The present invention relates to substituted imidazopyridazine compounds of general formula (I), which are Mps-1 (Monopolar Spindle 1) Kinase inhibitors (also known as Tyrosine Threonine Kinase, TTK) in which R 3 , R 5 , and A are as defined in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients. [structure]

Description

348 parts

›The present invention relates to substituted imidazopyridazine compounds…

The present invention relates to substituted imidazopyridazine compounds of general formula I as described and defined herein, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.

›BACKGROUND OF THE INVENTION · 1 of 2

The present invention relates to chemical compounds that inhibit Mps-1 (Monopolar Spindle 1) kinase (also known as Tyrosine Threonine Kinase, TTK). Mps-1 is a dual specificity Ser/Thr kinase which plays a key role in the activation of the mitotic checkpoint (also known as spindle checkpoint, spindle assembly checkpoint) thereby ensuring proper chromosome segregation during mitosis [Abrieu A et al., Cell, 2001, 106, 83-93]. Every dividing cell has to ensure equal separation of the replicated chromosomes into the two daughter cells. Upon entry into mitosis, chromosomes are attached at their kinetochores to the microtubules of the spindle apparatus. The mitotic checkpoint is a surveillance mechanism that is active as long as unattached kinetochores are present and prevents mitotic cells from entering anaphase and thereby completing cell division with unattached chromosomes [Suijkerbuijk S J and Kops G J, Biochemica et Biophysica Acta, 2008, 1786, 24-31; Musacchio A and Salmon E D, Nat Rev Mol Cell Biol., 2007, 8, 379-93]. Once all kinetochores are attached in a correct amphitelic, i.e. bipolar, fashion with the mitotic spindle, the checkpoint is satisfied and the cell enters anaphase and proceeds through mitosis. The mitotic checkpoint consists of complex network of a number of essential proteins, including members of the MAD (mitotic arrest deficient, MAD 1-3) and Bub (Budding uninhibited by benzimidazole, Bub 1-3) families, the motor protein CENP-E, Mps-1 kinase as well as other components, many of these being over-expressed in proliferating cells (e.g. cancer cells) and tissues [Yuan B et al., Clinical Cancer Research, 2006, 12, 405-10]. The essential role of Mps-1 kinase activity in mitotic checkpoint signalling has been shown by shRNA-silencing, chemical genetics as well as chemical inhibitors of Mps-1 kinase [Jelluma N et al., PLos ONE, 2008, 3, e2415; Jones M H et al., Current Biology, 2005, 15, 160-65; Dorer R K et al., Current Biology, 2005, 15, 1070-76; Schmidt M et al., EMBO Reports, 2005, 6, 866-72].

There is ample evidence linking reduced but incomplete mitotic checkpoint function with aneuploidy and tumourigenesis [Weaver B A and Cleveland D W, Cancer Research, 2007, 67, 10103-5; King R W, Biochimica et Biophysica Acta, 2008, 1786, 4-14]. In contrast, complete inhibition of the mitotic checkpoint has been recognised to result in severe chromosome missegregation and induction of apoptosis in tumour cells [Kops G J et al., Nature Reviews Cancer, 2005, 5, 773-85; Schmidt M and Medema R H, Cell Cycle, 2006, 5, 159-63; Schmidt M and Bastians H, Drug Resistance Updates, 2007, 10, 162-81]. Therefore, mitotic checkpoint abrogation through pharmacological inhibition of Mps-1 kinase or other components of the mitotic checkpoint represents a new approach for the treatment of proliferative disorders including solid tumours such as carcinomas and sarcomas and leukaemias and lymphoid malignancies or other disorders associated with uncontrolled cellular proliferation.

Established anti-mitotic drugs such as vinca alkaloids, taxanes or epothilones activate the SAC inducing a mitotic arrest either by stabilising or destabilising microtubule dynamics. This arrest prevents separation of sister chromatids to form the two daughter cells. Prolonged arrest in mitosis forces a cell either into mitotic exit without cytokinesis or into mitotic catastrophe leading to cell death.

In contrast, inhibitors of Mps-1 induce a SAC inactivation that accelerates progression of cells through mitosis resulting in severe chromosomal missegregation and finally in cell death.

These findings suggest that Mps-1 inhibitors should be of therapeutic value for the treatment of proliferative disorders associated with enhanced uncontrolled proliferative cellular processes such as, for example, cancer, inflammation, arthritis, viral diseases, neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, or fungal diseases in a warm-blooded animal such as man. Therefore, inhibitors of Mps-1 represent valuable compounds that should complement therapeutic options either as single agents or in combination with other drugs.

Different compounds have been disclosed in prior art which show an inhibitory effect on Mps-1 kinase. WO2010/124826A1 discloses substituted imidazoquinoxaline compounds as inhibitors of Mps-1 kinase or TTK. WO2011/026579A1 discloses substituted aminoquinoxalines as Mps-1 inhibitors. WO2011/063908A1, WO2011/064328A1 as well as WO2011/063907 A1 disclose triazolopyridine derivates as inhibitors of Mps-1 kinase.

Imidazopyridazine derivates have been disclosed for the treatment or prophylaxis of different diseases:

WO 2007/038314 A2 (Bristol-Myers Squibb Company) relates to fused heterocyclic compounds useful as kinase modulators, including MK2 modulation. In particular, WO 2007/038314 A2 relates to imidazo[1,2-b]pyridazines.

US patent application publication US 2008/0045536 A1 (Bristol-Myers Squibb Company) similarly relates to fused heterocyclic compounds useful as kinase modulators, including MK2 modulation. In particular, it relates to imidazo[1,2-b]pyridazines.

WO 2010/042699 A1 (Bristol-Myers Squibb Company) relates to fused heterocyclic compounds useful as kinase modulators, particularly CK2 modulation. In particular, WO 2010/042699 A1 relates to imidazo[1,2-b]pyridazines which are substituted with a nitrite group in position 3.

WO 2007/025090 A2 (Kalypsis, Inc.) relates to heterocyclic compounds useful as inhibitors of MEK kinase. In particular, WO 2007/025090 A2 relates inter alia to imidazo[1,2-b]pyridazines.

WO 1998/08847 A1 (Pfizer, Inc.) relates to heterocyclic compounds useful as corticotropin releasing factor (hormone) CRF (CRH) antagonists. In particular, WO 1998/08847 A1 relates inter alia to imidazo[1,2-b]pyridazines.

WO 20111013729A1 discloses fused imidazole derivatives as Mps-1 inhibitors. Among the disclosed fused imidazole derivates there are also imidazo[1,2-b]pyridazines. For example, WO 2011/013729A1 discloses compounds of formula C1:

›BACKGROUND OF THE INVENTION · 2 of 2

in which (X, Y, V, W) is (—N═, ═CR 1 —, ═N—, —CR 7 ═), (—CR 2 ═, ═N—, ═N—, —CR 7 ═), (—N═, αCR 1 —, ═N—, —N═) or (—N═, ═CR 1 —, —O—, —N═);

R 8 is substituted or unsubstituted cycloalkyl;

Z is a group represented by formula —NR 3 R 4 or a group represented by formula —OR 5 ;

A is substituted or unsubstituted aromatic hydrocarbon ring, substituted or unsibstituted aromatic heterocyclic ring, substituted or unsubstituted non-aromatic hydrocarbon ring or substituted or unsubstituted non-aromatic heterocyclic ring;

R 1 , R 3 , R 4 , R 5 , and R 6 represent a large variety of substituents (see WO 2011/013729A1, e.g. claim 1 ).

The inventors of the present invention surprisingly observed that compounds of general formula I as described and defined herein show a high activity in Mps-1 inhibition and show a high metabolic stability.

The state of the art described above does not describe the imidazopyridazine compounds of claims 1 to 8 , or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, as described and defined herein, and as hereinafter referred to as “compounds of the present invention”, or their pharmacological activity and stability. It has now been found, and this constitutes the basis of the present invention, that said compounds of the present invention have surprising and advantageous properties.

In particular, said compounds of the present invention have surprisingly been found to effectively inhibit Mps-1 kinase and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by Mps-1 kinase, such as, for example, haemotological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

›SUMMARY OF THE INVENTION · 1 of 2

The present invention covers compounds of general formula I:

in which:

A represents a

-group;

wherein * indicates the point of attachment of said groups with the rest of the molecule; Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group, or a group selected from

wherein * indicates the point of attachment of said groups with the rest of the molecule;

R 2 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl- or C 3 -C 6 -cycloalkyl-group;

wherein said C 3 -C 6 -cycloalkyl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4 groups selected from: halogen, —OH, —CN, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkyl-;

R 3 represents a hydrogen atom or a halogen atom, or a —CN, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, —(CH 2 ) m —C 2 -C 6 -alkenyl, —(CH 2 ) m —C 4 -C 8 -cycloalkenyl, —(CH 2 ) m —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, —C 1 -C 6 -alkyl-aryl, —C 1 -C 6 -alkyl-heteroaryl, heteroaryl-, C 1 -C 6 -alkyl-X—, —X—(CH 2 ) m —C 2 -C 6 -alkenyl, —X—(CH 2 ) m —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —OR 6 , —SR 6 , —S(═O)R 6 , —S(═O) 2 R 6 , —S(═O)(═NR 6a )R 6b , —S(═O) 2 N(R 6b )R 6c , —S— (CH 2 ) n —N(R 6a )R 6b or —S—(CH 2 ) n -(3- to 7-membered heterocycloalkyl) group;

wherein said C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, —(CH 2 ) m —C 2 -C 6 -alkenyl, —(CH 2 ) m —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, C 1 -C 6 -alkyl-X—, —X—(CH 2 ) m —C 2 -C 6 -alkenyl, —X—(CH 2 ) m —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C 1 -C 6 -alkyl-aryl, —C 1 -C 6 -alkyl-heteroaryl or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups;

R 4a , R 4b , R 4c , R 4d

represent, independently from each other, a hydrogen or halogen atom, or a —CN, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6a , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group;

R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) m —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl- or heteroaryl-group;

wherein said C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 4 -C 8 -cycloalkenyl-, aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4 R 8 groups;

R 6 , R 6a , R 6b , R 6c

represent, independently from each other, a hydrogen atom, or a C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, C 2 -C 6 -alkenyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, aryl-C 1 -C 6 -alkyl- or heteroaryl-C 1 -C 6 -alkyl-group;

R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b or —S(═O)(═NR 6c )R 6 group;

wherein said C 1 -C 6 -alkoxy-, aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2 or 3 C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkoxy-, —C(═O)O—R 6 or —OH groups; or when 2 R 7 groups are present ortho to each other on an aryl- or heteroaryl-ring, said 2 R 7 groups together form a bridge: *O(CH 2 ) 2 O*, *O(CH 2 )O*, *NH(C(═O))NH*, wherein * represent the point of attachment to said aryl- or heteroaryl-ring;

›SUMMARY OF THE INVENTION · 2 of 2

R 8 represents a hydrogen or halogen atom, or a —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 or —S(═O) 2 -(3- to 7-membered heterocycloalkyl) group;

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4 C 1 -C 6 -alkyl-groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5;

X represents S(═O) p , O, NR 6 , CR 6a R 6b or C═CR 6a R 6b ;

p is an integer of 0, 1 or 2;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

The present invention also relates to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.

›DETAILED DESCRIPTION OF THE INVENTION · 1 of 33

The terms as mentioned in the present text have preferably the following meanings:

The term “halogen atom” or “halo-” is to be understood as meaning a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine, bromine or iodine atom.

The term “C 1 -C 6 -alkyl” is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl group, or an isomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms (“C 1 -C 4 -alkyl”), e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, more particularly 1, 2 or 3 carbon atoms (“C 1 -C 3 -alkyl”), e.g. a methyl, ethyl, n-propyl- or iso-propyl group.

The term “halo-C 1 -C 6 -alkyl” is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term “C 1 -C 6 -alkyl” is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in identically or differently, i.e. one halogen atom being independent from another. Particularly, said halogen atom is F. Said halo-C 1 -C 6 -alkyl group is, for example, —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , or —CH 2 CF 3 .

The term “C 1 -C 6 -alkoxy” is to be understood as preferably meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula —O—C 1 -C 6 -alkyl, in which the term “C 1 -C 6 -alkyl” is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or an isomer thereof.

The term “halo-C 1 -C 6 -alkoxy” is to be understood as preferably meaning a linear or branched, saturated, monovalent C 1 -C 6 -alkoxy group, as defined supra, in which one or more of the hydrogen atoms is/are replaced, in identically or differently, by one or more halogen atoms. Particularly, said halogen atom is F. Said halo-C 1 -C 6 -alkoxy group is, for example, —OCF 3 , —OCHF 2 , —OCH 2 F, —OCF 2 CF 3 , or —OCH 2 CF 3 .

The term “C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl” is to be understood as preferably meaning a linear or branched, saturated, monovalent C 1 -C 6 -alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a C 1 -C 6 -alkoxy group, as defined supra, e.g. methoxyalkyl, ethoxyalkyl, propyloxyalkyl, iso-propoxyalkyl, butoxyalkyl, iso-butoxyalkyl, tert-butoxyalkyl, sec-butoxyalkyl, pentyloxyalkyl, iso-pentyloxyalkyl, hexyloxyalkyl group, or an isomer thereof.

The term “halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl” is to be understood as preferably meaning a linear or branched, saturated, monovalent C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl group, as defined supra, in which one or more of the hydrogen atoms is/are replaced, in identically or differently, by one or more halogen atoms. Particularly, said halogen atom is F. Said halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl group is, for example, —CH 2 CH 2 OCF 3 , —CH 2 CH 2 OCHF 2 , —CH 2 CH 2 OCH 2 F, —CH 2 CH 2 OCF 2 CF 3 , or —CH 2 CH 2 OCH 2 CF 3 .

The term “C 2 -C 6 -alkenyl” is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms (“C 2 -C 3 -alkenyl”), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other. Said alkenyl group is, for example, a vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl, 4-methylpent-3-enyl, (E)-3-methylpent-3-enyl, (Z)-3-methylpent-3-enyl, (E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl, (E)-1-methylpent-3-enyl, (Z)-1-methylpent-3-enyl, (E)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl, (E)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl, (E)-2-methylpent-2-enyl, (Z)-2-methylpent-2-enyl, (E)-1-methylpent-2-enyl, (Z)-1-methylpent-2-enyl, (E)-4-methylpent-1-enyl, (Z)-4-methylpent-1-enyl, (E)-3-methylpent-1-enyl, (Z)-3-methylpent-1-enyl, (E)-2-methylpent-1-enyl, (Z)-2-methylpent-1-enyl, (E)-1-methylpent-1-enyl, (Z)-1-methylpent-1-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl, 1-ethylbut-3-enyl, (E)-3-ethylbut-2-enyl, (Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl, (E)-1-ethylbut-2-enyl, (Z)-1-ethylbut-2-enyl, (E)-3-ethylbut-1-enyl, (Z)-3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E)-1-ethylbut-1-enyl, (Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E)-2-propylprop-1-enyl, (Z)-2-propylprop-1-enyl, (E)-1-propylprop-1-enyl, (Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1-enyl, (Z)-2-isopropylprop-1-enyl, (E)-1-isopropylprop-1-enyl, (Z)-1-isopropylprop-1-enyl, (E)-3,3-dimethylprop-1-enyl, (Z)-3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl, buta-1,3-dienyl, penta-1,4-dienyl, hexa-1,5-dienyl, or methylhexadienyl group. Particularly, said group is vinyl or allyl.

›DETAILED DESCRIPTION OF THE INVENTION · 2 of 33

The term “C 2 -C 6 -alkynyl” is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms (“C 2 -C 3 -alkynyl”). Said C 2 -C 6 -alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-inyl, hex-3-inyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-inyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or 3,3-dimethylbut-1-ynyl group. Particularly, said alkynyl group is ethynyl, prop-1-ynyl, or prop-2-inyl.

The term “C 3 -C 6 -cycloalkyl” is to be understood as meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms (“C 3 -C 6 -cycloalkyl”). Said C 3 -C 6 -cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl or a bicyclic hydrocarbon ring.

The term “C 4 -C 8 -cycloalkenyl” is to be understood as preferably meaning a monovalent, mono-, or bicyclic hydrocarbon ring which contains 4, 5, 6, 7 or 8 carbon atoms and one, two, three or four double bonds, in conjugation or not, as the size of said cycloalkenyl ring allows. Said C 4 -C 8 -cycloalkenyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclobutenyl, cyclopentenyl, or cyclohexenyl or a bicyclic hydrocarbon ring, e.g. a cylooctadienyl ring.

The term “3- to 7-membered heterocycloalkyl”, is to be understood as meaning a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 2, 3, 4, 5, or 6 carbon atoms, and one or more heteroatom-containing groups selected from C(═O), O, S, S(═O), S(═O) 2 , NR a , in which R a represents a hydrogen atom, or a C 1 -C 6 -alkyl- or halo-C 1 -C 6 -alkyl-group; it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, the nitrogen atom.

Particularly, said 3- to 7-membered heterocycloalkyl can contain 2, 3, 4, or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a “3- to 6-membered heterocycloalkyl”), more particularly said heterocycloalkyl can contain 4 or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a “5- to 6-membered heterocycloalkyl”).

Particularly, without being limited thereto, said heterocycloalkyl can be a 4-membered ring, such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, or a 7-membered ring, such as a diazepanyl ring, for example. Optionally, said heterocycloalkyl can be benzo fused.

Said heterocyclyl can be bicyclic, such as, without being limited thereto, a 5,5-membered ring, e.g. a hexahydrocyclopenta[c]pyrrol-2(1H)-yl) ring, or a 5,6-membered bicyclic ring, e.g. a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring, or for example.

As mentioned supra, said nitrogen atom-containing ring can be partially unsaturated, i.e. it can contain one or more double bonds, such as, without being limited thereto, a 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl ring, for example, or, it may be benzo-fused, such as, without being limited thereto, a dihydroisoquinolinyl ring, for example.

The term “4- to 8-membered heterocycloalkenyl”, is to be understood as meaning an unsaturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 4, 5, 6, 7 or 8 carbon atoms, and one or more heteroatom-containing groups selected from C(═O), O, S, S(═O), S(═O) 2 , NR a , in which R a represents a hydrogen atom, or a C 1 -C 6 -alkyl- or halo-C 1 -C 6 -alkyl-group; it being possible for said heterocycloalkenyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, the nitrogen atom. Examples of said heterocycloalkenyl may contain one or more double bonds, e.g. 4H-pyranyl, 2H-pyranyl, 3H-diazirinyl, 2,5-dihydro-1H-pyrrolyl, [1,3]dioxolyl, 4H-[1,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothiophenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl group, or, it may be benzo fused.

The term “aryl” is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, mono-, or bi- or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (a “C 6 -C 14 -aryl” group), particularly a ring having 6 carbon atoms (a “C 6 -aryl” group), e.g. a phenyl group; or a biphenyl group, or a ring having 9 carbon atoms (a “C 9 -aryl” group), e.g. an indanyl or indenyl group, or a ring having 10 carbon atoms (a “C 10 -aryl” group), e.g. a tetralinyl, dihydronaphthyl, or naphthyl group, or a ring having 13 carbon atoms, (a “C 13 -aryl” group), e.g. a fluorenyl group, or a ring having 14 carbon atoms, (a “C 14 -aryl” group), e.g. an anthranyl group.

The term “heteroaryl” is understood as preferably meaning a monovalent, monocyclic-, bicyclic- or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a “5- to 14-membered heteroaryl” group), particularly 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur, and in addition in each case can be benzocondensed. Particularly, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl etc., and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl, etc.

›DETAILED DESCRIPTION OF THE INVENTION · 3 of 33

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 term “C 1 -C 6 ”, as used throughout this text, e.g. in the context of the definition of “C 1 -C 6 -alkyl”, “C 1 -C 6 -haloalkyl”, “C 1 -C 6 -alkoxy”, or “C 1 -C 6 -haloalkoxy” is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C 1 -C 6 ” is to be interpreted as any sub-range comprised therein, e.g. C 1 -C 6 , C 2 -C 5 , C 3 -C 4 , C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 , C 1 -C 6 ; particularly C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 , C 1 -C 6 ; more particularly C 1 -C 4 ; in the case of “C 1 -C 6 -haloalkyl” or “C 1 -C 6 -haloalkoxy” even more particularly C 1 -C 2 .

Similarly, as used herein, the term “C 2 -C 6 ”, as used throughout this text, e.g. in the context of the definitions of “C 2 -C 6 -alkenyl” and “C 2 -C 6 -alkynyl”, is to be understood as meaning an alkenyl group or an alkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C 2 -C 6 ” is to be interpreted as any sub-range comprised therein, e.g. C 2 -C 6 , C 3 -C 5 , C 3 -C 4 , C 2 -C 3 , C 2 -C 4 , C 2 -C 5 ; particularly C 2 -C 3 .

Further, as used herein, the term “C 3 -C 6 ”, as used throughout this text, e.g. in the context of the definition of “C 3 -C 6 -cycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C 3 -C 6 ” is to be interpreted as any sub-range comprised therein, e.g. C 3 -C 6 , C 4 -C 5 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 5 -C 6 ; particularly C 3 -C 6 .

The term “substituted” means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term “optionally substituted” means optional substitution with the specified groups, radicals or moieties.

Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system.

As used herein, the term “leaving group” refers to an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons. Preferably, a leaving group is selected from the group comprising: halo, in particular chloro, bromo or iodo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromo-benzene)sulfonyloxy, (4-nitro-benzene)sulfonyloxy, (2-nitro-benzene)-sulfonyloxy, (4-isopropyl-benzene)sulfonyloxy, (2,4,6-tri-isopropyl-benzene)-sulfonyloxy, (2,4,6-trimethyl-benzene)sulfonyloxy, (4-tertbutyl-benzene)sulfonyloxy, benzenesulfonyloxy, and (4-methoxy-benzene)sulfonyloxy.

As used herein, the term “one or more times”, e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning “one, two, three, four or five times, particularly one, two, three or four times, more particularly one, two or three times, even more particularly one or two times”.

Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.

By “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

In accordance with a first aspect, the present invention is directed to compounds of general formula I:

in which:

A represents a

-group;

wherein * indicates the point of attachment of said groups with the rest of the molecule; Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group, or a group selected from

wherein * indicates the point of attachment of said groups with the rest of the molecule;

R 3 represents a hydrogen atom or a halogen atom, or a —CN, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, —(CH 2 ) m —C 2 -C 6 -alkenyl, —(CH 2 ) m —C 4 -C 8 -cycloalkenyl, —(CH 2 ) m —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, —C 1 -C 6 -alkyl-aryl, —C 1 -C 6 -alkyl-heteroaryl, heteroaryl-, C 1 -C 6 -alkyl-X—, —X—(CH 2 ) m —C 2 -C 6 -alkenyl, —X—(CH 2 ) m —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —OR 6 , —SR 6 , —S(═O)R 6 , —S(═O) 2 R 6 , —S(═O)(═NR 6a )R 6b , —S(═O) 2 N(R 6b )R 6c , —S— (CH 2 ) m —N(R 6a )R 6b or —S—(CH 2 ) m -(3- to 7-membered heterocycloalkyl) group;

›DETAILED DESCRIPTION OF THE INVENTION · 4 of 33

R 4a , R 4b , R 4c , R 4d

R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl- or heteroaryl-group;

R 6 , R 6a , R 6b , R 6c

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4 C 1 -C 6 -alkyl-groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5;

X represents S(═O) p , O, NR 6 , CR 6a R 6b or C═CR 6a R 6b ; and

p is an integer of 0, 1 or 2.

As defined supra, A represents a

-group;

wherein * indicates the point of attachment of said groups with the rest of the molecule.

In a preferred embodiment A represents a

-group.

In another preferred embodiment A represents a

-group.

In another preferred embodiment, the invention relates to compounds of formula I, supra, wherein A is selected from the group consisting of:

As defined supra, R 2 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl- or C 3 -C 6 -cycloalkyl-group;

›DETAILED DESCRIPTION OF THE INVENTION · 5 of 33

In a preferred embodiment, the invention relates to compounds of formula I, wherein:

R 2 represents a C 3 -C 6 -cycloalkyl-group;

In another preferred embodiment, the invention relates to compounds of formula I, wherein:

R 2 represents a C 3 -C 6 -cycloalkyl-group;

wherein said C 3 -C 6 -cycloalkyl-group is optionally substituted, identically or differently, with 1, 2, or 3 groups selected from: halogen, —OH, —CN, —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy. Preferably, the C 3 -C 6 -cycloalkyl-group is a cyclopropyl-group.

In another preferred embodiment, the invention relates to compounds of formula I, wherein:

R 2 represents a C 3 -C 6 -cycloalkyl-group;

wherein said C 3 -C 6 -cycloalkyl-group is optionally substituted, identically or differently, with 1 or 2 groups selected from: —CN, —C 1 -C 3 -alkyl, —C 1 -C 3 -alkoxy. Preferably, the C 3 -C 6 -cycloalkyl-group is a cyclopropyl-group.

In another preferred embodiment, the invention relates to compounds of formula I, wherein:

R 2 represents a cyclopropyl-group;

wherein said cyclopropyl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 groups selected from: halogen, —OH, —CN, —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy.

In another preferred embodiment, the invention relates to compounds of formula I, wherein:

R 2 represents a cyclopropyl-group;

wherein said cyclopropyl-group is optionally substituted, identically or differently, with 1 or 2 groups selected from: halogen, —OH, —CN, —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy.

In another preferred embodiment, the invention relates to compounds of formula I, wherein:

R 2 represents a cyclopropyl-group;

wherein said cyclopropyl-group is substituted, identically or differently, with 1 or 2 groups selected from: halogen, —CN, —C 1 -C 3 -alkyl, —C 1 -C 3 -alkoxy.

In another preferred embodiment, the invention relates to compounds of formula I, wherein:

R 2 represents a halo-C 1 -C 6 -alkyl-group.

In another preferred embodiment, the invention relates to compounds of formula I, wherein:

R 2 represents a C 1 -C 6 -alkyl-group;

wherein said C 1 -C 6 -alkyl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4 groups selected from: halogen, —OH, —CN, C 1 -C 6 -alkoxy-.

In another preferred embodiment, the invention relates to compounds of formula I, wherein:

R 2 represents a C 1 -C 4 -alkyl-group;

wherein said C 1 -C 4 -alkyl-group is optionally substituted, identically or differently, with 1, 2 or 3 groups selected from: halogen, —OH, —CN, —C 1 -C 4 -alkoxy.

In another preferred embodiment, the invention relates to compounds of formula I, wherein:

R 2 represents a methyl- or ethyl-group;

wherein said methyl- or ethyl-group is optionally substituted, identically or differently, with 1, 2 or 3 groups selected from: halogen, —OH, —CN.

In another preferred embodiment, the invention relates to compounds of formula I, wherein:

R 2 represents CH 3 or C 2 H 5 .

In another preferred embodiment, the invention relates to compounds of formula I, wherein:

R 2 represents a C 1 -C 3 -alkyl-group;

wherein said C 1 -C 3 -alkyl-group is optionally substituted, identically or differently, with 1, 2 or 3 groups selected from: halogen, —OH, —CN, —C 1 -C 3 -alkoxy.

The invention relates to compounds of formula I, wherein:

R 3 represents a hydrogen atom or a halogen atom, or a —CN, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, —(CH 2 ) m —C 2 -C 6 -alkenyl, —(CH 2 ) m —C 4 -C 8 -cycloalkenyl, —(CH 2 ) m —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 3 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, —C 1 -C 6 -alkyl-aryl, —C 1 -C 6 -alkyl-heteroaryl, heteroaryl-, C 1 -C 6 -alkyl-X—, —X—(CH 2 ) m —C 2 -C 6 -alkenyl, —X—(CH 2 ) m —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —OR 6 , —SR 6 , —S(═O)R 6 , —S(═O) 2 R 6 , —S(═O)(═NR 6a )R 6b , —S(═O) 2 N(R 6b )R 6c , —S—(CH 2 ) n —N(R 6a )R 6b or —S—(CH 2 ) n -(3- to 7-membered heterocycloalkyl) group;

wherein said C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, —(CH 2 ) m , —C 2 -C 6 -alkenyl, —(CH 2 ) m , —C 2 -C 6 -alkynyl, —(CH 2 ) m , —C 3 -C 6 -cycloalkyl, aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, C 1 -C 6 -alkyl-X—, —X—(CH 2 ) m —C 2 -C 6 -alkenyl, —X—(CH 2 ) m , —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m , —C 2 -C 6 -alkynyl, —X—(CH 2 ) m , —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C 1 -C 6 -alkyl-aryl, —C 1 -C 6 -alkyl-heteroaryl or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups.

In a preferred embodiment, the invention relates to compounds of formula I, supra, wherein:

R 3 represents a

C 1 -C 6 -alkyl-X—, —X—(CH 2 ) m —C 2 -C 6 -alkenyl, —X—(CH 2 ) n , —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) n , —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-, heteroaryl-, aryl-X— or heteroaryl-X— group; wherein said C 1 -C 6 -alkyl-X—, —X—(CH 2 ) m , —C 2 -C 6 -alkenyl, —X—(CH 2 ) m , —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m , —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-, heteroaryl-, aryl-X— or heteroaryl-X— group is optionally substituted, identically or differently, with 1, 2, 3, or 4 R 7 groups.

›DETAILED DESCRIPTION OF THE INVENTION · 6 of 33

In another preferred embodiment, the invention relates to compounds of formula I, supra, wherein:

R 3 represents a hydrogen atom or a halogen atom, or a C 1 -C 6 -alkoxy-, —(CH 2 ) m , —C 2 -C 6 -alkenyl, aryl-, aryl-X—, heteroaryl-X—, heteroaryl-, —(CH 2 ) m , —C 4 -C 8 -cycloalkenyl, —(CH 2 ) m , —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-, —C(═O)N(H)R 6a , —OR 6 , —SR 6 , —S(═O)R 6 , —S(═O) 2 R 6 , —S—(CH 2 ) n —N(R 6a )R 6b or —S—(CH 2 ) n -(3- to 7-membered heterocycloalkyl) group;

wherein said C 1 -C 6 -alkoxy-, aryl-, aryl-X—, heteroaryl-X— or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups.

In another preferred embodiment, the invention relates to compounds of formula I, supra, wherein:

R 3 represents a hydrogen atom or a halogen atom, or a —(CH 2 ) m , —C 2 -C 6 -alkenyl, —(CH 2 ) m —C 4 -C 8 -cycloalkenyl —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-, heteroaryl-, aryl-X—, heteroaryl-X—, —C(═O)N(H)R 6a , —OR 6 , —SR 6 , —S(═O)R 6 , —S(═O) 2 R 6 , —S—(CH 2 ), —N(R 6a )R 6b , or —S—(CH 2 ) n -(3- to 7-membered heterocycloalkyl) group;

wherein said aryl-, aryl-X—, heteroaryl-X— or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 R 7 groups.

In another preferred embodiment, the invention relates to compounds of formula I, supra, wherein:

R 3 represents an aryl-, —C 1 -C 6 -alkyl-aryl, aryl-X—, heteroaryl-X—, heteroaryl-, —C 1 -C 6 -alkyl-heteroaryl, heteroaryl-group; wherein said aryl-, aryl-X—, heteroaryl-X—, heteroaryl-, —C 1 -C 6 -alkyl-aryl or —C 1 -C 6 -alkyl-heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4 R 7 groups.

In another preferred embodiment, the invention relates to compounds of formula I, supra, wherein:

R 3 represents

a substituted or unsubstituted aryl-X— group, or a substituted or unsubstituted heteroaryl-X— group.

A preferred aryl-X— group is phenyl-X—.

Preferred heteroaryl-X— groups are quinolinyl-X—, pyridyl-X—, thienyl-X—, pyrazinyl-X—, imidazyl-X—, triazyl-X— and pyrazyl-X—.

R 3 is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups. In a preferred embodiment, the invention relates to compounds of formula I, wherein R 3 is optionally substituted, identically or differently, with 1 or 2 R 7 groups.

In another preferred embodiment, the invention relates to compounds of formula I, wherein R 3 is selected from the group consisting of:

The invention relates to compounds of formula I, supra, wherein:

R 4a , R 4b , R 4c , R 4d

represent, independently from each other, a hydrogen or halogen atom, or a —C N, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6a , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group.

In a preferred embodiment, the invention relates to compounds of formula I, supra, wherein:

R 4a , R 4c , R 4d represent a hydrogen atom, and R 4b represents a hydrogen atom, halogen atom or a C 1 -C 6 -alkyl-group.

In another preferred embodiment, the invention relates to compounds of formula I, supra, wherein:

R 4b , R 4c , R 4d represent a hydrogen atom, and R 4a represents a halogen atom, C 1 -C 6 -alkyl-, —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6a , —S(═O) 2 N(R 6a )R 6b , or —S(═O)(═NR 6c )R 6 group.

In another preferred embodiment, the invention relates to compounds of formula I, supra, wherein:

R 4b , R 4c , R 4d represent a hydrogen atom, and R 4a represents a halogen atom, C 1 -C 6 -alkyl- or —OR 6 group.

In another preferred embodiment, the invention relates to compounds of formula I, supra, wherein:

R 4a , R 4b , R 4c , and R 4d represent, independently from each other, a hydrogen or halogen atom, or a —CN, —OH, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, NC—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-group; with the proviso that at least one of the groups R 4b and R 4c is not a hydrogen atom.

In another preferred embodiment of the present invention R 4a and R 4d represent, independently from each other, a hydrogen or halogen atom, or a —CN, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkyl- or a halo-C 1 -C 6 -alkoxy-group.

In another preferred embodiment of the present invention R 4a and R 4d represent, independently from each other, a hydrogen or halogen atom, or a C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, or a halo-C 1 -C 6 -alkyl-group.

In another preferred embodiment of the present invention R 4a and R 4d represent hydrogen.

In another preferred embodiment of the present invention R 4b and R 4c represent independently from each other, a hydrogen or halogen atom, or a —CN, —OH, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-group; with the proviso that at least one of the groups R 4b and R 4c is not a hydrogen atom.

In another preferred embodiment of the present invention R 4b and R 4c represent independently from each other, a hydrogen or a C 1 -C 6 -alkyl-group; with the proviso that at least one of the groups Rob and R 4c is not a hydrogen atom.

In another preferred embodiment of the present invention R 4b and R 4c represent independently from each other, a hydrogen or a C 1 -C 4 -alkyl-group; with the proviso that at least one of the groups Rob and R 4c is not a hydrogen atom.

›DETAILED DESCRIPTION OF THE INVENTION · 7 of 33

In another preferred embodiment of the present invention one of the groups R 4b and R 4c represents a hydrogen atom while the other one represents a group selected from: halo-, —CN, —OH, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, NC—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, and halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-.

In another preferred embodiment of the present invention

either: R 4b ═C 1 -C 4 -alkyl- and R 4c =hydrogen;

or: R 4b =hydrogen and R 4c ═C 1 -C 4 -alkyl-.

In another preferred embodiment, the invention relates to compounds of formula I, wherein:

A represents a

group

wherein * indicates the point of attachment of said groups with the rest of the molecule; and

Z represents a —C(═O)N(H)R 2 or a —C(═S)N(H)R 2 group.

Preferably Z represents a —C(═O)N(H)R 2 group.

In another preferred embodiment, the invention relates to compounds of formula I, supra, wherein the following compounds (which are specifically disclosed in WO 2011/013729A1) are excluded:

The invention relates to compounds of formula I, supra, wherein:

In a preferred embodiment, the invention relates to compounds of formula I, supra, wherein:

R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl- or heteroaryl-group;

wherein said C 1 -C 6 -alkyl-, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-, or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4 R 8 groups.

In another preferred embodiment, the invention relates to compounds of formula I, supra, wherein:

R 5 represents a C 1 -C 6 -alkyl-, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl- or heteroaryl-group;

wherein said C 1 -C 6 -alkyl-, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-, heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4 R 8 groups.

In another preferred embodiment, the invention relates to compounds of formula I, wherein R 5 is selected from the group consisting of:

H, (CH 3 ) 2 CH—, CHF 2 —, CF 3 —, CF 3 —CH 2 —, CF 3 —CH 2 —CH 2 —, CF 3 —CH(OH)—, HO—CH 2 —, HO—C(CH 3 ) 2 —, HO—C(CH 3 ) 2 CH 2 —, HO—CH 2 —CH(OH)—, H 3 C—O—CH 2 —, H 2 N—CH 2 —CH 2 —, H 2 N—C(CH 3 ) 2 —, (CH 3 ) 2 N—CH 2 —, (CH 3 ) 2 N—CH 2 —CH 2 —, (CH 3 ) 2 N—CH 2 —CH 2 —CH 2 —, (CH 3 ) 2 N—C(CH 3 ) 2 —, H 3 C—S(═O) 2 —CH 2 —, H 3 C—S(═O) 2 —CH 2 —CH 2 —, HO—S(═O) 2 —CH 2 —, HO—S(═O) 2 —CH 2 —CH 2 —, NC—CH 2 —, H 3 C—C(═O)—N(H)—CH 2 , H 3 C—C(═O)—N(H)—CH 2 —CH 2 —, H 2 N—C(═O)—CH 2 —, (CH 3 ) 2 N—C(═O)—CH 2 —, H 3 C—N(H)—C(═O)—N(CH 3 )—CH 2 —CH 2 —,

In another preferred embodiment, with respect to compounds of formula I, supra, R 5 represents a 1,1,1-trifluoroethyl group.

The invention relates to compounds of formula I, supra, wherein:

R 6 , R 6a , R 6b and R 6c

In a preferred embodiment, the invention relates to compounds of formula I, supra, wherein:

R 6 , R 6a , R 6b , R 6c ,

represent, independently from each other, a hydrogen atom, or a C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl- or aryl-group.

In another preferred embodiment, the invention relates to compounds of formula I, wherein

R 6 , R 6a , R 6b , and R 6c represent, independently from each other, a hydrogen atom, or a C 1 -C 6 -alkyl-group.

The invention relates to compounds of formula I, supra, wherein:

›DETAILED DESCRIPTION OF THE INVENTION · 8 of 33

In a preferred embodiment, the invention relates to compounds of formula I, wherein R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, H 2 N—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , or —S(═O)(═NR 6c )R 6 group;

wherein said C 1 -C 6 -alkoxy-, aryl-, 3- to 7-membered heterocycloalkyl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, or 3 C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkoxy-, —C(═O)O—R 6 or —OH groups.

In another preferred embodiment, the invention relates to compounds of formula I, supra, wherein:

R 7 represents a hydrogen or halogen atom, or an HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, aryl-, heteroaryl-, —C(═O)N(R 6a )R 6b , —N(H)C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —OR 6 , —S(═O)R 6 or —S(═O) 2 R 6 , group;

wherein said C 1 -C 6 -alkoxy- or heteroaryl-group is optionally substituted, identically or differently, with a C 1 -C 4 -alkyl-, halo-C 1 -C 6 -alkoxy-, —C(═O)O—R 6 or —OH group; or when 2 R′ groups are present ortho- to each other on an aryl- or heteroaryl-ring, said 2 R 7 groups together form a bridge: *O(CH 2 ) 2 O*, *O(CH 2 )O*, *NH(C(═O))NH*, wherein * represent the point of attachment to said aryl- or heteroaryl-ring.

In another preferred embodiment, the invention relates to compounds of formula I, supra, wherein:

wherein said C 1 -C 6 -alkoxy- or heteroaryl-group is optionally substituted, identically or differently, with a C 1 -C 4 -alkyl-, halo-C 1 -C 6 -alkoxy-, —C(═O)O—R 6 or —OH group.

In another preferred embodiment, the invention relates to compounds of formula I, supra, wherein:

wherein said heteroaryl-group is optionally substituted with a C 1 -C 4 -alkyl group; or when 2 R 7 groups are present ortho- to each other on an aryl- or heteroaryl-ring, said 2 R 7 groups together form a bridge: *O(CH 2 ) 2 O*, *O(CH 2 )O*, *NH(C(═O))NH*, wherein * represent the point of attachment to said aryl- or heteroaryl-ring.

In another preferred embodiment, the invention relates to compounds of formula I, wherein R 7 represents a halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, H 2 N—C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl, —C(═O)N(H)R 6a , —N(R 6a )R 6b , —N(H)C(═O)R 6 , or —SR 6 group;

In another preferred embodiment, the invention relates to compounds of formula I, wherein R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, H 2 N—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , or —S(═O)(═NR 6c )R 6 group;

wherein said C 1 -C 6 -alkoxy-, aryl-, 3- to 7-membered heterocycloalkyl, or heteroaryl-group is optionally substituted, identically or differently, with 1 C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkoxy-, —C(═O)O—R 6 or —OH group.

In another preferred embodiment, the invention relates to compounds of formula I, wherein R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, H 2 N—C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl, —C(═O)N(H)R 6a , —N(R 6a )R 6b , —N(H)C(═O)R 6 or —SR 6 group;

wherein said C 1 -C 6 -alkoxy- or 3- to 7-membered heterocycloalkyl-group is optionally substituted, identically or differently, with one —C(═O)O—R 6 or —OH group.

In another preferred embodiment, the invention relates to compounds of formula I, supra, wherein 2 R 7 groups are present ortho to each other on the aryl- or heteroaryl-ring of the R 3 group;

said 2 R 7 groups together form a bridge:

*O(CH 2 ) 2 O*, *O(CH 2 )O*, *CH 2 (CH 2 ) 2 NH*, *CH 2 CH 2 N(R 6a )CH 2 *, *NH(C(═O))NH*, *C(H)═C(H)—C(═O)—N(H)*,

wherein * represent the point of attachment to said aryl- or heteroaryl-ring.

Preferably the 2 R 7 groups together form a bridge selected from:

›DETAILED DESCRIPTION OF THE INVENTION · 9 of 33

*CH 2 (CH 2 ) 2 NH*, *CH 2 CH 2 N(R 6a )CH 2 *, *C(H)═C(H)—C(═O)—N(H)*.

The invention relates to compounds of formula I, supra, wherein

R 8 represents a hydrogen or halogen atom, or a —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 or —S(═O) 2 -(3- to 7-membered heterocycloalkyl) group;

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4 C 1 -C 6 -alkyl-groups.

In a preferred embodiment, the invention relates to compounds of formula I, supra, wherein:

R 8 represents a halogen atom, or a —CN, —OH, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl, —C(═O)N(R 6a )R 6b , —N(R 6a )R 6b , —N(H)C(═O)R 6 , —N(R 6c )C(═O)N(R 6a )R 6b , —S(═O) 2 R 6 or —S(═O) 2 OH group.

In another preferred embodiment, the invention relates to compounds of formula I, supra, wherein:

R 8 represents a halogen atom, a —CN, —N(R 6a )R 6b , or —OR 6 group.

Preferably, R 8 represents a halogen atom, a —N(R 6a )R 6b or a —OR 6 group.

The invention relates to compounds of formula I, wherein

m is an integer of 0, 1, 2, 3, 4, 5 or 6.

In a preferred embodiment, with respect to compounds of formula I, supra, m is 0.

In another preferred embodiment, with respect to compounds of formula I, supra, m is 1.

The invention relates to compounds of formula I, wherein

n is an integer of 0, 1, 2, 3, 4 or 5.

In a preferred embodiment, with respect to compounds of formula I, supra, n is 1.

The invention relates to compounds of formula I, wherein

X is S, S(═O), S(═O) 2 , O, NR 6 , CR 6a R 6b or C═CR 6a R 6b .

In a preferred embodiment, the invention relates to compounds of formula I, wherein

X is S.

In another preferred embodiment, the invention relates to compounds of formula I, wherein

X is S(═O).

In another preferred embodiment, the invention relates to compounds of formula I, wherein

X is S(═O) 2 .

In another preferred embodiment, the invention relates to compounds of formula I, wherein

X is O.

In another preferred embodiment, the invention relates to compounds of formula I, wherein

X is NR 6 . Preferably, X is NH or N(CH 3 ). Most preferably, X is NH.

It should be noted that in a group of e.g. formula aryl-NR 6 — or heteroaryl-NR 6 — the substituent R 6 optionally can be attached to the aryl- or heteroaryl-ring, thereby—together with the N-atom—forming a heterocyclic ring fused to the aryl- or heteroaryl-ring. An example of such a fused ring system is the group:

in which * indicates the point of attachment of said group with the rest of the molecule. In other words, a group with the formula

in which * indicates the point of attachment of said group with the rest of the molecule, is an example of an aryl-X— group.

In another preferred embodiment, the invention relates to compounds of formula I, wherein

X is CR 6a R 6b . Preferably, X is CH 2 .

