in jj) above can be substituted as long as alkyl is not included, and the substituents in the case of polysubstitution may be the same or different, R ¹ and R ^{1 2} in addition to or in place of the above definitions may be taken together to form a C ₃ -C ₆ heterocycloalkyl ring, wherein said C ₃ -C ₆ heterocycloalkyl ring is at least 1 in the ring. One or more nitrogen, oxygen or sulfur atoms, and / or one or more — (CO) — or — (SO ₂ ) — groups, which comprise one nitrogen atom and optionally additionally in the ring, and / or Or optionally can comprise one or more double bonds, wherein the ring formed by R ¹ and R ² is optionally —CN, —Hal, —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, - by (CO) -R ⁶ or -COOR ^7, and / or mono- - or poly -Hal -, C ₁ -C ₆ alkoxy - or - by (CO) may be optionally substituted with -R ⁶ aryl or heteroaryl, may be substituted one or more times, in the case of polysubstituted here The compound according to claim 1, wherein the substituents of may be the same or different.

4). Q is phenyl, pyridyl, pyrimidinyl, thiophenyl, furyl, imidazolyl or pyrazolyl substituted with —OH—, —Hal—, —CN—, alkyl-, —OR ⁶ — or —NR ³ R ^4. 3. The compound according to 3.

5. R ¹ and R ² are the same or different and are —H, optionally further —Hal, —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 Selected from the group consisting of NR ³ R ⁴ -substituted C ₁ -C ₄ alkyl, which may be substituted one or more times by ³ (CO) -L or —NR ³ COOR ⁷ , wherein R ³ and R ⁴ can be the same or different C ₁ -C ₆ alkyl, or R ³ and R ⁴ can be taken together to form a C ₃ -C ₆ heterocycloalkyl ring, said C ₃ -C ₆ Heterocycloalkyl ring has at least one nitrogen in the ring Optionally comprising one or more nitrogen, oxygen or sulfur atoms and / or one or more — (CO) — or — (SO ₂ ) — groups, and / or Optionally comprising one or more double bonds, wherein R ⁶ and R ⁷ are the same or different and are —H, —OH, C ₁ -C ₆ alkoxy or C ₁ -C ₃ alkyl. Item 5. A compound according to Item 4.

6). R ¹ is selected from the group consisting of -H and C ₁ -C ₃ alkyl, C R ² is substituted with NR _³ R ^{₄ 3 ~C 4} alkyl, optionally additionally mono- - or poly -Hal-, _{-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 (CO) -L- or Selected from the group consisting of C ₃ -C ₄ alkyl, optionally substituted by —NR ³ COOR ⁷ —;

R ³ and R ⁴ are identical or different, optionally mono- - or poly -Hal -, - OH -, - CN-, C 1 ~C 6 alkyl -, C ₁ -C ₆ alkoxy -, C ₁ -C ₆ hydroxy alkyl -, 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 which may be substituted by -COOR ^7, a C ₁ -C ₆ alkyl or R ³ and R ⁴ together C ₃ -C _6, can form a heterocycloalkyl ring, said C ₃ -C ₆ heterocycloalkyl ring comprises at least one nitrogen atom in the ring and optionally additionally one or more nitrogen in the ring, oxygen Or a sulfur atom and / or 1 Or a plurality of — (CO) — or — (SO ₂ ) — groups and / or optionally one or more double bonds, and R ⁶ and R ⁷ are the same or different, H, -OH, a C ₁ -C ₆ alkoxy or C ₁ -C ₃ alkyl, a compound according to any one of claims 1 to 4.

7). (3-phenylimidazo [1,2-b] pyridazin-6-yl)-(3-pyrrolidin-1-ylpropyl) amine,
(3-morpholin-4-ylpropyl)-(3-phenyl-imidazo [1,2-b] pyridazin-6-yl) amine,
(3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl)-(3-pyrrolidin-1-ylpropyl) amine,
(3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl)-(3-morpholin-4-ylpropyl) amine,
[3- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-b] pyridazin-6-yl] pyridin-3-ylmethylamine,

