Patent Publication Number: US-8987273-B2

Title: Substituted imidazo[1,2-B]pyridazines

Description:
FIELD OF THE INVENTION 
     The invention relates to imidazo[1,2-b]pyridazines, a process for their manufacture and their use for the treatment of benign and malignant neoplasia. 
     KNOWN TECHNICAL BACKGROUND 
     Cancer is the second most prevalent cause of death in the United States, causing 450,000 deaths per year. While substantial progress has been made in identifying some of the likely environmental and hereditary causes of cancer, there is a need for additional therapeutic modalities that target cancer and related diseases. In particular there is a need for therapeutic methods for treating diseases associated with dysregulated growth/proliferation. 
     Cancer is a complex disease arising after a selection process for cells with acquired functional capabilities like enhanced survival/resistance towards apoptosis and a limitless proliferative potential. Thus, it is preferred to develop drugs for cancer therapy addressing distinct features of established tumors. 
     One pathway that has been shown to mediate important survival signals for mammalian cells comprises receptor tyrosine kinases like platelet-derived growth factor receptor (PDGF-R), human epidermal growth factor 2/3 receptor (HER2/3), or the insulin-like growth factor 1 receptor (IGF-1R). After activation the respectives by ligand, these receptors activate the phoshatidylinositol 3-kinase (Pi3K)/Akt pathway. The phoshatidylinositol 3-kinase (Pi3K)/Akt protein kinase pathway is central to the control of cell growth, proliferation and survival, driving progression of tumors. Therefore within the class of serine-threonine specific signalling kinases, Akt (protein kinase B; PKB) with the isoenzmyes Akt1 (PKBα), Akt2 (PKB β) and Akt3 (PKB γ) is of high interest for therapeutic intervention. Akt is mainly activated in a Pi3-kinase dependent manner and the activation is regulated through the tumor suppressor PTEN (phosphatase and tensin homolog), which works essentially as the functional antagonist of Pi3K. 
     The Pi3K/Akt pathway regulates fundamental cellular functions (e.g. transcription, translation, growth and survival), and is implicated in human diseases including diabetes and cancer. The pathway is frequently overactivated in a wide range of tumor entities including breast and prostate carcinomas. Upregulation can be due to overexpression or constitutively activation of receptor tyrosine kinases (e.g. EGFR, HER2/3), which are upstream and involved in its direct activation, or gain- or loss-of-function mutants of some of the components like loss of PTEN or mutated PTEN (Michelle M. Hill, Brian A. Hemmings, Pharmacology &amp; Therapeutics 93 (2002) 243-251). The pathway is targeted by genomic alterations including mutation, amplification and rearrangement more frequently than any other pathway in human cancer, with the possible exception of the p53 and retinoblastoma pathways. The alterations of the Pi3K/Akt pathway trigger a cascade of biological events, that drive tumor progression, survival, angiogenesis and metastasis. 
     Activation of Akt kinases promotes increased nutrient uptake, converting cells to a glucose-dependent metabolism that redirects lipid precursors and amino acids to anabolic processes that support cell growth and proliferation. These metabolic phenotype with overactivated Akt lead to malignancies that display a metabolic conversion to aerobic glycolysis (the Warburg effect). In that respect the Pi3K/Akt pathway is discussed to be central for survival despite unfavourable growth conditions such as glucose depletion or hypoxia. A further aspect of the activated PI3K/Akt pathway is to protect cells from programmed cell death (“apoptosis”) and is hence considered to transduce a survival signal. By acting as a modulator of anti-apoptotic signalling in tumor cells, the Pi3K/Akt pathway, in particular Akt itself is a target for cancer therapy (Constantine S. Mitsiades, Nicholas Mitsiades and Michael Koutsilieris, Current Cancer Drug Targets, 2004, 4, 235-256). Activated Akt phosphorylates and regulates several targets, e.g. BAD. GSK3 or FKHRL1, that affect different signalling pathways like cell survival, protein synthesis or cell movement. This Pi3K/Akt pathway also plays a major part in resistance of tumor cells to conventional anti-cancer therapies. Blocking the Pi3K/kt pathway could therefore simultaneously inhibit the proliferation of tumor cells (e.g. via the inhibition of the metabolic effect) and sensitize towards pro-apoptotic agents. 
     Akt inhibition selectively sensitized tumor cells to apoptotic stimuli like Trail. Camptothecin and Doxorubicin. Dependent on the genetic background/molecular apperations of tumors. Akt inhibitors might induce apoptotic cell death in monotherapy as well. 
     From WO 2008/070016 tricyclic Akt inhibitors are known which are alleged to be unspecific Akt kinase inhibitors. No data for any specific compounds are disclosed. Different Akt inhibitors are disclosed in WO 2009/021992, WO2010088177, WO2010114780. 
     In a recent disclosure, Y. Li et al (Bioorg. Med. Chem. Lett. 2009, 19, 834-836 and cited references therein) detail the difficulty in finding optimal Akt inhibitors. The potential application of Akt inhibitors in multiple disease settings, such as for example, cancer, makes the provision of further Akt inhibitors in addition to those currently available highly desirable. 
    
    
     DESCRIPTION OF THE INVENTION 
     A solution to the above problem is the provision of alternative Akt inhibitors. It has been found that the new substituted Imidazo[1,2-b]pyridazines compounds, which are described in detail below, have another profile than the existing AKT-inhibitors. 
     In accordance with a first aspect, the invention relates to compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein
     R1 is hydrogen, halogen, 2-6C-alkenylen-C(O)NH2, 2-6C-alkenylen-C(O)OR10, or a group selected from 1-6C-alkyl, 2-6C-alkenyl, 3-7C-cycloalkyl, aryl, heteroaryl,
       wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:   hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9.   
       R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl, 3-7C-cycloalkyl,
       wherein said 1-6C-alkyl being optionally substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-6C-alkoxy.   
       R3 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl,   R4 is phenyl optionally substituted, one or more times, identically or differently, with a substituent selected from: 1-6C-alkyl, halogen, cyano,   R5 is hydrogen, halogen,   R6 is hydrogen, 1-6C-alkyl,   R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl is optionally substituted in the same way of differently one or more times with halogen, hydroxy, mono- or di-1-4C-alkylamino, 1-4C-alkoxy, or,
       in the case of —NR8R9, R8 and R9 together with the nitrogen to which they are attached may also form a 3-6C-heterocyclic ring,   
       R10 is hydrogen, 1-6C-alkyl,   R11 is 1-4C-alkyl (optionally substituted in the same way of differently one or more times with halogen, hydroxy) or 3-7C-cycloalkyl,   X is (CH 2 ) n —,   n is 0, 1, 2, or 3,   Y is —CH 2 —, —CH(OH)—,
 
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
   

     A further aspect of the invention are compounds according to claim  1  or  2 , wherein
     R1 is hydrogen, halogen, 2-3C-alkenylen-C(O)NH2, 2-3C-alkenylen-C(O)OR10, or a group selected from 1-3C-alkyl, 2-3C-alkenyl, aryl, heteroaryl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
       hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-hydroxyalkyl, 1-3C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9,   
       R2 is hydrogen, halogen, cyano, or a group selected from 1-3C-alkyl,
       wherein said 1-3C-alkyl being optionally substituted, one or more times, identically or differently, with a substituent selected from: hydroxy, halogen, 1-3C-alkoxy.   
       R3 is hydrogen, 1-3C-alkyl,   R4 is phenyl optionally substituted, one or more times, identically or differently, with a substituent selected from: 1-3C-alkyl, halogen, cyano,   R5 is hydrogen, halogen.   R6 is hydrogen, 1-3C-alkyl,   R8, R9 which can be the same or different, is hydrogen, 1-3C-alkyl.   R10 is hydrogen, 1-3C-alkyl.   R11 is 1-4C-alkyl (optionally substituted in the same way of differently one or more times with halogen, hydroxy).   X is —(CH 2 ) n —,   n is 0, 1, 2, or 3,   Y is —CH 2 —, —CH(OH)—,
 
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
   

     Another aspect of the invention are compounds according to claim  1  or  2 , wherein
     R1 is hydrogen, halogen or a group selected from 1-6C-alkyl, 3-7C-cycloalkyl, aryl, heteroaryl,
       wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:   hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9,   
       R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl. 3-7C-cycloalkyl,
       wherein said 1-6C-alkyl being optionally substituted, one or more times, identically, or differently, with a substituent selected from: hydroxy, halogen, 1-6C-alkoxy,   
       R3 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl,   R4 is phenyl optionally substituted, one or more times, identically or differently, with a substituent selected from: 1-6C-alkyl, halogen, cyano,   R5 is hydrogen, halogen,   R6 is hydrogen, 1-6C-alkyl.   R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl is optionally substituted in the same way of differently one or more times with halogen, hydroxy, mono- or di-1-4C-alkylamino, 1-4C-alkoxy,
       or,   in the case of —NR8R9, R8 and R9 together with the nitrogen to which they are attached may also form a 3-6C-heterocyclic ring,   
       R10 is hydrogen, 1-6C-alkyl.   R11 is 1-4C-alkyl (optionally substituted in the same way of differently one or more times with halogen, hydroxy) or 3-7C-cycloalkyl,   X is (CH 2 ) n —,   n is 0, 1, 2, or 3,   Y is —CH 2 —, —CH(OH)—,
       or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.   
       

     A further aspect of the invention are compounds of formula (I) according to claim  1 , wherein
     R1 is hydrogen, halogen, 2-6C-alkenylen-C(O)NH2, 2-8C-alkenylen-C(O)OR10, or a group selected from 1-6C-alkyl, 2-6C-alkenyl, 3-7C-cycloalkyl, aryl, heteroaryl,
       wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:   hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9.   
       R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl, 3-7C-cycloalkyl,
       wherein said 1-6C-alkyl being optionally substituted, one or more times, identically or differently, with a substituent selected from:   hydroxy, halogen, 1-6C-alkoxy, R3 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl,   
       R4 is phenyl optionally substituted, one or more times, identically or differently, with a substituent selected from: 1-6C-alkyl, halogen, cyano,   R5 is hydrogen, halogen,   R6 is hydrogen,   R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl is optionally substituted in the same way of differently one or more times with halogen, hydroxy, mono- or di-1-4C-alkylamino, 1-4C-alkoxy,
       or,   in the case of —NR8R9, R8 and R9 together with the nitrogen to which they are attached may also form a 3-6C-heterocyclic ring,   
       R10 is hydrogen, 1-6C-alkyl,   R11 is 1-4C-alkyl (optionally substituted in the same way of differently one or more times with halogen, hydroxy) or 3-7C-cycloalkyl,   X is (CH 2 ) n —,   n is 0, 1, 2, or 3,   Y is —CH 2 —, —CH(OH)—,
 
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
   

     A further aspect of the invention are compounds of formula (I) according to claim wherein
     R1 is hydrogen, halogen, 2-3C-alkenylen-C(O)NH2, 2-3C-alkenylen-C(O)OR10, or a group selected from 1-3C-alkyl, 2-3C-alkenyl, aryl, heteroaryl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
       hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-hydroxyalkyl, 1-3C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9,   
       R2 is hydrogen, halogen, cyano, or a 1-3C-alkyl group,
       which is optionally substituted, one or more times, identically or differently, with a substituent selected from:   hydroxy, halogen, 1-3C-alkoxy,   
       R3 is hydrogen, 1-3C-alkyl,   R4 is phenyl optionally substituted, one or more times, identically or differently, with a substituent selected from: 1-3C-alkyl, halogen, cyano.   R5 is hydrogen, halogen.   R6 is hydrogen,   R8, R9 which can be the same or different, is hydrogen, 1-3C-alkyl.   R10 is hydrogen, 1-6C-alkyl,   R11 is 1-4C-alkyl (optionally substituted in the same way of differently one or more times with halogen, hydroxy).   X is (CH 2 ) n —,   n is 0, 1, 2, or 3,   Y is —CH 2 —, —CH(OH)—,
 
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, or stereoisomer.
   

     Another aspect of the invention are compounds of formula (I) 
     wherein 
     
         
         R1 is hydrogen, halogen or a group selected from 1-6C-alkyl, 3-7C-cycloalkyl, aryl, heteroaryl,
       wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:   hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9,   
     
         R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl, 3-7C-cycloalkyl,
       wherein said 1-6C-alkyl being optionally substituted, one or more times, identically, or differently, with a substituent selected from: hydroxy, halogen, 1-6C-alkoxy,   
     
         R3 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl, 
         R4 is phenyl optionally substituted, one or more times, identically or differently, with a substituent selected from: 1-6C-alkyl, halogen, cyano, 
         R5 is hydrogen, halogen, 
         R6 is hydrogen, 
         R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl is optionally substituted in the same way of differently one or more times with halogen, hydroxy, mono- or di-1-4C-alkylamino, 1-4C-alkoxy,
       or,   in the case of —NR8R9, R8 and R9 together with the nitrogen to which they are attached may also form a 3-6C-heterocyclic ring,   
     
         R10 is hydrogen, 1-6C-alkyl, 
         R11 is 1-4C-alkyl (optionally substituted in the same way of differently one or more times with halogen, hydroxy) or 3-7C-cycloalkyl, 
         X is (CH 2 ) n —, 
         n is 0, 1, 2, or 3, 
         Y is —CH 2 —, —CH(OH)—,
 
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
 
       
    
     A further aspect of the invention are compounds of formula (I) according to claim  1  or  2 , wherein
     R1 is hydrogen, halogen, 2-6C-alkenylen-C(O)NH2, 2-6C-alkenylen-C(O)OR10, or a group selected from 1-6C-alkyl, 2-6C-alkenyl, 3-7C-cycloalkyl, aryl, heteroaryl,
       wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:   hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9,   
       R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl, 3-7C-cycloalkyl,   R3 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl,   R4 is phenyl,   R5 is hydrogen,   R6 is hydrogen,   R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl is optionally substituted in the same way of differently one or more times with halogen, hydroxy, mono- or di-1-4C-alkylamino, 1-4C-alkoxy,
       or,   in the case of —NR8R9, R8 and R9 together with the nitrogen to which they are attached may also form a 3-6C-heterocyclic ring,   
       R10 is hydrogen, 1-6C-alkyl,   R11 is 1-4C-alkyl (optionally substituted in the same way of differently one or more times with halogen, hydroxy) or 3-7C-cycloalkyl,   X is (CH 2 ) n —,   n is 0, 1, 2, or 3,   Y is —CH 2 —, —CH(OH)—,
 
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, or stereoisomer.
   

     A further aspect of the invention are compounds of formula (I) according to claim  1  or  2 , wherein
     R1 is hydrogen, halogen, 2-3C-alkenylen-C(O)NH2, 2-3C-alkenylen-C(O)OR10, or a group selected from 1-3C-alkyl, 2-3C-alkenyl, aryl, heteroaryl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
       hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-hydroxyalkyl, 1-3C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9,   
       R2 is hydrogen, halogen, cyano, or a group selected from 1-3C-alkyl,   R3 is hydrogen, 1-3C-alkyl,   R4 is phenyl,   R5 is hydrogen,   R6 is hydrogen,   R8, R9 which can be the same or different, is hydrogen, 1-3C-alkyl   R10 is hydrogen, 1-3C-alkyl,   R11 is 1-3C-alkyl (optionally substituted in the same way of differently one or more times with halogen, hydroxy),   X is (CH 2 ) n —,   n is 0, 1, 2, or 3,   Y is —CH 2 —, —CH(OH)—,
 
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
   

     A further aspect of the invention are compounds of formula (I) 
     wherein 
     
         
         R1 is hydrogen, halogen or a group selected from 1-6C-alkyl, 3-7C-cycloalkyl, aryl, heteroaryl,
       wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:   hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl, 1-6C-alkoxy. —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, S(O) 2 R11, —S(O) 2 NR8R9,   
     
         R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl, 3-7C-cycloalkyl, 
         R3 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl, 
         R4 is phenyl, 
         R5 is hydrogen. 
         R6 is hydrogen, 
         R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl is optionally substituted in the same way of differently one or more times with halogen, hydroxy, mono- or di-1-4C-alkylamino, 1-4C-alkoxy,
       or,   in the case of —NR8R9, R8 and R9 together with the nitrogen to which they are attached may also form a 3-6C-heterocyclic ring,   
     
         R10 is hydrogen, 1-6C-alkyl, 
         R11 is 1-4C-alkyl (optionally substituted in the same way of differently one or more times with halogen, hydroxy) or 3-7C-cycloalkyl, 
         X is (CH 2 ) n —, 
         n is 0, 1, 2, or 3, 
         Y is —CH 2 —, —CH(OH)—,
 
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, or stereoisomer.
 
       
    
     A further aspect of the invention are compounds of formula (I) according to claim  1  or  2 , 
     wherein 
     
         
         R1 is hydrogen, halogen, 2-6C-alkenylen-C(O)NH2, 2-6C-alkenylen-C(O)OR10, or a group selected from 1-6C-alkyl, 2-6C-alkenyl, aryl, heteroaryl,
       wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:   hydroxy, halogen, 1-6C-alkyl, 1-4C-hydroxyalkyl, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9,   
     
         R2 is hydrogen, halogen, cyano, or 1-6C-alkyl, 
         R3 is hydrogen, 
         R4 is phenyl, 
         R5 is hydrogen. 
         R6 is hydrogen, 
         R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl is optionally substituted in the same way of differently one or more times with halogen, hydroxy, mono- or di-1-4C-alkylamino, 1-4C-alkoxy,
       or,   in the case of —NR8R9, R8 and R9 together with the nitrogen to which they are attached may also form a 3-6C-heterocyclic ring,   
     
         R10 is hydrogen, 1-6C-alkyl, 
         R11 is 1-4C-alkyl, 
         X is (CH 2 ) n —, 
         n is 1, 
         Y is —CH 2 —,
 
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, or stereoisomer.
 
       
    
     A further aspect of the invention are compounds of formula (I) according to claim  1  or  2 , 
     wherein 
     
         
         R1 is hydrogen, halogen, (2-3C-alkenylen)-C(O)NH2,
       (2-3C-alkenylen)-C(O)OR10, or a group selected from   1-3C-alkyl, 2-3C-alkenyl, aryl, heteroaryl,   wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:   hydroxy, halogen, 1-3C-alkyl, 1-3C-hydroxyalkyl, cyano, —C(O)NR8R9, C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9,   
     
         R2 is hydrogen, halogen, cyano, or 1-3C-alkyl, 
         R3 is hydrogen. 
         R4 is phenyl, 
         R5 is hydrogen, 
         R6 is hydrogen, 
         R8, R9 which can be the same or different, is hydrogen or 1-3C-alkyl. 
         R10 is hydrogen, 1-3C-alkyl. 
         R11 is 1-3C-alkyl, 
         X is (CH 2 ) n —, 
         n is 1, 
         Y is —CH 2 —,
 
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, or stereoisomer.
 
       
    
     Another aspect of the invention are compounds of formula (I) 
     wherein, 
     
         
         R1 is hydrogen, halogen or a group selected from 1-6C-alkyl, aryl, heteroaryl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
       hydroxy, halogen, 1-6C-alkyl, 1-4C-hydroxyalkyl, cyano, —C(O)NR8R9, C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9,   
     
         R2 is hydrogen, halogen, cyano, or from 1-6C-alkyl, 
         R3 is hydrogen, 
         R4 is phenyl, 
         R5 is hydrogen. 
         R6 is hydrogen, 
         R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl is optionally substituted in the same way of differently one or more times with halogen, hydroxy, mono- or di-1-4C-alkylamino, 1-4C-alkoxy,
       or,   in the case of —NR8R9, R8 and R9 together with the nitrogen to which they are attached may also form a 3-6C-heterocyclic ring.   
     
         R10 is hydrogen, 1-6C-alkyl, 
         R11 is 1-4C-alkyl, 
         X is —(CH 2 ) n —, 
         n is 1, 
         Y is —CH 2 —,
 
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, or stereoisomer.
 
       
    
     Another aspect of the invention are compounds of formula (I) 
     wherein, 
     
         
         R1 is hydrogen, halogen or a group selected from 1-3C-alkyl, aryl, heteroaryl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
       hydroxy, halogen, 1-3C-alkyl, 1-3C-hydroxyalkyl, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9,   
     
         R2 is hydrogen, halogen, cyano, or a group selected from 1-3C-alkyl. 
         R3 is hydrogen, 
         R4 is phenyl. 
         R5 is hydrogen. 
         R6 is hydrogen, 
         R8, R9 which can be the same or different, is hydrogen, 1-3C-alkyl or 3-6C-cycloalkyl, wherein said 1-3C-alkyl and 3-6C-cycloalkyl is optionally substituted in the same way of differently one or more times with halogen, hydroxy, mono- or di-1-3C-alkylamino, 1-3C-alkoxy,
       or,   in the case of —NR8R9, R8 and R9 together with the nitrogen to which they are attached may also form a 3-6C-heterocyclic ring.   
     
         R10 is hydrogen, 1-3C-alkyl, 
         R11 is 1-3C-alkyl. 
         X is (CH 2 ) n —, 
         n is 1, 
         Y is —CH 2 —,
 
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
 
       
    
     Another aspect of the invention are compounds of formula (I) 
     wherein, 
     
         
         R1 is hydrogen, halogen, 1-3C-alkyl, 2-3C-alkenyl, —(CH═CH)C(O)NH2, —(CH═CH)C(O)OR10, pyrazolyl (optionally substituted with methyl), pyridyl (optionally substituted with hydroxy, methoxy, —C(O)OR10), indazolyl, phenyl, wherein the phenyl group can optionally be substituted with a substituent selected from the group consisting of halogen, methyl, hydroxymethyl, cyano, C(O)NH 2 , —C(O)OR10, —S(O) 2 R11, SO 2 —NH 2 , 
         R2 is hydrogen, methyl, halogen (especially chlorine, bromine), 
         R3 is hydrogen, 
         R4 is phenyl, 
         R5 is hydrogen. 
         R6 is hydrogen, 
         R10 is 1-3C-alkyl, 
         R11 is 1-3C-alkyl, 
         X is —CH 2 —. 
         Y is —CH 2 —,
 
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, or stereoisomer.
 