It should be noted that in a group of e.g. formula aryl-CR 6a R 6b — or heteroaryl-CR 6a R 6b — the substituents R 6a and/or R 6b option ally can be attached to the aryl- or heteroaryl-ring, thereby forming one or more carbocyclic rings fused to the aryl- or heteroaryl-ring. An example of such a fused ring system is the group

in which * indicates the point of attachment of said group with the rest of the molecule. In other words, a group with the formula

in which * indicates the point of attachment of said group with the rest of the molecule, is an example of an aryl-X— group.

In another preferred embodiment, the invention relates to compounds of formula I, wherein

X is C═CR 6a R 6b . Preferably, X is C═CH 2 .

The invention relates to compounds of formula I, wherein

Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group, or a group selected from

wherein * indicates the point of attachment of said groups with the rest of the molecule.

In a preferred embodiment Z represents a —C(═O)N(H)R 2 group.

In another preferred embodiment Z represents a —C(═S)N(H)R 2 group.

In another preferred embodiment Z represents a

group.

In an embodiment of the above-mentioned aspects, the invention relates to compounds of formula I, according to any of the above-mentioned embodiments, in the form of or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

It is to be understood that the present invention relates also to any combination of the preferred embodiments described above.

Some examples of combinations are given hereinafter. However, the invention is not limited to these combinations.

In a preferred embodiment, the invention relates to compounds of general formula I, supra, in which:

A represents a

-group;

wherein * indicates the point of attachment of said groups with the rest of the molecule; Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group, or a group selected from

wherein * indicates the point of attachment of said groups with the rest of the molecule;

wherein said C 3 -C 6 -cycloalkyl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4-groups selected from: halogen, OH, —CN, C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl-;

›DETAILED DESCRIPTION OF THE INVENTION · 10 of 33

R 3 represents a hydrogen atom or a halogen atom, or a —CN, C 1 -C 6 -alkyl-, —(CH 2 ) m , —C 2 -C 6 -alkenyl —(CH 2 ) m , —C 4 -C 8 -cycloalkenyl —(CH 2 ) m , —C 2 -C 6 -alkynyl, —(CH 2 ) m , —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, a 3- to 7-membered heterocycloalkyl, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, —C 1 -C 6 -alkyl-aryl, —C 1 -C 6 -alkyl-heteroaryl, heteroaryl-, C 1 -C 6 -alkyl-X—, —X—(CH 2 ) m —C 2 -C 6 -alkenyl, —X—(CH 2 ) m —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —OR 6 , —SR 6 , —S(═O)R 6 , —S(═O) 2 R 6 , —S(═O)(═NR 6a )R 6b , —S(═O) 2 N(R 6b )R 6c , —S—(CH 2 ) n —N(R 6a )R 6b , or —S—(CH 2 ) m -(3- to 7-membered heterocycloalkyl) group;

wherein said C 1 -C 6 -alkyl-, —(CH 2 ) m —C 2 -C 6 -alkenyl, —(CH 2 ) m —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, a 3- to 7-membered heterocycloalkyl, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, C 1 -C 6 -alkyl-X—, —X—(CH 2 ) m —C 2 -C 6 -alkenyl, —X—(CH 2 ) m —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C 1 -C 6 -alkyl-aryl, —C 1 -C 6 -alkyl-heteroaryl or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 R 7 groups;

R 4a , R 4b , R 4c , R 4d

R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, —(CH 2 ) n —, —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl- or heteroaryl group;

R 6 , R 6a , R 6b , R 6c ,

represent, independently from each other, a hydrogen atom, or a C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, aryl-C 1 -C 6 -alkyl-, or heteroaryl-C 1 -C 6 -alkyl-group;

R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b ), —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group;

wherein said aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, or 3 C 1 -C 6 -alkyl groups; or when 2 R 7 groups are present ortho- to each other on an aryl-ring, said 2 R 7 groups together form a bridge: *O(CH 2 ) 2 O*, *O(CH 2 )O*, *NH(C(═O))NH*, wherein * represent the point of attachment to said aryl-ring;

R 8 represents a hydrogen or halogen atom, or a —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group or —S(═O) 2 -(3- to 7-membered heterocycloalkyl);

›DETAILED DESCRIPTION OF THE INVENTION · 11 of 33

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 C 1 -C 6 -alkyl-groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5;

X is S, S(═O), S(═O) 2 , O, NR 6 ;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds of general formula I, supra, in which:

A represents a

-group;

wherein * indicates the point of attachment of said groups with the rest of the molecule; Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group, or a group selected from

wherein * indicates the point of attachment of said groups with the rest of the molecule;

wherein said C 3 -C 6 -cycloalkyl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4-groups selected from: halogen, OH, —CN, C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl-;

R 3 represents a hydrogen atom or a halogen atom, or a —CN, C 1 -C 6 -alkyl-, —(CH 2 ) m —C 2 -C 6 -alkenyl-, —(CH 2 ) m —C 4 -C 8 -cycloalkenyl, —(CH 2 ) m , —C 2 -C 6 -alkynyl, —(CH 2 ) m , —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, —C 1 -C 6 -alkyl-aryl, —C 1 -C 6 -alkyl-heteroaryl, heteroaryl-, C 1 -C 6 -alkyl-X—, —X—(CH 2 ) m —C 2 -C 6 -alkenyl, —X—(CH 2 ) m —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —OR 6 , —SR 6 , —S(═O)R 6 , —S(═O) 2 R 6 , —S(═O)(═NR 6a )R 6b , —S(═O) 2 N(R 6b )R 6c , —S—(CH 2 ) n —N(R 6a )R 6b , or —S—(CH 2 ) n -(3- to 7-membered heterocycloalkyl) group;

wherein said C 1 -C 6 -alkyl-, —(CH 2 ) m —C 2 -C 6 -alkenyl, —(CH 2 ) m —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, C 1 -C 6 -alkyl-X—, —X—(CH 2 ) m —C 2 -C 6 -alkenyl, —X—(CH 2 ) m —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C 1 -C 6 -alkyl-aryl, —C 1 -C 6 -alkyl-heteroaryl, or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4 R 7 groups;

either

R 4a , R 4c , R 4d represent a hydrogen atom, and

R 4b represents a hydrogen atom or a halogen atom or a C 1 -C 6 -alkyl-group;

R 4b , R 4c , R 4d represent a hydrogen atom, and

R 4a represents a halogen atom or an C 1 -C 6 -alkyl-, —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6a , —S(═O) 2 N(R 6a )R 6b or —S(═O)(═NR 6c )R 6 group;

R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m , —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, a 3- to 7-membered heterocycloalkyl, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl- or heteroaryl-group;

wherein said C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl, C 4 -C 8 -cycloalkenyl-, aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 R 8 groups;

R 6 , R 6a , R 6b , R 6c ,

wherein said aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, or 3 C 1 -C 6 -alkyl-groups; or when 2 R 7 groups are present ortho to each other on an aryl-ring, said 2 R 7 groups together form a bridge: *O(CH 2 ) 2 O*, *O(CH 2 )O*, *NH(C(═O))NH*, wherein * represent the point of attachment to said aryl-ring;

›DETAILED DESCRIPTION OF THE INVENTION · 12 of 33

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 C 1 -C 6 -alkyl-groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5;

X is S, S(═O), S(═O) 2 , O, NR 6 ;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds of general formula I, supra, in which:

A represents a

-group;

wherein * indicates the point of attachment of said groups with the rest of the molecule; Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group, or a group selected from

wherein * indicates the point of attachment of said groups with the rest of the molecule;

R 3 represents a hydrogen atom or a halogen atom, or a —CN, C 1 -C 6 -alkyl-, —(CH 2 ) m —C 2 -C 6 -alkenyl, —(CH 2 ) m —C 4 -C 8 -cycloalkenyl —(CH 2 ) m —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, —C 1 -C 6 -alkyl-aryl, —C 1 -C 6 -alkyl-heteroaryl, heteroaryl-, C 1 -C 6 -alkyl-X—, —X—(CH 2 ) m —C 7 -C 6 -alkenyl, —X—(CH 7 ) m —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —OR 6 , —SR 6 , —S(═O)R 6 , —S(═O) 2 R 6 , —S(═O)(═NR 6a )R 6b , —S(═O) 2 N(R 6b )R 6c , —S—(CH 2 ) n —N(R 6a )R 6b , or —S—(CH 2 ) n -(3- to 7-membered heterocycloalkyl) group;

wherein said C 1 -C 6 -alkyl-, —(CH 2 ) m —C 2 -C 6 -alkenyl, —(CH 2 ) n , —C 2 -C 6 -alkynyl, —(CH 2 ) n , —C 3 -C 6 -cycloalkyl, aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, C 1 -C 6 -alkyl-X—, —X—(CH 2 ) m —C 2 -C 6 -alkenyl, —X—(CH 2 ), —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ), —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m (4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C 1 -C 6 -alkyl-aryl, —C 1 -C 6 -alkyl-heteroaryl, or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 R 7 groups;

either

R 4a , R 4c , R 4d represent a hydrogen atom, and

R 4b represents a hydrogen atom or a halogen atom or a C 1 -C 6 -alkyl group;

R 4b , R 4c , R 4d represent a hydrogen atom, and

R 4a represents a halogen atom or a C 1 -C 6 -alkyl-, —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6a , —S(═O) 2 N(R 6a )R 6b , or —S(═O)(═NR 6c )R 6 group;

R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl- or heteroaryl-group;

wherein said C 1 -C 6 -alkyl-, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 R 8 groups;

R 6 , R 6a , R 6b , R 6c

R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group;

›DETAILED DESCRIPTION OF THE INVENTION · 13 of 33

wherein said aryl-, heteroaryl- is optionally substituted, identically or differently, with 1, 2, or 3 C 1 -C 6 -alkyl groups; or when 2 R 7 groups are present ortho- to each other on an aryl-ring, said 2 R 7 groups together form a bridge: *O(CH 2 ) 2 O*, *O(CH 2 )O*, *NH(C(═O))NH*, wherein * represent the point of attachment to said aryl-ring;

R 8 represents a hydrogen or halogen atom, or a —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group, —S(═O) 2 -(3- to 7-membered heterocycloalkyl);

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl- is optionally substituted, identically or differently, with 1, 2, 3 or 4 C 1 -C 6 -alkyl-groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5;

X is S, S(═O), S(═O) 2 , O, NR 6 ;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds of general formula I, supra, in which:

A represents a

-group;

wherein * indicates the point of attachment of said groups with the rest of the molecule; Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group, or a group selected from

wherein * indicates the point of attachment of said groups with the rest of the molecule;

wherein said C 3 -C 6 -cycloalkyl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 groups selected from: halogen, OH, —CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkyl-;

R 3 represents a hydrogen atom or a halogen atom, or a —CN, C 1 -C 6 -alkyl-, —(CH 2 ) m —C 2 -C 6 -alkenyl —(CH 2 ) m —C 4 -C 8 -cycloalkenyl —(CH 2 ) m —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, —C1-C6-alkyl-aryl, —C1-C6-alkyl-heteroaryl, heteroaryl-, C 1 -C 6 -alkyl-X—, —X—(CH 2 ) m —C 2 -C 6 -alkenyl, —X—(CH 2 ) m —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —OR 6 , —SR 6 , —S(═O)R 6 , —S(═O) 2 R 6 , —S(═O)(═NR 6a )R 6b , —S(═O) 2 N(R 6b )R 6c , —S—(CH 2 ) n —N(R 6a )R 6b , or —S—(CH 2 ) n -(3- to 7-membered heterocycloalkyl) group;

wherein said C 1 -C 6 -alkyl-, —(CH 2 ) m —C 2 -C 6 -alkenyl, —(CH 2 ) m —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, C 1 -C 6 -alkyl-X—, —X—(CH 2 ) m —C 2 -C 6 -alkenyl, —X—(CH 2 ) m —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C 1 -C 6 -alkyl-aryl, —C 1 -C 6 -alkyl-heteroaryl, or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 R′ groups;

either

R 4a , R 4c , R 4d represent a hydrogen atom, and

R 4b represents a hydrogen atom or a halogen atom or a C 1 -C 6 -alkyl group;

R 4b , R 4c , R 4d represent a hydrogen atom, and

R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl- or heteroaryl group;

said C 1 -C 6 -alkyl-, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 R 8 groups;

R 6 , R 6a , R 6b , R 6c ,

›DETAILED DESCRIPTION OF THE INVENTION · 14 of 33

wherein said aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, or 3 C 1 -C 6 -alkyl groups; or when 2 R 7 groups are present ortho- to each other on an aryl ring, said 2 R 7 groups together form a bridge: *O(CH 2 ) 2 O*, *O(CH 2 )O*, *NH(C(═O))NH*, wherein * represent the point of attachment to said aryl ring;

R 8 represents a halogen atom, an —N(R 6a )R 6b or —OR 6 group;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5;

X is S, S(═O), S(═O) 2 , O, NR 6 ;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds of general formula I, supra, in which:

A represents a

-group;

wherein * indicates the point of attachment of said groups with the rest of the molecule; Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group,

or a

group;

wherein * indicates the point of attachment of said groups with the rest of the molecule; R 2 represents a hydrogen atom, or a C 1 -C 6 -alkyl- or C 3 -C 6 -cycloalkyl-group; R 3 represents a hydrogen atom or a halogen atom, or a —(CH 2 ) m —C 2 -C 6 -alkenyl, —(CH 2 ) m —C 4 -C 8 -cycloalkenyl —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-, aryl-X—, heteroaryl-X—, heteroaryl-, —C(═O)N(H)R 6a , —OR 6 , —SR 6 , —S(═O)R 6 , —S(═O) 2 R 6 , —S—(CH 2 ) n —N(R 6a )R 6b , or —S—(CH 2 ) n -(3- to 7-membered heterocycloalkyl) group;

wherein said aryl-, aryl-X—, heteroaryl-X— or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 R 7 groups;

either R 4a , R 4c , R 4d represent a hydrogen atom, and R 4b represents a hydrogen atom or a halogen atom or a C 1 -C 6 -alkyl group; or R 4b , R 4c , R 4d represent a hydrogen atom, and R 4a represents a halogen atom or a C 1 -C 6 -alkyl-, or —OR 6 group; R 5 represents a C 1 -C 6 -alkyl-, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl- or heteroaryl-group;

said C 1 -C 6 -alkyl-, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4 R 8 groups;

R 6 , R 6a , R 6b , R 6c ,

represent, independently from each other, a hydrogen atom, or a C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl- or aryl-group;

R 7 represents a hydrogen or halogen atom, or an HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, aryl-, heteroaryl-, —C(═O)N(R 6a )R 6b ), —N(H)C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —OR 6 , —S(═O)R 6 , or —S(═O) 2 R 6 group; wherein said heteroaryl-group is optionally substituted with a C 1 -C 4 -alkyl group;

or when 2 R 7 groups are present ortho- to each other on an aryl ring, said 2 R 7 groups together form a bridge: *O(CH 2 ) 2 O*, *O(CH 2 )O*, *NH(C(═O))NH*, wherein * represent the point of attachment to said aryl ring;

R 8 represents a halogen atom, a —N(R 6a )R 6b , or —OR 6 group; m is an integer of 0, 1, 2, 3, 4, 5 or 6; X is S, S(═O), S(═O) 2 , O, NR 6 ;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds of general formula I, supra, in which:

A represents a

-group;

wherein * indicates the point of attachment of said groups with the rest of the molecule; Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group, or a group selected from

wherein * indicates the point of attachment of said groups with the rest of the molecule;

R 3 represents a hydrogen atom or a halogen atom, or a —CN, C 1 -C 6 -alkyl-, —C 1 -C 6 -alkoxy, —(CH 2 ) m —C 2 -C 6 -alkenyl —(CH 2 ) m —C 4 -C 8 -cycloalkenyl —(CH 2 ) m —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, —C1-C6-alkyl-aryl, —C1-C6-alkyl-heteroaryl, heteroaryl-, C 1 -C 6 -alkyl-X—, —X—(CH 2 ) m —C 2 -C 6 -alkenyl, —X—(CH 2 ) m —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —OR 6 , —SR 6 , —S(═O)R 6 , —S(═O) 2 R 6 , —S(═O)(═NR 6a )R 6b , —S(═O) 2 N(R 6b )R 6c , —S— (CH 2 ) n —N(R 6a )R 6b , or —S—(CH 2 ) n -(3- to 7-membered heterocycloalkyl) group; said C 1 -C 6 -alkyl-, —C 1 -C 6 -alkoxy, —(CH 2 ) m —C 2 -C 6 -alkenyl, —(CH 2 ) m —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, C 1 -C 6 -alkyl-X—, —X—(CH 2 ) m —C 2 -C 6 -alkenyl, —X—(CH 2 ) m —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C 1 -C 6 -alkyl-aryl, —C 1 -C 6 -alkyl-heteroaryl or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups;

›DETAILED DESCRIPTION OF THE INVENTION · 15 of 33

R 4a , R 4b , R 4c , R 4d

wherein said C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m , —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, a 3- to 7-membered heterocycloalkyl, C 4 -C 8 -cycloalkenyl-, aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 R 8 groups;

R 6 , R 6a , R 6b , R 6c ,

R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group;

wherein said C 1 -C 6 -alkoxy-, aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, or 3 C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkoxy-, —C(═O)O—R 6 or —OH groups; or when 2 R 7 groups are present ortho- to each other on an aryl ring, said 2 R 7 groups together form a bridge: *O(CH 2 ) 2 O*, *O(CH 2 )O*, *NH(C(═O))NH*, wherein * represent the point of attachment to said aryl ring;

R 8 represents a hydrogen or halogen atom, or a —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 or —S(═O) 2 -(3- to 7-membered heterocycloalkyl) group;

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 C 1 -C 6 -alkyl-groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5;

X is S, S(═O), S(═O) 2 , O, NR 6 ;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds of general formula I, supra, in which:

A represents a

-group;

wherein * indicates the point of attachment of said groups with the rest of the molecule; Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group,

or a group selected from

wherein * indicates the point of attachment of said groups with the rest of the molecule;

R 3 represents a hydrogen atom or a halogen atom, or a —CN, C 1 -C 6 -alkyl-, —C 1 -C 6 -alkoxy, —(CH 2 ) m —C 2 -C 6 -alkenyl, —(CH 2 ) m —C 4 -C 8 -cycloalkenyl, —(CH 2 ) m —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, —C1-C6-alkyl-aryl, —C1-C6-alkyl-heteroaryl, heteroaryl-, C 1 -C 6 -alkyl-X—, —X— (CH 2 ) m —C 2 -C 6 -alkenyl, —X— (CH 2 ) m —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —OR 6 , —SR 6 , —S(═O)R 6 , —S(═O) 2 R 6 , —S(═O)(═NR 6a )R 6b , —S(═O) 2 N(R 6b )R 6c , —S—(CH 2 ) n —N(R 6a )R 6b , or —S—(CH 2 ) n -(3- to 7-membered heterocycloalkyl) group;

›DETAILED DESCRIPTION OF THE INVENTION · 16 of 33

wherein said C 1 -C 6 -alkyl-, —C 1 -C 6 -alkoxy, —(CH 2 ) m —C 2 -C 6 -alkenyl, —(CH 2 ) m —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, C 1 -C 6 -alkyl-X—, —X— (CH 2 ) m —C 2 -C 6 -alkenyl, —X— (CH 2 ) m —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C 1 -C 6 -alkyl-aryl, —C 1 -C 6 -alkyl-heteroaryl or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups;

R 4a , R 4b , R 4c , R 4d

R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, a 3- to 7-membered heterocycloalkyl, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl- or heteroaryl group;

wherein said C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, a 3- to 7-membered heterocycloalkyl, C 4 -C 8 -cycloalkenyl-, aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 R 8 groups;

R 6 , R 6a , R 6b , R 6c

R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b or —S(═O)(═NR 6c )R 6 group;

R 8 represents a hydrogen or halogen atom, or a —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group, —S(═O) 2 -(3- to 7-membered heterocycloalkyl);

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-, is optionally substituted, identically or differently, with 1, 2, 3, or 4 C 1 -C 6 -alkyl-groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5;

X is S, S(═O), S(═O) 2 , O, NR 6 ;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds of general formula I, supra, in which:

A represents a

-group;

wherein * indicates the point of attachment of said groups with the rest of the molecule; Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group,

or a group selected from

wherein * indicates the point of attachment of said groups with the rest of the molecule;

›DETAILED DESCRIPTION OF THE INVENTION · 17 of 33

R 3 represents a hydrogen atom or a halogen atom, or a —CN, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, —(CH 2 ) m —C 2 -C 6 -alkenyl, —(CH 2 ) m —C 4 -C 8 -cycloalkenyl —(CH 2 ) m —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, —C1-C6-alkyl-aryl, —C1-C6-alkyl-heteroaryl, heteroaryl-, C 1 -C 6 -alkyl-X—, —X— (CH 2 ) m —C 2 -C 6 -alkenyl, —X— (CH 2 ) m —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —OR 6 , —SR 6 , —S(═O)R 6 , —S(═O) 2 R 6 , —S(═O)(═NR 6a )R 6b , —S(═O) 2 N(R 6b )R 6c , —S—(CH 2 ) n —N(R 6a )R 6b , or —S—(CH 2 ) n -(3- to 7-membered heterocycloalkyl) group; wherein said C 1 -C 6 -alkyl-, —C 1 -C 6 -alkoxy, —(CH 2 ) m —C 2 -C 6 -alkenyl, —(CH 2 ) m —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, C 1 -C 6 -alkyl-X—, —X— (CH 2 ) m —C 2 -C 6 -alkenyl, —X— (CH 2 ) m —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C 1 -C 6 -alkyl-aryl, —C 1 -C 6 -alkyl-heteroaryl or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups;

either

R 4a , R 4c , R 4d represent a hydrogen atom, and

R 4b represents a hydrogen atom or a halogen atom or a C 1 -C 6 -alkyl group;

R 4b , R 4c , R 4d represent a hydrogen atom, and

R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ), —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, a 3- to 7-membered heterocycloalkyl, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl- or heteroaryl group;

wherein said C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) n , —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, a 3- to 7-membered heterocycloalkyl, C 4 -C 8 -cycloalkenyl-, aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 R 8 groups;

R 6 , R 6a , R 6b , R 6c ,

wherein said C 1 -C 6 -alkoxy-, aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2 or 3 C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkoxy-, —C(═O)O—R 6 or —OH groups; or when 2 R 7 groups are present ortho- to each other on an aryl ring, said 2 R 7 groups together form a bridge: *O(CH 2 ) 2 O*, *O(CH 2 )O*, *NH(C(═O))NH*, wherein * represent the point of attachment to said aryl ring;

R 8 represents a hydrogen or halogen atom, or a —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group, —S(═O) 2 -(3- to 7-membered heterocycloalkyl);

›DETAILED DESCRIPTION OF THE INVENTION · 18 of 33

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4 C 1 -C 6 -alkyl-groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5;

X is S, S(═O), S(═O) 2 , O, NR 6 ;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds of general formula I, supra, in which:

A represents a

-group;

wherein * indicates the point of attachment of said groups with the rest of the molecule; Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group,

or a group selected from

wherein * indicates the point of attachment of said groups with the rest of the molecule;

R 3 represents a hydrogen atom or a halogen atom, or a —CN, C 1 -C 6 -alkyl-, —C 1 -C 6 -alkoxy, —(CH 2 ) n , —C 2 -C 6 -alkenyl —(CH 2 ) n , —C 4 -C 8 -cycloalkenyl —(CH 2 ) m , —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, —C1-C6-alkyl-aryl, —C1-C6-alkyl-heteroaryl, heteroaryl-, C 1 -C 6 -alkyl-X—, —X—(CH 2 ) m —C 2 -C 6 -alkenyl, —X—(CH 2 ) n , —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —OR 6 , —SR 6 , —S(═O)R 6 , —S(═O) 2 R 6 , —S(═O)(═NR 6a )R 6b , —S(═O) 2 N(R 6b )R 6c , —S—(CH 2 ) n —N(R 6a )R 6b , or —S—(CH 2 ) n -(3- to 7-membered heterocycloalkyl) group;

wherein said C 1 -C 6 -alkyl-, —C 1 -C 6 -alkoxy, —(CH 2 ) m —C 2 -C 6 -alkenyl, —(CH 2 ) m —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl-, C 1 -C 6 -alkyl-X—, —X—(CH 2 ) m —C 2 -C 6 -alkenyl, —X—(CH 2 ) m —C 4 -C 8 -cycloalkenyl, —X—(CH 2 ) m —C 2 -C 6 -alkynyl, —X—(CH 2 ) m —C 3 -C 6 -cycloalkyl, —X—(CH 2 ) m -(3- to 7-membered heterocycloalkyl), —X—(CH 2 ) m -(4- to 8-membered heterocycloalkenyl), aryl-X—, heteroaryl-X—, —C 1 -C 6 -alkyl-aryl, —C 1 -C 6 -alkyl-heteroaryl or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups;

either

R 4a , R 4c , R 4d represent a hydrogen atom, and

R 4b represents a hydrogen atom or a halogen atom or a C 1 -C 6 -alkyl group;

R 4b , R 4c , R 4d represent a hydrogen atom, and

R 4a represents a halogen atom or an C 1 -C 6 -alkyl-, or —OR 6 O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6a , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group;

R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl- or heteroaryl group;

said C 1 -C 6 -alkyl-, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 R 8 groups;

R 6 , R 6a , R 6b , R 6C ,

R 8 represents a hydrogen or halogen atom, or a —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group, —S(═O) 2 -(3- to 7-membered heterocycloalkyl);

›DETAILED DESCRIPTION OF THE INVENTION · 19 of 33

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 C 1 -C 6 -alkyl-groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5;

X is S, S(═O), S(═O) 2 , O, NR 6 ;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

WO 2011/013729A1 discloses IC 50 values for the inhibition of Mps-1 (TTK) for a couple of compounds of formula C1, supra. However, WO 2011/013729A1 does not disclose any information about the metabolic stability of the compounds.

The inventors of the present invention surprisingly observed that compounds of general formula I, supra, in which R 3 is an aryl-X— or heteroaryl-X— group, and in which at least one of the groups R 4c and R 4b is not a hydrogen atom show a high inhibitory activity as well as a high metabolic stability.

Hence, in another preferred embodiment, the invention relates to compounds of general formula I:

in which:

A represents

wherein * indicates the point of attachment of said groups with the rest of the molecule;

Z represents a —C(═O)N(H)R 2 or a —C(═S)N(H)R 2 group;

R 2 represents a hydrogen atom, or a C 1 -C 6 -alkyl- or C 3 -C 6 -cycloalkyl-group;

wherein said C 1 -C 6 -alkyl- or C 3 -C 6 -cycloalkyl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 groups selected from: halogen, —OH, —CN, —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy;

R 3 represents an aryl-X— or a heteroaryl-X— group, or a

group, in which * indicates the point of attachment of said group with the rest of the molecule;

wherein said aryl-X—, heteroaryl-X— or

group

is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups; R 4a , R 4b , R 4c , R 4d

represent, independently from each other, a hydrogen or halogen atom, or a —CN, —OH, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, NC—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-group; with the proviso that at least one of the groups R 4b and R 4c is not a hydrogen atom;

R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl, C 2 -C 6 -alkenyl-, C 4 -C 3 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl- or heteroaryl-group;

said C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl, C 4 -C 8 -cycloalkenyl-, aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 R 8 groups; R 6 , R 6a , R 6b , R 6c ,

represent, independently from each other, a hydrogen atom, or a C 1 -C 6 -alkyl, HO—C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl, aryl, heteroaryl, aryl-C 1 -C 6 -alkyl-, or heteroaryl-C 1 -C 6 -alkyl-group;

R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, H 2 N—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , or —S(═O)(═NR 6c )R 6 group;

wherein said C 1 -C 6 -alkoxy-, aryl-, 3- to 7-membered heterocycloalkyl, or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, or 3 C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkoxy-, —C(═O)O—R 6 or —OH groups; or when 2 R 7 groups are present ortho to each other on an aryl or heteroaryl ring, said 2 R 7 groups together form a bridge: *O(CH 2 ) 2 O*, *O(CH 2 )O*, *CH 2 (CH 2 ) 2 NH*, *CH 2 CH 2 N(R 6a )CH 2 *, *NH(C(═O))NH*, *C(H)═C(H)—C(═O)—N(H)*, wherein * represent the point of attachment to said aryl or heteroaryl ring;

R 8 represents a hydrogen or halogen atom, or a —CN, —OH, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 OH, —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group, —S(═O) 2 -(3- to 7-membered heterocycloalkyl);

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 C 1 -C 6 -alkyl-groups;

›DETAILED DESCRIPTION OF THE INVENTION · 20 of 33

m is an integer of 0, 1, 2, 3, 4, 5 or 6; n is an integer of 0, 1, 2, 3, 4 or 5; and X is S, S(═O), S(═O) 2 , O, NR 6 , CR 6a R 6b , C═CR 6a R 6b .

In another preferred embodiment, the invention relates to compounds of formula I

in which:

A represents

wherein * indicates the point of attachment of said groups with the rest of the molecule;

Z represents a —C(═O)N(H)R 2 or a —C(═S)N(H)R 2 group;

R 2 represents a hydrogen atom, or a C 1 -C 6 -alkyl- or C 3 -C 6 -cycloalkyl-group;

R 3 represents an aryl-X— or a heteroaryl-X— group, or a

group, in which * indicates the point of attachment of said group with the rest of the molecule;

wherein said aryl-X—, heteroaryl-X— or

group

is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups; R 4a represents hydrogen; R 4d represents hydrogen;

one of the groups R 4b and R 4c represents a hydrogen atom while the other one represents a group selected from: halo-, —CN, —OH, C 1 -C 6 -alkyl- and C 1 -C 6 -alkoxy-;

R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl- or heteroaryl-group;

R 6 , R 6a , R 4b , R 4c ,

R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, H 2 N—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , or —S(═O)(═NR 6c )R 6 group;

wherein said C 1 -C 6 -alkoxy-, aryl-, 3- to 7-membered heterocycloalkyl, or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, or 3 C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkoxy-, —C(═O)O—R 6 or —OH groups; or when 2 R 7 groups are present ortho to each other on an aryl or heteroaryl ring, said 2 R′ groups together form a bridge: *O(CH 2 ) 2 O*, *O(CH 2 )O*, *CH 2 (CH 2 ) 2 NH*, *CH 2 CH 2 N(R 6a )CH 2 *, *NH(C(═O))NH*, *C(H)═C(H)—C(═O)—N(H)*, wherein * represent the point of attachment to said aryl or heteroaryl ring;

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 C 1 -C 6 -alkyl-groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6; n is an integer of 0, 1, 2, 3, 4 or 5; and X is S, S(═O), S(═O) 2 , O, NR 6 , CR 6a R 6b , C═CR 6a R 6b .

In another preferred embodiment, the invention relates to compounds of formula I

in which:

A represents

wherein * indicates the point of attachment of said groups with the rest of the molecule;

Z represents a —C(═O)N(H)R 2 or a —C(═S)N(H)R 2 group;

R 2 represents a C 1 -C 3 -alkyl- or C 3 -C 6 -cycloalkyl-group;

wherein said C 1 -C 3 -alkyl- or C 3 -C 6 -cycloalkyl-group is optionally substituted, identically or differently, with 1, 2 or 3 groups selected from: halogen, —OH, —CN, —C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy; R 3 represents an aryl-X— or a heteroaryl-X— group, or a

group, in which * indicates the point of attachment of said group with the rest of the molecule;

wherein said aryl-X—, heteroaryl-X— or

group

is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups; R 4a represents hydrogen; R 4d represents hydrogen;

›DETAILED DESCRIPTION OF THE INVENTION · 21 of 33

one of the groups R 4b and R 4c represents a hydrogen atom while the other one represents a group selected from: halo-, —CN, —OH, C 1 -C 6 -alkyl- and C 1 -C 6 -alkoxy-;

R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl- or heteroaryl-group;

said C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to to 7-membered heterocycloalkyl, C 4 -C 8 -cycloalkenyl-, aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 R 8 groups;

R 6 , R 6a , R 6b , R 6c ,

R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, H 2 N—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , or —S(═O)(═NR 6c )R 6 group;

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 C 1 -C 6 -alkyl-groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6; n is an integer of 0, 1, 2, 3, 4 or 5; and X is S, S(═O), S(═O) 2 , O, NR 6 , CR 6a R 6b , C═CR 6a R 6b .

In another preferred embodiment, the invention relates to compounds of formula I

in which:

A represents

wherein * indicates the point of attachment of said groups with the rest of the molecule;

Z represents a —C(═O)N(H)R 2 or a —C(═S)N(H)R 2 group;

R 2 represents a C 1 -C 3 -alkyl- or C 3 -C 6 -cycloalkyl-group;

R 3 represents a group selected from:

phenyl-X, quinolinyl-X—, pyridyl-X—, thienyl-X—, pyrazinyl-X—, imidazyl-X—, triazyl-X—, pyrazyl-X— and

wherein said group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups;

R 4a represents hydrogen;

R 4d represents hydrogen;

one of the groups Rob and R 4c represents a hydrogen atom while the other one represents halo- or a C 1 -C 6 -alkyl-group;

R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl, C 2 -C 6 -alkenyl-, C 4 -C 8 -cycloalkenyl-, C 2 -C 6 -alkynyl-, aryl- or heteroaryl-group;

›DETAILED DESCRIPTION OF THE INVENTION · 22 of 33

R 6 , R 6a , R 6b , R 4c

R 1 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, H 7 N—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , or —S(═O)(═NR 6c )R 6 group;

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 C 1 -C 6 -alkyl-groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5; and

X is S, S(═O), S(═O) 2 , O, NR 6 , CR 6a R 6b , C═CR 6a R 6b .

In another preferred embodiment, the invention relates to compounds of formula I

in which:

A represents

wherein * indicates the point of attachment of said groups with the rest of the molecule;

Z represents a —C(═O)N(H)R 2 or a —C(═S)N(H)R 2 group;

R 2 represents a C 1 -C 3 -alkyl- or C 3 -C 6 -cycloalkyl-group;

R 3 represents a group selected from:

phenyl-X, quinolinyl-X—, pyridyl-X—, thienyl-X—, pyrazinyl-X—, imidazyl-X—, triazyl-X—, pyrazyl-X— and

wherein said group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups;

R 4a represents hydrogen;

R 4d represents hydrogen;

one of the groups R 4b and R 4c represents a hydrogen atom while the other one represents a C 1 -C 4 -alkyl-group;

R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl, or heteroaryl-group;

said C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl, heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 R 8 groups;

R 6 , R 6a , R 6b , R 4c ,

R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, H 2 N—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , or —S(═O)(═NR 6c )R 6 group;

›DETAILED DESCRIPTION OF THE INVENTION · 23 of 33

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 C 1 -C 6 -alkyl-groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5; and

X is S, S(═O), S(═O) 2 , O, NR 6 , CR 6a R 6b , C═CR 6a R 6b .

In another preferred embodiment, the invention relates to compounds of formula I

in which:

A represents a

group;

wherein * indicates the point of attachment of said groups with the rest of the molecule; Z represents a —C(═O)N(H)R 2 or a —C(═S)N(H)R 2 group; R 2 represents a C 1 -C 3 -alkyl- or C 3 -C 6 -cycloalkyl-group;

R 3 represents a group selected from:

phenyl-X, quinolinyl-X—, pyridyl-X—, thienyl-X—, pyrazinyl-X—, imidazyl-X—, triazyl-X—, pyrazyl-X— and

wherein said group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups;

R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl, or heteroaryl-group;

R 6 , R 6a , R 6b , R 6c ,

R 7 represents a halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, H 2 N—C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl, 3- to 7-membered heterocycloalkyl, —C(═O)N(H)R 6a , —N(R 6a )R 6b ), —N(H)C(═O)R 6 , or —SR 6 group;

wherein said C 1 -C 6 -alkoxy-, or 3- to 7-membered heterocycloalkyl-group is optionally substituted, identically or differently, with 1, 2, or 3 C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkoxy-, —C(═O)O—R 6 or —OH groups; or when 2 R 7 groups are present ortho to each other on an aryl or heteroaryl ring, said 2 R 7 groups together form a bridge: *CH 2 (CH 2 ) 2 NH*, *CH 2 CH 2 N(R 6a )CH 2 *, *C(H)═C(H)—C(═O)—N(H)*, wherein * represent the point of attachment to said aryl or heteroaryl ring;

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 C 1 -C 6 -alkyl-groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5; and

X is S, S(═O), S(═O) 2 , O, NR 6 , CR 6a R 6b , C═CR 6a R 6b .

In another preferred embodiment, the invention relates to compounds of formula I

in which:

A represents a

group;

R 3 represents a group selected from: phenyl-X, quinolinyl-X—, pyridyl-X—, thienyl-X—, pyrazinyl-X—, imidazyl-X—, triazyl-X—, pyrazyl-X— and

wherein said group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups;

R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl, or heteroaryl-group;

R 6 , R 6a , R 6b , R 4c ,

represent, independently from each other, a hydrogen atom, or a C 1 -C 6 -alkyl-group;

›DETAILED DESCRIPTION OF THE INVENTION · 24 of 33

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 C 1 -C 6 -alkyl-groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5; and

X is S, S(═O), S(═O) 2 , O, NR 6 , CR 6a R 6b , C═CR 6a R 6b .

WO 2011/013729 A1 teaches that compounds of formula C1, supra, in which R 8 represents a cyclopropyl-group are preferred because they tendentially show higher activity in Mps-1 inhibition than compounds of formula C1 in which R 8 does not represent a cyclopropyl-group.

The inventors of the present invention surprisingly observed that compounds of formula C1 in which R 8 is a non-cyclic group rather than a cycloalkyl-group show higher metabolic stability. The inventors of the present invention surprisingly observed that compounds of formula C1 show especially high inhibitory effect on Mps-1 kinase if R 6 represents an aryl-X— or a heteroaryl-X— group in which X is defined as for compounds of formula I, supra.

So the combination of R 8 being a non-cyclic group with R 6 being an aryl-X— or a heteroaryl-X— group, results in compounds of superior inhibitory and metabolic properties.

Hence, in another preferred embodiment, the invention relates to compounds of formula I

in which:

A represents

wherein * indicates the point of attachment of said group with the rest of the molecule;

Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group;

R 2 represents a hydrogen atom, or a C 1 -C 6 -alkyl-group;

wherein said C 1 -C 6 -alkyl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4 groups selected from: halogen, —OH, —CN, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-;

R 3 represents an aryl-X— or a heteroaryl-X— group, wherein said aryl-X— or heteroaryl-X— group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups;

R 4a , R 4b , R 4c , R 4d

represent, independently from each other, a hydrogen or halogen atom, or a —CN, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, NC—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-group;

said C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 4 -C 8 -cycloalkenyl-, aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 8 groups;

R 6 , R 6a , R 6b , R 6c ,

R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O 2 )R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group;

wherein said aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2 or 3 C 1 -C 6 -alkyl-groups; or when 2 R 7 groups are present ortho- to each other on an aryl- or heteroaryl-ring, said 2 R 7 groups together form a bridge: *O(CH 2 ) 2 O*, *O(CH 2 )O*, *NH(C(═O))NH*, wherein * represent the point of attachment to said aryl- or heteroaryl-ring;

R 8 represents a hydrogen or halogen atom, or a —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O 2 )R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 or —S(═O) 2 -(3- to 7-membered heterocycloalkyl) group;

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group, is optionally substituted, identically or differently, with 1, 2, 3 or 4 C 1 -C 6 -alkyl-groups

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5; and

›DETAILED DESCRIPTION OF THE INVENTION · 25 of 33

X is selected from: S, S(═O), S(═O) 2 , O, NR 6 , CR 6a R 6b ;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In another preferred embodiment, the invention relates to compounds of general formula I:

in which:

A represents

wherein * indicates the point of attachment of said groups with the rest of the molecule;

Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group;

wherein * indicates the point of attachment of said groups with the rest of the molecule;

R 2 represents a hydrogen atom, or a C 1 -C 6 -alkyl-group;

wherein said C 1 -C 6 -alkyl-group is optionally substituted, identically or differently, with 1, 2, 3, or 4 groups selected from: halogen, OH, —CN, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-;

R 3 represents an aryl-X— or a heteroaryl-X— group, wherein said aryl-X— or heteroaryl-X— group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups;

R 4a , R 4b , R 4c , R 4d

are selected, independently from each other, from hydrogen, halogen, —CN, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-;

said C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 4 -C 8 -cycloalkenyl-, aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 8 groups;

R 6 , R 6a , R 6b , R 6c ,

R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O 2 )R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group;

wherein said aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2 or 3 C 1 -C 6 -alkyl-groups; or when 2 R 7 groups are present ortho- to each other on an aryl- or heteroaryl-ring, said 2 R′ groups together form a bridge: *O(CH 2 ) 2 O*, *O(CH 2 )O*, *NH(C(═O))NH*, wherein * represent the point of attachment to said aryl- or heteroaryl-ring;

R 8 represents a hydrogen or halogen atom, or a —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group, —S(═O) 2 -(3- to 7-membered heterocycloalkyl);

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group, is optionally substituted, identically or differently, with 1, 2, 3 or 4 C 1 -C 6 -alkyl-groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5; and

X is S, S(═O), S(═O) 2 , O, NR 6 or CR 6a R 6b .

In another preferred embodiment, the invention relates to compounds of general formula I:

in which:

A represents

wherein * indicates the point of attachment of said groups with the rest of the molecule;

Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group;

R 2 represents a C 1 -C 4 -alkyl-group;

wherein said C 1 -C 4 -alkyl-group is optionally substituted, identically or differently, with 1 or 2 groups selected from: halogen, —OH, —CN, C 1 -C 3 -alkyl-, C 1 -C 4 -alkoxy-;

R 3 represents an aryl-X— or a heteroaryl-X— group, wherein said aryl-X— or heteroaryl-X— group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups;

R 4a , R 4b , R 4c , R 4d

are selected, independently from each other, from hydrogen, halogen, —CN, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-;

R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, —(CH 2 ), —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 4 -C 8 -cycloalkenyl-, aryl- or heteroaryl-group;

›DETAILED DESCRIPTION OF THE INVENTION · 26 of 33

said C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 4 -C 3 -cycloalkenyl-, aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 8 groups;

R 6 , R 6a , R 6b , R 6c ,

R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O 2 )R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group;

wherein said aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, or 3 C 1 -C 6 -alkyl-groups; or when 2 R 7 groups are present ortho- to each other on an aryl- or heteroaryl-ring, said 2 R 7 groups together form a bridge: *O(CH 2 ) 2 O*, *O(CH 2 )O*, *NH(C(═O))NH*, wherein * represent the point of attachment to said aryl- or heteroaryl-ring;

R 8 represents a hydrogen or halogen atom, or a —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 or —S(═O) 2 -(3- to 7-membered heterocycloalkyl) group;

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group, is optionally substituted, identically or differently, with 1, 2, 3, or 4 C 1 -C 6 -alkyl-groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5; and

X is S, S(═O), S(═O) 2 , O, NR 6 or CR 6a R 6b .

In another preferred embodiment, the invention relates to compounds of general formula I:

in which:

A represents

wherein * indicates the point of attachment of said groups with the rest of the molecule;

Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group;

R 2 represents a methyl- or ethyl-group;

wherein said methyl- or ethyl-group is optionally substituted, identically or differently, with 1 or 2 groups selected from: halogen, —OH, —CN, C 1 -C 3 -alkoxy-;

R 3 represents an aryl-X— or a heteroaryl-X— group, wherein said aryl-X— or heteroaryl-X— group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 7 groups;

R 4a , R 4b , R 4c , R 4d

are selected, independently from each other, from hydrogen, halogen, —CN, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-;

R 5 represents a hydrogen atom, or a C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) n , —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 4 -C 8 -cycloalkenyl-, aryl- or heteroaryl-group;

said C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 4 -C 8 -cycloalkenyl-, aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 8 groups;

R 6 , R 6a , R 6b , R 6c ,

R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O 2 )R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a ) R 6b , —S(═O)(═NR 6c )R 6 group;

›DETAILED DESCRIPTION OF THE INVENTION · 27 of 33

R 8 represents a hydrogen or halogen atom, or a —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group, —S(═O) 2 -(3- to 7-membered heterocycloalkyl);

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group, is optionally substituted, identically or differently, with 1, 2, 3, or 4 C 1 -C 6 -alkyl-groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5; and

X is S, S(═O), S(═O) 2 , O, NR 6 or CR 6a R 6b .