(3-phenylimidazo [1,2-b] pyridazin-6-yl) pyridin-3-ylmethylamine,
(3-imidazo-1-ylpropyl)-(3-phenylimidazo [1,2-b] pyridazin-6-yl) amine,
(4-fluorobenzyl)-(3-phenylimidazo [1,2-b] pyridazin-6-yl) amine,
Cyclohexylmethyl (3-phenylimidazo [1,2-b] pyridazin-6-yl) amine,
(2,4-difluorobenzyl)-(3-phenylimidazo [1,2-b] pyridazin-6-yl) amine,

[3- (5-methyl-1H-pyrazol-4-yl) propyl]-(3-phenylimidazo [1,2-b] pyridazin-6-yl) amine,
1- [2- (3-phenylimidazo [1,2-b] pyridazin-6-ylamino) ethyl] imidazolidin-2-one,
(2-morpholin-4-ylethyl)-(3-phenylimidazo [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-phenylimidazo [1,2-b] pyridazin-6-yl) propane-1,3-diamine,

(3-phenylimidazo [1,2-b] pyridazin-6-yl)-(2-pyrrolidin-1-ylethyl) amine,
[3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl] pyridin-3-ylmethylamine,
[3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl]-(3-imidazol-1-ylpropyl) amine,
3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl)-(4-fluorobenzyl) amine,
3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl) cyclohexylmethylamine,

3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl)-(2,4-difluorobenzyl) amine,
1- {2- [3- (3-phenyl) imidazo [1,2-b] pyridazin-6-ylamino] ethyl} imidazolidin-2-one,
N ^* 4 ^* -[3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl] -N ^* 1 ^* , N ^* 1 ^* -diethylpentane-1,4-diamine,
N ′-[3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl] -N, N-diethylpropane-1,3-diamine,
[3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl]-(2-pyrrolidin-1-ylethyl) amine,

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

1- {2- [3- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-b] pyridazin-6-ylamino] ethyl} imidazolidin-2-one,
(3- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-b] pyridazin-6-yl)-(2-morpholin-4-ylethyl) 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 A 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-ylethyl) amine,

Pyridin-3-ylmethyl- (3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-yl) amine,
(4-fluorobenzyl)-(3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-yl) amine,
Cyclohexylmethyl- (3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-yl) amine,
(2,4-difluorobenzyl)-(3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-yl) amine,
[3- (5-methyl-1H-pyrazol-4-yl) propyl]-(3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-yl) amine,

1- [2- (3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-ylamino) ethyl] imidazolidin-2-one,
(2-morpholin-4-ylethyl)-(3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-yl) amine,
N ^* 1, N ^* , 1-diethyl-N ^* 4- [3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-yl] pentane-1,4-diamine,
N, N-diethyl-N ′-(3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-yl) propane-1,3-diamine,
(2-pyrrolidin-1-ylethyl)-(3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-yl) amine,

8). A process for the preparation of a compound according to any one of claims 1 to 7, comprising the following steps:
A1) reacting 3-amino-6-halopyrazine with chloroacetaldehyde to give 6-haloimidazo [1,2-b] pyridazine;
A2) reacting the product from step A1 with N-bromosuccinimide to give 3-bromo-6-halomidazo [1,2-b] pyridazine;
A3) The product from step A2 is reacted with compound NHR ¹ R ² in a Buchwald-Hartwig cross-coupling reaction to give (3-bromoimidazo [1,2-b] pyridazin-6-yl)-(R ¹ )-(R ² ) -amine,
A4) reacting the product from step A3 with a boronic acid which may be substituted, for example by the groups A and B, to give compounds of general formula I;

B1) reacting 3-amino-6-halopyrazine with chloroacetaldehyde to give 6-haloimidazo [1,2-b] pyridazine;
B2) reacting the product from step B1 with N-bromosuccinimide to give 3-bromo-6-haloimidazo [1,2-b] pyridazine;
B3) reacting the product from step B2 with a boronic acid which may be substituted, for example by the groups A and B, to give a compound of the general formula II
B4) The product from step B3 is converted to a compound of general formula I by reaction with compound NHR ¹ R ² in a Buchwald-Hartwig cross-coupling reaction; or