       
    
     Another aspect of the invention are compounds of formula (I) 
     wherein, 
     
         
         R1 is hydrogen, bromine, methyl, ethyl, —CH═CH2, —(CH═CH)C(O)NH2, —(CH═CH)C(O)OR10, pyrazolyl (optionally substituted with methyl), pyridyl (optionally substituted with hydroxy, methoxy, —C(O)OR10 (R10=methyl, ethyl)), indazolyl, phenyl, wherein the phenyl group can optionally be substituted with a substituent selected from the group consisting of
       fluoro, methyl, hydroxymethyl, cyano, C(O)NH2, —C(O)OR10, —S(O) 2 R11, SO 2 —NH 2 ,   
     
         R2 is hydrogen, methyl, chlorine, bromine, 
         R3 is hydrogen. 
         R4 is phenyl, 
         R5 is hydrogen. 
         R6 is hydrogen. 
         R10 is methyl, 
         R11 is methyl, 
         X is —CH 2 —, 
         Y is —CH 2 —,
 
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
 
       
    
     Another aspect of the invention are compounds of formula (I) 
     wherein, 
     
         
         R1 is hydrogen, bromine, methyl, phenyl, wherein the phenyl group can optionally be substituted with a substituent selected from the group consisting of halogen, methyl, hydroxymethyl, cyano, —C(O)OR10, —S(O) 2 R11, SO 2 —N(CH 3 ) 2 , SO 2 —NH 2 , 
         R2 is hydrogen. 
         R3 is hydrogen, 
         R4 is phenyl. 
         R5 is hydrogen. 
         R6 is hydrogen. 
         R10 is methyl. 
         R11 is methyl. 
         X is —CH 2 —. 
         Y is —CH 2 —,
 
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, or stereoisomer.
 
       
    
     In one aspect of the invention compounds of formula (I) as described above are selected from the group consisting of
     1-[4-(7-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,   1-[4-(3-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,   3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzonitrile,   1-{4-[3-(4-Methanesulfonylphenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzonitrile,   3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzoic acid methyl ester,   1-{4-[3-(4-Fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   1-[4-(7-Phenyl-3-p-tolyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,   (3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-methanol,   (4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-methanol formiate,   

     A further aspect of the invention are compounds of formula (I) as described above selected from the group consisting of
     4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzenesulfonamide hydrochloride,   1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine hydrochloride,   (5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-2-fluorophenyl)-methanol hydrochloride,   4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide hydrochloride,   3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide hydrochloride,   1-{4-[7-Phenyl-3-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   1-[4-(2-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine hydrochloride.   

     A further aspect of the invention are compounds of formula (I) as described above selected from the group consisting of
     5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-pyridin-2-ol   5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-pyridine-2-carboxylic acid methyl ester,   1-{4-[7-Phenyl-3-(2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   1-{4-[3-(1H-Indazol-6-yl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-nicotinic acid ethyl ester,   1-{4-[3-(5-Methoxypyridin-3-yl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide,   (5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-2-fluorophenyl)-methanol,   1-{4-[2-Methyl-7-phenyl-3-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   1-{4-[3-(4-Fluorophenyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide,   1-{4-[2-Methyl-7-phenyl-3-(2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   1-{4-[2-Methyl-7-phenyl-3-(5-methyl-2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   1-{4-[2-Bromo-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   1-{4-[2-Chloro-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   (E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamide,   1-[4-(7-Phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine   (E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamide,   (E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylic acid methyl ester,   1-[4-(2-Methyl-7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,   1-[4-(3-Ethyl-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine   

     In another aspect of the invention compounds of formula (I) as described above are selected from the group consisting of:
     1-[4-(7-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,   1-[4-(3-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,   3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzonitrile,   1-{4-[3-(4-Methanesulfonylphenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzonitrile,   3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzoic acid methyl ester,   1-{4-[3-(4-Fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   1-[4-(7-Phenyl-3-p-tolyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,   (3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-methanol,   (4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-methanol formiate,   4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzenesulfonamide hydrochloride,   1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine hydrochloride,   (5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-2-fluorophenyl)-methanol hydrochloride,   4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide hydrochloride,   3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide hydrochloride,   1-{4-[7-Phenyl-3-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   1-[4-(2-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine hydrochloride.   5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-pyridin-2-ol   5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-pyridine-2-carboxylic acid methyl ester   1-{4-[7-Phenyl-3-(2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   1-{4-[3-(1H-Indazol-6-yl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-nicotinic acid ethyl ester,   1-{4-[3-(5-Methoxypyridin-3-yl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide,   (5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-2-fluorophenyl)-methanol,   1-{4-[2-Methyl-7-phenyl-3-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   1-{4-[3-(4-Fluorophenyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide,   1-{4-[2-Methyl-7-phenyl-3-(2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   1-{4-[2-Methyl-7-phenyl-3-(5-methyl-2H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   1-{4-[2-Bromo-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   1-{4-[2-Chloro-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine,   (E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamide,   1-[4-(7-Phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,   (E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamide,   (E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylic acid methyl ester,   1-[4-(2-Methyl-7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine,   1-[4-(3-Ethyl-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine.   

     One aspect of the present invention are the compounds disclosed in the examples as well as the intermediates as used for their synthesis. 
     One aspect of the invention is intermediate (II) wherein Rx is R6 or a protecting group Ry is hydrogen or a protecting group, whereby Rx and Ry together, or Y and Rx together, may form a cyclic protecting group, whereby X, Y, R1, R2, R3, R4, R5 and R6 are defined according to claim  1  or preferably Rx is —C(O)OtBu, and Ry is hydrogen. 
     Another aspect of the invention are compounds of formula (I), wherein
     R1 is hydrogen, halogen, 2-6C-alkenylen-C(O)NH2, 2-6C-alkenylen-C(O)OR10, or a group selected from 1-6C-alkyl, 2-6C-alkenyl, 3-7C-cycloalkyl, aryl, heteroaryl,
       wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:   hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9,   
       

     For R1=2-6C-alkenyl, the 2-6C-alkenyl group is preferably unsubstituted, especially vinyl.
     R1 is hydrogen, halogen or a group selected from 1-6C-alkyl, 3-7C-cycloalkyl, aryl, heteroaryl,
       wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:   hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-4C-hydroxyalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9.   
       

     Another aspect of the invention are compounds of formula (I), wherein
     R1 is hydrogen, halogen or a group selected from 1-6C-alkyl, aryl, heteroaryl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
       hydroxy, halogen, 1-6C-alkyl, 1-4C-hydroxyalkyl, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11, —S(O) 2 R11, —S(O) 2 NR8R9.   
       

     Another aspect of the invention are compounds of formula (I), wherein
     R1 hydrogen, 1-3C-alkyl, phenyl (which is optionally substituted with cyano, methylsulfonyl, methoxycarbonyl, fluorine, methyl, hydroxymethyl, aminosulfonyl), bromine, pyrazolyl (which is optionally substituted with methyl), pyridyl (which is optionally substituted with hydroxy, methoxycarbonyl, ethoxycarbonyl, methoxy), indazolyl, —CH═CH—C(O)NH2, —CH═CH—C(O)—OCH3, 2-3C-alkenyl.   

     One aspect of the invention are compounds of formula (I), wherein
     R1 —CH═CH—C(O)—NH2 or —CH═CH—C(O)—OCH3.   

     Another aspect of the invention are compounds of formula (I), wherein
     R1 is hydrogen, bromine, methyl, phenyl, wherein the phenyl group can optionally be substituted with a substituent selected from the group consisting of halogen, methyl, hydroxymethyl, cyano, —C(O)OR10, —S(O) 2 R11, SO 2 —N(CH 3 ) 2 , SO 2 —NH2.   

     Another aspect of the invention are compounds of formula (I), wherein
     R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl, 3-7C-cycloalkyl,
       wherein said 1-6C-alkyl being optionally substituted, one or more times, identically or differently, with a substituent selected from:   hydroxy, halogen, 1-6C-alkoxy.   
       

     Another aspect of the invention are compounds of formula (I), wherein
     R2 is hydrogen, halogen, cyano, or a group selected from 1-6C-alkyl, 3-7C-cycloalkyl.   

     Another aspect of the invention are compounds of formula (I), wherein
     R2 is hydrogen, halogen, cyano, or a group 1-6C-alkyl.   

     Another aspect of the invention are compounds of formula (I), wherein
     R2 is hydrogen, methyl, bromine, chlorine.   

     Another aspect of the invention are compounds of formula (I), wherein
     R2 is hydrogen.   

     Another aspect of the invention are compounds of formula (I), wherein
     R2 is 1-6C-alkyl.   

     Another aspect of the invention are compounds of formula (I), wherein
     R2 is methyl.   

     Another aspect of the invention are compounds of formula (I), wherein
     R3 is hydrogen, 1-6C-alkyl, 3-7C-cycloalkyl.   

     Another aspect of the invention are compounds of formula (I), wherein
     R3 is hydrogen.   

     Another aspect of the invention are compounds of formula (I), wherein
     R4 is phenyl optionally substituted, one or more times, identically or differently, with a substituent selected from: 1-6C-alkyl, halogen, cyano.   

     Another aspect of the invention are compounds of formula (I), wherein
     R4 is phenyl.   

     Another aspect of the invention are compounds of formula (I), wherein
     R5 is hydrogen, halogen.   

     Another aspect of the invention are compounds of formula (I), wherein
     R5 is hydrogen.   

     Another aspect of the invention are compounds of formula (I), wherein
     R6 is hydrogen, 1-6C-alkyl.   

     Another aspect of the invention are compounds of formula (I), wherein
     R6 is hydrogen.   

     Another aspect of the invention are compounds of formula (I), wherein
     R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl, wherein said 1-4C-alkyl and 3-7C-cycloalkyl is optionally substituted in the same way of differently one or more times with halogen, hydroxy, mono- or di-1-4C-alkylamino, 1-4C-alkoxy,
       or,   in the case of —NR8R9, R8 and R9 together with the nitrogen to which they are attached may also form a 3-6C-heterocyclic ring.   
       

     Another aspect of the invention are compounds of formula (I), wherein
     R8, R9 which can be the same or different, is hydrogen, 1-4C-alkyl (optionally substituted in the same way of differently one or more times with halogen, hydroxy, mono- or di-1-4C-alkylamino, 1-4C-alkoxy), or 3-7C-cycloalkyl,
       or,   in the case of —NR8R9, R8 and R9 together with the nitrogen to which they are attached may also form a 3-6C-heterocyclic ring.   
       

     Another aspect of the invention are compounds of formula (I), wherein
     R10 is hydrogen, 1-6C-alkyl.   

     Another aspect of the invention are compounds of formula (I), wherein
     R10 is methyl.   

     Another aspect of the invention are compounds of formula (I), wherein
     R11 is 1-4C-alkyl (optionally substituted in the same way of differently one or more times with halogen, hydroxy) or 3-7C-cycloalkyl.   

     Another aspect of the invention are compounds of formula (I), wherein
     R11 is 1-4C-alkyl.   

     Another aspect of the invention are compounds of formula (I), wherein
     R11 is methyl.   

     Another aspect of the invention are compounds of formula (I), wherein
     X is (CH 2 ) n —.   

     Another aspect of the invention are compounds of formula (I), wherein
     X is —CH 2 —.   

     Another aspect of the invention are compounds of formula (I), wherein
     n is 0, 1, 2 or 3.   

     Another aspect of the invention are compounds of formula (I), wherein
     n is 0, 1 or 2.   

     Another aspect of the invention are compounds of formula (I), wherein
     n is 0 or 1.   

     Another aspect of the invention are compounds of formula (I), wherein
     n is 1.   

     Another aspect of the invention are compounds of formula (I), wherein
     Y is —CH 2 —, —CH(OH)—.   

     Another aspect of the invention are compounds of formula (I), wherein
     Y is —CH 2 .   