In another preferred embodiment, the invention relates to compounds of general formula I:

in which:

A represents

wherein * indicates the point of attachment of said groups with the rest of the molecule;

Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group;

R 2 represents a C 1 -C 4 -alkyl-group;

wherein said C 1 -C 4 -alkyl-group is optionally substituted, identically or differently, with 1 or 2 groups selected from: halogen, OH, —CN, C 1 -C 3 -alkyl-, C 1 -C 4 -alkoxy-;

R 3 represents an aryl-X— or heteroaryl-X— group; wherein said aryl-X— or heteroaryl-X— group is optionally substituted, identically or differently, with 1 or 2 R 7 groups;

R 4a , R 4b , R 4c , R 4d

are selected, independently from each other, from hydrogen, halogen, —CN, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-;

said C 1 -C 6 -alkyl-, —(CH 2 ) n —C 2 -C 6 -alkenyl, —(CH 2 ) n —C 2 -C 6 -alkynyl, —(CH 2 ) m —C 3 -C 6 -cycloalkyl, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl-C 1 -C 6 -alkyl-, heteroaryl-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, —C 1 -C 6 -alkyl-CN, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 7-membered heterocycloalkyl-, C 4 -C 8 -cycloalkenyl-, aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 8 groups;

R 6 , R 6a , R 6b , R 6c ,

R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O 2 )R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group;

R 8 represents a hydrogen or halogen atom, or a —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group, —S(═O) 2 —(3- to 7-membered heterocycloalkyl);

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group, is optionally substituted, identically or differently, with 1, 2, 3 or 4 C 1 -C 6 -alkyl-groups;

›DETAILED DESCRIPTION OF THE INVENTION · 28 of 33

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5; and

X is S, S(═O), S(═O) 2 , O, NR 6 or CR 6a R 6b .

In another preferred embodiment, the invention relates to compounds of general formula I:

in which:

A represents

wherein * indicates the point of attachment of said groups with the rest of the molecule;

Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group;

R 2 represents a C 1 -C 4 -alkyl-group;

wherein said C 1 -C 4 -alkyl-group is optionally substituted, identically or differently, with 1 or 2 groups selected from: halogen, —OH, —CN, C 1 -C 3 -alkyl-, C 1 -C 4 -alkoxy-;

R 3 is selected from aryl-X— or heteroaryl-X—; wherein said aryl-X— or heteroaryl-X— group is optionally substituted, identically or differently, with 1 or 2 R 7 groups;

R 4a , R 4b , R 4c , R 4d

are selected, independently from each other, from hydrogen, halogen, —CN, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkyl-, or halo-C 1 -C 6 -alkoxy-;

R 5 represents a hydrogen atom, C 1 -C 6 -alkyl-, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl- or heteroaryl-group;

wherein said C 1 -C 6 -alkyl-, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4 R 8 groups;

R 6 , R 6a , R 6b , R 6c ,

R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O 2 )R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group;

R 8 represents a hydrogen or halogen atom, or a —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O) 2 R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a )R 6b , —S(═O)(═NR 6c )R 6 group, —S(═O) 2 -(3- to 7-membered heterocycloalkyl);

wherein said 3- to 7-membered heterocycloalkyl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4 C 1 -C 6 -alkyl-groups;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5; and

X is S, S(═O), S(═O) 2 , O, NR 6 or CR 6a R 6b .

In another preferred embodiment, the invention relates to compounds of general formula I:

in which:

A represents

wherein * indicates the point of attachment of said groups with the rest of the molecule;

Z represents a —C(═O)N(H)R 2 or —C(═S)N(H)R 2 group;

R 2 represents a C 1 -C 4 -alkyl-group;

wherein said C 1 -C 4 -alkyl-group is optionally substituted, identically or differently, with 1 or 2 groups selected from: halogen, OH, —CN, C 1 -C 3 -alkyl-, C 1 -C 4 -alkoxy-;

R 3 represent an aryl-X— or heteroaryl-X— group; wherein said aryl-X— or heteroaryl-X— group is optionally substituted, identically or differently, with 1 or 2 R 7 groups;

R 4a , R 4b , R 4c , R 4d

are selected, independently from each other, from hydrogen, halogen, —CN, C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-;

R 5 represents a hydrogen atom, C 1 -C 6 -alkyl-, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl- or heteroaryl-group;

wherein said C 1 -C 6 -alkyl-, —(CH 2 ) m -(3- to 7-membered heterocycloalkyl), aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3 or 4 R 8 groups;

R 6 , R 6a , R 6b , R 6c ,

R 7 represents a hydrogen or halogen atom, or a HO—, —CN, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, R 6a (R 6b )N—C 1 -C 6 -alkyl-, HO—C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, 3- to 7-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R 6 , —C(═O)N(H)R 6a , —C(═O)N(R 6a )R 6b , —C(═O)O—R 6 , —N(R 6a )R 6b , —NO 2 , —N(H)C(═O)R 6 , —N(R 6c )C(═O)R 6 , —N(H)C(═O)N(R 6a )R 6b , —N(R 6c )C(═O)N(R 6a )R 6b , —N(H)C(═O)OR 6 , —N(R 6c )C(═O)OR 6 , —N(H)S(═O)R 6 , —N(R 6c )S(═O)R 6 , —N(H)S(═O) 2 R 6 , —N(R 6c )S(═O) 2 R 6 , —N═S(═O)(R 6a )R 6b , —OR 6 , —O(C═O)R 6 , —O(C═O)N(R 6a )R 6b , —O(C═O)OR 6 , —SR 6 , —S(═O)R 6 , —S(═O)N(H)R 6 , —S(═O)N(R 6a )R 6b , —S(═O 2 )R 6 , —S(═O) 2 N(H)R 6 , —S(═O) 2 N(R 6a ) R 6b , —S(═O)(═NR 6c )R 6 group;

›DETAILED DESCRIPTION OF THE INVENTION · 29 of 33

R 8 represents a halogen atom, a —CN, —N(R 6a )R 6b , or —OR 6 group;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

n is an integer of 0, 1, 2, 3, 4 or 5; and

X is S, S(═O), S(═O) 2 , O, NR 6 or CR 6a R 6b .

It is to be understood that the present invention relates to any sub-combination within any embodiment or aspect of the present invention of compounds of general formula I, supra.

More particularly still, the present invention covers compounds of general formula I which are disclosed in the Experimental Section of this text, infra.

The compounds of this invention may contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.

Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention.

Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.

In order to limit different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.

Further, the compounds of the present invention may exist as tautomers. For example, any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, or a triazole moiety for example can exist as a 1H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said 1H, 2H and 4H tautomers, namely:

The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.

Further, the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides.

Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorphs, or as a mixture of more than one polymorph, in any ratio.

The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.

The compounds of the present invention have surprisingly been found to effectively inhibit Mps-1 kinase and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by Mps-1 kinase, such as, for example, haemotological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

›DETAILED DESCRIPTION OF THE INVENTION · 30 of 33

Therefore, the compounds of formula I, supra, are expected to be valuable as therapeutic agents.

Accordingly, in another embodiment, the present invention is directed to a compound of general formula I, supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for use in the treatment or prophylaxis of a disease.

In another embodiment, the present invention provides a method of treating disorders associated with enhanced uncontrolled proliferative cellular processes in a patient in need of such treatment, comprising administering to the patient an effective amount of a compound of formula I.

The term “treating” or “treatment” as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma.

The term “subject” or “patient” includes organisms which are capable of suffering from a cell proliferative disorder or who could otherwise benefit from the administration of a compound of the invention, such as human and non-human animals. Preferred humans include human patients suffering from or prone to suffering from a cell proliferative disorder or associated state, as described herein. The term “non-human animals” includes vertebrates, e.g., mammals, such as non-human primates, sheep, cow, dog, cat and rodents, e.g., mice, and non-mammals, such as chickens, amphibians, reptiles, etc.

The terms “cell proliferative disorder” or “disorder associated with enhanced uncontrolled proliferative cellular processes” include disorders involving the undesired or uncontrolled proliferation of a cell. The compounds of the present invention can be utilized to prevent, inhibit, block, reduce, decrease, control, etc., cell proliferation and/or cell division, and/or produce apoptosis. This method comprises administering to a subject in need thereof, including a mammal, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate or solvate thereof which is effective to treat or prevent the disorder.

In another embodiment, the present invention is directed to a compound of general formula I, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for use in the treatment or prophylaxis of a disease, wherein said disease is a disease of uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is mediated by the mitogen-activated protein kinase (MEK-ERK) pathway, more particularly in which the disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is a haemotological tumour, a solid tumour and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

The present invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, in vivo hydrolysable esters, and co-precipitates.

The term “pharmaceutically acceptable salt” refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.

A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic, 2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic, dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic, methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.

Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1-amino-2,3,4-butantriol. Additionally, basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.

›DETAILED DESCRIPTION OF THE INVENTION · 31 of 33

Those skilled in the art will further recognise that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.

The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.

As used herein, the term “in vivo hydrolysable ester” is understood as meaning an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, C 1 -C 6 alkoxymethyl esters, e.g. methoxymethyl, C 1 -C 6 alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters, C 3 -C 8 cycloalkoxy-carbonyloxy-C 1 -C 6 alkyl esters, e.g. 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, e.g. 5-methyl-1,3-dioxolen-2-onylmethyl; and C 1 -C 6 -alkoxycarbonyloxyethyl esters, e.g. 1-methoxycarbonyloxyethyl, and may be formed at any carboxy group in the compounds of this invention.

An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. The present invention covers all such esters.

Compounds of formula I may be administered as the sole pharmaceutical agent or in combination with one or more additional therapeutic agents where the combination causes no unacceptable adverse effects. This combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of formula I and one or more additional therapeutic agents, as well as administration of the compound of formula I and each additional therapeutic agent in its own separate pharmaceutical dosage formulation. For example, a compound of formula I and a therapeutic agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate dosage formulations.

Where separate dosage formulations are used, the compound of formula I and one or more additional therapeutic agents may be administered at essentially the same time (e.g., concurrently) or at separately staggered times (e.g., sequentially).

In another aspect, the invention provides a pharmaceutical composition comprising a compound of general formula I, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, and a pharmaceutically acceptable diluent or carrier.

Preferably, the pharmaceutical combination comprises:

one or more compounds of general formula I, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same; and one or more agents selected from: a taxane, such as Docetaxel, Paclitaxel, or Taxol; an epothilone, such as Ixabepilone, Patupilone, or Sagopilone; Mitoxantrone; Predinisolone; Dexamethasone; Estramustin; Vinblastin; Vincristin; Doxorubicin; Adriamycin; Idarubicin; Daunorubicin; Bleomycin; Etoposide; Cyclophosphamide; Ifosfamide; Procarbazine; Melphalan; 5-Fluorouracil; Capecitabine; Fludarabine; Cytarabine; Ara-C; 2-Chloro-2″-deoxyadenosine; Thioguanine; an anti-androgen, such as Flutamide, Cyproterone acetate, or Bicalutamide; Bortezomib; a platinum derivative, such as Cisplatin, or Carboplatin; Chlorambucil; Methotrexate; and Rituximab.

In still another aspect, the invention provides a process for preparing a pharmaceutical composition. The process includes the step of combining at least one compound of formula I as defined above with at least one pharmaceutically acceptable carrier, and bringing the resulting combination into a suitable administration form.

In still another aspect, the invention provides use of a compound of formula I as defined above for manufacturing a pharmaceutical composition for the treatment or prevention of a cell proliferative disorder. In certain embodiments, the cell proliferative disorder is cancer.

The active component of formula I can act systemically and/or locally. For this purpose, it can be applied in a suitable manner, for example orally, parenterally, pulmonally, nasally, sublingually, lingually, buccally, rectally, transdermally, conjunctivally, otically, or as an implant or stent.

When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

Regardless of the route of administration selected, the compounds of the invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.

›DETAILED DESCRIPTION OF THE INVENTION · 32 of 33

Actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

In accordance with another aspect, the present invention covers methods of preparing compounds of the present invention.

In accordance with a first embodiment, the present invention relates to a method of preparing a compound of general formula I, supra, said method comprising the step of allowing an intermediate compound of general formula IV:

in which A, and R 5 are as defined for general formula I, supra, and R 3′ is a leaving group;

to react with a compound of general formula IVa:

R 3 —Y IVa

in which R 3 is as defined for general formula I, supra, and Y is a substituent which is displaced in a coupling reaction, such as a hydrogen atom, or a boronic acid group, or a boronic ester group, for example;

thereby giving a compound of general formula I:

in which A, R 3 , and R 5 are as defined for general formula I, supra.

In accordance with a second embodiment, the present invention also relates to a method of preparing a compound of general formula I, supra, said method comprising the step of allowing an intermediate compound of general formula Ia:

in which R 3 and R 5 are as defined for general formula I, supra;

and A′ is

wherein * indicates the point of attachment of said group with the rest of the molecule; R 4a , R 4b , R 4c and R 4d are as defined for general formula I, supra, and Z′ represents a group selected from:

—C(═O)OH, —C(═S)OH, —C(═O)O—(C 1 -C 6 -alkyl) or —C(═S)O—(C 1 -C 6 -alkyl);

to react with a compound of general formula Ib:

H 2 NR 2 Ib

in which R 2 is as defined as for general formula I, supra, thereby giving, upon optional deprotection, a compound of general formula I:

in which R 3 , R 5 and A are as defined for general formula I, supra.

In accordance with a third embodiment, the present invention also relates to a method of preparing a compound of general formula I, supra, said method comprising the step of allowing an intermediate compound of general formula II:

in which R 3 and R 5 are as defined for general formula I, supra, and Q 2 is a leaving group, preferably Q 2 is a halogen atom;

to react with a compound of general formula IIa:

A-Y IIa

in which A is as defined for general formula I, supra, and Y is a substituent which is displaced in a coupling reaction, such as a boronic acid group, or an ester of a boronic acid group, for example,

thereby giving, upon optional deprotection, a compound of general formula I:

in which R 3 , R 5 and A are as defined for general formula I, supra.

In accordance with a fourth embodiment, the present invention also relates to a method of preparing a compound of general formula I, supra, said method comprising the step of allowing an intermediate compound of general formula VII:

in which R 3 and A are as defined for general formula I, supra, and Q 1 is a leaving group, for example a halogen atom,

to react with a compound of general formula VIIIa:

R 5 —CH 2 —NH 2 VIIa

in which R 5 is as defined for general formula I, supra,

thereby giving, upon optional deprotection, a compound of general formula I:

in which R 3 , R 5 and A are as defined for general formula I, supra.

In accordance with a forth embodiment, the present invention also relates to a method of preparing a compound of general formula I, supra, said method comprising the step of allowing an intermediate compound of general formula VII:

in which R 3 and A are as defined for general formula I, supra, and Q 1 is an optionally protected NH 2 -group

to react with a compound of general formula VIIb:

O═CHR 5 VIIb

in which R 5 is as defined for general formula I, supra,

thereby giving, upon optional deprotection, a compound of general formula I:

in which R 3 , R 5 and A are as defined for general formula I, supra.

In accordance with a further aspect, the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of general formula I, particularly in the method described herein.

In particular, the present invention covers intermediate compounds of general formula Ia:

in which R 3 and R 5 are as defined for general formula I, supra;

and A′ is

—C(═O)OH, —C(═S)OH, —C(═O)O—(C 1 -C 6 -alkyl) or —C(═S)O—(C 1 -C 6 -alkyl).

In accordance with yet another aspect, the present invention covers the use of the intermediate compounds of general formula Ia:

in which R 3 and R 5 are as defined for general formula I, supra;

and A′ is

—C(═O)OH, —C(═S)OH, —C(═O)O—(C 1 -C 6 -alkyl) or —C(═S)O—(C 1 -C 6 -alkyl);

for the preparation of a compound of general formula I as defined supra.

In accordance with yet another aspect, the present invention covers intermediate compounds of general formula II:

in which R 3 and R 5 are as defined for general formula I, supra, and Q 2 is a leaving group, preferably Q 2 is a halogen atom.

In accordance with yet another aspect, the present invention covers the use of the intermediate compounds of general formula II:

in which R 3 and R 5 are as defined for general formula I, supra, and Q 2 is a leaving group, preferably Q 2 is a halogen atom;

for the preparation of a compound of general formula I as defined supra.

In accordance with yet another aspect, the present invention covers intermediate compounds of general formula IV:

in which A, and R 5 are as defined for general formula I, supra, and R 3′ is a leaving group.

›DETAILED DESCRIPTION OF THE INVENTION · 33 of 33

In accordance with yet another aspect, the present invention covers the use of the intermediate compounds of general formula IV:

in which A, and R 5 are as defined for general formula I, supra, and R 3′ is a leaving group, for the preparation of a compound of general formula I as defined supra.

In accordance with a further aspect, the present invention covers intermediate compounds of general formula VII:

in which A, and R 3 are as defined for general formula I, supra, and Q 1 represents an optionally protected NH 2 -group or a leaving group.

In accordance with yet another aspect, the present invention covers the use of the intermediate compounds of general formula VII:

in which A, and R 3 are as defined for general formula I, supra, and Q 1 represents an optionally protected NH 2 -group or a leaving group;

for the preparation of a compound of general formula I as defined supra.

›EXPERIMENTAL SECTION · 1 of 2

The following Table lists the abbreviations used in this paragraph, and in the Examples section.

Abbreviation Meaning EDC 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide DIPEA N,N-diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide Pd(dppf)Cl 2 Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) NMR nuclear magnetic resonance spectroscopy Rt Room temperature RT Retention time in minutes MW molecular weight NMP N-methylpyrrolidinone Oxone Potassium peroxymonosulfate UPLC ultra performance liquid chromatography

Synthesis of Compounds of General Formula I of the Present Invention

Compounds of general formula I can be synthesized as depicted in the Scheme, with

A, R 3 , R 5 having the meaning as given for general formula I, supra; R 3′ , Q 2 representing leaving groups; and Q 1 represents an optionally protected NH 2 -group or a leaving group.

Examples for typical leaving groups include but are not limited to halogen atoms like a chlorine, bromine or iodine atom, or S(O) p R 6 -groups (wherein p is 0, 1, or 2, and R 6 is as defined for general formula I, supra) like a methylsulfonyl-group, or a triflate- or nonaflate-group.

The Scheme exemplifies routes that allow variations for R 3 , R 3′ , R 5 , Q 1 , Q 2 and A during the synthesis. Functional moieties in R 3 , R 3′ , R 5 , Q 1 , Q 2 and A can be converted at every suitable stage of the synthesis.

However, also other routes were used for synthesis of the target compounds. Compounds of formula X may be commercially available or can be synthesized according to procedures known to persons skilled in the art, for example applying procedures described in WO2007/38314A2.

A leaving group Q 2 can be introduced in compounds of general formula X, VI or III by procedures known to persons skilled in the art to give compounds of general formula IX, V or II. As an example, halogens can be introduced using halogenation reagents like N-iodosuccinimide (NIS), N-bromosuccinimide (NBS), or N-chlorosuccinimide (NCS), in an inert solvent like N,N-dimethylformamide or 1-methylpyrrolidin-2-one, for example, at temperatures ranging from room temperature to the boiling point of the solvent, for example.

Compounds of general formula I, IV or VIII can be obtained from compounds of general formula II, V or IX via a coupling reaction between a reagent of formula Y-A, in which A is defined supra and Y represents a suitable functional group by which the group A can be transferred to the Q-group bearing carbon atom of compounds of formula II, V or IX. Examples of suitable functional groups for Y in A-Y include boronic acids A-B(OH) 2 , or esters of boronic acids A-B(OC 1 -C 6 -alkyl) 2 . Said coupling reactions are performed in the presence of suitable catalysts, such as, for example, palladium based catalysts like, for example, Palladium (II) acetate, tetrakis(triphenylphosphine)palladium (0), bis(triphenylphosphine)-palladium (II) chloride or (1,1,-bis(diphenylphosphino) ferrocene)-dichloropalladium (II) and optionally suitable additives such as, for example, phosphines like, for example, P(oTol) 3 or triphenylphosphine and optionally with a suitable base, such as, for example, potassium carbonate, sodium 2-methylpropan-2-olate, tetrabutylammonium fluoride or tribasic potassium phosphate in a suitable solvent, such as, for example, tetrahydrofuran. Examples of such coupling reactions may be found in the textbook entitled “Metal-Catalyzed Cross-Coupling Reactions”, Armin de Meijere (Editor), Francois Diederich (Editor) September 2004, Wiley Interscience ISBN: 978-3-527-30518-6.

Compounds of general formula I, II, III or VII can be obtained from compounds of general formula IV, V, VI or VIII via a coupling reaction using a reagent of formula Y—R 3 in which R 3 is defined supra and Y represents a suitable functional group by which the group R 3 can be transferred to the R 3 ′ bearing carbon atom of compounds of formula IV, V, VI or VIII. Examples of suitable functional groups Y for the use in coupling reactions are given supra for the preparation of compounds of general formula I, IV or VIII from compounds of general formula II, V or IX.

The coupling reactions include metal catalyzed coupling reactions like Sonogashira coupling reactions with alkynes for alkyne introduction, Heck coupling reactions with alkenes for alkene introduction, Hartwig Buchwald coupling reactions with amines for amine introduction.

Y in Y—R 3 may also represent an acidic hydrogen that can be removed by suitable bases, for example sodium hydride, in a suitable solvent, such as DMSO or tetrahydrofuran at temperatures ranging from rt to the boiling point. The resulting nucleophiles, like, for example, primary or secondary amines, alkoxides, thiolates or carbon anion bearing groups can be used to replace R 3 ′ in compounds of general formula IV, V, VI or VIII to add secondary or tertiary amines, ethers, thioethers or carbon-atom attached groups to give compounds of general formula I, II, III or VII.

Compounds of general formula I, II, III or VII containing primary or secondary amines, ethers or thioether can also be build by Ullmann-type coupling reactions in the presence of suitable catalysts, such as, for example, copper based catalysts like copper(II)diacetate in presence of a suitable base, like for example, caesium carbonate staring from compounds of general formula IV, V, VI or VIII in which R 3 ′ represents a leaving group such as, for example, an iodine, bromine or chlorine atom. Optionally, suitable ligands like N,N-dimethylglycine or phenyl hydrogen pyrrolidin-2-ylphosphonate can be added.

In the case Q 1 represents a leaving group, the introduction of a R 5 —CH 2 -group can be achieved by nucleophilic substitution of Q 1 in compounds of formula VII, VIII, IX or X i.e. by a reaction with suitable amines R 5 —CH 2 —NH 2 in the presence of a suitable base, such as, for example DIPEA in a suitable solvent such as N,N-dimethylformamide or 1-methylpyrrolidin-2-one, at temperatures ranging from room temperature to the boiling point of the solvent to give amines of general formula I, IV, V or VI.

›EXPERIMENTAL SECTION · 2 of 2

In the case Q 1 represents a leaving group, the introduction of a R 5 —CH 2 -group can also be achieved in a coupling reaction in which Q 1 in compounds of formula VII, VIII, IX or X is reacted with suitable amines R 5 —CH 2 —NH 2 optionally in the presence of a suitable catalyst, such as Pd 2 dba 3 and BINAP for example, and optionally with a suitable base, such as, for example, sodium tert-butylate in a suitable solvent, such as, for example, N,N-dimethylformamide or 1-methylpyrrolidin-2-one to give amines of general formula I, IV, V or VI.

In the case Q 1 represents an optionally protected NH 2 -group the introduction of a R 5 —CH 2 -group, after deprotection to a NH 2 -group, can be achieved by a reductive amination reaction using an aldehyde of formula O═CHR 5 , a suitable reducing agent, for example sodium tris(acetato-kappaO)(hydrido)borate or sodium cyanoborohydride in a suitable solvent like, for example, acetic acid at reaction temperatures ranging from room temperature to the boiling point of the solvent.

Residues in compounds of formula I, II, III, IV, V, VI, VII, VIII, IX or X can be optionally modified. For example, thioethers can be oxidized using oxidation reagents like 3-chlorobenzenecarboperoxoic acid, oxone or dimethyldioxirane in inert solvents like dichloromethane or acetone, respectively. Depending on the stoichiometric ratio of oxidation reagent to the afore mentioned compounds sulfoxides or sulfones or mixtures thereof will be obtained.

Further, the compounds of formula I of the present invention can be converted to any salt as described herein, by any method which is known to the person skilled in the art. Similarly, any salt of a compound of formula I of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.

The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallisation. In some cases, impurities may be removed by stirring using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash chromatography, using for example pre-packed silica gel cartridges, e.g. from Separtis such as Isolute® Flash silica gel or Isolute® Flash NH2 silica gel in combination with a suitable chromatographic system such as a Flashmaster II (Separtis) or an Isolera system (Biotage) and eluents such as, for example, gradients of hexane/EtOAc or DCM/methanol. In some cases, the compounds may be purified by preparative HPLC using, for example, a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionisation mass spectrometer in combination with a suitable pre-packed reverse phase column and eluants such as, for example, gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.

›EXAMPLES

Analytical UPLC-MS was performed as follows:

Method A: System: UPLC Acquity (Waters) with PDA Detector and Waters ZQ mass spectrometer; Column: Acquity BEH C18 1.7 μm 2.1×50 mm; Temperature: 60° C.; Solvent A: Water+0.1% formic acid; Solvent B: acetonitrile; Gradient: 99% A→1% A (1.6 min)→1% A (0.4 min); Flow: 0.8 mL/min; Injection Volume: 1.0 μl (0.1 mg-1 mg/mL sample concentration); Detection: PDA scan range 210-400 nm-Fixed and ESI (+), scan range 170-800 m/z

General:

All reactions were run under an atmosphere of argon in degassed solvents unless stated otherwise.

›Examples306

›Example 1

1-({6-[(2E/Z)-But-2-en-2-yl]-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol

A mixture of 47.5 mg (112 μmol) 1-({6-chloro-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol which was prepared according to intermediate example 1a, 47.3 mg (2E/Z)-but-2-en-2-ylboronic acid, 1.6 mL n-propanol, 228 μL 1-methylpyrrolidin-2-one, 168 μL of an aqueous 2M potassium carbonate solution, 1.47 mg triphenylphosphine, and 7.9 mg bis(triphenylphosphine)palladium (II) chloride was stirred at 120° C. for 2 hours under microwave irradiation. Solvent was removed and the residue was purified by chromatography to give 20.7 mg (40%) of the title compounds.

1 H-NMR (DMSO-d6): δ=0.81-0.91 (4H), 1.15 (6H), 1.72 (3H), 1.93 (1H), 2.05 (3H), 3.13+3.26 (2H), 4.75+4.77 (1H), 5.73 (1H), 6.16+6.18 (1H), 6.75 (1H), 7.19+7.45 (1H), 7.65+7.76 (2H), 7.90+7.95 (1H), 8.06+8.14 (2H), 11.79+12.09 (1H) ppm.

Intermediate Example 1a

1-({6-Chloro-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol

A mixture comprising 700 mg (1.91 mmol) 1-[(6-chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)amino]-2-methylpropan-2-ol which was prepared according to intermediate example 1b, 610 mg [4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]boronic acid, which was prepared according to intermediate example 1d, 156 mg (1,1,-bis(diphenylphosphino)ferrocene)-dichloropalladium (II), 2.86 mL aqueous 2M tribasic potassium phosphate solution and 8.2 mL tetrahydrofuran was stirred at 45° C. for 12 hours. Water was added and the mixture was extracted with ethyl acetate and methanol. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by chromatography to give 345 mg (43%) of the title compound.

Intermediate Example 1b

1-[(6-Chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)amino]-2-methylpropan-2-ol

To a solution of 1.20 g (3.35 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c in 24 mL N,N-dimethylformamide were added 895 mg 1-amino-2-methylpropan-2-ol and the mixture was stirred at 40° C. overnight. Water was added and the mixture was extracted with dichloromethane and methanol. The organic phase was washed with water and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 798 mg (65%) of the title compound.

Intermediate Example 1c

8-Bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine

A mixture comprising 100 g (430 mmol) 8-bromo-6-chloroimidazo[1,2-b]pyridazine which was prepared according to a procedure described in US2007/78136 (WO2007/38314), 145 g N-iodosuccinimide, 5 percent per weight conc. hydrochloric acid and 1 L trichloromethane was heated at reflux for 6 hours. 20 g N-iodosuccinimide were added and heating was continued for additional 3 hours. The precipitate was removed and the filtrate was washed with 1N sodium hydroxide solution, brine and dried over sodium sulfate. After filtration and removal of solvent diisopropyl ether was added and the residue was stirred at 23° C. overnight. The precipitate was filtered off and dried to give 66.6 g (43%) of the title compound.

Intermediate Example 1d

2-Cyclopropyl-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-imidazole

A mixture comprising 42.1 g (160 mmol) 5-(4-bromophenyl)-2-cyclopropyl-1H-imidazole which was prepared according to intermediate example 1e, 60.9 g 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane, 3.05 g dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine, 1.46 g tris-(dibenzylidenacetone)-dipalladium(0), 23.5 g potassium acetate and 267 mL 1,4-dioxane was stirred at 110° C. for 4 hours. After cooling to 23° C., ethyl acetate and 1M hydrochloric acid were added and the pH was adjusted to 8.0 by adding 5% sodium hydroxide solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by crystallisation to give 33.5 g (67%) of the title compound.

Intermediate Example 1e

5-(4-Bromophenyl)-2-cyclopropyl-1H-imidazole

To a solution of 89.0 g (320 mmol) 2-bromo-1-(4-bromophenyl)ethanone in 2.0 L N,N-dimethylformamide were added cyclopropanecarboximidamide hydrochloride, 132.8 g potassium carbonate and the mixture was stirred at 23° C. overnight. After removal of the solvent, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by crystallisation to give 42.1 g (50%) of the title compound.

›Example 2

1-({3-[4-(2-Cyclopropyl-1H-imidazol-5-yl)phenyl]-6-[(1E/Z)-prop-1-en-1-yl]imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol

47.5 mg (112 μmol) 1-({6-chloro-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol which was prepared according to intermediate example 1a were transformed in analogy to example 1 using (1E/Z)-prop-1-en-1-ylboronic acid to give after working up and purification 34.1 mg (71%) of the title compounds.

1 H-NMR (DMSO-d6): δ=0.81-0.93 (4H), 1.16 (6H), 1.83-1.98 (4H), 3:13+3.26 (2H), 4.76 (1H), 6.34-6.46 (2H), 6.59-6.78 (2H), 7.19+7.45 (1H), 7.66+7.76 (2H), 7.85+7.91 (1H), 8.08+8.15 (2H), 11.79+12.11 (1H) ppm.

›Example 3

3-[4-(2-Cyclopropyl-1H-imidazol-5-yl)phenyl]-N-isobutyl-6-(pyridin-4-yl) imidazo[1,2-b]pyridazin-8-amine

50 mg (123 μmol) 6-chloro-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-N-isobutylimidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 3a were transformed in analogy to example 1 using pyridin-4-ylboronic acid to give after working up and purification 10.9 mg (20%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.82-0.91 (4H), 0.94 (6H), 1.94 (1H), 2.04 (1H), 3.26 (2H), 6.74 (1H), 7.49 (1H), 7.68 (1H), 7.82 (2H), 7.98 (1H), 8.05 (2H), 8.16 (2H), 8.72 (2H), 11.82+12.13 (1H) ppm.

Intermediate Example 3a

6-Chloro-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-N-isobutylimidazo[1,2-b]pyridazin-8-amine

200 mg (570 μmol) 6-chloro-3-iodo-N-isobutylimidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 3b were transformed in analogy to intermediate example 1a to give after working up and purification 114 mg (49%) of the title compound.

Intermediate Example 3b

6-Chloro-3-iodo-N-isobutylimidazo[1,2-b]pyridazin-8-amine

200 mg (558 μmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c were transformed in analogy to intermediate example 1b using 2-methylpropan-1-amine to give after working up and purification 188 mg (96%) of the title compound.

›Example 4

3-[4-(2-Cyclopropyl-1H-imidazol-5-yl)phenyl]-6-(pyridin-4-yl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]imidazo[1,2-b]pyridazin-8-amine

50 mg (115 μmol) 6-chloro-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-N-[(2S)-tetrahydrofuran-2-yl methyl]imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 4a were transformed in analogy to example 1 using pyridin-4-ylboronic acid to give after working up and purification 4.4 mg (8%) of the title compound.

1 H-NMR (CDCl 3 ): δ=1.01-1.12 (4H), 1.73 (1H), 1.95 (2H), 2.09 (2H), 3.44 (1H), 3.53 (1H), 3.78 (1H), 3.92 (1H), 4.21 (1H), 6.50 (1H), 7.21 (1H), 7.70 (2H), 7.74 (1H), 7.85 (2H), 8.07 (2H), 8.17 (1H), 8.63 (2H) ppm.

Intermediate Example 4a

6-Chloro-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-N-[(2S)-tetrahydrofuran-2-yl methyl]imidazo[1,2-b]pyridazin-8-amine

232 mg (613 μmol) 6-chloro-3-iodo-N-[(2S)-tetrahydrofuran-2-ylmethyl]imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 4b were transformed in analogy to intermediate example 1a to give after working up and purification 118 mg (44%) of the title compound.

Intermediate Example 4b

6-Chloro-3-iodo-N-[(2S)-tetrahydrofuran-2-ylmethyl]imidazo[1,2-b]pyridazin-8-amine

500 mg (1.40 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c were transformed in analogy to intermediate example 1b using 1[(2S)-tetrahydrofuran-2-yl]methanamine to give after working up and purification 497 mg (94%) of the title compound.

›Example 5

3-[4-(2-Cyclopropyl-1H-imidazol-5-yl)phenyl]-6-(pyridin-4-yl)-N-[(2R)-tetrahydrofuran-2-ylmethyl]imidazo[1,2-b]pyridazin-8-amine

50 mg (115 μmol) 6-chloro-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-N-[(2R)-tetrahydrofuran-2-yl methyl]imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 5a were transformed in analogy to example 1 using pyridin-4-ylboronic acid to give after working up and purification 6.1 mg (11%) of the title compound.

Intermediate Example 5a

6-Chloro-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-N-[(2R)-tetrahydrofuran-2-yl methyl]imidazo[1,2-b]pyridazin-8-amine

247 mg (652 μmol) 6-chloro-3-iodo-N-[(2R)-tetrahydrofuran-2-ylmethyl]imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 5b were transformed in analogy to intermediate example 1a to give after working up and purification 112 mg (39%) of the title compound.

Intermediate Example 5b

6-Chloro-3-iodo-N-[(2R)-tetrahydrofuran-2-ylmethyl]imidazo[1,2-b]pyridazin-8-amine

500 mg (1.40 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c were transformed in analogy to intermediate example 1b using 1-[(2R)-tetrahydrofuran-2-yl]methanamine to give after working up and purification 513 mg (97%) of the title compound.

›Example 6

3-[4-(2-Cyclopropyl-1H-imidazol-5-yl)phenyl]-6-(4-fluorophenyl)-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine

40 mg (90 μmol) 6-chloro-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 6a were transformed in analogy to example 1 using (4-fluorophenyl)boronic acid to give after working up and purification 3.6 mg (7%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.97-1.09 (4H), 2.00 (2H), 2.59 (2H), 3.73 (2H), 5.97 (1H), 6.37 (1H), 7.14-7.26 (3H), 7.75-7.84 (3H), 7.96 (2H), 8.13 (2H) ppm.

Intermediate Example 6a

6-Chloro-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-N-(3,3,3-trifluoropropyl) imidazo[1,2-b]pyridazin-8-amine

330 mg (845 μmol) 6-chloro-3-iodo-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 6b were transformed in analogy to intermediate example 1a to give after working up and purification 220 mg (58%) of the title compound.

Intermediate Example 6b

6-Chloro-3-iodo-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine

1.96 g (5.46 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c were transformed in analogy to intermediate example 1b using 3,3,3-trifluoropropan-1-amine to give after working up and purification 1.58 g (74%) of the title compound.

›Example 7

N-cyclopropyl-4-{6-(4-fluorophenyl)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

76 mg (184 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 1 using (4-fluorophenyl)boronic acid to give after working up and purification 25.7 mg (30%) of the title compound.

1 H-NMR (CDCl 3 /CD 3 OD): δ=0.61 (2H), 0.86 (2H), 1.37 (6H), 2.47 (3H), 2.88 (1H), 3.33 (2H), 6.38 (1H), 7.13 (2H), 7.39 (1H), 7.69 (1H), 7.83-7.91 (3H), 7.94 (1H) ppm.

Intermediate Example 7a

4-{6-Chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

700 mg (1.91 mmol) 1-[(6-chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)amino]-2-methylpropan-2-ol which was prepared according to intermediate example 1b were transformed in analogy to intermediate example 1a using N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide which was prepared according to intermediate example 7b to give after working up and purification 360 mg (46%) of the title compound.

Intermediate Example 7b

N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

To a solution of 260 g (1.02 mol) 4-bromo-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7c in 2 L dioxane at 23° C. were added 390 g bis-(pinacolato)-diboron, 19.5 g 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 150 .g potassium acetate and 9.37 g tris-(dibenzylidenaceton)-dipalladium(0) and the mixture was refluxed for 6 h. After cooling to 23° C., water and ethyl acetate were added and the mixture stirred for 15 min. The organic phase was washed with water, dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography to give 308 g (56%) of the title compound.

1 H-NMR (300 MHz, CDCl 3 ): δ=0.59 (2H), 0.85 (2H), 1.33 (6H), 2.41 (3H), 2.87 (1H), 5.94 (1H), 7.28 (1H), 7.60 (1H), 7.63 (1H) ppm.

Intermediate Example 7c

4-Bromo-N-cyclopropyl-2-methylbenzamide

To a stirred solution of 300 g (1.4 mol) 4-bromo-2-methylbenzoic acid in 8.4 L dichloromethane at 23° C. were added 79.6 g cyclopropanamine and 320.9 g EDC. After stirring overnight, the solution was washed with water and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The remaining solid was triturated with diisopropyl ether, filtered, washed and dried in vaccuo to yield 260 g (73%) of the title compound.

›Example 8

1-({3-[4-(2-Cyclopropyl-1H-imidazol-5-yl)phenyl]-6-(4-fluorophenyl)imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol

70 mg (166 μmol) 1-({6-chloro-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol which was prepared according to intermediate example 1a were transformed in analogy to example 1 using (4-fluorophenyl)boronic acid to give after working up and purification 4.9 mg (6%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.80-0.94 (4H), 1.18 (6H), 1.93 (1H), 3.39 (2H), 4.79 (1H), 6.77 (1H), 6.86 (1H), 7.21+7.48 (1H), 7.85 (2H), 7.70+7.81 (2H), 7.94+7.99 (1H), 8.06-8.24 (4H), 11.81+12.12 (1H) ppm.

›Example 9

1-({3-[4-(2-Cyclopropyl-1H-imidazol-5-yl)phenyl]-6-(pyridin-4-yl)imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol

47.5 mg (112 μmol) 1-({6-chloro-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol which was prepared according to intermediate example 1a were transformed in analogy to example 1 using pyridin-4-ylboronic acid to give after working up and purification 12.5 mg (23%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.82-0.92 (4H), 1.19 (6H), 1.93 (1H), 3.42 (2H), 4.79 (1H), 6.89 (1H), 7.01 (1H), 7.22+7.49 (1H), 7.72+7.83 (2H), 7.97-8.08 (3H), 8.15+8.23 (2H), 8.73 (2H), 7.82+12.13 (1H) ppm.

›Example 10

N-cyclopropyl-2-methyl-4-{6-(1-methyl-1H-pyrazol-5-yl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

40 mg (91 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a were transformed in analogy to example 1 using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give after working up and purification 7.2 mg (16%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.64 (2H), 0.90 (2H), 2.52 (3H), 2.58 (2H), 2.93 (1H), 3.72 (2H), 4.20 (3H), 5.95 (1H), 6.01 (1H), 6.28 (1H), 6.66 (1H), 7.42 (1H), 7.55 (1H), 7.79 (1H), 7.85 (1H), 7.89 (1H) ppm.

Intermediate Example 10a

4-{6-Chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

500 mg (1.28 mmol) 6-chloro-3-iodo-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 6b were transformed in analogy to intermediate example 1a using N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give after working up and purification 139 mg (25%) of the title compound.

›Example 11

3-(3-Amino-1H-indazol-6-yl)-N-isobutyl-6-phenylimidazo[1,2-b]pyridazin-8-amine

To a solution of 46 mg (119 μmol) 2-fluoro-4-[8-(isobutylamino)-6-phenylimidazo[1,2-b]pyridazin-3-yl]benzonitrile which was prepared according to intermediate example 11a in 2.5 mL n-butanol were added 232 μL hydrazine hydrate and the mixture was heated at 120° C. overnight. The precipitate was filtered, washed with 2-propanol and dried to give 26.5 mg (53%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.94 (6H), 2.04 (1H), 3.26 (2H), 5.33 (2H), 6.63 (1H), 7.46-7.58 (5H), 7.74 (1H), 8.00 (1H), 8.07 (2H), 8.38 (1H), 11.53 (1H) ppm.

Intermediate Example 11a

2-Fluoro-4-[8-(isobutylamino)-6-phenylimidazo[1,2-b]pyridazin-3-yl]benzonitrile

100 mg (291 μmol) 4-[6-chloro-8-(isobutylamino)imidazo[1,2-b]pyridazin-3-yl]-2-fluorobenzonitrile which was prepared according to intermediate example 11b were transformed in analogy to example 1 using phenylboronic acid to give after working up and purification 49 mg (44%) of the title compound.

Intermediate Example 11b

4-[6-Chloro-8-(isobutylamino)imidazo[1,2-b]pyridazin-3-yl]-2-fluorobenzonitrile

500 mg (1.43 mmol) 6-Chloro-3-iodo-N-isobutylimidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 3b were transformed in analogy to intermediate example 1a using (4-cyano-3-fluorophenyl)boronic acid to give after working up and purification 217 mg (44%) of the title compound.

›Example 12

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-phenylimidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

250 mg (604 μmol) 4-{6-Chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 1 using phenylboronic acid to give after working up and purification 48 mg (17%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 1.18 (6H), 2.39 (3H), 2.81 (1H), 3.39 (2H), 4.78 (1H), 6.80 (1H), 6.90 (1H), 7.40 (1H), 7.46-7.55 (3H), 8.00-8.07 (4H), 8.13 (1H), 8.30 (1H) ppm.

›Example 13

N-cyclopropyl-4-[8-(isobutylamino)-6-(pyridin-4-yl)imidazo[1,2-b]pyridazin-3-yl]benzenecarbothioamide

A mixture of 40 mg (108 μmol) 4-[8-(isobutylamino)-6-(pyridin-4-yl)imidazo[1,2-b]pyridazin-3-yl]benzaldehyde which was prepared according to intermediate example 13a, 3.45 mg sulfur, 37 μL cyclopropanamine and 250 μL dimethyl sulfoxide were heated at 100° C. under microwave irradiation for 4 hours. The mixture was stirred at 90° C. overnight, the solvent was evaporated and the residue purified by chromatography to give 4.8 mg (10%) of the title compound.

1 H-NMR (CDCl 3 /CD 3 OD): δ=0.80 (2H), 1.03 (2H), 1.08 (6H), 2.08 (1H), 3.21 (2H), 3.40 (1H), 6.40 (1H), 7.78-7.89 (5H), 8.12 (2H), 8.69 (2H) ppm.

Intermediate Example 13a

4-[8-(Isobutylamino)-6-(pyridin-4-yl)imidazo[1,2-b]pyridazin-3-yl]benzaldehyde

To a solution of 63 mg (152 μmol) 3-[4-(1,3-dioxolan-2-yl)phenyl]-N-isobutyl-6-(pyridin-4-yl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 13b, in 2.8 mL acetone were added 190 μL 4N hydrochloric acid and the mixture was stirred at 23° C. for 2 hours. Saturated hydrogen carbonate solution was added and the mixture was extracted with dichloromethane. The organic phase was dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 41 mg (73%) of the title compound.

Intermediate Example 13b

3-[4-(1,3-Dioxolan-2-yl)phenyl]-N-isobutyl-6-(pyridin-4-yl)imidazo[1,2-b]pyridazin-8-amine

105 mg (282 μmol) 6-chloro-3-[4-(1,3-dioxolan-2-yl)phenyl]-N-isobutylimidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 13c were transformed in analogy to example 1 using pyridin-4-ylboronic acid to give after working up and purification 64 mg (55%) of the title compound.

Intermediate Example 13c

6-Chloro-3-[4-(1,3-dioxolan-2-yl)phenyl]-N-isobutylimidazo[1,2-b]pyridazin-8-amine

500 mg (1.43 mmol) 6-Chloro-3-iodo-N-isobutylimidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 3b were transformed in analogy to intermediate example 1a using 2-[4-(1,3-dioxolan-2-yl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to give after working up and purification 314 mg (47%) of the title compound.