C1) reacting 3-amino-6-halopyrazine with chloroacetaldehyde to give 6-haloimidazo [1,2-b] pyridazine;
C2) The product from step C1 is reacted with compound NHR ¹ R ² in a Buchwald-Hartwig cross-coupling reaction to give imidazo [1,2-b] pyridazin-6-yl)-(R ¹ )-(R ² )-converted to amine,
C3) reacting the product from step C2 with N-bromosuccinimide to give (3-bromoimidazo [1,2-b] pyridazin-6-yl)-(R ¹ )-(R ² ) -amine;
C4) reacting the product from step C3 with a boronic acid, which may be substituted by groups A and B, for example, to give compounds of the general formula I
Process for the preparation of compounds of general formula I having

9. Use of a compound according to any one of claims 1 to 7 for preparing a pharmaceutical composition.
Ten. A method for inhibiting cellular kinases, in particular kinases from the protein kinase C family, such as the group of PKC theta (θ), delta (δ), iota (ι), alpha (α) and zeta (ζ). Use of a compound according to any one of -7.
11． 10. The production of a pharmaceutical composition for the treatment or prevention of a disease associated with overexpression or mutation of a cellular kinase, in particular the cellular kinase according to claim 10. Use of the described compounds.
12． The disease is selected from the group consisting of epidermal hyperproliferation, such as psoriasis, Alzheimer's disease, autoinflammatory disease, Crohn's disease, hyperimmune response, contact dermatitis, atopic dermatitis, multiple sclerosis, ALS, diabetes, asthma The use according to claim 9, which is an established disease.

13. 10. Use according to claim 9, for regulating the immune response, in particular reducing it, e.g. avoiding organ rejection after transplantation.
14. A process for the manufacture of a pharmaceutical composition comprising mixing a physiologically effective amount of a compound according to any one of claims 1 to 7 with at least one pharmaceutical excipient and manufacturing a dosage form. A method consisting of
15． A method for the treatment or prophylaxis of a disease associated with overexpression or mutation of cellular kinases, in particular the disease according to claim 12, comprising the physiological treatment of the compound according to any one of claims 1-7. A method comprising administering a pharmaceutical composition comprising an effective amount to a person suffering from or at risk of suffering from the disease.

16． Intermediates of general formula IIa:

[In the above formula,
Y is -H or -Hal;
R ¹ and R ² are the same or different, and j) -H, and jj) mono- - or poly -Hal -, - 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 - which may be substituted by, 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, consisting of aryl or heteroaryl is selected from the group, the C ₃ -C ₆ heterocycloalkyl ring One or more nitrogen in the ring by Nozomu, oxygen and / or sulfur atoms, and / or one or more - (CO) - or -SO ₂ - group, and / or 1 or comprise a plurality of double bonds And the substituents in the case of polysubstitution may be the same or different;

R ¹ and R ² in addition to or in place of the defined above definition, taken together may form a C ₃ -C ₆ heterocycloalkyl ring, wherein the C ₃ -C ₆ heterocycloalkyl in the ring At least one nitrogen atom and optionally additionally one or more nitrogen, oxygen or sulfur atoms in the ring and / or one or more — (CO) — or — (SO ₂ ) — A group and / or one or more double bonds, wherein the ring formed by R ¹ and R ² is optionally —CN, —Hal, —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, - by (CO) -R ⁶ or -COOR ^7, And / or mono- or poly-H al-, C ₁ ~C ₆ alkoxy -, C ₁ -C ₆ haloalkoxy - or - by (CO) aryl or heteroaryl which may be substituted by -R ^6, may be mono- or polysubstituted Where the substituents in the case of polysubstitution may be the same or different;

R ³ and R ⁴ are the same or different, and j) -H, and jj) mono- - or poly -Hal -, - 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 - which may be substituted by, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ ~ Selected from the group consisting of C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ heterocycloalkyl, aryl or heteroaryl, wherein said C ₃ -C ₆ heterocycloalkyl ring is If desired, one or more in the ring Group, an oxygen or sulfur atom, and / or one or more - (CO) - or -SO ₂ - group, and / or can contain one or more double bonds, wherein in the case of multi-substituted substituent The groups may be the same or different;