     In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein R6 is hydrogen and R5 is hydrogen. 
     In another embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein R6 is hydrogen, R5 is hydrogen and R4 is an unsubstituted phenyl moiety. 
     In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein R5 is hydrogen and R4 is an unsubstituted phenyl moiety. 
     Another aspect of the invention relates to the group of compounds obtained by combinations and subcombinations of all residues as disclosed in the examples. 
     DEFINITIONS 
     Constituents which are optionally substituted as stated herein, may be substituted, unless otherwise noted, one or more times, independently from one another at any possible position. When any variable occurs more than one time in any constituent, each definition is independent. 
     Unless defined otherwise in the claims the constituents defined below can optionally be substituted, one or more times, identically or differently, with a substituent selected from: 
     hydroxy, halogen, cyano, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9, cyano, (═O), —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHS(O) 2 R11. An alkyl constituent being substituted more times by halogen includes also a completely halogenated alkyl moiety such as e.g. CF3. 
     Should a constituent be composed of more than one part, e.g. —O-(1-6Calkyl)-3-7C-cycloalkyl, the position of a possible substituent can be at any of these parts at any suitable position. A hyphen at the beginning of the constituent marks the point of attachment to the rest of the molecule. Should a ring be substituted the substitutent could be at any suitable position of the ring, also on a ring nitrogen atom. 
     The term “comprising” when used in the specification includes “consisting of”. 
     If it is referred to “as mentioned above” or “mentioned above” within the description it is referred to any of the disclosures made within the specification in any of the preceding pages. 
     “suitable” within the sense of the invention means chemically possible to be made by methods within the knowledge of a skilled person. 
     If it is referred to “compounds of formula (I)” it is understood that it is referred to compounds of formula (I) as claimed in the compound claims. 
     “1-6C-alkyl” is a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Examples are methyl, ethyl, n propyl, iso-propyl, n butyl, iso-butyl, sec-butyl and tert-butyl, pentyl, hexyl, preferably 1-4 carbon atoms (1-4C-alkyl), more preferably 1-3 carbon atoms (1-3C-alkyl). Other alkyl constituents mentioned herein having another number of carbon atoms shall be defined as mentioned above taking into account the different length of their chain 
     “1-4C-Haloalkyl” is a straight-chain or branched alkyl group having 1 to 4 carbon atoms in which at least one hydrogen is substituted by a halogen atom. Examples are chloromethyl or 2-bromoethyl. For a partially or completely fluorinated C1-C4-alkyl group, the following partially or completely fluorinated groups are considered, for example: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, tetrafluoroethyl, and penta-fluoroethyl, whereby fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, or 1,1,1-trifluoroethyl are preferred. Partially or completely fluorinated C1-C4-alkyl groups are considered to be encompassed by the term 1-4C-haloalkyl. 
     “Mono- or di-1-4C-alkylamino” radicals contain in addition to the nitrogen atom, independently one or two of the above mentioned 1-4C-alkyl radicals. Examples are the methyamino, the ethylamino, the isopropylamino, the dimethylamino, the diethylamino and the diisopropylamino radical. 
     “2-6C-Alkenyl” is a straight chain or branched alkenyl radical having 2 to 4 carbon atoms. Examples are the but-2-enyl, but-3-enyl (homoallyl), prop-1-enyl, prop-2-enyl (allyl) and the ethenyl (vinyl) radicals. 
     “2-6-Alkenylen” is defined as above except that this moiety is bound to other groups/rest of the compound of formula (I) on both sides resulting in spacer position between two groups, e.g. for R1=“2-6-alkenylen-C(O)NH2” the alkenylen group is a spacer between the heterocycle of formula (I) and the group “—C(O)NH2”. 
     “Halogen” within the meaning of the present invention is iodine, bromine, chlorine or fluorine, preferably “halogen” within the meaning of the present invention is chlorine or fluorine. 
     “1-4C-Hydroxyalkyl” is a straight-chain or branched alkyl group having 1 to 4 carbon atoms whereby the hydroxyl group may be bound at any of the carbon atoms of the chain. Examples are hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, (HO)CH 2 —CH(CH 3 )—, (CH 3 ) 2 —C(OH)—, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, hydroxymethyl is preferred. 
     “1-6C-Alkoxy” represents radicals, which in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. Examples which may be mentioned are the hexoxy, pentoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pro-poxy, isopropoxy, ethoxy and methoxy radicals, preferred are methoxy, ethoxy, propoxy, isopropoxy. 
     “Aryl” represents a mono-, or bicyclic aromatic carbocyclic radical having, as a rule, 6 to 10 carbon atoms; by way of example phenyl or naphthyl. Phenyl is preferred. 
     “3-7C-Cycloalkyl” stands for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclopropyl. 
     The term “heteroaryl” represents a monocyclic 5- or 6-membered aromatic heterocycle comprised without being restricted thereto, the 5-membered heteroaryl radicals furyl, thienyl, pyrrolyl, oxa-zolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl (1,2,4-triazolyl, 1,3,4-triazolyl or 1,2,3-triazolyl), thiadiazolyl (1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl or 1,2,4-thiadiazolyl) and oxadiazolyl (1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl or 1,2,4-oxadiazolyl), as well as the 6-membered heteroaryl radicals pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl as well as bicyclic moieties such as e.g. benzofuranyl, benzothienyl, indazolyl, purinyl, chinolinyl, isochinolinyl, phthalazinyl, naphthyridinyl, chinocalinyl, chinazolinyl, cinnolinyl, pteridinyl, indolizinyl, indolyl, isoindolyl. Preferred 5- or 6-membered heteroaryl radicals are furanyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl. More preferred 5- or 6-membered heteroaryl radicals are furan-2-yl, thien-2-yl, pyrrol-2-yl, thiazolyl, oxazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl or pyridazin-3-yl. Preferred bicyclic radical is indazolyl. 
     In general and unless otherwise mentioned, the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof. Thus, for some illustrative non-restricting example, the term pyridinyl or pyridinylene includes pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene. 
     The heteroarylic groups mentioned herein may be substituted by their given substituents or parent molecular groups, unless otherwise noted, at any possible position, such as e.g. at any substitutable ring carbon or ring nitrogen atom. Analogously it is being understood that it is possible for any heteroaryl group to be attached to the rest of the molecule via any suitable atom if chemically suitable. Unless otherwise noted, any heteroatom of a heteroarylic ring with unsatisfied valences mentioned herein is assumed to have the hydrogen atom(s) to satisfy the valences. Unless otherwise noted, rings containing quaternizable amino- or imino-type ring nitrogen atoms (—N═) may be preferably not quaternized on these amino- or imino-type ring nitrogen atoms by the mentioned substituents or parent molecular groups. 
     In the case of —NR8R9, when R8 and R9 together with the nitrogen atom to which they are attached form a 3-6C-heterocyclic ring, the term “3-6C-heterocyclic ring” includes all saturated heterocyclic rings containing 4 to 7 ring atoms and having 1 or 2 nitrogen atoms, or 1 nitrogen atom and 1 oxygen atom. The 3-6C-heterocyclic ring may be optionally substituted one or more times, identically or differently, with a substituent selected from: 1-4C-alkyl, 1-4C-haloalkyl, 1-4C-alkoxy, hydroxy, fluorine, whereby the 1-4C-alkyl may be optionally further substituted with hydroxy. Preferred examples are azetidine, 3-hydroxyazetidine, 3-fluoroazetidine, 3,3-difluoroazetidine, pyrrolidine, 3-hydroxypyrrolidine, piperidine, 3-hydroxypiperidine, 4-hydroxypiperidine, 3-fluoropiperidine, 3,3-difluoropiperidine, 4-fluoropiperidine, 4,4-difluoropiperidine, piperazine, N-methyl-piperazine. N-(2-hydroxyethylypiperazine, morpholine. 
     The NR8R9 group includes, for example, NH 2 , N(H)CH 3 , N(CH 3 ) 2 , N(H)CH 2 CH 3  and N(CH 3 )CH 2 CH 3 . In the case of —NR8R9, when R8 and R9 together with the nitrogen atom to which they are attached form a 3-6C-heterocyclic ring, the term “3-6C-heterocyclic ring” is defined above. 
     The NH(CO)R11 group includes for example NH(CO)CH 3 . NH(CO)C 2 H 5 , NH(CO)C 3 H 7 , NH(CO)CH(CH 3 ) 2 . 
     The NHS(O) 2 R11 group includes for example NHS(O) 2 CH 3 , NHS(O) 2 C 2 H 5 , NHS(O) 2 C 3 H 7 , NHS(O) 2 CH(CH 3 ) 2 . 
     The C(O)NR8R9 group includes, for example, C(O)NH 2 , C(O)N(H)CH 3 , C(O)N(CH 3 ) 2 , C(O)N(H)CH 2 CH 3 , C(O)N(CH 3 )CH 2 CH 3  or C(O)N(CH 2 CH 3 ) 2 . In the case of —NR8R9, when R8 and R9 together with the nitrogen atom to which they are attached form a 3-6C-heterocyclic ring, the term “3-6C-heterocyclic ring” is defined above. 
     The C(O)OR10 group includes for example C(O)OH, C(O)OCH 3 , C(O)OC 2 H 5 , C(O)C 3 H 7 , C(O)CH(CH 3 ) 2 , C(O)OC 4 H 9 , C(O)OC 5 H 11 , C(O)OC 6 H 13 ; for C(O)O(1-6Calkyl) the alkyl part may be straight or branched. 
     Salts of the compounds according to the invention include all inorganic and organic acid addition salts and salts with bases, especially all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases, particularly all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases customarily used in pharmacy. 
     One aspect of the invention are salts of the compounds according to the invention including all inorganic and organic acid addition salts, especially all pharmaceutically acceptable inorganic and organic acid addition salts, particularly all pharmaceutically acceptable inorganic and organic acid addition salts customarily used in pharmacy. Another aspect of the invention are the salts with di- and tricarboxylic acids. 
     Examples of acid addition salts include, but are not limited to, hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, salts of sulfamic acid, formates, acetates, propionates, citrates, D-gluconates, benzoates, 2-(4-hydroxybenzoyl)-benzoates, butyrates, salicylates, sulfosalicylates, lactates, maleates, laurates, malates, fumarates, succinates, oxalates, malonates, pyruvates, acetoacetates, tartarates, stearates, benzensulfonates, toluenesulfonates, methanesulfonates, trifluoromethansulfonates, 3-hydroxy-2-naphthoates, benzenesulfonates, naphthalinedisulfonates and trifluoroacetates. 
     Examples of salts with bases include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, meglumine, ammonium, salts optionally derived from NH 3  or organic amines having from 1 to 16 C-atoms such as e.g. ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylendiamine. N-methylpiperindine and guanidinium salts. 
     The salts include water-insoluble and, particularly, water-soluble salts. 
     According to the person skilled in the art the compounds of formula (I) according to this invention as well as their salts may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are therefore all solvates and in particular all hydrates of the compounds of formula (I) according to this invention as well as all solvates and in particular all hydrates of the salts of the compounds of formula (I) according to this invention. 
     The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as  2 H (deuterium),  3 H (tritium),  13 C,  14 C,  15 N,  17 O,  18 O,  32 P,  33 P,  33 S,  34 S,  35 S,  36 S,  18 F,  36 Cl,  82 Br,  123 I,  124 I,  129 I and  131 I, respectively. Certain isotopic variations of a compound of the invention, for example, those in which one or more radioactive isotopes such as  3 H or  14 C are incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e.,  14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents. 
     The term “combination” in the present invention is used as known to persons skilled in the art and may be present as a fixed combination, a non-fixed combination or kit-of-parts. 
     A “fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity. One example of a “fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a “fixed combination” is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture. 
     A non-fixed combination or “kit-of-parts” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the said first active ingredient and the said second active ingredient are present separately. The components of the non-fixed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered. 
     The term “another profile” as used in the description of the invention means that the compounds according to the invention possess a differentiating selectivity to words AKT1 and AKT2. 
     The term “(chemotherapeutic) anti-cancer agents”, includes but is not limited to (i) alkylating/carbamylating agents such as Cyclophosphamid (Endoxan®), Ifosfamid (Holoxan®), Thiotepa (Thiotepa Lederle®), Melphalan (Alkeran®), or chloroethylnitrosourea (BCNU); (ii) platinum derivatives like cis-platin (Platinex® BMS), oxaliplatin (Eloxatin®), satraplatin or carboplatin (Cabroplat® BMS); (iii) antimitotic agents/tubulin inhibitors such as vinca alkaloids (vincristine, vinblastine, vinorelbine), taxanes such as Paclitaxel (Taxol®), Docetaxel (Taxotere®) and analogs as well as new formulations and conjugates thereof (like the nanoparticle formulation Abraxane® with paclitaxel bound to albumin), epothilones such as Epothilone B (Patupilone®), Azaepothilone (Ixabepilone®) or Sagopilone; (iv) topoisomerase inhibitors such as anthracyclines (exemplified by Doxorubicin/Adriblastin®), epipodophyllotoxines (examplified by Etoposide/Etopophos®) and camptothecin and camptothecin analogs (exemplified by Irinotecan/Camptosar® or Topotecan/Hycamtin®); (v) pyrimidine antagonists such as 5-fluorouracil (5-FU), Capecitabine (Xeloda®), Arabinosylcytosine Cytarabin (Alexan®) or Gemcitabine (Gemzar®); (vi) purin antagonists such as 6-mercaptopurine (Puri-Nethol®), 6-thioguanine or fludarabine (Fludara®) and (vii) folic acid antagonists such as methotrexate (Farmitrexat®) or premetrexed (Alimta®). 
     The term “target specific anti-cancer agent”, includes but is not limited to (i) kinase inhibitors such as e.g. Imatinib (Glivec®), ZD-1839/Gefitinib (Iressa®), Bay43-9006 (Sorafenib, Nexavar®), SU11248/Sunitinib (Sutent®), OSI-774 Erlotinib (Tarceva®), Dasatinib (Sprycel®), Lapatinib (Tykerb®), or, see also below, Vatalanib, Vandetanib (Zactima®) or Pazopanib; (ii) proteasome inhibitors such as PS-341/Bortezumib (Velcade®); (iii) histone deacetylase inhibitors like SAHA (Zolinza®), PXD101, MS275, MGCD0103, Depsipeptide/FK228, NVP-LBH589, Valproic acid (VPA), CRA PCI-24781, ITF2357, SB939 and butyrates (iv) heat shock protein 90 inhibitors like 17-allylaminogeldanamycin (17-AAG) or 17-dimethylaminogeldanamycin (17-DMAG); (v) vascular targeting agents (VTAs) like combretastin A4 phosphate or AVE8062/AC7700 and anti-angiogenic drugs like the VEGF antibodies, such as Bevacizumab (Avastin®), or KDR tyrosine kinase inhibitors such as PTK787 ZK222584 (Vatalanib®) or Vandetanib (Zactima®) or Pazopanib; (vi) monoclonal antibodies such as Trastuzumab (Herceptin®), Rituximab (MabThera/Rituxan®), Alemtuzumab (Campath®), Tositumomab (Bexxar®), C225/Cetuximab (Erbitux®), Avastin (see above) or Panitumumab (Vectibix®) as well as mutants and conjugates of monoclonal antibodies, e.g. Gemtuzumab ozogamicin (Mylotarg®) or Ibritumomab tiuxetan (Zevalin®), and antibody fragments; (vii) oligonucleotide based therapeutics like G-3139/Oblimersen (Genasense® or the DNMT1 inhibitor MG98; (viii) Toll-like receptor/TLR 9 agonists like Promune®, TLR 7 agonists like Imiquimod (Aldara®) or Isatoribine and analogues thereof, or TLR 7/8 agonists like Resiquimod as well as immunostimulatory RNA as TLR 7/8 agonists; (ix) protease inhibitors; (x) hormonal therapeutics such as anti-estrogens (e.g. Tamoxifen or Raloxifen), anti-androgens (e.g. Flutamide or Casodex), LHRH analogs (e.g. Leuprolide, Goserelin or Triptorelin) and aromatase inhibitors (e.g. Femara, Arimedex or Aromasin). 
     Other “target specific anti-cancer agents” include bleomycin, retinoids such as all-trans retinoic acid (ATRA), DNA methyltransferase inhibitors such as 5-Aza-2′-deoxycytidine (Decitabine, Dacogen®) and 5-azacytidine (Vidaza®), alanosine, cytokines such as interleukin-2, interferons such as interferon α2 or interferon-γ, bcl2 antagonists (e.g. ABT-737 or analogs), death receptor agonists, such as TRAIL, DR4/5 agonistic antibodies, FasL and TNF-R agonists (e.g. TRAIL receptor agonists like mapatumumab or lexatumumab). 
     Specific examples of anti-cancer agents include, but are not limited to 5 FU, actinomycin D, ABARELIX, ABCIXIMAB, ACLARUBICIN, ADAPALENE, ALEMTUZUMAB, ALTRETAMINE, AMINOGLUTETHIMIDE, AMIPRILOSE, AMRUBICIN, ANASTROZOLE, ANCITABINE, ARTEMISININ, AZATHIOPRINE, BASILIXIMAB, BENDAMUSTINE, BEVACIZUMAB, BEXXAR, BICALUTAMIDE, BLEOMYCIN, BORTEZOMIB, BROXURIDINE, BUSULFAN, CAMPATH, CAPECITABINE, CARBOPLATIN, CARBOQUONE, CARMUSTINE, CETRORELIX, CHLORAMBUCIL, CHLORMETHINE, CISPLATIN, CLADRIBINE, CLOMIFENE, CYCLOPHOSPHAMIDE, DACARBAZINE, DACLIZUMAB, DACTINOMYCIN, DASATINIB, DAUNORUBICIN, DECITABINE, DESLORELIN, DEXRAZOXANE, DOCETAXEL, DOXIFLURIDINE, DOXORUBICIN, DROLOXIFENE, DROSTANOLONE, EDELFOSINE, EFLORNITHINE, EMITEFUR, EPIRUBICIN, EPITIOSTANOL, EPTAPLATIN, ERBITUX, ERLOTINIB, ESTRAMUSTINE, ETOPOSIDE, EXEMESTANE, FADROZOLE, FINASTERIDE, FLOXURIDINE, FLUCYTOSINE, FLUDARABINE, FLUOROURACIL, FLUTAMIDE, FORMESTANE, FOSCARNET, FOSFESTROL, FOTEMUSTINE, FULVESTRANT, GEFITINIB, GENASENSE, GEMCITABINE, GLIVEC, GOSERELIN, GUSPERIMUS, HERCEPTIN, IDARUBICIN, IDOXURIDINE, IFOSFAMIDE, IMATINIB, IMPROSULFAN, INFLIXIMAB, IRINOTECAN, IXABEPILONE, LANREOTIDE, LAPATINIB, LETROZOLE, LEUPRORELIN, LOBAPLATIN, LOMUSTINE, LUPROLIDE, MELPHALAN, MERCAPTOPURINE, METHOTREXATE, METUREDEPA, MIBOPLATIN, MIFEPRISTONE, MILTEFOSINE, MIRIMOSTIM, MITOGUAZONE, MITOLACTOL, MITOMYCIN, MITOXANTRONE, MIZORIBINE, IVIOTEXAFIN, MYLOTARG, NARTOGRASTIM, NEBAZUMAB, NEDAPLATIN, NILUTAMIDE, NIMUSTINE, OCTREOTIDE, ORMELOXIFENE, OXALIPLATIN. PACLITAXEL, PALIVIZUMAB, PANITUMUMAB, PATUPILONE, PAZOPANIB, PEGASPARGASE, PEGFILGRASTIM, PEMETREXED, PENTETREOTIDE, PENTOSTATIN, PERFOSFAMIDE, PIPOSULFAN, PIRARUBICIN, PLICAMYCIN, PREDNIMUSTINE, PROCARBAZINE, PROPAGERMANIUM, PROSPIDIUM CHLORIDE, RALOXIFEN, RALTITREXED, RANIMUSTINE, RANPIRNASE, RASBURICASE, RAZOXANE, RITUXIMAB, RIFAMPICIN, RITROSULFAN, ROMURTIDE, RUBOXISTAURIN, SAGOPILONE, SARGRAMOSTIM, SATRAPLATIN, SIROLIMUS, SOBUZOXANE, SORAFENIB, SPIROMUSTINE, STREPTOZOCIN, SUNITINIB, TAMOXIFEN, TASONERMIN, TEGAFUR, TEMOPORFIN, TEMOZOLOMIDE, TENIPOSIDE, TESTOLACTONE, THIOTEPA, THYMALFASIN, TIAMIPRINE, TOPOTECAN, TOREMIFENE, TRAIL, TRASTUZUMAB, TREOSULFAN, TRIAZIQUONE, TRIMETREXATE, TRIPTORELIN, TROFOSFAMIDE, UREDEPA, VALRUBICIN, VATALANIB, VANDETANIB, VERTEPORFIN, VINBLASTINE, VINCRISTINE, VINDESINE, VINORELBINE, VOROZOLE, ZEVALIN and ZOLINZA. 
     The compounds according to the invention and their salts can exist in the form of tautomers which are included in the embodiments of the invention. 
     The compounds of the invention may, depending on their structure, exist in different stereoisomeric forms. These forms include configurational isomers or optionally conformational isomers (enantiomers and/or diastereoisomers including those of atropisomers). The present invention therefore includes enantiomers, diastereoisomers as well as mixtures thereof. From those mixtures of enantiomers and/or disastereoisomers pure stereoisomeric forms can be isolated with methods known in the art, preferably methods of chromatography, especially high pressure liquid chromatography (HPLC) using achiral or chiral phase. The invention further includes all mixtures of the stereoisomers mentioned above independent of the ratio, including the racemates. 
     Some of the compounds and salts according to the invention may exist in different crystalline forms (polymorphs) which are within the scope of the invention. 
     Furthermore, derivatives of the compounds of formula (I) and the salts thereof which are converted into a compound of formula (I) or a salt thereof in a biological system (bioprecursors or pro-drugs) are covered by the invention. Said biological system is e.g. a mammalian organism, particularly a human subject. The bioprecursor is, for example, converted into the compound of formula (I) or a salt thereof by metabolic processes. 
     The intermediates used for the synthesis of the compounds of claims  1 - 5  as described below, as well as their use for the synthesis of the compounds of claims  1 - 5 , are one further aspect of the present invention. Preferred intermediates are intermediate of formula (II) as well as the Intermediate Examples as disclosed below. 
     The compounds according to the invention can be prepared according to the following schemes: 
     
       
         
         
             
             
         
       
     
     The compounds according to the invention can be prepared according to reaction scheme 1 wherein X, Y, R1, R2*), R3, R4, R5 and R6 have the meanings defined in claim  1 ; Rx has the meaning of R6 and may also be a protecting group: Ry is H, or a protecting group, whereby Rx and Ry together, or Y and Rx together, may form a cyclic protecting group; Hal is a halogen; Xa is a leaving group such as halogen, or a sulfonyl ester, preferably Cl, Br, I, OTs, OTf, or ONf; M is —B(OH) 2 , Sn(1-4C-alkyl) 3 , ZnCl, ZnBr, ZnI, or, 
     
       
         
         
             
             
         
       
     
     Compounds of general formula (I) may be prepared from compounds of general formula (II). Rx may optionally be R6, or a protecting group, or other such precursor which requires further manipulation. For example, Rx in compounds of general formula (II) may be a protecting group such as the Boc group, —CO(OtBu), or Rx and Ry, together with the nitrogen to which they are attached, form a cyclic protecting group such as a phthalimide. Preparation of compounds of general formula (I) may thus be accomplished by use of an appropriate deprotection reaction, such as in the case of a Boc group, acidic reaction conditions, for example, with a solution of 4M hydrogen chloride in dioxane, in an appropriate solvent, such as for example DCM and methanol, at ambient temperature. Further conditions to deprotect the Boc group, or further protecting groups that may be suitable for use in blocking the amino functionality in compounds of general formula (II), including their synthesis and deprotection, are found, for example, in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley &amp; Sons, 1999, 3rd Ed., or in P. Kocienski, Protecting Groups, Thieme Medical Publishers, 2000. Similarly, when Ry is not H, then Ry is a protecting group, such as for example when Rx and Ry together form a cyclic protecting group such as for example a phthalamide. 
     Compounds of general formula (II) may be prepared by reacting a compound of general formula (III) with a compound R-M, for example by a transition metal catalysed C—C bond formation. The transition metal catalysed C—C bond formation reaction can, for example, be achieved if M has the meaning of, 
                         
and Xa is Cl, in a suitable solvent such as THF, NMP, DMF, DME, dioxane or mixtures of the above, in the presence of a suitable base, such as aqueous sodium carbonate or potassium carbonate solution, at a suitable temperature, such as from 60° C. to 120° C. and by employing a suitable metal catalyst, such as a palladium catalyst, for example 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) [Pd(dppf)Cl 2 ], bis(tri-tert.-butylphosphin)palladium(0) [Pd(PtBu 3 ) 2 ], or Pd(PPh 3 ) 4 .
 
     Compounds of general formula (III) may be prepared by introducing a leaving group Xa into a compound of general formula (IV). This transformation can, for example, be achieved by reacting a compound of general formula (IV) with N-bromosuccinimide or N-chlorosuccinimide. However, this transformation is restricted to compounds in which R2 is H or alkyl or cycloalkyl. 
     *) R2=halogen is introduced in compounds in which R1 is not hydrogen, as an example reference is made to examples 6 and 7. 
     Compounds of general formula (IV) may be prepared by reacting a compound of general formula (V) with a compound of general formula (VI), for example by a transition metal catalysed C—C bond formation. The transition metal catalysed C—C bond formation reaction can, for example, be achieved if M has the meaning of, 
                         
and Xa is Cl, in a suitable solvent such as THF, NMP, DMF, DME, dioxane or mixtures of the above, in the presence of a suitable base, such as aqueous sodium carbonate or potassium carbonate solution, at a suitable temperature, such as from 60° C. to 120° C. and by employing a suitable metal catalyst, such as a palladium catalyst, for example 1,1′-bis(diphenylphosphino)ferroceneldichloropalladium(II) [Pd(dppf)Cl 2 ], bis(tri-tert.-butylphosphin)palladium(0) [Pd(PtBu 3 ) 2 ], or Pd(PPh 3 ) 4 .
 
     Compounds of general formula (VI) may be prepared from compounds of general formula (VII) using known methods, for example, if M has the meaning of 
                         
by way of a palladium catalysed borylation reaction, using a suitable metal complex such as a palladium complex formed in situ from a suitable palladium salt and a suitable phosphine ligand, for example, PdCl 2 (CH 3 CN) 2  and SPhos (CAS 657408-07-6), or a preformed palladium complex such as a suitable boron reagent, such as pinacol borane, or bis(pinacolato)diboron (CAS 73183-34-3), a suitable solvent, such as dioxane, DMSO, or THF, and elevated temperatures, such as up to the boiling point of the solvent, preferably 80-120° C. An analogue procedure for the palladium catalysed borylation of aryl halides using pinacol borane is reported by Buchwald et al in J. Org. Chem. 2008, p5589. Alternatively, borylation may be achieved by halogen-metal exchange, followed by quenching of the anion with a suitable borate ester. For example, compounds of general formula (VII) may be reacted with 2 Eq of sec-butyl lithium or n-butyl lithium in a suitable solvent such as THF, at suitable temperature, such as from −78° C. to 20° C., preferably from −78° C. to −50° C., followed by reaction with methyl pinacol borate or isopropyl pinacol borate. Analogous procedures are known in the literature, such as in EP1870099.
 
     Compounds of general formula (VII) and (VIII) are either commercially available, may be prepared using the methods described below, may be prepared using known methods, or may be prepared by analogous methods to those known by the person skilled in the art. 
     One aspect of the invention is the reaction of compounds of general formulae (V) and (VI) followed by introduction of a leaving group to form a compound of general formula (III). A further aspect is the introduction of R1 to form a compound of general formula (II) as well as deprotection of the compound of general formula (II) to form a compound of general formula (I). 
     
       
         
         
             
             
         
       
     
     Compounds of general formula (V) may be prepared according to reaction scheme 2 by reaction of (IX) with a compound (XIII), wherein R2, R3 and R4 have the meanings defined above; Ka and Xb are halogen. The compounds (XIII) are commercially available. The compounds of general formula (V) and (IX) and (XIII) are described in US 2007/0078136 (WO2007/1038314) as well. 
     Another aspect of the invention is the intermediate of general formula (III) 
                         
wherein
     Rx is R6 or a protecting group   Ry is hydrogen or a protecting group.
       whereby Rx and Ry together, or Y and Rx together, may form a cyclic protecting group,
 
whereby X, Y, R1, R2, R3, R4, R5 and R6 are defined according to claim  1  as well as its use for the production of the compounds of general formula (I).
   