›Example 14

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-phenylimidazo[1,2-b]pyridazin-3-yl}benzamide

176 mg (440 μmol) which 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropylbenzamide was prepared according to intermediate example 14a were transformed in analogy to example 1 using phenylboronic acid to give after working up and purification 42 mg (21%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.56 (2H), 0.67 (2H), 1.19 (6H), 2.85 (1H), 3.40 (2H), 4.78 (1H), 6.82 (1H), 6.93 (1H), 7.46-7.55 (3H), 7.93 (2H), 8.05 (2H), 8.09 (1H), 8.33 (2H), 8.45 (1H) ppm.

Intermediate Example 14a

4-{6-Chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropylbenzamide

976 mg (2.66 mmol) 1-[(6-chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)amino]-2-methylpropan-2-ol which was prepared according to intermediate example 1b were transformed in analogy to intermediate example 1a using [4-(cyclopropylcarbamoyl)phenyl]boronic acid to give after working up and purification 602 mg (57%) of the title compound.

›Example 15

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(methylsulfanyl) imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

To a solution of 83 mg (201 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a in 1.0 mL dimethyl sulfoxide were added 70 mg sodium methanethiolate and the mixture was heated under microwave irradiation at 70° C. for 1 hour. The mixture was poured into water and extracted with dichloromethane and methanol. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by recrystallisation to give 46.7 mg (55%) of the title compound.

›Example 16

3-[4-(2-Cyclopropyl-1H-imidazol-5-yl)phenyl]-6-[(1E)-prop-1-en-1-yl]-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine

35 mg (78 μmol) 6-chloro-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 6a were transformed in analogy to example 1 using (1E)-prop-1-en-1-ylboronic acid to give after working up and purification 3.6 mg (10%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.95-1.04 (4H), 1.95 (3H), 2.00 (1H), 2.55 (2H), 3.62 (2H), 6.10 (1H), 6.46 (1H), 6.61 (1H), 7.16 (1H), 7.67 (1H), 7.70 (2H), 8.05 (2H) ppm.

›Example 17

N-cyclopropyl-4-{8-[(2-methoxy-2-methylpropyl)amino]-6-(pyridin-4-yl) imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

60 mg (140 μmol) 4-{6-Chloro-8-[(2-methoxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 17a were transformed in analogy to example 1 using pyridin-4-ylboronic acid to give after working up and purification 18.7 mg (28%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.64 (2H), 0.90 (2H), 1.33 (6H), 2.54 (3H), 2.93 (1H), 3.28 (3H), 3.38 (2H), 6.11 (1H), 6.18 (1H), 6.42 (1H), 7.44 (1H), 7.80-7.85 (3H), 7.92 (1H), 8.00 (1H), 8.71 (2H) ppm.

Intermediate Example 17a

4-{6-Chloro-8-[(2-methoxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

145 mg (380 μmol) 6-chloro-3-iodo-N-(2-methoxy-2-methylpropyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 17b were transformed in analogy to intermediate example 1a using N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give after working up and purification 131 mg (81%) of the title compound.

Intermediate Example 17b

6-Chloro-3-iodo-N-(2-methoxy-2-methylpropyl)imidazo[1,2-b]pyridazin-8-amine

250 mg (698 μmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c were transformed in analogy to intermediate example 1b using 2-methoxy-2-methylpropan-1-amine to give after working up and purification 260 mg (98%) of the title compound.

›Example 18

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(methylsulfonyl) imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

To a solution of 38.7 mg (91 μmol) N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(methylsulfanyl)imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide which was prepared according to intermediate example 15 in 1.2 mL N,N-dimethylformamide were added 168 mg Oxone and the mixture was stirred at 23° C. for 2.5 days. Water was added and the mixture was extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 18.5 mg (39%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.65 (2H), 1.15 (6H), 2.37 (3H), 2.80 (1H), 3.34 (2H), 3.38 (3H), 4.79 (1H), 6.76 (1H), 7.40 (1H), 7.71 (1H), 7.95 (1H), 7.99 (1H), 8.16 (1H), 8.32 (1H) ppm.

›Example 19

N-cyclopropyl-4-{6-(4-fluorophenyl)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

200 mg (500 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropylbenzamide which was prepared according to intermediate example 14a were transformed in analogy to example 1 using (4-fluorophenyl)boronic acid to give after working up and purification 136 mg (59%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.56 (2H), 0.68 (2H), 1.18 (6H), 2.85 (1H), 3.39 (2H), 4.79 (1H), 6.81 (1H), 6.94 (1H), 7.35 (2H), 7.93 (2H), 8.09 (1H), 8.11 (2H), 8.31 (2H), 8.46 (1H) ppm.

›Example 20

N-cyclopropyl-4-{6-[2-(hydroxymethyl)phenyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

172 mg (393 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a were transformed in analogy to example 1 using [2-(hydroxymethyl)phenyl]boronic acid to give after working up and purification 29.1 mg (14%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.58 (2H), 0.85 (2H), 2.48 (3H), 2.58 (2H), 2.88 (1H), 3.72 (2H), 3.96 (1H), 4.41 (2H), 6.16 (1H), 6.19 (1H), 6.24 (1H), 7.38 (1H), 7.45-7.52 (3H), 7.60 (1H), 7.61 (1H), 7.70 (1H), 7.72 (1H) ppm.

›Example 21

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

100 mg (242 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 1 using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give after working up and purification 35.9 mg (31%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.65 (2H), 1.17 (6H), 2.35 (3H), 2.80 (1H), 3.35 (2H), 4.13 (3H), 4.76 (1H), 6.62 (1H), 6.89 (1H), 7.00 (1H), 7.37 (1H), 7.51 (1H), 7.93 (1H), 7.97 (1H), 7.98 (1H), 8.30 (1H) ppm.

›Example 22

3-[4-(2-Cyclopropyl-1H-imidazol-5-yl)phenyl]-6-ethenyl-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine

55 mg (123 μmol) 6-chloro-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 6a were transformed in analogy to example 1 using 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane to give after working up and purification 3.2 mg (6%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.95-1.03 (4H), 1.99 (1H), 2.56 (2H), 3.64 (2H), 5.58 (1H), 6.07 (1H), 6.18 (1H), 6.76 (1H), 7.16 (1H), 7.68-7.74 (3H), 8.05 (2H) ppm.

›Example 23

N-cyclopropyl-2-methyl-4-{6-[(1E/Z)-prop-1-en-1-yl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

75 mg (171 μmol) 4-{6-Chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a were transformed in analogy to example 1 using (1E)-prop-1-en-1-ylboronic acid to give after working up and purification 3.0 mg (4%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.90 (2H), 1.98 (3H), 2.47-2.65 (2H), 2.54 (3H), 2.92 (1H), 3.67 (2H), 5.91 (1H), 5.98 (1H), 6.46 (1H), 6.60+6.66 (1H), 7.25 (1H), 7.43 (1H), 7.73 (1H), 7.90 (1H), 7.96 (1H) ppm.

›Example 24

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(1E/Z)-prop-1-en-1-yl]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (181 μmol) 4-{6-Chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 1 using (1E)-prop-1-en-1-ylboronic acid to give after working up and purification 22 mg (29%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.89 (2H), 1.43 (6H), 1.95+2.16 (3H), 2.51 (3H), 2.92 (1H), 3.32 (2H), 4.33 (1H), 5.99 (1H), 6.07+6.14 (1H), 6.37 (1H), 6.41 (1H), 6.57+6.63 (1H), 7.39 (1H), 7.66+7.70 (1H), 7.84+7.87 (1H), 7.94 (1H) ppm.

›Example 25

4-{6-[(2E)-But-2-en-2-yl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (181 μmol) 4-{6-Chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 1 to give after working up and purification 7.0 mg (8%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.62 (2H), 0.88 (2H), 1.45 (6H), 1.79 (3H), 2.11 (3H), 2.50 (3H), 2.91 (1H), 3.32 (2H), 5.02 (1H), 5.77 (1H), 5.97 (1H), 6.00 (1H), 6.50 (1H), 7.38 (1H), 7.70 (1H), 7.89 (1H), 7.91 (1H) ppm.

›Example 26

3-[4-(2-Cyclopropyl-1H-imidazol-5-yl)phenyl]-6-(pyridin-4-yl)-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine

70 mg (157 μmol) 6-Chloro-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 6a were transformed in analogy to example 1 using pyridin-4-ylboronic acid to give after working up and purification 3.2 mg (4%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.92-0.98 (4H), 1.98 (1H), 2.58 (2H), 3.32 (2H), 3.69 (2H), 6.42 (1H), 7.15 (1H), 7.72 (2H), 7.75 (1H), 7.87 (2H), 8.04 (2H), 8.65 (2H) ppm.

›Example 27

6-[(2E)-But-2-en-2-yl]-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine

50 mg (112 μmol) 6-Chloro-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 6a were transformed in analogy to example 1 to give after working up and purification 3.0 mg (5%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.95-1.02 (4H), 1.78 (3H), 1.99 (1H), 2.12 (3H), 2.46-2.63 (2H), 3.62 (2H), 5.78 (1H), 5.96 (1H), 7.16 (1H), 7.69 (2H), 7.73 (1H), 8.05 (2H) ppm.

›Example 28

N-cyclopropyl-4-{6-(4-fluorophenyl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (114 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a were transformed in analogy to example 1 using (4-fluorophenyl)boronic acid to give after working up and purification 5.4 mg (9%) of the title compound.

1 H-NMR (CDCl 3 /CD 3 OD): δ=0.59 (2H), 0.86 (2H), 2.48 (3H), 2.58 (2H), 2.86 (1H), 3.68 (2H), 6.36 (1H), 7.16 (2H), 7.41 (1H), 7.74 (1H), 7.85-8.03 (4H) ppm.

›Example 29

(RS) 3-[4-(2-Cyclopropyl-1H-imidazol-5-yl)phenyl]-6-(pyridin-4-yl)-N-(tetrahydro-2H-pyran-2-ylmethyl)imidazo[1,2-b]pyridazin-8-amine

53 mg (118 μmol) (RS)-6-Chloro-3-[4-(2-cyclopropyl-1H-imidazol-4-yl)phenyl]-Netrahydro-2H-pyran-2-ylmethyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 29a were transformed in analogy to example 1 using pyridin-4-ylboronic acid to give after working up and purification 6.2 mg (10%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.99-1.09 (4H), 1.45-2.07 (7H), 3.34-3.55 (3H), 3.67 (1H), 4.06 (1H), 6.26 (1H), 6.44 (1H), 7.24 (1H), 7.79 (2H), 7.83 (1H), 7.88 (2H), 8.13 (2H), 8.74 (2H) ppm.

Intermediate Example 29a

(RS)-6-Chloro-3-[4-(2-cyclopropyl-1H-imidazol-4-yl)phenyl]-Netrahydro-2H-pyran-2-ylmethyl)imidazo[1,2-b]pyridazin-8-amine

105 mg (267 μmol) (RS)-6-chloro-3-iodo-N-(tetrahydro-2H-pyran-2-ylmethyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 29b were transformed in analogy to intermediate example 1a to give after working up and purification 61 mg (51%) of the title compound.

Intermediate Example 29b

(RS)-6-Chloro-3-iodo-N-(tetrahydro-2H-pyran-2-ylmethyl)imidazo[1,2-b]pyridazin-8-amine

530 mg (1.48 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c were transformed in analogy to intermediate example 1b using 1-[(2RS)-tetrahydro-2H-pyran-2-yl]methanamine to give after working up and purification 214 mg (37%) of the title compound.

›Example 30

(RS)—N-cyclopropyl-2-methyl-4-[8-{[(2-methyltetrahydrofuran-2-yl)methyl]amino}-6-(pyridin-4-yl)imidazo[1,2-b]pyridazin-3-yl]benzamide

50 mg (114 μmol) (RS)-4-(6-Chloro-8-{[(2-methyltetrahydrofuran-2-yl)methyl]amino}imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 30a were transformed in analogy to example 1 using pyridin-4-ylboronic acid to give after working up and purification 12.5 mg (22%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.64 (2H), 0.89 (2H), 1.35 (3H), 1.81 (1H), 1.91-2.10 (3H), 2.54 (3H), 2.93 (1H), 3.45 (2H), 3.93 (2H), 6.10 (1H), 6.20 (1H), 6.50 (1H), 7.44 (1H), 7.79-7.84 (3H), 7.92 (1H), 7.99 (1H), 8.71 (2H) ppm.

Intermediate Example 30a

(RS)-4-(6-Chloro-8-{[(2-methyltetrahydrofuran-2-yl)methyl]amino}imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide

150 mg (382 μmol) (RS)-6-chloro-3-iodo-N-[(2-methyltetrahydrofuran-2-yl)methyl]imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 30b were transformed in analogy to intermediate example 1a using N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give after working up and purification 110 mg (65%) of the title compound.

Intermediate Example 30b

(RS) 6-Chloro-3-iodo-N-[(2-methyltetrahydrofuran-2-yl)methyl]imidazo[1,2-b]pyridazin-8-amine

250 mg (698 μmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c were transformed in analogy to intermediate example 1b using 1-[(2RS)-2-methyltetrahydrofuran-2-yl]methanamine to give after working up and purification 262 mg (96%) of the title compound.

›Example 31

N-cyclopropyl-2-methyl-4-[6-(pyridin-4-yl)-8-{[(2S)-tetrahydrofuran-2-ylmethyl]amino}imidazo[1,2-b]pyridazin-3-yl]benzamide

49 mg (115 μmol) 4-(6-Chloro-8-{[(2S)-tetrahydrofuran-2-ylmethyl]amino}imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 31a were transformed in analogy to example 1 using pyridin-4-ylboronic acid to give after working up and purification 3.6 mg (6%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.64 (2H), 0.90 (2H), 1.75 (1H), 1.98 (2H), 2.11 (1H), 2.55 (3H), 2.93 (1H), 3.46 (1H), 3.60 (1H), 3.82 (1H), 3.96 (1H), 4.24 (1H), 6.01 (1H), 6.23 (1H), 6.50 (1H), 7.45 (1H), 7.83 (1H), 7.84 (2H), 7.93 (1H), 8.00 (1H), 8.74 (2H) ppm.

Intermediate Example 31a

4-(6-Chloro-8-{[(2S)-tetrahydrofuran-2-ylmethyl]amino}imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide

232 mg (613 μmol) 6-chloro-3-iodo-N-[(2S)-tetrahydrofuran-2-ylmethyl]imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 4b were transformed in analogy to intermediate example 1a using N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give after working up and purification 98 mg (38%) of the title compound.

›Example 32

N-cyclopropyl-4-{6-(4-fluorophenyl)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzenecarbothioamide

33 mg (82 μmol) 4-{6-(4-fluorophenyl)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzaldehyde which was prepared according to intermediate example 32a were transformed in analogy to example 13 to give after working up and purification 3.3 mg (8%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.75-0.88 (4H), 1.18 (6H), 3.40 (2H), 3.47 (1H), 4.78 (1H), 6.81 (1H), 6.95 (1H), 7.35 (2H), 7.84 (2H), 8.07 (1H), 8.11 (2H), 8.26 (2H), 10.16 (1H) ppm.

Intermediate Example 32a

4-{6-(4-Fluorophenyl)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzaldehyde

48 mg (107 μmol) 1-({3-[4-(1,3-dioxolan-2-yl)phenyl]-6-(4-fluorophenyl)imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol which was prepared according to intermediate example 32b were transformed in analogy to intermediate example 13a to give after working up and purification 34.6 mg (76%) of the title compound.

Intermediate Example 32b

1-({3-[4-(1,3-Dioxolan-2-yl)phenyl]-6-(4-fluorophenyl)imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol

100 mg (257 μmol) 1-({6-chloro-3-[4-(1,3-dioxolan-2-yl)phenyl]imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol which was prepared according to intermediate example 32c were transformed in analogy to example 1 using (4-fluorophenyl)boronic acid to give after working up and purification 50.0 mg (43%) of the title compound.

Intermediate Example 32c

1-({3-[4-(1,3-Dioxolan-2-yl)phenyl]-6-(4-fluorophenyl)imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol

2.65 g (7.2 mmol) 1-[(6-chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)amino]-2-methylpropan-2-ol which was prepared according to intermediate example 1b were transformed in analogy to intermediate example 1a using 2-[4-(1,3-dioxolan-2-yl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to give after working up and purification 1.36 g (48%) of the title compound.

›Example 33

N-cyclopropyl-2-methyl-4-[6-(1-methyl-1H-pyrazol-5-yl)-8-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}imidazo[1,2-b]pyridazin-3-yl]benzamide

63 mg (148 μmol) 4-(6-chloro-8-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 33a were transformed in analogy to example 1 using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give after working up and purification 10.6 mg (14%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.64 (2H), 0.89 (2H), 1.72 (1H), 1.97 (2H), 2.09 (1H), 2.50 (3H), 2.92 (1H), 3.40 (1H), 3.53 (1H), 3.81 (1H), 3.95 (1H), 4.17 (3H), 4.21 (1H), 6.05 (1H), 6.17 (1H), 6.30 (1H), 6.63 (1H), 7.39 (1H), 7.52 (1H), 7.76 (1H), 7.83 (1H), 7.88 (1H) ppm.

Intermediate Example 33a

4-(6-Chloro-8-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide

247 mg (652 μmol) 6-chloro-3-iodo-N-[(2R)-tetrahydrofuran-2-ylmethyl]imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 5b were transformed in analogy to intermediate example 1a using N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give after working up and purification 127 mg (46%) of the title compound.

›Example 34

N-cyclopropyl-2-methyl-4-[6-(1-methyl-1H-pyrazol-5-yl)-8-{[(2S)-tetrahydrofuran-2-ylmethyl]amino}imidazo[1,2-b]pyridazin-3-yl]benzamide

49 mg (115 μmol) 4-(6-chloro-8-{[(2S)-tetrahydrofuran-2-ylmethyl]amino}imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 31a were transformed in analogy to example 1 using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give after working up and purification 8.5 mg (15%) of the title compound.

›Example 35

N-cyclopropyl-2-methyl-4-[6-(pyridin-4-yl)-8-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}imidazo[1,2-b]pyridazin-3-yl]benzamide

63 mg (148 μmol) 4-(6-chloro-8-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 33a were transformed in analogy to example 1 using pyridin-4-ylboronic acid to give after working up and purification 4.2 mg (6%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.64 (2H), 0.90 (2H), 1.75 (1H), 1.98 (2H), 2.11 (1H), 2.55 (3H), 2.93 (1H), 3.46 (1H), 3.59 (1H), 3.82 (1H), 3.96 (1H), 4.24 (1H), 6.02 (1H), 6.20 (1H), 6.49 (1H), 7.45 (1H), 7.83 (1H), 7.84 (2H), 7.93 (1H), 8.01 (1H), 8.73 (2H) ppm.

›Example 36

(RS)—N-cyclopropyl-4-{8-[(1,4-dioxan-2-ylmethyl)amino]-6-(pyridin-4-yl)imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

88 mg (199 μmol) (RS)-4-{6-chloro-8-[(1,4-dioxan-2-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 36a were transformed in analogy to example 1 using pyridin-4-ylboronic acid to give after working up and purification 2.9 mg (3%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.62 (2H), 0.88 (2H), 2.52 (3H), 2.90 (1H), 3.36-4.01 (9H), 6.06 (1H), 6.23 (1H), 6.46 (1H), 7.44 (1H), 7.80 (1H), 7.84 (2H), 7.90 (1H), 7.98 (1H), 8.70 (2H) ppm.

Intermediate Example 36a

(RS)-4-{6-Chloro-8-[(1,4-dioxan-2-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

200 mg (507 μmol) (RS)-6-chloro-N-(1,4-dioxan-2-ylmethyl)-3-iodoimidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 36b were transformed in analogy to intermediate example 1a using N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give after working up and purification 93.6 mg (42%) of the title compound.

Intermediate Example 36b

(RS)-6-Chloro-N-(1,4-dioxan-2-ylmethyl)-3-iodoimidazo[1,2-b]pyridazin-8-amine

500 mg (1.40 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c were transformed in analogy to intermediate example 1b using 1-[(2RS)-1,4-dioxan-2-yl]methanamine to give after working up and purification 520 mg (94%) of the title compound.

›Example 37

(RS)—N-cyclopropyl-2-methyl-4-{6-(pyridin-4-yl)-8-[(tetrahydro-2H-pyran-2-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

63 mg (143 μmol) which (RS)-4-{6-chloro-8-[(tetrahydro-2H-pyran-2-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide was prepared according to intermediate example 37a were transformed in analogy to example 1 using pyridin-4-ylboronic acid to give after working up and purification 4.0 mg (5%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.88 (2H), 1.40-2.03 (6H), 2.53 (3H), 2.91 (1H), 3.33-3.55 (3H), 3.66 (1H), 4.05 (1H), 6.18 (1H), 6.43 (1H), 6.47 (1H), 7.44 (1H), 7.80 (1H), 7.83 (2H), 7.91 (1H), 7.98 (1H), 8.70 (2H) ppm.

Intermediate Example 37a

(RS)-4-{6-Chloro-8-[(tetrahydro-2H-pyran-2-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

100 mg (255 μmol) 6-chloro-3-iodo-N-(tetrahydro-2H-pyran-2-ylmethyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 29b were transformed in analogy to intermediate example 1a using N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give after working up and purification 68 mg (61%) of the title compound.

›Example 38

N-cyclopropyl-4-{6-[2-(hydroxymethyl)phenyl]-8-[(2-methoxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

62 mg (145 μmol) 4-{6-chloro-8-[(2-methoxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 17a were transformed in analogy to example 1 using [2-(hydroxymethyl)phenyl]boronic acid to give after working up and purification 24.8 mg (33%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.58 (2H), 0.84 (2H), 1.31 (6H), 2.47 (3H), 2.87 (1H), 3.28 (3H), 3.34 (2H), 4.13 (1H), 4.38 (2H), 6.19 (1H), 6.21 (1H), 6.25 (1H), 7.36 (1H), 7.42-7.49 (3H), 7.59 (1H), 7.61 (1H), 7.70 (1H), 7.72 (1H) ppm.

›Example 39

N-cyclopropyl-4-{8-[(2-methoxy-2-methylpropyl)amino]-6-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

70 mg (164 μmol) 4-{6-chloro-8-[(2-methoxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 17a were transformed in analogy to example 1 using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give after working up and purification 30 mg (37%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.89 (2H), 1.31 (6H), 2.50 (3H), 2.91 (1H), 3.27 (3H), 3.32 (2H), 4.16 (3H), 6.10 (1H), 6.17 (1H), 6.25 (1H), 6.62 (1H), 7.38 (1H), 7.51 (1H), 7.76 (1H), 7.83 (1H), 7.87 (1H) ppm.

›Example 40

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-vinylimidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

100 mg (242 μmol) 4-{6-Chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 1 using 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane to give after working up and purification 13 mg (12%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.89 (2H), 1.43 (6H), 2.52 (3H), 2.92 (1H), 3.35 (2H), 5.56 (1H), 5.97 (1H), 6.07 (1H), 6.22 (1H), 6.37 (1H), 6.73 (1H), 7.40 (1H), 7.71 (1H), 7.50 (1H), 7.94 (1H) ppm.

›Example 41

N-cyclopropyl-2-methyl-4-{8-[(3,3,3-trifluoropropyl)amino]-6-vinylimidazo[1,2-b]pyridazin-3-yl}benzamide

100 mg (228 μmol) 4-{6-Chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a were transformed in analogy to example 1 using 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane to give after working up and purification 11.4 mg (10%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.62 (2H), 0.89 (2H), 2.52 (3H), 2.56 (2H), 2.92 (1H), 3.69 (2H), 5.60 (1H), 5.92 (1H), 5.95 (1H), 6.09 (1H), 6.20 (1H), 6.77 (1H), 7.42 (1H), 7.75 (1H), 7.91 (1H), 7.95 (1H) ppm.

›Example 42

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (121 μmol) 4-{6-Chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 1 using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine to give after working up and purification 10.5 mg (18%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.65 (2H), 1.16 (6H), 2.37 (3H), 2.61 (2H), 2.80 (1H), 3.05 (2H), 3.31 (2H), 3.56 (1H), 6.54 (1H), 6.66-6.74 (2H), 7.35 (1H), 7.97 (1H), 8.03 (1H), 8.04 (1H), 8.26 (1H), 8.28 (1H) ppm.

›Example 43

4-{6-(Cyclohex-1-en-1-yl)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropylbenzenecarbothioamide

20.6 mg (53 μmol) 4-{6-(cyclohex-1-en-1-yl)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzaldehyde which was prepared according to intermediate example 43a were transformed in analogy to example 13 to give after working up and purification 3.2 mg (13%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.75-0.85 (4H), 1.15 (6H), 1.61 (2H), 1.71 (2H), 2.22 (2H), 2.52 (2H), 3.13 (2H), 3.49 (1H), 4.77 (1H), 6.51 (1H), 6.63 (1H), 6.68 (1H), 7.83 (2H), 8.01 (1H), 8.21 (2H), 10.12 (1H) ppm.

Intermediate Example 43a

4-{6-(Cyclohex-1-en-1-yl)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzaldehyde

97 mg (223 μmol) 1-({6-(cyclohex-1-en-1-yl)-3-[4-(1,3-dioxolan-2-yl)phenyl]imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol which was prepared according to intermediate example 43b were transformed in analogy to intermediate example 13a to give after working up and purification 24 mg (25%) of the title compound.

Intermediate Example 43b

1-({6-(Cyclohex-1-en-1-yl)-3-[4-(1,3-dioxolan-2-yl)phenyl]imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol

100 mg (257 μmol) 1-({6-chloro-3-[4-(1,3-dioxolan-2-yl)phenyl]imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol which was prepared according to intermediate example 32c were transformed in analogy to example 1 using cyclohex-1-en-1-ylboronic acid to give after working up and purification 97 mg (87%) of the title compound.

›Example 44

N-cyclopropyl-4-{6-[2-(hydroxymethyl)phenyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzenecarbothioamide

72.3 mg (164 μmol) 4-{6-[2-(hydroxymethyl)phenyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzaldehyde which was prepared according to intermediate example 44a were transformed in analogy to example 13 to give after working up and purification 6.6 mg (7%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.76 (2H), 1.00 (2H), 2.58 (2H), 3.37 (1H), 3.72 (2H), 3.96 (1H), 4.40 (2H), 6.16 (1H), 6.25 (1H), 7.46-7.51 (3H), 7.59 (1H), 7.76 (1H), 7.77 (2H), 7.84 (2H), 7.89 (1H) ppm.

Intermediate Example 44a

4-{6-[2-(Hydroxymethyl)phenyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzaldehyde

52 mg (107 μmol) (2-{3-[4-(1,3-dioxolan-2-yl)phenyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-6-yl}phenyl)methanol which was prepared according to intermediate example 44b were transformed in analogy to intermediate example 13a to give after working up and purification 72.3 mg (76%) of the title compound.

Intermediate Example 44b

(2-{3-[4-(1,3-Dioxolan-2-yl)phenyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-6-yl}phenyl)methanol

100 mg (242 μmol) 6-chloro-3-[4-(1,3-dioxolan-2-yl)phenyl]-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 44c were transformed in analogy to example 1 using [2-(hydroxymethyl)phenyl]boronic acid to give after working up and purification 52 mg (44%) of the title compound.

Intermediate Example 44c

6-Chloro-3-[4-(1,3-dioxolan-2-yl)phenyl]-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine

800 mg (2.05 Mmol) 6-chloro-3-iodo-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 6b were transformed in analogy to intermediate example 1a using 2-[4-(1,3-dioxolan-2-yl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to give after working up and purification 332 mg (35%) of the title compound.

›Example 45

N-cyclopropyl-4-{6-(1-methyl-1H-pyrazol-5-yl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzenecarbothioamide

27 mg (65 μmol) 4-{6-(1-methyl-1H-pyrazol-5-yl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzaldehyde which was prepared according to intermediate example 45a were transformed in analogy to example 13 to give after working up and purification 1.8 mg (5%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.82 (2H), 1.07 (2H), 2.59 (2H), 3.42 (1H), 3.73 (2H), 4.19 (3H), 6.08 (1H), 6.29 (1H), 6.66 (1H), 7.56 (1H), 7.64 (1H), 7.84 (2H), 7.85 (1H), 8.07 (2H) ppm.

Intermediate Example 45a

4-{6-(1-Methyl-1H-pyrazol-5-yl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzaldehyde

73 mg (159 μmol) 3-[4-(1,3-dioxolan-2-yl)phenyl]-6-(1-methyl-1H-pyrazol-5-yl)-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 45b were transformed in analogy to intermediate example 13a to give after working up and purification 27 mg (41%) of the title compound.

Intermediate Example 45b

3-[4-(1,3-Dioxolan-2-yl)phenyl]-6-(1-methyl-1H-pyrazol-5-yl)-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine

100 mg (242 μmol) 6-chloro-3-[4-(1,3-dioxolan-2-yl)phenyl]-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 44c were transformed in analogy to example 1 using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give after working up and purification 73 mg (66%) of the title compound.

›Example 46

N-cyclopropyl-4-{6-[3-(hydroxymethyl)phenyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzenecarbothioamide

39.1 mg (89 μmol) 4-{6-[3-(hydroxymethyl)phenyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzaldehyde which was prepared according to intermediate example 46a were transformed in analogy to example 13 to give after working up and purification 2.0 mg (4%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.83 (2H), 1.07 (2H), 2.56 (2H), 3.43 (1H), 3.68 (2H), 4.82 (2H), 6.00 (1H), 6.40 (1H), 7.50 (2H), 7.71 (1H), 7.79-7.90 (5H), 8.15 (2H) ppm.

Intermediate Example 46a

4-{6-[3-(Hydroxymethyl)phenyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzaldehyde

167 mg (μmol) (3-{3-[4-(1,3-dioxolan-2-yl)phenyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-6-yl}phenyl)methanol which was prepared according to intermediate example 46b were transformed in analogy to intermediate example 13a to give after working up and purification 39.1 mg (37%) of the title compound.

Intermediate Example 46b

(3-{3-[4-(1,3-Dioxolan-2-yl)phenyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-6-yl}phenyl)methanol

100 mg (242 μmol) 6-chloro-3-[4-(1,3-dioxolan-2-yl)phenyl]-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 44c were transformed in analogy to example 1 using [3-(hydroxymethyl)phenyl]boronic acid to give after working up and purification 83.5 mg (71%) of the title compound.

›Example 47

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(pyridin-4-yl)imidazo[1,2-b]pyridazin-3-yl}benzenecarbothioamide

48 mg (124 μmol) 4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(pyridin-4-yl)imidazo[1,2-b]pyridazin-3-yl}benzaldehyde which was prepared according to intermediate example 47a were transformed in analogy to example 13 to give after working up and purification 4.7 mg (6%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.76-0.88 (4H), 1.18 (6H), 3.38-3.52 (3H), 4.79 (1H), 6.93 (1H), 7.09 (1H), 7.86 (2H), 8.04 (2H), 8.12 (1H), 8.27 (2H), 8.73 (2H), 10.16 (1H) ppm.

Intermediate Example 47a

4-{8-[(2-Hydroxy-2-methylpropyl)amino]-6-(pyridin-4-yl)imidazo[1,2-b]pyridazin-3-yl}benzaldehyde

69 mg (160 μmol) 1-({3-[4-(1,3-dioxolan-2-yl)phenyl]-6-(pyridin-4-yl)imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol which was prepared according to intermediate example 47b were transformed in analogy to intermediate example 13a to give after working up and purification 51.5 mg (83%) of the title compound.

Intermediate Example 47b

1-({3-[4-(1,3-Dioxolan-2-yl)phenyl]-6-(pyridin-4-yl)imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol

200 mg (514 μmol) 1-({6-chloro-3-[4-(1,3-dioxolan-2-yl)phenyl]imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol which was prepared according to intermediate example 32c were transformed in analogy to example 1 using pyridin-4-ylboronic acid to give after working up and purification 51.5 mg (23%) of the title compound.

›Example 48

N-cyclopropyl-4-{6-cyclopropyl-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

A solution of 31 mg (72 μmol) N-cyclopropyl-2-methyl-4-{8-[(3,3,3-trifluoropropyl)amino]-6-vinylimidazo[1,2-b]pyridazin-3-yl}benzamide which was prepared according to example 41 in 3.5 mL tetrahydrofuran was cooled to 3° C., 5 mL of diazomethane solution in diethyl ether was added followed by 0.81 mg palladium(II) diacetate and the mixture was stirred for 1 hour. The solvents were removed and the residue was purified by chromatography to give 5.8 mg (18%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.89 (2H), 1.00-1.11 (4H), 2.00 (1H), 2.53 (3H), 2.47-2.61 (2H), 2.92 (1H), 3.65 (2H), 5.78 (1H), 5.91 (1H), 5.93 (1H), 7.41 (1H), 7.73 (1H), 7.91 (1H), 7.92 (1H) ppm.

›Example 49

N-cyclopropyl-4-{6-(4-fluorophenyl)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-3-methoxybenzamide

75 mg (174 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-3-methoxybenzamide which was prepared according to intermediate example 49a were transformed in analogy to example 1 using (4-fluorophenyl)boronic acid to give after working up and purification 18.5 mg (22%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.57 (2H), 0.69 (2H), 1.19 (6H), 2.85 (1H), 3.39 (2H), 3.89 (3H), 4.78 (1H), 6.77 (1H), 6.87 (1H), 7.31 (2H), 7.54 (1H), 7.56 (1H), 7.87 (1H), 8.03 (2H), 8.25 (1H), 8.51 (1H) ppm.

›Example 49a

4-{6-Chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-3-methoxybenzamide

1.0 g (2.73 mmol) 1-[(6-Chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)amino]-2-methylpropan-2-ol which was prepared according to intermediate example 1b were transformed in analogy to intermediate example 1a using [4-(cyclopropylcarbamoyl)-2-methoxyphenyl]boronic acid which was prepared according to intermediate example 49b to give after working up and purification 741 mg (60%) of the title compound.

›Example 49b

[4-(Cyclopropylcarbamoyl)-2-methoxyphenyl]boronic acid

A suspension of 3.0 g (15.3 mmol) 4-(dihydroxyboryl)-3-methoxybenzoic acid, 874 mg cyclopropanamine and 3.5 g N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide in 93 mL dichloromethane was stirred overnight at 23° C.

Water was added and the mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by chromatography to give 2.60 g (72%) of the title compound.

›Example 50

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-3-yl}-3-methoxybenzamide

75 mg (174 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-3-methoxybenzamide which was prepared according to intermediate example 49a were transformed in analogy to example 1 using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give after working up and purification 14.8 mg (18%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.57 (2H), 0.69 (2H), 1.17 (6H), 2.83 (1H), 3.35 (2H), 3.85 (3H), 4.01 (3H), 4.77 (1H), 6.59 (1H), 6.85 (1H), 6.95 (1H), 7.47 (1H), 7.51 (1H), 7.53 (1H), 7.81 (1H), 8.03 (1H), 8.49 (1H) ppm.

›Example 51

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(phenylsulfanyl) imidazo[1,2-b]pyridazin-3-yl}-3-methoxybenzamide (A) and

N-cyclopropyl-3-hydroxy-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(phenylsulfanyl)imidazo[1,2-b]pyridazin-3-yl}benzamide (B)

To a solution of 76.9 mg benzenethiol in 1.0 mL dimethyl sulfoxide were added 27.9 mg sodium hydride (60%) and the mixture was stirred at 23° C. for 1 hour. Then 50 mg (116 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-3-methoxybenzamide which was prepared according to intermediate example 49a were added and the mixture was heated at 120° C. using microwave irradiation for 1 hour. Water was added and the mixture was extracted with dichloromethane and methanol. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by chromatography to give 8.0 mg (18%) of the title compound A and 15.3 mg (27%) of the title compound B.

1 H-NMR (DMSO-d6) of A: δ=0.56 (2H), 0.69 (2H), 1.10 (6H), 2.82 (1H), 3.19 (2H), 3.27 (3H), 4.70 (1H), 6.19 (1H), 6.97 (1H), 7.22 (1H), 7.41-7.47 (4H), 7.53-7.58 (2H), 7.85 (1H), 7.86 (1H), 8.44 (1H) ppm.

1 H-NMR (DMSO-d6) of B: δ=0.54 (2H), 0.66 (2H), 1.10 (6H), 2.80 (1H), 3.18 (2H), 4.70 (1H), 6.17 (1H), 6.98 (1H), 7.04 (1H), 7.33 (1H), 7.42-7.48 (3H), 7.55-7.61 (2H), 7.87 (1H), 7.95 (1H), 8.33 (1H), 10.13 (1H) ppm.

›Example 52

N-cyclopropyl-4-{6-(4-fluorophenyl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-3-methoxybenzamide

65 mg (143 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-3-methoxybenzamide which was prepared according to intermediate example 52a were transformed in analogy to example 1 using (4-fluorophenyl)boronic acid to give after working up and purification 14.3 mg (18%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.66 (2H), 0.91 (2H), 2.59 (2H), 2.95 (1H), 3.75 (2H), 3.97 (3H), 6.00 (1H), 6.32 (1H), 6.39 (1H), 7.17 (2H), 7.33 (1H), 7.58 (1H), 7.90 (2H), 8.01 (1H), 8.37 (1H) ppm.

Intermediate Example 52a

4-{6-Chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-3-methoxybenzamide

484 mg (1.24 mmol) 6-chloro-3-iodo-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 6b were transformed in analogy to intermediate example 1a using [4-(cyclopropylcarbamoyl)-2-methoxyphenyl]boronic acid which was prepared according to intermediate example 49b to give after working up and purification 163 mg (29%) of the title compound.

›Example 53

N-cyclopropyl-3-methoxy-4-{6-(1-methyl-1H-pyrazol-5-yl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

65 mg (143 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-3-methoxybenzamide which was prepared according to intermediate example 52a were transformed in analogy to example 1 using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give after working up and purification 3.6 mg (5%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.66 (2H), 0.91 (2H), 2.58 (2H), 2.94 (1H), 3.72 (2H), 3.94 (3H), 4.11 (3H), 6.04 (1H), 6.27 (1H), 6.31 (1H), 6.64 (1H), 7.27 (1H), 7.53 (1H), 7.58 (1H), 7.95 (1H), 8.13 (1H) ppm.

›Example 54

N-cyclopropyl-4-{6-[2-(hydroxymethyl)phenyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-3-methoxybenzamide

50 mg (110 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-3-methoxybenzamide which was prepared according to intermediate example 52a were transformed in analogy to example 1 using [2-(hydroxymethyl)phenyl]boronic acid to give after working up and purification 11.8 mg (18%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.60 (2H), 0.85 (2H), 2.58 (2H), 2.88 (1H), 3.73 (2H), 3.90 (3H), 4.39 (2H), 5.12 (1H), 6.13 (1H), 6.24 (1H), 6.34 (1H), 7.22 (1H), 7.43-7.49 (3H), 7.55 (1H), 7.58 (1H), 7.79 (1H), 7.84 (1H) ppm.

›Example 55

N-cyclopropyl-4-{6-[(2-methoxyphenyl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (114 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a were transformed in analogy to example 51 using 2-methoxybenzenethiol to give after working up and purification 9.2 mg (14%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.61 (2H), 0.88 (2H), 2.36 (3H), 2.47 (2H), 2.89 (1H), 3.52 (2H), 3.77 (3H), 5.88 (1H), 6.01 (1H), 6.28 (1H), 6.97-7.07 (2H), 7.16 (1H), 7.48 (1H), 7.57-7.65 (3H), 7.67 (1H) ppm.

›Example 56

(RS)—N-cyclopropyl-2-methyl-4-[8-{[(4-methylmorpholin-2-yl)methyl]amino}-6-(phenylsulfanyl)imidazo[1,2-b]pyridazin-3-yl]benzamide

75 mg (165 μmol) (RS)-4-(6-chloro-8-{[(4-methylmorpholin-2-yl)methyl]amino}imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 56a were transformed in analogy to example 51 using benzenethiol to give after working up and purification 21.6 mg (25%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 1.70 (1H), 1.93 (1H), 2.13 (3H), 2.20 (3H), 2.53 (1H), 2.64 (1H), 2.79 (1H), 3.25-3.34 (2H), 3.43 (1H), 3.62 (1H), 3.73 (1H), 6.10 (1H), 7.10 (1H), 7.42 (1H), 7.45-7.51 (3H), 7.59-7.67 (3H), 7.71 (1H), 7.92 (1H), 8.23 (1H) ppm.

Intermediate Example 56a

(RS)-4-(6-Chloro-8-{[(4-methylmorpholin-2-yl)methyl]amino}imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide

352 mg (864 μmol) (RS)-6-chloro-3-iodo-N-[(4-methylmorpholin-2-yl)methyl]imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 56b were transformed in analogy to intermediate example 1a using N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give after working up and purification 372 mg (95%) of the title compound.

Intermediate Example 56b

(RS)-6-Chloro-3-iodo-N-[(4-methylmorpholin-2-yl)methyl]imidazo[1,2-b]pyridazin-8-amine

370 mg (1.03 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c were transformed in analogy to intermediate example 1b using 1-[(2RS)-4-methylmorpholin-2-yl]methanamine to give after working up and purification 359 mg (85%) of the title compound.

›Example 57

4-{8-[(2-Amino-2-methylpropyl)amino]-6-(4-fluorophenyl)imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

100 mg (242 μmol) 4-{8-[(2-amino-2-methylpropyl)amino]-6-chloroimidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 57a were transformed in analogy to example 1 using (4-fluorophenyl)boronic acid to give after working up and purification 17.9 mg (14%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.90 (2H), 1.25 (2H), 1.29 (6H), 2.55 (3H), 2.93 (1H), 3.27 (2H), 5.94 (1H), 6.34 (1H), 6.41 (1H), 7.17 (2H), 7.45 (1H), 7.81 (1H), 7.91-7.98 (3H), 8.04 (1H) ppm.

Intermediate Example 57a

4-{8-[(2-Amino-2-methylpropyl)amino]-6-chloroimidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

1.07 g (2.93 mmol) N 1 -(6-chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)-2-methylpropane-1,2-diamine which was prepared according to intermediate example 57b were transformed in analogy to intermediate example 1a using N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give after working up and purification 809 mg (64%) of the title compound.

Intermediate Example 57b

N 1 -(6-chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)-2-methylpropane-1,2-diamine

2.00 g (5.58 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c were transformed in analogy to intermediate example 1b using 2-methylpropane-1,2-diamine to give after working up and purification 1.08 g (53%) of the title compound.

›Example 58

4-{8-[(2-Amino-2-methylpropyl)amino]-6-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

100 mg (242 μmol) 4-{8-[(2-amino-2-methylpropyl)amino]-6-chloroimidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 57a were transformed in analogy to example 1 using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give after working up and purification 27.5 mg (22%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.64 (2H), 0.90 (2H), 1.25 (2H), 1.28 (6H), 2.52 (3H), 2.93 (1H), 3.23 (2H), 4.20 (3H), 5.97 (1H), 6.29 (1H), 6.42 (1H), 6.64 (1H), 7.41 (1H), 7.53 (1H), 7.79 (1H), 7.86 (1H), 7.90 (1H) ppm.

›Example 59

4-{8-[(2-Amino-2-methylpropyl)amino]-6-[2-(hydroxymethyl)phenyl]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

100 mg (242 μmol) 4-{8-[(2-amino-2-methylpropyl)amino]-6-chloroimidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 57a were transformed in analogy to example 1 using [2-(hydroxymethyl)phenyl]boronic acid to give after working up and purification 30.0 mg (23%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.59 (2H), 0.85 (2H), 1.25 (2H), 1.28 (6H), 2.49 (3H), 2.89 (1H), 3.25 (2H), 4.40 (2H), 5.30 (1H), 6.07 (1H), 6.30 (1H), 6.47 (1H), 7.38 (1H), 7.43-7.50 (3H), 7.60 (1H), 7.64 (1H), 7.73 (1H), 7.74 (1H) ppm.

›Example 60

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(4-hydroxyphenyl) sulfanyl]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide (A) and

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(4-methoxyphenyl)sulfanyl]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide (B)

75 mg (181 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 4-methoxybenzenethiol to give after working up and purification 50 mg (43%) of the title compound A and 8.8 mg (5%) of the title compound B.

