HK1206009B - Amino-substituted imidazopyridazines - Google Patents

Description

Amino-substituted imidazopyridazines

The present invention relates to amino-substituted imidazopyridazine compounds of general formula (I) as described and defined herein, to methods of preparing said compounds, to intermediate compounds useful for 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.

Background

The present invention relates to compounds that inhibit MKNK1 kinase (also known as MAP kinase interacting kinase, Mnk1) and MKNK2 kinase (also known as MAP kinase interacting kinase, Mnk 2). Human MKNK comprises a set of four proteins encoded by two genes (gene symbols: MKNK1 and MKNK2) by alternative splicing. Type b lacks the C-terminal MAP kinase binding domain. The catalytic domains of MKNK1 and MKNK2 are very similar and contain a unique DFD (Asp-Phe-Asp) motif in subdomain VII, which is typically DFG (Asp-Phe-Gly) among other protein kinases and is believed to alter ATP binding [ Jauch et al, structure13,1559-1568,2005 and Jauch et al, EMBO J25, 4020-. MKNK1a binds to and is activated by ERK and p38MAP kinases, but not JNK 1. MKNK2a binds to and is only activated by ERK. MKNK1b had low activity under all conditions, MKNK2b had basal activity independent of ERK or p38MAP kinase [ Buxade M et al, Frontiersin Bioscience5359-5374, 1/5 2008 ].

MKNK phosphorylated eukaryotic initiation factor 4E (eIF4E), heterogeneous nuclear RNA-binding protein A1(hnRNPA1), polypyrimidine tract-binding protein-related splicing factor (PSF), cytoplasmic phospholipase A2(cPLA2) and Sprouty 2(hSPRY2) [ Buxade M et al, Frontiers in Bioscience5359-5374,2008, 5.1.2008 ].

eIF4E is an oncogene that is amplified in many cancers and is shown in the KO-mouse study [ Konicek et al, Cell Cycle 7:16,2466-2471, 2008; ueda et al, Mol Cell Biol 24,6539-6549,2004], are phosphorylated only by the MKNK protein. eIF4E plays a key role in translation of cellular mRNA. eIF4E binds to the 7-methylguanosine cap at the 5' end of cellular mRNA and delivers them to the ribosome as part of the eIF4F complex, which also includes eIF4G and eIF 4A. Although all capped mrnas require eIF4E for translation, mRNA pools were aberrantly dependent on elevated eIF4E activity for translation. These so-called "weak mRNAs" are generally translated less efficiently due to their long and complex 5' UTR region, and they encode proteins that play an important role in all aspects of malignancy, including VEGF, FGF-2, c-Myc, cyclin D1, survivin, BCL-2, MCL-1, MMP-9, heparanase, and the like. expression and function of eIF4E is elevated in a variety of human cancers and is directly associated with disease progression [ Konicek et al, Cell Cycle 7:16,2466-2471,2008 ].

MKNK1 and MKNK2 are the only kinases known to phosphorylate eIF4E at Ser 209. The overall translation rate is not affected by phosphorylation of eIF4E, but it has been shown that eIF4E phosphorylation promotes polysome formation (i.e., multiple ribosomes on a single mRNA) that ultimately enables a "weak mRNA" to be translated more efficiently [ Buxade M et al, Frontiers in Bioscience5359-5374,2008 5 months 1 ]. Alternatively, phosphorylation of eIF4E by MKNK protein facilitates the release of eIF4E from the 5' cap, allowing the 48S complex to move along the "weak mRNA" to locate the initiation codon [ Blagden SP and Willis AE, Nat Rev ClinOncol.8(5):280-91,2011 ]. Thus, increased eIF4E phosphorylation predicts a poor prognosis for non-small cell lung Cancer patients [ Yoshizawa et al, Clin Cancer Res.16(1):240-8,2010 ]. Other data suggest a functional role for MKNK 1in carcinogenesis, as overexpression of constitutively activated MKNK1 (but not kinase dead MKNK1) in mouse embryonic fibroblasts promoted tumor formation [ Chrestensen c.a. et al, Genes Cells 12, 1133-. Furthermore, increased MKNK protein phosphorylation and activity is associated with overexpression of HER2 in breast cancer [ Chrestensen, c.a. et al, j.biol.chem.282,4243-4252,2007 ]. In a model using E μ -Myc transgenic hematopoietic stem cells for tumor generation in mice, MKNK1 that is constitutively activated (rather than kinase dead) also promotes tumor growth. Similar results were obtained when eIF4E with the S209D mutation was analyzed. The S209D mutation mimics phosphorylation at the MKNK1 phosphorylation site. In contrast, the non-phosphorylatable form of eIF4E attenuates tumor growth [ Wendel HG et al, GenesDev.21(24):3232-7,2007 ]. Selective MKNK inhibitors that block phosphorylation of eIF4E induced apoptosis and inhibited proliferation of cancer cells and soft agar growth in vitro. This inhibitor also inhibited the growth halo of experimental B16 melanoma lung metastases and the growth of subcutaneous HCT116 colon cancer xenograft tumors without affecting body weight [ Konicek et al, cancer Res.71(5):1849-57,2011 ]. In summary, phosphorylation of eIF4E by MKNK protein activity promotes cell proliferation and survival and is critical for malignant transformation. Inhibition of MKNK activity may provide an easily manageable cancer treatment.

WO 2007/025540 a2(Bayer Schering Pharma AG) relates to substituted imidazo [1,2-b ] pyridazines as kinase inhibitors, in particular PKC (protein kinase C) inhibitors, in particular PKC θ inhibitors.

WO2007/025090 a2(Kalypsis, Inc.) relates to heterocyclic compounds which are useful as inhibitors of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (Erk) kinase (abbreviated "MEK"). In particular, WO2007/025090 a2 relates inter alia to imidazo [1,2-b ] pyridazine.

WO 2007/013673 a1(Astellas Pharma Inc.) relates to fused heterocycles as inhibitors of lymphocyte protein tyrosine kinases (abbreviated "LCK"). In particular, WO 2007/013673A 1 relates inter alia to imidazo [1,2-b ] pyridazines.

WO 2007/147646 a1(Bayer Schering Pharma AG) relates to oxo-substituted imidazo [1,2-b ] pyridazines as kinase inhibitors, in particular PKC (protein kinase C) inhibitors, in particular PKC θ inhibitors.

WO 2008/025822 a1(cellzome (uk) Ltd.) relates to oxadiazodiazine derivatives for use as kinase inhibitors. In particular, WO 2008/025822 a1 relates inter alia to imidazo [1,2-b ] pyridazines useful as kinase inhibitors, in particular inducible T cell kinase (abbreviated as "Itk") inhibitors.

WO 2008/030579 a2(Biogen Idec MA Inc.) relates to modulators of interleukin-1 (IL-1) receptor associated kinase (abbreviated as "IRAK"). In particular, WO 2008/030579A 2 relates inter alia to imidazo [1,2-b ] pyridazines.

WO 2008/058126 a2(Supergen, Inc.) relates inter alia to imidazo [1,2-b ] pyridazine derivatives which act as protein kinase inhibitors, in particular PIM kinase inhibitors.

WO 2009/060197 a1(Centro Nacional de investigations Oncology (CNIO)) relates to imidazopyridazines which are useful as inhibitors of protein kinases such as PIM family kinases.

US 4,408,047(Merck & co., Inc.) relates inter alia to imidazopyridazines with 3-amino-2-OR-propoxy substituents, which have β -adrenergic blocking activity.

WO 03/018020A 1(Takeda Chemical Industries, Ltd.) relates to inhibitors against c-Jun N-terminal kinases comprising compounds which are inter alia imidazo [1,2-b ] pyridazine.

WO 2008/052734 a1(Novartis AG) relates to heterocyclic compounds as anti-inflammatory agents. In particular, said compound is in particular imidazo [1,2-b ] pyridazine. The compounds are useful for treating diseases mediated by the ALK-5 and/or ALK-4 receptors, and also for treating diseases mediated by the PI3K receptor, the JAK-2 receptor, and the TRK receptor.

WO 2008/072682 a1(Daiichi Sankyo Company, Limited) relates to imidazo [1,2-b ] pyridazine derivatives having an inhibitory effect on TNF- α production, playing a role in pathological models of inflammatory and/or autoimmune diseases.

WO 2008/079880 a1(Alcon Research, Ltd.) relates to 6-aminoimidazo [1,2-b ] pyridazine analogs useful as Rho-kinase inhibitors for the treatment of glaucoma and ocular hypertension.

WO 2009/091374 a2(Amgen Inc.) relates to fused heterocyclic derivatives. The selected compounds are effective in preventing and treating diseases, such as hepatocyte growth factor ("HGF") diseases.

In j.med.chem.,2005,487604-7614 is an article entitled "Structural base of inhibition specificity of the Protoprogene Proviral Insertion Site in molecular MurineLeukemia Virus (PIM-1) Kinase", and discloses inter alia imidazo [1,2-b ] as an inhibitor structure for the studies described therein]Pyridazine.

In j.med.chem.,2010,536618-Some specific imidazo [1,2-b ] compounds identified as MKNK-1 inhibitors are disclosed]Pyridazine.

In Cancer Res, 3 months and 1 day 2011,711849-1857 is an article entitled "Therapeutic inhibition of MAP kinase interacting inhibition blocks Erukinductive inhibition factor 4 Ephosporylation and supressures out of experimental residues", and discloses in particular that the known antifungal agent Cercosporamide (Cercosporide) is an inhibitor of MKNK 1.

However, the above prior art does not describe specific substituted imidazopyridazine compounds of general formula (I) of the present invention as defined herein, i.e. such imidazo [1,2-b ] pyridazinyl moieties, as described and defined herein and hereinafter referred to as "compounds of the present invention", or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, or the pharmacological activity thereof, as defined herein:

-in its 3-position:

a group;

-a group having the following structure in its 6-position:

wherein:

denotes the point of attachment of the group to the rest of the molecule,

-R1 represents a linear C optionally substituted as defined herein₁-C₆-alkyl-, branched C₃-C₆-alkyl-or C₃-C₆-cycloalkyl-, and

-R5 represents:

or:

a substituent as defined herein;

or:

o together with the nitrogen atom to which it is attached and the carbon atom of R1 form a 3-to 7-membered cyclic amine group as defined herein;

it has now been found that the compounds of the invention have surprising and advantageous properties and this forms the basis of the present invention.

In particular, it has surprisingly been found that said compounds of the invention effectively inhibit MKNK-1 kinase and are therefore useful for the treatment or prevention of diseases caused by, or accompanied by, uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response or an inappropriate cellular inflammatory response, in particular wherein said uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by MKNK-1 kinase, such as hematological tumors, solid tumors and/or metastases thereof, such as leukemias and myelodysplastic syndromes, malignant lymphomas, head and neck tumors including brain tumors and brain metastases, tumors, and/or metastases thereof, Breast, gastrointestinal, endocrine, breast and other gynecological tumors including non-small cell and small cell lung tumors, urinary system tumors including kidney, bladder and prostate tumors, skin tumors and sarcomas, and/or metastases thereof.

Disclosure of Invention

According to a first aspect, the present invention covers a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same:

wherein:

represents:

a group;

wherein denotes the point of attachment of the group to the rest of the molecule; and is

R1 represents linear C₁-C₆-alkyl-, branched C₃-C₆-alkyl-or C₃-C₆-cycloalkyl, optionally substituted once or more times independently from each other with substituents selected from:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, aryl-, -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH₂、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)₂R’、-N(R’)S(＝O)₂R’、-N＝S(＝O)(R’)R”、-OH、C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH₂、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C₁-C₆-alkyl-S-, -S (═ O) R', -S (═ O)₂R’、-S(＝O)₂NH₂、-S(＝O)₂NHR’、-S(＝O)₂N(R’)R”；

R2 represents a hydrogen atom;

r3 represents a substituent selected from:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, -C (═ O) R', -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-NH₂、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH₂、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH₂、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO₂、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)₂R’、-N(R’)S(＝O)₂R’、-N＝S(＝O)(R’)R”、-OH、C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, -OC (═ O) R', -SH, C₁-C₆-alkyl-S-, -S (═ O) R', -S (═ O)₂R’、-S(＝O)₂NH₂、-S(＝O)₂NHR’、-S(＝O)₂N(R’)R”、-S(＝O)(＝NR’)R”；

R4 represents a substituent selected from:

hydrogen atom, halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-optionally substituted once or more times independently of each other with R substituents; heteroaryl-optionally substituted once or more times independently of each other with an R substituent; -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH₂、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH₂、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH₂、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO₂、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)₂R’、-N(R’)S(＝O)₂R’、-N＝S(＝O)(R’)R”、-OH、C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH₂、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C₁-C₆-alkyl-S-, -S (═ O) R', -S (═ O)₂R’、-S(＝O)₂NH₂、-S(＝O)₂NHR’、-S(＝O)₂N(R’)R”、-S(＝O)(＝NR’)R”；

R represents a substituent selected from the group consisting of:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, -C (═ O) R', -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH₂、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH₂、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH₂、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO₂、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)₂R’、-N(R’)S(＝O)₂R’、-N＝S(＝O)(R’)R”、-OH、C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH₂、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C₁-C₆-alkyl-S-, -S (═ O) R', -S (═ O)₂R’、-S(＝O)₂NH₂、-S(＝O)₂NHR’、-S(＝O)₂N(R’)R”、-S(＝O)(＝NR’)R”；

R' and R "independently of each other represent a substituent selected from the group consisting of:

C₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-, C₁-C₆-a haloalkyl group;

r5 represents:

or:

-a substituent selected from: c₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-, aryl-, -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-S(＝O)R’、-S(＝O)₂R’；

Or:

-together with the nitrogen atom to which it is attached and the carbon atom of R1 form a 3-to 7-membered cyclic amine group, optionally substituted with a substituent selected from:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, aryl-, -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH₂、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)₂R’、-N(R’)S(＝O)₂R’、-N＝S(＝O)(R’)R”、-OH、C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH₂、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C₁-C₆-alkyl-S-, -S (═ O) R', -S (═ O)₂R’、-S(＝O)₂NH₂、-S(＝O)₂NHR’、-S(＝O)₂N(R’)R”；

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

The terms mentioned herein preferably have the following meanings:

the term "halogen atom", "halo-" or "halogen-" is understood to mean a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The term "C₁-C₆Alkyl "is understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon radical having 1,2, 3,4, 5 or 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl or 1, 2-dimethylbutyl or isomers thereof. In particular, the radicals have 1,2, 3 or 4 carbon atoms ("C)₁-C₄-alkyl "), such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly said group having 1,2 or 3 carbon atoms (" C)₁-C₃-alkyl "), such as methyl, ethyl, n-propyl or isopropyl.

The term "halo-C₁-C₆Alkyl is understood to preferably mean a linear or branched, saturated monovalent hydrocarbon radical in which one or more hydrogen atoms are replaced by halogen atoms in the same or different manner (i.e. independently of one another between the halogen atoms), where the term "C" is used₁-C₆-alkyl "is as defined above. In particular, the halogen atom is F. Said halo-C₁-C₆Alkyl is, for example, -CF₃、-CHF₂、-CH₂F、-CF₂CF₃or-CH₂CF₃。

The term "C₁-C₆Alkoxy is to be understood as preferably meaning a linear or branched, saturated monovalent hydrocarbon radical of the formula-O-alkyl, where the term "alkyl" is defined as above, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentoxy, isopentoxy or n-hexoxy, or isomers thereof.

The term "halo-C₁-C₆Alkoxy is understood as preferably meaning a linear or branched, saturated, monovalent C as defined above in which one or more hydrogen atoms are replaced by halogen atoms in the same or different manner₁-C₆-alkoxy groups. In particular, the halogen atom is F. Said halo-C₁-C₆Alkoxy is, for example, -OCF₃、-OCHF₂、-OCH₂F、-OCF₂CF₃or-OCH₂CF₃。

The term "C₁-C₆-alkoxy-C₁-C₆Alkyl is understood to preferably denote C wherein one or more hydrogen atoms are defined as above, in the same or different manner₁-C₆An alkoxy group substituted linear or branched saturated monovalent alkyl group as defined above or their isomers, wherein the term "C₁-C₆Alkyl "is as defined above, e.g. methoxyalkyl, ethoxyalkyl, propoxyalkyl, isopropoxyalkyl, butoxyalkyl, isobutoxyalkyl, tert-butoxyalkyl, sec-butoxyalkyl, pentoxyalkyl, isopentyloxyalkyl, hexyloxyalkyl.

The term "halo-C₁-C₆-alkoxy-C₁-C₆Alkyl is understood to preferably mean a linear or branched, saturated monovalent C as defined above in which one or more hydrogen atoms are replaced by halogen atoms in the same or different manner₁-C₆-alkoxy-C₁-C₆-an alkyl group. In particular, the halogen atom is F. Said halo-C₁-C₆-alkoxy-C₁-C₆Alkyl is, for example, -CH₂CH₂OCF₃、-CH₂CH₂OCHF₂、-CH₂CH₂OCH₂F、-CH₂CH₂OCF₂CF₃or-CH₂CH₂OCH₂CF₃。

The term "C₂-C₆Alkenyl "is understood to preferably mean a linear or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2,3,4, 5 or 6 carbon atoms, in particular 2 or 3 carbon atoms (" C)₂-C₃-alkenyl "), it being understood that in case the alkenyl group comprises more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl group is, for example, 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, m, (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-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-ethylprop-4-enyl-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, methyl-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) vinyl, but-1, 3-dienyl, penta-1, 4-dienyl, hex-1, 5-dienyl or methylhexadienyl. In particular, the group is vinyl or allyl.

The term "C₂-C₆Alkynyl is understood as preferably meaning a linear or branched monovalent hydrocarbon radical which contains one or more triple bonds and has 2,3,4, 5 or 6 carbon atoms, in particular 2 or 3 carbon atoms ("C)₂-C₃-alkynyl "). Said C is₂-C₆Alkynyl 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-ynyl, hex-3-ynyl, 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-2-ynyl, 1-propylprop-2-ynyl, 3-methylbut-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylbut-2-ynyl, 2-methylbut-ynyl, 3-methylbut-2-ynyl, 1-isopropylprop-2-ynyl, 2-dimethylbut-3-ynyl, 1-dimethylbut-2-ynyl or 3, 3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

The term "C₃-C₁₀Cycloalkyl is understood to mean a saturated, monovalent, monocyclic or bicyclic hydrocarbon ring having 3,4, 5,6, 7,8, 9 or 10 carbon atoms ("C)₃-C₁₀-cycloalkyl "). Said C is₃-C₁₀Cycloalkyl is, for example, a monocyclic hydrocarbon ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon ring such as a perhydropentalenene or decahydronaphthalene ring. In particular the ring contains 3,4, 5 or 6 carbon atoms ("C)₃-C₆-cycloalkyl ").