R ³ and R ⁴ may be combined to form a C ₃ -C ₆ heterocycloalkyl ring in addition to or instead of the above definition, wherein the C ₃ -C ₆ heterocycloalkyl is in the ring At least one nitrogen atom and optionally additionally one or more nitrogen, oxygen or sulfur atoms in the ring and / or one or more — (CO) — or — (SO ₂ ) — A group, and / or one or more double bonds, wherein the ring formed by R ³ and R ⁴ may optionally be —CN, —Hal, —OH, C ₁ -C ₆ alkyl. , C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxyalkyl or by —NR ⁶ R ⁷ , —CONR ⁶ R ⁷ , — (CO) —R ⁶ or —COOR ⁷ And / or mono-if Poly -Hal-, C ₁ ~C ₆ alkoxy - or - by (CO) which may be substituted with -R ⁶ aryl or heteroaryl, may be mono- or polysubstituted, wherein the poly-substituted The substituents in the case may be the same or different;

R ⁶ and R ⁷ are the same or different and j) —H and jj) C ₁ -C ₆ alkyl, C ₁ which may be substituted by mono- or poly-Hal-, —OH—, —CN—. -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ heterocycloalkyl, selected from the group consisting of aryl or heteroaryl, wherein the C ₃ -C ₆ heterocycloalkyl, one or more nitrogen atoms in the ring, oxygen atom or sulfur atom, and / or one or more - (CO) - or - (SO ₂₎ - group, and / or one or A plurality of double bonds may be included, and the substituents in the case of polysubstitution may be the same or different.)
And isomers, diastereomers, enantiomers and salts thereof.

17． Intermediates of general formula IIb:

[In the above formula,
Q is aryl or heteroaryl;

A and B are the same or different, and
i) H, Hal, -OH, -NR 3 R 4, -CN or -NO _2,
ii) optionally mono - or poly _{-Hal -, - OH-, C 3} ~C 6 heterocycloalkyl -, - NR ³ R ⁴ - or - is to be replaced (CO) in -NR ^3-L- C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl, wherein said C ₃ -C ₆ heteroalkyl is in the ring May contain one or more nitrogen, oxygen 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, or -O- (CH _{2) p} - aryl,
Selected from the group consisting of
Where the substituents in the case of polysubstitution may be the same or different;

A and B may be combined to form a Q-fused C ₅ -C ₇ cycloalkyl or C ₅ -C ₇ heterocycloalkyl ring in addition to or in place of the above definitions, in the latter case Can comprise at least one oxygen or one nitrogen atom in the ring and optionally further one or more oxygen, nitrogen or sulfur atoms and / or one or more — (CO ) - or - (SO ₂₎ - may comprise group, and / or one or more double bonds;
p is 0-4;

L mono desired - or poly -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 C ₁ -C ₆ alkyl, or C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl, which may be substituted by-, wherein said C ₃ -C ₆ heterocycloalkyl is in the ring Comprising 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. Well;

X is chlorine, bromine, O—SO ₂ —CF ₃ or O—SO ₂ —C ₄ F ₉ ;
R ³ and R ⁴ are the same or different, and
j) -H, and
jj) optionally mono - or poly -Hal -, - 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 ) C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ , which may be substituted by -R ⁶ -or -COOR ⁷ Cycloalkyl, C ₃ -C ₆ heterocycloalkyl, aryl or heteroaryl, wherein said C ₃ -C ₆ heterocycloalkyl is one or more nitrogen, oxygen and / or sulfur atoms in the ring, and / or 1 or Multiple-(CO)-or - (SO ₂₎ - group, and / or one or more may also comprise a double bond, and the substituent in the case of polysubstitution may be the same or different)
Selected from the group consisting of;

The R ³ and R ⁴ groups can be combined to form a C ₃ -C ₆ heterocycloalkyl ring in addition to or in place of the above definition, wherein the C ₃ -C ₆ heterocycloalkyl ring is At least one nitrogen atom in the ring and optionally further one or more nitrogen, oxygen or sulfur atoms and / or one or more — (CO) — or — (SO ₂ ) in the ring. )-Groups, and / or may comprise one or more double bonds; wherein the ring formed by R ³ and R ⁴ is optionally -CN, -Hal, -OH, C _1- C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ ^{alkoxyalkyl, -NR 6 R 7, -CONR 6} R 7, - (CO) -R 6 or -COOR by ^7, and / or mono - if Poly -Hal-, C ₁ ~C ₆ alkoxy - or - (CO) -R ⁶ - by an aryl or heteroaryl may be optionally substituted with, may be monosubstituted or polysubstituted, where The substituents in the case of polysubstitution may be the same or different;