1 H-NMR (DMSO-d6) of A: δ=0.49 (2H), 0.65 (2H), 1.11 (6H), 2.21 (3H), 2.79 (1H), 3.19 (2H), 4.72 (1H), 6.12 (1H), 6.82-6.91 (3H), 7.12 (1H), 7.42 (2H), 7.65 (1H), 7.70 (1H), 7.91 (1H), 8.22 (1H), 10.04 (1H) ppm.

1 H-NMR (CDCl 3 ) of B: δ=0.64 (2H), 0.90 (2H), 1.39 (6H), 2.37 (3H), 2.92 (1H), 3.24 (2H), 3.88 (3H), 4.09 (1H), 5.30 (1H), 5.92 (1H), 5.97 (1H), 6.36 (1H), 6.96 (2H), 7.12 (1H), 7.50-7.58 (3H), 7.61 (1H) ppm.

›Example 61

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(3-hydroxyphenyl) sulfanyl]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide (A) and

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(3-methoxyphenyl)sulfanyl]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide (B)

75 mg (181 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 3-methoxybenzenethiol to give after working up and purification 26.9 mg (21%) of the title compound A and 14.9 mg (15%) of the title compound B.

1 H-NMR (DMSO-d6) of A: δ=0.49 (2H), 0.65 (2H), 1.11 (6H), 2.22 (3H), 2.79 (1H), 3.20 (2H), 4.71 (1H), 6.21 (1H), 6.85 (1H), 6.94-7.02 (3H), 7.15 (1H), 7.25 (1H), 7.73 (1H), 7.74 (1H), 7.94 (1H), 8.23 (1H), 9.73 (1H) ppm.

1 H-NMR (CDCl 3 ) of B: δ=0.63 (2H), 0.90 (2H), 1.40 (6H), 2.37 (3H), 2.92 (1H), 3.23 (2H), 3.73 (3H), 5.94 (1H), 6.02 (1H), 6.50 (1H), 6.97 (1H), 7.13-7.20 (3H), 7.22 (1H), 7.33 (1H), 7.56-7.63 (3H) ppm.

›Example 62

N-cyclopropyl-4-{6-[(3-fluorophenyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-3-hydroxybenzamide (A) and

N-cyclopropyl-4-{6-[(3-fluorophenyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-3-methoxybenzamide (B)

150 mg (349 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-3-methoxybenzamide which was prepared according to intermediate example 49a were transformed in analogy to example 51 using 3-fluorobenzenethiol to give after working up and purification 3.3 mg (2%) of the title compound A and 2.5 mg (1%) of the title compound B.

1 H-NMR (DMSO-d6) of A: δ=0.53 (2H), 0.66 (2H), 1.11 (6H), 2.80 (1H), 3.21 (2H), 4.71 (1H), 6.24 (1H), 7.06 (2H), 7.26 (1H), 7.33-7.52 (4H), 7.86 (1H), 7.94 (1H), 8.33 (1H), 10.18 (1H) ppm.

1 H-NMR (DMSO-d6) of B: δ=0.55 (2H), 0.69 (2H), 1.11 (6H), 2.82 (1H), 3.22 (2H), 3.84 (3H), 4.70 (1H), 6.26 (1H), 7.04 (1H), 7.21-7.30 (2H), 7.36 (1H), 7.39-7.49 (3H), 7.84 (1H), 7.85 (1H), 8.44 (1H) ppm.

›Example 63

N-cyclopropyl-4-{6-[(4-hydroxy-3-methylphenyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (181 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 2-methyl-4-sulfanylphenol to give after working up and purification 27.6 mg (28%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 1.11 (6H), 2.10 (3H), 2.20 (3H), 2.79 (1H), 3.18 (2H), 4.70 (1H), 6.11 (1H), 6.86 (1H), 6.88 (1H), 7.10 (1H), 7.25 (1H), 7.32 (1H), 7.67 (1H), 7.71 (1H), 7.92 (1H), 8.21 (1H), 9.87 (1H) ppm.

›Example 64

N-cyclopropyl-4-{6-[(5-fluoro-2-methylphenyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (181 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 5-fluoro-2-methylbenzenethiol to give after working up and purification 47.7 mg (48%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.65 (2H), 1.12 (6H), 2.19 (3H), 2.31 (3H), 2.79 (1H), 3.23 (2H), 4.71 (1H), 6.27 (1H), 7.01 (1H), 7.06 (1H), 7.29 (1H), 7.42-7.49 (2H), 7.57 (1H), 7.67 (1H), 7.94 (1H), 8.23 (1H) ppm.

›Example 65

N-cyclopropyl-4-{6-[(4-fluoro-3-methylphenyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (181 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 4-fluoro-3-methylbenzenethiol to give after working up and purification 25.9 mg (26%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.65 (2H), 1.11 (6H), 2.18 (3H), 2.22 (3H), 2.79 (1H), 3.22 (2H), 4.71 (1H), 6.22 (1H), 6.97 (1H), 7.08 (1H), 7.25 (1H), 7.48 (1H), 7.59 (2H), 7.67 (1H), 7.93 (1H), 7.23 (1H) ppm.

›Example 66

N-cyclopropyl-4-{6-[(3-fluoro-4-methylphenyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (181 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 3-fluoro-4-methylbenzenethiol to give after working up and purification 41.7 mg (42%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.65 (2H), 1.12 (6H), 2.19 (3H), 2.28 (3H), 2.79 (1H), 3.23 (2H), 4.72 (1H), 6.27 (1H), 6.99 (1H), 7.07 (1H), 7.34 (1H), 7.39 (1H), 7.44 (1H), 7.63 (1H), 7.69 (1H), 7.94 (1H), 8.25 (1H) ppm.

›Example 67

N-cyclopropyl-4-{6-[(3-fluoro-5-methylphenyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (181 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 3-fluoro-5-methylbenzenethiol to give after working up and purification 33 mg (33%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 1.12 (6H), 2.21 (3H), 2.30 (3H), 2.79 (1H), 3.22 (2H), 4.70 (1H), 6.27 (1H), 7.05 (1H), 7.13 (1H), 7.16 (1H), 7.26 (1H), 7.27 (1H), 7.70 (1H), 7.73 (1H), 7.95 (1H), 8.24 (1H) ppm.

›Example 68

N-cyclopropyl-4-{6-[(3,5-difluorophenyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (181 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 3,5-difluorobenzenethiol to give after working up and purification 5.7 mg (6%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 1.12 (6H), 2.22 (3H), 2.79 (1H), 3.24 (2H), 4.71 (1H), 6.34 (1H), 7.12 (1H), 7.16 (1H), 7.35-7.40 (3H), 7.71 (1H), 7.74 (1H), 7.96 (1H), 8.25 (1H) ppm.

›Example 69

N-cyclopropyl-4-{6-[(4-fluoro-2-methylphenyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (181 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 4-fluoro-3-methylbenzenethiol to give after working up and purification 32.1 mg (32%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.65 (2H), 1.12 (6H), 2.18 (3H), 2.35 (3H), 2.79 (1H), 3.22 (2H), 4.72 (1H), 6.23 (1H), 6-95 (1H), 7.05 (1H), 7.15 (1H), 7.34 (1H), 7.53 (1H), 7.63 (1H), 7.65 (1H), 7.92 (1H), 8.23 (1H) ppm.

›Example 70

N-cyclopropyl-4-{6-[(2-fluorophenyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (181 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 2-fluorobenzenethiol to give after working up and purification 36.8 mg (38%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 1.13 (6H), 2.18 (3H), 2.78 (1H), 3.24 (2H), 4.72 (1H), 6.31 (1H), 7.00 (1H), 7.03 (1H), 7.32 (1H), 7.40 (1H), 7.53 (1H), 7.61 (1H), 7.64 (1H), 7.69 (1H), 7.93 (1H), 8.22 (1H) ppm.

›Example 71

N-cyclopropyl-4-{6-[(4-fluorophenyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (181 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 4-fluorobenzenethiol to give after working up and purification 31.6 mg (33%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.65 (2H), 1.12 (6H), 2.19 (3H), 2.79 (1H), 3.22 (2H), 4.72 (1H), 6.24 (1H), 6.97 (1H), 7.08 (1H), 7.33 (2H), 7.58 (1H), 7.64-7.71 (3H), 7.92 (1H), 8.23 (1H) ppm.

›Example 72

4-{6-[(2E)-But-2-en-2-yl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-3-methoxybenzamide

75 mg (174 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-3-methoxybenzamide which was prepared according to intermediate example 49a were transformed in analogy to example 1 using (2Z)-but-2-en-2-ylboronic acid to give after working up and purification 26.9 mg (33%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.57 (2H), 0.68 (2H), 1.16 (6H), 1.81 (3H), 1.99 (3H), 2.84 (1H), 3.28 (2H), 3.89 (3H), 4.75 (1H), 6.40 (1H), 6.48 (1H), 6.58 (1H), 7.51 (1H), 7.53 (1H), 7.85 (1H), 8.32 (1H), 8.47 (1H) ppm.

›Example 73

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(2-hydroxyphenyl) sulfanyl]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide (A) and

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(2-methoxyphenyl)sulfanyl]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide (B)

100 mg (242 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 2-methoxybenzenethiol to give after working up and purification 43.1 mg (35%) of the title compound A and 5.8 mg (4%) of the title compound B.

1 H-NMR (DMSO-d6) of A: δ=0.49 (2H), 0.65 (2H), 1.11 (6H), 2.20 (3H), 2.78 (1H), 3.19 (2H), 4.72 (1H), 6.14 (1H), 6.82-6.90 (2H), 6.97 (1H), 7.07 (1H), 7.33 (1H), 7.44 (1H), 7.66 (1H), 7.71 (1H), 7.91 (1H), 8.22 (1H), 9.96 (1H) ppm.

1 H-NMR (CDCl 3 ) of B: δ=0.63 (2H), 0.89 (2H), 1.39 (6H), 2.35 (3H), 2.91 (1H), 3.23 (2H), 3.77 (3H), 4.62 (1H), 5.92 (1H), 5.97 (1H), 6.42 (1H), 6.99 (1H), 7.03 (1H), 7.13 (1H), 7.47 (1H), 7.56-7.64 (4H) ppm.

›Example 74

N-cyclopropyl-3-hydroxy-4-{6-(phenylsulfanyl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

29.5 mg (67 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-3-methoxybenzamide which was prepared according to intermediate example 52a were transformed in analogy to example 51 using benzenethiol to give after working up and purification 19 mg (52%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.88 (2H), 2.44 (2H), 2.92 (1H), 3.55 (2H), 5.81 (1H), 6.12 (1H), 6.22 (1H), 7.22 (1H), 7.33 (1H), 7.41-7.54 (4H), 7.58-7.66 (3H), 9.01 (1H) ppm.

›Example 75

N-cyclopropyl-4-{6-(3-fluorophenoxy)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (121 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 3-fluorophenol to give after working up and purification 13.9 mg (22%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.47 (2H), 0.63 (2H), 1.16 (6H), 2.14 (3H), 2.76 (1H), 3.27 (2H), 4.74 (1H), 6.18 (1H), 7.02 (1H), 7.08-7.14 (2H), 7.16 (1H), 7.24 (1H), 7.47 (1H), 7.67 (1H), 7.77 (1H), 7.92 (1H), 8.21 (1H) ppm.

›Example 76

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-phenoxyimidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (121 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using phenol to give after working up and purification 15.1 mg (25%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.59 (2H), 0.86 (2H), 1.38 (6H), 2.26 (3H), 2.86 (1H), 3.29 (2H), 3.74 (1H), 5.91 (1H), 6.02 (1H), 6.42 (1H), 7.19 (2H), 7.23 (2H), 7.41 (2H), 7.57 (1H), 7.66 (1H), 7.70 (1H) ppm.

›Example 77

N-cyclopropyl-2-methyl-4-{6-phenoxy-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

50 mg (114 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a were transformed in analogy to example 51 using phenol to give after working up and purification 5.7 mg (9%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.60 (2H), 0.87 (2H), 2.29 (3H), 2.57 (2H), 2.88 (1H), 1.97 (2H), 5.84 (1H), 5.90 (1H), 5.97 (1H), 7.20-7.30 (4H), 7.44 (2H), 7.60 (1H), 7.73 (1H), 7.74 (1H) ppm.

›Example 78

4-{8-[(2-Amino-2-methylpropyl)amino]-6-[(3-fluorophenyl)sulfanyl]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

250 mg (605 μmol) 4-{8-[(2-amino-2-methylpropyl)amino]-6-chloroimidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 57a were transformed in analogy to example 51 using 3-fluorobenzenethiol to give after working up and purification 9.8 mg (3%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.89 (2H), 1.24 (6H), 1.80 (2H), 2.39 (3H), 2.91 (1H), 3.14 (2H), 5.91 (1H), 5.97 (1H), 6.34 (1H), 7.12 (1H), 7.22 (1H), 7.32-7.42 (3H), 7.62 (1H), 7.64 (1H), 7.69 (1H) ppm.

›Example 79

N-cyclopropyl-4-{6-[(3-fluoro-5-methylphenyl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (114 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a were transformed in analogy to example 51 using 3-fluoro-5-methylbenzenethiol to give after working up and purification 6.9 mg (11%) of the title compound.

1 H-NMR (CDCl 3 +CD 3 OD): δ=0.61 (2H), 0.88 (2H), 2.35 (3H), 2.39 (3H), 2.48 (2H), 2.89 (1H), 3.54 (2H), 5.89 (1H), 6.07 (1H), 6.46 (1H), 6.96 (1H), 7.17 (1H), 7.21 (1H), 7.23 (1H), 7.63 (1H), 7.66 (1H), 7.68 (1H) ppm.

›Example 80

N-cyclopropyl-4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (114 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a were transformed in analogy to example 51 using 3-fluorophenol to give after working up and purification 9.1 mg (15%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.60 (2H), 0.87 (2H), 2.32 (3H), 2.57 (2H), 2.89 (1H), 3.67 (2H), 5.87 (1H), 5.89 (1H), 6.12 (1H), 6.94-7.08 (3H), 7.25 (1H), 7.39 (1H), 7.60 (1H), 7.72 (2H) ppm.

›Example 81

N-cyclopropyl-4-{6-(2-fluoro-5-methylphenoxy)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (121 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 2-fluoro-5-methylphenol to give after working up and purification 5.2 mg (8%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.46 (2H), 0.63 (2H), 1.17 (6H), 2.09 (3H), 2.29 (3H), 2.76 (1H), 3.29 (2H), 4.75 (1H), 6.23 (1H), 7.02 (1H), 7.10-7.16 (2H), 7.23 (1H), 7.27 (1H), 7.62 (1H), 7.70 (1H), 7.92 (1H), 8.21 (1H) ppm.

›Example 82

4-{6-(3-Cyanophenoxy)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

50 mg (121 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 3-hydroxybenzonitrile to give after working up and purification 5.8 mg (9%) of the title compound.

1 H-NMR (CDCl 3 +CD 3 OD): δ=0.63 (2H), 0.86 (2H), 1.42 (6H), 2.35 (3H), 2.90 (1H), 3.32 (2H), 5.88 (1H), 6.26 (1H), 6.66 (1H), 7.30 (1H), 7.46 (1H), 7.49-7.60 (4H), 7.65 (1H), 7.72 (1H) ppm.

›Example 83

N-cyclopropyl-4-{6-[(3-fluorophenyl)sulfonyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide (A) and

(RS)—N-cyclopropyl-4-{6-[(3-fluorophenyl)sulfinyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide (B)

To a solution of 50 mg (121 μmol) N-cyclopropyl-4-{6-[(3-fluorophenyl) sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, which was prepared according to intermediate example 209 in 1.0 mL dichloromethane were added 0.71 mg methyl(trioxo)rhenium, 1.77 mg isonicotinonitrile and 58 μL aqueous hydrogen peroxide (30%). The mixture was stirred for two days at 23° C., poured into sodium thiosulfate solution and extracted with dichloromethane. The organic phase was dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 14.9 mg (53%) of the title compound A and 4.5 mg (8%) of the title compound B.

1 H-NMR (CDCl 3 +CD 3 OD) of A: δ=0.65 (2H), 0.90 (2H), 2.47 (3H), 2.59 (2H), 2.92 (1H), 3.75 (2H), 6.08 (1H), 6.76 (1H), 6.77 (1H), 7.33 (1H), 7.38 (1H), 7.53-7.65 (3H), 7.81 (1H), 7.82 (1H), 7.88 (1H) ppm.

1 H-NMR (CDCl 3 ) of B: δ=0.65 (2H), 0.92 (2H), 2.55 (5H), 2.94 (1H), 3.73 (2H), 5.98 (1H), 6.37 (1H), 6.60 (1H), 7.17 (1H), 7.46 (1H), 7.50 (1H), 7.56 (1H), 7.60 (1H), 7.74-7.84 (3H) ppm.

›Example 84

N-cyclopropyl-2-methyl-4-{6-(phenylsulfanyl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzenecarbothioamide

59.1 mg (130 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzenecarbothioamide which was prepared according to intermediate example 84a were transformed in analogy to example 51 using benzenethiol to give after working up and purification 7.1 mg (9%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.75 (2H), 1.05 (2H), 2.30 (3H), 2.47 (2H), 3.41 (1H), 3.56 (2H), 5.87 (2H), 7.16 (1H), 7.27 (1H), 7.41-7.50 (3H), 7.57-7.71 (5H) ppm.

Intermediate Example 84a

4-{6-Chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzenecarbothioamide

A mixture comprising 100 mg (228 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a, 25.4 mg phosphorus pentasulfide and 0.47 mL pyridine were heated at 115° C. for 4 hours. Water and brine were added and the mixture was extracted several times with ethyl acetate. The combined organic layers were dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by chromatography to give 65.7 mg (63%) of the title compound.

›Example 85

4-{6-(3-Chlorophenoxy)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

50 mg (121 μmol) 4-{6-Chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 3-chlorophenol to give after working up and purification 9.3 mg (14%) of the title compound.

1 H-NMR (DMSO-d6): 0.3=0.47 (2H), 0.63 (2H), 1.16 (6H), 2.14 (3H), 2.77 (1H), 3.29 (2H), 4.74 (1H), 6.18 (1H), 7.03 (1H), 7.17 (1H), 7.25 (1H), 7.33 (1H), 7.44 (1H), 7.47 (1H), 7.67 (1H), 7.74 (1H), 7.93 (1H), 8.22 (1H) ppm.

›Example 86

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(4-methoxyphenoxy) imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (121 μmol) 4-{6-Chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 4-methoxyphenol to give after working up and purification 22.5 mg (35%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.47 (2H), 0.63 (2H), 1.16 (6H), 2.11 (3H), 2.77 (1H), 3.27 (2H), 3.75 (3H), 4.75 (1H), 6.13 (1H), 6.91 (1H), 6.98 (2H), 7.15 (1H), 7.18 (2H), 7.65 (1H), 7.77 (1H), 7.91 (1H), 8.21 (1H) ppm.

›Example 87

N-cyclopropyl-4-{6-(3-fluoro-5-methylphenoxy)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (121 μmol) 4-{6-Chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 3-fluoro-5-methylphenol to give after working up and purification 12.0 mg (19%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.47 (2H), 0.63 (2H), 1.15 (6H), 2.15 (3H), 2.31 (3H), 2.77 (1H), 3.27 (2H), 4.73 (1H), 6.16 (1H), 6.90-7.06 (4H), 7.17 (1H), 7.69 (1H), 7.78 (1H), 7.92 (1H), 8.22 (1H) ppm.

›Example 88

N-cyclopropyl-4-{6-(3-fluoro-5-methylphenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (114 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a were transformed in analogy to example 51 using 3-fluoro-5-methylphenol to give after working up and purification 7.6 mg (12%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.47 (2H), 0.63 (2H), 2.15 (3H), 2.32 (3H), 2.67 (2H), 2.77 (1H), 3.59 (2H), 6.11 (1H), 6.95 (2H), 7.03 (1H), 7.17 (1H), 7.65-7.75 (2H), 7.78 (1H), 7.93 (1H), 8.22 (1H) ppm.

›Example 89

N-cyclopropyl-4-{6-[(3-fluorophenyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

300 mg (725 μmol) 4-{6-Chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 3-fluorobenzenethiol to give after working up and purification 27.9 mg (7%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 1.12 (6H), 2.20 (3H), 2.79 (1H), 3.23 (2H), 4.71 (1H), 6.29 (1H), 7.04 (1H), 7.12 (1H), 7.33 (1H), 7.43 (1H), 7.46-7.53 (2H), 7.66 (1H), 7.71 (1H), 7.94 (1H), 8.23 (1H) ppm.

›Example 90

4-{6-(4-Chlorophenoxy)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

50 mg (121 μmol) 4-{6-Chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 4-chlorophenol to give after working up and purification 14.5 mg (23%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.47 (2H), 0.64 (2H), 1.16 (6H), 2.13 (3H), 2.77 (1H), 3.28 (2H), 4.74 (1H), 6.18 (1H), 7.00 (1H), 7.17 (1H), 7.30 (2H), 7.50 (2H), 7.64 (1H), 7.73 (1H), 7.92 (1H), 8.22 (1H) ppm.

›Example 91

4-{6-(3-Chloro-4-fluorophenoxy)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

50 mg (121 μmol) 4-{6-Chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 3-chloro-4-fluorophenol to give after working up and purification 16.2 mg (24%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.47 (2H), 0.64 (2H), 1.16 (6H), 2.13 (3H), 2.77 (1H), 3.28 (2H), 4.74 (1H), 6.18 (1H), 7.02 (1H), 7.18 (1H), 7.32 (1H), 7.51 (1H), 7.66 (2H), 7.72 (1H), 7.93 (1H), 8.22 (1H) ppm.

›Example 92

N-cyclopropyl-4-{6-(2,3-difluorophenoxy)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (121 μmol) 4-{6-Chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 2,3-difluorophenol to give after working up and purification 5.8 mg (9%) of the title compound.

1 H-NMR (CDCl 3 +CD 3 OD): δ=0.59 (2H), 0.85 (2H), 1.38 (6H), 2.24 (3H), 2.86 (1H), 3.31 (2H), 5.98 (1H), 6.16 (1H), 6.53 (1H), 7.02-7.14 (3H), 7.17 (1H), 7.47 (1H), 7.61 (2H), ppm.

›Example 93

N-cyclopropyl-4-{6-(2-fluorophenoxy)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (121 μmol) 4-{6-Chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 2-fluorophenol to give after working up and purification 4.2 mg (7%) of the title compound.

1 H-NMR (DMSO-d6): 0.3=0.46 (2H), 0.63 (2H), 1.17 (6H), 2.08 (3H), 2.46 (2H), 2.76 (1H), 4.75 (1H), 6.25 (1H), 7.03 (1H), 7.11 (1H), 7.24-7.45 (4H), 7.59 (1H), 7.67 (1H), 7.92 (1H), 8.21 (1H) ppm.

›Example 94

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(3-isopropylphenoxy) imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (121 μmol) 4-{6-Chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 3-isopropylphenol to give after working up and purification 9.0 mg (14%) of the title compound.

1 H-NMR (CDCl 3 +CD 3 OD): δ=0.58 (2H), 0.84 (2H), 1.22 (6H), 1.36 (6H), 2.24 (3H), 2.33 (1H), 2.85 (1H), 2.89 (1H), 3.27 (2H), 5.88 (1H), 6.15 (1H), 6.44 (1H), 7.02 (1H), 7.03 (1H), 7.10 (1H), 7.17 (1H), 7.31 (1H), 7.59 (1H), 7.64 (1H), 7.68 (1H) ppm.

›Example 95

4-{6-(4-Chloro-3-fluorophenoxy)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

50 mg (121 μmol) 4-{6-Chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 4-chloro-3-fluorophenol to give after working up and purification 4.0 mg (6%) of the title compound.

1 H-NMR (CDCl 3 +CD 3 OD): δ=0.60 (2H), 086 (2H), 1.37 (6H), 2.31 (3H), 2.34 (1H), 2.87 (1H), 3.29 (2H), 5.89 (1H), 6.09 (1H), 6.57 (1H), 6.98 (1H), 7.09 (1H), 7.15 (1H), 7.42 (1H), 7.55 (1H), 7.67 (2H) ppm.

›Example 96

N-cyclopropyl-4-{6-(3,5-dimethylphenoxy)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (109 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 3,5-dimethylphenol to give after working up and purification 14.6 mg (27%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.61 (2H), 0.87 (2H), 1.45 (6H), 2.28 (3H), 2.33 (6H), 2.89 (1H), 3.31 (2H), 3.83 (1H), 5.86 (1H), 5.92 (1H), 6.59 (1H), 6.83 (2H), 6.87 (1H), 7.21 (1H), 7.63 (1H), 7.65 (1H), 7.73 (1H) ppm.

Intermediate Example 96a

4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

809 mg (1.97 mmol) 1-[(6-bromo-3-iodoimidazo[1,2-b]pyridazin-8-yl)amino]-2-methylpropan-2-ol which was prepared according to intermediate example 96b were transformed in analogy to intermediate example 1a using N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give after working up and purification 659 mg (73%) of the title compound.

Intermediate Example 96b

1-[(6-bromo-3-iodoimidazo[1,2-b]pyridazin-8-yl)amino]-2-methylpropan-2-ol

1.0 g (2.48 mmol) 6,8-dibromo-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 96c were transformed in analogy to intermediate example 1b using 1-amino-2-methylpropan-2-ol to give after working up and purification 915 mg (90%) of the title compound.

Intermediate Example 96c

6,8-dibromo-3-iodoimidazo[1,2-b]pyridazine

A mixture comprising 3.64 g (10.5 mmol) 6,8-dibromoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 96d, 2.8 g N-iodosuccinimide, 72.6 mL N,N-dimethylformamide was heated at 60° C. for 3 hours. 1.4 g N-iodosuccinimide were added and heating was continued for additional 4 hours. Most of the solvent was removed, water was added and the mixture was extracted with dichloromethane. The organic phase was washed with water, sodium thiosulfate solution and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 3.64 g (86%) of the title compound.

Intermediate Example 96d

6,8-dibromoimidazo[1,2-b]pyridazine

A mixture of 5.0 (14.0 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c, 30 mL of hydrogen bromide solution in acetic acid (33%) was stirred at 120° C. for 1 hour under microwave irradiation. The mixture was poured into water and extracted with dichloromethane. The organic phase was washed with sodium thiosulfate and sodium hydrogencarbonate solution and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 3.0 g (78%) of the title compound.

›Example 97

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(3-methylphenoxy) imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (109 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 3-methylphenol to give after working up and purification 17.1 mg (32%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.61 (2H), 0.87 (2H), 1.46 (6H), 2.26 (3H), 2.37 (3H), 2.89 (1H), 3.31 (2H), 5.87 (1H), 5.94 (1H), 6.61 (1H), 6.98-7.09 (3H), 7.19 (1H), 7.29 (1H), 7.59 (1H), 7.63 (1H), 7.70 (1H) ppm.

›Example 98

4-{6-Chloro-8-[(2-sulfamoylethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropylbenzamide

8-Bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine (0.3 mmol) which was prepared according to intermediate example 1c, 2-aminoethanesulfonamide hydrochloride (1:1) (0.3 mmol, 1.0 eq)) and DIPEA (3 eq, 157 μL) were combined with 3 mL NMP in a sealed vial and heated at 160° C. under microwave irradiation for 30 min. After cooling, [4-(cyclopropylcarbamoyl)phenyl]boronic acid (1.2 eq, 74 mg), Pd(dppf)Cl 2 (0.2 eq, 49 mg) and potassium carbonate (3 eq, 900 μL, 1M in water) were added and the mixture was heated at 80° C. overnight. After cooling, the solution was filtered and subjected to preparative HPLC to give 4-{6-chloro-8-[(2-sulfamoylethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl benzamide (45 mg, 35%): UPLC-MS: RT=−0.92 min; m/z (ES+) 435.9 [MH+]; required MW=434.9.

Intermediate Example 99

4-{6-Chloro-8-[(2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

6 g (16.7 mmol) 8-Bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c were transformed in analogy to example 98 using 2-methylpropan-1-amine and N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give after working up and purification 1.27 g (19%) of the title compound.

UPLC-MS: RT=1.32 min; m/z (ES+) 398.9 [MH+]; required MW=397.9.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.65 (2H), 0.90 (6H), 1.96 (1H), 2.35 (3H), 2.80 (1H), 3.12 (2H), 6.29 (1H), 7.36 (1H), 7.84 (1H), 7.91 (1H), 7.96 (1H), 7.99 (1H), 8.29 (1H) ppm.

›Example 100

N-cyclopropyl-4-{8-[(2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

100 mg (260 μmol) 4-{6-chloro-8-[(2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropylbenzamide which was prepared according to intermediate example 100a were dissolved in 50 mL ethanol and subjected to flow hydrogenation using an H-Cube with cartridge Pd/C 10% CATCART 30 at 30° C., 10 bar and 0.8 mL/min flow. Purification by RP-HPLC yielded 21.1 mg (23%) of the title compound.

UPLC-MS: RT=1.13 min; m/z (ES+) 350.4 [MH+]; required MW=349.4.

1 H-NMR (DMSO-d6): δ=0.56 (2H), 0.67 (2H), 0.90 (6H), 1.96 (1H), 2.82 (1H), 3.11 (2H), 6.15 (1H), 7.54 (1H), 7.87 (2H), 8.04 (1H), 8.12 (1H), −8.21 (2H), 8.43 (1H) ppm.

Intermediate Example 100a

4-{6-chloro-8-[(2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropylbenzamide

1 mmol 6-chloro-3-iodo-N-(2-methylpropyl)imidazo[1,2-b]pyridazin-8-amine (10 mL, 0.1 M in NMP), which was prepared according to intermediate example 100b, 1.5 mmol [4-(cyclopropylcarbamoyl)phenyl]boronic acid, 0.2 mmol Pd(dppf)Cl 2 and 3 mmol potassium carbonate (3 mL, 1M in water, 3 eq) were combined in a sealed vial and heated at 150° C. for 180 min. After cooling, the mixture was treated with water and extracted with ethyl acetate, the combined organic layers were dried and concentrated, purified by flash silica gel column chromatography (Ethyl acetate:Petroleum ether 1:5) give 115 mg (30%) of the title compound.

UPLC-MS: RT=1.29 min; m/z (ES+) 384.9 [MH+]; required MW 383.9.

1 H-NMR (DMSO-d6): δ=0.60 (2H), 0.72 (2H), 0.93 (6H), 2.0 (1H), 2.87 (1H), 3.34 (2H), 6.33 (1H), 7.92 (1H), 8.07 (2H), 8.16 (2H), 8.48 (1H) ppm.

Intermediate Example 100b

6-chloro-3-iodo-N-(2-methylpropyl)imidazo[1,2-b]pyridazin-8-amine

To a solution of 200 mg (0.558 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c in 4 mL N,N-dimethylformamide were added 122 mg 2-methylpropan-1-amine and the mixture was stirred at rt overnight. Water was added and the mixture was extracted with dichloromethane and methanol. The organic phase was washed with water and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 188 mg (96%) of the title compound.

UPLC-MS: RT=1.36 min; m/z (ES+) 351.6 [MH+]; required MW 350.6.

1 H-NMR (DMSO-d6): δ=1.04 (6H), 2.00 (1H), 3.13 (2H), 6.00 (1H), 7.27 (1H), 7.53 (1H) ppm.

›Example 101

3-[4-(2-Cyclopropyl-1H-imidazol-5-yl)phenyl]-6-ethenyl-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine

0.1 mmol 4-{6-chloro-8-[(2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropylbenzamide (1 mL, 0.1 M in NMP), which was prepared according to intermediate example 100a, 0.4 mmol 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (0.8 mL, 0.5 M in NMP, 4 eq), 0.02 mmol Pd(dppf)Cl 2 (0.3 eq, 800 μL, 0.0375 M in NMP) and 0.3 mmol potassium carbonate (0.3 mL, 1M in water, 3 eq) were combined in a sealed vial and heated at 150° C. under microwave irradiation for 90 min. After cooling, the solution was filtered and subjected to preparative HPLC to give 4.2 mg (8%) of the title compound.

UPLC-MS: RT=1.34 min; m/z (ES+) 484.6 [MH+]; required MW=483.6.

The following compound examples were prepared analogously to the procedure described above using the appropriate intermediate and the appropriate boronic acid building block [LC-MS data such as retention time (RT in min) or observed mass peak were collected using LC-MS Method A unless explicitly stated]:

The following compound examples were prepared analogously to the procedure described for example 51 using the appropriate alcohol or thiol building block [LC-MS data such as retention time (RT in min) or observed mass peak were collected using LC-MS Method A unless explicitly stated]:

›Example 175

3-[4-(2-Cyclopropyl-1H-imidazol-5-yl)phenyl]-6-ethenyl-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine

52 mg (150 μmol) 6-chloro-3-iodo-N-(2-methylpropyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 100b were transformed in analogy to intermediate example 1a using phenylboronic acid to give after working up and purification 7.4 mg (17%) of the title compound.

UPLC-MS: RT=1.50 min; m/z (ES+) 301.8 [MH+]; required

MW=300.8.

The following compound examples were prepared analogously to the procedure described above using the appropriate boronic acid building block [LC-MS data such as retention time (RT in min) or observed mass peak were collected using LC-MS Method A unless explicitly stated]:

›Example 185

4-{6-Chloro-8-[(thiophen-2-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N,N-dimethylbenzamide

117 mg (300 μmol) 6-chloro-3-iodo-N-(thiophen-2-ylmethyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 185a were transformed in analogy to intermediate example 100a using [4-(dimethylcarbamoyl)phenyl]boronic acid to give after working up and purification 15 mg (12%) of the title compound.

UPLC-MS: RT=1.25 min; m/z (ES + ) 412.9 [MH+]; required MW 411.9.

Intermediate Example 185a

6-chloro-3-iodo-N-(thiophen-2-ylmethyl)imidazo[1,2-b]pyridazin-8-amine

6-chloro-3-iodo-N-(thiophen-2-ylmethyl)imidazo[1,2-b]pyridazin-8-amine was prepared in analogy to example 100b using 1-(thiophen-2-yl)methanamine which was prepared according to intermediate example 1c to give after working up and purification 80% of the title compound.

The following compound examples were prepared analogously to the procedure described for example 185 using the appropriate boronic acid building block [LC-MS data such as retention time (RT in min) or observed mass peak were collected using LC-MS Method A unless explicitly stated]:

›Example 192

N-cyclopropyl-4-[8-({(2S)-2-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethyl}amino)-6-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-3-yl]benzamide

To a mixture of 52 mg (94 mot) 4-[6-chloro-8-({(2S)-2-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethyl}amino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropylbenzamide which was prepared according to intermediate example 192a, 33 mg 1-methyl-1H-pyrazol-5-yl) boronic acid, 6.5 mg tetrakis(triphenylphosphin)palladium in 1 mL of ethanol and 1 mL of toluene was added 0.26 mL of an aqueous 10% sodiumbicarbonate solution and the mixture was stirred at 120° C. for 2 hours under microwave irradiation. Then the mixture was filtered, the solvent was removed and the residue was purified by chromatography to give 36 mg of the title compounds.

1H-NMR (DMSO-d6): δ=0.49-0.68 (4H), 1.24 (3H), 1.32 (3H), 2.62 (1H), 3.31-3.95 (3H), 3.60-4.05 (3H), 4.12 (3H), 6.54 (1H), 6.85 (1H), 7.31 (1H) 7.90 (2H), 8.07 (1H), 8.18 (2H), 8.45 (1H), ppm.

Intermediate Example 192a

4-[6-chloro-8-({(2S)-2-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethyl}amino) imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropylbenzamide

300 mg (684 μmol) (1S)-2-[(6-chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)amino]-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol which was prepared according to intermediate example 192b were transformed in analogy to intermediate example 1a using [4-(cyclopropylcarbamoyl)phenyl]boronic acid to give after working up and purification 17 mg (5%) of the title compound.

Intermediate Example 192b

(1S)-2-[(6-chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)amino]-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol

700 mg (1.95 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c were transformed in analogy to intermediate example 1b using (1S)-2-amino-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol to give after working up and purification 512 mg (60%) of the title compound.

›Example 193

N-cyclopropyl-4-{8-[(2-methylpropyl)amino]-6-(methylsulfanyl)imidazo[1,2-b]pyridazin-3-yl}benzamide

A solution of 450 mg (1172 μmol) of 4-[6-chloro-8-(isobutylamino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropylbenzamide, which was prepared according to intermediate example 100a, and 330 mg (4690 μmol) sodiummethylsulfide in 8 mL of dimethylsulfoxide was heated for 60 min at 70° C. in the microwave. Then the mixture was poured onto water and the precipitate was collected and dried under vacuum to yield 460 mg of the title compound as a white solid.

1 H-NMR (DMSO-d6): δ=0.52-0.71 (4H), 0.88 (6H), 1.94 (1H), 2.56 (3H), 2.84 (1H), 3.08 (2H), 6.08 (1H), 7.49 (1H), 7.88 (2H), 7.97 (1H), 8.22 (2H), 8.43 (1H) ppm.

›Example 194

(RS)—N-cyclopropyl-2-methyl-4-{8-[(2-methylpropyl)amino]-6-[(tetrahydrofuran-2-ylmethyl)sulfanyl]imidazo[1,2-b]pyridazin-3-yl}benzamide

A solution of 45 mg (377 μmol) of (RS)-tetrahydrofuran-2-ylmethanethiol in 1 mL of dimethylsulfoxide was treated with 14 mg (350 μmol) of sodium hydride and stirred at room temperature for 2 hours. Then 100 mg (251 μmol) of 4-[6-chloro-8-(isobutylamino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methylbenzamide, which was prepared according to intermediate example 194a, was added and the mixture was heated for 2 hours at 70° C. Then the mixture was purified by reversed phase chromatography to yield 12 mg of the title compound.

1 H-NMR (DMSO-d6): δ=0.48-0.68 (4H), 0.88 (6H), 1.63-1.99 (4H), 2.36 (3H), 2.81 (1H), 3.08 (2H), 3.22-3.36 (2H), 3.62 (1H), 3.76 (1H), 4.12 (1H), 6.04 (1H), 7.32 (1H), 7.50 (1H), 7.90 (1H), 7.93 (1H), 8.04 (1H), 8.29 (1H) ppm.

Intermediate Example 194a

4-[6-chloro-8-(isobutylamino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methylbenzamide

3.54 g (10.1 mmol) 6-Chloro-3-iodo-N-isobutylimidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 3b were transformed in analogy to intermediate example 1a using [4-(cyclopropylcarbamoyl)-3-methylphenyl]boronic acid to give after working up and purification 1.79 g (45%) of the title compound.

›Example 195

N-cyclopropyl-2-methyl-4-{8-[(2-methylpropyl)amino]-6-(1H-pyrazol-5-yl) imidazo[1,2-b]pyridazin-3-yl}benzamide

To a mixture of 125 mg (314 μmol) 4-[6-chloro-8-(isobutylamino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methylbenzamide, which was prepared according to example 194a, 111 mg (942 μmol) 1H-pyrazol-5-yl boronic acid, 44 mg Tetrakis(triphenylphosphin)palladium in 2 mL of ethanol and 2 mL of toluene was added 0.63 mL of an aqueous 10% sodiumbicarbonate solution and the mixture was stirred at 120° C. for 2 hours under microwave irradiation. Then the mixture was filtered and concentrated and purified by chromatography to give 41 mg of the title compound.

1 H-NMR (DMSO-d6): δ=0.48-0.69 (4H), 0.91 (6H), 2.02 (1H), 2.39 (3H), 2.82 (1H), 3.17 (2H), 6.72 (1H), 6.78 (1H), 7.39 (1H), 7.85 (1H), 8.00 (1H), 8.10-8.17 (2H), 8.29 (1H), ppm.

›Example 196

N-cyclopropyl-2-methyl-4-{8-[(2-methylpropyl)amino]-6-(methylsulfanyl) imidazo[1,2-b]pyridazin-3-yl}benzamide

A solution of 50 mg (126 μmol) of 4-[6-chloro-8-(isobutylamino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methylbenzamide, which was prepared according to example 194a, and 35 mg (503 μmol) sodiummethylsulfide in 1 mL of dimethylsulfoxide was heated for 30 min at 70° C. in the microwave. Then the mixture was poured onto water and the precipitate was collected and dried under vacuum to yield 26 mg of the title compound as a yellow solid.

1 H-NMR (DMSO-d6): δ=0.47-0.68 (4H), 0.88 (6H), 1.94 (1H), 2.35 (3H), 2.55 (3H) 2.80 (1H), 3.08 (2H), 6.06 (1H), 7.32 (1H), 7.47 (1H), 7.90 (1H), 7.98 (1H), 8.05 (1H), 8.29 (1H), ppm.

›Example 197

N-cyclopropyl-2-methyl-4-{8-[(2-methylpropyl)amino]-6-(phenylsulfanyl) imidazo[1,2-b]pyridazin-3-yl}benzamide

A solution of 180 mg (1634 μmol) of thiophenol in 10 mL of dimethylsulfoxide was treated with 64 mg (1608 μmol) of sodium hydride and stirred at room temperature for 2 hours. Then 100 mg (251 μmol) of 4-[6-chloro-8-(isobutylamino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methylbenzamide, which was prepared according to intermediate example 194a, was added and the mixture was heated for 1.5 hours at 140° C. Then the mixture poured onto ice water and the precipitate was collected and subsequently purified by normal phase chromatography to yield 112 mg of the title compound.

1 H-NMR (DMSO-d6): δ=0.48-0.69 (4H), 0.84 (6H), 1.87 (1H), 2.21 (3H), 2.79 (1H), 3.03 (2H), 5.99 (1H), 7.10 (1H), 7.49 (3H), 7.61-7.71 (5H), 7.92 (1H), 8.24 (1H), ppm.

›Example 198

N-cyclopropyl-2-methyl-4-{8-[(2-methylpropyl)amino]-6-(phenylsulfonyl) imidazo[1,2-b]pyridazin-3-yl}benzamide

To a solution of 105 mg (223 μmol) of N-cyclopropyl-2-methyl-4-{8-[(2-methylpropyl)amino]-6-(phenylsulfanyl)imidazo[1,2-b]pyridazin-3-yl}benzamide, which was prepared according to example 197, in 15 mL of DMF was added and 684 mg (1113 μmol) OXONE (potassium peroxymonosulfate) in small portions. The mixture was stirred over night, then cooled to 0° C. and poured onto 200 mL of cold water. The precipitate was collected and purified with normal phase chromatography to yield 97 mg of the title compound as a yellow solid.

1 H-NMR (DMSO-d6): δ=0.50-0.69 (4H), 0.91 (6H), 1.99 (1H), 2.30 (3H), 2.56 (1H), 3.41 (2H), 4.31 (1H), 6.71 (1H), 7.28 (1H), 7.66-7.81 (5H), 8.03 (2H), 8.12 (1H), 8.31 (1H), 8.43 (1H) ppm.

›Example 199

3-[4-(Cyclopropylcarbamoyl)-3-methylphenyl]-N-(2-hydroxyethyl)-8-[(2-methylpropyl)amino]imidazo[1,2-b]pyridazine-6-carboxamide

A solution of 100 mg (251 μmol) of 4-[6-chloro-8-(isobutylamino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methylbenzamide, which was prepared according to example 194a, 46 mg (754 μmol) aminoethanol, 66 mg (251 μmol) molybdonhexacarbonyl, 80 mg (754 μmol) sodiumbicarbonate, 5.6 mg (25 μmol) palladium(II) acetate and 7.3 mg (25 μmol) tri-tert-butylphosphine tetrafluorborate in 3 mL of dioxane was heated in the microwave for 2 hours at 140° C. Then the mixture was directly submitted to reversed phase chromatography to yield 13 mg of the title compound.

1 H-NMR (DMSO-d6): δ=0.48-0.69 (4H), 0.91 (6H), 1.99 (1H), 2.38 (3H), 2.81 (1H), 3.17 (2H), 3.38 (3H), 3.53 (2H), 5.99 (1H), 6.61 (1H), 7.36 (1H), 7.84 (1H), 8.00-8.09 (3H), 8.16 (1H), 8.29 (1H), ppm.

›Example 200

N-cyclopropyl-4-{8-[(2-methylpropyl)amino]-6-(methylsulfonyl)imidazo[1,2-b]pyridazin-3-yl}benzamide

To a solution of 410 mg (1037 μmol) of N-cyclopropyl-4-{8-[(2-methylpropyl)amino]-6-(methylsulfanyl)imidazo[1,2-b]pyridazin-3-yl}benzamide, which was prepared according to example 193, in 15 mL of DMF was added and 1912 mg (3110 μmol) OXONE (potassium peroxymonosulfate) in small portions. The mixture was stirred over night, then cooled to 0° C. and poured onto 200 mL of cold water. The precipitate was collected and dried under vacuum to yield 291 mg of the title compound as a yellow solid.