The term "C₄-C₁₀Cycloalkenyl is understood as preferably meaning a monovalent monocyclic or bicyclic hydrocarbon ring which contains 4,5, 6, 7,8, 9 or 10 carbon atoms and 1,2, 3 or 4 conjugated or unconjugated double bonds, provided that the size of the cycloalkenyl ring allows this. For example, the C₄-C₁₀Cycloalkenyl is a monocyclic hydrocarbon ring such as cyclobutenyl, cyclopentenyl or cyclohexenyl, or a bicyclic hydrocarbon ring, for example:

the term "3-to 10-membered heterocycloalkyl" is understood to mean a saturated, monovalent, monocyclic or bicyclic hydrocarbon ring having 2,3,4, 5,6, 7,8 or 9 carbon atoms and one or moreA plurality is selected from C (═ O), O, S, S (═ O), S (═ O)₂、NR^aWherein R is^aRepresents a hydrogen atom or C₁-C₆-alkyl-or halo-C₁-C₆-alkyl-; the heterocycloalkyl group may be attached to the rest of the molecule through any of the carbon atoms or the nitrogen atom (if present).

In particular, the 3-to 10-membered heterocycloalkyl group can have 2,3,4, or 5 carbon atoms and one or more of the above-described heteroatom-containing groups ("3-to 6-membered heterocycloalkyl"), more particularly, the heterocycloalkyl group can have 4 or 5 carbon atoms and one or more of the above-described heteroatom-containing groups ("5-to 6-membered heterocycloalkyl").

In particular, the heterocycloalkyl group may be, for example but not limited to: 4-membered rings such as azetidinyl (azetidinyl), oxetanyl (oxyethanyl); 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl (dithianyl), thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as a diazepanyl ring. Optionally, the heterocycloalkyl group can be benzofused.

The heterocyclyl group may be bicyclic, for example but not limited to a5, 5 membered ring, such as a hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl ring, or a5, 6 membered bicyclic ring, such as a hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl ring.

As mentioned above, the nitrogen atom containing ring may be partially unsaturated, i.e. it may contain one or more double bonds, such as, but not limited to, a2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadiazinyl, 4, 5-dihydrooxazolyl or 4H- [1,4] thiazinyl ring, or it may be benzo-fused, such as, but not limited to, a dihydroisoquinolinyl ring.

The term "4-to 10-membered heterocycloalkenyl" is understood to mean an unsaturated, monovalent, monocyclic or bicyclic hydrocarbon ring having 3,4, 5,6, 7,2,8 or 9 carbon atoms and one or more selected from C (═ O), O, S, S (═ O), S (═ O)₂、NR^aWherein R is^aRepresents a hydrogen atom or C₁-C₆-alkyl or halo-C₁-C₆-an alkyl group; the heterocycloalkenyl group may be attached to the rest of the molecule through any of the carbon atoms or the nitrogen atom (if present). Examples of said heterocycloalkenyl may comprise one or more double bonds, such as 4H-pyranyl, 2H-pyranyl, 3H-bisaziridinyl, 2, 5-dihydro-1H-pyrrolyl, [1,3 ]]-dioxolyl ([1, 3)]dioxolyl)、4H-[1,3,4]Thiadiazinyl, 2, 5-dihydrofuryl, 2, 3-dihydrofuryl, 2, 5-dihydrothienyl (dihydrothiophenyl), 2, 3-dihydrothienyl, 4, 5-dihydrooxazolyl or 4H- [1,4 [ ]]Thiazinyl, or it may be benzo-fused.

The term "3-to 7-membered cyclic amine group" is understood to mean a group selected from:

wherein:

rx represents a hydrogen atom, C₁-C₆-alkyl-or halo-C₁-C₆-alkyl-; and is

Denotes the point of attachment of the group to the rest of the molecule.

The term "aryl" is understood to mean preferably a mono-, bi-or tricyclic hydrocarbon ring having a monovalent aromatic or partially aromatic character with 6, 7,8, 9, 10, 11, 12, 13 or 14 carbon atoms ("C₆-C₁₄Aryl "), in particular a ring having 6 carbon atoms (" C)₆-aryl "), such as phenyl; or biphenyl, or having 9 carbonsRing of atoms (' C)₉-aryl "), such as indanyl or indenyl, or a ring having 10 carbon atoms (" C₁₀Aryl), such as tetralinyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C₁₃Aryl radicals), such as the fluorenyl radical, or a ring having 14 carbon atoms ("C)₁₄Aryl "), for example anthracenyl.

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 ("5-to 14-membered heteroaryl"), in particular 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being, for example, oxygen, nitrogen or sulfur), and which, in addition, may be benzo-fused in each case. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl (thia-4H-pyrazoyl), and the like, and benzo derivatives thereof, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl or oxepinyl (oxapinyl) and the like.

In general and unless otherwise indicated, the heteroaryl or heteroarylene includes all possible isomeric forms thereof, e.g., positional isomers thereof. Thus, for some illustrative, non-limiting examples, the term pyridyl or pyridinylene includes pyridin-2-yl, pyridinylene-2-yl, pyridin-3-yl, pyridinylene-3-yl, pyridin-4-yl and pyridinylene-4-yl; alternatively, the term thienyl or thienylene includes thien-2-yl, thien-3-yl, and thien-3-yl.

As used throughout this document, for example at "C₁-C₆-alkyl group "," C₁-C₆-haloalkyl "," C₁-C₆-alkoxy "or" C₁-C₆The term "C" as used in the context of the definition of-haloalkoxy₁-C₆"is understood to mean an alkyl group having a limited number of carbon atoms from 1 to 6, i.e. 1,2, 3,4, 5 or 6 carbon atoms. It is also understood that the term "C" refers to₁-C₆"is to be understood as any subrange comprised therein, such as C₁-C₆、C₂-C₅、C₃-C₄、C₁-C₂、C₁-C₃、C₁-C₄、C₁-C₅(ii) a In particular C₁-C₂、C₁-C₃、C₁-C₄、C₁-C₅、C₁-C₆(ii) a More particularly C₁-C₄(ii) a In "C₁-C₆-haloalkyl "or" C₁-C₆In the case of a haloalkoxy group, more particularly C₁-C₂。

Similarly, as used herein, throughout this document, for example at "C₂-C₆-alkenyl "and" C₂-C₆The term "C" as used in the context of the definition of-alkynyl₂-C₆"is understood to mean alkenyl or alkynyl groups having a limited number of carbon atoms of 2 to 6, i.e. 2,3,4, 5 or 6 carbon atoms. It is also understood that the term "C" refers to₂-C₆"should be interpreted as including any sub-range therein, such as C₂-C₆、C₃-C₅、C₃-C₄、C₂-C₃、C₂-C₄、C₂-C₅(ii) a In particular C₂-C₃。

In addition, as used herein,as used throughout this document, for example at "C₃-C₆The term "C" as used in the context of the definition of-cycloalkyl₃-C₆"is understood to mean cycloalkyl having a limited number of carbon atoms of from 3 to 6, i.e. 3,4, 5 or 6 carbon atoms. It is also understood that the term "C" refers to₃-C₆"should be interpreted as including any sub-range therein, such as C₃-C₆、C₄-C₅、C₃-C₅、C₃-C₄、C₄-C₆、C₅-C₆(ii) a In particular C₃-C₆。

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 at the present time 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 optionally substituted with a specified group, radical or moiety.

A substituent of a ring system refers to a substituent attached to an aromatic or non-aromatic ring system, e.g., the substituent replaces an available hydrogen on the ring system.

The term "one or more times" as used herein (for example in the definition of a substituent of a compound of general formula (la) according to the invention) is to be understood as meaning once, twice, three times, four times or five times, especially once, twice, three times or four times, more especially once, twice or three times, even more especially once or twice.

The invention also includes all suitable isotopic variations of the compounds of the invention. Isotopic variations of the compounds of the present invention are defined as those in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that can be incorporated into compounds of the invention include hydrogenIsotopes of carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, respectively, e.g.²H (deuterium),³H (tritium),¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³²P、³³P、³³S、³⁴S、³⁵S、³⁶S、¹⁸F、³⁶Cl、⁸²Br、¹²³I、¹²⁴I、¹²⁹I and¹³¹I. certain isotopic variations of the compounds of the present invention, for example, wherein one or more are introduced³H or¹⁴Those of the radioactive isotopes of C are useful for drug and/or substrate tissue distribution studies. Tritiated isotopes and carbon-14 (i.e., carbon-14) are particularly preferred for ease of preparation and detectability¹⁴C) An isotope. Furthermore, substitution with isotopes such as deuterium may afford certain therapeutic benefits resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and may therefore be preferred in some circumstances. Isotopic variations of the compounds of the present invention can generally be prepared by conventional methods known to those skilled in the art, for example by the methods illustrated or by the preparation methods described in the examples below using appropriate isotopic variations of suitable reagents.

As the words are used herein: the plural forms of a compound, salt, polymorph, hydrate, solvate, etc. also mean a single compound, salt, polymorph, isomer, hydrate, solvate, etc.

"stable compound" or "stable structure" refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

The compounds of the present invention may contain one or more asymmetric centers, depending on the location and nature of the different substituents desired. Asymmetric carbon atoms may exist in either the (R) or (S) configuration, with only one asymmetric center yielding a racemic mixture and multiple asymmetric centers yielding a diastereomeric mixture. In some cases, asymmetry may also exist due to hindered rotation about a particular bond, for example, the central bond connects two substituted aromatic rings of a particular compound.

The compounds of the invention may contain a sulfur atom, which may be asymmetric, such as an asymmetric sulfoxide or sulfoximine (sulfoximine) of the structure:

for example

Wherein denotes an atom which may be bonded to the rest of the molecule.

The ring substituents may also be present in cis or trans form. All such configurations (including enantiomers and diastereomers) are contemplated to be within the scope of the present invention.

Preferred compounds are those that produce a more desirable biological activity. Isolated, pure or partially purified isomers and stereoisomers, or racemic or diastereomeric mixtures of the compounds of the invention are also included within the scope of the invention. Purification and isolation of such materials can be accomplished by standard techniques known in the art.

Optical isomers may be obtained by resolution of the racemic mixture according to conventional methods, for example by use of optically active acids or bases to form diastereomeric salts, or by formation of covalent diastereomers. Examples of suitable acids are tartaric acid, diacetyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Mixtures of diastereomers may be separated into their individual diastereomers by methods known in the art (e.g., by chromatography or fractional crystallization) based on their physical and/or chemical differences. The optically active base or acid is then released from the separated diastereomeric salt. Another different method of separating optical isomers involves the use of chiral chromatography (e.g., a chiral HPLC column) with or without conventional derivatization, which can be optimally selected to maximize separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Daicel, e.g., chiralel OD and chiralel OJ, all of which are routinely selected. Enzymatic separation may also be used with or without derivatization. Likewise, the optically active compounds of the present invention can be obtained by chiral synthesis using optically active starting materials.

To define between the different types of isomers, reference is made to IUPAC Rules Section E (Pureappl Chem 45,11-30,1976).

The present invention includes all possible stereoisomers of the compounds of the invention, either as single stereoisomers or as any mixture of said stereoisomers (e.g. R-or S-isomers, or E-or Z-isomers) in any proportion. Separation of individual stereoisomers (e.g. individual enantiomers or individual diastereomers) of the compounds of the invention may be achieved by any suitable prior art method (e.g. chromatography, particularly, for example, chiral chromatography).

In addition, the compounds of the present invention may exist in tautomeric forms. For example, any compound of the invention comprising a pyrazolyl group as heteroaryl may, for example, exist in the form of a 1H tautomer or a 2H tautomer, or even in the form of a mixture of any amount of the two tautomers, or a triazolyl group may, for example, exist in the form of a 1H tautomer, a 2H tautomer or a 4H tautomer, or even in the form of a mixture of any amount of the 1H, 2H and 4H tautomers, i.e.:

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

In addition, the compounds of the present invention may exist in the form of N-oxides, which are defined as compounds of the present invention in which at least one nitrogen is oxidized. The present invention includes all such possible N-oxides.

The invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, especially pharmaceutically acceptable salts, and co-precipitates.

The compounds of the invention may be present in the form of hydrates or solvates, wherein the compounds of the invention comprise as structural element of the crystal lattice of the compound a polar solvent, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions. In the case of stoichiometric solvates (e.g. hydrates) there may be semi (hemi-) solvates or hydrates, (semi-) solvates or hydrates, mono-solvates or hydrates, sesquisolvates or hydrates, di-solvates or hydrates, tri-solvates or hydrates, tetra-solvates or hydrates, pentasolvates or hydrates, etc. respectively. The present invention includes all such hydrates or solvates.

In addition, the compounds of the invention may be present in free form, for example in the form of a free base, a free acid or a zwitterion, or in the form of a salt. The salt may be any salt, which may be an organic addition salt or an inorganic addition salt, in particular any pharmaceutically acceptable organic or inorganic addition salt commonly used in pharmacy.

The term "pharmaceutically acceptable salts" refers to relatively non-toxic, inorganic or organic acid addition salts of the compounds of the present invention. See, for example, S.M.Berge et al, "Pharmaceutical Salts," J.pharm.Sci.1977,66, 1-19.

Suitable pharmaceutically acceptable salts of the compounds of the invention may be, for example, acid addition salts of the compounds of the invention having a nitrogen atom in the chain or ring which are sufficiently basic, for example with the following inorganic acids: such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid (disufuric acid), phosphoric acid or nitric acid, or acid addition salts with organic acids such as: such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid (hemisulfuric acid), or thiocyanic acid.

In addition, another suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt (e.g., sodium or potassium salt), an alkaline earth metal salt (e.g., calcium or magnesium salt), an ammonium salt, or a salt with an organic base which affords a physiologically acceptable cation, such as a salt with: n-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1, 6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, tris (hydroxymethyl) aminomethane, aminopropanediol, sovak-base, 1-amino-2, 3, 4-butanetriol. In addition, the basic nitrogen-containing groups may be quaternized with the following agents: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromide, and the like.

Those skilled in the art will also recognize that acid addition salts of the claimed compounds can be prepared by reacting the compounds with the appropriate inorganic or organic acid by any of a variety of known methods. Alternatively, the alkali metal salts and alkaline earth metal salts of the acidic compounds of the present invention are prepared by reacting the compounds of the present invention with an appropriate base by various known methods.

The invention includes all possible salts of the compounds of the invention, either in the form of their individual salts or in the form of any mixture of said salts in any proportion.

The term "in vivo hydrolysable ester" as used herein is understood to mean an in vivo hydrolysable ester of a compound of the invention which comprises a carboxy or hydroxy group, for example a pharmaceutically acceptable ester which can be hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for the carboxyl group include, for example, alkyl esters, cycloalkyl esters and optionally substituted phenylalkyl esters, in particular benzyl esters, C₁-C₆Alkoxymethyl esters (e.g. methoxymethyl ester), C₁-C₆Alkanoyloxymethyl esters (e.g. pivaloyloxymethyl esters, phthalidyl esters), C₃-C₈cycloalkoxy-carbonyloxy-C₁-C₆Alkyl esters (e.g., 1-cyclohexylcarbonyloxyethyl ester), 1, 3-dioxole-2-carbonylmethyl ester (1, 3-dioxolen-2-onylmester) (e.g., 5-methyl-1, 3-dioxole-2-carbonylmethyl ester), and C₁-C₆Alkoxycarbonyloxyethyl esters (e.g. 1-methoxycarbonyloxyethyl ester) and the ester may be formed on any of the carboxyl groups of the compounds of the invention.

In vivo hydrolysable esters of compounds of the invention which contain a hydroxy group include inorganic acid esters (e.g. phosphate esters), [ α ] acyloxyalkyl ethers and related compounds which are cleaved by in vivo hydrolysis of the ester to form the parent hydroxy group. Examples of [ α ] acyloxyalkyl ethers include acetoxymethoxy ether (acetoxymethyloxy) and 2,2-dimethylpropionyloxymethoxy ether (2, 2-dimethylpropionyloxymethyloxy). The selection of groups which form in vivo hydrolysable esters with hydroxyl groups include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, alkoxycarbonyl groups (to form alkyl carbonates), dialkylcarbamoyl and N- (dialkylaminoethyl) -N-alkylcarbamoyl groups (to form carbamates), dialkylaminoacetyl and carboxyacetyl groups. The present invention includes all such esters.