       

     It is known to the person skilled in the art that, if there are a number of reactive centers on a starting or intermediate compound, it may be necessary to block one or more reactive centers temporarily by protective groups in order to allow a reaction to proceed specifically at the desired reaction center. A detailed description for the use of a large number of proven protective groups is found, for example, in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley &amp; Sons, 1999, 3rd Ed., or in P. Kocienski, Protecting Groups, Thieme Medical Publishers, 2000. 
     The compounds according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as chromatography on a suitable support material. Furthermore, reverse phase preparative HPLC of compounds of the present invention which possess a sufficiently basic or acidic functionality, may result in the formation of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. Salts of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. Additionally, the drying process during the isolation of compounds of the present invention may not fully remove traces of cosolvents, especially such as formic acid or trifluoroacetic acid, to give solvates or inclusion complexes. The person skilled in the art will recognise which solvates or inclusion complexes are acceptable to be used in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base, solvate, inclusion complex) of a compound of the present invention as isolated as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity. 
     Salts of the compounds of formula (I) according to the invention can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added. The acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art. 
     Pure diastereomers and pure enantiomers of the compounds and salts according to the invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis and by splitting up enantiomeric and diasteriomeric mixtures obtained in synthesis. 
     Enantiomeric and diastereomeric mixtures can be split up into the pure enantiomers and pure diastereomers by methods known to a person skilled in the art. Preferably, diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography. Enantiomeric mixtures can be separated e.g. by forming diastereomers with a chiral auxiliary agent, resolving the diastereomers obtained and removing the chiral auxiliary agent. As chiral auxiliary agents, for example, chiral acids can be used to separate enantiomeric bases such as e.g. mandelic acid and chiral bases can be used to separate enantiomeric acids via formation of diastereomeric salts. Furthermore, diastereomeric derivatives such as diastereomeric esters can be formed from enantiomeric mixtures of alcohols or enantiomeric mixtures of acids, respectively, using chiral acids or chiral alcohols, respectively, as chiral auxiliary agents. Additionally, diastereomeric complexes or diastereomeric clathrates may be used for separating enantiomeric mixtures. Alternatively, enantiomeric mixtures can be split up using chiral separating columns in chromatography. Another suitable method for the isolation of enantiomers is the enzymatic separation. 
     One preferred aspect of the invention is the process for the preparation of the compounds of claims  1 - 5  according to the examples. 
     Optionally, compounds of the formula (I) can be converted into their salts, or, optionally, salts of the compounds of the formula (I) can be converted into the free compounds. Corresponding processes are customary for the skilled person. 
     Optionally, compounds of the formula (I) can be converted into their N-oxides. The N-oxide may also be introduced by way of an intermediate. N-oxides may be prepared by treating an appropriate precursor with an oxidizing agent, such as meta-chloroperbenzoic acid, in an appropriate solvent, such as dichloromethane, at suitable temperatures, such as from 0° C. to 40° C., whereby room temperature is generally preferred. Further corresponding processes for forming N-oxides are customary for the skilled person. 
     Commercial Utility 
     The compounds of formula (I) and the stereoisomers of the compounds of formula (I) according to the invention are hereinafter referred to as the compounds of the invention. In particular, the compounds of the invention are pharmaceutically acceptable. The compounds according to the invention have valuable pharmaceutical properties, which make them commercially utilizable. In particular, they inhibit the Pi3K/Akt pathway and exhibit cellular activity. They are expected to be commercially applicable in the therapy of diseases (e.g. diseases dependent on overactivated Pi3K/Akt). An abnormal activation of the PI3K/AKT pathway is an essential step towards the initiation and maintenance of human tumors and thus its inhibition, for example with AKT inhibitors, is understood to be a valid approach for treatment of human tumors. For a recent review see Garcia-Echeverria et al (Oncogene, 2008, 27, 551-5526). 
     Cellular activity and analogous terms in the present invention is used as known to persons skilled in the art, as an example, inhibition of phosphorylation, inhibition of cellular proliferation, induction of apoptosis or chemosensitization. 
     Chemosensitization and analogous terms in the present invention is used as known to persons skilled in the art. These stimuli include, for example, effectors of death receptor and survival pathways as well as cytotoxic/chemotherapeutic and targeted agents and finally radiation therapy. Induction of apoptosis and analogous terms according to the present invention are used to identify a compound which executes programmed cell death in cells contacted with that compound or in combination with other compounds routinely used for therapy. 
     Apoptosis in the present invention is used as known to persons skilled in the art. Induction of apoptosis in cells contacted with the compound of this invention might not necessarily be coupled with inhibition of cell proliferation. Preferably, the inhibition of proliferation and/or induction of apoptosis are specific to cells with aberrant cell growth. 
     Furthermore, the compounds according to the present invention inhibit protein kinase activity in cells and tissues, causing a shift towards dephosphorylated substrate proteins and as functional consequence, for example the induction of apoptosis, cell cycle arrest and/or sensitization towards chemotherapeutic and target-specific cancer drugs. In a preferred embodiment, inhibition of the Pi3K/Akt pathway induces cellular effects as mentioned herein, alone, or in combination with standard cytotoxic or targeted cancer drugs. 
     In addition inhibition of AKT signaling pathway was found to inhibit retinal neovascularisation in the oxygene induced retinopathy model as well as a potential therapeutic use of a AKT inhibition on choroidal neovascularisation was shown (Wang et al., Acta Histochem. Cytochem. 44(2): 103-111, 2011; Yang et al., Investigative Ophthalmology &amp; Visual Science (IOVS), April 2009, Vol. 50, No. 4) These results lead to the conclusion that AKT inhibition could provide a useful therapy for ocular diseases associated with ocular neovascularisation like e.g. Age Related Macula Degeneration (AMD), Macula Degeneration (MD) und diabetic retinopathy. 
     Thus one embodiment of the invention includes methods of treatment of ocular diseases associated with ocular neovasculariation especially AMD, MD und diabetic retinopathy comprising administering a compound of general formula (I) as well as the use of those compounds for the treatment of said diseases. 
     Compounds according to the present invention exhibit anti-proliferative and/or pro-apoptotic and/or chemosensitizing properties. Accordingly, the compounds of the present invention are useful for the treatment of hyperproliferative disorders, in particular cancer. Therefore the compounds of the present invention are useful to induce an anti-proliferative and/or pro-apoptotic and/or chemosensitizing effect in mammals, such as humans, suffering from a hyperproliferative disorders, like cancer. 
     The invention further relates to a compound according to the invention or a pharmaceutically acceptable salt thereof, for the treatment and/or prophylaxis, preferably treatment of (hyper)proliferative diseases and/or disorders responsive to induction of apoptosis, which include benign neoplasia and malignant neoplasia, especially malignant neoplasia, including cancer and the tumor types as disclosed below. 
     Compounds according to the present invention exhibit anti-proliferative and/or pro-apoptotic properties in mammals such as humans due to inhibition of metabolic activity of cancer cells which are able to survive despite of unfavourable growth conditions such as glucose depletion, hypoxia or other chemo stress. 
     Thus, the compounds according to the present invention are useful for treating, ameliorating or preventing diseases of benign or malignant behaviour as described herein, such as e.g. for inhibiting cellular neoplasia. 
     Neoplasia in the present invention is used as known to persons skilled in the art. A benign neoplasia is described by hyperproliferation of cells, incapable of forming an aggressive, metastasizing tumor in-vivo. In contrast, a malignant neoplasia is described by cells with multiple cellular and biochemical abnormalities, capable of forming a systemic disease, for example forming tumor metastasis in distant organs. 
     The compounds according to the present invention can be preferably used for the treatment of malignant neoplasia. Examples of malignant neoplasia treatable with the compounds according to the present invention include solid and hematological tumors. Solid tumors can be exemplified by tumors of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands (e.g. thyroid and adrenal cortex), esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva. Malignant neoplasias include inherited cancers exemplified by Retinoblastoma and Wilms tumor. In addition, malignant neoplasias include primary tumors in said organs and corresponding secondary tumors in distant organs (“tumor metastases”). Hematological tumors can be exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic and acute myeloid leukemia (CML AML), acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, and cancers of unknown primary site as well as AIDS related malignancies. 
     It is noted that a malignant neoplasia does not necessarily require the formation of metastases in distant organs. Certain tumors exert devastating effects on the primary organ itself through their aggressive growth properties. These can lead to the destruction of the tissue and organ structure finally resulting in failure of the assigned organ function and death. 
     Drug resistance is of particular importance for the frequent failure of standard cancer therapeutics. This drug resistance is caused by various cellular and molecular mechanisms. One aspect of drug resistance is caused by constitutive activation of anti-apoptotic survival signals with PKB/Akt as a key signalling kinase. Inhibition of the Pi3K/Akt pathway leads to a resensitization towards standard chemotherapeutic or target specific cancer therapeutics. As a consequence, the commercial applicability of the compounds according to the present invention is not limited to 1 st  line treatment of cancer patients. In a preferred embodiment, cancer patients with resistance to cancer chemotherapeutics or target specific anti-cancer drugs are also amenable for treatment with these compounds for e.g. 2 nd  or 3 rd  line treatment cycles. In particular, the compounds according to the present invention might be used in combination with standard chemotherapeutic or targeted drugs to resensitize tumors towards these agents. 
     Compounds according to the present invention are suitable for treatment, prevention or amelioration of the diseases of benign and malignant behavior as described above, such as e.g. benign or malignant neoplasia, particularly cancer, especially a cancer that is sensitive to Pi3K/Akt pathway inhibition. 
     The present invention further includes a method for treating, preventing or ameliorating mammals, including humans, preferably treating mammals, including humans, which are suffering from one of the abovementioned conditions, illnesses, disorders or diseases. The method is characterized in that a pharmacologically active and therapeutically effective and tolerable amount of one or more of the compounds according to the present invention is administered to the subject in need of such treatment. 
     The present invention further includes a method for treating, preventing or ameliorating diseases responsive to inhibition of the Pi3K/Akt pathway, in a mammal, including human, preferably treating diseases responsive to inhibition of the Pi3K/Akt pathway, in a mammal, including human, comprising administering a pharmacologically active and therapeutically effective and tolerable amount of one or more of the compounds according to the present invention to said mammal. 
     The present invention further includes a method for inhibiting protein kinase activity in cells comprising administering a pharmacologically active and therapeutically effective and tolerable amount of one or more of the compounds according to the present invention to a patient in need of such therapy. 
     The present invention further includes a method for treating hyperproliferative diseases of benign or malignant behaviour and/or disorders responsive to induction of apoptosis, such as e.g. cancer, particularly any of those cancer diseases described above, in a mammal, comprising administering a pharmacologically active and therapeutically effective and tolerable amount of one or more of the compounds according to the present invention to said mammal. 
     The present invention further includes a method for inhibiting cellular hyperproliferation or arresting aberrant cell growth in a mammal, comprising administering a pharmacologically active and therapeutically effective and tolerable amount of one or more of the compounds according to the present invention to said mammal. 
     The present invention further includes a method for inducing apoptosis in the therapy of beningn or malignant neoplasia, particularly cancer, comprising administering a pharmacologically active and therapeutically effective and tolerable amount of one or more of the compounds according to the present invention to a subject in need of such therapy. 
     The present invention further includes a method for inhibiting protein kinase activity in cells comprising administering a pharmacologically active and therapeutically effective and tolerable amount of one or more of the compounds according to the present invention to a patient in need of such therapy. 
     The present invention further includes a method for sensitizing towards chemotherapeutic or target-specific anti-cancer agents in a mammal, comprising administering a pharmacologically active and therapeutically effective and tolerable amount of one or more of the compounds according to the present invention to said mammal. 
     The present invention further includes a method for treating benign and/or malignant neoplasia, especially malignant neoplasia, particularly cancer, in a mammal, including human, comprising administering a pharmacologically active and therapeutically effective and tolerable amount of one or more of the compounds according to the present invention to said mammal. 
     The present invention further includes a method for treating solid and hematological tumors, whereby solid tumors can be exemplified by tumors of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands (e.g. thyroid and adrenal cortex), esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva. Malignant neoplasias include inherited cancers exemplified by Retinoblastoma and Wilms tumor. In addition, malignant neoplasias include primary tumors in said organs and corresponding secondary tumors in distant organs (“tumor metastases”). and hematological tumors can be exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic and acute myeloid leukemia (CML AML), acute lymphoblastic leukemia (ALL). Hodgkins disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, and cancers of unknown primary site as well as AIDS related malignancies. 
     The present invention further relates to the use of the compounds for the production of pharmaceutical compositions, which are employed for the treatment, prophylaxis, and/or amelioration of one or more of the illnesses mentioned, preferably for the treatment of one or more of the illnesses mentioned. 
     The present invention further relates to the use of the compounds for the manufacture of pharmaceutical compositions for treating, preventing or ameliorating, preferably treating hyperproliferative diseases and/or disorders responsive to the induction of apoptosis, such as e.g. beningn or malignant neoplasia, especially malignant neoplasia, in particular cancer, especially those cancer diseases and tumor types mentioned above. 
     The present invention further relates to the use of the compounds according to this invention for the production of pharmaceutical compositions for treating, preventing or ameliorating, preferably treating benign or malignant neoplasia, especially malignant neoplasia, particularly cancer, such as e.g. any of those cancer diseases and tumor types described above. 
     The invention further relates to a compound according to the invention or a pharmaceutically acceptable salt thereof, for the treatment and/or prophylaxis, preferably treatment of diseases, especially for the treatment and/or prophylaxis, preferably treatment of (hyper)proliferative diseases and/or disorders responsive to induction of apoptosis, which include benign neoplasia and malignant neoplasia, including cancer. 
     The invention further related to the use of a compound according to the invention or a pharmaceutically acceptable salt thereof, for the production of a pharmaceutical composition for the treatment, prevention or amelioration of a disease mediated by a dysregulated function of a single protein kinase or multiple protein kinases and/or disorders responsive to the induction of apoptosis. 
     The invention further relates to a pharmaceutical composition comprising at least one compound of general formula (I) according to any of claims  1  to  6 , together with at least one pharmaceutically acceptable auxiliary 
     The invention in addition relates to a pharmaceutical composition, comprising a compound according to the invention or a pharmaceutically acceptable salt thereof, for the treatment and/or prophylaxis, preferably treatment of (hyper)proliferative diseases and/or disorders responsive to induction of apoptosis, which include benign neoplasia and malignant neoplasia, including cancer. 
     The present invention further relates to the use of compounds and pharmaceutically acceptable salts according to the present invention for the manufacture of pharmaceutical compositions, which can be used for sensitizing towards chemotherapeutic and/or target specific anti-cancer agents. 
     The present invention further relates to the use of compounds according to the present invention for the manufacture of pharmaceutical compositions, which can be used for sensitizing towards radiation therapy of those diseases mentioned herein, particularly cancer. 
     The present invention further relates to the use of the compounds according to the present invention for the manufacture of pharmaceutical compositions, which can be used in the treatment of diseases sensitive to protein kinase inhibitor therapy and different to cellular neoplasia. These non-malignant diseases include, but are not limited to benign prostate hyperplasia, neurofibromatosis, dermatoses, and myelodysplastic syndromes. 
     The present invention further relates to pharmaceutical compositions comprising one or more of the compounds according to this invention and a pharmaceutically acceptable carrier or diluent. 
     The present invention further relates to pharmaceutical compositions comprising one or more of the compounds according to this invention and pharmaceutically acceptable auxiliaries and/or excipients. 
     The pharmaceutical compositions according to this invention are prepared by processes, which are known per se and familiar to the person skilled in the art. As pharmaceutical compositions, the compounds of the invention (=active compounds) are either employed as such, or preferably in combination with suitable pharmaceutical auxiliaries and/or excipients, e.g. in the form of tablets, coated tablets, dragees, pills, cachets, granules, capsules, caplets, suppositories, patches (e.g. as TTS), emulsions (such as e.g. micro-emulsions or lipid emulsions), suspensions (such as e.g. nano suspensions), gels, solubilisates or solutions (e.g. sterile solutions), or encapsuled in liposomes or as beta-cyclodextrine or beta-cyclodextrin derivative inclusion complexes or the like, the active compound content advantageously being between 0.1 and 95% and where, by the appropriate choice of the auxiliaries and/or excipients, a pharmaceutical administration form (e.g. a delayed release form or an enteric form) exactly suited to the active compound and/or to the desired onset of action can be achieved. 
     The person skilled in the art is familiar with auxiliaries, vehicles, excipients, diluents, carriers or adjuvants which are suitable for the desired pharmaceutical formulations, preparations or compositions on account of his/her expert knowledge. In addition to solvents, gel formers, ointment bases and other active compound excipients, for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers (such as e.g. polyoxyethylenglyceroltriricinoleat 35, PEG 400, Tween 80, Captisol, Solutol HS15 or the like), colorants, complexing agents, permeation promoters, stabilizers, fillers, binders, thickeners, disintegrating agents, buffers, pH regulators (e.g. to obtain neutral, alkaline or acidic formulations), polymers, lubricants, coating agents, propellants, tonicity adjusting agents, surfactants, flavorings, sweeteners or dyes, can be used. 
     In particular, auxiliaries and/or excipients of a type appropriate to the desired formulation and the desired mode of administration are used. 
     The administration of the compounds, pharmaceutical compositions or combinations according to the invention may be performed in any of the generally accepted modes of administration available in the art. Illustrative examples of suitable modes of administration include intravenous, oral, nasal, parenteral, topical, transdermal and rectal delivery. Oral and intravenous deliveries are preferred. 
     Generally, the pharmaceutical compositions according to the invention can be administered such that the dose of the active compound is in the range customary for Pi3K/Akt pathway inhibitors. In particular, a dose in the range of from 0.01 to 4000 mg of the active compound per day is preferred for an average adult patient having a body weight of 70 kg. In this respect, it is to be noted that the dose is dependent, for example, on the specific compound used, the species treated, age, body weight, general health, sex and diet of the subject treated, mode and time of administration, rate of excretion, severity of the disease to be treated and drug combination. 
     The pharmaceutical composition can be administered in a single dose per day or in multiple subdoses, for example, 2 to 4 doses per day. A single dose unit of the pharmaceutical composition can contain e.g. from 0.01 mg to 4000 mg, preferably 0.1 mg to 2000 mg, more preferably 0.5 to 1500 mg, most preferably 1 to 500 mg, of the active compound. Furthermore, the pharmaceutical composition can be adapted to weekly, monthly or even more infrequent administration, for example by using an implant, e.g. a subcutaneous or intramuscular implant, by using the active compound in form of a sparingly soluble salt or by using the active compound coupled to a polymer. 
     The present invention further relates to comprising one or more first active ingredients selected from the compounds of the invention and one or more second active ingredients selected from chemotherapeutic anti-cancer agents and target-specific anti-cancer agents e.g. for treating, preventing or ameliorating diseases responsive or sensitive to inhibition of the Pi3K/Akt pathway, such as hyperproliferative diseases of benign or malignant behaviour and/or disorders responsive to the induction of apoptosis, particularly cancer, such as e.g. any of those cancer diseases described above. 
     The invention further relates to the use of a pharmaceutical composition comprising one or more of the compounds according to this invention as sole active ingredient(s) and a pharmaceutically acceptable carrier or diluent in the manufacture of pharmaceutical products for the treatment and/or prophylaxis of the illnesses mentioned above. 
     Depending upon the particular disease, to be treated or prevented, additional therapeutic active agents, which are normally administered to treat or prevent that disease, may optionally be coadministered with the compounds according to this invention. As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease are known as appropriate for the disease being treated. 
     The anti-cancer agents mentioned herein above as combination partners of the compounds according to this invention are meant to include pharmaceutically acceptable derivatives thereof, such as e.g. their pharmaceutically acceptable salts. 
     The person skilled in the art is aware of the total daily dosage(s) and administration form(s) of the additional therapeutic agent(s) coadministered. Said total daily dosage(s) can vary within a wide range depending from the agent combined. 
     In practicing the present invention, the compounds according to his invention may be administered in combination therapy separately, sequentially, simultaneously, concurrently or chronologically staggered (such as e.g. as combined unit dosage forms, as separate unit dosage forms, as adjacent discrete unit dosage forms, as fixed or non-fixed combinations, as kit-of-parts or as admixtures) with one or more standard therapeutics (chemotherapeutic and/or target specific anti-cancer agents), in particular art-known anti-cancer agents, such as any of e.g. those mentioned above. 
     In this context, the present invention further relates to a combination comprising a first active ingredient, which is at least one compound according to this invention, and a second active ingredient, which is at least one art-known anti-cancer agent, such as e.g. one or more of those mentioned herein above, for separate, sequential, simultaneous, concurrent or chronologically staggered use in therapy, such as e.g. in therapy of any of those diseases mentioned herein. 
     The present invention further relates to a pharmaceutical composition comprising a first active ingredient, which is at least one compound according to this invention, and a second active ingredient, which is at least one art-known anti-cancer agent, such as e.g. one or more of those mentioned herein above, and, optionally, a pharmaceutically acceptable carrier or diluent, for separate, sequential, simultaneous, concurrent or chronologically staggered use in therapy. 
     The present invention further relates to a combination product comprising 
     a.) at least one compound according to this invention formulated with a pharmaceutically acceptable carrier or diluent, and 
     b.) at least one art-known anti-cancer agent, such as e.g. one or more of those mentioned herein above, formulated with a pharmaceutically acceptable carrier or diluent. 
     The present invention further relates to a kit comprising a compound of general formula (I) according to claim  1 . 
     The present invention further relates to a kit-of-parts comprising a preparation of a first active ingredient, which is a compound according to this invention, and a pharmaceutically acceptable carrier or diluent; a preparation of a second active ingredient, which is an art-known anti-cancer agent, such as one of those mentioned above, and a pharmaceutically acceptable carrier or diluent; for simultaneous, concurrent, sequential, separate or chronologically staggered use in therapy. Optionally, said kit comprises instructions for its use in therapy, e.g. to treat hyperproliferative diseases and diseases responsive or sensitive to inhibition of the Pi3K/Akt pathway, such as e.g. beningn or malignant neoplasia, particularly cancer, more precisely, any of those cancer diseases described above. 
     The present invention further relates to a combined preparation comprising at least one compound according to this invention and at least one art-known anti-cancer agent for simultaneous, concurrent, sequential or separate administration. 
     The present invention further relates to combinations, compositions, formulations, preparations or kits according to the present invention having Pi3K/Akt pathway inhibitory activity. 
     In addition, the present invention further relates to a method for treating in combination therapy hyperproliferative diseases and/or disorders responsive to the induction of apoptosis, such as e.g. cancer, in a patient comprising administering a combination, composition, formulation, preparation or kit as described herein to said patient in need thereof. 
     In addition, the present invention further relates to a method for treating hyperproliferative diseases of benign or malignant behaviour and/or disorders responsive to the induction of apoptosis, such as e.g. cancer, in a patient comprising administering in combination therapy separately, simultaneously, concurrently, sequentially or chronologically staggered a pharmaceutically active and therapeutically effective and tolerable amount of a pharmaceutical composition, which comprises a compound according to this invention and a pharmaceutically acceptable carrier or diluent, and a pharmaceutically active and therapeutically effective and tolerable amount of one or more art-known anti-cancer agents, such as e.g. one or more of those mentioned herein, to said patient in need thereof. 
     In further addition, the present invention relates to a method for treating, preventing or ameliorating hyperproliferative diseases and/or disorders responsive to induction of apoptosis, such as e.g. benign or malignant neoplasia, e.g. cancer, particularly any of those cancer diseases mentioned herein, in a patient comprising administering separately, simultaneously, concurrently, sequentially or chronologically staggered to said patient in need thereof an amount of a first active compound, which is a compound according to the present invention, and an amount of at least one second active compound, said at least one second active compound being a standard therapeutic agent, particularly at least one art-known anti-cancer agent, such as e.g. one or more of those chemotherapeutic and target-specific anti-cancer agents mentioned herein, wherein the amounts of the first active compound and said second active compound result in a therapeutic effect. 
     In yet further addition, the present invention relates to a method for treating, preventing or ameliorating, especially treating hyperproliferative diseases and/or disorders responsive to induction of apoptosis, such as e.g. benign or malignant neoplasia, especially malignanr neoplasia, e.g. cancer, particularly any of those cancer diseases and tumor types mentioned herein, in a patient comprising administering a combination according to the present invention. 
     In addition, the present invention further relates to the use of a composition, combination, formulation, preparation or kit according to this invention in the manufacture of a pharmaceutical product, such as e.g. a commercial package or a medicament, for treating, preventing or ameliorating, especially treating hyperproliferative diseases, and/or disorders responsive to the induction of apoptosis, such as e.g. malignant or benign neoplasia, especially malignant neoplasia, such as e.g. cancer, particularly those diseases and tumor types mentioned herein. 
     The present invention further relates to a commercial package comprising one or more compounds of the present invention together with instructions for simultaneous, concurrent, sequential or separate use with one or more chemotherapeutic and/or target specific anti-cancer agents, such as e.g. any of those mentioned herein. 
     The present invention further relates to a commercial package consisting essentially of one or more compounds of the present invention as sole active ingredient together with instructions for simultaneous, concurrent, sequential or separate use with one or more chemotherapeutic and/or target specific anti-cancer agents, such as e.g. any of those mentioned herein. 
     The present invention further relates to a commercial package comprising one or more chemotherapeutic and/or target specific anti-cancer agents, such as e.g. any of those mentioned herein, together with instructions for simultaneous, concurrent, sequential or separate use with one or more compounds according to the present invention. 
     The compositions, combinations, preparations, formulations, kits or packages mentioned in the context of the combination therapy according to this invention may also include more than one of the compounds according to this invention and/or more than one of the art-known anti-cancer agents mentioned. 
     The first and second active ingredient of a combination or kit-of-parts according to this invention may be provided as separate formulations (i.e. independently of one another), which are subsequently brought together for simultaneous, concurrent, sequential, separate or chronologically staggered use in combination therapy; or packaged and presented together as separate components of a combination pack for simultaneous, concurrent, sequential, separate or chronologically staggered use in combination therapy. 
     The type of pharmaceutical formulation of the first and second active ingredient of a combination or kit-of-parts according to this invention can be according, i.e. both ingredients are formulated in separate tablets or capsules, or can be different, i.e. suited for different administration forms, such as e.g. one active ingredient is formulated as tablet or capsule and the other is formulated for e.g. intravenous administration. 
     The amounts of the first and second active ingredients of the combinations, compositions or kits according to this invention may together comprise a therapeutically effective amount for the treatment, prophylaxis or amelioration of a hyperproliferative diseases and/or a disorder responsive to the induction of apoptosis, particularly one of those diseases mentioned herein, such as e.g. malignant or benign neoplasia, especially malignant neoplasia, e.g. cancer, like any of those cancer diseases and tumor types mentioned herein. 
     In addition, compounds according to the present invention can be used in the pre- or post-surgical treatment of cancer. 
     In further addition, compounds of the present invention can be used in combination with radiation therapy. 
     As will be appreciated by persons skilled in the art, the invention is not limited to the particular embodiments described herein, but covers all modifications of said embodiments that are within the spirit and scope of the invention as defined by the appended claims. 
     The following examples illustrate the invention in greater detail, without restricting it. Further compounds according to the invention, of which the preparation is not explicitly, described, can be prepared in an analogous way. 
     The compounds, which are mentioned in the examples and the salts thereof represent preferred embodiments of the invention as well as a claim covering all subcombinations of the residues of the compound of formula (I) as disclosed by the specific examples. 
     The term “according to” within the experimental section is used in the sense that the procedure referred to is to be used “analogously to”. 
     Experimental Part 
     The following table lists the abbreviations used in this paragraph and in the Intermediate Examples and Examples section as far as they are not explained within the text body. NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered. Chemical names were generated using AutoNom2000 as implemented in MDL ISIS Draw. In some cases generally accepted names of commercially available reagents were used in place of AutoNom2000 generated names. 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Abbreviation 
                 Meaning 
               