1 H-NMR (DMSO-d6): δ=0.53-0.71 (4H), 0.91 (6H), 2.00 (1H), 2.84 (1H), 3.20 (2H), 3.38 (3H), 6.58 (1H), 7.92 (2H), 8.19-8.23 (3H), 8.37 (1H), 8.46 (1H), ppm.

›Example 201

N-cyclopropyl-2-methyl-4-{8-[(2-methylpropyl)amino]-6-(propylsulfanyl) imidazo[1,2-b]pyridazin-3-yl}benzamide

A solution of 100 mg (251 μmol) of 4-[6-chloro-8-(isobutylamino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methylbenzamide, which was prepared according to example 194a, and 49 mg (503 μmol) sodium propane-1-thiolate in 1 mL of dimethylsulfoxide was heated for 60 min at 70° C. in the microwave. Then the mixture was purified by reversed phase chromatography to yield 18.5 mg of the title compound.

1 H-NMR (DMSO-d6): δ=0.49-0.66 (4H), 0.88 (6H), 1.00 (3H), 1.74 (2H), 1.94 (1H), 2.36 (3H), 2.79 (1H), 3.05-3.15 (4H), 6.02 (1H), 7.33 (1H), 7.47 (1H), 7.90 (1H), 7.96 (1H), 8.03 (1H), 8.29 (1H) ppm.

›Example 202

N-cyclopropyl-2-methyl-4-{8-[(2-methylpropyl)amino]-6-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-3-yl}benzamide

To a mixture of 100 mg (251 μmol) 4-[6-chloro-8-(isobutylamino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methylbenzamide, which was prepared according to example 194a, 95 mg (750 μmol) 1-methyl-1H-pyrazol-5-yl) boronic acid, 35 mg Tetrakis(triphenylphosphin)palladium in 2 mL of ethanol and 2 mL of toluene was added 0.5 mL of an aqueous 10% sodiumbicarbonate solution and the mixture was stirred at 120° C. for 2 hours under microwave irradiation. Then water and was added and the organic layer was washed with water and brine, concentrated and purified by chromatography to give 99 mg of the title compound.

1 H-NMR (DMSO-d6): δ=0.49-0.67 (4H), 0.93 (6H), 2.00 (1H), 2.36 (3H), 2.80 (1H), 3.21 (3H), 4.13 (3H), 6.46 (1H), 6.90 (1H), 7.37 (1H), 7.50 (1H), 7.65 (1H), 7.92-7.97 (3H), 8.29 (1H) ppm.

›Example 203

N-cyclopropyl-2-methyl-4-{6-(methylsulfanyl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

The title compound was prepared according to the procedure described for example 193 employing 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide, which was prepared according to intermediate example 10a.

1 H-NMR (DMSO-d6): δ=0.48-0.70 (4H), 2.36 (3H), 2.54-2.70 (6H), 2.82 (1H), 3.54 (2H), 6.16 (1H), 7.35 (1H), 7.51 (1H), 7.92 (1H), 7.97 (1H), 8.05 (1H), 8.28 (1H), ppm.

›Example 204

N-cyclopropyl-4-{6-[(2-hydroxyethyl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

The title compound was prepared according to the procedure described for example 194 employing 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide, which was prepared according to intermediate example 10a.

1 H-NMR (DMSO-d6): δ=0.47-0.70 (4H), 2.36 (3H), 2.53-2.70 (4H), 2.81 (1H), 3.52 (2H), 3.71 (2H), 4.97 (1H), 6.13 (1H), 7.33 (1H), 7.53 (1H), 7.92 (1H), 8.02 (1H), 8.29 (1H), ppm.

Intermediate Example 205

(RS)-4-{6-Chloro-8-[(3,3,3-trifluoro-2-hydroxypropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

650 mg (1.60 mmol) (RS)-3-[(6-chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)amino]-1,1,1-trifluoropropan-2-ol which was prepared according to intermediate example 205a were transformed in analogy to intermediate example 1a using N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide which was prepared according to intermediate example 7b to give after working up and purification 430 mg (59%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48-0.68 (4H), 2.36 (3H), 2.81 (1H), 3.45-3.62 (2H), 4.31 (1H), 6.40 (2H), 6.58 (1H), 7.37 (1H), 7.81 (1H), 7.85 (1H), 7.90 (1H), 8.00 (1H), 8.29 (1H), ppm.

Intermediate Example 205a

(RS)-3-[(6-chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)amino]-1,1,1-trifluoropropan-2-ol

8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c was transformed in analogy to intermediate example 1b using (RS)-(3,3,3-trifluoro-2-hydroxypropyl)amine to provide the title compound.

›Example 206

(RS)N-cyclopropyl-2-methyl-4-{6-(methylsulfanyl)-8-[(3,3,3-trifluoro-2-hydroxypropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

The title compound was prepared according to the procedure described for example 193 employing (RS)-4-{6-chloro-8-[(3,3,3-trifluoro-2-hydroxypropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide, which was prepared according to example 205.

1 H-NMR (DMSO-d6): δ=0.48-0.70 (4H), 2.36 (3H), 2.56 (3H), 2.80 (1H), 3.47 (1H), 3.58 (1H), 4.30 (1H), 6.19 (1H), 6.56 (1H), 7.29 (1H), 7.35 (1H), 7.93 (1H), 7.97 (1H), 8.06 (1H), 8.28 (1H), ppm.

›Example 207

N-cyclopropyl-2-methyl-4-{6-(phenylsulfanyl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

The title compound was prepared according to the procedure described for example 197 employing 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide, which was prepared according to intermediate example 10a.

1 H-NMR (DMSO-d6): δ=0.48-0.70 (4H), 2.20 (3H), 2.54-2.70 (4H), 2.82 (1H), 3.50 (2H), 6.13 (1H), 7.09 (1H), 7.46-7.70 (8H), 7.94 (1H), 8.22 (1H), ppm.

›Example 208

(RS)—N-cyclopropyl-2-methyl-4-{6-(1-methyl-1H-pyrazol-5-yl)-8-[(3,3,3-trifluoro-2-hydroxypropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

The title compound was prepared according to the procedure described for example 211 employing

(RS)-4-{6-chloro-8-[(3,3,3-trifluoro-2-hydroxypropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide, which was prepared according to example 205.

1 H-NMR (DMSO-d6): δ=0.48-0.67 (4H), 2.36 (3H), 2.80 (1H), 3.47 (1H), 3.58 (1H), 4.32 (1H), 6.58 (2H), 6.90 (1H), 7.37 (1H), 7.48 (1H), 7.51 (1H), 7.91-8.00 (3H), 8.29 (1H), ppm.

›Example 209

N-cyclopropyl-4-{6-[(3-fluorophenyl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

1 H-NMR (DMSO-d6): δ=0.49-0.66 (4H), 2.20 (3H), 2.53-2.70 (4H), 2.78 (1H), 3.54 (2H), 6.20 (1H), 7.12 (1H), 7.34 (1H), 7.43-7.71 (6H), 7.95 (1H), 8.23 (1H), ppm.

›Example 210

N-cyclopropyl-4-(6-{[2-(diethylamino)ethyl]sulfanyl}-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl)-2-methylbenzamide

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.65 (2H), 0.86 (6H), 2.36 (3H), 2.59-2.71 (4H), 2.79 (1H), 3.23-3.33 (multiple H, overlaps with water peak), 3.54 (2H), 6.13 (1H), 7.32 (1H), 7.52 (1H), 7.91 (1H), 7.95 (1H), 8.02 (1H) 8.28 (1H), ppm.

›Example 211

N-cyclopropyl-4-{8-[(3-hydroxypropyl)amino]-6-(1-methyl-1H-pyrazol-5-yl) imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

To a mixture of 51 mg (128 mot) 4-{6-chloro-8-[(3-hydroxypropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide, which was prepared in analogy to example 205 employing 3-hydroxy-n-propylamine, 80 mg (380 μmol) 1-methyl-1H-pyrazol-5-yl) boronic acid pinacol ester, 18 mg Tetrakis(triphenylphosphin)palladium in 1 mL of ethanol and 1 mL of toluene was added 0.27 mL of an aqueous 10% sodiumbicarbonate solution and the mixture was stirred at 120° C. for 2 hours under microwave irradiation. Then water and ethyl acetate was added and the organic layer was washed with water and brine, concentrated and treated with dichloromethane. The remaining undisolved solid yielded 25 mg of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.66 (2H), 1.78 (2H), 2.35 (3H), 2.80 (1H), 3.41-3.51 (4H), 6.47 (1H), 6.88 (1H), 7.36 (1H), 7.51 (1H), 7.62 (1H), 7.91-7.97 (3H), (1H), 8.29 (1H), ppm.

›Example 212

N-cyclopropyl-2-methyl-4-{6-(phenylsulfonyl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

50 mg (98 μmol) N-cyclopropyl-2-methyl-4-{6-(phenylsulfanyl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide which was prepared according to example 207 were transformed in analogy to example 18 to give after working up and purification 30.2 mg (57%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.67 (2H), 2.31 (3H), 2.70 (2H), 2.81 (1H), 3.29 (2H), 6.81 (1H), 7.28 (1H), 7.65-7.82 (5H), 8.03 (1H), 8.06 (1H), 8.15 (1H), 8.30 (1H), 8.36 (1H) ppm.

›Example 213

4-{6-(5-Cyanopyridin-3-yl)-8-(isobutylamino)imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

200 mg (503 μmol) 4-[6-chloro-8-(isobutylamino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 194a were transformed in analogy to example 202 using 5-cyanopyridin-3-yl boronic acid to give after working up and purification 80.9 mg (33%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.62 (2H), 0.92 (6H), 2.04 (1H), 2.39 (3H), 2.81 (1H), 3.26 (2H), 6.83 (1H), 7.41 (1H), 7.76 (1H), 8.01-8.10 (3H), 8.30 (1H), 8.93 (1H), 9.10 (1H), 9.49 (1H), ppm.

›Example 214

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(phenylsulfanyl) imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

100 mg (242 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 55 using benzenethiol to give after working up and purification 113.5 mg (96%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 1.11 (6H), 2.19 (3H), 2.79 (1H), 3.21 (2H), 4.71 (1H), 6.23 (1H), 6.97 (1H), 7.08 (1H), 7.44-7.52 (3H), 7.58-7.65 (3H), 7.70 (1H), 7.93 (1H), 8.22 (1H) ppm.

›Example 215

N-cyclopropyl-2-methyl-4-(6-{[2-(morpholin-4-yl)ethyl]sulfanyl}-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl)benzamide

100 mg (228 μmol) 4-{6-Chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a were transformed in analogy to example 55 using 2-(morpholin-4-yl)ethanethiol to give after working up and purification 78.2 mg (59%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 2.30-2.39 (4H), 2.37 (3H), 2.57-2.71 (4H), 2.80 (1H), 3.28 (2H), 3.47-3.57 (6H), 6.13 (1H), 7.33 (1H), 7.53 (1H), 7.90 (1H), 7.96 (1H), 7.98 (1H), 8.29 (1H) ppm.

›Example 216

(RS)—N-cyclopropyl-4-{6-[(3-fluorophenyl)sulfanyl]-8-[(3,3,3-trifluoro-2-hydroxypropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

95 mg (191 μmol) (RS)-4-{6-chloro-8-[(3,3,3-trifluoro-2-hydroxypropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 205 were transformed in analogy to example 194 using 3-fluorobenzenethiol to give after working up and purification 54 mg (49%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 2.20 (3H), 2.79 (1H), 3.45-3.62 (2H), 4.26 (1H), 6.24 (1H), 6.56 (1H), 7.13 (1H), 7.35 (1H), 7.50 (1H), 7.51-7.56 (3H), 7.65 (1H), 7.71 (1H), 7.97 (1H), 8.25 (1H), ppm.

›Example 217

N-cyclopropyl-4-{6-[(3,3-dimethylbutyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (181 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 3,3-dimethylbutane-1-thiol to give after working up and purification 29.2 mg (31%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 0.89 (9H), 1.13 (6H), 1.54 (2H), 2.35 (3H), 2.79 (1H), 3.13 (2H), 3.21 (2H), 4.72 (1H), 6.17 (1H), 6.81 (1H), 7.29 (1H), 7.91 (1H), 7.98 (1H), 7.99 (1H), 8.28 (1H) ppm.

›Example 218

N-cyclopropyl-4-{6-[(2,6-difluorophenyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (181 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 2,6-difluorobenzenethiol to give after working up and purification 6.5 mg (6%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.89 (2H), 1.40 (6H), 2.33 (3H), 2.91 (1H), 3.29 (2H), 5.96 (1H), 6.05 (1H), 6.55 (1H), 7.00-7.11 (3H), 7.41-7.53 (3H), 7.57 (1H) ppm.

›Example 219

N-cyclopropyl-4-{6-[(3-fluorophenyl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-3-hydroxybenzamide

75 mg (165 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-3-methoxybenzamide which was prepared according to intermediate example 52a were transformed in analogy to intermediate example 51 using 3-fluorobenzenethiol to give after working up and purification 24.0 mg (27%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.54 (2H), 0.66 (2H), 2.60 (2H), 2.80 (1H), 3.52 (2H), 6.13 (1H), 7.07 (1H), 7.28 (1H), 7.34 (1H), 7.38-7.53 (3H), 7.71 (1H), 7.85 (1H), 7.94 (1H), 8.34 (1H), 10.12 (1H) ppm.

›Example 220

N-cyclopropyl-4-{6-[2-(hydroxymethyl)phenyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

5.25 g (12.7 mmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 1 using [2-(hydroxymethyl)phenyl]boronic acid to give after working up and purification 4.90 g (80%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 1.18 (6H), 2.36 (3H), 2.82 (1H), 3.32 (2H), 4.66 (2H), 4.75 (1H), 5.13 (1H), 6.45 (1H), 6.95 (1H), 7.35 (1H), 7.39 (1H), 7.45-7.52 (2H), 7.66 (1H), 7.95 (1H), 8.00 (1H), 8.01 (1H), 8.26 (1H) ppm.

›Example 221

4-{6-[(2E)-but-2-en-2-yl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

115 mg (262 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a were transformed in analogy to example 1 using (2Z)-but-2-en-2-ylboronic acid to give after working up and purification 7.2 mg (6%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.65 (2H), 1.84 (3H), 2.07 (3H), 2.36 (3H), 2.67 (2H), 2.80 (1H), 3.61 (2H), 6.43 (1H), 6.49 (1H), 7.32 (1H), 7.35 (1H), 7.97 (1H), 8.03 (1H), 8.07 (1H), 8.27 (1H) ppm.

›Example 222

N-cyclopropyl-4-{6-[2-(fluoromethyl)phenyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

To a solution of 329 mg (677 μmol) N-cyclopropyl-4-{6-[2-(hydroxymethyl)phenyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide which was prepared according to example 220 in 13 mL dichloromethane at 3° C. were added 98 μL N-ethyl-N-(trifluoro-lambda 4 -sulfanyl)ethanamine. After stirring for 10 minutes, the solution was poured into water and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with sodium hydrogencarbonate solution and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 28.6 mg (8%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.61 (2H), 0.87 (2H), 1.47 (6H), 2.48 (3H), 2.90 (1H), 3.36 (2H), 5.21 (1H), 5.58 (2H), 5.97 (1H), 6.26 (1H), 6.71 (1H), 7.37 (1H), 7.46 (1H), 7.51 (1H), 7.58 (1H), 7.64 (1H), 7.74 (1H), 7.81 (1H), 7.88 (1H) ppm.

›Example 223

N-cyclopropyl-4-{6-(2-methoxyphenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

150 mg (343 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a were transformed in analogy to example 51 using 2-methoxyphenol to give after working up and purification 8.1 mg (5%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.60 (2H), 0.88 (2H), 2.26 (3H), 2.57 (2H), 2.89 (1H), 3.68 (2H), 3.78 (3H), 5.82 (1H), 5.94 (1H), 5.98 (1H), 7.01 (1H), 7.05 (1H), 7.18 (1H), 7.22 (1H), 7.27 (1H), 7.55 (1H), 7.70 (1H), 7.72 (1H) ppm.

›Example 224

N-cyclopropyl-4-{6-[(2-hydroxyphenyl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

100 mg (228 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a were transformed in analogy to example 51 using 2-methoxybenzenethiol to give after working up and purification 5.1 mg (4%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 2.21 (3H), 2.59 (2H), 2.79 (1H), 3.49 (2H), 6.05 (1H), 6.87 (1H), 6.98 (1H), 7.07 (1H), 7.34 (1H), 7.46 (1H), 7.56 (1H), 7.67 (1H), 7.72 (1H), 7.93 (1H), 8.23 (1H), 9.96 (1H) ppm.

›Example 225

N-cyclopropyl-4-{6-(3-methoxyphenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

150 mg (343 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a were transformed in analogy to example 51 using 3-methoxyphenol to give after working up and purification 5.1 mg (3%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.60 (2H), 0.87 (2H), 2.31 (3H), 2.56 (2H), 2.89 (1H), 3.66 (2H), 3.80 (3H), 5.85 (1H), 5.88 (1H), 6.03 (1H), 6.79-6.88 (3H), 7.24 (1H), 7.33 (1H), 7.63 (1H), 7.73 (1H), 7.79 (1H) ppm.

›Example 226

N-cyclopropyl-4-{6-[(3,3-dimethylbutyl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

100 mg (228 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a were transformed in analogy to example 51 using 3,3-dimethylbutane-1-thiol to give after working up and purification 3.6 mg (3%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.90 (2H), 0.94 (9H), 1.62 (2H), 2.51 (3H), 2.52 (2H), 2.92 (1H), 3.19 (2H), 3.61 (2H), 5.84-5.93 (3H), 7.37 (1H), 7.69 (1H), 7.88 (1H), 7.91 (1H) ppm.

›Example 227

N-cyclopropyl-4-{6-[(4-methoxyphenyl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

100 mg (228 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a were transformed in analogy to example 51 using 4-methoxybenzenethiol to give after working up and purification 16.8 mg (13%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.90 (2H), 2.40 (3H), 2.47 (2H), 2.92 (1H), 3.57 (2H), 3.88 (3H), 5.82-5.93 (3H), 6.98 (2H), 7.17 (1H), 7.54-7.63 (4H), 7.69 (1H) ppm.

›Example 228

N-cyclopropyl-2-methyl-4-{6-(pyridin-4-yl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

250 mg (571 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a were transformed in analogy to example 1 using pyridin-4-ylboronic acid to give after working up and purification 6.7 mg (2%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.89 (2H), 2.53 (3H), 2.61 (2H), 2.91 (1H), 3.72 (2H), 6.20 (1H), 6.43 (1H), 6.67 (1H), 7.44 (1H), 7.80 (1H), 7.82 (2H), 7.89 (1H), 7.96 (1H), 8.72 (2H) ppm.

›Example 229

(RS)—N-cyclopropyl-4-[6-(4-fluorophenyl)-8-{[(4-methylmorpholin-2-yl)methyl]amino}imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide

50 mg (110 μmol) (RS)-4-[6-chloro-8-({[(2S)-4-methylmorpholin-2-yl]methyl}amino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 56a were transformed in analogy to example 1 using (4-fluorophenyl)boronic acid to give after working up and purification 12.2 mg (22%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 1.80 (1H), 1.96 (1H), 2.14 (3H), 2.39 (3H), 2.54 (1H), 2.74 (1H), 2.81 (1H), 3.45-3.55 (3H), 3.72-3.80 (2H), 6.72 (1H), 7.34 (2H), 7.39 (2H), 8.00 (1H), 8.03 (1H), 8.06-8.12 (3H), 8.30 (1H), ppm.

›Example 230

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(pyridin-4-yl)imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

200 mg (483 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 1 using pyridin-4-ylboronic acid to give after working up and purification 28.3 mg (12%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.69 (2H), 0.91 (2H), 1.49 (6H), 2.46 (3H), 2.96 (1H), 3.33 (2H), 4.99 (1H), 6.23 (1H), 6.53 (1H), 6.58 (1H), 7.29 (1H), 7.66 (2H), 7.70 (1H), 7.76 (1H), 7.82 (1H), 8.57 (2H) ppm.

›Example 231

N-cyclopropyl-2-methyl-4-[6-(methylsulfanyl)-8-{[2-(morpholin-4-ylsulfonyl)ethyl]amino}imidazo[1,2-b]pyridazin-3-yl]benzamide

46 mg (89 μmol) 4-(6-chloro-8-{[2-(morpholin-4-ylsulfonyl)ethyl]amino}imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 231a were transformed in analogy to example 51 using sodium methanethiolate to give after working up and purification 12 mg (25%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.65 (2H), 2.36 (3H), 2.57 (3H), 2.80 (1H), 3.14 (4H), 3.44 (2H), 3.60 (4H), 3.69 (2H), 6.15 (1H), 7.35 (1H), 7.43 (1H), 7.93 (1H), 7.98 (1H), 8.06 (1H), 8.28 (1H) ppm.

Intermediate Example 231a

4-(6-chloro-8-{[2-(morpholin-4-ylsulfonyl)ethyl]amino}imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide

650 mg (1.38 mmol) 6-chloro-3-iodo-N-[2-(morpholin-4-ylsulfonyl)ethyl]imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 231b were transformed in analogy to intermediate example 1a using N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give after working up and purification 102 mg (14%) of the title compound.

Intermediate Example 231b

6-chloro-3-iodo-N-[2-(morpholin-4-ylsulfonyl)ethyl]imidazo[1,2-b]pyridazin-8-amine

1.00 g (2.79 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c were transformed in analogy to intermediate example 1b using 2-(morpholin-4-ylsulfonyl)ethanamine to give after working up and purification 650 mg (49%) of the title compound.

›Example 232

N-cyclopropyl-4-{6-(4-fluoro-2-methylphenyl)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

100 mg (242 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 1 using (4-fluoro-2-methylphenyl)boronic acid to give after working up and purification 19.0 mg (15%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.47 (2H), 0.64 (2H), 1.15 (6H), 2.33 (3H), 2.38 (3H), 2.78 (1H), 3.31 (2H), 4.71 (1H), 6.36 (1H), 6.95 (1H), 7.12 (1H), 7.19 (1H), 7.32 (1H), 7.47 (1H), 7.92 (1H), 7.98 (1H), 7.99 (1H), 8.24 (1H) ppm.

›Example 233

N-cyclopropyl-4-{6-(2-fluorophenyl)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

100 mg (242 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 1 using (2-fluorophenyl)boronic acid to give after working up and purification 10.0 mg (8%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.64 (2H), 1.16 (6H), 2.36 (3H), 2.79 (1H), 3.31 (2H), 4.74 (1H), 6.57 (1H), 7.00 (1H), 7.31-7.40 (3H), 7.52 (1H), 7.78 (1H), 8.01 (1H), 8.03 (1H), 8.06 (1H), 8.26 (1H) ppm.

›Example 234

4-{6-(5-cyanopyridin-3-yl)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

200 mg (483 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 1 using (5-cyanopyridin-3-yl)boronic acid to give after working up and purification 19.0 mg (8%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 1.19 (6H), 2.39 (3H), 2.81 (1H), 3.42 (2H), 4.79 (1H), 6.96 (1H), 7.08 (1H), 7.41 (1H), 8.01 (1H), 8.04 (1H), 8.10 (1H), 8.31 (1H), 8.91 (1H), 9.11 (1H), 9.50 (1H) ppm.

›Example 235

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

100 mg (242 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 1 using [1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]boronic acid to give after working up and purification 25 mg (19%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.65 (2H), 1.17 (6H), 2.36 (3H), 2.80 (1H), 3.37 (2H), 4.22 (3H), 4.77 (1H), 6.73 (1H), 7.07 (1H), 7.37 (1H), 7.46 (1H), 7.91 (1H), 7.94 (1H), 8.00 (1H), 8.30 (1H) ppm.

›Example 236

(RS)-4-{6-(cyclohex-1-en-1-yl)-8-[(3,3,3-trifluoro-2-hydroxypropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

85 mg (187 μmol) (RS)-4-{6-chloro-8-[(3,3,3-trifluoro-2-hydroxypropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to example 205 were transformed in analogy to intermediate example 1 using cyclohex-1-en-1-ylboronic acid to give after working up and purification 4.0 mg (4%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.62 (2H), 1.58 (2H), 1.68 (2H), 2.20 (2H), 2.34 (3H), 2.49 (2H), 2.77 (1H), 3.48 (1H), 3.64 (1H), 4.28 (1H), 6.46 (1H), 6.54 (1H), 6.65 (1H), 7.05 (1H), 7.33 (1H), 7.94 (1H), 8.01 (1H), 8.02 (1H), 8.23 (1H) ppm.

›Example 237

N-cyclopropyl-2-methyl-4-[8-{[(1-methyl-1H-pyrazol-5-yl)methyl]amino}-6-(methylsulfanyl)imidazo[1,2-b]pyridazin-3-yl]benzamide

100 mg (229 μmol) 4-(6-chloro-8-{[(1-methyl-1H-pyrazol-5-yl)methyl]amino}imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 237a were transformed in analogy to example 51 using sodium methanethiolate to give after working up and purification 75 mg (72%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 2.35 (3H), 2.53 (3H), 2.80 (1H), 3.79 (3H), 4.58 (2H), 6.14 (2H), 7.25 (1H), 7.34 (1H), 7.92-8.02 (3H), 8.05 (1H), 8.28 (1H) ppm.

Intermediate Example 237a

4-(6-chloro-8-{[(1-methyl-1H-pyrazol-5-yl)methyl]amino}imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide

500 mg (1.29 mmol) 6-chloro-3-iodo-N-[(1-methyl-1H-pyrazol-5-yl)methyl]imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 237b were transformed in analogy to intermediate example 1a using N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give after working up and purification 277 mg (47%) of the title compound.

Intermediate Example 237b

6-chloro-3-iodo-N-[(1-methyl-1H-pyrazol-5-yl)methyl]imidazo[1,2-b]pyridazin-8-amine

1.00 g (2.79 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c were transformed in analogy to intermediate example 1b using 1-(1-methyl-1H-pyrazol-5-yl)methanamine to give after working up and purification 1.00 g (92%) of the title compound.

›Example 238

N-cyclopropyl-4-{6-[(3-hydroxyphenyl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

100 mg (228 μmol) 4-{6-chloro-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 10a were transformed in analogy to example 51 using 3-methoxybenzenethiol to give after working up and purification 68 mg (65%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 2.23 (3H), 2.60 (2H), 2.79 (1H), 3.52 (2H), 6.11 (1H), 6.86 (1H), 6.98 (1H), 7.01 (1H), 7.15 (1H), 7.26 (1H), 7.63 (1H), 7.73 (1H), 7.74 (1H), 7.94 (1H), 8.21 (1H), 9.69 (1H) ppm.

›Example 239

N-cyclopropyl-4-(8-[(2-hydroxy-2-methylpropyl)amino]-6-{[2-(morpholin-4-yl)ethyl]sulfanyl}imidazo[1,2-b]pyridazin-3-yl)-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 2-(morpholin-4-yl)ethanethiol to give after working up and purification 45.4 mg (50%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 1.13 (6H), 2.30-2.40 (4H), 2.37 (3H), 2.61 (2H), 2.80 (1H), 3.22 (2H), 3.27 (2H), 3.51 (4H), 4.71 (1H), 6.18 (1H), 6.81 (1H), 7.33 (1H), 7.89 (1H), 7.96 (1H), 7.98 (1H), 8.28 (1H) ppm.

›Example 240

(RS)—N-cyclopropyl-4-{6-[(2,2-difluorocyclopropyl)methoxy]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

325 mg (785 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using [(1RS)-2,2-difluorocyclopropyl]methanol to give after working up and purification 12.3 mg (3%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.64 (2H), 0.89 (2H), 1.29 (1H), 1.43 (6H), 1.56 (1H), 2.15 (1H), 2.49 (3H), 2.92 (1H), 3.27 (2H), 4.34 (2H), 4.78 (1H), 5.70 (1H), 6.01 (1H), 6.42 (1H), 7.38 (1H), 7.60 (1H), 7.80 (1H), 7.83 (1H) ppm.

›Example 241

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(2,2,3,3-tetrafluoro-4-hydroxybutoxy)imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide (A) and

N-cyclopropyl-4-(8-[(2-hydroxy-2-methylpropyl)amino]-6-{[(1E)-2,3,3-trifluoro-4-hydroxybut-1-en-1-yl]oxy}imidazo[1,2-b]pyridazin-3-yl)-2-methylbenzamide

250 mg (604 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a were transformed in analogy to example 51 using 2,2,3,3-tetrafluorobutane-1,4-diol to give after working up and purification 38.3 mg (12%) of the title compound A and 88.7 mg (28%) of the title compound B.

1 H-NMR (DMSO-d6) of A: δ=0.50 (2H), 0.65 (2H), 1.14 (6H), 2.35 (3H), 2.80 (1H), 3.26 (2H), 3.90 (2H), 4.71 (1H), 4.89 (2H), 6.01 (2H), 6.89 (1H), 7.33 (1H), 7.90 (1H), 7.93 (1H), 7.97 (1H), 7.28 (1H) ppm.

1 H-NMR (DMSO-d6) of B: δ=0.50 (2H), 0.65 (2H), 1.14 (6H), 2.35 (3H), 2.80 (1H), 3.26 (2H), 3.85 (2H), 4.70 (1H), 5.93 (1H), 6.18 (1H), 7.17 (1H), 7.33 (1H), 7.70 (1H), 7.89 (1H), 7.96 (1H), 8.02 (1H), 8.29 (1H) ppm.

›Example 242

N-cyclopropyl-4-(8-[(2-hydroxy-2-methylpropyl)amino]-6-{[4-(trifluoromethyl)phenyl]sulfanyl}imidazo[1,2-b]pyridazin-3-yl)-2-methylbenzamide

50 mg (109 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 4-(trifluoromethyl)benzenethiol to give after working up and purification 23 mg (36%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.47 (2H), 0.65 (2H), 1.13 (6H), 2.17 (3H), 2.78 (1H), 3.25 (2H), 4.70 (1H), 6.37 (1H), 7.04-7.10 (2H), 7.59 (1H), 7.69 (1H), 7.79 (4H), 7.95 (1H), 8.18 (1H) ppm.

›Example 243

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-phenoxyimidazo[1,2-b]pyridazin-3-yl}benzenecarbothioamide

127 mg (316 μmol) 4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-phenoxyimidazo[1,2-b]pyridazin-3-yl}benzaldehyde which was prepared according to intermediate example 243a were transformed in analogy to example 13 to give after working up and purification 47 mg (30%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.71-0.87 (4H), 1.16 (6H), 3.26 (2H), 3.41 (1H), 4.72 (1H), 6.16 (1H), 6.99 (1H), 7.21-7.30 (3H), 7.44 (2H), 7.57 (2H), 7.91 (2H), 7.99 (1H), 10.05 (1H) ppm.

Intermediate Example 243a

4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-phenoxyimidazo[1,2-b]pyridazin-3-yl}benzaldehyde

152 mg (340 μmol) 1-({3-[4-(1,3-dioxolan-2-yl)phenyl]-6-phenoxyimidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol which was prepared according to intermediate example 243b were transformed in analogy to intermediate example 13a to give after working up and purification 132 mg (96%) of the title compound.

Intermediate Example 243b

1-({3-[4-(1,3-dioxolan-2-yl)phenyl]-6-phenoxyimidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol

250 mg (643 μmol) 1-({6-chloro-3-[4-(1,3-dioxolan-2-yl)phenyl]imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol which was prepared according to intermediate example 32c were transformed in analogy to example 51 using phenol to give after working up and purification 157 mg (55%) of the title compound.

›Example 244

N-cyclopropyl-4-{6-(3-fluorophenoxy)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzenecarbothioamide

79 mg (188 μmol) 4-{6-(3-fluorophenoxy)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzaldehyde which was prepared according to intermediate example 244a were transformed in analogy to example 13 to give after working up and purification 22 mg (22%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.72-0.86 (4H), 1.15 (6H), 3.41 (2H), 3.49 (1H), 4.72 (1H), 6.18 (1H), 7.03-7.15 (3H), 7.21 (1H), 7.47 (1H), 7.60 (2H), 7.92 (2H), 8.00 (1H), 10.07 (1H) ppm.

Intermediate Example 244a

4-{6-(3-fluorophenoxy)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzaldehyde

92 mg (198 μmol) 1-({3-[4-(1,3-dioxolan-2-yl)phenyl]-6-(3-fluorophenoxy)imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol which was prepared according to intermediate example 244b were transformed in analogy to intermediate example 13a to give after working up and purification 80 mg (96%) of the title compound.

Intermediate Example 244b

1-({3-[4-(1,3-dioxolan-2-yl)phenyl]-6-(3-fluorophenoxy)imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol

250 mg (643 μmol) 1-({6-chloro-3-[4-(1,3-dioxolan-2-yl)phenyl]imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol which was prepared according to intermediate example 32c were transformed in analogy to example 51 using 3-fluorophenol to give after working up and purification 94.2 mg (32%) of the title compound.

›Example 245

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(phenylsulfanyl) imidazo[1,2-b]pyridazin-3-yl}benzenecarbothioamide

105 mg (251 μmol) 4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(phenylsulfanyl)imidazo[1,2-b]pyridazin-3-yl}benzaldehyde which was prepared according to intermediate example 245a were transformed in analogy to example 13 to give after working up and purification 27.3 mg (21%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.75-0.87 (4H), 1.12 (6H), 3.22 (2H), 3.43 (1H), 4.69 (1H), 6.24 (1H), 6.98 (1H), 7.46-7.59 (5H), 7.63 (2H), 7.82 (2H), 7.99 (1H), 10.07 (1H) ppm.

Intermediate Example 245a

4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(phenylsulfanyl)imidazo[1,2-b]pyridazin-3-yl}benzaldehyde

155 mg (335 μmol) 1-({3-[4-(1,3-dioxolan-2-yl)phenyl]-6-(phenylsulfanyl)imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol which was prepared according to intermediate example 245b were transformed in analogy to intermediate example 13a to give after working up and purification 109 mg (78%) of the title compound.

Intermediate Example 245b

1-({3-[4-(1,3-dioxolan-2-yl)phenyl]-6-(phenylsulfanyl)imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol

250 mg (643 μmol) 1-({6-chloro-3-[4-(1,3-dioxolan-2-yl)phenyl]imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol which was prepared according to intermediate example 32c were transformed in analogy to example 51 using benzenethiol to give after working up and purification 154 mg (52%) of the title compound.

›Example 246

N-cyclopropyl-4-{6-[(3-fluorophenyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzenecarbothioamide

94 mg (215 μmol) 4-{6-[(3-fluorophenyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzaldehyde which was prepared according to intermediate example 246a were transformed in analogy to example 13 to give after working up and purification 9.2 mg (8%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.75-0.87 (4H), 1.12 (6H), 3.23 (2H), 3.44 (1H), 4.71 (1H), 6.31 (1H), 7.07 (1H), 7.35 (1H), 7.44 (1H), 7.48-7.55 (2H), 7.58 (2H), 7.85 (2H), 8.01 (1H), 10.10 (1H) ppm.

Intermediate Example 246a

4-{6-[(3-fluorophenyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzaldehyde

108 mg (225 μmol) 1-({3-[4-(1,3-dioxolan-2-yl)phenyl]-6-[(3-fluorophenyl)sulfanyl]imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol which was prepared according to intermediate example 246b were transformed in analogy to intermediate example 13a to give after working up and purification 95 mg (97%) of the title compound.

Intermediate Example 246b

1-({3-[4-(1,3-dioxolan-2-yl)phenyl]-6-[(3-fluorophenyl)sulfanyl]imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol

250 mg (643 μmol) 1-({6-chloro-3-[4-(1,3-dioxolan-2-yl)phenyl]imidazo[1,2-b]pyridazin-8-yl}amino)-2-methylpropan-2-ol which was prepared according to intermediate example 32c were transformed in analogy to example 51 using 3-fluorobenzenethiol to give after working up and purification 103.2 mg (33%) of the title compound.

›Example 247

N-cyclopropyl-2-methyl-4-(6-{[4-(trifluoromethyl)phenyl]sulfanyl}-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl)benzamide

50 mg (104 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 4-(trifluoromethyl)benzenethiol to give after working up and purification 20.2 mg (32%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.60 (2H), 0.86 (2H), 2.37 (3H), 2.51 (2H), 2.87 (1H), 3.57 (2H), 5.95 (1H), 6.04 (1H), 6.54 (1H), 7.08 (1H), 7.48 (1H), 7.55 (1H), 7.66 (2H), 7.68 (1H), 7.73 (2H) ppm.

Intermediate Example 247a

4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

1.00 g (2.3 mmol) 6-bromo-3-iodo-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 247b were transformed in analogy to intermediate example 1a using N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide which was prepared according to intermediate example 7b to give after working up and purification 580 mg (52%) of the title compound.

Intermediate Example 247b

6-bromo-3-iodo-N-(3,3,3-trifluoropropyl)imidazo[1,2-b]pyridazin-8-amine

2.30 g (5.71 mmol) 6,8-dibromo-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 96c were transformed in analogy to intermediate example 1b using 3,3,3-trifluoropropan-1-amine to give after working up and purification 2.0 g (81%) of the title compound.

›Example 248

N-cyclopropyl-4-{6-[(2,5-difluorophenyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (109 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 2,5-difluorobenzenethiol to give after working up and purification 10.4 mg (17%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 1.14 (6H), 2.20 (3H), 2.79 (1H), 3.25 (2H), 4.71 (1H), 6.35 (1H), 7.04 (1H), 7.08 (1H), 7.42-7.51 (2H), 7.57 (1H), 7.62 (1H), 7.66 (1H), 7.94 (1H), 8.22 (1H) ppm.

›Example 249

N-cyclopropyl-4-{6-[(3,4-difluorophenyl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (104 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 3,4-difluorobenzenethiol to give after working up and purification 5.0 mg (8%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.64 (2H), 0.90 (2H), 2.42 (3H), 2.52 (2H), 2.93 (1H), 3.61 (2H), 5.88 (1H), 8.90 (1H), 5.94 (1H), 7.20-7.28 (2H), 7.39 (1H), 7.51 (1H), 7.56 (1H), 7.57 (1H), 7.70 (1H) ppm.

›Example 250

N-cyclopropyl-4-{6-[(4-fluorophenyl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (104 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 4-fluorobenzenethiol to give after working up and purification 3.8 mg (7%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.64 (2H), 0.90 (2H), 2.41 (3H), 2.50 (2H), 2.93 (1H), 3.59 (2H), 5.87 (1H), 5.88 (1H), 5.96 (1H), 7.15 (2H), 7.19 (1H), 7.55 (1H), 7.59 (1H), 7.64 (2H), 7.70 (1H) ppm.

›Example 251

N-cyclopropyl-4-{6-[(3,5-difluorophenyl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (104 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 3,5-difluorobenzenethiol to give after working up and purification 2.9 mg (5%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.90 (2H), 2.43 (3H), 2.52 (2H), 2.93 (1H), 3.62 (2H), 5.86 (1H), 5.96 (1H), 6.00 (1H), 6.88 (1H), 7.18 (2H), 7.29 (1H), 7.65 (1H), 7.69 (1H), 7.73 (1H) ppm.

›Example 252

N-cyclopropyl-4-{6-[(2,3-difluorophenyl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (104 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 2,3-difluorobenzenethiol to give after working up and purification 1.6 mg (3%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.90 (2H), 2.39 (3H), 2.54 (2H), 2.93 (1H), 3.62 (2H), 5.85 (1H), 5.97 (1H), 6.10 (1H), 7.16 (1H), 7.20 (1H), 7.33 (1H), 7.41 (1H), 7.56 (1H), 7.57 (1H), 7.69 (1H) ppm.

›Example 253

N-cyclopropyl-4-{6-(4-fluorophenoxy)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (109 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 4-fluorophenol to give after working up and purification 27.5 mg (49%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.47 (2H), 0.63 (2H), 1.16 (6H), 2.13 (3H), 2.77 (1H), 3.27 (2H), 4.73 (1H), 6.16 (1H), 6.95 (1H), 7.16 (1H), 7.24-7.34 (4H), 7.64 (1H), 7.73 (1H), 7.91 (1H), 8.19 (1H) ppm.

›Example 254

N-cyclopropyl-4-{6-(3,4-difluorophenoxy)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (109 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 3,4-difluorophenol to give after working up and purification 18.1 mg (31%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.47 (2H), 0.64 (2H), 1.16 (6H), 2.14 (3H), 2.77 (1H), 3.27 (2H), 4.73 (1H), 6.17 (1H), 7.00 (1H), 7.13 (1H), 7.18 (1H), 7.51 (1H), 7.56 (1H), 7.65 (1H), 7.75 (1H), 7.91 (1H), 8.21 (1H) ppm.

›Example 255

N-cyclopropyl-4-{6-[(2,5-difluorophenyl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (104 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 2,5-difluorobenzenethiol to give after working up and purification 13.3 mg (22%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.62 (2H), 0.90 (2H), 2.39 (3H), 2.53 (2H), 2.92 (1H), 3.62 (2H), 5.87 (1H), 5.97 (1H), 6.06 (1H), 7.14-7.23 (3H), 7.39 (1H), 7.57 (1H), 7.59 (1H), 7.70 (1H) ppm.

›Example 256

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(4-isopropoxyphenoxy)imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 4-isopropoxyphenol to give after working up and purification 13.7 mg (15%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.60 (2H), 0.87 (2H), 1.36 (6H), 1.44 (6H), 2.30 (3H), 2.89 (1H), 3.31 (2H), 4.52 (1H), 5.87 (1H), 5.93 (1H), 6.52 (1H), 6.91 (2H), 7.11 (2H), 7.19 (1H), 7.58 (1H), 7.64 (1H), 7.74 (1H) ppm.

›Example 257

N-cyclopropyl-4-{6-(4-isopropoxyphenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 4-isopropoxyphenol to give after working up and purification 9.3 mg (10%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.59 (2H), 0.88 (2H), 1.37 (6H), 2.32 (3H), 2.56 (2H), 2.88 (1H), 3.66 (2H), 4.53 (1H), 5.84 (1H), 5.88 (1H), 5.91 (1H), 6.93 (2H), 7.14 (2H), 7.22 (1H), 7.62 (1H), 7.73 (1H), 7.79 (1H) ppm.

›Example 258

N-cyclopropyl-4-{6-(2,3-difluorophenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

100 mg (207 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 2,3-difluorophenol to give after working up and purification 22 mg (19%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.60 (2H), 0.88 (2H), 2.29 (3H), 2.58 (2H), 2.89 (1H), 3.70 (2H), 5.86 (1H), 5.96 (1H), 6.07 (1H), 7.06-7.17 (3H), 7.22 (1H), 7.53 (1H), 7.66 (1H), 7.71 (1H) ppm.

›Example 259

N-cyclopropyl-4-{6-(2-fluoro-5-methylphenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

100 mg (207 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 2-fluoro-5-methylphenol to give after working up and purification 23 mg (20%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.60 (2H), 0.88 (2H), 2.27 (3H), 2.35 (3H), 2.58 (2H), 2.89 (1H), 3.68 (2H), 5.84 (1H), 5.95 (1H), 6.11 (1H), 7.00-7.16 (3H), 7.21 (1H), 7.55 (1H), 7.71 (2H) ppm.

›Example 260

N-cyclopropyl-4-{6-(3,4-difluorophenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

100 mg (207 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 3,4-difluorophenol to give after working up and purification 36 mg (31%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.61 (2H), 0.88 (2H), 2.34 (3H), 2.57 (2H), 2.90 (1H), 3.68 (2H), 5.86 (1H), 5.87 (1H), 6.04 (1H), 6.99 (1H), 7.11-7.29 (3H), 7.59 (1H), 7.71 (1H), 7.72 (1H) ppm.

›Example 261

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(2-thienylsulfanyl) imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using thiophene-2-thiol to give after working up and purification 34 mg (41%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.65 (2H), 1.12 (6H), 2.26 (3H), 2.80 (1H), 1.64 (2H), 4.70 (1H), 6.21 (1H), 7.01 (1H), 7.17 (1H), 7.23 (1H), 7.47 (1H), 7.71 (1H), 7.76 (1H), 7.94 (2H), 8.23 (1H) ppm.