In addition, the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

According to a second embodiment of said first aspect, the present invention covers a compound of general formula (I) as defined above, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, wherein:

represents:

a group;

wherein denotes the point of attachment of the group to the rest of the molecule; and is

R1 represents linear C₁-C₆-alkyl-, branched C₃-C₆-alkyl-or C₃-C₆-cycloalkyl, optionally substituted once or more times independently from each other with substituents selected from:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, aryl-, -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH₂、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)₂R’、-N(R’)S(＝O)₂R’、-N＝S(＝O)(R’)R”、-OH、C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH₂、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C₁-C₆-alkyl-S-, -S (═ O) R', -S (═ O)₂R’、-S(＝O)₂NH₂、-S(＝O)₂NHR’、-S(＝O)₂N(R’)R”；

R2 represents a hydrogen atom;

r3 represents a substituent selected from:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, -OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-;

r4 represents a substituent selected from:

hydrogen atom, halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-optionally substituted once or more times independently of each other with R substituents; heteroaryl-optionally substituted once or more times independently of each other with an R substituent; -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH₂、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH₂、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH₂、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO₂、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)₂R’、-N(R’)S(＝O)₂R’、-N＝S(＝O)(R’)R”、-OH、C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH₂、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C₁-C₆-alkyl-S-, -S (═ O) R', -S (═ O)₂R’、-S(＝O)₂NH₂、-S(＝O)₂NHR’、-S(＝O)₂N(R’)R”、-S(＝O)(＝NR’)R”；

R represents a substituent selected from the group consisting of:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, -C (═ O) R', -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH₂、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH₂、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH₂、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO₂、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)₂R’、-N(R’)S(＝O)₂R’、-N＝S(＝O)(R’)R”、-OH、C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH₂、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C₁-C₆-alkyl-S-, -S (═ O) R', -S (═ O)₂R’、-S(＝O)₂NH₂、-S(＝O)₂NHR’、-S(＝O)₂N(R’)R”、-S(＝O)(＝NR’)R”；

R' and R "independently of each other represent a substituent selected from the group consisting of:

C₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-, C₁-C₆-a haloalkyl group;

r5 represents:

or:

-a substituent selected from: c₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-, aryl-, -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-S(＝O)R’、-S(＝O)₂R’；

Or:

-together with the nitrogen atom to which it is attached and the carbon atom of R1 form a 3-to 7-membered cyclic amine group, optionally substituted with a substituent selected from:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, aryl-, -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH₂、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)₂R’、-N(R’)S(＝O)₂R’、-N＝S(＝O)(R’)R”、-OH、C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH₂、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C₁-C₆-alkyl-S-, -S (═ O) R', -S (═ O)₂R’、-S(＝O)₂NH₂、-S(＝O)₂NHR’、-S(＝O)₂N(R’)R”；

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

According to a third embodiment of said first aspect, the present invention covers a compound of general formula (I) as defined above, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, wherein:

represents:

a group;

wherein denotes the point of attachment of the group to the rest of the molecule; and is

R1 represents linear C₁-C₆-alkyl-, branched C₃-C₆-alkyl-or C₃-C₆-cycloalkyl, optionally substituted once or more times independently from each other with substituents selected from:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, aryl-, -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH₂、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)₂R’、-N(R’)S(＝O)₂R’、-N＝S(＝O)(R’)R”、-OH、C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH₂、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C₁-C₆-alkyl-S-, -S (═ O) R', -S (═ O)₂R’、-S(＝O)₂NH₂、-S(＝O)₂NHR’、-S(＝O)₂N(R’)R”；

R2 represents a hydrogen atom;

r3 represents a substituent selected from:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, -OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-;

r4 represents a substituent selected from:

hydrogen atom, halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl group, C₃-C₁₀-cycloalkyl-, aryl-, heteroaryl-;

r' and R "independently of each other represent a substituent selected from the group consisting of:

C₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-, C₁-C₆-a haloalkyl group;

r5 represents:

or:

-a substituent selected from: c₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-, aryl-, -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-S(＝O)R’、-S(＝O)₂R’；

Or:

-forms together with the nitrogen atom to which it is attached and the carbon atom of R1 a 3-to 7-membered cyclic amine group;

n represents an integer of 0 or 1.

According to a fourth embodiment of said first aspect, the present invention covers a compound of general formula (I) as defined above, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, wherein:

represents:

a group;

wherein denotes the point of attachment of the group to the rest of the molecule; and is

R1 represents linear C₁-C₅-alkyl-, branched C₃-C₅-alkyl-or C₄-C₆-cycloalkyl, optionally substituted once or more times independently from each other with substituents selected from:

C₁-C₆-alkyl-or aryl-;

r2 represents a hydrogen atom;

r3 represents a substituent selected from:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, -OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-;

r4 represents a substituent selected from:

hydrogen atom, halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl group, C₃-C₁₀-cycloalkyl-, aryl-, heteroaryl-;

r' and R "independently of each other represent a substituent selected from the group consisting of:

C₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-, C₁-C₆-a haloalkyl group;

r5 represents:

or:

-a substituent selected from: c₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-, aryl-, -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-S(＝O)R’、-S(＝O)₂R’；

Or:

-forms together with the nitrogen atom to which it is attached and the carbon atom of R1 a 3-to 7-membered cyclic amine group;

n represents an integer of 0 or 1.

According to a fifth embodiment of said first aspect, the present invention covers a compound of general formula (I) as defined above or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, wherein:

represents:

a group;

wherein denotes the point of attachment of the group to the rest of the molecule; and is

R1 represents linear C₁-C₅-alkyl-, optionally substituted once with substituents which are:

aryl-;

r2 represents a hydrogen atom;

r3 represents a substituent selected from:

halogen atom, C₁-C₆-alkoxy-;

r4 represents a hydrogen atom;

r5 represents:

or:

-a substituent selected from: c₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-, C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-;

or:

-forms together with the nitrogen atom to which it is attached and the carbon atom of R1 a 3-to 7-membered cyclic amine group;

n represents an integer of 0 or 1.

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

represents:

a group;

wherein denotes the point of attachment of the group to the rest of the molecule.

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

r1 represents linear C₁-C₆-alkyl-, branched C₃-C₆-alkyl-or C₃-C₆-cycloalkyl, optionally substituted once or more times independently from each other with substituents selected from:

halogen atom, -CN, C₁-C₆-alkyl-、C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, aryl-, -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH₂、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)₂R’、-N(R’)S(＝O)₂R’、-N＝S(＝O)(R’)R”、-OH、C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH₂、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C₁-C₆-alkyl-S-, -S (═ O) R', -S (═ O)₂R’、-S(＝O)₂NH₂、-S(＝O)₂NHR’、-S(＝O)₂N(R’)R”。

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

r2 represents a hydrogen atom.

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

r3 represents a substituent selected from:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, -C (═ O) R', -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-NH₂、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH₂、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH₂、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO₂、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)₂R’、-N(R’)S(＝O)₂R’、-N＝S(＝O)(R’)R”、-OH、C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, -OC (═ O) R', -SH, C₁-C₆-alkyl-S-, -S (═ O) R', -S (═ O)₂R’、-S(＝O)₂NH₂、-S(＝O)₂NHR’、-S(＝O)₂N(R’)R”、-S(＝O)(＝NR’)R”。

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

r4 represents a substituent selected from:

hydrogen atom, halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-optionally substituted once or more times independently of each other with R substituents; heteroaryl-optionally substituted once or more times independently of each other with an R substituent; -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH₂、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH₂、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH₂、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO₂、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)₂R’、-N(R’)S(＝O)₂R’、-N＝S(＝O)(R’)R”、-OH、C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH₂、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C₁-C₆-alkyl-S-, -S (═ O) R', -S (═ O)₂R’、-S(＝O)₂NH₂、-S(＝O)₂NHR’、-S(＝O)₂N(R’)R”、-S(＝O)(＝NR’)R”。

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

r represents a substituent selected from the group consisting of:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, -C (═ O) R', -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OR’、-NH₂、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)C(＝O)NH₂、-N(H)C(＝O)NHR’、-N(H)C(＝O)N(R’)R”、-N(R’)C(＝O)NH₂、-N(R’)C(＝O)NHR’、-N(R’)C(＝O)N(R’)R”、-N(H)C(＝O)OR’、-N(R’)C(＝O)OR’、-NO₂、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)₂R’、-N(R’)S(＝O)₂R’、-N＝S(＝O)(R’)R”、-OH、C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH₂、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C₁-C₆-alkyl-S-, -S (═ O) R', -S (═ O)₂R’、-S(＝O)₂NH₂、-S(＝O)₂NHR’、-S(＝O)₂N(R’)R”、-S(＝O)(＝NR’)R”。

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

r' and R "independently of each other represent a substituent selected from the group consisting of:

C₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-, C₁-C₆-haloalkyl.

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

r5 represents:

-a substituent selected from: c₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-, aryl-, -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-S(＝O)R’、-S(＝O)₂R’。

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

r5 represents:

-together with the nitrogen atom to which it is attached and the carbon atom of R1 form a 3-to 7-membered cyclic amine group, optionally substituted with a substituent selected from:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, aryl-, -C (═ O) NH₂、-C(＝O)N(H)R’、-C(＝O)N(R’)R”、-C(＝O)OH、-C(＝O)OR’、-NH₂、-NHR’、-N(R’)R”、-N(H)C(＝O)R’、-N(R’)C(＝O)R’、-N(H)S(＝O)R’、-N(R’)S(＝O)R’、-N(H)S(＝O)₂R’、-N(R’)S(＝O)₂R’、-N＝S(＝O)(R’)R”、-OH、C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, -OC (═ O) R', -OC (═ O) NH₂、-OC(＝O)NHR’、-OC(＝O)N(R’)R”、-SH、C₁-C₆-alkyl-S-, -S (═ O) R', -S (═ O)₂R’、-S(＝O)₂NH₂、-S(＝O)₂NHR’、-S(＝O)₂N(R’)R”。

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

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

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

r3 represents a substituent selected from:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, -OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-;

according to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

r4 represents a substituent selected from:

hydrogen atom, halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl group, C₃-C₁₀-cycloalkyl-, aryl-, heteroaryl-.

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

r5 represents:

-together with the nitrogen atom to which it is attached and the carbon atom of R1 form a 3-to 7-membered cyclic amine group.

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

n represents an integer of 0 or 1.

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

r1 represents linear C₁-C₅-alkyl-, branched C₃-C₅-alkyl-or C₄-C₆-cycloalkyl, optionally substituted once or more times independently from each other with substituents selected from:

C₁-C₆-alkyl-or aryl-.

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

r1 represents linear C₁-C₅-alkyl-, optionally substituted once with substituents which are:

aryl-.

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

r3 represents a substituent selected from:

halogen atom, C₁-C₆-alkoxy-.

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

r4 represents a hydrogen atom.

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

r' and R "independently of each other represent a substituent selected from the group consisting of:

C₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-.

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

r5 represents:

-a substituent selected from: c₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-, C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-.

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

n represents an integer of 0.

According to another embodiment of the above aspects, the present invention relates to a compound of formula (I) wherein:

n represents an integer of 1.

According to another embodiment of the above aspect, the present invention relates to a compound of formula (I) according to any of the above embodiments in the form of 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 to any subcombination within any embodiment or aspect of the compounds of formula (I) of the invention described above.

More particularly, the present invention encompasses compounds of general formula (I) as disclosed in the examples section below.

According to another aspect, the present invention encompasses a method of preparing a compound of the invention, said method comprising the steps described in the experimental part herein.

According to another aspect, the present invention encompasses intermediate compounds useful in the preparation of the compounds of general formula (I) of the present invention, in particular in the processes described herein. In particular, the invention encompasses compounds of general formula (V):

wherein A, R2, R3, R4 and n are as defined above for the compound of formula (I), and X represents a leaving group, for example a halogen atom (such as a chlorine atom, a bromine atom or an iodine atom), or a perfluoroalkylsulfonate group (such as a trifluoromethylsulfonate group or a nonafluorobutylsulfonate group).

According to another aspect, the invention covers the use of an intermediate compound of general formula (V) for the preparation of a compound of general formula (I) as defined above:

wherein A, R2, R3, R4 and n are as defined above for the compound of formula (I), and X represents a leaving group such as a halogen atom (e.g. a chlorine atom, a bromine atom or an iodine atom), or a perfluoroalkylsulfonate group (e.g. a trifluoromethylsulfonate group).

Experimental part

The following table lists the abbreviations used in this section and in the examples section.

Abbreviations	Means of
		DMF	Dimethyl formamide
DMSO	Dimethyl sulfoxide

THF	Tetrahydrofuran (THF)
		NMR	Nuclear magnetic resonance
MS	Mass spectrometry
		Rt	Retention time
HPLC,LC	High performance liquid chromatography
		H	Hour(s)
min	Minute (min)

Synthesis of Compounds (overview)

The compounds of the invention can be prepared as described in the following section. Scheme 1 and the procedures described below illustrate a general synthetic route for the compounds of general formula (I) of the present invention and are not limiting. It will be apparent to those skilled in the art that the order of transformations illustrated in scheme 1 can be varied in a number of ways. Thus, the order of transformations illustrated in scheme 1 is not limiting. Additionally, interconversion of any of substituents R1, R2, R3, R4, R5, and a may be achieved before and/or after the exemplified transformations. These modifications may be, for example, the introduction of protecting groups, cleavage of protecting groups, exchange, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to those skilled in the art. These transformations include those that introduce functionality that allows for further interconversion of substituents. Suitable protecting Groups and their introduction and cleavage are well known to those skilled in the art (see, e.g., t.w.greene and p.g.m.wuts in Protective Groups in Organic Synthesis, 3 rd edition, Wiley 1999). Specific examples are described in subsequent paragraphs. Furthermore, it is possible that two or more successive steps may be carried out without work-up between the steps, for example a "one-pot" reaction, as is well known to the person skilled in the art.

Route 1:

wherein A, R1, R2, R3, R4, R5 and n are as defined above, and X and Y represent a leaving group such as a halogen atom (e.g., a chlorine atom, a bromine atom or an iodine atom), or a perfluoroalkylsulfonate group (e.g., a trifluoromethylsulfonate group or a nonafluorobutylsulfonate group).

In a first step, a compound of formula a (i.e. dichloropyridazine with a suitable X substituent) may be reacted with ammonia at elevated temperature and pressure to give a compound of formula B [ similar to WO200733080, which is incorporated herein by reference in its entirety ].

In a second step, the compound of the general formula B is reacted with, for example, chloroacetaldehyde diacetal or bromoacetaldehyde diacetal to give the bicyclic ring system C [ analogously to DE102006029447, which is incorporated herein by reference in its entirety ].

The 3-position activation of the bicyclic system can be achieved, for example, by brominating or iodinating the compound of formula C using N-bromo-succinimide or N-iodo-succinimide, respectively, to give the compound of formula D.

In the fourth step, the group A- [ R3 ] can be achieved using a suitable catalytic coupling reaction, using, for example, a boronic acid or a stannane (stannane)]_nThis gives compounds of the general formula E.

The compound of formula E is used as a central intermediate for the introduction of various side chains comprising an alcohol function, which leads to the imidazopyridazine-ethers of formula (I). Introduction of the side chain can be achieved, for example, by using a base such as sodium hydride. Depending on the nature of the side chains, it may be necessary to carry out these reactions at elevated temperatures. It may also be necessary to introduce side chains with suitable protecting groups on the functional groups that may interfere with the desired reaction.

As illustrated in scheme 2, the fourth and fifth steps of the described steps may also be interchanged.

Route 2:

according to one embodiment, the present invention also relates to a process for the preparation of a compound of general formula (I) as defined above, said process comprising reacting an intermediate compound of general formula (V):

wherein A, R2, R3, R4 and n are as defined above for the compound of formula (I), and X represents a leaving group, such as a halogen atom (e.g. a chlorine atom, a bromine atom or an iodine atom), or a perfluoroalkylsulfonate group (e.g. trifluoromethylsulfonate or nonafluorobutylsulfonate),

a step of reacting with a compound of the general formula (III):

wherein R1 and R5 are as defined above for the compounds of formula (I),

thereby obtaining a compound of formula (I):

wherein A, R1, R2, R3, R4, R5 and n are as defined above.

General part

The chemical Name was generated using ACD/Name Batch Version 12.01.

HPLC method:

the method comprises the following steps:

the instrument comprises the following steps: waters Acquity UPLCMS ZQ 4000; column: acquity UPLC BEH C181.7 μm,50 × 2.1mm; eluent A: water +0.05 vol% formic acid, eluent B: acetonitrile +0.05 vol% formic acid; gradient: 1-99% B at 0-1.6min, 99% B at 1.6-2.0 min; flow rate: 0.8 mL/min; temperature: 60 ℃; sample introduction amount: 2 mu L of the solution; DAD scan: 210-400 nm; ELSD

The method 2 comprises the following steps:

the instrument comprises the following steps: waters Acquity uplmcs SQD 3001; column: acquity UPLC BEH C181.7 μm,50 × 2.1mm; eluent A: water +0.1 vol% formic acid (95%), eluent B: acetonitrile; gradient: 0-1.6min 1-99% B,1.6-2.0min 99% B; flow rate: 0.8 mL/min; temperature: 60 ℃; sample introduction amount: 2 mu L of the solution; DAD scan: 210-400 nm; ELSD

The method 3 comprises the following steps:

the instrument comprises the following steps: waters Acquity UPLCMS SQD; column: acquity UPLC BEH C181.7 μm,50 × 2.1mm; eluent A: water +0.05 vol% formic acid (95%), eluent B: acetonitrile +0.05 vol% formic acid (95%); gradient: 0-1.6min 1-99% B,1.6-2.0min 99% B; flow rate: 0.8 mL/min; temperature: 60 ℃; sample introduction amount: 2 mu L of the solution; DAD scan: 210-400 nm; ELSD

Method 4 apparatus: waters Acquity UPLCMS SQD; column: acquity UPLC BEH C181.7 μm,50 × 2.1mm; eluent A: water +0.1 vol% formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6min 1-99% B,1.6-2.0min 99% B; flow rate: 0.8 mL/min; temperature: 60 ℃; sample introduction amount: 2 mu L of the solution; DAD scan: 210-400 nm; ELSD

Intermediates

Intermediate 1

3-bromo-6-chloro-imidazo [1,2-b ] pyridazine

3-bromo-6-chloro-imidazo [1,2-b ] pyridazine is synthesized as follows, for example, as described in WO 2007/147646 or DE 102006029447:

step 1: preparation of 6-chloroimidazo [1,2-b ] pyridazine:

5.0g (38.6mmol) of 3-amino-6-chloropyridazine are heated together with 4.7mL (40mmol) of chloroacetaldehyde (55% content in water) in 15mL of n-butanol at 120 ℃ for a period of 5 days. After completion of the reaction, the reaction mixture was added to a saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with saturated sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17g (70%) of the desired product were isolated in the form of an amorphous white solid.

¹H-NMR (chloroform-d) [ ppm ]]＝7.06(1H)；7.79(1H)；7.92(1H)；7.96(1H).

Step 2: preparation of 3-bromo-6-chloroimidazo [1,2-b ] pyridazine:

478mg (3.11mmol) of 6-chloroimidazo [1,2-b ] pyridazine is introduced into 10mL of chloroform under argon, and 664mg (3.73mmol) of N-bromosuccinimide is added while cooling on ice. After the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction mixture was then mixed with water and ethyl acetate, saturated sodium bicarbonate solution was added, and the phases were separated. The aqueous phase was extracted three more times with ethyl acetate. The combined organic phases are then washed with saturated sodium chloride solution and dried over sodium sulfate. Finally the solvent was removed in vacuo and the desired product was isolated in quantitative yield as an amorphous white solid, which was used in subsequent reactions without further chromatographic purification.

¹H-NMR (chloroform-d) [ ppm ]]＝7.12(1H)；7.79(1H)；7.90(1H).