               
                   
                   
               
             
            
               
                   
                 Boc 
                 t-Butoxycarbonyl 
               
               
                   
                 Br 
                 broad 
               
               
                   
                 Cl 
                 chemical ionisation 
               
               
                   
                 D 
                 doublet 
               
               
                   
                 Dd 
                 doublet of doublet 
               
               
                   
                 DAD 
                 diode array detector 
               
               
                   
                 DBU 
                 1,5-diazabicyclo(5.4.0)undec-5-ene 
               
               
                   
                 DCM 
                 dichloromethane 
               
               
                   
                 DIP 
                 diisopropylether 
               
               
                   
                 EtOAc 
                 ethyl acetate 
               
               
                   
                 Eq. 
                 equivalent 
               
               
                   
                 ESI 
                 electrospray (ES) ionisation 
               
               
                   
                 HPLC 
                 high performance liquid chromatography 
               
               
                   
                 LC-MS 
                 liquid chromatography mass spectrometry 
               
               
                   
                 M 
                 multiplet 
               
               
                   
                 MS 
                 mass spectrometry 
               
               
                   
                 n-BuLi 
                 n-Butyllithium 
               
               
                   
                 NBS 
                 N-Bromo-Succinimide 
               
               
                   
                 NMP 
                 N-methyl pyrrolidone 
               
               
                   
                 NMR 
                 nuclear magnetic resonance spectroscopy: 
               
               
                   
                   
                 chemical shifts (δ) are given in ppm. 
               
               
                   
                 ONf 
                 nonafluorobutanesulfonate 
               
               
                   
                 OTf 
                 trifluoromethanesulfonate 
               
               
                   
                 OTs 
                 tosylate 
               
               
                   
                 Pd(dppf)Cl 2   
                 1,1′ bis(diphenylphosphino)ferrocene]dichloro- 
               
               
                   
                   
                 palladium(II) 
               
               
                   
                 Pd(PtBu 3 ) 2   
                 bis (tri-tert.-butylphosphin)palladium(0) 
               
               
                   
                   
                 [Pd(PtBu 3 ) 2 ], 
               
               
                   
                 q 
                 quartet 
               
               
                   
                 r.t. or rt 
                 room temperature 
               
               
                   
                 RT 
                 retention time (as measured either with HPLC 
               
               
                   
                   
                 or UPLC) in minutes 
               
               
                   
                 S 
                 singlet 
               
               
                   
                 T 
                 triplet 
               
               
                   
                 THF 
                 tetrahydrofuran 
               
               
                   
                 UPLC 
                 ultra performance liquid chromatography 
               
               
                   
                   
               
            
           
         
       
     
     Other abbreviations have their meanings customary per se to the skilled person. The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way. 
     EXAMPLES 
     UPLC-MS Standard Procedures 
     Analytical UPLC-MS was performed as described below. The masses (m/z) are reported from the positive mode electrospray ionisation unless the negative mode is indicated (ES−). 
     In most of the cases method A is used. If not, it is indicated. 
     UPLC-MS Method A 
     Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 50×2.1 mm, Eluent A: water+0.1% formic acid, Eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate 0.8 ml/min; Temperature: 60° C.; Injection: 2 μl; DAD scan: 210-400 nm. 
     UPLC-MS Method B 
     Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 50×2.1 mm; Eluent A: water+0.2% ammonia, Eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Row rate 0.8 ml/min; Temperature: 60° C.; Injection: 2 μl: DAD scan: 210-400 nm; ELSD. 
     UPLC-MS Method C 
     Instrument: Waters Acquity UPLC-MS ZQ4000: Column: Acquity UPLC BEH C18 1.7 50×2.1 mm; Eluent A: water+0.05% formic acid Eluent B: acetonitrile+0.05% formic acid; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Row rate 0.8 ml/min; Temperature: 60° C.; Injection: 2 μl; DAD scan: 210-400 nm. 
     UPLC-MS Method D 
     Instrument: Waters Acquity UPLC-MS ZQ4000; Column: Acquity UPLC BEH 018 1.7 50×2.1 mm: Eluent A: water+0.2% ammonia, Eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate 0.8 ml/min; Temperature: 6000; Injection: 2 μl; DAD scan: 210-400 nm; ELSD. 
     Intermediate Example Int-1-0 
     
       
         
         
             
             
         
       
     
     6-chloro-7-phenyl-imidazo[1,2-b]pyridazine 
     Step 1: 4-phenyl-1,2-dihydro-pyridazine-3,6-dione 
     46 g (264.1 mmol) 3-Phenyl-furan-2,5-dione were suspended in 1.56 L water. After addition of 34.4 g (264.1 mmol) hydrazine sulfate the reaction mixture was heated to reflux (bath temperature: 115° C.) and kept there for five hours. During the night the reaction mixture was kept at a bath temperature of 98° C. After cooling the precipitate was sucked off, washed with water (100 mL) and dried at 40° C. yielding 47.6 g (95.8%) of the title compound. 
     Step 2: 3,6-dichloro-4-phenyl-pyridazine 
     47.5 g (252.4 mmol) 4-Phenyl-1,2-dihydro-pyridazine-3,6-dione were suspended in 235 mL (2.52 mol) phosphorus oxychloride. The suspension was heated over night at 80° C. The reaction mixture was poured on 4.5 L water and stirred for 60′. The precipitate was sucked off, washed with water (500 mL) and dried in a vacuum furnace at 40° C. yielding 56.8 g of the title compound which contains yet some water. 
     Step 3: 6-chloro-5-phenyl-pyridazin-3-yl-amine 
     36.5 g (162 mmol) 3,6-Dichloro-4-phenyl-pyridazine were suspended in 1000 mL aqueous ammonia solution (25%) and stirred in an autoclave for 18 hours at 100° C. The reaction mixture was transferred into a separating funnel and the phases were separated. The aqueous phase was washed twice with dichloromethane. The combined organic phases were washed twice with water, the solvent was evaporated and the crude residue (two regioisomers, 6-chloro-5-phenyl-pyridazin-3-yl-amine and 6-chloro-4-phenyl-pyridazin-3-yl-amine 20.2 g=60.6%) was used without further purification in the next step. 
     Step 4: 6-chloro-7-phenyl-imidazo[1,2-b]pyridazine 
     The mixture of 6-chloro-5-phenyl-pyridazin-3-yl-amine and 6-chloro-4-phenyl-pyridazin-3-yl-amine (20.2 g=0.1 mol) was suspended in 300 mL water and 30 mL THF. After addition of 32 mL (0.51 mol) chloracetaldehyde diethylacetal the reaction mixture was heated for five hours at reflux. Additional 32 mL (0.51 mol) chloracetaldehyde diethylacetal were added and heating was continued for another six hours. The reaction mixture was diluted with ethyl acetate and extracted three times. The organic phase was dried (sodium sulfate), filtrated and the solvent was removed. The residue was purified by chromatography (Biotage, eluents: ethyl acetate/hexane). 6.8 g (30.1%) of the title compound, 6-chloro-7-phenyl-imidazo[1,2-b]pyridazine, and 6.4 g (28.4%) of the regioisomer, 6-chloro-8-phenyl-imidazo[1,2-b]pyridazine, were obtained. 
       1 H-NMR (300 MHz, dDMSO): δ 8.38 (s, 1H), 8.20 (s, 1H), 7.88 (s, 1H), 7.39-7.62 (m, 5H). 
     Intermediate Example Int-1-1 
     
       
         
         
             
             
         
       
     
     6-Chloro-2-methyl-7-phenyl-imidazo[1,2-b]pyridazine 
     The mixture of 6-chloro-5-phenyl-pyridazin-3-yl-amine and 6-Chloro-4-phenyl-pyridazin-3-yl-amine (intermediate example Int-1-0, step 3, 65 g=316 mmol) in 65 mL tetrahydrofurane and 650 mL water was heated with 74.5 g (800 mmol) chloroacetone in analogy to the synthesis of the intermediate example Int-1-0, step 4, for 18 hours at reflux. After the usual work up and purification of the residue by chromatography (Biotage Isolera, Kronlab 8 cm, eluents: dichloromethane/methanol) and subsequent crystallization (methyl-tert.butylether/hexane) 11.69 g (30.4%) of the title compound were obtained. 
       1 H-NMR (300 MHz, CDCl 3 ): δ 8.10-8.16 (2H), 7.76 (1H), 7.50-7.59 (3H), 7.14 (1H), 2.51 (s, 3H). 
     Intermediate Example Int-2-0 
     
       
         
         
             
             
         
       
     
     {1-[4-(7-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester 
     100 mg (0.44 mmol) 6-Chloro-7-phenyl-imidazo[1,2-b]pyridazine (intermediate example Int-1-0) in 1.5 mL DME, 178.8 mg (0.48 mmol) {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, 0.85 mL aqueous sodium carbonate (10%) and 16 mg (0.02 mmol) 1,1 bis(diphenylphosphino)ferrocenedichloropalladium(II) were put in a microwave vial (no complete dissolution). The reaction mixture was degassed with argon, the vial closed with a cap and put in a heating block. The reaction mixture was stirred for 18 h at 90° C. (complete dissolution). Due to the still presence of starting material additional 86 mg boronic ester, 0.42 mL aqueous base and 8 mg palladium catalyst were added and stirring was continued for 6 hours at 90° C. 20 mL water and 100 mL dichloromethane were added and the reaction mixture was vigorously stirred for one hour. After separation of the organic phase the aqueous phase was extracted once more with dichloromethane. The combined organic extracts were washed with water and dried over sodium sulfate. After removal of the drying agent the solvent was evaporated and the residue was purified by chromatography on silicagel (eluents: dichloromethane/methanol) yielding 109 mg (56.8%) of the desired compound which was yet slightly contaminated. 
     MS (ES+, M+1): 441 
       1 H-NMR (400 MHz, CDCl 3 ): δ 8.03 (s, 1H), 7.98 (s, 1H), 7.83 (s, 1H), 7.22-7.41 (m, 7H), 7.12-7.22 (m, 2H), 2.40-2.65 (m, 4H), 1.95-2.18 (m, 1H), 1.72-1.93 (m, 1H), 1.12-1.53 (m, 9H). 
     Intermediate Example Int-2-1 
     
       
         
         
             
             
         
       
     
     {1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester 
     198 mg (0.45 mmol) {1-[4-(7-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester (intermediate example Int-2-0) and 80 mg (0.45 mmol) N-bromosuccinimid were heated in 3.6 mL trichloromethane at reflux for one hour. The solvent was evaporated and the residue was purified by chromatography on silicagel (eluents: dichloromethane/methanol) yielding 115.6 mg (49.5%) of the desired bromo compound. 
     MS (ES+, M+1): 519/521 
       1 H-NMR (400 MHz, dDMSO): δ 8.18 (s, 1H), 7.98 (s, 1H), 7.15-7.35 (m, 9H), 2.20-2.43 (m, 4H), 1.83-2.03 (m, 1H), 1.64-1.82 (m, 1H), 0.96-1.40 (m, 9H). 
     Intermediate Example Int-2-2 
     
       
         
         
             
             
         
       
     
     {1-[4-(2-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester 
     The title compound had been prepared by reacting 6-chloro-2-methyl-7-phenyl-imidazo[1,2-b]pyridazine (intermediate example Int-1-1) with {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester in analogy as described in intermediate example Int-2-0. 
     UPLC-MS: RT=1.51 min; m/z=455 (ES+, M+1) 
     Intermediate Example Int-2-3 
     
       
         
         
             
             
         
       
     
     {1-[4-(3-Bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester 
     The title compound had been prepared by reacting {1-[4-(2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester (intermediate example Int-2-2) with NBS in chloroform in analogy as described in intermediate example Int-2-1. 
     UPLC-MS: RT=1.79 min; m/z=533/535 (ES+, M+1) 
     Intermediate Example Int-3-0 
     
       
         
         
             
             
         
       
     
     {1-[4-(3-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester 
     101 mg (0.19 mmol) {1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester (intermediate example Int-2-1) were dissolved in 0.95 mL THF. After addition of 0.49 mL (0.97 mmol) of methylzinc chloride (2M solution in THF) and 7.9 mg (0.01 mmol) bis(diphenylphosphino)ferrocenedichloropalladium(II) the reaction mixture was heated for 40′ in the microwave at 100° C. The reaction mixture was poured on water (30 mL) and extracted twice with ethyl acetate (50 mL each). The combined organic extracts were washed with water and dried over sodium sulfate. After filtration and evaporation of the solvent the residue was purified by chromatography on silicagel (eluents: dichloromethane/methanol) yielding 18.5 mg of the desired compound which was 90% pure. 
     MS (ES+, M+1): 455 
       1 H-NMR (300 MHz, CD 3 OD): δ7.90 (s, 1H), 7.59 (s, 1H), 7.10-7.47 (m, 9H), 2.62 (s, 3H), 2.29-2.55 (m, 4H), 1.95-2.18 (m, 1H), 1.73-1.95 (m, 1H), 1.01-1.49 (m, 9H). 
     Intermediate Example Int-3-1 
     
       
         
         
             
             
         
       
     
     (1-{4-[3-(3-Cyanophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}cyclobutyl)-carbamic acid tert.-butyl ester 
     311 mg (0.6 mmol) {1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-1, were dissolved in 6.2 mL THF. After addition of 6 mL (3 mmol) of 3-(cyanophenyl)zinc iodide (0.5M solution in THF) and 23 mg (0.03 mmol) bis(diphenylphosphino)ferrocenedichloropalladium(II) the reaction mixture was heated for 40′ in the microwave at 100° C. Additional 6 mL (3 mmol) of 3-(cyanophenyl)zinc iodide (0.5M solution in THF) and 46 mg (0.06 mmol) catalysator were added and the mixture was heated in the microwave for an additional hour at 100° C. The reaction mixture was poured on water (100 mL) and extracted twice with ethyl acetate (100 mL each). The combined organic extracts were washed with water and dried over sodium sulfate. After filtration and evaporation of the solvent the residue was purified by chromatography on silicagel (eluents: dichloromethane/methanol) yielding 121 mg of the desired compound which however were strongly contaminated. 
     UPLC-MS: RT=1.53 min; m/z=543 (ES+, M+1) 
     Intermediate Example Int-3-2 
     
       
         
         
             
             
         
       
     
     (1-{4-[3-(4-Methanesulfonyl-phenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert.-butyl ester 
     170 mg (0.33 mmol) {1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-1, 130.9 mg (0.66 mmol) 4-(methanesulfonylphenyl)boronic acid, 26.7 mg (0.03 mmol) 1,1 bis(diphenylphosphino)ferrocenedichloropalladium(II) and 104 mg (0.98 mmol) sodium carbonate in 3.5 mL dioxane and 0.64 mL water were heated in a microwave vial which had been sealed with a microwave cap for 18 hours at 105° C. (heating block). The reaction mixture was poured on water/dichloromethane and vigorously stirred for 30′. The organic phase was separated, washed twice with brine, dried (sodium sulfate) and filtrated. The solvent was evaporated and the crude residue (127.9 mg) was used in the next step without further purification. 
     The following intermediate examples had been prepared in analogy according to intermediate example Int-3-2 by reacting {1-[4-(3-bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-1, with the appropriate boronic acid. 
     
       
         
           
               
               
               
               
             
               
                   
               
               
                 Intermediate 
                   
                   
                 UPLC-MS 
               
               
                 example 
                 Structure/Name 
                 1H-NMR 
                 resp. MS 
               
               
                   
               
             
            
               
                 Int-3-3 
                                   
   (1-{4-[3-(4-cyanophenyl)-7-phenyl- imidazo[1,2-b]pyridazin-6-yl]- phenyl}cyclobutyl)-carbamic acid tert.- butyl ester 
                 (400 MHz, dDMSO): δ 8.57 (s, 1H), 8.49 (d, 2H), 8.25 (s, 1H), 7.96 (d, 2H), 7.42 (d, 2H), 7.21-7.38 (m, 7H), 2.28-2.40 (m, 2H), 2.04-2.15 (m, 2H), 1.92-2.04 (m, 1H), 1.55-1.69 (m, 1H). 
                 Method B: RT = 1.52 min; m/z = 542 (ES+, M + 1) 
               
               
                   
               
               
                 Int-3-4 
                                   
   3-{6-[4-(1-tert-Butoxycarbonylamino- cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2- b]pyridazin-3-yl}-benzoic acid methyl ester 
                   
                 Method B: RT = 1.54 min; m/z = 575 (ES+, M + 1) 
               
               
                   
               
               
                 Int-3-5 
                                   
   1-{4-[3-(4-Fluorophenyl)-7-phenyl- imidazo[1,2-b]pyridazin-6-yl]-phenyl}- cyclobutyl)-carbamic acid tert-butyl ester 
                   
                 RT = 1.55 min; m/z = 535 (ES+, M + 1) 
               
               
                   
               
               
                 Int-3-6 
                                   
   {1-[4-(7-Phenyl-3-p-tolyl-imidazo[1,2- b]pyridazin-6-yl)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester 
                   
                 Method B: RT = 1.60 min; m/z = 531 (ES+, M + 1) 
               
               
                   
               
               
                 Int-3-7 
                                   
   (1-{4-[3-(3-Hydroxymethyl-phenyl)-7- phenyl-imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutyl)-carbamic acid tert- butyl ester 
                   
                 Method B: RT = 1.45 min; m/z = 547 (ES+, M + 1) 
               
               
                   
               
               
                 Int-3-8 
                                   
   (1-{4-[3-(4-Hydroxymethyl-phenyl)-7- phenyl-imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutyl)-carbamic acid tert- butyl ester 
                   
                 Method B: RT = 1.44 min; m/z = 547 (ES+, M + 1) 
               
               
                   
               
               
                 Int-3-9 
                                   
   (1-{4-[3-(4-Dimethylsulfamoyl-phenyl)-7- phenyl-imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutyl)-carbamic acid tert- butyl ester 
                   
                 Method B: RT = 1.54 min; m/z = 624 (ES+, M + 1) 
               
               
                   
               
               
                 Int-3-10 
                                   
   (1-{4-[7-Phenyl-3-(4-sulfamoyl-phenyl)- imidazo[1,2-b]pyridazin-6-yl]-phenyl}- cyclobutyl)-carbamic acid tert-butyl ester 
                   
                 RT = 1.39 min; m/z = 596 (ES+, M + 1) 
               
               
                   
               
               
                 Int-3-11 
                                   
   (1-{4-[3-(4-Fluoro-hydroxymethyl-phenyl)- 7-phenyl-imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutyl)-carbamic acid tert- butyl ester 
                   
                 RT = 1.44 min; m/z = 565 (ES+, M + 1) 
               
               
                   
               
               
                 Int-3-12 
                                   
   (1-{4-[3-(4-Carbamoyl-phenyl)-7-phenyl- imidazo[1,2-b]pyridazin-6-yl]-phenyl}- cyclobutyl)-carbamic acid tert-butyl ester 
                   