›Example 262

N-cyclopropyl-4-{6-(3,5-difluorophenoxy)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

200 mg (436 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 3,5-difluorophenol to give after working up and purification 34.6 mg (15%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.47 (2H), 0.63 (2H), 1.15 (6H), 2.17 (3H), 2.77 (1H), 3.27 (2H), 4.74 (1H), 6.19 (1H), 7.08 (1H), 7.12-7.22 (4H), 7.68 (1H), 7.79 (1H), 7.93 (1H), 8.23 (1H) ppm.

›Example 263

N-cyclopropyl-4-(8-[(2-hydroxy-2-methylpropyl)amino]-6-{[(3S)-2-oxopyrrolidin-3-yl]oxy}imidazo[1,2-b]pyridazin-3-yl)-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using (3S)-3-hydroxypyrrolidin-2-one to give after working up and purification 3.2 mg (4%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.64 (2H), 0.89 (2H), 1.40 (6H), 2.20 (1H), 2.49 (3H), 2.80 (1H), 2.92 (1H), 3.27 (2H), 3.37-3.51 (2H), 4.04 (1H), 5.33 (1H), 5.82 (1H), 6.09 (1H), 6.18 (1H), 6.34 (1H), 7.38 (1H), 7.57 (1H), 7.74 (1H), 7.80 (1H) ppm.

›Example 264

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(6-methylpyridin-3-yl)oxy]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 6-methylpyridin-3-ol to give after working up and purification 24.5 mg (30%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.66 (2H), 1.19 (6H), 2.14 (3H), 2.51 (3H), 2.80 (1H), 3.32 (2H), 4.76 (1H), 6.23 (1H), 7.02 (1H), 7.19 (1H), 7.37 (1H), 7.64 (1H), 7.68 (1H), 7.73 (1H), 7.94 (1H), 8.22 (1H), 8.43 (1H) ppm.

›Example 265

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(pyrimidin-5-yloxy) imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

200 mg (436 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using pyrimidin-5-ol to give after working up and purification 34.6 mg (15%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.64 (2H), 0.89 (2H), 1.48 (6H), 2.30 (3H), 2.92 (1H), 3.35 (2H), 4.81 (1H), 5.87 (1H), 6.41 (1H), 6.62 (1H), 7.23 (1H), 7.45 (1H), 7.51 (1H), 7.58 (1H), 8.52 (2H), 9.05 (1H) ppm.

›Example 266

4-{6-(3-chlorophenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 3-chlorophenol to give after working up and purification 13.9 mg (17%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.61 (2H), 0.88 (2H), 2.34 (3H), 2.58 (2H), 2.90 (1H), 3.68 (2H), 5.82 (1H), 5.89 (1H), 5.97 (1H), 7.15 (1H), 7.25 (1H), 7.27 (1H), 7.31 (1H), 7.36 (1H), 7.63 (1H), 7.72 (1H), 7.74 (1H) ppm.

›Example 267

4-{6-(4-chlorophenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 4-chlorophenol to give after working up and purification 12.6 mg (12.6%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.61 (2H), 0.88 (2H), 2.33 (3H), 2.57 (2H), 2.90 (1H), 3.68 (2H), 5.83 (1H), 5.89 (1H), 5.96 (1H), 7.19 (2H), 7.25 (1H), 7.40 (2H), 7.58 (1H), 7.72 (1H), 7.73 (1H) ppm.

›Example 268

N-cyclopropyl-4-{6-[(2-fluorophenyl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 2-fluorobenzenethiol to give after working up and purification 31.8 mg (39%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.62 (2H), 0.90 (2H), 2.37 (3H), 2.51 (2H), 2.92 (1H), 3.60 (2H), 5.83 (1H), 5.89 (1H), 5.94 (1H), 7.16 (1H), 7.20 (1H), 7.25 (1H), 7.51 (1H), 7.56 (1H), 7.59 (1H), 7.66 (1H), 7.70 (1H) ppm.

›Example 269

N-cyclopropyl-4-{6-[(5-fluoro-2-methylphenyl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 5-fluoro-2-methylbenzenethiol to give after working up and purification 6.1 mg (7%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.90 (2H), 2.39 (3H), 2.40 (3H), 2.50 (2H), 2.92 (1H), 3.59 (2H), 5.86 (1H), 5.89 (1H), 5.93 (1H), 7.10 (1H), 7.19 (1H), 7.31 (1H), 7.38 (1H), 7.57 (1H), 7.60 (1H), 7.71 (1H) ppm.

›Example 270

N-cyclopropyl-4-(6-{[2-(hydroxymethyl)phenyl]sulfanyl}-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl)-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using (2-sulfanylphenyl)methanol to give after working up and purification 12.3 mg (15%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.90 (2H), 2.34 (3H), 2.51 (2H), 2.92 (1H), 3.61 (2H), 4.83 (2H), 5.86 (1H), 5.89 (1H), 5.94 (1H), 7.14 (1H), 7.41 (1H), 7.42 (1H), 7.50 (1H), 7.57 (1H), 7.65 (1H), 7.68 (1H), 7.70 (1H) ppm.

›Example 271

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(3-methoxyphenyl)sulfanyl]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 3-isopropoxybenzenethiol to give after working up and purification 18.5 mg (20%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.65 (2H), 1.11 (6H), 1.18 (6H), 2.21 (3H), 2.78 (1H), 3.20 (2H), 4.58 (1H), 4.71 (1H), 6.21 (1H), 6.95-7.05 (2H), 7.08-7.16 (3H), 7.34 (1H), 7.71 (1H), 7.73 (1H), 7.94 (1H), 8.23 (1H) ppm.

›Example 272

(RS)—N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(pyrrolidin-3-ylamino)imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (109 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using (RS)-pyrrolidin-3-amine to give after working up and purification 18 mg (36%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.65 (2H), 1.16 (6H), 1.86 (1H), 2.15 (1H), 2.36 (3H), 2.80 (1H), 3.21 (2H), 3.28 (1H), 3.45 (1H), 3.53-3.65 (2H), 3.71 (1H), 4.27 (1H), 5.68 (1H), 6.36 (1H), 7.31 (1H), 7.78 (1H), 8.07 (1H), 8.10 (1H), 8.26 (1H), 8.29 (1H) ppm.

›Example 273

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(3-isopropylphenyl)sulfanyl]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 3-isopropylbenzenethiol to give after working up and purification 14.0 mg (15%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.64 (2H), 1.10 (6H), 1.14 (6H), 2.18 (3H), 2.78 (1H), 2.88 (1H), 3.18 (2H), 4.71 (1H), 6.18 (1H), 6.98 (1H), 7.08 (1H), 7.34-7.43 (3H), 7.45 (1H), 7.64 (1H), 7.71 (1H), 7.94 (1H), 8.22 (1H) ppm.

›Example 274

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(pyridin-2-yloxy) imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using pyridin-2-ol to give after working up and purification 11.0 mg (14%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.64 (2H), 1.14 (6H), 2.33 (3H), 2.79 (1H), 3.27 (2H), 4.73 (1H), 6.33 (1H), 6.47 (1H), 6.48 (1H), 7.21 (1H), 7.33 (1H), 7.54 (1H), 7.79 (1H), 7.82 (1H), 7.91 (1H), 8.03 (1H), 8.24 (1H) ppm.

›Example 275

N-cyclopropyl-4-{6-[3-(2-hydroxy-2-methylpropoxy)phenoxy]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (109 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 3-{2-methyl-2-[(triisopropylsilyl)oxy]propoxy}phenol to give after working up and purification 2.3 mg (4%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.46 (2H), 0.63 (2H), 1.14 (6H), 1.15 (6H), 2.14 (3H), 2.76 (1H), 3.27 (2H), 3.66 (2H), 4.59 (1H), 4.74 (1H), 6.14 (1H), 6.76-6.86 (3H), 6.97 (1H), 7.16 (1H), 7.31 (1H), 7.70 (1H), 7.79 (1H), 7.92 (1H), 8.21 (1H) ppm.

›Example 276

N-cyclopropyl-4-{6-[(3-fluorophenyl)sulfanyl]-8-[(2-hydroxyethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (174 μmol) 4-{6-bromo-8-[(2-hydroxyethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 276a were transformed in analogy to example 51 using 3-fluorobenzenethiol to give after working up and purification 14.5 mg (17%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.65 (2H), 2.20 (3H), 2.78 (1H), 3.33 (2H), 3.57 (2H), 4.82 (1H), 6.19 (1H), 7.12 (1H), 7.33 (1H), 7.38-7.54 (4H), 7.66 (1H), 7.71 (1H), 7.94 (1H), 8.23 (1H) ppm.

Intermediate Example 276a

4-{6-bromo-8-[(2-hydroxyethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

1.98 g (5.17 mmol) 2-[(6-bromo-3-iodoimidazo[1,2-b]pyridazin-8-yl)amino]ethanol which was prepared according to intermediate example 276b were transformed in analogy to intermediate example 1a using N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give after working up and purification 1.27 g (51%) of the title compound.

Intermediate Example 276b

2-[(6-bromo-3-iodoimidazo[1,2-b]pyridazin-8-yl)amino]ethanol

2.50 g (6.21 mmol) 6,8-dibromo-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 96c were transformed in analogy to intermediate example 1b using 2-aminoethanol to give after working up and purification 1.99 g (81%) of the title compound.

›Example 277

N-cyclopropyl-4-{6-(3-fluorophenoxy)-8-[(2-hydroxyethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (174 μmol) 4-{6-bromo-8-[(2-hydroxyethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamid which was prepared according to intermediate example 276a were transformed in analogy to example 51 using 3-fluorophenol to give after working up and purification 17.2 mg (21%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.46 (2H), 0.63 (2H), 2.14 (3H), 2.76 (1H), 3.38 (2H), 3.62 (2H), 4.84 (1H), 6.08 (1H), 7.07-7.20 (3H), 7.24 (1H), 7.41 (1H), 7.48 (1H), 7.66 (1H), 7.76 (1H), 7.92 (1H), 8.21 (1H) ppm.

›Example 278

N-cyclopropyl-2-methyl-4-{6-(2,2,3,3-tetrafluoro-4-hydroxybutoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide (A) and

N-cyclopropyl-2-methyl-4-(6-{[(1E)-2,3,3-trifluoro-4-hydroxybut-1-en-1-yl]oxy}-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl)benzamide

100 mg (207 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 2,2,3,3-tetrafluorobutane-1,4-diol to give after working up and purification 5.2 mg (4%) of the title compound A and 5.3 mg (4%) of the title compound B.

1 H-NMR (DMSO-d6) of A: δ=0.50 (2H), 0.65 (2H), 2.35 (3H), 2.65 (2H), 2.80 (1H), 3.56 (2H), 3.91 (2H), 4.91 (2H), 5.97 (1H), 6.00 (1H), 7.33 (1H), 7.60 (1H), 7.90 (1H), 7.92 (1H), 7.97 (1H), 8.27 (1H) ppm.

1 H-NMR (DMSO-d6) of B: δ=0.50 (2H), 0.66 (2H), 2.35 (3H), 2.66 (2H), 2.80 (1H), 3.59 (2H), 3.86 (2H), 5.92 (1H), 6.14 (1H), 7.33 (1H), 7.70 (1H), 7.84 (1H), 7.89 (1H), 7.97 (1H), 8.02 (1H), 8.28 (1H) ppm.

›Example 279

2-{3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-6-yl}-5-fluoro-benzoic acid methyl ester

600 mg (1.31 mmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 1 using [4-fluoro-2-(methoxycarbonyl)phenyl]boronic acid. After working up 19 mL tetrahydrofuran were added to the crude product and the suspension was cooled to 3° C. 21.8 mL of a freshly prepared diazomethane solution in diethyl ether were added in portions over 2 hours. The solvent was removed and the residue purified by chromatography to give 52.7 mg (9%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.65 (2H), 1.17 (6H), 2.36 (3H), 2.80 (1H), 3.33 (2H), 3.47 (3H), 4.75 (1H), 6.52 (1H), 6.96 (1H), 7.30 (1H), 7.51-7.59 (2H), 7.78 (1H), 7.92 (1H), 7.97 (1H), 8.04 (1H), 8.23 (1H) ppm.

›Example 280

N-cyclopropyl-4-{6-(2-hydroxyphenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

A mixture of 28.0 mg (53 μmol) N-cyclopropyl-4-{6-(2-methoxyphenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide which was prepared according to example 223, 44.8 mg sodium methanethiolate and 350 μL N,N-dimethylformamide was heated under microwave irradiation for 30 minutes at 120° C. The mixture was poured into water, the pH was adjusted between 7 and 8 by addition of ammonium chloride and extracted with a mixture of dichloromethane and methanol. The combined organic phases were dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 11.5 mg (40%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.47 (2H), 0.63 (2H), 2.09 (3H), 2.68 (2H), 2.76 (1H), 3.59 (2H), 6.08 (1H), 6.83 (1H), 6.97 (1H), 7.05-7.17 (3H), 7.55 (1H), 7.62 (1H), 7.75 (1H), 7.90 (1H), 8.18 (1H), 9.53 (1H) ppm.

›Example 281

N-cyclopropyl-4-{6-(3-fluorophenoxy)-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (150 μmol) 4-{6-bromo-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 281a were transformed in analogy to example 51 using 3-fluorophenol to give after working up and purification 33.7 mg (40%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.66 (2H), 1.32 (2H), 1.78 (1H), 2.04 (2H), 2.17 (3H), 2.59 (4H), 2.79 (1H), 3.22 (2H), 6.09 (1H), 7.15 (2H), 7.18 (1H), 7.27 (1H), 7.50 (1H), 7.68 (1H), 7.72 (1H), 7.78 (1H), 7.93 (1H), 8.22 (1H) ppm.

Intermediate Example 281a

4-{6-bromo-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

2.22 g (4.90 mmol) 6-bromo-3-iodo-N-(tetrahydro-2H-thiopyran-4-ylmethyl)imidazo[1,2-b]pyridazin-8-amine which was prepared according to intermediate example 281b were transformed in analogy to intermediate example 1a using N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to give after working up and purification 1.49 g (55%) of the title compound.

Intermediate Example 281b

6-bromo-3-iodo-N-(tetrahydro-2H-thiopyran-4-ylmethyl)imidazo[1,2-b]pyridazin-8-amine

2.31 g (5.75 mmol) 6,8-dibromo-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 96c were transformed in analogy to intermediate example 1b using 1-(tetrahydro-2H-thiopyran-4-yl)methanamine to give after working up and purification 2.23 g (81%) of the title compound.

›Example 282

N-cyclopropyl-4-{6-(3-fluoro-5-methylphenoxy)-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (150 μmol) 4-{6-bromo-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 281a were transformed in analogy to example 51 using 3-fluoro-5-methylphenol to give after working up and purification 14.1 mg (16%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.66 (2H), 1.32 (2H), 1.77 (1H), 2.04 (2H), 2.18 (3H), 2.34 (3H), 2.59 (4H), 2.79 (1H), 3.22 (2H), 6.07 (1H), 6.96 (1H), 6.97 (1H), 7.04 (1H), 7.20 (1H), 7.68-7.74 (2H), 7.80 (1H), 7.93 (1H), 8.23 (1H) ppm.

›Example 283

N-cyclopropyl-4-{6-(2-fluorophenoxy)-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (150 μmol) 4-{6-bromo-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 281a were transformed in analogy to example 51 using 2-fluorophenol to give after working up and purification 26.6 mg (32%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.66 (2H), 1.33 (2H), 1.80 (1H), 2.06 (2H), 2.11 (3H), 2.60 (4H), 2.78 (1H), 3.23 (2H), 6.16 (1H), 7.13 (1H), 7.30 (1H), 7.37 (1H), 7.43 (1H), 7.47 (1H), 7.61 (1H), 7.69 (1H), 7.74 (1H), 7.93 (1H), 8.21 (1H) ppm.

›Example 284

N-cyclopropyl-2-methyl-4-{6-(phenylsulfanyl)-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

75 mg (150 μmol) 4-{6-bromo-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 281a were transformed in analogy to example 51 using benzenethiol to give after working up and purification 45.3 mg (54%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.65 (2H), 1.22 (2H), 1.60 (1H), 1.91 (2H), 2.21 (3H), 2.52 (4H), 2.78 (1H), 3.08 (2H), 5.99 (1H), 7.10 (1H), 7.44-7.53 (3H), 7.59-7.73 (5H), 7.91 (1H), 8.24 (1H) ppm.

›Example 285

N-cyclopropyl-4-{6-[(3-fluorophenyl)sulfanyl]-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (150 μmol) 4-{6-bromo-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 281a were transformed in analogy to example 51 using 3-fluorobenzenethiol to give after working up and purification 9.8 mg (11%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 1.23 (2H), 1.64 (1H), 1.93 (2H), 2.21 (3H), 2.53 (4H), 2.79 (1H), 3.11 (2H), 6.10 (1H), 7.13 (1H), 7.34 (1H), 7.44 (1H), 7.48-7.54 (2H), 7.68 (1H), 7.72 (1H), 7.74 (1H), 7.93 (1H), 8.25 (1H) ppm.

›Example 286

N-cyclopropyl-4-{6-[(3-fluoro-5-methylphenyl)sulfanyl]-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (150 μmol) 4-{6-bromo-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 281a were transformed in analogy to example 51 using 3-fluoro-5-methylbenzenethiol to give after working up and purification 9.1 mg (10%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.65 (2H), 1.23 (2H), 1.62 (1H), 1.92 (2H), 2.21 (3H), 2.31 (3H), 2.52 (4H), 2.79 (1H), 3.11 (2H), 6.07 (1H), 7.14 (1H), 7.17 (1H), 7.26-7.32 (2H), 7.68-7.76 (3H), 7.93 (1H), 8.25 (1H) ppm.

›Example 287

N-cyclopropyl-4-{6-[(3-hydroxyphenyl)sulfanyl]-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

100 mg (200 μmol) 4-{6-bromo-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 281a were transformed in analogy to example 51 using 3-methoxybenzenethiol to give after working up and purification 14 mg (12%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 1.22 (2H), 1.58 (1H), 1.90 (2H), 2.24 (3H), 2.52 (4H), 2.79 (1H), 3.07 (2H), 5.95 (1H), 6.86 (1H), 6.96 (1H), 7.01 (1H), 7.17 (1H), 7.26 (1H), 7.69 (1H), 7.73-7.80 (2H), 7.92 (1H), 8.24 (1H), 9.76 (1H) ppm.

›Example 288

N-cyclopropyl-2-methyl-4-{6-(pyridin-3-yloxy)-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

75 mg (150 μmol) 4-{6-bromo-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 281a were transformed in analogy to example 51 using pyridin-3-ol to give after working up and purification 25.2 mg (31%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.46 (2H), 0.63 (2H), 1.30 (2H), 1.76 (1H), 2.02 (2H), 2.12 (3H), 2.57 (4H), 2.76 (1H), 3.20 (2H), 6.13 (1H), 7.13 (1H), 7.51 (1H), 7.60 (1H), 7.68 (1H), 7.76 (1H), 7.80 (1H), 7.90 (1H), 8.21 (1H), 8.48 (1H), 8.57 (1H) ppm.

›Example 289

N-cyclopropyl-4-{6-[(2-hydroxyphenyl)sulfanyl]-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (150 μmol) 4-{6-bromo-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 281a were transformed in analogy to example 51 using 2-methoxybenzenethiol to give after working up and purification 40.9 mg (48%) of the title compound.

1 H-NMR (DMSO-d6): 0.5=0.49 (2H), 0.65 (2H), 1.20 (2H), 1.57 (1H), 1.88 (2H), 2.23 (3H), 2.52 (4H), 2.79 (1H), 3.03 (2H), 5.86 (1H), 6.87 (1H), 6.98 (1H), 7.12 (1H), 7.34 (1H), 7.46 (1H), 7.60 (1H), 7.72 (1H), 7.74 (1H), 7.90 (1H), 8.23 (1H), 10.01 (1H) ppm.

›Example 290

N-cyclopropyl-4-{6-(4-fluorophenoxy)-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (150 μmol) 4-{6-bromo-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 281a were transformed in analogy to example 51 using 4-fluorophenol to give after working up and purification 45.6 mg (54%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.46 (2H), 0.63 (2H), 1.29 (2H), 1.75 (1H), 2.02 (2H), 2.12 (3H), 2.56 (4H), 2.76 (1H), 3.19 (2H), 6.06 (1H), 7.15 (1H), 7.23-7.35 (4H), 7.63 (1H), 7.68 (1H), 7.72 (1H), 7.90 (1H), 8.21 (1H) ppm.

›Example 291

4-{6-(4-chloro-3-fluorophenoxy)-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (150 μmol) 4-{6-bromo-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 281a were transformed in analogy to example 51 using 4-chloro-3-fluorophenol to give after working up and purification 5.4 mg (6%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.64 (2H), 0.91 (2H), 1.54 (2H), 1.80 (1H), 2.20 (2H), 2.37 (3H), 2.65-2.79 (4H), 2.93 (1H), 3.26 (2H), 5.86 (1H), 5.87 (1H), 5.97 (1H), 7.04 (1H), 7.16 (1H), 7.30 (1H), 7.46 (1H), 7.62 (1H), 7.74 (2H) ppm.

›Example 292

4-{6-(4-chlorophenoxy)-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (150 μmol) 4-{6-bromo-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 281a were transformed in analogy to example 51 using 4-chlorophenol to give after working up and purification 30.7 mg (36%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.46 (2H), 0.63 (2H), 1.29 (2H), 1.75 (1H), 2.02 (2H), 2.12 (3H), 2.56 (4H), 2.77 (1H), 3.19 (2H), 6.07 (1H), 7.16 (1H), 7.31 (2H), 7.50 (2H), 7.62 (1H), 7.72 (2H), 7.90 (1H), 8.21 (1H) ppm.

›Example 293

N-cyclopropyl-4-{6-(2,3-difluorophenoxy)-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (150 μmol) 4-{6-bromo-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 281a were transformed in analogy example 51 using 2,3-difluorophenol to give after working up and purification 19.1 mg (22%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.60 (2H), 0.88 (2H), 1.52 (2H), 1.79 (1H), 2.19 (2H), 2.30 (3H), 2.61-2.79 (4H), 2.89 (1H), 3.25 (2H), 5.82 (1H), 5.92 (2H), 7.05-7.17 (3H), 7.22 (1H), 7.54 (1H), 7.68 (1H), 7.70 (1H) ppm.

›Example 294

4-[6-(4-chlorophenoxy)-8-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methylbenzamide (A) and

4-[6-(4-chlorophenoxy)-8-({[(cis/trans)-1-oxidotetrahydro-2H-thiopyran-4-yl]methyl}amino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methylbenzamide (B)

To a solution of 22.4 mg (41 μmol) 4-{6-(4-chlorophenoxy)-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to example 292 in 327 μL trichloromethane were added 13.7 mg 3-chlorobenzenecarboperoxoic acid (77%) and the mixture was stirred at 23° C. for 40 minutes. Saturated sodium hydrogencarbonate solution was added and the solvents were removed. The residue was purified by chromatography to give 9.1 mg (38%) of the title compound A and 3.1 mg (13%) of a cis/trans-mixture of the title compounds B.

1 H-NMR (DMSO-d6) of A: δ=0.47 (2H), 0.63 (2H), 1.66 (2H), 1.98-2.15 (3H), 2.12 (3H), 2.77 (1H), 2.97-3.15 (4H), 3.25 (2H), 6.16 (1H), 7.17 (1H), 7.30 (2H), 7.50 (2H), 7.62 (1H), 7.72 (1H), 7.79 (1H), 7.91 (1H), 8.19 (1H) ppm.

1 H-NMR (DMSO-d6) of B: δ=0.46 (2H), 0.63 (2H), 1.65 (2H), 1.95-2.17 (3H), 2.12 (3H), 2.76 (1H), 2.96-3.16 (4H), 3.27 (2H), 6.17 (1H), 7.16 (1H), 7.30 (2H), 7.50 (2H), 7.62 (1H), 7.72 (1H), 7.82 (1H), 7.91 (1H), 8.22 (1H) ppm.

›Example 295

N-cyclopropyl-4-[8-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}-6-(4-fluorophenoxy)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide (A) and

N-cyclopropyl-4-[6-(4-fluorophenoxy)-8-({[(cis/trans)-1-oxidotetrahydro-2H-thiopyran-4-yl]methyl}amino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide (B)

37 mg (70 μmol) N-cyclopropyl-4-{6-(4-fluorophenoxy)-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide which was prepared according to example 290 were transformed in analogy to example 294 to give after working up and purification 5.2 mg (13%) of the title compound A and 1.7 mg (4%) of a cis/trans-mixture of the title compounds B.

1 H-NMR (DMSO-d6) of A: δ=0.47 (2H), 0.63 (2H), 1.66 (2H), 1.95-2.17 (3H), 2.12 (3H), 2.76 (1H), 2.97-3.16 (4H), 3.22 (2H), 6.15 (1H), 7.15 (1H), 7.23-7.36 (4H), 7.63 (1H), 7.72 (1H), 7.76 (1H), 7.90 (1H), 8.19 (1H) ppm.

1 H-NMR (DMSO-d6) of B: δ=0.47 (2H), 0.63 (2H), 1.38 (1H), 1.64-2.26 (5H), 2.12 (3H), 2.57 (2H), 2.67-2.88 (2H), 3.19 (2H), 6.11 (1H), 7.15 (1H), 7.22-7.35 (4H), 7.63 (1H), 7.68-7.77 (2H), 7.90 (1H), 8.19 (1H) ppm.

›Example 296

N-cyclopropyl-4-[8-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}-6-(pyridin-3-yloxy)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide (A) and

N-cyclopropyl-2-methyl-4-[8-({[(cis)-1-oxidotetrahydro-2H-thiopyran-4-yl]methyl}amino)-6-(pyridin-3-yloxy)imidazo[1,2-b]pyridazin-3-yl]benzamide (B) and

N-cyclopropyl-2-methyl-4-[8-({[(trans)-1-oxidotetrahydro-2H-thiopyran-4-yl]methyl}amino)-6-(pyridin-3-yloxy)imidazo[1,2-b]pyridazin-3-yl]benzamide (C)

17.1 mg (33 μmol) N-cyclopropyl-2-methyl-4-{6-(pyridin-3-yloxy)-8-[(tetrahydro-2H-thiopyran-4-ylmeth yl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide which was prepared according to example 288 were transformed in analogy to example 294 to give after working up and purification 6.7 mg (37%) of the title compound A, 2.4 mg (12%) of the title compound B and 3.1 mg (16%) of the title compound C.

1 H-NMR (CDCl 3 ) of A: δ=0.61 (2H), 0.88 (2H), 1.96-2.11 (3H), 2.29 (2H), 2.32 (3H), 2.89 (1H), 3.04 (2H), 3.14 (2H), 3.37 (2H), 5.90 (1H), 5.92 (1H), 6.51 (1H), 7.24 (1H), 7.40 (1H), 7.55 (1H), 7.62 (1H), 7.64 (1H), 7.72 (1H), 8.54 (1H), 8.61 (1H) ppm.

1 H-NMR (CDCl 3 ) of B: δ=0.61 (2H), 0.88 (2H), 1.87-2.01 (3H), 2.24 (2H), 2.32 (3H), 2.48 (2H), 2.89 (1H), 3.10 (2H), 3.33 (2H), 5.89 (1H), 5.92 (1H), 6.02 (1H), 7.24 (1H), 7.39 (1H), 7.56 (1H), 7.62 (1H), 7.66 (1H), 7.71 (1H), 8.53 (1H), 8.60 (1H) ppm.

1 H-NMR (CDCl 3 ) of C: δ=0.61 (2H), 0.88 (2H), 1.57 (2H), 1.99 (1H), 2.29 (2H), 2.31 (3H), 2.68 (2H), 2.89 (1H), 3.30 (2H), 3.40 (2H), 5.87-5.92 (2H), 5.99 (1H), 7.23 (1H), 7.39 (1H), 7.55 (1H), 7.62 (1H), 7.65 (1H), 7.71 (1H), 8.53 (1H), 8.60 (1H) ppm.

›Example 297

N-cyclopropyl-4-[8-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}-6-(2-fluorophenoxy)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide

19.7 mg (37 μmol) N-cyclopropyl-4-{6-(2-fluorophenoxy)-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide which was prepared according to example 283 were transformed in analogy to example 294 to give after working up and purification 9.8 mg (47%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.60 (2H), 0.88 (2H), 1.94-2.08 (3H), 2.26 (3H), 2.28 (2H), 2.89 (1H), 3.02 (2H), 3.13 (2H), 3.36 (2H), 5.82 (1H), 5.94 (1H), 5.99 (1H), 7.17-7.33 (5H), 7.53 (1H), 7.68 (1H), 7.71 (1H) ppm.

›Example 298

N-cyclopropyl-4-[8-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}-6-(3-fluorophenoxy)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide (A) and

N-cyclopropyl-4-[6-(3-fluorophenoxy)-8-({[(cis/trans)-1-oxidotetrahydro-2H-thiopyran-4-yl]methyl}amino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide (B)

25.5 mg (48 μmol) N-cyclopropyl-4-{6-(3-fluorophenoxy)-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide which was prepared according to example 281 were transformed in analogy to example 294 to give after working up and purification 12.3 mg (43%) of the title compound A and 5.6 mg (21%) of a cis/trans-mixture of the title compounds B.

1 H-NMR (CDCl 3 ) of A: δ=0.61 (2H), 0.88 (2H), 1.93-2.08 (3H), 2.28 (2H), 2.33 (3H), 2.89 (1H), 3.02 (2H), 3.13 (2H), 3.35 (2H), 5.84 (1H), 5.86 (1H), 6.04 (1H), 6.95-7.09 (3H), 7.25 (1H), 7.39 (1H), 7.61 (1H), 7.72 (1H), 7.74 (1H) ppm.

1 H-NMR (CDCl 3 ) of B: δ=0.60 (2H), 0.88 (2H), 1.55 (1H), 1.89 (1H), 1.97 (1H), 2.15-2.31 (2H), 2.32 (3H), 2.47+2.67 (2H), 2.89 (1H), 3.08+3.39 (2H), 3.29 (2H), 5.84+5.87 (1H), 5.89 (1H), 6.13 (1H), 6.95-7.07 (3H), 7.25 (1H), 7.39 (1H), 7.61 (1H), 7.72 (1H), 7.74 (1H) ppm.

›Example 299

N-cyclopropyl-4-{6-[4-fluoro-2-(hydroxymethyl)phenyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

250 mg (545 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 1 using [4-fluoro-2-(hydroxymethyl)phenyl]boronic acid which was prepared according to intermediate example 299a to give after working up and purification 239 mg (87%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.64 (2H), 1.15 (6H), 2.34 (3H), 2.79 (1H), 3.28 (2H), 4.65 (2H), 4.73 (1H), 5.31 (1H), 6.41 (1H), 6.97 (1H), 7.19 (1H), 7.32 (1H), 7.40 (1H), 7.53 (1H), 7.91 (1H), 7.95 (1H), 7.99 (1H), 8.26 (1H) ppm.

Intermediate Example 299a

[4-fluoro-2-(hydroxymethyl)phenyl]boronic acid

To a solution of 2.60 g (7.97 mmol) (4-fluoro-2-{[(triisopropylsilyl)oxy]methyl}phenyl)boronic acid which was prepared according to intermediate example 299b in 10 mL dichloromethane were added 6.14 mL trifluoroacetic acid and the mixture was stirred for 16 hours at 23° C. The solvent was removed and the residue crystallized from n-hexane to give 682 mg (50%) of the title compound.

Intermediate Example 299b

(4-fluoro-2-{[(triisopropylsilyl)oxy]methyl}phenyl)boronic acid

To a solution of 6.00 g (16.6 mmol) [(2-bromo-5-fluorobenzyl)oxy](triisopropyl)silane which was prepared according to intermediate example 299c in 60 mL tetrahydrofuran were added 7.31 mL n-butyllithium (2.5M in hexane) at −78° C. After 20 minutes of stirring 5.58 mL trimethyl borate were added and stirring was continued for additional 60 minutes. The mixture was allowed to warm to 23° C., poured into a saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by chromatography to give 3.16 g (58%) of the title compound.

Intermediate Example 299c

[(2-bromo-5-fluorobenzyl)oxy](triisopropyl)silane

To a solution of 5.00 g (24.4 mmol) (2-bromo-5-fluorophenyl)methanol in 100 mL N,N-dimethylformamide were added 2.49 g imidazole, 6.20 mL chloro(triisopropyl)silane, 1.49 g N,N-dimethylpyridin-4-amine and the mixture was stirred at 23° C. for 2 days. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by chromatography to give 8.17 g (93%) of the title compound.

›Example 300

N-cyclopropyl-4-{6-[(3,4-difluorophenyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

200 mg (436 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 3,4-difluorobenzenethiol to give after working up and purification 5.8 mg (2%) of the title compound.

1 H-NMR (CDCl 3 /CD 3 OD): δ=0.62 (2H), 0.88 (2H), 1.33 (6H), 2.37 (3H), 2.89 (1H), 3.22 (2H), 5.95 (1H), 6.13 (1H), 6.42 (1H), 7.17 (1H), 7.21 (1H), 7.35 (1H), 7.47 (1H), 7.51 (1H), 7.52 (1H), 7.62 (1H) ppm.

›Example 301

N-cyclopropyl-4-(8-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}-6-[(3-fluorophenyl)sulfanyl]imidazo[1,2-b]pyridazin-3-yl)-2-methylbenzamide

25 mg (47 μmol) 4-(6-bromo-8-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl}amino]imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 301a were transformed in analogy to example 51 using 3-fluorobenzenethiol to give after working up and purification 13.0 mg (48%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.65 (2H), 1.62 (2H), 1.94 (1H), 2.01 (2H), 2.20 (3H), 2.79 (1H), 2.96-3.11 (4H), 3.23 (2H), 6.25 (1H), 7.11 (1H), 7.34 (1H), 7.44 (1H), 7.49 (1H), 7.54 (1H), 7.65 (1H), 7.70 (1H), 7.82 (1H), 7.94 (1H), 8.24 (1H) ppm.

Intermediate Example 301a

4-(6-bromo-8-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide (A) and

4-(6-bromo-8-({[(cis/trans)-1-oxidotetrahydro-2H-thiopyran-4-yl]methyl}amino)imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide (B)

328 mg (655 μmol) 4-{6-bromo-8-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 281a were transformed in analogy to example 294 to give after working up and purification 167 mg (48%) of the title compound A and 128 mg (38%) of the title compounds B.

›Example 302

N-cyclopropyl-4-[8-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}-6-(phenylsulfanyl)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide

25 mg (47 μmol) 4-(6-bromo-8-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl}amino]imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 301a were transformed in analogy to example 51 using benzenethiol to give after working up and purification 10.1 mg (26%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.65 (2H), 1.61 (2H), 1.91 (1H), 1.99 (2H), 2.19 (3H), 2.78 (1H), 2.96-3.12 (4H), 3.20 (2H), 6.15 (1H), 7.08 (1H), 7.44-7.53 (3H), 7.58-7.65 (3H), 7.69 (1H), 7.77 (1H), 7.93 (1H), 8.23 (1H) ppm.

›Example 303

N-cyclopropyl-2-methyl-4-[8-({[(cis)-1-oxidotetrahydro-2H-thiopyran-4-yl]methyl}amino)-6-(phenylsulfanyl)imidazo[1,2-b]pyridazin-3-yl]benzamide (A) and

N-cyclopropyl-2-methyl-4-[8-({[(trans)-1-oxidotetrahydro-2H-thiopyran-4-yl]methyl}amino)-6-(phenylsulfanyl)imidazo[1,2-b]pyridazin-3-yl]benzamide (B)

25 mg (48 μmol) 4-(6-bromo-8-({[(cis/trans)-1-oxidotetrahydro-2H-thiopyran-4-yl]methyl}amino)imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 301a were transformed in analogy to example 51 using benzenethiol to give after working up and purification 3.7 mg (14%) of the title compound A and 2.5 mg (9%) of the title compound B.

1 H-NMR (CDCl 3 ) of A: δ=0.62 (2H), 0.89 (2H), 1.75-1.88 (3H), 2.15 (2H), 2.38 (3H), 2.42 (2H), 2.91 (1H), 3.05 (2H), 3.19 (2H), 5.87 (1H), 5.89 (1H), 5.97 (1H), 7.20 (1H), 7.41-7.50 (3H), 7.61-7.686 (4H), 7.69 (1H) ppm.

1 H-NMR (CDCl 3 ) of B: δ=0.62 (2H), 0.89 (2H), 1.46 (2H), 1.83 (1H), 2.17 (2H), 2.39 (3H), 2.60 (2H), 2.92 (1H), 3.15 (2H), 3.34 (2H), 5.82 (1H), 5.85 (1H), 5.90 (1H), 7.21 (1H), 7.42-7.51 (3H), 7.61-7.68 (4H), 7.70 (1H) ppm.

›Example 304

N-cyclopropyl-4-(6-[(3-fluorophenyl)sulfanyl]-8-({[(cis)-1-oxidotetrahydro-2H-thiopyran-4-yl]methyl}amino)imidazo[1,2-b]pyridazin-3-yl)-2-methylbenzamide (A) and

N-cyclopropyl-4-(6-[(3-fluorophenyl)sulfanyl]-8-({[(trans)-1-oxidotetrahydro-2H-thiopyran-4-yl]methyl}amino)imidazo[1,2-b]pyridazin-3-yl)-2-methylbenzamide (B)

25 mg (48 μmol) 4-(6-bromo-8-({[(cis/trans)-1-oxidotetrahydro-2H-thiopyran-4-yl]methyl}amino)imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 301a were transformed in analogy to example 81 using 3-fluorobenzenethiol to give after working up and purification 7.4 mg (27%) of the title compound A and 4.8 mg (18%) of the title compound B.

1 H-NMR (CDCl 3 ) of A: δ=0.63 (2H), 0.89 (2H), 1.74-1.89 (3H), 2.17 (2H), 2.40 (3H), 2.43 (2H), 2.92 (1H), 3.06 (2H), 3.22 (2H), 5.90 (1H), 5.92 (1H), 5.98 (1H), 7.15 (1H), 7.23 (1H), 7.35-7.44 (3H), 7.63 (1H), 7.65 (1H), 7.69 (1H) ppm.

1 H-NMR (CDCl 3 ) of B: δ=0.62 (2H), 0.90 (2H), 1.49 (2H), 0.87 (1H), 2.20 (2H), 2.40 (3H), 2.62 (2H), 2.92 (1H), 3.19 (2H), 3.35 (2H), 5.87 (2H), 5.93 (1H), 7.15 (1H), 7.24 (1H), 7.35-7.44 (3H), 7.64 (1H), 7.65 (1H), 7.70 (1H) ppm.

›Example 305

N-cyclopropyl-4-{6-[(4-fluorophenyl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

A mixture comprising 75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a, 3 mL dimethyl sulfoxide, 61.1 mg 1,1-binaphthalene-2,2′-diylbis(diphenylphosphine), 30.0 mg tris(dibenzylideneacetone)dipalladium (0) and 55 mg sodium 2-methylpropan-2-olate were heated to 160° C. under microwave irradiation for one hour. The reaction mixture was poured into water and extracted with dichloromethane. The combined organic phases were dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 11.3 mg (14%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.52 (2H), 0.66 (2H), 1.18 (6H), 2.37 (3H), 2.81 (1H), 3.15 (2H), 4.81 (1H), 5.85 (1H), 6.55 (1H), 7.10 (2H), 7.35 (1H), 7.65 (2H), 7.76 (1H), 7.84 (1H), 8.04 (1H), 8.29 (1H), 8.94 (1H) ppm.

›Example 306

4-{6-anilino-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using aniline to give after working up and purification 15.8 mg (21%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 1.18 (6H), 2.38 (3H), 2.81 (1H), 3.16 (2H), 4.81 (1H), 5.89 (1H), 6.53 (1H), 6.90 (1H), 7.27 (2H), 7.34 (1H), 7.66 (2H), 7.77 (1H), 7.85 (1H), 8.12 (1H), 8.30 (1H), 8.92 (1H) ppm.

›Example 307

N-cyclopropyl-4-{6-[(3,4-difluorophenyl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (109 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 3,4-difluoroaniline to give after working up and purification 8.3 mg (14%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 1.18 (6H), 2.36 (3H), 2.81 (1H), 3.16 (2H), 4.80 (1H), 5.85 (1H), 6.65 (1H), 7.22 (1H), 7.31 (1H), 7.34 (1H), 7.76 (1H), 7.82 (1H), 7.91 (1H), 8.00 (1H), 8.30 (1H), 9.17 (1H) ppm.

›Example 308

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(3-methylphenyl) amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (109 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using m-toluidine to give after working up and purification 8.3 mg (16%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.66 (2H), 1.18 (6H), 2.25 (3H), 2.36 (3H), 2.81 (1H), 3.15 (2H), 4.81 (1H), 5.89 (1H), 6.51 (1H), 6.71 (1H), 7.14 (1H), 7.33 (1H), 7.40 (1H), 7.51 (1H), 7.77 (1H), 7.95 (1H), 8.01 (1H), 8.29 (1H), 8.83 (1H) ppm.

›Example 309

N-cyclopropyl-4-{6-[(5-fluoro-2-methylphenyl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide e

50 mg (109 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 5-fluoro-2-methylaniline to give after working up and purification 5.9 mg (11%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.64 (2H), 1.19 (6H), 2.23 (3H), 2.26 (3H), 2.79 (1H), 3.17 (2H), 4.82 (1H), 6.15 (1H), 6.51 (1H), 6.74 (1H), 7.18 (1H), 7.23 (1H), 7.77-7.87 (3H), 7.95 (1H), 8.01 (1H), 8.25 (1H) ppm.

›Example 310

4-{6-[(4-chlorophenyl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

50 mg (109 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 4-chloroaniline to give after working up and purification 8.1 mg (15%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.52 (2H), 0.67 (2H), 1.18 (6H), 2.38 (3H), 2.81 (1H), 3.16 (2H), 4.80 (1H), 5.87 (1H), 6.60 (1H), 7.29 (2H), 7.37 (1H), 7.67 (2H), 7.77 (1H), 7.84 (1H), 8.02 (1H), 8.30 (1H), 9.08 (1H) ppm.

The following compound examples were prepared analogously to the procedure described for example 51 using the appropriate intermediate and the appropriate alcohols, thiols, or amines [LC-MS data such as retention time (RT in min) or observed mass peak were collected using LC-MS Method A unless explicitly stated]:

The following compound examples were prepared analogously to the procedure described for example 101 using the appropriate intermediate and the appropriate boronic acid building block [LC-MS data such as retention time (RT in min) or observed mass peak were collected using LC-MS Method A unless explicitly stated]:

›Example 348

4-{6-[(4-chloro-2-fluorophenyl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 4-chloro-2-fluoroaniline to give after working up and purification 3.1 mg (3%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.65 (2H), 1.18 (6H), 2.31 (3H), 2.79 (1H), 3.16 (2H), 4.79 (1H), 6.15 (1H), 6.59 (1H), 7.19 (1H), 7.31 (1H), 7.43 (1H), 7.77 (1H), 7.79 (1H), 7.95 (1H), 8.15 (1H), 8.27 (1H), 8.63 (1H) ppm.

›Example 349

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(5-methoxy-2-methylphenyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 5-methoxy-2-methylaniline to give after working up and purification 9.1 mg (10%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.64 (2H), 1.18 (6H), 2.17 (3H), 2.22 (3H), 2.78 (1H), 3.16 (2H), 3.62 (3H), 4.81 (1H), 6.04 (1H), 6.43 (1H), 6.56 (1H), 7.08 (1H), 7.20 (1H), 7.34 (1H), 7.80 (1H), 7.85 (1H), 7.88 (1H), 8.02 (1H), 8.23 (1H) ppm.

›Example 350

N-cyclopropyl-4-{6-[4-fluoro-2-(hydroxymethyl)phenyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (104 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 1 using [4-fluoro-2-(hydroxymethyl)phenyl]boronic acid to give after working up and purification 10.4 mg (18%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.64 (2H), 2.34 (3H), 2.67 (2H), 2.79 (1H), 3.61 (2H), 4.65 (2H), 5.34 (1H), 6.36 (1H), 7.20 (1H), 7.33 (1H), 7.41 (1H), 7.59 (1H), 7.67 (1H), 7.91 (1H), 7.95 (1H), 8.01 (1H), 8.27 (1H) ppm.

›Example 351

N-cyclopropyl-4-{6-[(3,5-difluorophenyl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 3,5-difluoroaniline to give after working up and purification 4.9 mg (6%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.66 (2H), 1.18 (6H), 2.35 (3H), 2.81 (1H), 3.17 (2H), 4.80 (1H), 5.87 (1H), 6.67 (1H), 6.73 (1H), 7.30-7.39 (3H), 7.77 (1H), 7.79 (1H), 8.01 (1H), 8.31 (1H), 9.40 (1H) ppm.