Intermediate 2

3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine

13.9g (59.8mmol) of 3-bromo-6-chloro-imidazo [1,2-b ] pyridazine are suspended in 508mL of 1, 4-dioxane. 10.1g (62.8mmol) of 2-benzofuranylboronic acid, 2.76g (2.29mmol) of tetrakis (triphenylphosphine) palladium- (0) and 90mL (180mmol) of 2M aqueous sodium carbonate are added. The resulting mixture was heated to 100 ℃ for 24 hours.

400mL of saturated aqueous ammonium chloride solution was added. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. The solvent was evaporated and the resulting solid material was then immersed (digest) in 40mL of a mixture of dichloromethane and methanol (8:2), filtered off and dried in vacuo to give 5.42g (44%) of the title compound as a solid material.

¹H-NMR(300MHz,DMSO-d₆):[ppm]＝7.23-7.40(2H),7.51(1H),7.59-7.67(2H),7.77(1H),8.33-8.40(2H).

LCMS (method 1) R_t＝1.35min；MS(ESIpos)m/z＝270[M+H]⁺.

Intermediate 3

6-chloro-3- (4-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine

In analogy to 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine, 6-chloro-3- (4-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine was prepared from 1.68g (7.22mmol) 3-bromo-6-chloroimidazo [1,2-b ] pyridazine to give a 43% yield of solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝3.96(3H),6.85-6.91(1H),7.25-7.38(2H),7.52-7.59(2H),8.37-8.43(2H)

LCMS (method 1) R_t＝1.31min；MS(ESIpos)m/z＝300[M+H]⁺.

Intermediate 4

6-chloro-3- (5-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine

In analogy to 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine, 6-chloro-3- (5-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine was prepared from 1.74g (7.5mmol) 3-bromo-6-chloroimidazo [1,2-b ] pyridazine to give a yield of 45% of a solid substance.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝3.81(3H),6.91-6.99(1H),7.33(1H),7.50-7.60(3H),8.35-8.42(2H).

LCMS (method 1) R_t＝1.29min；MS(ESIpos)m/z＝300[M+H]⁺.

Intermediate 5

6-chloro-3- (5-chloro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine

Step 1: a mixture of 2g (13mmol) of 7-chloro-1-benzofuran in dry THF (100mL) was cooled to-78 ℃. 7.9mL (19.7mmol) of a solution of n-butyllithium in hexane were added, and the resulting mixture was stirred at-78 ℃ for 1 hour. 5.3mL (19.7mmol) of tributyltin chloride was added. The reaction was stirred at room temperature overnight.

Methanol was added carefully and the solvent was evaporated. The residue obtained was purified by flash chromatography to give 6.2g of the corresponding crude 2-stannylbenzofuran, which was used in step 2 without further purification.

Step 2: 2.34g (10.1mmol) 3-bromo-6-chloro-imidazo [1,2-b ] pyridazine, 5.79g (13.1mmol) crude 2-stannylbenzofuran of step 1, 192mg (1mmol) copper (I) iodide and 354mg (0.5mmol) bis (triphenylphosphine) palladium (II) chloride are stirred in 100mL THF at 85 ℃ under an inert atmosphere in a sealed pressure tube for 19 h. The solvent was evaporated and the resulting solid was leached in methanol and filtered off to give 2.73g of the title compound as a solid which was used as crude product in the subsequent reaction.

LCMS (method 3) R_t＝1.00min；MS(ESIpos)m/z＝304[M+H]⁺.

Intermediate 6

6-chloro-3- (5-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine

In analogy to 6-chloro-3- (5-chloro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine, 6-chloro-3- (5-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine was prepared from 513mg (2.21mmol) of 3-bromo-6-chloroimidazo [1,2-b ] pyridazine to yield 166mg of a solid substance (approx. 57% purity). This material was used in the subsequent step without further purification.

LCMS (method 4) R_t＝1.37min；MS(ESIpos)m/z＝288[M+H]+.

Intermediate 7

6-chloro-3- (4-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine

In analogy to 6-chloro-3- (5-chloro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine, 6-chloro-3- (4-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine was prepared from 921mg (3.96mmol) 3-bromo-6-chloroimidazo [1,2-b ] pyridazine to give 929mg of a solid substance which was used as crude product.

1H-NMR(300MHz,DMSO-d₆),[ppm]＝7.09-7.23(1H),7.32-7.45(1H),7.55(3H),8.41(2H).

LCMS (method 3) Rt ═ 1.42 min; ms (esipos) M/z 288[ M + H ] +.

Examples

Example 1

3- (1-benzofuran-2-yl) -6- [2- (morpholin-2-yl) ethoxy ] imidazo [1,2-b ] pyridazine

In an ice bath, 68.1mg (0.52mmol) of 2- (2-morpholinyl) ethanol are added to 18.3mg (0.46mmol) of sodium hydride (60% in mineral oil) in 4mL of anhydrous tetrahydrofuran. Stirring in an ice bath for 15min, then 70mg (0.26mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at 40 ℃ for 72 h.

The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 45mg (47%) of the product as a solid material.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝1.86-1.96(2H),2.40(1H),2.56-2.68(2H),2.82(1H),3.43(1H),3.52-3.60(1H),3.73(1H),4.53-4.60(2H),7.01(1H),7.24-7.35(2H),7.59-7.65(2H),7.67-7.74(1H),8.10-8.18(2H).

LC-MS (method 3) R_t＝0.78min；MS(ESIpos)m/z＝365[M+H]⁺.

Example 2

3- (4-methoxy-1-benzofuran-2-yl) -6- [ (2R) -morpholin-2-ylmethoxy ] imidazo [1,2-b ] pyridazine

191mg (1.6mmol) of (R) -2-hydroxymethylmorpholine were added to 64mg (1.6mmol) of sodium hydride (60% in mineral oil) in 24mL of anhydrous tetrahydrofuran in an ice bath. Stirring in an ice bath for 15min, then 120mg (0.4mmol) 6-chloro-3- (4-methoxy-1-benzofuran-2-yl) -imidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at room temperature for 24 h.

The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 21mg (14%) of the product as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝2.63-2.73(3H),2.95(1H),3.48(1H),3.77(1H),3.92(4H),4.41(2H),6.83(1H),7.04(1H),7.19-7.33(2H),7.53(1H),8.02-8.18(2H).

LC-MS (method 3) R_t＝0.81min；MS(ESIpos)m/z＝381[M+H]⁺.

Example 3

3- (1-benzofuran-2-yl) -6- (morpholin-2-ylmethoxy) imidazo [1,2-b ] pyridazine

Step 1: 2.0g (8.9mmol) of tert-butyl 2- (hydroxymethyl) morpholine-4-carboxylate are added to 188mg (7.83mmol) of sodium hydride (60% in mineral oil) in 24mL of anhydrous tetrahydrofuran in an ice bath. After stirring in an ice bath for 15 minutes, 1.2g (4.45mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at room temperature for 4 days.

The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The resulting crude product (3.3g) was used in step 2 without further purification.

Step 2: to 2.2g of the crude product of step 1in 36mL of dichloromethane was added 8.9mL of trifluoroacetic acid. The mixture was stirred for 3 h. Aqueous ammonia was added until the mixture reached a basic pH. Brine was added and the mixture was extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate and concentrated. 1.68g of a solid material was obtained in the form of a crude product.

A small sample (75mg) was purified by HPLC to give 18mg of the product as a solid.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝2.64-2.75(3H),2.94-3.02(1H),3.51(1H),3.76-3.92(1H),4.45(2H),7.06(1H),7.23-7.37(2H),7.60-7.66(1H),7.72(1H),8.12-8.19(2H).

LC-MS (method 3) R_t＝0.81min；MS(ESIpos)m/z＝381[M+H]⁺.

Example 4

N- (3- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } propyl) -2, 2-dimethylpropan-1-amine

75mg (0.52mmol) of (3- [ (2, 2-dimethylpropyl) amino ] propan-1-ol are added to 18mg (0.45mmol) of sodium hydride (60% in mineral oil) in 4mL of anhydrous tetrahydrofuran in an ice bath, stirring is carried out for 15 minutes in an ice bath, 70mg (0.26mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are then added, the ice bath is removed, and the reaction mixture is stirred at 40 ℃ for 16 h.

The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 56mg (57%) of the product as a solid.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝0.83(9H),1.93-2.02(2H),2.26(2H),2.72(2H),4.56(2H),7.00(1H),7.24-7.35(2H),7.58(1H),7.60-7.64(1H),7.66-7.70(1H),8.13(2H).

LC-MS (method 4) R_t＝0.90min；MS(ESIpos)m/z＝379[M+H]⁺.

Example 5

3- (5-methoxy-1-benzofuran-2-yl) -6- [ (2R) -morpholin-2-ylmethoxy ] imidazo [1,2-b ] pyridazine

191mg (1.6mmol) of (R) -2-hydroxymethylmorpholine were added to 64mg (1.6mmol) of sodium hydride (60% in mineral oil) in 3mL of anhydrous tetrahydrofuran in an ice bath. Stirring in an ice bath for 15min, then 120mg (0.40mmol) 6-chloro-3- (5-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at room temperature for 24 h.

The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 20mg (13%) of the product as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝2.66-2.71(3H),2.87-2.96(1H),3.41-3.56(1H),3.79(5H),4.42(2H),6.90(1H),7.04(1H),7.24(1H),7.48-7.58(2H),8.06-8.19(2H).

LC-MS (method 3) R_t＝0.83min；MS(ESIpos)m/z＝381[M+H]⁺.

Example 6

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -N- (cyclopropylmethyl) ethylamine

In an ice bath 87mg (0.74mmol) of 2- [ (cyclopropylmethyl) amino ] ethan-1-ol are added to 26mg (0.65mmol) of sodium hydride (60% in mineral oil) in 5mL of anhydrous tetrahydrofuran. After stirring in an ice bath for 15 minutes, 100mg (0.37mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at 40 ℃ for 16 h.

The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 56mg (43%) of the product as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝0.08-0.17(2H),0.34-0.45(2H),0.85-0.98(1H),2.54(2H),3.11(2H),4.58(2H),7.03(1H),7.23-7.37(2H),7.59-7.66(2H),7.71(1H),8.12-8.23(2H).

LC-MS (method 4) R_t＝0.82min；MS(ESIpos)m/z＝349[M+H]⁺.

Example 7

3- (1-benzofuran-2-yl) -6- [ (2R) -morpholin-2-ylmethoxy ] imidazo [1,2-b ] pyridazine

355mg (2.97mmol) of (R) -2-hydroxymethylmorpholine were added to 119mg (2.97mmol) of sodium hydride (60% in mineral oil) in 6mL of anhydrous tetrahydrofuran in an ice bath. After stirring in an ice bath for 15 minutes, 200mg (0.74mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at room temperature for 24 h.

The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 67mg (25%) of the product as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝2.62-2.73(3H),2.92-3.02(1H),3.43-3.57(1H),3.72-3.93(2H),4.44(2H),7.05(1H),7.21-7.40(2H),7.59-7.66(2H),7.70-7.75(1H),8.12-8.20(2H).

LC-MS (method 3) R_t＝0.78min；MS(ESIpos)m/z＝351[M+H]⁺.

Example 8

3- (1-benzofuran-2-yl) -6- {2- [ (3R) -morpholin-3-yl ] ethoxy } imidazo [1,2-b ] pyridazine

In an ice bath 68mg (0.52mmol) of 2- [ (3R) -morpholin-3-yl ] ethanol are added to 18mg (0.45mmol) of sodium hydride (60% in mineral oil) in 4mL of anhydrous tetrahydrofuran. Stirring in an ice bath for 15min, then 70mg (0.26mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at 40 ℃ for 15 h.

The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography to give 38mg (40%) of the product as a solid.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝1.81(2H),2.70-2.78(2H),2.85-2.95(1H),3.11(1H),3.34-3.38(1H),3.65(1H),3.76(1H),4.59(2H),7.04(1H),7.27-7.38(2H),7.62-7.68(2H),7.73(1H),8.16(2H).

LC-MS (method 3) R_t＝0.73min；MS(ESIpos)m/z＝365[M+H]⁺.

Example 9

3- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -N- (propan-2-yl) propan-1-amine

89mg (0.74mmol) of 3- (propan-2-ylamino) propan-1-ol are added to 26mg (0.65mmol) of sodium hydride (60% in mineral oil) in 5mL of anhydrous tetrahydrofuran in an ice bath. After stirring in an ice bath for 15 minutes, 100mg (0.37mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at room temperature for 16 h.

The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and ethyl acetate was added. The resulting precipitate was filtered off, washed with water and ethyl acetate, and dried in vacuo to give 124mg (95%) of the product as a solid.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝1.23(6H),2.19-2.29(2H),3.11(2H),4.61(2H),7.03(1H),7.24-7.36(2H),7.60-7.65(1H),7.67(1H),7.71-7.76(1H),8.14-8.21(2H).

LC-MS (method 2) R_t＝0.85min；MS(ESIpos)m/z＝351[M+H]⁺.

Example 10

N- (2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } ethyl) propan-2-amine

78mg (0.74mmol) of 2- (isopropylamino) ethan-1-ol are added to 26mg (0.65mmol) of sodium hydride (60% in mineral oil) in 5mL of anhydrous tetrahydrofuran in an ice bath. After stirring in an ice bath for 15 minutes, 100mg (0.37mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at room temperature for 16 h.

The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 65mg (46%) of the product as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.00(6H),3.00(2H),3.39(1H),4.53(2H),6.96-7.06(1H),7.23-7.36(2H),7.59-7.66(2H),7.68-7.74(1H),8.12-8.18(2H).

LC-MS (method 4) R_t＝0.80min；MS(ESIpos)m/z＝337[M+H]⁺.

Example 11

3- (1-benzofuran-2-yl) -6- [ (2S) -morpholin-2-ylmethoxy ] imidazo [1,2-b ] pyridazine

355mg (2.97mmol) of (S) -2-hydroxymethylmorpholine were added to 119mg (2.97mmol) of sodium hydride (60% in mineral oil) in 6mL of anhydrous tetrahydrofuran in an ice bath. After stirring in an ice bath for 15 minutes, 200mg (0.74mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at room temperature for 24 h.

The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give 280mg of crude product. 49mg of the crude product was purified by HPLC to give 2mg of the product as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝2.64-2.72(3H),2.94(1H),3.42-3.54(1H),3.72-3.89(2H),4.44(2H),7.06(1H),7.23-7.36(2H),7.60-7.65(2H),7.73(1H),8.12-8.20(2H).

LC-MS (method 3) R_t＝0.76min；MS(ESIpos)m/z＝351[M+H]⁺.

Example 12

N- (2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } ethyl) -2, 2-dimethylpropan-1-amine

In an ice bath 68mg (0.52mmol) of 2- [ (2, 2-dimethylpropyl) amino ] ethanol are added to 18mg (0.46mmol) of sodium hydride (60% in mineral oil) in 4mL of anhydrous tetrahydrofuran. Stirring in an ice bath for 15min, then 70mg (0.26mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at 40 ℃ for 72 h.

The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 50mg (53%) of the product as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝0.84(9H),2.35(2H),3.01(2H),4.55(2H),7.03(1H),7.23-7.36(2H),7.62(2H),7.67-7.72(1H),8.11-8.17(2H).

LC-MS (method 4) R_t＝0.89min；MS(ESIpos)m/z＝365[M+H]⁺.

Example 13

3- (1-benzofuran-2-yl) -6- {2- [ (3S) -morpholin-3-yl ] ethoxy } imidazo [1,2-b ] pyridazine

96mg (0.52mmol) of (S) -2- (morpholin-3-yl) ethanol are added in an ice bath to 18mg (0.46mmol) of sodium hydride (60% in mineral oil) in 4mL of anhydrous tetrahydrofuran. Stirring in an ice bath for 15min, then 70mg (0.26mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at 40 ℃ for 15 h.

The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography to give 51mg (54%) of the product as a solid.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝1.81(2H),2.73-2.80(2H),2.86-2.95(1H),3.12(1H),3.33-3.40(1H),3.65(1H),3.76(1H),4.59(2H),7.03(1H),7.27-7.38(2H),7.62-7.67(2H),7.70-7.75(1H),8.16(2H).

LC-MS (method 3) R_t＝0.74min；MS(ESIpos)m/z＝365[M+H]⁺.

Example 14

6- (azetidin-3-ylmethoxy) -3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine

64mg (0.52mmol) of 3- (hydroxymethyl) azetidine hydrochloride are added to 41mg (1.04mmol) of sodium hydride (60% in mineral oil) in 4mL of anhydrous tetrahydrofuran in an ice bath. Stirring in an ice bath for 15min, then 70mg (0.26mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at 40 ℃ for 72 h.

The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 39mg (46%) of the product as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝3.18(1H),3.50-3.60(2H),3.66-3.77(2H),4.63(2H),7.03(1H),7.22-7.37(2H),7.60-7.66(2H),7.70-7.76(1H),8.12-8.19(2H).

LC-MS (method 3) R_t＝0.74min；MS(ESIpos)m/z＝321[M+H]⁺.

Example 15

3- (1-benzofuran-2-yl) -6- {2- [ (2S) -pyrrolidin-2-yl ] ethoxy } imidazo [1,2-b ] pyridazine

Step 1: to 9.3g (40.4mmol) of [ (2S) -1- (tert-butoxycarbonyl) pyrrolidin-2-yl ] acetic acid in 116mL of tetrahydrofuran was added dropwise 40mL of borane-dimethylsulfide complex. The resulting mixture was stirred at 80 ℃ for 2 h.

The mixture was carefully poured into saturated aqueous sodium bicarbonate. The aqueous layer was extracted with methyl tert-butyl ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to give 6.2g of crude product, which was used in step 2 without further purification.

Step 2: in an ice bath, 1.37g (6.39mmol) of the crude product of step 1 are added to 224mg (5.62mmol) of sodium hydride (60% in mineral oil) in 34mL of anhydrous tetrahydrofuran. After stirring in an ice bath for 15 minutes, 861mg (3.19mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at room temperature for 24 h.

The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The resulting crude product (2.1g) was used in step 3 without further purification.

And step 3: to 1.4g of the crude product from step 2 in 28mL of dichloromethane was added 4.9mL of trifluoroacetic acid. The mixture was stirred for 1 h. Aqueous sodium hydroxide solution was added until the mixture reached basic pH. Brine was added and the mixture was extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate and concentrated.