R ⁶ and R ⁷ are the same or different, and j) —H, and jj) C ₁ -C ₆ alkyl, C, which may be substituted with mono- or poly-Hal-, —OH—, —CN—, 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, selected from the group consisting of, wherein Wherein the C ₃ -C ₆ heterocycloalkyl is one or more nitrogen, oxygen and / or sulfur atoms and / or one or more — (CO) — or —SO ₂ — groups and / or 1 in the ring. Or it may contain a plurality of double bonds, and the substituents in the case of polysubstitution may be the same or different.)
And its isomers, diastereomers, enantiomers and salts.

Claims (14)

Formula I:

[In the above formula,
Q is aryl or heteroaryl, excluding pyrimidine;
A and B are the same or different, and
i) -H, -Hal, -OH, -NR 3 R 4 or -CN,
ii) -OH, which may be mono- or polysubstituted by -SO ₂ NR ³ R ⁴ or ^{_{-SO 2 R 3, C 1 ~C}} 6 alkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ Haloalkoxy, and
^{iii) -NR 3 (CO) -L} , - (CO) -R 6, -O (CH2) pR 6 (p is 0-4), or ^{_{-NR 3 (SO 2) R 4}} ,
Selected from the group consisting of
Wherein the substituents may be the same or different in the case of a multi-substituted; or A and B may be taken together to form a Q fusion C ₅ -C ₇ heterocycloalkyl ring, said Comprising at least one oxygen in the ring;
L is C ₁ -C ₆ alkyl;
One of R ¹ and R ² is H, and the other of R ¹ and R ² is
j) -H, and
jj) OH-, C ₃ ~C ₆ cycloalkyl -, C ₃ -C ₆ heterocycloalkyl -, aryl -, heteroaryl -, - NR ³ R ^4, or -SO ₂ NR ³ R ^4, by mono- or polysubstituted by that there is, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, or C ₃ -C ₆ heterocycloalkyl,
Or a — (CH ₂ ) _r R ⁸ group (where r is a number from 0 to 3 and R ⁸ is a group selected from the group consisting of

Is)
Wherein aryl is optionally present in the R ¹ or R ^2, heteroaryl, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl _{group, -Hal, -OH, -C 1 ~C} 6 May be mono- or polysubstituted by alkyl, -C ₁ -C ₆ haloalkyl, -C ₁ -C ₆ alkoxy, -CO ₂ R ⁷ , or -SO ₂ NR ³ R ⁴ ; The substituents in the case may be the same or different;
Provided that two or more aryl or heteroaryl groups cannot be substituents on the same carbon atom in R ¹ or R ² ; or R ¹ and R ² together are C ₃ -C ₆ hetero can form a cycloalkyl ring, wherein the C ₃ -C ₆ heterocycloalkyl ring comprises at least one nitrogen atom in the ring;
R ³ and R ⁴ are the same or different and are —H or C ₁ -C ₆ alkyl;
In addition to the above definitions, the R ³ and R ⁴ groups can be taken together to form a C ₃ -C ₆ heterocycloalkyl ring, wherein the C ₃ -C ₆ heterocycloalkyl ring is at least one in the ring. Comprising a nitrogen atom and optionally further comprising one or more nitrogen, oxygen or sulfur atoms in the ring;
R ⁷ is —H or C ₁ -C ₆ alkyl]
A process for preparing a compound represented by the following steps:
A1) converting 3-amino-6-halopyridazine to 6-haloimidazo [1,2-b] pyridazine (II);
A2) converting the product from step A1 to 3-halo-6-haloimidazo [1,2-b] pyridazine (III);
A3) The product from step A2 is changed to a compound of general formula IIa by reaction with compound NHR ¹ R ² ,
A4) converting the product from step A3 to a compound of general formula I; or B1) converting 3-amino-6-halopyridazine to 6-haloimidazo [1,2-b] pyridazine (II);
B2) converting the product from step B1 to 3-halo-6-haloimidazo [1,2-b] pyridazine (III);
B3) converting the product from step B2 to a compound of general formula IIb;
B4) converting the product from step B3 to a compound of general formula I; or C1) converting 3-amino-6-halopyridazine to 6-haloimidazo [1,2-b] pyridazine (II);
C2) The product from step C1 is converted to imidazo [1,2-b] pyridazin-6-yl)-(R ¹ )-(R ² ) -amine (IV) by reaction with compound NHR ¹ R ^2. Converted,
C3) converting the product from step C2 to a compound of general formula IIa;
C4) converting the product from step C3 to a compound of general formula I,