                 RT = 1.33 min; m/z = 560 (ES+, M + 1) 
               
               
                   
               
               
                 Int-3-13 
                                   
   (1-{4-[3-(3-Carbamoyl-phenyl)-7-phenyl- imidazo[1,2-b]pyridazin-6-yl]-phenyl}- cyclobutyl)-carbamic acid tert-butyl ester 
                   
                 RT = 1.34 min; m/z = 560 (ES+, M + 1) 
               
               
                   
               
               
                 Int-3-14 
                                   
   4-{6-[4-(1-tert-Butoxycarbonylamino- cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2- b]pyridazin-3-yl)-pyrazole-1-carboxylic acid tert-butyl ester 
                   
                 RT = 1.56 min; m/z = 607 (ES+, M + 1) 
               
               
                   
               
               
                 Int-3-15 
                                   
   (1-{4-[3-(6-Hydroxy-pyridin-3-yl)-7-phenyl- imidazo[1,2-b]pyridazin-6-yl]-phenyl}- cyclobutyl)-carbamic acid tert-butyl ester 
                   
                 RT = 1.23 min; m/z = 534 (ES+, M + 1) 
               
               
                   
               
               
                 Int-3-16 
                                   
   5-{6-[4-(1-tert-Butoxycarbonylamino- cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2- b]pyridazin-3-yl}-pyridine-2-carboxylic acid methyl ester 
                   
                 RT = 1.44 min; m/z = 576 (ES+, M + 1) 
               
               
                   
               
               
                 Int-3-17 
                                   
   5-{6-[4-(1-tert-Butoxycarbonylamino- cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2- b]pyridazin-3-yl}-pyrazole-1-carboxylic acid tert-butyl ester 
                   
                 RT = 1.32 min; m/z = 507 (ES+, M + 1- Boc residue) 
               
               
                   
               
               
                 Int-3-18 
                                   
   (1-{4-[3-(1H-indazol-6-yl)-7-phenyl- imidazo[1,2-b]pyridazin-6-yl]-phenyl}- cyclobutyl)-carbamic acid tert-butyl ester 
                   
                 UPLC-MS: RT = 1.41 min; m/z = 557 (ES+, M + 1) 
               
               
                   
               
               
                 Int-3-19 
                                   
   5-{6-[4-(1-tert-Butoxycarbonylamino- cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2- b]pyridazin-3-yl}-nicotinic acid ethyl ester 
                   
                 UPLC-MS: RT = 1.53 min; m/z = 590 (ES+, M + 1) 
               
               
                   
               
               
                 Int-3-20 
                                   
   (1-{4-[3-(5-Methoxypyridin-3-yl)-7-phenyl- imidazo[1,2-b]pyridazin-6-yl]-phenyl}- cyclobutyl)-carbamic acid tert-butyl ester 
                   
                 UPLC-MS: RT = 1.44 min; m/z = 548 (ES+, M + 1) 
               
               
                   
               
            
           
         
       
     
     Intermediate Example Int-4-0 
     
       
         
         
             
             
         
       
     
     (1-{4-[3-(3-Carbamoyl-phenyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester 
     150 mg (0.28 mmol) {1-[4-(3-Bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-3, 92.8 mg (0.56 mmol) 3-(carbamoylphenyl)boronic acid, 22.9 mg (0.028 mmol) 1,1 bis(diphenylphosphino)ferrocenedichloropalladium(II) and 89.4 mg (0.84 mmol) sodium carbonate in 3 mL dioxane and 0.4 mL water (both solvents had been degassed) were heated in the microwave for 30 minutes at 105° C. The reaction mixture was poured on water/dichloromethane/saturated ammonium chloride and vigorously stirred for 30′. The organic phase was separated, washed twice with brine, dried (sodium sulfate) and filtrated. The solvent was evaporated and the crude residue (210 mg&gt;100%) was used without further purification in the next step. 
     UPLC-MS (method C): RT=1.39 min; m/z=574 (ES+, M+1) 
     The following intermediate examples had been prepared in analogy according to intermediate example Int-4-0 by reacting {1-[4-(3-bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-3, with the appropriate boronic acids. 
     
       
         
           
               
               
               
               
             
               
                   
               
               
                 Intermediate 
                   
                   
                 UPLC-MS resp. 
               
               
                 example 
                 Structure/Name 
                 1H-NMR 
                 MS 
               
               
                   
               
             
            
               
                 Int-4-1 
                                   
   (1-{4-[3-(4-Fluoro-hydroxymethyl-phenyl)- 2-methyl-7-phenyl-imidazo[1,2-b]pyridazin- 6-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester 
                   
                 RT = 1.59 min; m/z = 579 (ES+, M + 1) 
               
               
                   
               
               
                 Int-4-2 
                                   
   4-{6-[4-(1-tert-Butoxycarbonylamino- cyclobutyl)-phenyl]-2-methyl-7-phenyl- imidazo[1,2-b]pyridazin-3-yl}-pyrazole-1- carboxylic acid tert-butyl ester 
                   
                 RT = 1.40 min; m/z = 521 (ES+, M + 1-Boc residue) 
               
               
                   
               
               
                 Int-4-3 
                                   
   1-{4-[3-(4-Fluorophenyl)-2-methyl-7- phenyl-imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutyl)-carbamic acid tert- butyl ester 
                   
                 RT = 1.72 min; m/z = 549 (ES+, M + 1) 
               
               
                   
               
               
                 Int-4-4 
                                   
   (1-{4-[3-(4-Carbamoyl-phenyl)-2-methyl-7- phenyl-imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutyl)-carbamic acid tert- butyl ester 
                   
                 RT = 1.44 min; m/z = 574 (ES+, M + 1) 
               
               
                   
               
               
                 Int-4-5 
                                   
   5-{6-[4-(1-tert-Butoxycarbonylamino- cyclobutyl)-phenyl]-2-methyl-7-phenyl- imidazo[1,2-b]pyridazin-3-yl}-pyrazole-1- carboxylic acid tert-butyl ester 
                   
                 RT = 1.47 min; m/z = 521 (ES+, M + 1-Boc residue) 
               
               
                   
               
               
                 Int-4-6 
                                   
   5-{6-[4-(1-tert-Butoxycarbonylamino- cyclobutyl)-phenyl]-2-methyl-7-phenyl- imidazo[1,2-b]pyridazin-3-yl}-3-methyl- pyrazole-1-carboxylic acid tert-butyl ester 
                   
                 RT = 1.74 min; m/z = 535 (ES+, M + 1-Boc residue) 
               
               
                   
               
            
           
         
       
     
     Example 1 
     
       
         
         
             
             
         
       
     
     1-[4-(7-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine 
     105 mg (0.24 mmol) {1-[4-(7-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, (intermediate example Int-2-0, slightly contaminated), were stirred with 2.3 mL 4M hydrogen chloride in dioxane for 10 days at room temperature. After evaporation of the solvent the residue was brought to pH 9 with saturated aqueous sodium bicarbonate solution. The mixture was stirred for four hours. The precipitate was sucked off and washed with water. The solid substance was dissolved in dichloromethane and purified by chromatography on silicagel (eluents: dichloromethane/methanol) resulting in 49.6 mg of the desired compound which was however yet contaminated. Due to these impurities the compound was again purified by HPLC yielding 21.1 mg (23.7%) of the title compound. 
     MS (ES+, M+1): 341 
       1 H-NMR (400 MHz, dDMSO): δ 8.32 (s, 1H), 8.10 (s, 1H), 7.83 (s, 1H), 7.35 (d, 2H), 7.15-7.32 (m, 7H), 2.20-2.40 (m, 2H), 1.88-2.09 (m, 3H), 1.53-1.69 (m, 1H). 
     Example 1.1 
     
       
         
         
             
             
         
       
     
     1-[4-(2-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine hydrochloride 
     100 mg (0.22 mmol) {1-[4-(2-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, (intermediate example int-2-2), were stirred with 7.5 mL 4M hydrogen chloride in dioxane over night at room temperature. After evaporation of the solvent the residue was treated with a mixture of methyl-tert. butylether and dichloromethane (1:1) and stirred over night at room temperature. The precipitate was filtered off yielding 132 mg (76%) of the title compound. 
     UPLC-MS: RT=0.83 min; m/z=338 (ES+, M-NH 2 ) 
       1 H-NMR (300 MHz, dDMSO): δ 8.80-9.05 (s, br., 3H), 8.38 (s, 1H), 8.18-8.31 (m, 4H), 8.18 (s, 1H), 7.75 (d, 2H), 7.55-7.68 (m, 3H), 2.54-2.70 (m, 4H), 2.48 (s, completely obscured by the signal of the solvent, 3H), 2.10-2.30 (m, 1H), 1.72-1.90 (m, 1H). 
     Example 2 
     1-[4-(3-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine 
     
       
         
         
             
             
         
       
     
     18 mg (0.04 mmol) {1-[4-(3-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester (intermediate example Int-3-0) were dissolved in 01 mL dioxane. 0.4 mL 4M hydrogen chloride in dioxane were added and the mixture was stirred over night at room temperature. The solvent was evaporated and the residue was treated with saturated sodium bicarbonate solution. After stirring for one hour the reaction mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with water and dried (sodium sulfate). After removal of the solvent the residue was purified by chromatography on silicagel (eluents dichloromethane/methanol) and additional HPLC yielding 2.3 mg (14%) of the title compound. 
     MS (ES+, M+1): 355 
       1 H-NMR (300 MHz, CD 3 OD): δ 8.53 (br, NH 2 , partly exchanged, 2H), 7.93 (s, 1H), 7.62 (s, 1H), 7.38-7.52 (m, 4H), 7.12-7.38 (m, 5H), 2.55-2.75 (m with a singulet within, 5H), 2.35-2.55 (m, 2H), 2.09-2.26 (m, 1H), 1.79-1.98 (m, 1H). 
     
       
         
         
             
             
         
       
     
     Example 3 
     3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzonitrile 
     115 mg (0.2 mmol) (1-{4-[3-(Cyanophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}cyclobutyl)-carbamic acid tert.-butyl ester, intermediate example Int-3-1, were stirred with 10 mL 4M hydrogen chloride in dioxane for five days at room temperature. The solvent was evaporated and the residue was treated with saturated sodium bicarbonate solution. After stirring for two hours the reaction mixture was extracted twice with dichloromethane. The combined organic extracts were washed with water and dried (sodium sulfate). After evaporating of the solvent the residue was purified by HPLC yielding 6.2 mg of the title compound which is 90% pure. 
     UPLC-MS (method B): RT=1.34 min; m/z=442 (ES+, M+1) 
       1 H-NMR (300 MHz, CD 3 OD): δ 8.67 (s, 1H), 8.49 (d, 1H), 8.32 (s, 1H), 8.08 (s, 1H), 7.59-7.75 (m, 2H), 7.40-7.59 (m, 4H), 7.15-7.40 (m, 5H), 2.58-2.80 (m, 2H), 2.33-2.58 (m, 2H), 2.10-2.29 (m, 1H), 1.80-2.29 (m, 1H). 
     Example 4 
     1-{4-[3-(4-Methanesulfonylphenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine 
     
       
         
         
             
             
         
       
     
     120 mg (0.2 mmol) (1-{4-[3-(4-Methanesulfonyl-phenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert.-butyl ester, intermediate example Int-3-2, were stirred with 10 mL 4M hydrogen chloride in dioxane for 23 hours at room temperature. The solvent was evaporated and the residue was treated with saturated sodium bicarbonate solution (pH 9). After stirring for two hours 100 mL dichloromethane were added and stirring was continued for one hour. The organic phase was separated and the aqueous phase was extracted once more with dichloromethane (50 mL). The combined organic extracts were washed with water, brine, dried, filtrated and the solvent was evaporated. The crude product (97.8 mg) was purified by HPLC to yield 20.8 mg of the title compound. 
       1 H-NMR (300 MHz, dDMSO): δ 8.52 (s, 1H), 8.50 (d, 2H), 8.29 (s, 1H), 8.03 (d, 2H), 7.18-7.49 (m, 9H), 3.28 (s, 3H), 2.29-2.42 (m, partly obscured by the signal of the solvent, 2H), 1.90-2.19 (m, 3H), 1.53-1.70 (m, 1H). 
     The following examples had been prepared in analogy according to example 4 by cleaving the protecting group in the corresponding intermediate examples and subsequent purification or in the case of the hydrochlorides by filtering the title compounds off as described in example 1.1. 
     
       
         
           
               
               
               
               
             
               
                   
               
               
                   
                   
                   
                 UPLC-MS 
               
               
                 Example 
                 Structure/Name 
                 1H-NMR 
                 resp. MS 
               
               
                   
               
             
            
               
                 4.1 
                                   
   4-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2- b]pyridazin-3-yl}-benzonitrile 
                 (400 MHz, dDMSO): δ 8.57 (s, 1H), 8.49 (d, 2H), 8.25 (s, 1H), 7.96 (d, 2H), 7.42 (d, 2H), 7.21-7.38 (m, 7H), 2.28- 2.40 (m, 2H), 2.04-2.15 (m, 2H), 1.92-2.04 (m, 1H), 1.55-1.69 (m, 1H).  
                 (ES+, M − NH 2 ): 425 
               
               
                   
               
               
                 4.2 
                                   
   3-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2- b]pyridazin-3-yl}-benzoic acid methyl ester 
                   1 H-NMR (300 MHz, dDMSO): δ 9.03 (s, 1H), 8.38-8.51 (m, 2H), 8.21 (s, 1H), 7.93 (d, 1H), 7.67 (dd, 1H), 7.15-7.48 (m, 9H), 3.89 (s, 3H), 2.25-2.39 (m, 2H), 1.89- 2.10 (m, 3H), 1.52-1.68 (m, 1H). 
                 RT = 1.00 min; m/z = 458 (ES+, M − NH 2 ) 
               
               
                   
               
               
                 4.3 
                                   
   1-{4-[3-(4-Fluorophenyl)-7-phenyl- imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutylamine 
                   1 H-NMR (300 MHz, dDMSO): δ 8.31 (s, 1H), 8.15-8.30 (m, 4H), 7.19- 7.48 (m, 10H), 2.31-2.48 (m, partly obscured by the signal of the solvent, 2H), 2.10-2.30 (m, 2H), 1.92-2.12 (m, 1H), 1.58- 1.76 (m, 1H). 
                 RT = 0.99 min; m/z = 418 (ES+, M − NH 2 ) 
               
               
                   
               
               
                 4.4 
                                   
   1-[4-(7-Phenyl-3-p-tolyl- imidazo[1,2-b]pyridazin-6-yl)- phenyl]-cyclobutylamine 
                   
                 RT = 1.02 min; m/z = 431 (ES+, M + 1) 
               
               
                   
               
               
                 4.5 
                                   
   (3-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2- b]pyridazin-3-yl}-phenyl)-methanol 
                   
                 Method B: RT = 1.23 min; m/z = 430 (ES+, M − NH 2 ) 
               
               
                   
               
               
                 4.6 
                                   
   (4-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2- b]pyridazin-3-yl}-phenyl)-methanol formiate 
                 (400 MHz, dDMSO): δ 8.30 (s, 1H), 8.21 (s, 1H), 8.19 (s, 1H), 8.17 (d, 2H), 7.38-7.48 (m, 4H), 7.19-7.38 (m, 7H), 4.52 (s, 2H), 2.32-2.42 (m, 2H), 2.09-2.20 (m, 2H), 1.92-2.05 (m, 1H), 1.59- 1.72 (m, 1H). 
                 Method B: RT = 1.11 min; m/z = 447 (ES+, M + 1) 
               
               
                   
               
               
                 4.7 
                                   
   4-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2- b]pyridazin-3-yl}- benzenesulfonamide hydrocloride 
                 (400 MHz, dDMSO): δ 8.75-8.92 (s, br., 3H), 8.64 (s, 1H), 8.32-8.40 (m, 3H), 7.96 (d, 2H), 7.25-7.59 (m, 11H), 2.48- 2.59 (m, 4H), 2.10-2.22 (m, 1H), 1.69-1.82 (m, 1H). 
                 RT = 0.83 min; m/z = 479 (ES+, M − NH 2 ) 
               
               
                   
               
               
                 4.8 
                                   
   1-[4-(3-Bromo-7-phenyl- imidazo[1,2-b]pyridazin-6-yl)- phenyl]-cyclobutylamine hydrochloride 
                 (300 MHz, dDMSO): δ 8.69-8.89 (s, br., 3H), 8.21 (s, 1H), 8.05 (s, 1H), 7.50 (d, 2H), 7.39 (d, 2H), 7.20-7.38 (m, 5H), 2.48-2.59 (m, 4H), 2.10- 2.22 (m, 1H), 1.69-1.82 (m, 1H). 
                 RT = 0.92 min; m/z = 402/404 (ES+, M − NH 2 ) 
               
               
                   
               
               
                 4.9 
                                   
   (5-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2- b]pyridazin-3-yl}-2-fluorophenyl)- methanol hydrochloride 
                 (400 MHz, dDMSO): δ 8.72-8.92 (s, br., 3H), 8.54 (s, 1H), 8.38 (s, 1H), 8.28-8.34 (m, 1H), 8.08- 8.15 (m, 1H), 7.42-7.58 (m, 4H), 7.25-7.42 (m, 6H), 4.63 (s, 2H), 2.49- 2.60 (m, partly obscured by the signal of the solvent, 4H), 2.09-2.22 (m, 1H), 1.69-1.83 (m, 1H). 
                 Method C: RT = 0.83 min; m/z = 448 (ES+, M − NH 2 ) 
               
               
                   
               
               
                 4.10 
                                   
   4-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2- b]pyridazin-3-yl}-benzamide hydrochloride 
                 (300 MHz, dDMSO): δ 8.72-8.89 (s, br., 3H), 8.60 (s, 1H), 8.35 (s, 1H), 8.30 (d, 2H), 8.01 (d, 2H), 7.26-7.59 (m, 11H), 2.49-2.61 (m, partly obscured by the signal of the solvent, 4H), 2.05- 2.28 (m, 1H), 1.68-1.85 (m, 1H). 
                 RT = 0.81 min; m/z = 443 (ES+, M − NH 2 ) 
               
               
                   
               
               
                 4.11 
                                   
   3-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2- b]pyridazin-3-yl}-benzamide hydrochloride 
                 (400 MHz, dDMSO): δ 8.78-8.90 (s, br., 3H), 8.69 (s, 1H), 8.63 (s, 1H), 8.39 (s, 1H), 8.35 (d, 1H), 8.15 (s, 1H), 7.92 (d, 1H), 7.62 (dd, 1H), 7.42-7.58 (m, 5H), 7.25- 7.42 (m, 5H), 2.49-2.61 (m, partly obscured by the signal of the solvent, 4H), 2.10-2.22 (m, 1H), 1.68-1.82 (m, 1H). 
                 RT = 0.82 min; m/z = 443 (ES+, M − NH 2 ) 
               
               
                   
               
               
                 4.12 
                                   
   1-{4-[7-Phenyl-3-(1H-pyrazol-4-yl)- imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutylamine 
                 (400 MHz, dDMSO): δ 8.35 (s, 2H), 8.25 (s, 1H), 8.16 (s, 1H), 8.13 (s, 1H), 7.38-7.48 (m, 4H), 7.20- 7.38 (m, 5H), 2.35-2.48 (m, partly obscurd by the signal of the solvent, 2H), 2.18-2.30 (m, 2H), 1.98- 2.10 (m, 1H), 1.62-1.75 (m, 1H). 
                 RT = 0.77 min; m/z = 390 (ES+, M − NH 2 ) 
               
               
                   
               
               
                 4.13 
                                   
   5-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2- b]pyridazin-3-yl}-pyridin-2-ol 
                 (400 MHz, dDMSO): δ 8.43 (d, 1H), 8.22 (s, 1H), 8.19 (s, 1H), 8.11 (d, 1H), 7.15-7.45 (m, 10H), 6.51 (d, 1H), 2.25- 2.40 (m, 2H), 1.90-2.13 (m, 3H), 1.53-1.69 (m, 1H). 
                 RT = 0.76 min; m/z = 417 (ES+, M − NH 2 ) 
               
               
                   
               
               
                 4.14 
                                   
   5-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2- b]pyridazin-3-yl}-pyridine-2- carboxylic acid methyl ester 
                 (400 MHz, CDCl 3 ): δ 9.68 (d, 1H), 8.68 (d, 1H), 8.31 (s, 1H), 8.29 (d, 1H), 8.09 (s, 1H), 7.17- 7.48 (m, 9H), 4.09 (s, 3H), 2.49-2.61 (m, 2H), 2.00-2.28 (m, 3H), 1.72- 1.90 (m, partly obscured by the water signal of the solvent, 1H). 
                 RT = 0.91 min; m/z = 459 (ES+, M − NH 2 ) 
               
               
                   
               
               
                 4.15 
                                   
   1-{4-[7-Phenyl-3-(2H-pyrazol-3-yl)- imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutylamine 
                 (400 MHz, CD 3 OD): δ 8.23 (s, 1H), 8.08 (s, 1H), 7.67-7.88 (m, 1H), 7.18- 7.52 (m, 10H), 2.52-2.69 (m, 2H), 2.25-2.40 (m, 2H), 2.05-2.20 (m, 1H), 1.72-1.90 (m, 1H). 
                 RT = 0.83 min; m/z = 407 (ES+, M + 1) 
               
               
                   
               
               
                 4.16 
                                   
   1-{4-[3-(1H-indazol-6-yl)-7-phenyl- imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutylamine 
                 (400 MHz, CD 3 OD): δ 8.64 (s, 1H), 8.29 (s, 1H), 8.01-8.10 (m, 2H), 7.80- 7.90 (m, 2H), 7.40-7.55 (m, 4H), 7.20-7.39 (m, 5H), 2.59-2.72 (m, 2H), 2.38-2.51 (m, 2H), 2.09- 2.22 (m, 1H), 1.80-1.93 (m, 1H). 
                 RT = 0.89 min; m/z = 460 (ES+, M − NH 2 ) 
               
               
                   
               
               
                 4.17 
                                   
   5-{6-[4-(1-Amino-cyclobutyl)- phenyl]-7-phenyl-imidazo[1,2- b]pyridazin-3-yl}-nicotinic acid ethyl ester 
                 (300 MHz, CD 3 OD): δ 9.52 (d, 1H), 9.32 (d, 1H), 9.05 (d, 1H), 8.39 (s, 1H), 8.07 (s, 1H), 7.38-7.50 (m, 4H), 7.20- 7.38 (m, 5H), 4.43 (q, 2H), 2.45-2.62 (m, 2H), 2.19-2.32 (m, 2H), 1.99- 2.18 (m, 1H), 1.68-1.82 (m, 1H), 1.41 (t, 3H). 
                 RT = 0.90 min; m/z = 490 (ES+, M + 1) 
               
               
                   
               
               
                 4.18 
                                   
   1-{4-[3-(5-Methoxypyridin-3-yl)-7- phenyl-imidazo[1,2-b]pyridazin-6- yl]-phenyl}-cyclobutylamine 
                 (300 MHz, CD 3 OD): δ 8.99 (d, 1H), 8.39 (s, 1H), 8.33 (d, 1H), 8.21 (d, 1H), 8.08 (s, 1H), 7.39-7.51 (m, 4H), 7.22- 7.39 (m, 5H), 3.95 (s, 3H), 2.50-2.66 (m, 2H), 2.25-2.41 (m, 2H), 2.01- 2.22 (m, 1H), 1.70-1.90 (m, 1H). 
                 RT = 0.83 min; m/z = 448 (ES+, M + 1) 
               
               
                   
               
            
           
         
       
     
     Example 5 
     
       
         
         
             
             
         
       
     
     3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-benzamide 
     210 mg Crude (1-{4-[3-(3-carbamoyl-phenyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester, intermediate example Int-4-0, were stirred with 15 mL 4M hydrogen chloride in dioxane over night at room temperature. The solvent was evaporated and the residue was dissolved in methanol/dichloromethane. Methyl-tert.butylether was added until the product precipitated. The reaction mixture was stirred for one hour and the precipitate was sucked off. The crystals were dissolved in methanol and given on a ForaPak Rxn CX column. The column was washed with 100 mL methanol and the product was eluted with methanol/NH 3 . After evaporation of the solvents the residue was purified by HPLC to yield 39.3 mg of the title compound. 
       1 H-NMR (400 MHz, dDMSO): δ 8.38-8.48 (m, 3H), 8.15 (d, 2H), 8.08 (s, 1H), 8.01 (s, 1H), 7.91-7.99 (m, 2H), 7.51-7.69 (m, 6H), 7.42 (s, 1H), 2.59 (s, 3H), 2.40-2.52 (m, obscured by the signal of the solvent, 2H), 2.21-2.32 (m, 2H), 1.98-2.11 (m, 1H), 1.83-1.78 (m, 1H). 
     The following examples had been prepared in analogy according to example 5 by cleaving the protecting group in the corresponding intermediate examples and subsequent purification, 
     
       
         
           
               
               
               
               
             
               
                   
               
               
                   
                   
                   
                 UPLC-MS resp. 
               