The residue was purified by HPLC to give 725mg of the product as a solid material.

1H-NMR(300MHz,DMSO-d₆),[ppm]＝1.57-1.72(1H),1.77-2.01(2H),2.11-2.32(3H),3.09-3.24(2H),3.64(1H),4.51-4.70(2H),7.02(1H),7.24-7.37(2H),7.60-7.66(2H),7.67-7.74(1H),8.13-8.23(2H).

LC-MS (method 1) R_t＝0.82min；MS(ESIpos)m/z＝349[M+H]⁺.

Example 16

3- (1-benzofuran-2-yl) -6- (piperidin-2-ylmethoxy) imidazo [1,2-b ] pyridazine

Step 1: in an ice bath, 1.95g (8.9mmol) of tert-butyl 2- (hydroxymethyl) piperidine-1-carboxylate are added to 313mg (7.83mmol) of sodium hydride (60% in mineral oil) in 24mL of anhydrous tetrahydrofuran. After stirring in an ice bath for 15 minutes, 1.2g (4.45mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at room temperature for 4 days.

The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The resulting crude product (1.65g) was used in step 2 without further purification.

Step 2: to the crude product of step 1in 36mL of dichloromethane was added 8.9mL of trifluoroacetic acid. The mixture was stirred for 3 h. Aqueous ammonia was added until the mixture reached a basic pH. Brine was added and the mixture was extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate and concentrated.

The residue was purified by HPLC to give 358mg (23%) of the product as a solid material.

¹H-NMR(500MHz,DMSO-d₆),[ppm]＝1.32-1.49(3H),1.62(1H),1.84(2H),2.66-2.71(1H),3.09(1H),3.17(1H),4.40-4.45(1H),4.46-4.51(1H),7.07(1H),7.30-7.35(1H),7.36-7.40(1H),7.65(1H),7.66-7.69(1H),7.74-7.78(1H),8.19-8.23(2H).

LC-MS (method 1) R_t＝0.82min；MS(ESIpos)m/z＝349[M+H]⁺.

Example 17

N- (2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } ethyl) cyclopropylamine

77mg (0.74mmol) of 2- (cyclopropylamino) ethan-1-ol are added to 26mg (0.65mmol) of sodium hydride (60% in mineral oil) in 5mL of anhydrous tetrahydrofuran in an ice bath. After stirring in an ice bath for 15 minutes, 100mg (0.37mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at room temperature for 16 h.

The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was leached in methanol to give 25mg (20%) of the title compound as a solid substance.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝0.70-0.94(4H),2.82(1H),3.58(2H),4.81(2H),7.04(1H),7.24-7.38(2H),7.61-7.67(2H),7.71(1H),8.17-8.25(2H).

LC-MS (method 2) R_t＝0.82min；MS(ESIpos)m/z＝335[M+H]⁺.

Example 18

N- (2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } ethyl) -2-methylpropan-2-amine

In an ice bath 61mg (0.52mmol) of 2- (tert-butylamino) ethan-1-ol are added to 18.3mg (0.46mmol) of sodium hydride (60% in mineral oil) in 4mL of anhydrous tetrahydrofuran. Stirring in an ice bath for 15min, then 70mg (0.26mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at 40 ℃ for 72 h.

The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was leached in methyl tert-butyl ether to give 73mg (80%) of the title compound as a solid.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝1.05(9H),2.96(2H),4.49(2H),7.02(1H),7.24-7.35(2H),7.62(2H),7.68-7.73(1H),8.11-8.16(2H).

LC-MS (method 4) R_t＝0.82min；MS(ESIpos)m/z＝351[M+H]⁺.

Example 19

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -N- (propan-2-yl) propan-1-amine

In an ice bath 61mg (0.52mmol) of 1- (isopropylamino) propan-2-ol are added to 18.3mg (0.46mmol) of sodium hydride (60% in mineral oil) in 4mL of anhydrous tetrahydrofuran. Stirring in an ice bath for 15min, then 70mg (0.26mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at 40 ℃ for 16 h.

The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 52mg (57%) of the title compound as a solid substance.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝0.97(6H),1.46(3H),2.74-2.84(2H),2.96(1H),5.25-5.35(1H),6.97(1H),7.24-7.35(2H),7.59(1H),7.62(1H),7.71(1H),8.14(2H).

LC-MS (method 4) R_t＝0.84min；MS(ESIpos)m/z＝351[M+H]⁺.

Example 20

3- (5-chloro-1-benzofuran-2-yl) -6- [ (2R) -morpholin-2-ylmethoxy ] imidazo [1,2-b ] pyridazine

189mg (1.58mmol) of (R) -2-hydroxymethylmorpholine are added to 63mg (1.58mmol) of sodium hydride (60% in mineral oil) in 4mL of anhydrous tetrahydrofuran in an ice bath. Stirring in an ice bath for 15min, then 120mg (0.4mmol) 6-chloro-3- (5-chloro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at room temperature for 16 h.

The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was leached in methanol to give the title compound as a solid matter in an amount of 15mg (10%).

1H-NMR(300MHz,DMSO-d₆),[ppm]＝2.57-2.72(3H),2.93(1H),3.48(1H),3.73-3.88(2H),4.42(2H),7.07(1H),7.33(1H),7.59(1H),7.66(1H),7.80(1H),8.13-8.19(2H).

LC-MS (method 3) R_t＝0.88min；MS(ESIpos)m/z＝385[M+H]⁺.

Example 21

3- (1-benzofuran-2-yl) -6- [ (2R) -pyrrolidin-2-ylmethoxy ] imidazo [1,2-b ] pyridazine

In an ice bath 5g (49.4mmol) of (R) -2- (hydroxymethyl) pyrrolidine are added to 2.97g (74.2mmol) of sodium hydride (60% in mineral oil) in 466mL of anhydrous tetrahydrofuran. Stirring in an ice bath for 15min, then 6.67g (24.7mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at 40 ℃ for 16 h.

The reaction mixture was carefully poured into brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography to give 5.6g (68%) of the title compound as a solid substance.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.46-2.13(4H),2.73-2.89(2H),3.45-3.57(1H),4.26-4.33(2H),6.96-7.02(1H),7.29(2H),7.55(1H),7.61(1H),7.69-7.75(1H),8.12(2H).

LC-MS (method 3) R_t＝0.79min；MS(ESIpos)m/z＝335[M+H]⁺.

Example 22

3- (1-benzofuran-2-yl) -6- (piperidin-3-yloxy) imidazo [1,2-b ] pyridazine

In an ice bath 5g (49.4mmol) piperidin-3-ol were added to 2.96g (74.2mmol) sodium hydride (60% in mineral oil) in 500mL anhydrous tetrahydrofuran. Stirring in an ice bath for 15min, then 6.67g (24.7mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at 40 ℃ for 12 h.

The reaction mixture was carefully poured into brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The residue was leached in ethyl acetate to give 5.5g (60%) of the title compound as a solid material.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝1.54-1.83(3H),2.23-2.32(1H),2.54-2.63(1H),2.75(1H),2.81-2.89(1H),3.33(2H),5.06(1H),7.00(1H),7.27-7.39(2H),7.54(1H),7.63-7.67(1H),7.72-7.76(1H),8.13-8.18(2H).

LC-MS (method 3) R_t＝0.80min；MS(ESIpos)m/z＝335[M+H]⁺.

Example 23

3- (1-benzofuran-2-yl) -6- [ (2S) -pyrrolidin-2-ylmethoxy ] imidazo [1,2-b ] pyridazine

In an ice bath 5g (49.4mmol) of (S) -2-hydroxymethylpyrrolidine were added to 2.96g (74.2mmol) of sodium hydride (60% in mineral oil) in 466mL of anhydrous tetrahydrofuran. Stirring in an ice bath for 15min, then 6.67g (24.7mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at 40 ℃ for 12 h.

The reaction mixture was carefully poured into brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography to give 6.1g (62%) of the title compound as a solid.

¹H NMR(300MHz,DMSO-d₆)[ppm]＝1.83-2.21(4H),3.40-3.56(2H),3.58-3.80(2H),4.17(1H),4.63-5.21(1H),7.03(1H),7.21-7.41(2H),7.49-7.79(3H),7.88-8.07(2H).

LC-MS (method 3) R_t＝0.78min；MS(ESIpos)m/z＝335[M+H]⁺.

Example 24

1- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -N-methylpropan-2-amine

132mg (1.48mmol) of 2- (methylamino) propan-1-ol are added to 59.3mg (1.48mmol) of sodium hydride (60% in mineral oil) in 7.5mL of anhydrous DMF at 0-5 ℃. After stirring in an ice bath for 5 minutes, 200mg (0.74mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and stirred at room temperature for 1.5 hours.

The reaction mixture was poured into half-saturated ammonium chloride solution and extracted four times with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 107.6mg (45%) of the product.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.21(3H),2.43(3H),3.15-3.28(1H),4.46(2H),7.02(1H),7.23-7.37(2H),7.57-7.65(2H),7.69(1H),8.11-8.20(2H).

LC-MS (method 2) R_t＝0.83min；MS(ESIpos)m/z＝323[M+H]⁺.

Example 25

3- (5-chloro-1-benzofuran-2-yl) -6- {2- [ (2S) -pyrrolidin-2-yl ] ethoxy } imidazo [1,2-b ] pyridazine

Step 1: to 9.3g (40.4mmol) of [ (2S) -1- (tert-butoxycarbonyl) pyrrolidin-2-yl ] acetic acid in 116mL of tetrahydrofuran was added dropwise 40mL of borane-dimethylsulfide complex. The resulting mixture was stirred at 80 ℃ for 2 h.

The mixture was carefully poured into saturated aqueous sodium bicarbonate. The aqueous layer was extracted with methyl tert-butyl ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to give 6.2g of crude product, which was used in step 2 without further purification.

Step 2: in an ice bath, 150mg (0.7mmol) of the crude product of step 1 are added to 37mg (0.93mmol) of sodium hydride (60% in mineral oil) in 6mL of anhydrous tetrahydrofuran. After stirring in an ice bath for 15min, 189mg (0.47mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at room temperature for 18 h.

The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The resulting crude product (327mg) was used in step 3 without further purification.

And step 3: to 327mg of the crude product from step 2 in 5.8mL of dichloromethane was added 1.3mL of trifluoroacetic acid. The mixture was stirred for 1.5 h. Aqueous ammonia was added until the mixture reached a basic pH. Brine was added and the mixture was extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate and concentrated.

The residue was purified by HPLC to give 45mg (17%) of the product as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.38-1.53(1H),1.67-1.86(2H),1.95-2.12(3H),2.87-3.06(2H),3.31-3.43(2H),4.60(2H),7.02-7.10(1H),7.33-7.41(1H),7.67(2H),7.79-7.85(1H),8.15-8.23(2H).

LC-MS (method 3) R_t＝0.90min；MS(ESIpos)m/z＝383[M+H]⁺.

Example 26

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -N-methylpropan-1-amine

132mg (1.48mmol) of 1- (methylamino) propan-2-ol are added to 59.3mg (1.48mmol) of sodium hydride (60% in mineral oil) in 7.5mL of anhydrous DMF at 0-5 ℃. After stirring in an ice bath for 5 minutes, 200mg (0.74mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and stirred at room temperature for 1.5 hours.

The reaction mixture was poured into half-saturated ammonium chloride solution and extracted four times with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 21mg (9%) of the product.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝1.45(3H),2.36(3H),2.80-2.87(1H),2.90-2.98(1H),5.33-5.43(1H),6.96(1H),7.24-7.36(2H),7.58(1H),7.60-7.65(1H),7.68-7.74(1H),8.14(2H).

LC-MS (method 2) R_t＝0.83min；MS(ESIpos)m/z＝323[M+H]⁺.

Example 27

Formic acid-N- (2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -2-phenylethyl) propan-2-amine (1:1)

199mg (1.11mmol) of 2- (isopropylamino) -1-phenylethanol are added to 44.5mg (1.11mmol) of sodium hydride (60% in mineral oil) in 7.5mL of anhydrous DMF at 0-5 ℃. After stirring in an ice bath for 5 minutes, 150mg (0.56mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and stirred at room temperature for 3 hours. The reaction mixture was poured into half-saturated ammonium chloride solution and extracted four times with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 105mg (41%) of the product.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝1.05(6H),2.86-2.97(1H),3.00-3.07(1H),3.18-3.26(1H),6.11-6.16(1H),7.17(1H),7.25-7.44(6H),7.61(3H),7.75-7.81(2H),8.11(1H),8.17-8.24(2H).

LC-MS (method 2) R_t＝0.98min；MS(ESIpos)m/z＝413[M+H]⁺.

Example 28

N- (2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -2-phenylethyl) -2-methylpropan-1-amine

215mg (1.11mmol) of 2- (isobutylamino) -1-phenylethanol are added at 0-5 ℃ to 44.5mg (1.11mmol) of sodium hydride (60% in mineral oil) in 7.5mL of anhydrous DMF. After stirring in an ice bath for 5 minutes, 150mg (0.56mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and stirred at room temperature for 1.5 hours. The reaction mixture was poured into half-saturated ammonium chloride solution and extracted four times with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 101mg (43%) of the product.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝0.84(6H),1.61-1.72(1H),2.45(2H),2.93-3.00(1H),3.12-3.20(1H),6.09-6.15(1H),7.16(1H),7.24-7.43(6H),7.60(3H),7.74-7.79(1H),8.10(1H),8.18(1H).

LC-MS (method 2) R_t＝1.11min；MS(ESIpos)m/z＝427[M+H]⁺.

Example 29

(-) -2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -N-methyl-2-phenylethylamine

56mg (0.371mmol) of rac-2- (methylamino) -1-phenylethanol are added at 0-5 ℃ to 7.4mg (0.185mmol) of sodium hydride (60% in mineral oil) in 2.5mL of anhydrous DMF. After stirring in an ice bath for 30 minutes, 50mg (0.185mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and stirred at room temperature for 3 hours.

The reaction mixture was poured into half-saturated ammonium chloride solution and extracted four times with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 44mg (62%) of the product.

LC-MS (method 2) R_t＝0.99min；MS(ESIpos)m/z＝385[M+H]⁺.

The enantiomers were separated by chiral HPLC (Chiralpak IA 5 μm,250X30mm, hexane/ethanol 90:10+ 0.1% diethylamine, 40 mL/min).

Peak 1: 20mg, α ═ -432.2 ° (1.00; CHCl₃)

¹H-NMR (300MHz, chloroform-d), [ ppm [ (] ppm ]]＝2.55(3H),3.04(1H),3.28(1H),6.16(1H),6.90(1H),7.18(1H),7.24-7.35(3H),7.40(2H),7.48-7.57(3H),7.63(1H),7.90(1H),8.09(1H).

Example 30

N- (2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -2-phenylethyl) -2, 2-dimethylpropan-1-amine

361.6mg (1.48mmol) of 2- [ (2, 2-dimethylpropyl) amino ] -1-phenylethanol hydrochloride are added at 0-5 ℃ to 118.6mg (2.97mmol) of sodium hydride (60% in mineral oil) in 10mL of anhydrous DMF. After stirring in an ice bath for 5 minutes, 200mg (0.74mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and stirred at room temperature for 1.5 hours. The reaction mixture was poured into half-saturated ammonium chloride solution and extracted four times with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 186mg (57%) of the product.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝0.83(9H),2.41(2H),2.94-3.02(1H),3.14-3.23(1H),6.09-6.16(1H),7.17(1H),7.24-7.44(6H),7.60(3H),7.74-7.79(1H),8.10(1H),8.19(1H).

LC-MS (method 2) R_t＝1.03min；MS(ESIpos)m/z＝441[M+H]⁺.

Example 31

3- (1-benzofuran-2-yl) -6- [ (3R) -pyrrolidin-3-yloxy ] imidazo [1,2-b ] pyridazine

1.551g (17.80mmol) of (3R) -pyrrolidin-3-ol are added to 712mg (17.80mmol) of sodium hydride (60% in mineral oil) in 60mL of anhydrous DMF at 0-5 ℃. After stirring in an ice bath for 5 minutes, 2.4g (8.90mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and stirred at room temperature overnight. The reaction mixture was poured into a saturated ammonium chloride solution, and extracted ten times with 100mL of chloroform. The combined organic phases were dried over magnesium sulfate and concentrated. The crude product was combined with a second batch of the same amount under the same conditions. The residue was purified on silica gel with dichloromethane and methanol. The collected fractions were concentrated and leached with 2-isopropoxypropane. The solid was filtered off, washed with diethyl ether and dried under vacuum at room temperature for the weekend to give 2.55g (43%) of the product.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝1.90-1.99(1H),2.15-2.26(1H),2.79-2.88(1H),2.89-2.98(1H),2.99-3.05(1H),3.22-3.26(1H,and water signal),5.50-5.56(1H),6.97(1H),7.24-7.35(2H),7.58-7.65(2H),7.74(1H),8.08-8.17(2H).

LC-MS (method 2) R_t＝0.81min；MS(ESIpos)m/z＝321[M+H]⁺.

[ α ] ═ 62.5 °, (methanol, 0.28)

Example 32

3- (1-benzofuran-2-yl) -6- [ (3R) -piperidin-3-yloxy ] imidazo [1,2-b ] pyridazine

200mg (1.45mmol) of (3R) -piperidin-3-ol hydrochloride are added to 116.3mg (2.91mmol) of sodium hydride (60% in mineral oil) in 7mL of anhydrous DMF at 0-5 ℃. After stirring in an ice bath for 5 minutes, 196mg (0.73mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added. The ice bath was removed and stirred at room temperature overnight. The reaction mixture was poured into saturated ammonium chloride solution and extracted four times with ethyl acetate. The combined organic phases were washed twice with brine, dried over magnesium sulfate and concentrated. The crude product was treated with 5mL DMSO. The solid was filtered off and washed with water. It was dried under vacuum at 45 ℃ to yield 155mg (63%) of product.

¹H-NMR (400MHz, chloroform-d), [ ppm ] C]＝1.69(1H),1.85-2.03(2H),2.22-2.32(1H),2.84-2.92(1H),2.92-3.00(1H),3.10(1H),3.35(1H),5.14-5.22(1H),6.80(1H),7.24-7.36(2H,and chloroform signal),7.45(1H),7.55(1H),7.65(1H),7.90(1H),8.18(1H).