Wherein R ¹ , R ² , A and B are as described above and X and Y are halogen.
Comprising steps,
Process for the preparation of compounds of general formula I. The following stages:
A1) 3-amino-6-halopyridazine is reacted with chloroacetaldehyde to give 6-haloimidazo [1,2-b] pyridazine;
A2) reacting the product from step A1 with N-bromosuccinimide to give 3-bromo-6-halomidazo [1,2-b] pyridazine;
A3) The product from step A2 is reacted with compound NHR ¹ R ² in a Buchwald-Hartwig cross-coupling reaction to give (3-bromoimidazo [1,2-b] pyridazin-6-yl)-(R ¹ )-(R ² ) -amine,
A4) reacting the product from step A3 with a boronic acid which may be substituted by groups A and B to give compounds of general formula I; or B1) 3-amino-6-halopyridazine with chloroacetaldehyde To give 6-haloimidazo [1,2-b] pyridazine,
B2) reacting the product from step B1 with N-bromosuccinimide to give 3-bromo-6-haloimidazo [1,2-b] pyridazine;
B3) reacting the product from step B2 with a boronic acid which may be substituted by groups A and B to give compounds of general formula IIb
B4) The product from step B3 is converted to a compound of general formula I by reaction with compound NHR ¹ R ² in a Buchwald-Hartwig cross-coupling reaction; or C1) 3-amino-6-halopyridazine is chloro React with acetaldehyde to give 6-haloimidazo [1,2-b] pyridazine;
C2) The product from step C1 is reacted with compound NHR ¹ R ² in a Buchwald-Hartwig cross-coupling reaction to give imidazo [1,2-b] pyridazin-6-yl)-(R ¹ )-(R ² )-converted to amine,
C3) The product from step C2 is reacted with N-bromosuccinimide to give (3-bromoimidazo [1,2-b] pyridazin-6-yl)-(R ¹ )-(R ² ) -amine. ,
C4) reacting the product from step C3 with a boronic acid optionally substituted by groups A and B to give a compound of general formula I
The method of claim 1 . Q is phenyl, pyridyl, thiophenyl, furyl, imidazolyl or pyrazolyl, which may be mono- or polysubstituted with —OH—, —Hal, —CN, alkyl-, —OR ⁶ or —NR ³ R ^4. The method according to claim 1 or 2 . (3-phenylimidazo [1,2-b] pyridazin-6-yl)-(3-pyrrolidin-1-ylpropyl) amine,
(3-morpholin-4-ylpropyl)-(3-phenylimidazo [1,2-b] pyridazin-6-yl) amine,
(3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl)-(3-pyrrolidin-1-ylpropyl) amine,
(3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl)-(3-morpholin-4-ylpropyl) amine,
[3- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-b] pyridazin-6-yl] pyridin-3-ylmethylamine,
(3-phenylimidazo [1,2-b] pyridazin-6-yl) pyridin-3-ylmethylamine,
(3-imidazo-1-ylpropyl)-(3-phenylimidazo [1,2-b] pyridazin-6-yl) amine,
(4-fluorobenzyl)-(3-phenylimidazo [1,2-b] pyridazin-6-yl) amine,
Cyclohexylmethyl- (3-phenylimidazo [1,2-b] pyridazin-6-yl) amine,
(2,4-difluorobenzyl)-(3-phenylimidazo [1,2-b] pyridazin-6-yl) amine,
[3- (5-methyl-1H-pyrazol-4-yl) propyl]-(3-phenylimidazo [1,2-b] pyridazin-6-yl) amine,
1- [2- (3-phenylimidazo [1,2-b] pyridazin-6-ylamino) ethyl] imidazolidin-2-one,
(2-morpholin-4-ylethyl)-(3-phenylimidazo [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-phenylimidazo [1,2-b] pyridazin-6-yl) propane-1,3-diamine,
(3-phenylimidazo [1,2-b] pyridazin-6-yl)-(2-pyrrolidin-1-ylethyl) amine,
[3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl] pyridin-3-ylmethylamine,
[3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl]-(3-imidazol-1-ylpropyl) amine,
3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl)-(4-fluorobenzyl) amine,
3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl) cyclohexylmethylamine,
3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl)-(2,4-difluorobenzyl) amine,
1- {2- [3- (3-phenyl) imidazo [1,2-b] pyridazin-6-ylamino] ethyl} imidazolidin-2-one,
N ^* 4 ^* -[3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl] -N ^* 1 ^* , N ^* 1 ^* -diethylpentane-1,4-diamine,
N ′-[3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl] -N, N-diethylpropane-1,3-diamine,
[3- (3-chlorophenyl) imidazo [1,2-b] pyridazin-6-yl]-(2-pyrrolidin-1-ylethyl) amine,
(3-imidazol-1-ylpropyl)-[3- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-b] pyridazin-6-yl] amine,
(4-fluorobenzyl)-[3- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-b] pyridazin-6-yl] amine,
Cyclohexylmethyl- [3- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-b] pyridazin-6-yl] amine,
(2,4-difluorobenzyl)-[3- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-b] pyridazin-6-yl] amine,
[3- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-b] pyridazin-6-yl]-[5-methyl-1H-pyrazol-4-ylpropyl] amine,
1- {2- [3- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-b] pyridazin-6-ylamino] ethyl} imidazolidin-2-one,
(3- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-b] pyridazin-6-yl)-(2-morpholin-4-ylethyl) 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 A 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-ylethyl) amine,
Pyridin-3-ylmethyl- (3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-yl) amine,
(4-fluorobenzyl)-(3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-yl) amine,
Cyclohexylmethyl- (3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-yl) amine,
(2,4-difluorobenzyl)-(3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-yl) amine,
[3- (5-methyl-1H-pyrazol-4-yl) propyl]-(3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-yl) amine,
1- [2- (3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-ylamino) ethyl] imidazolidin-2-one,
(2-morpholin-4-ylethyl)-(3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-yl) amine,
N ^* 1, N ^* , 1-diethyl-N ^* 4- [3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-yl] pentane-1,4-diamine,
N, N-diethyl-N ′-[3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-yl] propane-1,3-diamine,
(2-pyrrolidin-1-ylethyl)-(3-thiophen-3-ylimidazo [1,2-b] pyridazin-6-yl) amine,
In a compound, or a di-diastereomer, enantiomer, or salt thereof. The following compounds:

Or its di-diastereomer, enantiomer, or salt. A pharmaceutical composition comprising the compound according to claim 4 or 5 . Claims for the treatment of benign tumor, malignant tumor, leukemia, lymphoma, sarcoma, neuroblastoma, Wilms tumor, bladder, breast, lung, pancreas, prostate, renal malignant neoplasm or epithelial neoplasm 6. The pharmaceutical composition according to 6 . The pharmaceutical composition according to claim 7 , wherein the leukemia is myeloid leukemia and the sarcoma is osteosarcoma or chondrosarcoma. The pharmaceutical composition according to claim 7 for the treatment of breast cancer or its metastasized cancer. Epidermal hyperproliferation, Alzheimer's disease, autoinflammatory disease, fibrosis, trauma healing disorder, diabetic retinopathy, nephropathy, age-related macular degeneration, Crohn's disease, hyperimmune response, contact dermatitis, atopic dermatitis A pharmaceutical composition according to claim 6 for the treatment of a disease selected from the group consisting of: multiple sclerosis, ALS, diabetes, asthma. 11. The pharmaceutical composition according to claim 10 , wherein the epidermal hyperproliferation is psoriasis. A method for preparing a pharmaceutical composition comprising mixing a physiologically effective amount of a compound according to claim 4 or 5 with at least one pharmaceutical excipient and producing a dosage form. Intermediates of general formula IIa:

(In the above formula,
Y is a halogen atom; and R ¹ and R ² have the meaning as defined in claim 1). Intermediates of general formula IIb:

(Wherein Q, A and B have the meanings defined in claim 1 and X is bromine, O—SO ₂ —CF ₃ or O—SO ₂ —C ₄ F ₉ ).