›Example 352

N-cyclopropyl-4-{6-[(2,3-difluorophenyl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 2,3-difluoroaniline to give after working up and purification 4.3 mg (5%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 1.18 (6H), 2.30 (3H), 2.79 (1H), 3.17 (2H), 4.80 (1H), 6.16 (1H), 6.62 (1H), 7.02 (1H), 7.12 (1H), 7.28 (1H), 7.80 (2H), 7.92 (1H), 8.00 (1H), 8.27 (1H), 8.77 (1H) ppm.

›Example 353

N-cyclopropyl-4-{6-[(3-fluoro-4-methoxyphenyl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 3-fluoro-4-methoxyaniline to give after working up and purification 16.8 mg (19%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.66 (2H), 1.18 (6H), 2.35 (3H), 2.81 (1H), 3.15 (2H), 3.77 (3H), 4.80 (1H), 5.82 (1H), 6.55 (1H), 7.06 (1H), 7.21 (1H), 7.32 (1H), 7.70 (1H), 7.75 (1H), 7.83 (1H), 8.04 (1H), 8.29 (1H), 8.91 (1H) ppm.

›Example 354

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(4-methoxyphenyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 4-methoxyaniline to give after working up and purification 11.4 mg (13%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 1.18 (6H), 2.37 (3H), 2.81 (1H), 3.14 (2H), 3.70 (3H), 4.80 (1H), 5.83 (1H), 6.46 (1H), 6.86 (2H), 7.33 (1H), 7.55 (2H), 7.75 (1H), 7.85 (1H), 8.10 (1H), 8.29 (1H), 8.71 (1H) ppm.

›Example 355

4-{6-[(3-chlorophenyl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 3-chloroaniline to give after working up and purification 15.4 mg (18%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.66 (2H), 1.18 (6H), 2.36 (3H), 2.81 (1H), 3.16 (2H), 4.80 (1H), 5.88 (1H), 6.64 (1H), 6.92 (1H), 7.27 (1H), 7.36 (1H), 7.71 (1H), 7.58 (1H), 7.83 (1H), 7.93 (1H), 7.95 (1H), 8.28 (1H), 9.15 (1H) ppm.

›Example 356

N-cyclopropyl-4-{6-[(2,4-difluorophenyl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 2,4-difluoroaniline to give after working up and purification 5.0 mg (6%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.65 (2H), 1.18 (6H), 2.28 (3H), 2.79 (1H), 3.14 (2H), 4.80 (1H), 6.06 (1H), 6.54 (1H), 7.04 (1H), 7.27 (1H), 7.30 (1H), 7.78 (1H), 7.79 (1H), 7.94 (1H), 7.99 (1H), 8.25 (1H), 8.48 (1H) ppm.

›Example 357

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(pyridin-2-ylamino) imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using pyridin-2-amine to give after working up and purification 10.1 mg (12%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 1.18 (6H), 2.39 (3H), 2.81 (1H), 3.16 (2H), 4.80 (1H), 6.27 (1H), 6.60 (1H), 6.91 (1H), 7.36 (1H), 7.69 (1H), 7.80 (1H), 7.86 (1H), 8.01 (1H), 8.08 (1H), 8.23 (1H), 8.31 (1H), 9.48 (1H) ppm.

›Example 358

N-cyclopropyl-4-{6-[(4-fluorophenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 4-fluoroaniline to give after working up and purification 20.1 mg (24%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.52 (2H), 0.66 (2H), 2.37 (3H), 2.68 (2H), 2.81 (1H), 3.49 (2H), 5.79 (1H), 7.11 (2H), 7.28 (1H), 7.35 (1H), 7.65 (2H), 7.77 (1H), 7.84 (1H), 8.04 (1H), 8.29 (1H), 8.98 (1H) ppm.

›Example 359

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(pyridin-3-ylamino) imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using pyridin-2-amine to give after working up and purification 12.6 mg (13%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 1.19 (6H), 2.39 (3H), 2.81 (1H), 3.17 (2H), 4.82 (1H), 5.91 (1H), 6.66 (1H), 7.28 (1H), 7.34 (1H), 7.78 (1H), 7.81 (1H), 8.06 (1H), 8.11 (1H), 8.13 (1H), 8.31 (1H), 8.80 (1H), 9.13 (1H) ppm.

›Example 360

N-cyclopropyl-4-{6-[(2-fluoro-4-methylphenyl)sulfanyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 2-fluoro-4-methylbenzenethiol to give after working up and purification 43.2 mg (48%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.65 (2H), 1.13 (6H), 2.19 (3H), 2.39 (3H), 2.79 (1H), 3.24 (2H), 4.72 (1H), 6.29 (1H), 6.97 (1H), 7.00 (1H), 7.14 (1H), 7.25 (1H), 7.52 (1H), 7.57 (1H), 7.64 (1H), 7.93 (1H), 8.24 (1H) ppm.

›Example 361

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(3-isopropoxyphenoxy)imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 3-isopropoxyphenol to give after working up and purification 33.3 mg (37%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.46 (2H), 0.63 (2H), 1.15 (6H), 1.20 (6H), 2.14 (3H), 2.76 (1H), 3.27 (2H), 4.58 (1H), 4.74 (1H), 6.14 (1H), 6.73-6.83 (3H), 6.96 (1H), 7.15 (1H), 7.30 (1H), 7.70 (1H), 7.80 (1H), 7.92 (1H), 8.21 (1H) ppm.

›Example 362

N-cyclopropyl-4-{6-[(2-fluoro-4-methylphenyl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 2-fluoro-4-methylbenzenethiol to give after working up and purification 30.3 mg (34%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.66 (2H), 2.19 (3H), 2.40 (3H), 2.64 (2H), 2.80 (1H), 3.55 (2H), 6.23 (1H), 7.01 (1H), 7.15 (1H), 7.26 (1H), 7.53 (1H), 7.57 (1H), 7.64 (1H), 7.66 (1H), 7.94 (1H), 8.25 (1H) ppm.

›Example 363

4-{6-[4-chloro-2-(hydroxymethyl)phenyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 1 using [4-chloro-2-(hydroxymethyl)phenyl]boronic acid to give after working up and purification 22.5 mg (26%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.64 (2H), 1.15 (6H), 2.33 (3H), 2.79 (1H), 3.31 (2H), 4.64 (2H), 4.73 (1H), 5.32 (1H), 6.42 (1H), 7.00 (1H), 7.32 (1H), 7.43 (1H), 7.51 (1H), 7.65 (1H), 7.91 (1H), 7.95 (1H), 8.00 (1H), 8.26 (1H) ppm.

›Example 364

4-{6-[4-chloro-2-(hydroxymethyl)phenyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 1 using [4-chloro-2-(hydroxymethyl)phenyl]boronic acid to give after working up and purification 15.6 mg (18%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.64 (2H), 2.33 (3H), 2.67 (2H), 2.79 (1H), 3.61 (2H), 4.64 (2H), 5.35 (1H), 6.37 (1H), 7.32 (1H), 7.43 (1H), 7.57 (1H), 7.65 (1H), 7.68 (1H), 7.91 (1H), 7.94 (1H), 8.01 (1H), 8.26 (1H) ppm.

›Example 365

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(pyridin-4-ylamino) imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using pyridin-4-amine to give after working up and purification 10.7 mg (14%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.52 (2H), 0.67 (2H), 1.18 (6H), 2.40 (3H), 2.82 (1H), 3.18 (2H), 4.81 (1H), 5.95 (1H), 6.77 (1H), 7.38 (1H), 7.59 (2H), 7.81 (1H), 7.83 (1H), 8.06 (1H), 8.27-8.35 (3H), 9.45 (1H) ppm.

›Example 366

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(6-methoxypyridin-3-yl)-amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 4-methoxyaniline to give after working up and purification 27 mg (33%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.65 (2H), 1.18 (6H), 2.36 (3H), 2.80 (1H), 3.15 (2H), 3.79 (3H), 4.80 (1H), 5.83 (1H), 6.55 (1H), 6.77 (1H), 7.30 (1H), 7.76 (1H), 7.77 (1H), 7.92 (1H), 8.09 (1H), 8.28 (1H), 8.45 (1H), 8.82 (1H) ppm.

›Example 367

N-cyclopropyl-4-{6-[(2-fluoro-5-methylphenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 2-fluoro-5-methylaniline to give after working up and purification 18.7 mg (22%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.65 (2H), 2.23 (3H), 2.28 (2H), 2.68 (3H), 2.79 (1H), 3.48 (2H), 6.10 (1H), 6.79 (1H), 7.09 (1H), 7.24-7.32 (2H), 7.78 (1H), 7.87 (1H), 7.90 (1H), 7.94 (1H), 8.25 (1H), 8.47 (1H) ppm.

›Example 368

4-{6-anilino-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using aniline to give after working up and purification 21.1 mg (26%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 2.38 (3H), 2.68 (2H), 2.81 (1H), 3.49 (2H), 5.84 (1H), 6.90 (1H), 7.23-7.31 (3H), 7.34 (1H), 7.66 (2H), 7.78 (1H), 7.84 (1H), 8.12 (1H), 8.30 (1H), 8.96 (1H) ppm.

›Example 369

N-cyclopropyl-4-{6-[(2-fluorophenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 2-fluoroaniline to give after working up and purification 12.0 mg (14%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.65 (2H), 2.32 (3H), 2.68 (2H), 2.80 (1H), 3.49 (2H), 6.14 (1H), 7.00 (1H), 7.14 (1H), 7.23 (1H), 7.26-7.34 (2H), 7.79 (1H), 7.81 (1H), 8.02 (1H), 8.17 (1H), 8.27 (1H), 8.57 (1H) ppm.

›Example 370

N-cyclopropyl-4-(6-{[2-(hydroxymethyl)phenyl]amino}-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-O-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using (2-aminophenyl)methanol to give after working up and purification 5.2 mg (6%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.64 (2H), 2.25 (3H), 2.69 (2H), 2.78 (1H), 3.50 (2H), 4.55 (2H), 5.30 (1H), 5.94 (1H), 7.05 (1H), 7.18-7.29 (3H), 7.38 (1H), 7.77-7.87 (3H), 8.01 (1H), 8.07 (1H), 8.24 (1H) ppm.

›Example 371

N-cyclopropyl-4-{6-[(3-fluoro-5-methylphenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 3-fluoro-5-methylaniline to give after working up and purification 20.2 mg (23%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.66 (2H), 2.25 (3H), 2.35 (3H), 2.68 (2H), 2.81 (1H), 3.49 (2H), 5.82 (1H), 6.53 (1H), 7.05 (1H), 7.29-7.39 (2H), 7.54 (1H), 7.77 (1H), 7.87 (1H), 7.98 (1H), 8.30 (1H), 9.12 (1H) ppm.

›Example 372

4-{6-[(4-chloro-3-fluorophenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 4-chloro-3-fluoroaniline to give after working up and purification 16.9 mg (19%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 2.36 (3H), 2.68 (2H), 2.81 (1H), 3.50 (2H), 5.81 (1H), 7.26 (1H), 7.35 (1H), 7.39 (1H), 7.44 (1H), 7.77 (1H), 7.80 (1H), 7.95 (1H), 7.98 (1H), 8.31 (1H), 9.36 (1H) ppm.

›Example 373

N-cyclopropyl-4-{6-[(3,4-difluorophenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 3,4-difluoroaniline to give after working up and purification 11.9 mg (14%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 2.36 (3H), 2.68 (2H), 2.81 (1H), 3.50 (2H), 5.79 (1H), 7.22 (1H), 7.28-7.39 (3H), 7.77 (1H), 7.81 (1H), 7.91 (1H), 8.00 (1H), 8.30 (1H), 9.20 (1H) ppm.

›Example 374

4-{6-[(4-chlorophenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 4-chloroaniline to give after working up and purification 14.3 mg (17%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.52 (2H), 0.67 (2H), 2.38 (3H), 2.68 (2H), 2.81 (1H), 3.49 (2H), 5.82 (1H), 7.30 (2H), 7.33 (1H), 7.38 (1H), 7.68 (2H), 7.78 (1H), 7.84 (1H), 8.02 (1H), 8.30 (1H), 9.12 (1H) ppm.

›Example 375

N-cyclopropyl-4-{6-[(5-fluoro-2-methylphenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 5-fluoro-2-methylaniline to give after working up and purification 6.6 mg (8%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.64 (2H), 2.24 (3H), 2.26 (3H), 2.63-2.85 (3H), 3.50 (2H), 6.11 (1H), 6.75 (1H), 7.19 (1H), 7.24 (1H), 7.29 (1H), 7.78-7.86 (3H), 7.96-8.03 (2H), 8.25 (1H) ppm.

›Example 376

4-{6-[(4-chloro-2-fluorophenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 4-chloro-2-fluoroaniline to give after working up and purification 10.8 mg (12%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 2.31 (3H), 2.68 (2H), 2.80 (1H), 3.49 (2H), 6.12 (1H), 7.21 (1H), 7.32 (1H), 7.35 (1H), 7.46 (1H), 7.79 (1H), 7.80 (1H), 7.96 (1H), 8.18 (1H), 8.28 (1H), 8.69 (1H) ppm.

›Example 377

4-{6-[(5-chloro-2-methylphenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 5-chloro-2-methylaniline to give after working up and purification 9.7 mg (11%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.64 (2H), 2.24 (3H), 2.26 (3H), 2.70 (2H), 2.78 (1H), 3.50 (2H), 6.06 (1H), 7.00 (1H), 7.21 (1H), 7.26 (1H), 7.29 (1H), 7.83 (1H), 7.89 (1H), 7.91-7.95 (2H), 8.04 (1H), 8.23 (1H) ppm.

›Example 378

N-cyclopropyl-4-{6-[(3,5-difluorophenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 3,5-difluoroaniline to give after working up and purification 14.7 mg (17%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.66 (2H), 2.35 (3H), 2.68 (2H), 2.81 (1H), 3.51 (2H), 5.80 (1H), 6.69 (1H), 7.31-7.38 (3H), 7.43 (1H), 7.78 (1H), 7.79 (1H), 8.00 (1H), 8.31 (1H), 9.43 (1H) ppm.

›Example 379

4-{6-[(3-chlorophenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 3-chloroaniline to give after working up and purification 16.7 mg (19%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.66 (2H), 2.36 (3H), 2.68 (2H), 2.81 (1H), 3.50 (2H), 5.82 (1H), 6.93 (1H), 7.28 (1H), 7.32-7.39 (2H), 7.50 (1H), 7.79 (1H), 7.83 (1H), 7.92 (1H), 7.94 (1H), 8.28 (1H), 9.18 (1H) ppm.

›Example 380

N-cyclopropyl-4-{6-[(2,3-difluorophenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 2,3-difluoroaniline to give after working up and purification 6.6 mg (8%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.65 (2H), 2.31 (3H), 2.68 (2H), 2.80 (1H), 3.50 (2H), 6.13 (1H), 7.02 (1H), 7.13 (1H), 7.28 (1H), 7.37 (1H), 7.79 (1H), 7.81 (1H), 7.95 (1H), 7.99 (1H), 8.28 (1H), 8.81 (1H) ppm.

›Example 381

N-cyclopropyl-2-methyl-4-{6-[3-(propan-2-yloxy)phenoxy]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 3-isopropoxyaniline to give after working up and purification 4.8 mg (5%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.46 (2H), 0.63 (2H), 1.21 (6H), 2.14 (3H), 2.67 (2H), 2.76 (1H), 3.58 (2H), 4.58 (1H), 6.09 (1H), 6.75-6.84 (3H), 7.15 (1H), 7.31 (1H), 7.66 (1H), 7.70 (1H), 7.79 (1H), 7.93 (1H), 8.21 (1H) ppm.

›Example 382

N-cyclopropyl-4-{6-[(4-fluoro-3-methylphenyl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 4-fluoro-3-methylaniline to give after working up and purification 16.5 mg (19%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.66 (2H), 1.18 (6H), 2.18 (3H), 2.34 (3H), 2.81 (1H), 3.15 (2H), 4.80 (1H), 5.84 (1H), 6.52 (1H), 7.02 (1H), 7.34 (1H), 7.44-7.51 (2H), 7.75 (1H), 7.92 (1H), 7.96 (1H), 8.27 (1H), 8.83 (1H) ppm.

›Example 383

N-cyclopropyl-4-{6-[(2-fluoro-5-methylphenyl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 2-fluoro-5-methylaniline to give after working up and purification 10.5 mg (12%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.65 (2H), 1.18 (6H), 2.23 (3H), 2.28 (3H), 2.79 (1H), 3.15 (2H), 4.79 (1H), 6.13 (1H), 6.52 (1H), 6.79 (1H), 7.09 (1H), 7.27 (1H), 7.78 (1H), 7.86 (1H), 7.88 (1H), 7.95 (1H), 8.25 (1H), 8.42 (1H) ppm.

›Example 384

N-cyclopropyl-4-{6-[(2-fluorophenyl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 2-fluoroaniline to give after working up and purification 8.3 mg (10%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.65 (2H), 1.18 (6H), 2.31 (3H), 2.80 (1H), 3.16 (2H), 4.79 (1H), 6.17 (1H), 6.54 (1H), 7.00 (1H), 7.14 (1H), 7.22 (1H), 7.28 (1H), 7.78 (1H), 7.81 (1H), 8.02 (1H), 8.14 (1H), 8.27 (1H), 8.52 (1H) ppm.

›Example 385

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(3-isopropylphenyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 3-isopropylaniline to give after working up and purification 11.6 mg (14%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.66 (2H), 1.16 (6H), 1.18 (6H), 2.37 (3H), 2.74-2.87 (2H), 3.15 (2H), 4.79 (1H), 5.89 (1H), 6.51 (1H), 6.79 (1H), 7.18 (1H), 7.26 (1H), 7.32 (1H), 7.68 (1H), 7.76 (1H), 7.93 (1H), 8.02 (1H), 8.28 (1H), 8.84 (1H) ppm.

›Example 386

N-cyclopropyl-4-(6-{[4-(2-hydroxyethyl)phenyl]amino}-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl)-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 2-(4-aminophenyl)ethanol to give after working up and purification 10.6 mg (13%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.52 (2H), 0.66 (2H), 1.18 (6H), 2.38 (3H), 2.64 (2H), 2.81 (1H), 3.15 (2H), 3.54 (2H), 4.57 (1H), 4.80 (1H), 5.87 (1H), 6.49 (1H), 7.10 (2H), 7.34 (1H), 7.55 (2H), 7.76 (1H), 7.84 (1H), 8.12 (1H), 8.31 (1H), 8.82 (1H) ppm.

›Example 387

N-cyclopropyl-4-{6-[(3-fluoro-2-methylphenyl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 3-fluoro-2-methylbenzenethiol to give after working up and purification 35.3 mg (42%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 2.18 (3H), 2.27 (3H), 2.62 (2H), 2.79 (1H), 3.54 (2H), 6.19 (1H), 7.06 (1H), 7.30-7.42 (2H), 7.48 (1H), 7.55 (1H), 7.65 (1H), 7.68 (1H), 7.95 (1H), 8.24 (1H) ppm.

›Example 388

N-cyclopropyl-4-{6-[(2-methoxyphenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

200 mg (415 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 2-methoxyaniline to give after working up and purification 68.3 mg (31%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.65 (2H), 2.35 (3H), 2.69 (2H), 2.80 (1H), 3.29 (3H), 3.49 (2H), 6.28 (1H), 6.87-7.05 (3H), 7.21 (1H), 7.31 (1H), 7.78 (1H), 7.84 (1H), 8.02 (1H), 8.09 (1H), 8.24-8.32 (2H) ppm.

›Example 389

N-cyclopropyl-2-methyl-4-{6-[2-(methylamino)phenoxy]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 2-(methylamino)phenol to give after working up and purification 35.1 mg (43%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.65 (2H), 2.33 (3H), 2.46 (2H), 2.80 (1H), 3.25 (2H), 3.29 (3H), 5.21 (1H), 6.84 (1H), 6.95 (1H), 7.06 (1H), 7.14 (1H), 7.19 (1H), 7.31 (1H), 7.82 (1H), 8.04 (1H), 8.09 (1H), 8.26 (1H), 9.54 (1H) ppm.

›Example 390

N-cyclopropyl-4-{6-(5-fluoro-2-methylphenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 5-fluoro-2-methylphenol to give after working up and purification 31.5 mg (38%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.46 (2H), 0.63 (2H), 2.10 (6H), 2.69 (2H), 2.76 (1H), 3.60 (2H), 6.16 (1H), 7.07 (1H), 7.13 (1H), 7.18 (1H), 7.37 (1H), 7.60 (1H), 7.69 (1H), 7.72 (1H), 7.93 (1H), 8.21 (1H) ppm.

›Example 391

N-cyclopropyl-4-{6-(5-fluoro-2-methylphenoxy)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (109 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 5-fluoro-2-methylphenol to give after working up and purification 29.4 mg (54%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.46 (2H), 0.73 (2H), 1.17 (6H), 2.10 (6H), 2.76 (1H), 3.28 (2H), 4.76 (1H), 6.20 (1H), 6.98 (1H), 7.06 (1H), 7.13 (1H), 7.17 (1H), 7.36 (1H), 7.61 (1H), 7.71 (1H), 7.92 (1H), 8.21 (1H) ppm.

›Example 392

4-(6-{[4-chloro-2-(hydroxymethyl)phenyl]sulfanyl}-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using (5-chloro-2-sulfanylphenyl)methanol to give after working up and purification 49.0 mg (55%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.65 (2H), 2.19 (3H), 2.63 (2H), 2.79 (1H), 3.54 (2H), 4.58 (2H), 5.43 (1H), 6.21 (1H), 7.06 (1H), 7.42 (1H), 7.47 (1H), 7.58-7.70 (4H), 7.94 (1H), 8.24 (1H) ppm.

›Example 393

4-(6-{[4-chloro-2-(hydroxymethyl)phenyl]sulfanyl}-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using (5-chloro-2-sulfanylphenyl)methanol to give after working up and purification 57.0 mg (63%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.65 (2H), 1.13 (6H), 2.19 (3H), 2.79 (1H), 3.24 (2H), 4.57 (2H), 4.72 (1H), 5.42 (1H), 6.28 (1H), 6-98 (1H), 7.06 (1H), 7.41 (1H), 7.48 (1H), 7.59 (1H), 7.61 (1H), 7.64 (1H), 7.92 (1H), 8.23 (1H) ppm.

›Example 394

N-cyclopropyl-4-{6-[(3-fluoro-5-methylphenyl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 3-fluoro-5-methylaniline to give after working up and purification 9.7 mg (11%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 1.18 (6H), 2.24 (3H), 2.34 (3H), 2.81 (1H), 3.16 (2H), 4.81 (1H), 5.89 (1H), 6.52 (1H), 6.61 (1H), 7.05 (1H), 7.32 (1H), 7.53 (1H), 7.76 (1H), 7.88 (1H), 7.98 (1H), 8.29 (1H), 9.11 (1H) ppm.

›Example 395

4-{6-(2-aminophenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 2-aminophenol to give after working up and purification 25.6 mg (32%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.47 (2H), 0.63 (2H), 2.13 (3H), 2.69 (2H), 2.76 (1H), 3.58 (2H), 4.92 (2H), 6.08 (1H), 6.58 (1H), 6.79 (1H), 6.97 (1H), 7.03 (1H), 7.13 (1H), 7.59 (1H), 7.67 (1H), 7.83 (1H), 7.91 (1H), 8.20 (1H) ppm.

›Example 396

4-{6-(2-amino-4-fluorophenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide (A) and

N-cyclopropyl-4-{6-[(4-fluoro-2-hydroxyphenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide (B)

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 2-amino-5-fluorophenol to give after working up and purification 14.8 mg (18%) of the title compound A and 12.6 mg (15%) of the title compound B.

1 H-NMR (DMSO-d6) of A: δ=0.47 (2H), 0.64 (2H), 2.15 (3H), 2.69 (2H), 2.77 (1H), 3.58 (2H), 5.27 (2H), 6.08 (1H), 6.34 (1H), 6.55 (1H), 7.03 (1H), 7.15 (1H), 7.60 (1H), 7.67 (1H), 7.83 (1H), 7.92 (1H), 8.22 (1H) ppm.

1 H-NMR (DMSO-d6) of B: δ=0.50 (2H), 0.66 (2H), 2.34 (3H), 2.68 (2H), 2.81 (1H), 3.49 (2H), 6.38 (1H), 6.55 (1H), 6.79 (1H), 7.26 (1H), 7.30 (1H), 7.76 (1H), 7.82 (1H), 8.04 (1H), 8.09 (1H), 8.14 (1H), 8.29 (1H), 9.86 (1H) ppm.

›Example 397

4-{6-(2-chloro-3-fluorophenoxy)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 2-chloro-3-fluoroaniline to give after working up and purification 6.0 mg (6%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 1.17 (6H), 2.36 (3H), 2.81 (1H), 3.17 (2H), 4.83 (1H), 5.95 (1H), 6.68 (1H), 7.28 (1H), 7.35 (1H), 7.40 (1H), 7.76 (1H), 7.81 (1H), 7.95 (1H), 7.99 (1H), 8.31 (1H), 9.51 (1H) ppm.

›Example 398

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(3-methoxy-2-methylphenyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 3-methoxy-2-methylaniline to give after working up and purification 16.7 mg (20%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.64 (2H), 1.18 (6H), 2.06 (3H), 2.21 (3H), 2.78 (1H), 3.15 (2H), 3.77 (3H), 4.81 (1H), 5.97 (1H), 6.40 (1H), 6.73 (1H), 7.13 (1H), 7.18 (1H), 7.24 (1H), 7.79 (2H), 8.01 (2H), 8.22 (1H) ppm.

›Example 399

N-cyclopropyl-4-{6-[(2-hydroxyphenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

40 mg (76 μmol) N-cyclopropyl-4-{6-[(2-methoxyphenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide which was prepared according to example 388 were transformed in analogy to intermediate example 280 to give after working up and purification 14.7 mg (36%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 2.35 (3H), 2.68 (2H), 2.80 (1H), 3.48 (2H), 6.28 (1H), 6.73-6.88 (3H), 7.17 (1H), 7.30 (1H), 7.77 (1H), 7.83 (1H), 7.91 (1H), 8.10 (1H), 8.18 (1H), 8.28 (1H), 9.80 (1H) ppm.

›Example 400

N-cyclopropyl-4-{6-[(4-fluoro-3-methoxyphenyl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to intermediate example 305 using 4-fluoro-3-methoxyaniline to give after working up and purification 20.3 mg (24%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 1.18 (6H), 2.33 (3H), 2.81 (1H), 3.16 (2H), 3.67 (3H), 4.80 (1H), 5.85 (1H), 6.57 (1H), 7.08 (1H), 7.23 (1H), 7.28 (1H), 7.33 (1H), 7.75 (1H), 7.86 (1H), 7.99 (1H), 8.27 (1H), 8.91 (1H) ppm.

›Example 401

4-{6-[(4-chloro-3-fluorophenyl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to intermediate example 305 using 4-chloro-3-fluoroaniline to give after working up and purification 5.6 mg (7%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.52 (2H), 0.66 (2H), 1.18 (6H), 2.37 (3H), 2.82 (1H), 3.17 (2H), 4.81 (1H), 5.91 (1H), 6.69 (1H), 7.28 (1H), 7.35 (1H), 7.41 (1H), 7.76 (1H), 7.81 (1H), 7.95 (1H), 7.99 (1H), 8.31 (1H), 9.41 (1H) ppm.

›Example 402

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(2-methoxyphenyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (109 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 2-methoxyaniline to give after working up and purification 59.7 mg (35%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 1.18 (6H), 2.35 (3H), 2.80 (1H), 3.17 (2H), 3.84 (3H), 4.78 (1H), 6.29 (1H), 6.43 (1H), 6.88-6.96 (2H), 7.00 (1H), 7.31 (1H), 7.77 (1H), 7.84 (1H), 7.92 (1H), 8.09 (1H), 8.25 (1H), 8.29 (1H) ppm.

›Example 403

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(3-methoxyphenyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

150 mg (327 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 3-methoxyaniline to give after working up and purification 44.4 mg (24%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.67 (2H), 1.18 (6H), 2.36 (3H), 2.81 (1H), 3.15 (2H), 3.66 (3H), 4.80 (1H), 5.88 (1H), 6.48 (1H), 6.55 (1H), 7.16 (1H), 7.20-7.28 (2H), 7.32 (1H), 7.77 (1H), 7.86 (1H), 8.08 (1H), 8.29 (1H), 8.90 (1H) ppm.

›Example 404

4-{6-[(5-chloro-2-methylphenyl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 5-chloro-2-methylaniline to give after working up and purification 6.2 mg (7%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.64 (2H), 1.19 (6H), 2.23 (3H), 2.26 (3H), 2.78 (1H), 3.17 (2H), 4.82 (1H), 6.10 (1H), 6.52 (1H), 6.99 (1H), 7.20 (1H), 7.26 (1H), 7.82 (1H), 7.88-7.96 (3H), 8.01 (1H), 8.23 (1H) ppm.

›Example 405

4-{6-[(2-chloro-4-fluorophenyl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 2-chloro-4-fluoroaniline to give after working up and purification 7.3 mg (8%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.64 (2H), 1.18 (6H), 2.24 (3H), 2.78 (1H), 3.17 (2H), 4.80 (1H), 5.72 (1H), 6.09 (1H), 6.53 (1H), 7.23 (1H), 7.49 (1H), 7.76 (1H), 7.79 (1H), 7.90 (1H), 7.92 (1H), 8.23 (1H), 8.25 (1H) ppm.

›Example 406

N-cyclopropyl-4-{6-[(6-fluoropyridin-3-yl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

50 mg (109 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 6-fluoropyridin-3-amine to give after working up and purification 9.9 mg (18%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 1.18 (6H), 2.37 (3H), 2.81 (1H), 3.17 (2H), 4.80 (1H), 5.87 (1H), 6.67 (1H), 7.10 (1H), 7.34 (1H), 7.76 (1H), 7.78 (1H), 8.00 (1H), 8.16 (1H), 8.29 (1H), 8.50 (1H), 9.17 (1H) ppm.

›Example 407

4-{6-(cyclopentylamino)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

50 mg (109 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using cyclopentanamine to give after working up and purification 10.8 mg (20%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.64 (2H), 1.15 (6H), 1.43-1.72 (6H), 1.97 (2H), 2.34 (3H), 2.79 (1H), 3.06 (2H), 3.99 (1H), 4.76 (1H), 5.61 (1H), 6.17 (1H), 6.37 (1H), 7.29 (1H), 7.72 (1H), 7.99 (1H), 8.17 (1H), 8.24 (1H) ppm.

›Example 408

4-{6-(cyclopent-3-en-1-ylamino)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

100 mg (218 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using cyclopent-3-en-1-amine to give after working up and purification 12.8 mg (12%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.64 (2H), 1.15 (6H), 2.25 (1H), 2.28 (1H), 2.34 (3H), 2.73-2.83 (3H), 3.07 (2H), 4.32 (1H), 4.76 (1H), 5.61 (1H), 5.73 (2H), 6.21 (1H), 6.57 (1H), 7.31 (1H), 7.73 (1H), 8.02 (1H), 8.13 (1H), 8.25 (1H) ppm.

›Example 409

N-cyclopropyl-4-{6-[(3-ethenylphenyl)amino]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using 3-vinylaniline to give after working up and purification 28.0 mg (33%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 1.18 (6H), 2.34 (3H), 2.81 (1H), 3.16 (2H), 4.81 (1H), 5.18 (1H), 5.67 (1H), 5.89 (1H), 6.56 (1H), 6.64 (1H), 7.03 (1H), 7.24 (1H), 7.31 (1H), 7.62 (1H), 7.63 (1H), 7.77 (1H), 7.91 (1H), 8.01 (1H), 8.29 (1H), 8.94 (1H) ppm.

›Example 410

N-cyclopropyl-4-{6-[(6-fluoropyridin-3-yl)oxy]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 6-fluoropyridin-3-ol to give after working up and purification 4.1 mg (5%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.47 (2H), 0.64 (2H), 1.17 (6H), 2.14 (3H), 2.77 (1H), 3.28 (2H), 4.75 (1H), 6.24 (1H), 7.07 (1H), 7.17 (1H), 7.32 (1H), 7.61 (1H), 7.68 (1H), 7.92 (1H), 8.03 (1H), 8.23 (1H), 8.25 (1H) ppm.

›Example 411

5-({3-[4-(cyclopropylcarbamoyl)-3-methylphenyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)nicotinamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 5-hydroxynicotinamide to give after working up and purification 22.0 mg (25%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.46 (2H), 0.63 (2H), 1.17 (6H), 2.09 (3H), 2.76 (1H), 3.13 (2H), 4.75 (1H), 6.27 (1H), 7.10 (1H), 7.13 (1H), 7.61 (1H), 7.64 (1H), 7.69 (1H), 7.92 (1H), 8.17-8.22 (3H), 8.72 (1H), 8.96 (1H) ppm.

›Example 412

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(pyrazin-2-ylsulfanyl) imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using pyrazine-2-thiol to give after working up and purification 17.5 mg (21%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.65 (2H), 1.13 (6H), 2.23 (3H), 2.79 (1H), 3.25 (2H), 4.71 (1H), 6.48 (1H), 7.16 (1H), 7.19 (1H), 7.66 (1H), 7.71 (1H), 7.97 (1H), 8.25 (1H), 8.58 (1H), 8.61 (1H), 8.83 (1H) ppm.

›Example 413

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 4-methyl-4H-1,2,4-triazole-3-thiol to give after working up and purification 17.5 mg (21%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 1.14 (6H), 2.28 (3H), 2.80 (1H), 3.25 (2H), 3.61 (3H), 4.73 (1H), 6.38 (1H), 7.17 (1H), 7.21 (1H), 7.48 (1H), 7.60 (1H), 7.96 (1H), 8.28 (1H), 8.93 (1H) ppm.

›Example 414

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-(1H-pyrazol-5-yloxy) imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 1H-pyrazol-5-ol to give after working up and purification 5.5 mg (7%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.64 (2H), 1.15 (6H), 2.25 (3H), 2.78 (1H), 3.26 (2H), 4.75 (1H), 6.13 (1H), 6.16 (1H), 6.98 (1H), 7.23 (1H), 7.73-7.80 (2H), 7.91 (1H), 7.93 (1H), 8.26 (1H), 12.45 (1H) ppm.

›Example 415

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(5-methyl-1H-pyrazol-3-yl)oxy]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using 5-methyl-1H-pyrazol-3-ol to give after working up and purification 6.3 mg (8%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.64 (2H), 1.15 (6H), 2.23 (3H), 2.26 (3H), 2.79 (1H), 3.26 (2H), 4.74 (1H), 5.92 (1H), 6.11 (1H), 6.96 (1H), 7.24 (1H), 7.77 (1H), 7.90 (1H), 7.96 (1H), 8.26 (1H), 12.13 (1H) ppm.

›Example 416

4-{6-(cyclohexylamino)-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (164 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 305 using cyclohexanamine to give after working up and purification 7.8 mg (10%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.64 (2H), 1.11-1.42 (5H), 1.15 (6H), 1.60 (1H), 1.73 (2H), 2.03 (2H), 2.35 (3H), 2.79 (1H), 3.06 (2H), 3.56 (1H), 4.77 (1H), 5.61 (1H), 6.17 (1H), 6.25 (1H), 7.28 (1H), 7.72 (1H), 7.95 (1H), 8.16 (1H), 8.26 (1H) ppm.

›Example 417

4-{6-[(2-amino-4-fluorophenyl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 2-amino-4-fluorobenzenethiol to give after working up and purification 23.7 mg (27%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.48 (2H), 0.65 (2H), 2.24 (3H), 2.60 (2H), 2.79 (1H), 3.49 (2H), 5.75 (2H), 6.02 (1H), 6.40 (1H), 6.58 (1H), 7.12 (1H), 7.38 (1H), 7.60 (1H), 7.74 (1H), 7.75 (1H), 7.93 (1H), 8.24 (1H) ppm.

›Example 418

N-cyclopropyl-4-{6-[2-methoxy-3-(propan-2-yl)phenoxy]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 3-isopropyl-2-methoxyphenol to give after working up and purification 45 mg (48%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.45 (2H), 0.63 (2H), 1.16 (6H), 2.06 (3H), 2.60-2.80 (3H), 3.17-3.26 (1H), 3.60 (2H), 3.71 (3H), 6.17 (1H), 7.04-7.23 (4H), 7.61 (1H), 7.67 (1H), 7.71 (1H), 7.94 (1H), 8.19 (1H) ppm.

›Example 419

N-cyclopropyl-2-methyl-4-{6-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using 4-methyl-4H-1,2,4-triazole-3-thiol to give after working up and purification 29.4 mg (35%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 2.28 (3H), 2.66 (2H), 2.80 (1H), 3.57 (2H), 3.61 (3H), 6.35 (1H), 7.20 (1H), 7.46 (1H), 7.59 (1H), 7.84 (1H), 7.96 (1H), 8.27 (1H), 8.93 (1H) ppm.

›Example 420

N-cyclopropyl-2-methyl-4-{6-(pyrazin-2-ylsulfanyl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 51 using pyrazine-2-thiol to give after working up and purification 28.6 mg (34%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.49 (2H), 0.64 (2H), 2.23 (3H), 2.64 (2H), 2.79 (1H), 3.57 (2H), 6.43 (1H), 7.18 (1H), 7.64 (1H), 7.69 (1H), 7.83 (1H), 7.97 (1H), 8.25 (1H), 8.57-8.62 (2H), 8.86 (1H) ppm.

›Example 421

N-cyclopropyl-4-(6-{[(1RS,2RS)-2-hydroxycyclohexyl]oxy}-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl)-2-methylbenzamide

50 mg (109 μmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 96a were transformed in analogy to example 51 using (1RS,2RS)-cyclohexane-1,2-diol to give after working up and purification 2.8 mg (5%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.65 (2H), 1.13 (6H), 1.23-1.39 (4H), 1.66 (2H), 1.89 (1H), 2.36 (3H), 2.80 (1H), 3.19 (2H), 3.54 (1H), 4.65 (1H), 4.72 (1H), 4.82 (1H), 5.72 (1H), 5.84 (1H), 6.66 (1H), 7.33 (1H), 7.87 (1H), 7.91 (1H), 8.08 (1H), 8.29 (1H) ppm.

›Example 422

N-cyclopropyl-4-{6-[(4-fluoro-3-methoxyphenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

100 mg (207 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 4-fluoro-3-methoxyaniline to give after working up and purification 43.1 mg (38%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 2.33 (3H), 2.67 (2H), 2.81 (1H), 3.49 (2H), 3.67 (3H), 5.78 (1H), 7.08 (1H), 7.19-7.37 (4H), 7.76 (1H), 7.85 (1H), 7.99 (1H), 8.27 (1H), 8.94 (1H) ppm.

›Example 423

N-cyclopropyl-2-methyl-4-{6-[(3-methylphenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using m-toluidine to give after working up and purification 14.5 mg (17%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.90 (2H), 2.35 (3H), 2.43-2.58 (2H), 2.51 (3H), 2.61 (1H), 2.92 (1H), 3.59 (2H), 5.64 (1H), 5.78 (1H), 5.91 (1H), 6.25 (1H), 6.89 (1H), 7.22 (1H), 7.35 (1H), 7.40 (1H), 7.65 (1H), 7.90 (1H), 7.92 (1H) ppm.

›Example 424

N-cyclopropyl-4-{6-[(3-fluoro-4-methoxyphenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 3-fluoro-4-methoxyaniline to give after working up and purification 21.0 mg (24%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.64 (2H), 0.90 (2H), 2.44-2.60 (2H), 2.51 (3H), 2.92 (1H), 3.59 (2H), 3.89 (3H), 5.55 (1H), 5.78 (1H), 5.94 (1H), 6.20 (1H), 6.92 (1H), 7.06 (1H), 7.41 (1H), 7.55 (1H), 7.64 (1H), 7.83 (1H), 7.92 (1H) ppm.

›Example 425

N-cyclopropyl-4-{6-[(4-methoxyphenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 4-methoxyaniline to give after working up and purification 17.8 mg (21%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.90 (2H), 2.43-2.60 (2H), 2.51 (3H), 2.92 (1H), 3.57 (2H), 3.82 (3H), 5.56 (1H), 5.77 (1H), 5.91 (1H), 6.10 (1H), 6.91 (2H), 7.35-7.42 (3H), 7.64 (1H), 7.83 (1H), 7.98 (1H) ppm.

›Example 426

N-cyclopropyl-4-{6-[(3-methoxy-2-methylphenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

150 mg (311 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 3-methoxy-2-methylaniline to give after working up and purification 21.3 mg (12%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.62 (2H), 0.89 (2H), 2.20 (3H), 2.47 (3H), 2.50 (2H), 2.92 (1H), 3.55 (2H), 3.87 (3H), 5.63 (1H), 5.81 (1H), 5.89 (1H), 6.00 (1H), 6.72 (1H), 7.16-7.25 (2H), 7.36 (1H), 7.65 (1H), 7.84 (1H); 7.93 (1H) ppm.

›Example 427

N-cyclopropyl-4-(6-{[4-(2-hydroxyethyl)phenyl]amino}-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl)-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 2-(4-aminophenyl)ethanol to give after working up and purification 9.2 mg (10%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.52 (2H), 0.66 (2H), 2.38 (3H), 2.58-2.77 (4H), 2.82 (1H), 3.41-3.59 (4H), 4.59 (1H), 5.82 (1H), 7.11 (2H), 7.24 (1H), 7.34 (1H), 7.56 (2H), 7.77 (1H), 7.83 (1H), 8.12 (1H), 8.32 (1H), 8.86 (1H) ppm.

›Example 428

N-cyclopropyl-4-{6-[(4-fluoro-3-methylphenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 4-fluoro-3-methylaniline to give after working up and purification 11.9 mg (14%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.63 (2H), 0.89 (2H), 2.25 (3H), 2.42-2.56 (2H), 2.48 (3H), 2.92 (1H), 3.53 (2H), 5.57 (1H), 5.87 (1H), 5.99 (1H), 6.39 (1H), 6.95 (1H), 7.21-7.34 (2H), 7.36 (1H), 7.62 (1H), 7.85 (1H), 7.87 (1H) ppm.

›Example 429

N-cyclopropyl-4-{6-[(6-methoxypyridin-3-yl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

75 mg (156 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 6-methoxypyridin-3-amine to give after working up and purification 8.7 mg (10%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.50 (2H), 0.64 (2H), 2.37 (3H), 2.68 (2H), 2.80 (1H), 3.30 (3H), 3.49 (2H), 5.77 (1H), 6.78 (1H), 7.25-7.35 (2H), 7.77 (2H), 7.93 (1H), 8.09 (1H), 8.29 (1H), 8.46 (1H), 8.86 (1H) ppm.

›Example 430

N-cyclopropyl-4-{6-[(5-methoxy-2-methylphenyl)amino]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

150 mg (311 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a were transformed in analogy to example 305 using 5-methoxy-2-methylaniline to give after working up and purification 15.5 mg (9%) of the title compound.

1 H-NMR (CDCl 3 ): δ=0.62 (2H), 0.89 (2H), 2.26 (3H), 2.48 (3H), 2.52 (2H), 2.92 (1H), 3.58 (2H), 3.73 (3H), 5.65 (1H), 5.79 (1H), 5.89 (1H), 5.96 (1H), 6.62 (1H), 7.14 (1H), 7.31 (1H), 7.38 (1H), 7.66 (1H), 7.87 (1H), 7.90 (1H) ppm.

›Example 431

N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(2-hydroxyphenyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide

40 mg (80 μmol) N-cyclopropyl-4-{8-[(2-hydroxy-2-methylpropyl)amino]-6-[(2-methoxyphenyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide which was prepared according to example 402 were transformed in analogy to example 280 to give after working up and purification 5.8 mg (13%) of the title compound.

1 H-NMR (DMSO-d6): δ=0.51 (2H), 0.66 (2H), 1.17 (6H), 2.36 (3H), 2.81 (1H), 3.17 (2H), 4.76 (1H), 6.28 (1H), 6.40 (1H), 6.71-6.89 (3H), 7.30 (1H), 7.76 (1H), 7.80-7.91 (2H), 8.11 (1H), 8.16 (1H), 8.29 (1H), 9.90 (1H) ppm.

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IPC · International Patent Classification

Section A — Human necessities

A61K31/5025
A61K31/5377
A61K45/06
A61K31/506

Section C — Chemistry; metallurgy

C07D471/04
C07D487/04

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