LC-MS (method 2) R_t＝0.78min；MS(ESIpos)m/z＝335[M+H]⁺.

Example 33

3- (4-fluoro-1-benzofuran-2-yl) -6- [ (2R) -morpholin-2-ylmethoxy ] imidazo [1,2-b ] pyridazine

In an ice bath, 51mg (0.43mmol) of (2R) -morpholin-2-ylmethanol are added to 17mg (0.43mmol) of sodium hydride (60% in mineral oil) in 4mL of anhydrous tetrahydrofuran. Stirring in an ice bath for 15min, then 74mg (0.22mmol) 6-chloro-3- (4-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at 40 ℃ for 18 h.

The reaction mixture was carefully poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by HPLC to give 49mg (55%) of the title compound as a solid substance.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝2.54-2.72(3H),2.94(1H),3.42-3.54(1H),3.77(1H),3.82-3.91(1H),4.43(2H),7.03-7.17(2H),7.35(1H),7.52(1H),7.58(1H),8.14-8.20(2H).

LC-MS (method 4) R_t＝0.81min；MS(ESIpos)m/z＝369[M+H]⁺.

Example 34

3- (5-fluoro-1-benzofuran-2-yl) -6- [ (2R) -morpholin-2-ylmethoxy ] imidazo [1,2-b ] pyridazine

In an ice bath, 33mg (0.29mmol) of (2R) -morpholin-2-ylmethanol are added to 12mg (0.29mmol) of sodium hydride (60% in mineral oil) in 4mL of anhydrous tetrahydrofuran. Stirring in an ice bath for 15min, then 69mg (0.14mmol) 6-chloro-3- (5-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine are added. The ice bath was removed and the reaction mixture was stirred at 40 ℃ for 18 h.

The reaction mixture was carefully poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by HPLC to give 14mg (24%) of the title compound as a solid substance.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝2.65-2.77(3H),2.99(1H),3.47-3.55(1H),3.80(1H),3.83-3.91(1H),4.44(2H),7.04-7.10(1H),7.15(1H),7.53(1H),7.60(1H),7.65(1H),8.14-8.19(2H).

LC-MS (method 4) R_t＝0.82min；MS(ESIpos)m/z＝369[M+H]⁺.

Furthermore, the compounds of formula (I) of the present invention may be converted into any of the salts described herein by any method known to those skilled in the art. Similarly, any salt of a compound of formula (I) of the present invention may be converted to the free compound by any method known to those skilled in the art.

Pharmaceutical compositions of the compounds of the invention

The invention also relates to pharmaceutical compositions comprising one or more compounds of the invention. These compositions can be used to achieve a desired pharmacological effect by administration to a patient in need thereof. For the purposes of the present invention, a patient is a mammal, including a human, in need of treatment for a particular condition or disease. Accordingly, the present invention includes pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the present invention or a salt thereof. A pharmaceutically acceptable carrier is preferably one that is relatively non-toxic and non-injurious to a patient at concentrations consistent with effective activity of the active ingredient, such that any side effects caused by the carrier do not destroy the beneficial effects of the active ingredient. A pharmaceutically effective amount of a compound is preferably one that results in or affects the particular condition being treated. The compounds of the present invention may be administered together with pharmaceutically acceptable carriers well known in the art in any effective conventional dosage unit form including immediate release, sustained release and timed release formulations in the following manner: oral, parenteral, topical, nasal, ocular (ophthalmic), sublingual, rectal, vaginal administration and the like.

For oral administration, the compounds may be formulated into solid or liquid preparations such as capsules, pills, tablets, troches (troche), lozenges (lozenge), melt gels (melt), powders, solutions, suspensions or emulsions and may be prepared according to methods known in the art for the preparation of pharmaceutical compositions. The solid unit dosage form may be a capsule, which may be of the ordinary hard or soft capsule type, containing, for example, surfactants, lubricants, and inert fillers (e.g., lactose, sucrose, calcium phosphate, and corn starch).

In another embodiment, the compounds of the invention can be compressed into tablets with conventional tablet bases (e.g., lactose, sucrose, and corn starch) and in combination with: binders (e.g., acacia, corn starch or gelatin), disintegrating agents to aid in the disintegration and dissolution of the tablet after administration (e.g., potato starch, alginic acid, corn starch and guar gum, gum tragacanth, acacia), lubricants to improve the flowability of the tablet granulation and to prevent adhesion of the tablet materials to the surfaces of the tablet die and punch (e.g., talc, stearic acid or magnesium stearate, calcium stearate or zinc stearate), dyes, colorants, and flavoring agents (e.g., peppermint, oil of wintergreen or cherry flavoring) to improve the organoleptic properties of the tablets and make them more acceptable to the patient. Suitable excipients for oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols (e.g., ethanol, benzyl alcohol and polyvinyl alcohol), with or without the addition of pharmaceutically acceptable surfactants, suspending agents or emulsifying agents. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar or both.

Dispersible powders and granules are suitable for use in the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, such as those described above, may also be present.

The pharmaceutical composition of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) natural gums, for example gum acacia and gum tragacanth, (2) natural phosphatides, for example soya bean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, (4) condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. The suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate; one or more colorants; one or more flavoring agents; and one or more sweetening agents, such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent and a preservative (e.g., methyl and propyl parabens) as well as flavoring and coloring agents.

The compounds of the invention may also be administered parenterally, i.e., subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly or intraperitoneally, in injectable doses of the compounds, preferably in a physiologically acceptable diluent with a pharmaceutical carrier, which may be a sterile liquid or a mixture of liquids, such as water, saline, aqueous dextrose and related sugar solutions, alcohols such as ethanol, isopropanol or cetyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2, 2-dimethyl-1, 1-dioxolane-4-methanol, ethers such as poly (ethylene glycol) 400, oils, fatty acids, fatty acid esters or glycerides or acetylated glycerides, with or without the addition of pharmaceutically acceptable surfactants such as soaps or detergents, suspending agents such as pectin, carbomer, methylcellulose, hypromellose or carboxymethylcellulose, or emulsifying agents and other pharmaceutically acceptable adjuvants.

Exemplary oils useful in the parenteral formulations of the invention are those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium and triethanolamine salts, and suitable detergents include cationic detergents such as dimethyl dialkyl ammonium halides, alkyl pyridinium halides and alkylamine acetates; anionic detergents such as alkyl sulfonates, aryl sulfonates and olefin sulfonates, alkyl sulfates and alkyl sulfosuccinates, olefin sulfates and olefin sulfosuccinates, ether sulfates and ether sulfosuccinates, and monoglyceride sulfates and monoglycerides sulfosuccinates; nonionic detergents such as fatty amine oxides, fatty acid alkanolamides, and poly (oxyethylene-oxypropylene), ethylene oxide copolymers or propylene oxide copolymers; and amphoteric detergents such as alkyl-beta-aminopropionates and 2-alkylimidazoline quats, and mixtures thereof.

The parenteral compositions of the invention will typically comprise from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be advantageously employed. To minimize or eliminate irritation at the injection site, such compositions may comprise a nonionic surfactant having a hydrophilic-lipophilic balance (HLB) of preferably from about 12 to about 17. The amount of surfactant in such formulations is preferably from about 5% to about 15% by weight. The surfactant may be a single component having the above HLB, or a mixture of two or more components having the desired HLB.

Exemplary surfactants for parenteral formulations are polyethylene sorbitan fatty acid esters, such as sorbitan monooleate, and the high molecular weight adducts of ethylene oxide with a hydrophobic base formed by the condensation of propylene oxide and propylene glycol.

The pharmaceutical composition may be in the form of a sterile aqueous suspension for injection. Such suspensions may be formulated according to known methods using: suitable dispersing or wetting agents and suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide (for example lecithin), a condensation product of an alkylene oxide with a fatty acid (for example polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (for example heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (for example polyoxyethylene sorbitol monooleate), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (for example polyoxyethylene sorbitan monooleate).

The sterile injectable preparation may also be a sterile solution or suspension for injection in a non-toxic parenterally-acceptable diluent or solvent. Diluents and solvents which can be used are, for example, water, ringer's solution, isotonic sodium chloride solution and isotonic glucose solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. In this regard, any less irritating fixed oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids (e.g., oleic acid) may be used in the preparation of injectables.

The compositions of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycols.

Another formulation used in the methods of the invention utilizes a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or discontinuous infusion of a controlled amount of a compound of the present invention. The construction and use of transdermal patches for delivering agents is well known in the art (see, e.g., U.S. patent No.5,023,252 issued on 6/11 of 1991, which is incorporated herein by reference). Such patches may be configured for continuous, pulsed, or on-demand delivery of the agent.

Controlled release formulations for parenteral administration include liposomal microspheres, polymeric microspheres, and polymeric gel formulations known in the art.

It may be desirable or necessary to deliver the pharmaceutical composition to a patient by a mechanical delivery device. The construction and use of mechanical delivery devices for delivering pharmaceutical agents is well known in the art. Direct techniques such as administering drugs directly to the brain typically involve placing a drug delivery catheter into the ventricular system of the patient to bypass the blood brain barrier. One such implantable delivery system for delivering agents to specific anatomical locations of the body is described in U.S. patent No.5,011,472 issued on 30/4 1991.

The compositions of the present invention may also contain, as necessary or desired, other conventional pharmaceutically acceptable formulation ingredients, which are commonly referred to as carriers or diluents. Conventional procedures for preparing such compositions into suitable dosage forms may be used. Such ingredients and procedures include those described in the following references, all of which are incorporated herein by reference: powell, M.F. et al, "Complex of Excipients for particulate Formulations" PDA Journal of pharmaceutical Science & Technology 1998,52(5), 238-; strickley, R.G, "partial formulations of Small Molecule Therapeutics marked in the United States (1999) -Part-1," PDA Journal of Pharmaceutical Science & Technology 1999,53(6), 324-; and Nema, S. et al, "Excipients and the same Use in Injectable Products," PDAjournal of Pharmaceutical Science & Technology 1997,51(4),166- "171.

Common pharmaceutical ingredients that may be used to formulate the composition for the intended route of administration include:

acidulants (examples include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);

alkalizing agents (examples include, but are not limited to, ammonia, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine (triethanolamine), triethanolamine (trolamine));

adsorbents (examples include, but are not limited to, powdered cellulose and activated carbon);

aerosol propellants (examples include, but are not limited to, carbon dioxide, CCl₂F₂、F₂ClC-CClF₂And CClF₃)；

Air displacement agents (examples include, but are not limited to, nitrogen and argon);

antifungal preservatives (examples include, but are not limited to, benzoic acid, butyl paraben, ethyl paraben, methyl paraben, propyl paraben, sodium benzoate);

antibacterial preservatives (examples include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, and thimerosal);

antioxidants (examples include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, thioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite);

adhesive substances (examples include, but are not limited to, block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones, polysiloxanes, and styrene-butadiene copolymers);

buffering agents (examples include, but are not limited to, potassium metaphosphate, dipotassium hydrogen phosphate, sodium acetate, anhydrous sodium citrate, and sodium citrate dihydrate);

a carrier (examples include, but are not limited to, acacia syrup, flavoring elixir, cherry syrup, cocoa syrup, orange syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection, and bacteriostatic water for injection);

chelating agents (examples include, but are not limited to, edetate disodium and edetic acid);

coloring agents (examples include, but are not limited to FD & C Red No.3, FD & C Red No.20, FD & C Yellow No.6, FD & C Blue No.2, D & C Green No.5, D & C Orange No.5, D & C Red No.8, caramel, and Red iron oxide);

clarifying agents (examples include, but are not limited to, bentonite);

emulsifying agents (examples include, but are not limited to, acacia, cetomacrogol, cetyl alcohol, glycerol monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate);

encapsulating agents (examples include, but are not limited to, gelatin and cellulose acetate phthalate);

flavors (examples include, but are not limited to, anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil, and vanillin);

humectants (examples include, but are not limited to, glycerin, propylene glycol, and sorbitol);

abrasives (examples include, but are not limited to, mineral oil and glycerin);

oils (examples include, but are not limited to, peanut oil (arachis oil), mineral oil, olive oil, peanut oil (parautoil), sesame oil, and vegetable oils);

ointment bases (examples include, but are not limited to, lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment);

penetration enhancers (transdermal delivery) (examples include, but are not limited to, mono-or polyhydric alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalins, terpenes, amides, ethers, ketones, and ureas);

plasticizers (examples include, but are not limited to, diethyl phthalate and glycerol);

solvents (examples include, but are not limited to, ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection, and sterile water for rinsing);

hardening agents (examples include, but are not limited to, cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax, and yellow wax);

suppository bases (examples include, but are not limited to, cocoa butter and polyethylene glycol (mixtures));

surfactants (examples include, but are not limited to, benzalkonium chloride, nonoxynol 10, octoxynol 9, polysorbate 80, sodium lauryl sulfate, and sorbitan monopalmitate);

suspending agents (examples include, but are not limited to, agar, bentonite, carbomer, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, kaolin, methylcellulose, tragacanth and magnesium aluminum silicate);

sweetening agents (examples include, but are not limited to, aspartame, dextrose, glycerin, mannitol, propylene glycol, saccharin sodium, sorbitol, and sucrose);

tablet antiadherents (examples include, but are not limited to, magnesium stearate and talc);

tablet binders (examples include, but are not limited to, acacia, alginic acid, sodium carboxymethylcellulose, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);

tablet and capsule diluents (examples include, but are not limited to, dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium phosphate, sorbitol, and starch);

tablet coatings (examples include, but are not limited to, liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, methyl cellulose, ethyl cellulose, cellulose acetate phthalate, and shellac);

tablet direct compression excipients (examples include, but are not limited to, dibasic calcium phosphate);

tablet disintegrating agents (examples include, but are not limited to, alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, crospovidone, sodium alginate, sodium starch glycolate, and starch);

tablet glidants (examples include, but are not limited to, colloidal silicon dioxide, corn starch, and talc);

tablet lubricants (examples include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, and zinc stearate);

tablet/capsule opacifiers (examples include but are not limited to titanium dioxide);

tablet polishes (examples include, but are not limited to, carnauba wax and white wax);

thickening agents (examples include, but are not limited to, beeswax, cetyl alcohol, and paraffin wax);

tonicity agents (examples include, but are not limited to, glucose and sodium chloride);

viscosity increasing agents (examples include, but are not limited to, alginic acid, bentonite, carbomer, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium alginate, and gum tragacanth); and

wetting agents (examples include, but are not limited to, heptadecaethyleneoxycetanol (heptadecaethyleneoxycetanol), lecithin, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

The pharmaceutical composition of the present invention can be exemplified as follows:

sterile intravenous solution: sterile water for injection can be used to prepare a 5mg/mL solution of the desired compound of the invention, with the pH adjusted as necessary. The solution was diluted to 1-2mg/mL with sterile 5% glucose for administration and administered as an intravenous infusion over about 60 minutes.

Lyophilized powder for intravenous administration: sterile preparations can be prepared from (i)100-1000mg of the desired compound of the invention in the form of a lyophilized powder, (ii)32-327mg/mL sodium citrate, and (iii)300-3000mg dextran 40. The formulation is reconstituted to a concentration of 10-20mg/mL with sterile saline for injection or 5% glucose, then further diluted to 0.2-0.4mg/mL with saline or 5% glucose and administered as an intravenous bolus or intravenous infusion over 15-60 minutes.

Intramuscular injection suspension: the following solutions or suspensions can be prepared for intramuscular injection:

50mg/mL of the desired Water-insoluble Compound of the invention

5mg/mL sodium carboxymethylcellulose

4mg/mL TWEEN 80

9mg/mL sodium chloride

9mg/mL benzyl alcohol

Hard capsule: a large number of unit capsules were prepared by filling standard two-piece hard capsules with 100mg of powdered active ingredient, 150mg of lactose, 50mg of cellulose and 6mg of magnesium stearate, respectively.

Soft capsule: a mixture of the active ingredient in a digestible oil (such as soybean oil, cottonseed oil or olive oil) is prepared and injected by a positive displacement pump into molten gelatin to form a soft capsule containing 100mg of the active ingredient. The capsules were washed and dried. The active ingredient may be dissolved in a mixture of polyethylene glycol, glycerol and sorbitol to prepare a water-miscible drug mixture.

Tablet formulation: a number of tablets were prepared by conventional procedures such that the dosage unit contained 100mg of active ingredient, 0.2mg of colloidal silicon dioxide, 5mg of magnesium stearate, 275mg of microcrystalline cellulose, 11mg of starch and 98.8mg of lactose. Suitable aqueous and non-aqueous coatings may be employed to increase palatability, improve appearance and stability, or delay absorption.

Immediate release tablet/capsule: these are solid oral dosage forms prepared by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the drug. The active ingredient is mixed in a liquid containing ingredients such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze-drying and solid-state extraction techniques. The pharmaceutical compound can be tableted with a viscoelastic and thermoelastic sugar and a polymer or effervescent component to produce a porous matrix that is quick-releasing without the need for water.

Combination therapy

The term "combination" in the present invention is used as known to the person skilled in the art and may be present in the form of a fixed combination, a non-fixed combination or a kit.

The "fixed combination" in the present invention is used as known to the person skilled in the art and is defined as a combination wherein the first active ingredient and the second active ingredient are present together in one unit dosage form or in a single entity. An example of a "fixed combination" is a pharmaceutical composition, wherein the first active ingredient and the second active ingredient are present in a mixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination, wherein the first active ingredient and the second active ingredient are present in one unit, but not in the form of a mixture.

The non-fixed combination or "kit" according to the invention is used as known to the person skilled in the art and is defined as wherein the first active ingredient and the second active ingredient are present in more than one unit. An example of a non-fixed combination or kit is a combination, wherein the first active ingredient and the second active ingredient are present separately. The components of the ambulatory combination or kit can be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.

The compounds of the present invention may be administered as a single agent or in combination with one or more other agents, wherein the combination does not cause unacceptable adverse effects. The invention also relates to such combinations. For example, the compounds of the present invention can be combined with known chemotherapeutic or anti-cancer agents (e.g., agents that combat hyperproliferative diseases or other indications, etc.), as well as with mixtures and combinations thereof. Other indications include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, anti-metabolites, DNA-intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, or anti-hormones.