               
                 Example 
                 Structure/Name 
                 1H-NMR 
                 MS 
               
               
                   
               
             
            
               
                 5.1 
                                   
   (5-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2- methyl-7-phenyl-imidazo[1,2- b]pyridazin-3-yl}-2-fluorophenyl)- methanol 
                 (300 MHz, dDMSO): δ 8.42 (d, 2H), 8.18 (d, 2H), 7.91- 8.03 (m, 2H), 7.68-7.80 (m, 1H), 7.49-7.68 (m, 5H), 7.28- 7.42 (m, 1H), 4.66 (s, 2H), 2.57 (s, 3H), 2.38-2.60 (m, completely obscured by the signal of the solvent, 2H), 2.19-2.35 (m, 2H), 1.92- 2.13 (m, 1H), 1.60-1.80 (m, 1H). 
                 RT = 1.03 min; m/z = 523 (ES−, M − 1) 
               
               
                   
               
               
                 5.2 
                                   
   1-{4-[2-Methyl-7-phenyl-3-(1H-pyrazol- 4-yl)-imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutylamine 
                 (400 MHz, CD 3 OD): δ 8.35 (2H), 8.01-8.15 (m, 4H), 7.68 (s, 1H), 7.60 (d, 2H), 7.50-7.59 (m, 3H), 2.60-2.72 (m, 2H), 2.62 (s, 3H), 2.33- 2.48 (m, 2H), 2.09-2.22 (m, 1H), 1.79-1.92 (m, 1H). 
                 RT = 0.88 min; m/z = 404 (ES+, M − NH 2 ) 
               
               
                   
               
               
                 5.3 
                                   
   1-{4-[3-(4-Fluorophenyl)-2-methyl-7- phenyl-imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutylamine 
                   
                 RT = 1.11 min; m/z = 493 (ES−, M − 1) 
               
               
                   
               
               
                 5.4 
                                   
   4-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2- methyl-7-phenyl-imidazol[1,2- b]pyridazin-3-yl}-benzamide 
                 (400 MHz, dDMSO): δ 8.38- 8.45 (m, 2H), 8.01-8.12 (m, 5H), 8.00 (s, 1H), 7.93 (d, 2H), 7.50-7.65 (m, 5H), 7.41 (s, br., 1H), 2.59 (s, 3H), 2.38-2.45 (m, slightly obscured by the signal of the solvent, 2H), 2.10-2.21 (m, 2H), 1.92-2.05 (m, 1H), 1.59- 1.72 (m, 1H). 
                 RT = 0.89 min; m/z = 518 (ES−, M − 1) 
               
               
                   
               
               
                 5.5 
                                   
   1-{4-[2-Methyl-7-phenyl-3-(2H-pyrazol- 3-yl)-imidazo[1,2-b]pyridazin-6-yl]- phenyl}-cyclobutylamine 
                 (400 MHz, CD 3 OD): δ 8.08- 8.13 (m, 4H), 7.82 (d, 1H), 7.78 (s, 1H), 7.50-7.65 (m, 5H), 7.13 (br., 1H), 2.70 (s, 3H), 2.55-2.68 (m, 2H), 2.25- 2.39 (m, 2H), 2.05-2.19 (m, 1H), 1.72-1.88 (m, 1H). 
                 RT = 0.85 min; m/z = 338 (ES+, M − NH 2 -pyrazol) 
               
               
                   
               
               
                 5.6 
                                   
   1-{4-[2-Methyl-7-phenyl-3-(5-methyl-2H- pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6- yl]-phenyl}-cyclobutylamine 
                 (300 MHz, CD 3 OD): δ 8.02- 8.20 (m, 4H), 7.79 (s, 1H), 7.49-7.69 (m, 5H), 6.85 (br., 1H), 2.57-2.72 (m, 5H), 2.42 (s, 3H), 2.29-2.41 (m, 2H), 2.05-2.22 (m, 1H), 1.74-1.92 (m, 1H). 
                 RT = 0.89 min; m/z = 338 (ES+, M − NH 2 - methylpyrazol) 
               
               
                   
               
            
           
         
       
     
     
       
         
         
             
             
         
       
     
     Example 6 
     1-{4-[2-Bromo-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine 
     Step 1: (1-{4-[2-bromo-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester 
     100 mg (0.19 mmol) 1-{4-[3-(4-Fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester, intermediate example Int-3-5, and 49.9 mg (0.28 mmol) N-bromosuccinimide in 1.5 mL trichloromethane were heated at reflux over night. The solvent was evaporated and the residue dissolved in dichloromethane. The organic phase was extracted trice with saturated sodium hydrogencarbonate, with water and brine and dried (sodium sulfate). After evaporation of the solvent the residue was purified by chromatography on silicagel yielding 36 mg (31.4%) of the title compound. 
       1 H-NMR (300 MHz, dDMSO): δ 8.18 (s, 1H), 7.82-7.96 (m, 2H), 7.54 (br., 1H), 7.32-7.48 (m, 2H), 7.12-7.32 (m, 9H), 2.19-2.40 (m, 4H), 1.82-2.00 (m, 1H), 1.60-1.80 (m, 1H), 0.98-1.38 (m, 9H). 
     Step 2: 1-{4-[2-Bromo-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine 
     36 mg (0.06 mmol) (1-{4-[2-Bromo-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester in 2.7 mL 4M hydrogen chloride in dioxane were stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in methanol and given on a ForaPak Rxn CX column. The column was washed with 100 mL methanol and the product was eluted with methanol/NH 3  yielding 29 mg (91.5%) of the title compound. 
       1 H-NMR (400 MHz, dDMSO): δ 8.19 (s, 1H), 7.85-7.95 (m, 2H), 7.15-7.45 (m, 11H), 2.26-2.40 (m, 2H), 2.03-2.18 (m, 2H), 1.89-2.03 (m, 1H), 1.55-1.69 (m, 1H). 
     Example 7 
     
       
         
         
             
             
         
       
     
     1-{4-[2-Chloro-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine 
     Step 1: (1-{4-[2-chloro-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester 
     100 mg (0.19 mmol) 1-{4-[3-(4-Fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester, intermediate example Int-3-5, and 37.5 mg (0.28 mmol) N-chlorosuccinimide in 1.5 mL trichloromethane were boiled over night. The solvent was evaporated and the residue dissolved in dichloromethane. The organic phase was extracted trice with saturated sodium hydrogencarbonate, with water and brine and dried (sodium sulfate). The solvent was evaporated and the residue was purified by chromatography on silicagel yielding 12.1 mg (11.4%) of the title compound. 
       1 H-NMR (300 MHz, dDMSO): δ 8.19 (s, 1H), 7.86-8.01 (m, 2H), 7.58 (br., 1H), 7.33-7.49 (m, 2H), 7.12-7.32 (m, 9H), 2.18-2.40 (m, 4H), 1.82-2.01 (m, 1H), 1.60-1.80 (m, 1H), 0.94-1.40 (m, 9H). 
     Step 2: 1-{4-[2-chloro-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutylamine 
     12.1 mg (0.98 mmol) (1-{4-[2-Chloro-3-(4-fluorophenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester in 1 mL 4M hydrogen chloride in dioxane were stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in methanol and given on a ForaPak Rxn CX column. The column was washed with 100 mL methanol and the product was eluted with methanol/NH 3  yielding 9.8 mg (93.4%) of the title compound. 
       1 H-NMR (300 MHz, dDMSO): δ 8.19 (s, 1H), 7.88-8.01 (m, 2H), 7.13-7.49 (m, 11H), 2.35-2.50 (m, partly obscured by the signal of the solvent, 2H), 2.19-2.29 (m, 2H), 1.90-2.11 (m, 1H), 1.58-1.78 (m, 1H). 
     
       
         
         
             
             
         
       
     
     Example 8 
     (E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamide 
     Step 1: (1-{4-[3-((E)-2-carbamoyl-vinyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester 133 mg (0.256 mmol) {1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-1, 36.4 mg 
     (0.5 mmol) acrylamide, 13.3 mg (0.04 mmol) tri-2-tolylphosphane, 5.8 mg (0.026 mmol) palladium(II)acetate and 0.041 mL (0.292 mmol) triethylamine in 1.8 mL degassed acetonitrile were heated in the microwave at 110° C. for one hour. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated; washed with brine, dried, and the solvent was removed. The crude product (162 mg&gt;100%) was used in the next step without further purification. 
     UPLC-MS: RT=1.26 min; m/z=510 (ES+, M+1) 
     Step 2: (E)-3-{6-[4-(1-amino-cyclobutyl)-phenyl]-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamide 
     162 mg Crude (1-{4-[3-((E)-2-carbamoyl-vinyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester were stirred in 10.2 mL 4M hydrogen chloride in dioxane for 16 hours at room temperature. After evaporation of the solvent the residue was dissolved in methanol and given on a PoraPak Rxn CX column. The column was washed with 100 mL methanol and the product was eluted with methanol/NH 3  yielding 34 mg (13%) of the title compound which was however strongly contaminated. 
     UPLC-MS: RT=0.76 min; m/z=393 (ES+, M-NH 2 ) 
     Example 9 
     
       
         
         
             
             
         
       
     
     1-[4-(7-Phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine 
     Step 1: {1-[4-(7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester 
     133 mg (0.256 mmol) {1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-1, 61.6 mg (0.256 mmol) 2,4,6-trivinyl-cyclotriboroxane, 29.6 mg (0.026 mmol) tetrakis triphenylphosphine palladium(0) and 35.4 mg (0.256 mmol) potassium carbonate in 2 mL dimethoxyethane and 0.7 mL water were heated in a microwave vial (heating block) at 110° C. for 16 hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated, washed with brine, dried, and the solvent was removed. The crude product (168 mg&gt;100%) was used in the next step without further purification. 
     UPLC-MS: RT=1.51 min; m/z=467 (ES+, M+1) 
     Step 2: 1-[4-(7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine 
     168 mg Of the crude {1-[4-(7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester were stirred in 11.5 mL 4M hydrogen chloride in dioxane for 16 hours at room temperature. After evaporation of the solvent the residue was dissolved in methanol and given on a PoraPak Rxn CX column. The column was washed with 100 mL methanol and the product was eluted with methanol/NH 3  yielding 34 mg (21.6%) of the title compound which was however slightly contaminated. 
     UPLC-MS: RT=0.82 min; m/z=411 (ES−, M−1) 
     Example 10 
     
       
         
         
             
             
         
       
     
     (E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamide 
     Step 1: (1-{4-[3-((E)-2-carbamoyl-vinyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester 
     200 mg (0.375 mmol) {1-[4-(3-Bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, (intermediate example Int-2-3), 53.3 mg (0.75 mmol) acrylamide, 19.4 mg (0.064 mmol) tri-2-tolylphosphane, 16.8 mg (0.075 mmol) palladium(II) acetate and 0.06 mL (0.427 mmol) triethylamine in 2.6 mL degassed acetonitrile were heated in the microwave at 110° C. for three hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated, washed with brine, dried, and the solvent was removed. The crude product (247 mg) was used in the next step without further purification. 
     UPLC-MS: RT=1.40 min; m/z=524 (ES+, M+1) 
     Step 2: (E)-3-{6-[4-(1-amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylamide 
     247 mg Of the crude (1-{4-[3-((E)-2-carbamoyl-vinyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester were stirred in 15 mL 4M hydrogen chloride in dioxane for 22 hours at room temperature. The solvent was evaporated and the residue was treated with saturated sodium bicarbonate solution (pH 9). After stirring for one hour 100 mL dichloromethane were added and stirring was continued for one hour. The organic phase was separated and the aqueous phase was extracted once more with dichloromethane (50 mL). The combined organic extracts were washed with water and brine, dried, filtrated and the solvent was evaporated. The crude product (197.2 mg) was purified by HPLC to yield 50.3 mg of the title compound which was however contaminated. 
       1 H-NMR (300 MHz, CD 3 OD): δ 818 (d, 2H), 8.02-8.12 (m, 2H), 8.01 (d, 1H), 7.82 (s, 1H), 7.65 (d, 2H), 7.48-7.62 (m, 3H), 7.23 (d, 1H), 2.52-2.73 (m, 5H), 2.29-2.49 (m, 2H), 2.03-2.22 (m, 1H), 1.75-1.93 (m, 1H). 
     Example 11 
     
       
         
         
             
             
         
       
     
     (E)-3-{6-[4-(1-Amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylic acid methyl ester 
     Step 1: (E)-3-{6-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylic acid methyl ester 
     200 mg (0.375 mmol) {1-[4-(3-Bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-3, 64.5 mg (0.75 mmol) methyl acrylate, 19.4 mg (0.064 mmol) tri-2-tolylphosphane, 16.8 mg (0.075 mmol) palladium(II) acetate and 0.06 mL (0.427 mmol) triethylamine in 2.6 mL degassed acetonitrile were heated in the microwave at 110° C. for three hours. Due to an incomplete reaction additional 32.2 mg (0.375 mmol) methyl acrylate and 8.5 mg (0.037 mmol) palladium(II) acetate were added, and heating in the microwave was continued for three hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated, washed twice with brine, dried, and the solvent was removed. The crude product (300 mg) was used in the next step without further purification. 
     UPLC-MS: RT=1.67 min; m/z=539 (ES+, M+1) 
     Step 2: (E)-3-{6-[4-(1-amino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylic acid methyl ester 
     299 mg Of the crude (E)-3-{6-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-3-yl}-acrylic acid methyl ester were stirred in 17.6 mL 4M hydrogen chloride in dioxane for 22 hours at room temperature. The solvent was evaporated and the residue was treated with saturated sodium bicarbonate solution (pH 9). After stirring for one hour 100 mL dichloromethane were added and stirring was continued for one hour. The organic phase was separated and the aqueous phase was extracted once more with dichloromethane (50 mL). The combined organic extracts were washed with water and brine, dried, filtrated and the solvent was evaporated. The crude product (236 mg) was purified by HPLC to yield 40 mg of the title compound. 
       1 H-NMR (400 MHz, CD 3 OD): δ 8.03-8.12 (m, 4H), 7.92 (d, 1H), 7.81 (s, 1H), 7.50-7.65 (m, 5H), 7.18 (d, 1H), 3.82 (s, 3H), 2.58-2.69 (m, 2H), 2.56 (s, 3H), 2.26-2.40 (m, 2H), 2.08-2.21 (m, 1H), 1.75-1.90 (m, 1H). 
     Example 12 
     
       
         
         
             
             
         
       
     
     1-[4-(2-Methyl-7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine 
     Step 1: {1-[4-(2-methyl-7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester 
     200 mg (0.375 mmol) {1-[4-(3-Bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-3, 90.3 mg (0.375 mmol) 2,4,6-trivinyl-cyclotriboroxane, 43 mg (0.038 mmol) tetrakis triphenylphosphine palladium(0) and 51.8 mg (0.375 mmol) potassium carbonate in 2.9 mL dimethoxyethane and 1 mL water were heated in a microwave vial at 110° C. for 16 hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated and the aqueous phase extracted once more with dichloromethane. The combined organic extracts were washed twice with brine, dried, and the solvent was removed. The crude product (244 mg) was used in the next step without further purification. 
     UPLC-MS: RT=1.70 min; m/z=481 (ES+, M+1) 
     Step 2: 1-[4-(2-methyl-7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine 
     244 mg Of the crude {1-[4-(2-methyl-7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester were stirred in 16.1 mL 4M hydrogen chloride in dioxane for 22 hours at room temperature. The reaction mixture was worked up as described in the previous example. The crude product (178 mg) was purified by HPLC to yield 35.3 mg of the title compound. 
       1 H-NMR (300 MHz, CD 3 OD): δ 8.01-8.19 (m, 4H), 7.75 (s, 1H), 7.49-7.68 (m, 5H), 7.07-7.21 (m, 1H), 6.40 (d, 1H), 5.57 (d, 1H), 2.51-2.70 (m, 5H), 2.25-2.40 (m, 2H), 2.03-2.20 (m, 1H), 1.72-1.90 (m, 1H). 
     Example 13 
     
       
         
         
             
             
         
       
     
     1-[4-(3-Ethyl-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine 
     14.3 mg (0.04 mmol) 1-[4-(2-Methyl-7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine, example 12, were given in five mL ethyl acetate (no complete dissolution). After addition of a catalytic amount of palladium/charcoal (10%) the reaction mixture was stirred under a hydrogen atmosphere for three hours. Due to an incomplete reaction one mL ethanol was added and stirring was continued over night. The catalyst was sucked off via a glass fibre filter and washed with ethanol. After evaporation of the solvents 11.9 mg (66.2%) of the title compound were obtained which were slightly contaminated. 
       1 H-NMR (300 MHz, CD 3 OD): δ 8.15 (d, 2H), 7.99-8.12 (m, 2H), 7.69 (s, 1H), 7.65 (d, 2H), 7.42-7.60 (m, 3H), 3.13 (q, 2H), 2.60-2.75 (m, 2H), 2.33-2.52 (m, 5H), 2.08-2.26 (m, 1H), 1.80-1.95 (m, 1H), 1.34 (t, 3H). 
     Biological Investigations 
     The following assays can be used to illustrate the commercial utility of the compounds according to the present invention. 
     Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein
         the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and   the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.       

     Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch. 
     Biological Assay 1.0 
     Akt1 Kinase Assay 
     Akt1 inhibitory activity of compounds of the present invention was quantified employing the Akt1 TR-FRET assay as described in the following paragraphs. His-tagged human recombinant kinase full-length Akt1 expressed in insect cells was purchased form Invitrogen (part number PV 3599). As substrate for the kinase reaction the biotinylated peptide biotin-Ahx-KKLNRTLSFAEPG (C-terminus in amide form) was used which can be purchased e.g. from the company Biosynthan GmbH (Berlin-Buch, Germany). 
     For the assay 50 nl of a 100 fold concentrated solution of the test compound in DMSO was pipetted into a black low volume 384 well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μl of a solution of Akt1 in assay buffer [50 mM TRIS/HCl pH 7.5, 5 mM MgCl 2 , 1 mM dithiothreitol, 0.02% (v/v) Triton X-100 (Sigma)] were added and the mixture was incubated for 15 min at 22° C. to allow pre-binding of the test compounds to the enzyme before the start of the kinase reaction. Then the kinase reaction was started by the addition of 3 μl of a solution of adenosine-tri-phosphate (ATP, 16.7 μM=&gt;final conc. in the 5 μl assay volume is 10 μM) and substrate (1.67 μM=&gt;final conc. in the 5 μl assay volume is 1 μM) in assay buffer and the resulting mixture was incubated for a reaction time of 60 min at 22° C. The concentration of Akt1 in the assay was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, typical enzyme concentrations were in the range of about 0.05 ng/μl (final conc. in the 5 μl assay volume). 
     The reaction was stopped by the addition of 5 μl of a solution of HTRF detection reagents (200 nM streptavidine-XL665 [Cisbio] and 1.5 nM anti-phosho-Serine antibody [Millipore, cat. #35-001] and 0.75 nM LANCE Eu-W 1024 labeled anti-mouse IgG antibody [Perkin Elmer]) in an aqueous EDTA-solution (100 mM EDTA, 0.1% (w/v) bovine serum albumin in 50 mM HEPES/NaOH pH 7.5). 
     The resulting mixture was incubated 1 h at 22° C. to allow the binding of the biotinylated phosphorylated peptide to the streptavidine-XL665 and the antibodies. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the anti-mouse-IgG-Eu-Chelate to the streptavidine-XL665. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. The data were normalised (enzyme reaction without inhibitor=0% inhibition, all other assay components but no enzyme=100% inhibition). Normally test compound were tested on the same microtiter plate at 10 different concentrations in the range of 20 μM to 1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM, dilution series prepared before the assay at the level of the 100 fold conc. stock solutions by serial 1:3 dilutions) in duplicate values for each concentration and IC 50  values were calculated by a 4 parameter fit using an inhouse software. 
     Biological Assay 2.0 
     Akt2 Kinase Assay 
     Akt2 inhibitory activity of compounds of the present invention was quantified employing the Akt2 TR-FRET assay as described in the following paragraphs. 
     His-tagged human recombinant kinase full-length Akt2 expressed in insect cells and activated by PDK1 was purchased form Invitrogen (part number PV 3975). As substrate for the kinase reaction the biotinylated peptide biotin-Ahx-KKLNRTLSFAEPG (C-terminus in amide form) was used which can be purchased e.g. from the company Biosynthan GmbH (Berlin-Buch, Germany). 
     For the assay 50 nl of a 100 fold concentrated solution of the test compound in DMSO was pipetted into a black low volume 384 well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μl of a solution of Akt2 in assay buffer [50 mM TRIS/HCl pH 7.5, 5 mM MgCl 2 , 1 mM dithiothreitol, 0.02% (v/v) Triton X-100 (Sigma)] were added and the mixture was incubated for 15 min at 22° C. to allow pre-binding of the test compounds to the enzyme before the start of the kinase reaction. Then the kinase reaction was started by the addition of 3 μl of a solution of adenosine-tri-phosphate (ATP, 16.7 μM=&gt;final conc. in the 5 μl assay volume is 10 μM) and substrate (1.67 μM=&gt;final conc. in the 5 μl assay volume is 1 μM) in assay buffer and the resulting mixture was incubated for a reaction time of 60 min at 22° C. The concentration of Akt2 in the assay was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, typical enzyme concentrations were in the range of about 0.2 ng/μl (final conc. in the 5 μl assay volume). 
     The reaction was stopped by the addition of 5 μl of a solution of HTRF detection reagents (200 nM streptavidine-XL665 [Cisbio] and 1.5 nM anti-phosho-Serine antibody [Millipore, cat. #35-001] and 0.75 nM LANCE Eu-W 1024 labeled anti-mouse IgG antibody [Perkin Elmer]) in an aqueous EDTA-solution (100 mM EDTA, 0.1%/w/v\ bovine serum albumin in 50 mM HEPES/NaOH pH 7.5). 
     The resulting mixture was incubated 1 h at 22° C. to allow the binding of the biotinylated phosphorylated peptide to the streptavidine-XL665 and the antibodies. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the anti-mouse-IgG-Eu-Chelate to the streptavidine-XL665. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a TR-FRET reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. The data were normalised (enzyme reaction without inhibitor=0% inhibition, all other assay components but no enzyme=100% inhibition). Normally test compound were tested on the same microtiter plate at 10 different concentrations in the range of 20 μM to 1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM, dilution series prepared before the assay at the level of the 100 fold conc. stock solutions by serial 1:3 dilutions) in duplicate values for each concentration and IC 50  values were calculated by a 4 parameter fit using an inhouse software. 
     Preferred compounds of the present invention show in either the Akt1 or Akt2 kinase assay: median IC 50 &lt;5 μM, more preferably, median IC 50 &lt;0.5 μM, even more preferably, median IC 50 ≦0.1 μM. 
     The following Table gives selected data for selected Examples of the present invention. 
     
       
         
           
               
               
               
             
               
                   
               
               
                   
                 Akt1, median 
                 Akt2, median 
               
               
                 Example 
                 IC 50 , μM 
                 IC 50 , μM 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 1-0 
                 0.246 
                 1.439 
               
               
                 1-1 
                 17.257 
                 20.000 
               
               
                 2-0 
                 0.441 
                 1.726 
               
               
                 3-0 
                 0.005 
                 0.082 
               
               
                 4-0 
                 0.110 
                 0.278 
               
               
                 4-1 
                 0.129 
                 0.136 
               
               
                 4-2 
                 0.004 
                 0.058 
               
               
                 4-3 
                 0.036 
                 0.081 
               
               
                 4-4 
                 0.044 
                 0.277 
               
               
                 4-5 
                 0.006 
                 0.037 
               
               
                 4-6 
                 0.019 
                 0.123 
               
               
                 4-7 
                 0.047 
                 0.151 
               
               
                 4-8 
                 0.074 
                 0.264 
               
               
                 4-9 
                 0.009 
                 0.092 
               
               
                  4-10 
                 0.027 
                 0.118 
               
               
                  4-11 
                 0.013 
                 0.068 
               
               
                  4-12 
                 0.009 
                 0.067 
               
               
                  4-13 
                 0.146 
                 0.431 
               
               
                  4-14 
                 0.019 
                 0.115 
               
               
                  4-15 
                 0.011 
                 0.070 
               
               
                  4-16 
                 0.011 
                 0.022 
               
               
                  4-17 
                 0.007 
                 0.110 
               
               
                  4-18 
                 0.005 
                 0.046 
               
               
                 5-0 
                 15.038 
                 16.764 
               
               
                 5-1 
                 10.115 
                 16.725 
               
               
                 5-2 
                 4.780 
                 not tested 
               
               
                 5-3 
                 4.428 
                 5.107 
               
               
                 5-4 
                 12.083 
                 4.823 
               
               
                 5-5 
                 2.732 
                 5.228 
               
               
                 5-6 
                 14.853 
                 17.150 
               
               
                 6-0 
                 0.068 
                 0.041 
               
               
                 7-0 
                 0.099 
                 0.106 
               
               
                 8-0 
                 0.038 
                 0.222 
               
               
                 9-0 
                 0.044 
                 0.326 
               
               
                 10-0  
                 18.031 
                 20.000 
               
               
                 11-0  
                 5.966 
                 10.120 
               
               
                 12-0  
                 8.937 
                 16.689 
               
               
                 13-0  
                 20.000 
                 20.000 
               
               
                   
               
            
           
         
       
     
     Cellular Assays 3.0 
     p-AKT1/2/3-S473, -T308, and p-4E-BP1-T70 assays 
     The molecular mechanism of action was investigated in a set of experiments to assess the inhibition of the PI3K-AKT-mTOR pathway in responsive cell lines such as KPL4 breast tumour cell line (PIK3CAH1047R, HER2O/E and hormone independent). The phospho-substrates of PI3K-AKT-mTOR axis were used as the read-outs to reflect pathway inhibition. Cells were seeded at 60-80% confluency per well in 96-well cell culture plates. After overnight incubation at 37° C. 5% CO2, cells were treated with compounds and vehicle at 37° C. for 2 hours. Thereafter, cells were lysed in 150 μl lysis buffer and the levels of phospho-AKT at T308 and S473 and p-4E-BP1 at T70 sites were determined with the corresponding AlphaScreen® SureFire® assay kits (Perkin Elmer: 4E-BP1 Assay Kit Cat # TRG4E2S10K; Akt 1/2/3 p-Ser 473 #TGRA4S500 and Akt 1/2/3 p-Thr 308 #TGRA3S500 as well as IgG detection Kit #6760617M) as described in the manuals. All measurements where at least done in duplicates and confirmed by independent repetition. 
     Alternatively pAKT-S473 was measured using the “Akt Duplex” of the MULTI-SPOT® Assay System (Fa. Meso Scale Discovery, Cat# N41100B-1) following manufacturers instructions. Each assay used 20 μg of protein extract and measured total AKT and p-AKT content simultaneously in one well. All measurements where at least done in duplicates and confirmed by independent repetition. Values for P-AKT are expressed as percentage of P-AKT level compared to total-AKT content of the extracts. 
     The following Table gives selected data for selected Examples of the present invention. 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                   
                 pAKT-S743 median 
               
               
                   
                 Example 
                 IC 50 , μM 
               
               
                   
                   
               
             
            
               
                   
                 1-0 
                 not tested 
               
               
                   
                 1-1 
                 10.00 
               
               
                   
                 2-0 
                 not tested 
               
               
                   
                 3-0 
                 1.55 
               
               
                   
                 4-0 
                 not tested 
               
               
                   
                 4-1 
                 not tested 
               
               
                   
                 4-2 
                 not tested 
               
               
                   
                 4-3 
                 not tested 
               
               
                   
                 4-4 
                 not tested 
               
               
                   
                 4-5 
                 0.03 
               
               
                   
                 4-6 
                 0.03 
               
               
                   
                 4-7 
                 0.16 
               
               
                   
                 4-8 
                 0.11 
               
               
                   
                 4-9 
                 0.04 
               
               
                   
                  4-10 
                 0.07 
               
               
                   
                  4-11 
                 0.02 
               
               
                   
                  4-12 
                 0.01 
               
               
                   
                  4-13 
                 0.16 
               
               
                   
                  4-14 
                 0.92 
               
               
                   
                  4-15 
                 0.00 
               
               
                   
                  4-16 
                 not tested 
               
               
                   
                  4-17 
                 0.06 
               
               
                   
                  4-18 
                 0.00 
               
               
                   
                 5-0 
                 10.00 
               
               
                   
                 5-1 
                 10.00 
               
               
                   
                 5-2 
                 10.00 
               
               
                   
                 5-3 
                 9.17 
               
               
                   
                 5-4 
                 10.00 
               
               
                   
                 5-5 
                 4.11 
               
               
                   
                 5-6 
                 10.00 
               
               
                   
                 6-0 
                 0.41 
               
               
                   
                 7-0 
                 0.61 
               
               
                   
                 8-0 
                 0.05 
               
               
                   
                 9-0 
                 0.03 
               
               
                   
                 10-0  
                 10.00 
               
               
                   
                 11-0  
                 10.00 
               
               
                   
                 12-0  
                 10.00 
               
               
                   
                 13-0  
                 10.00 
               
               
                   
                   
               
            
           
         
       
     
     Biological Assay 4.0 
     Tumor Cell Proliferation Assays 
     Compounds were tested in a cell-based assay that measures the capacity of the compounds to inhibit tumour cell proliferation following a 72 h drug exposure. Cell viability is determined using CellTiter-Glow® (CTG, Promega, cat# G757112/3). The CellTiter-Glo® Luminescent Cell Viability Assay is a homogeneous method to determine the number of viable cells in culture. Detection is based on using the luciferase reaction to measure the amount of ATP from viable cells. The amount of ATP in cells correlates with cell viability. Within minutes after a loss of membrane integrity, cells lose the ability to synthesize ATP, and endogenous ATPases destroy any remaining ATP; thus the levels of ATP fall precipitously. 
     Cells were plated at 3000-5000 cells/well (depending on the cell lines) in 90 μL growth medium on MTPs (Corning; #3603, black plate, clear flat bottom). For each cell line assayed, cells were plated onto a separate plate for determination of fluorescence at t=0 hour and t=72 hour time points. Following overnight incubation at 37° C., chemiluminescence values for the t=0 samples were determined after adding 10 μl medium and 100 μl CTG solution according to manufacture protocol. Plates for the t=72 hour time points were treated with compounds diluted into growth medium at ten times final concentration added in 10 μL to the cell culture plate. Cells were then incubated for 72 hours at 37° C. Chemiluminescence values for the t=72 hour samples were determined. For data analysis, briefly, data from 24 h plate where used to reflect 100% inhibition of growth (“Ci”) and DMSO control for uninhibited growth (“C0”) and analyzed using MTS software package for IC 50  and Hill coefficient. Experiments were controlled using a reference compound as standard. 
     The following Table gives selected data for selected Examples of the present invention. 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                   
                 KPL-4 proliferation 
               
               
                   
                 Example 
                 IC 50 , μM 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 1-0 
                 3.54 
               
               
                   
                 1-1 
                 10.00 
               
               
                   
                 2-0 
                 not tested 
               
               
                   
                 3-0 
                 1.71 
               
               
                   
                 4-0 
                 1.85 
               
               
                   
                 4-1 
                 2.03 
               
               
                   
                 4-2 
                 2.56 
               
               
                   
                 4-3 
                 1.91 
               
               
                   
                 4-4 
                 6.00 
               
               
                   
                 4-5 
                 1.31 
               
               
                   
                 4-6 
                 1.59 
               
               
                   
                 4-7 
                 1.75 
               
               
                   
                 4-8 
                 2.38 
               
               
                   
                 4-9 
                 1.56 
               
               
                   
                  4-10 
                 1.26 
               
               
                   
                  4-11 
                 1.41 
               
               
                   
                  4-12 
                 0.55 
               
               
                   
                  4-13 
                 3.36 
               
               
                   
                  4-14 
                 6.02 
               
               
                   
                  4-15 
                 1.40 
               
               
                   
                  4-16 
                 5.17 
               
               
                   
                  4-17 
                 6.20 
               
               
                   
                  4-18 
                 1.81 
               
               
                   
                 5-0 
                 3.85 
               
               
                   
                 5-1 
                 2.11 
               
               
                   
                 5-2 
                 2.75 
               
               
                   
                 5-3 
                 2.28 
               
               
                   
                 5-4 
                 2.38 
               
               
                   
                 5-5 
                 3.69 
               
               
                   
                 5-6 
                 9.22 
               
               
                   
                 6-0 
                 1.89 
               
               
                   
                 7-0 
                 3.03 
               
               
                   
                 8-0 
                 2.42 
               
               
                   
                 9-0 
                 1.87 
               
               
                   
                 10-0  
                 2.49 
               
               
                   
                 11-0  
                 5.28 
               
               
                   
                 12-0  
                 3.20 
               
               
                   
                 13-0  
                 2.47 
               
               
                   
                   
               
            
           
         
       
     
     Example 5.0 
     Caco2 Permeability Assay 
     Caco-2 cells (purchased from DSMZ Braunschweig, Germany) were seeded at a density of 4.5×10 4  cell per well on 24 well insert plates, 0.4 μm pore size, and grown for 15 days in DMEM medium supplemented with 10% fetal bovine serum, 1% GlutaMAX (100×, GIBCO), 100 U/ml penicillin, 100 μg/ml streptomycin (GIBCO) and 1% non essential amino acids (100×). Cells were maintained at 37° C. in a humified 5% CO 2  atmosphere. Medium was changed every 2-3 day. Before running the permeation assay, the culture medium was replaced by a FCS-free hepes-carbonate transport puffer (pH 7.2) For assessment of monolayer integrity the transepithelial electrical resistance (TEER) was measured. Test compounds were predissolved in DMSO and added either to the apical or basolateral compartment in final concentration of 2 μM. Before and after 2 h incubation at 37° C. samples were taken from both compartments. Analysis of compound content was done after precipitation with methanol by LC/MS/NAS analysis. Permeability (Papp) was calculated in the apical to basolateral (A→B) and basolateral to apical (B→A) directions. The apparent permeability was calculated using following equation:
 
 P   app =( V   r   /P   o )(1 /S )( P   2   /t )
 
     Where V r  is the volume of medium in the receiver chamber; P o  is the measured peak area of the test drug in the donor chamber at t=0, S the surface area of the monolayer, P 2  is the measured peak area of the test drug in the acceptor chamber after 2 h of incubation, and t is the incubation time. The efflux ratio basolateral (B) to apical (A) was calculated by dividing the P app  B-A by the P app  A-B. In addition the compound recovery was calculated. As assay control reference compounds were analyzed in parallel. 
     Example 6.0 
     In Vivo Rat Pharmacokinetics 
     For in vivo pharmacokinetic experiments test compounds were administered to male Wistar rats intravenously at doses of 0.3 to 1 mg/kg and intragastral at doses of 0.6 to 10 mg/kg formulated as solutions using solubilizers such as PEG400 in well-tolerated amounts. 
     For pharmacokinetics after intravenous administration test compounds were given as i.v. bolus and blood samples were taken at 2 min, 8 min, 15 min, 30 min. 45 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after dosing. Depending on the expected half-life additional samples were taken at later time points (e.g. 48 h, 72 h). For pharmacokinetics after intragastral administration test compounds were given intragastral to fasted rats and blood samples were taken at 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after dosing. Depending on the expected half-life additional samples were taken at later time points (e.g. 48 h, 72 h). Blood was collected into Lithium-Heparintubes (Monovetten® Sarstedt) and centrifuged for 15 min at 3000 rpm. An aliquot of 100 μL from the supernatant (plasma) was taken and precipitated by addition of 400 μL cold acetonitrile and frozen at −20° C. over night. Samples were subsequently thawed and centrifuged at 3000 rpm, 4° C. for 20 minutes. Aliquots of the supernatants were taken for analytical testing using an Agilent 1200 HPLC-system with LCMS/MS detection. PK parameters were calculated by non-compartmental analysis using a PK calculation software. 
     PK parameters derived from concentration-time profiles after i.v.: CLplasma: Total plasma clearance of test compound (in L/kg/h); CLblood: Total blood clearance of test compound: CLplasma*Cp/Cb (in L/kg/h) with Cp/Cb being the ratio of concentrations in plasma and blood. PK parameters calculated from concentration time profiles after i.g.: Cmax: Maximal plasma concentration (in mg/L); Cmaxnorm: Cmax divided by the administered dose (in kg/L); Tmax: Time point at which Cmax was observed (in h). Parameters calculated from both, i.v. and i.g. concentration-time profiles: AUCnorm: Area under the concentration-time curve from t=0 h to infinity (extrapolated) divided by the administered dose (in kg*h/L); AUC(0−tlast)norm: Area under the concentration-time curve from t=0 h to the last time point for which plasma concentrations could be measured divided by the administered dose (in kg*h/L); t½: terminal half-life (in h); F: oral bioavailability: AUCnorm after intragastral administration divided by AUCnorm after intravenous administration (in %). 
     The person skilled in the art will be aware of methods to show in vivo efficacy of anti-cancer compounds. By way of illustration, the following example describes methods of quantifying the in vivo efficacy in a mouse xenograft model. The skilled person will be able to apply such principles to derive models from alternative tumor material. 
     Example 7.0 
     In Vivo Xenograft Mechanism of Action Study 
     To demonstrate that compounds act in tumours by the anticipated mode of action phosphorylation of the AKT protein was investigated in PC3 prostate tumours treated once with 50 mg/kg compound. 
     To this extent PC3 human prostate tumours were xenografted onto athymic nude mice. PC3 tumour cells were cultivated according to ATCC protocols in recommended media contained 10% FCS and harvested for transplantation in a subconfluent (70%) state. 3×10 6  tumour cells suspended in 50% Matrigel were subcutaneously implantated into the inguinal region of male mice. Tumours were allowed to grow to the predetermined size of 60-80 mm 2 . When the tumours were approximately in size, the animals were randomized to treatment and control groups (groups size: 9 animals) and treatment was started. Animals were treated once with 50 mg/kg compound or vehicle per oral administration (p.o.) carried out via a gastric tube. Treatment of each animal was based on individual body weight. At 2, 5 and 24 hours post treatment 3 animals each were sacrificed and the PC3 tumours excised. Tumour samples of approximately 5×5×5 mm were lysed on ice in MSD lysis buffer in the presence of protease and phosphatase inhibitors using Tissue Lyzer (Qiagen, Germany). The levels of p-AKT S473 in extracts from tumour tissue were analysed in an ELISA based assay. This assay is based on the “Akt Duplex” of the MULTI-SPOT® Assay System (Fa. Meso Scale Discovery, Cat# N41100B-1) following manufacturers instructions. Each assay used 20 μg of protein extract and measured total AKT and p-AKT content simultaneously in one well. All measurements where at least done in duplicates and confirmed by independent repetition. Values for P-AKT are expressed as percentage of P-AKT level compared to total-AKT content of the extracts. Vehicle treated tumours were analyzed to determine the basal level of P-AKT in this model and used as a normalization control to determine the % P-AKT relative to vehicle levels. 
     Preferred compounds of the present invention show in this assay: relative to vehicle levels P-AKT &lt;30% at 2 hours post treatment, more preferably at 5 hours post treatment, even more preferably at 24 hours post treatment. 
     Example 7.1 
     In Vivo Xenograft Efficacy Study 
     To determine the therapeutic efficacy and tolerability of compounds, tumour growth of PC3 prostate tumours xenografted onto nude mice may be observed. Mice were treated either with vehicle or compounds. 
     To this extent PC3 xenografts were established as described above. Tumours were allowed to grow to the predetermined size of 25-35 mm 2 . When the tumours were approximately in size, the animals were randomized to treatment and control groups (groups size: 8 animals) and treatment was started. Treatment of each animal was based on individual body weight and oral administration (p.o.) was carried out via a gastric tube. The oral application volumes were 10 ml/kg for mice. Mice were treated once daily with 50 mg/kg compounds. 
     Tumour response was assessed by determination of the tumour area (product of the longest diameter and its perpendicular) using a calliper. The animal body weight was monitored as a measure for treatment-related toxicity. Measurement of tumour area and body weight were performed 2-3 times weekly. Statistical analysis was assessed using the SigmaStat software. A one way analysis of variance was performed, and differences to the control were compared by a pair-wise comparison procedure (Dunn&#39;s method). T/C ratios (Treatment/Control) were calculated with final tumour weights at study end.