The term "chemotherapeutic anti-cancer agent" includes, but is not limited to: 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY 1000394, BAY 86-9766(RDEA 119, belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, calcium folinate, calcium levofolinate, capecitabine, carboplatin, carmofluorine, carmustine, rituximab, celecoxib, simox-white blood, cetuximab, cisplatin, chlorambucil, chloropasoprene, mechlorethamine, chloroparazine, capecitabine, cladribine, clofarabine, phosphamide, loratadine, and other, Cyclopropylterone, cytarabine, dacarbazine, actinomycin D, daltephrosin alpha, dasatinib, daunorubicin, decitabine, degarelix, dinil interleukin 2, desuzumab, deslorelin, dibromospiro-ammonium chloride, docetaxel, doxifluridine, doxorubicin + estrone, eculizumab, edrecolomab, etiloamine, eltromapa, endostatin, enocitabine, epirubicin, epithisterol, erythrosin alpha, betagliptin, esplatin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastimbine, fludarabine, flutamide, formestane, fotemustine, fulvestramustine, gallium nitrate, ganciclovir, gazettuzumab, gemcitabine, glutethioninb, glutethionin, gortimidox, histrexostat, histamine dihydrochloride, Himalaridine, hydroxyurea, I-125seeds (I-125seeds), ibandronic acid, temomomazumab, idarubicin, ifosfamide, imatinib, imiqimod, improsulfan, interferon alpha, interferon beta, interferon gamma, ipilimumab, irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide, letrozole, leuprolide, levamisole, lisuride, lobaplatin, lomustine, lonidamine, maxol, medroxyprogesterone, megestrol, melphalan, melandrone, mercaptopurine, methotrexate, methoxsalene, methoxamine, methomyl valerate, methyltestosterone, mifamustine, miltefosine, mibevacrol, mibefraplatin, dibromomannitol, mitomycin, mitotane, mitoxantrone, nelitabine, nilotinib, nilutaline, mibruxiu, mikamuragliptin, mibeuramicin, mibeuramicitabine, irinotecan, ibandron, ibriturin, ibritude, Nimotuzumab, nimustine, nitrendezine, ofatumumab, omeprazole, oproteileukin, oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103seed (palladium-103seed), pamidronic acid, parlimumab, pazopanib, pemetrexed, PEG-betaethylparaben, pefilgrastim, peimetrexed alpha-2 b, pemetrexed, pentazocine, pentostatin, pellomycin, perfosfamide, piscibacil, pirarubicin, plerixafot, plicamycin, chitosan, estradiol polyphosphate, polysaccharide-k, porfimer sodium, pralatrexate, poitemustine, procarbazine, quinovone, raloxifene, raltitrexed, ranimustine, ranibizaril, regoligine, ritinib, risedronate, rituximab, and ropamide, Romidepsin, sargrastim, sipuleucel-T, cilazan, sobuzosin, sodium glycinbisoxazole, sorafenib, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tasolinamine, tegafur + gimeracil + oteracil, temoporfine, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, cetripiprep, thymalfasin, thioguanine, tolbizumab, topotecan, toremifene, tositumomab, trabepotadine, trastuzumab, trooshu, tretinoin, trostastaphyl, triptorelin, trofosfamide, tryptophan, ubenix, pentametiranib, valvactide, vincamufenib, vinblastine, vindesine, glass microspheres, yttrium 90, vinorelbine, valtrex, valdecoxib, trexadone, trexadine, trexatilin, trexadine, trexapridine, tretinob, tretinomycin, vinpocin, vinorelbine, vindesine, vinorelb, Netastatin, netastatin ester, zoledronic acid and zorubicin.

The compounds of the invention may also be administered in combination with a protein therapeutic. Such protein therapeutics suitable for treating cancer or other angiogenic disorders and suitable for use with the compositions of the invention include, but are not limited to, interferons (e.g., alpha, beta, or gamma interferon), hyperactivating (superagonistic) monoclonal antibodies, Tuebingen, TRP-1 protein vaccines, Colostrinin, anti-FAP antibodies, YH-16, gemtuzumab, infliximab, cetuximab, trastuzumab, dinil interleukin 2, rituximab, alpha 1 thymosin, bevacizumab, mecamylamine, linmecamylamine (mecastin rinfabate), omprex interleukin, natalizumab, rhmbcp, MFE-1 + ZD-2767-P, ABT-828, ErbB 2-specific immunotoxin, SGN-35, MT-103, linnfibate, AS-1402-flavonoid, B43-genistein, AS-1402-43-p, L-19 series radioimmunotherapeutic agents, AC-9301, NY-ESO-1 vaccine, IMC-1C11, CT-322, rhCC10, r (m) CRP, MORAB-009, Avermectin, MDX-1307, Her-2 vaccine, APC-8024, NGR-hTNF, rhH1.3, IGN-311, endostatin, Voluoximab, PRO-1762, Lysimazumab, SGN-40, pertuzumab, EMD-273063, L19-IL-2 fusion protein, PRX-321, CNTO-328, MDX-214, tegafur peptide, CAT-3888, Rabevacizumab, radioisotope-emitting radioactive isotope cross-linked lintuzumab, EM-1421, HyperAcute vaccine, Simon interleukin, galiximab, HPV-16-E7, Javin-3501, Javelin-prostate cancer, melanoma-prostate cancer, NY-ESO-1 vaccine, EGF vaccine, CYT-004-MelQbG10, WT1 peptide, ogovazumab, ofatumumab, zalutumab, betulin, WX-G250, Albuferon, aflibercept, desuzumab, vaccine, CTP-37, efletuzumab or 131I-chTNT-1/B. Monoclonal antibodies useful as protein therapeutics include, but are not limited to, molobuzumab-CD 3, abciximab, edrotuzumab, daclizumab, gemtuzumab (gentuzumab), alemtuzumab, ibritumomab (ibritumomab), cetuximab, bevacizumab (bevicizumab), efuzumab, adalimumab, omalizumab, morromumab-CD 3, rituximab, daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.

A compound of general formula (I) as defined herein may optionally be administered in combination with one or more of the following: ARRY-162, ARRY-300, ARRY-704, AS-703026, AZD-5363, AZD-8055, BEZ-235, BGT-226, BKM-120, BYL-719, CAL-101, CC-223, CH-5132799, ridolimus, E-6201, enzastarin, GDC-0032, GDC-0068, GDC-0623, GDC-0941, GDC-0973, GDC-0980, GSK-2110183, GSK-2126458, GSK-2141795, MK-2206, novolimus, OSI-027, piperacillin, PF-04691502, PF-05212384, PX-866, rapamycin, RG-7167, RO-4987655, RO-5126766, mestinib, TAK-733, trametinb (trametinib), triciribine, n-01, XL-147, wxl-XL, gazernib-55, GDC-8, GDC-098, gdl, GDC-0980, GDC-356458, and optionally, ZSTK-474.

In general, the use of cytotoxic and/or cytostatic agents in combination with a compound or composition of the invention will serve the following functions:

(1) better efficacy in reducing tumor growth or even eliminating tumors than either agent administered alone,

(2) allowing for the administration of smaller amounts of the administered chemotherapeutic agent,

(3) providing a chemotherapeutic treatment that is well tolerated by patients and has fewer harmful pharmacological complications than observed with single agent chemotherapy and certain other combination therapies,

(4) allows the treatment of a wider range of different cancer types in mammals (particularly humans),

(5) providing a higher response in the treated patient,

(6) provides longer survival in the treated patient compared to standard chemotherapy treatment,

(7) provide longer tumor progression time, and/or

(8) At least as good efficacy and tolerability as the agents used alone are obtained as compared to known cases where other cancer agents produce antagonistic effects in combination.

Method for sensitizing cells to radiation

In a different embodiment of the invention, the compounds of the invention can be used to sensitize cells to radiation. That is, treatment of cells with a compound of the invention prior to radiation therapy of the cells makes the cells more susceptible to DNA damage and cell death than they would be if the cells were not subjected to any treatment with a compound of the invention. In one aspect, a cell is treated with at least one compound of the invention.

Accordingly, the present invention also provides a method of killing cells, wherein one or more compounds of the invention are administered to the cells along with conventional radiation therapy.

The invention also provides methods of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of the invention to cause or induce cell death prior to treating the cell. In one aspect, after treating the cells with one or more compounds of the invention, the cells are treated with at least one compound, at least one method, or a combination thereof to cause DNA damage for inhibiting the function of normal cells or killing the cells.

In one embodiment, the cells are killed by treating the cells with at least one DNA damaging agent. That is, after treating a cell with one or more compounds of the invention sensitizes the cell to cell death, the cell is treated with at least one DNA-damaging agent to kill the cell. DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g., cisplatin), ionizing radiation (X-ray, ultraviolet radiation), carcinogens, and mutagenic agents.

In another embodiment, the cells are killed by treating the cells with at least one method to cause or induce DNA damage. Such methods include, but are not limited to: activating a cellular signal transduction pathway (which causes DNA damage when the pathway is activated), inhibiting a cellular signal transduction pathway (which causes DNA damage when the pathway is inhibited), and inducing a biochemical change in a cell (wherein the change causes DNA damage). As a non-limiting example, DNA repair pathways in a cell may be inhibited, thereby preventing repair of DNA damage and resulting in abnormal accumulation of DNA damage in a cell.

In one aspect of the invention, the compounds of the invention are administered prior to irradiation or other induction that causes DNA damage in the cell. In another aspect of the invention, the compounds of the invention are administered concurrently with irradiation or other induction that causes DNA damage to cells. In yet another aspect of the invention, the compounds of the invention are administered immediately after the initiation of irradiation or other induction that causes DNA damage to the cells.

In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo.

As described above, it has surprisingly been found that the compounds of the present invention effectively inhibit MKNK-1 and are therefore useful for the treatment or prevention of diseases caused by or accompanied by uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response or an inappropriate cellular inflammatory response, in particular wherein said uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by MKNK-1, e.g. hematological tumors, solid tumors and/or metastases thereof, such as leukemias and myelodysplastic syndromes, malignant lymphomas, head and neck tumors including brain tumors and brain metastases, tumors of the neck, and/or metastases thereof, Breast, gastrointestinal, endocrine, breast and other gynaecological tumours including non-small cell and small cell lung tumours, urological tumours including renal, bladder and prostate tumours, skin tumours and sarcomas, and/or metastases thereof.

Thus, according to another of its aspects, the present invention relates to a compound of general formula (I) as described and defined herein 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 prevention of a disease as described above.

Thus, another particular aspect of the invention is the use of a compound of general formula (I) as described above 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 the prophylaxis or treatment of a disease.

Accordingly, another particular aspect of the present invention is the use of a compound of general formula (I) as described above for the preparation of a pharmaceutical composition for the treatment or prevention of a disease.

The diseases mentioned in the first two paragraphs are diseases caused by or accompanied by uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response or an inappropriate cellular inflammatory response, in particular wherein said uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by MKNK-1, such as hematological tumors, solid tumors and/or metastases thereof, e.g. leukemia and myelodysplastic syndrome, malignant lymphomas, head and neck tumors including brain tumors and brain metastases, breast tumors including non-small cell lung tumors and small cell lung tumors, gastrointestinal tumors, inflammatory diseases, Endocrine tumors, breast tumors and other gynecological tumors, urological tumors including renal tumors, bladder tumors and prostate tumors, skin tumors and sarcomas, and/or metastases thereof.

In the context of the present invention, in particular in the context of an "inappropriate cellular immune response or inappropriate cellular inflammatory response" as used herein, the term "inappropriate" is to be understood as preferably meaning a response which is weaker or stronger than the normal response and which is associated with, causes or leads to the pathology of the disease.

Preferably, the use is for the treatment or prevention of a disease, wherein the disease is a hematological tumor, a solid tumor and/or metastases thereof.

Methods of treating hyperproliferative disorders

The present invention relates to methods of treating hyperproliferative disorders in mammals using the compounds of the present invention and compositions thereof. The compounds may be used to inhibit, block, reduce, etc., cell proliferation and/or cell division and/or induce apoptosis. The method comprises administering to a mammal, including a human, in need thereof an amount of a compound of the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, and the like, effective to treat the condition. Hyperproliferative disorders include, but are not limited to, psoriasis, keloids and other hyperplasia affecting the skin, Benign Prostatic Hyperplasia (BPH), solid tumors such as breast cancer, respiratory tract cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and their distant metastases. Such conditions also include lymphomas, sarcomas and leukemias.

Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are not limited to, small cell lung cancer and non-small cell lung cancer as well as bronchial adenomas and pleural pneumococcal tumors.

Examples of brain cancers include, but are not limited to, brainstem and hypothalamic gliomas, cerebellum and brain astrocytomas, medulloblastomas, ependymomas, and neuroectodermal and pineal tumors.

Tumors of the male reproductive organs include, but are not limited to, prostate cancer and testicular cancer. Tumors of female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancers, as well as uterine sarcomas.

Tumors of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small intestine, and salivary gland cancers.

Urinary tract tumors include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureter cancer, urinary tract cancer, and human papillary renal cancer.

Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to, squamous cell carcinoma, kaposi's sarcoma, malignant melanoma, merkel cell skin cancer, and non-melanoma skin cancer.

Head and neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer, and squamous cell. Lymphomas include, but are not limited to, AIDS-related lymphoma, non-hodgkin's lymphoma, cutaneous T-cell lymphoma, burkitt's lymphoma, hodgkin's disease, and central nervous system lymphoma.

Sarcomas include, but are not limited to, soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas, lymphosarcomas, and rhabdomyosarcomas.

Leukemias include, but are not limited to, acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

These conditions have been well characterized in humans, but also exist in other mammals with similar etiologies, and can be treated by administering the pharmaceutical compositions of the present invention.

Reference throughout this document to the use of the term "treating" or "treatment" is conventional, e.g., to manage or care for an individual for the purpose of combating, alleviating, reducing, alleviating, ameliorating the condition of a disease or disorder, such as sarcoma, and the like.

Methods of treating kinase disorders

The invention also provides methods for treating disorders associated with abnormal mitogen extracellular kinase activity including, but not limited to, stroke, heart failure, hepatomegaly, cardiac enlargement, diabetes, alzheimer's disease, cystic fibrosis, symptoms of xenograft rejection, septic shock, or asthma.

Such conditions, including those mentioned in the background section above (e.g., cancer), can be treated with an effective amount of a compound of the invention. However, such cancers and other diseases may be treated with the compounds of the present invention regardless of the mechanism of action and/or the relationship of the kinase to the condition.

The phrase "abnormal kinase activity" or "abnormal tyrosine kinase activity" includes any abnormal expression or activity of the gene encoding the kinase or the polypeptide encoded thereby. Examples of such aberrant activity include, but are not limited to, overexpression of the gene or polypeptide; gene amplification; mutations that produce constitutively active or highly active kinase activity; gene mutation, deletion, substitution, addition, and the like.

The present invention also provides methods of inhibiting kinase activity, particularly mitogen extracellular kinase activity, comprising administering an effective amount of a compound of the present invention, including salts, polymorphs, metabolites, hydrates, solvates, prodrugs (e.g., esters) and diastereomeric forms thereof. Kinase activity may be inhibited in cells (e.g., in vitro) or in cells of a mammalian subject, particularly a human patient in need of treatment.

Methods of treating angiogenic disorders

The invention also provides methods of treating conditions and diseases associated with excessive and/or abnormal angiogenesis.

Inappropriate and abnormal expression of angiogenesis can be harmful to an organism. Many pathological states are associated with growth of unrelated (extra) blood vessels. These include, for example, diabetic retinopathy, ischemic retinal vein occlusion, and retinopathy of prematurity [ Aiello et al, New engl.j.med.1994,331, 1480; peer et al, lab. invest.1995,72,638], age-related macular degeneration [ AMD; see Lopez et al invest, opthalmols, vis, sci, 1996,37,855], neovascular glaucoma, psoriasis, retrocrystallic fibroplasia, angiofibroma, inflammation, Rheumatoid Arthritis (RA), restenosis, in-stent restenosis, restenosis following vascular grafts, and the like. In addition, the increased blood supply associated with cancerous and tumor tissue promotes growth, resulting in rapid tumor enlargement and metastasis. In addition, the growth of new blood and lymph vessels in tumors provides an exit route for cancerous cells (renegade cells), promoting metastasis and leading to the spread of cancer. Thus, the compounds of the present invention may be used to treat and/or prevent any of the aforementioned angiogenic disorders, for example by inhibiting and/or reducing angiogenesis; inhibit, block, reduce, etc., endothelial cell proliferation or other types associated with angiogenesis, and cause cell death or apoptosis of such cells.

Dosage and administration

Effective dosages of the compounds of the present invention for the treatment of each of the desired indications can be readily determined based on standard laboratory techniques known to evaluate compounds for the treatment of hyperproliferative and angiogenic disorders, by standard toxicity tests, as well as by standard pharmacological tests for determining treatment of the disorders described hereinabove in mammals, and by comparing these results with those of known drugs used to treat these disorders. The amount of active ingredient administered in the treatment of one of these conditions may vary widely depending on the following considerations: the particular compound and dosage unit employed, the mode of administration, the course of treatment, the age and sex of the patient to be treated, and the nature and extent of the condition being treated.

The total amount of active ingredient to be administered is generally from about 0.001mg/kg to about 200mg/kg body weight/day, and preferably from about 0.01mg/kg to about 20mg/kg body weight/day. A clinically useful dosing regimen will be one to three times daily to once every four weeks. In addition, a "drug withdrawal period" (where no drug is administered to the patient for a certain period of time) may be advantageous for the overall balance between pharmacological effects and tolerance. A unit dose may contain from about 0.5mg to about 1500mg of the active ingredient and may be administered one or more times per day, or less than once per day. The average daily dose administered by injection, including intravenous, intramuscular, subcutaneous and parenteral injection, and using infusion techniques, may preferably be from 0.01 to 200mg/kg of total body weight. The average daily rectal dosage regimen is preferably from 0.01 to 200mg/kg of total body weight. The average daily vaginal dosage regimen is preferably 0.01-200mg/kg total body weight. The average daily topical dosage regimen is preferably 0.1-200mg administered once to four times daily. The transdermal concentration is preferably the concentration required to maintain a daily dose of 0.01-200 mg/kg. The average daily inhaled dose regimen is preferably from 0.01 to 100mg/kg of total body weight.

The specific starting and maintenance dosage regimen for each patient will, of course, vary depending upon the following factors: the nature and severity of the condition as determined by the clinician, the activity of the particular compound used, the age and general health of the patient, the time of administration, the route of administration, the rate of excretion of the drug, the drug combination, and the like. Thus, the desired therapeutic regimen and the amount of a compound of the invention, or a pharmaceutically acceptable salt or ester or composition thereof, to be administered can be determined by one skilled in the art using routine therapeutic testing.

Preferably, the disease to which the method is directed is a hematological tumor, a solid tumor and/or metastases thereof.

The compounds of the invention are particularly useful in the treatment and prevention (i.e. prevention) of tumor growth and metastasis, particularly of solid tumors of all indications and stages, with or without prior treatment of said tumor growth.

Methods for testing for specific pharmacological or pharmaceutical properties are well known to those skilled in the art.

The example test experiments described herein are intended to illustrate the invention and the invention is not limited to the examples provided.

And (3) biological determination:

the examples were tested one or more times in the selected bioassay. When tested more than once, the data is reported as a mean or median value, where:

● mean, also called arithmetic mean, represents the total number of values obtained divided by the number of times tested, and

the median value ● represents the median of the sets of values when arranged in ascending or descending order. If the number of values in the data set is odd, the median value is the middle value. If the number of values in the data set is even, the median value is the arithmetic mean of the two intermediate values.

The examples were synthesized one or more times. When synthesized more than once, the data from the bioassay represents mean or median values calculated using a data set obtained by testing one or more synthetic batches.

MKNK1 kinase assay

MKNK 1-inhibitory activity of the compounds of the invention was quantified using the MKNK1TR-FRET assay as described in the following paragraphs.

Recombinant fusion proteins of glutathione-S-transferase (GST, N-terminal) and human full-length MKNK1 (amino acids 1-424 and T344D of accession No. BAA 19885.1) expressed in insect cells using a baculovirus expression system and purified by glutathione Sepharose affinity chromatography were purchased from Carna Biosciences (product No. 02-145) and used as enzymes. The biotinylated peptide biotin-Ahx-IKKRKLTRRKSLKG (C-terminus in the form of an amide) was used as a substrate for kinase reactions, which are available, for example, from Biosyntan (Berlin-Buch, Germany).

For the assay, 50nL of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μ L of MKNK 1in aqueous assay buffer [50mM HEPES pH 7.5,5mM magnesium chloride, 1.0mM dithiothreitol, 0.005% (v/v) Nonidet-P40(Sigma) ] was added, and the mixture was incubated at 22 ℃ for 15min to pre-bind the test compound to the enzyme before starting the kinase reaction. The kinase reaction was then started by adding a solution of 3 μ L of adenosine triphosphate (ATP,16.7 μ M ═ 10 μ M final concentration in 5 μ L assay volume) and substrate (0.1 μ M ═ 0.06 μ M final concentration in 5 μ L assay volume) in assay buffer and incubating the resulting mixture at 22 ℃ for a reaction time of 45 min. The concentration of MKNK1 was adjusted according to the activity of the enzyme batch and was chosen appropriately to bring the assay in the linear range, typical concentrations were in the range of 0.05 μ g/ml. The reaction was stopped by adding 5. mu.L of TR-FRET detection reagent (5nM streptavidin-XL 665[ Cisbio Bioassays, Codolet, France ] and 1nM anti-ribosomal protein S6(pSer236) -antibody [ #44921G ] from Invitrogen and 1nMLANCE EU-W1024 labeled ProteinG [ Perkin-Elmer, product number AD0071]) in aqueous EDTA (100mMEDTA, 0.1% (W/v) bovine serum albumin in 50mM HEPES pH 7.5).

The resulting mixture was incubated at 22 ℃ for 1h to allow the formation of a complex between the phosphorylated biotinylated peptide and the detection reagent. The amount of phosphorylated substrate is then assessed by measuring the resonance energy transfer from the Eu-chelate to the streptavidin-XL. Thus, fluorescence emission at 620nm and 665nm after excitation at 350nm is measured using a TR-FRET reader, for example (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and 622nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor 0% inhibition with all other assay components without enzyme 100% inhibition). Typically, test compounds are tested at 11 different concentrations on the same microtiter plate, two values are tested for each concentration, and IC is calculated using 4-parameter fitting₅₀Values, said concentrations being 20. mu.M to 0.1nM (20. mu.M, 5.9. mu.M, 1.7. mu.M, 0.51. mu.M, 0.15. mu.M, 44nM, 13nM, 3.8nM, 1.1nM, M,

0.33nM and 0.1nM, the dilution series prepared separately by 1:3.4 serial dilutions at 100-fold level of concentrated DMSO solution before assay).

Table 1: MKNK1IC₅₀

Examples	MKNK1IC50[nM]
		1	4
3	4
		4	4
6	7
		8	6
9	7
		10	8

11	12
		12	11
13	9
		15	12
16	16
		17	8
18	24
		19	16
21	15
		22	25
23	25
		25	39
27	36
		28	59
29	98
		30	227
31	22
		32	28
33	10
		34	10

MKNK1 kinase high ATP assay

The TR-FRET based MKNK1 high ATP assay as described in the following paragraphs was used to quantify MKNK 1-inhibitory activity of the compounds of the invention at high ATP after their pre-incubation with MKNK 1.

Recombinant fusion proteins of glutathione-S-transferase (GST, N-terminal) and human full-length MKNK1 (amino acids 1-424 and T344D of accession No. BAA 19885.1) expressed in insect cells using a baculovirus expression system and purified by glutathione Sepharose affinity chromatography were purchased from Carna Biosciences (product No. 02-145) and used as enzymes. The biotinylated peptide biotin-Ahx-IKKRKLTRRKSLKG (C-terminus in the form of an amide) was used as a substrate for kinase reactions, which are available, for example, from Biosyntan (Berlin-Buch, Germany).

For the assay, 50nL of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μ L of MKNK 1in aqueous assay buffer [50mM HEPES pH 7.5,5mM magnesium chloride, 1.0mM dithiothreitol, 0.005% (v/v) Nonidet-P40(Sigma) ] was added, and the mixture was incubated at 22 ℃ for 15min to pre-bind the test compound to the enzyme before starting the kinase reaction. The kinase reaction was then started by adding 3 μ L of a solution of adenosine triphosphate (ATP,3.3mM ═ 2mM final concentration in 5 μ L assay volume) and substrate (0.1 μ M ═ 0.06 μ M final concentration in 5 μ L assay volume) in assay buffer and the resulting mixture was incubated at 22 ℃ for a reaction time of 30 min. The concentration of MKNK1 was adjusted according to the activity of the enzyme batch and was chosen appropriately to bring the assay in the linear range, typical concentrations were in the range of 0.003 μ g/mL. The reaction was stopped by adding 5. mu.L of TR-FRET detection reagent (5nM streptavidin-XL 665[ Cisbio Bioassays, Codolet, France ] and 1nM anti-ribosomal protein S6(pSer236) -antibody [ #44921G ] from Invitrogen and 1nMLANCE EU-W1024 labeled ProteinG [ Perkin-Elmer, product number AD0071]) in aqueous EDTA (100mMEDTA, 0.1% (W/v) bovine serum albumin in 50mM HEPES pH 7.5).

The resulting mixture was incubated at 22 ℃ for 1h to allow the formation of a complex between the phosphorylated biotinylated peptide and the detection reagent. The amount of phosphorylated substrate is then assessed by measuring the resonance energy transfer from the Eu-chelate to the streptavidin-XL. Thus, fluorescence emissions at 620nm and 665nm after excitation at 350nm are measured using a TR-FRET reader, such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and 622nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor 0% inhibition with all other assay components without enzyme 100% inhibition). Typically, test compounds are tested at 11 different concentrations on the same microtiter plate, two values are tested for each concentration, and IC is calculated using 4-parameter fitting₅₀Values, the concentration of 20 u M to 0.1nM (e.g., 20. mu.M, 5.9. mu.M, 1.7. mu.M, 0.51. mu.M, 0.15. mu.M, 44nM, 13nM, 3.8nM, 1.1nM, 0.33nM and 0.1nM, the dilution series being prepared separately by serial dilution at 100-fold the level of concentrated DMSO solution prior to assay, the exact concentration being variable depending on the pipette used).

Table 2: MKNK1 high ATP IC₅₀

Examples	MKNK1 high ATP IC50[nM]
		1	6
2	11
		3	12
4	13
		5	18
6	18
		7	19
8	20
		9	20
10	23
		11	24
12	25
		13	25
14	27
		15	30
16	32
		17	36
18	37
		19	38
20	41
		21	44
22	53
		23	53
24	55
		25	91
26	93
		27	75
28	114
		29	124

30	239
		31	49
32	53
		33	15
34	11

CDK2/CycE kinase assay

CDK 2/CycE-inhibitory activity of compounds of the invention was quantified using the CDK2/CycE TR-FRET assay as described in the following paragraphs.

Recombinant fusion proteins of GST and human CDK2 and of GST and human CycE, which were expressed in insect cells (Sf9) and purified by glutathione-agarose affinity chromatography, were purchased from ProQinase GmbH (Freiburg, Germany). The biotinylated peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus in amide form) was used as a substrate for kinase reactions, available for example from the JERINI peptide science (Berlin, Germany).

For the assay, 50nL of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μ L of CDK2/CycE was added in aqueous assay buffer [50mM Tris/hcl ph8.0,10mM magnesium chloride, 1.0mM dithiothreitol, 0.1mM sodium n-vanadate, 0.01% (v/v) Nonidet-P40(Sigma) ], and the mixture was incubated at 22 ℃ for 15min to pre-bind the test compound to the enzyme before starting the kinase reaction. The kinase reaction was then started by adding a solution of 3 μ L of adenosine triphosphate (ATP,16.7 μ M ═ 10 μ M final concentration in 5 μ L assay volume) and substrate (1.25 μ M ═ 0.75 μ M final concentration in 5 μ L assay volume) in assay buffer and incubating the resulting mixture at 22 ℃ for a reaction time of 25 min. The concentration of CDK2/CycE was adjusted according to the activity of the enzyme batches and was chosen appropriately to bring the assay in a linear range, with a typical concentration in the range of 130 ng/mL. The reaction was stopped by adding 5. mu.L of TR-FRET detection reagent (0.2. mu.M streptavidin-XL 665[ Cisbio Bioassays, Codolet, France ] and 1nM anti-RB from BD Pharmingen (pSer807/pSer811) -antibody [ #558389] and 1.2nM LANCE EU-W1024 labeled anti-mouse IgG antibody [ Perkin-Elmer, product AD0077, alternatively terbium-cryptate-labeled anti-mouse IgG antibody from Cisbio Bioassays ]) in aqueous EDTA (100mM EDTA, 0.2% (W/v) bovine serum albumin in 100mM HEPES/sodium hydroxide pH 7.0).

The resulting mixture was incubated at 22 ℃ for 1h to allow the formation of a complex between the phosphorylated biotinylated peptide and the detection reagent. The amount of phosphorylated substrate is then assessed by measuring the resonance energy transfer from the Eu-chelate to the streptavidin-XL. Thus, fluorescence emissions at 620nm and 665nm after excitation at 350nm are measured using a TR-FRET reader, such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and 622nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor 0% inhibition with all other assay components without enzyme 100% inhibition). Typically, test compounds are tested at 11 different concentrations on the same microtiter plate, two values are tested for each concentration, and IC is calculated using 4-parameter fitting₅₀Values, the concentration was 20. mu.M to 0.1nM (20. mu.M, 5.9. mu.M, 1.7. mu.M, 0.51. mu.M, 0.15. mu.M, 44nM, 13nM, 3.8nM, 1.1nM, 0.33nM and 0.1nM, the dilution series prepared separately by 1:3.4 serial dilutions at 100-fold the level of concentrated DMSO solution prior to assay).

PDGFR beta kinase assay

PDGFR β inhibitory activity of compounds of the invention was quantified using the PDGFR β HTRF assay as described in the following paragraphs.

As kinase, GST-His fusion protein containing the C-terminal fragment of human PDGFR β (amino acids 561-. Biotinylated poly-Glu, Tyr (4:1) copolymer (#61GT0BLA) from Cis biointentation (Marcoule, France) was used as a substrate for the kinase reaction.

For the assay, 50nL of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μ L of PDGFR β was added in aqueous assay buffer [50mM HEPES/sodium hydroxide pH 7.5,10mM magnesium chloride, 2.5mM dithiothreitol, 0.01% (v/v) Triton-X100(Sigma) ], and the mixture was incubated at 22 ℃ for 15min to pre-bind the test compound to the enzyme before starting the kinase reaction. The kinase reaction was then started by adding 3 μ L of a solution of adenosine triphosphate (ATP,16.7 μ M ═ 10 μ M final concentration in 5 μ L assay volume) and substrate (2.27 μ g/mL ═ 1.36 μ g/mL [ about 30nM ] final concentration in 5 μ L assay volume) in assay buffer and incubating the resulting mixture at 22 ℃ for a reaction time of 25 min. The PDGFR β concentration in the assay was adjusted according to enzyme batch activity and was chosen appropriately to bring the assay in the linear range, with typical enzyme concentrations ranging from about 125pg/μ L (final concentration in a5 μ L assay volume). The reaction was stopped by adding 5. mu.L of HTRF detection reagent (200nM streptavidin-XLent [ Cis BioInternational ] and 1.4nM PT 66-Eu-chelate (europium-chelate labeled anti-phosphotyrosine antibody from Perkin Elmer [ PT 66-Tb-chelate from Cis BioInternational can also be used instead of PT 66-Eu-chelate ]) in a solution of aqueous EDTA (100mM EDTA, 0.2% (w/v) bovine serum albumin in 50mM HEPES/sodium hydroxide pH 7.5).

The resulting mixture was incubated at 22 ℃ for 1h to bind biotinylated phosphorylated peptides to the streptavidin-XLent and PT 66-Eu-chelate. The amount of phosphorylated substrate was subsequently assessed by measuring the resonance energy transfer from PT 66-Eu-chelate to streptavidin-XLent. Thus, fluorescence emissions at 620nm and 665nm after excitation at 350nm were measured using an HTRF reader, such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and 622nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor 0% inhibition with all other assay components without enzyme 100% inhibition). Typically, test compounds are tested at 10 different concentrations on the same microtiter plate, two values are tested for each concentration, and IC is calculated using 4-parameter fitting₅₀Values, the concentration was 20. mu.M to 0.1nM (20. mu.M, 6.7. mu.M, 2.2. mu.M, 0.74. mu.M, 0.25. mu.M, 82nM, 27nM, 9.2nM, 3.1nM and 1nM, the dilution series prepared separately by 1:3 serial dilutions at the level of 100-fold concentrated stock solution prior to assay).

Fyn kinase assay

The His 6-tagged human recombinant kinase domain at the C-terminus of human T-Fyn was used as kinase, which was expressed in baculovirus-infected insect cells (purchased from Invitrogen, P3042). The biotinylated peptide biotin-KVEKIGEGTYGVV (C-terminus in the form of an amide) is used as a substrate for kinase reactions, which are available, for example, from Biosynthan GmbH (Berlin-Buch, Germany).

For the assay, 50nL of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μ L of a solution of T-Fyn in aqueous assay buffer [25mM Tris/hcl pH 7.2,25mM magnesium chloride, 2mM dithiothreitol, 0.1% (w/v) bovine serum albumin, 0.03% (v/v) Nonidet-P40(Sigma) ], and the mixture was incubated at 22 ℃ for 15min to pre-bind the test compound to the enzyme prior to starting the kinase reaction. The kinase reaction was then started by adding a solution of 3 μ L of adenosine triphosphate (ATP,16.7 μ M ═ 10 μ M final concentration in 5 μ L assay volume) and substrate (2 μ M ═ 1.2 μ M final concentration in 5 μ L assay volume) in assay buffer and the resulting mixture was incubated at 22 ℃ for a reaction time of 60 min. The concentration of Fyn is adjusted according to the activity of the enzyme batch and is chosen appropriately to bring the assay in the linear range, typical concentration is 0.13 nM. The reaction was stopped by adding 5. mu.L of a solution of HTRF detection reagent (0.2. mu.M streptavidin-XL [ Cisbio Bioassays, Codolet, France ] and 0.66nM PT 66-Eu-chelate (europium-chelate labeled anti-phosphotyrosine antibody from Perkin Elmer [ PT 66-Tb-cryptate from Cisbio Bioassays can also be used instead of PT 66-Eu-chelate ]) in aqueous EDTA solution (125mM EDTA, bovine serum albumin pH 7.0 in 50mM HEPES/sodium hydroxide).

The resulting mixture was incubated at 22 ℃ for 1h to bind biotinylated phosphorylated peptides to the streptavidin-XL and PT 66-Eu-chelate. The amount of phosphorylated substrate was subsequently assessed by measuring the resonance energy transfer from PT 66-Eu-chelate to streptavidin-XL. Thus, fluorescence emissions at 620nm and 665nm after excitation at 350nm were measured using an HTRF reader, such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and 622nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor 0% inhibition with all other assay components without enzyme 100% inhibition). Typically, test compounds are tested at 10 different concentrations on the same microtiter plate, two values are tested for each concentration, and IC is calculated using 4-parameter fitting₅₀Values, the concentration was 20. mu.M to 0.1nM (20. mu.M, 6.7. mu.M, 2.2. mu.M, 0.74. mu.M, 0.25. mu.M, 82nM, 27nM, 9.2nM, 3.1nM and 1nM, the dilution series prepared separately by 1:3 serial dilutions at the level of 100-fold concentrated stock solution prior to assay).

Flt4 kinase assay

Flt4TR-FRET assays as described in the following paragraphs were used to quantify the Flt4 inhibitory activity of compounds of the invention.

As kinase, GST-His fusion proteins containing the C-terminal fragment of human Flt4 (amino acids 799-1298), purchased from Proqinase [ Freiburg i.Brsg., Germany ], expressed in insect cells [ SF9] and purified by affinity chromatography were used. The biotinylated peptide biotin-Ahx-GGEEEEYFELVKKKK (C-terminus in amide form, available from Biosyntan, Berlin-Buch, Germany) was used as a substrate for the kinase reaction.

For the assay, 50nL of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μ L of Flt4 in aqueous assay buffer [25mM HEPES pH 7.5,10mM magnesium chloride, 2mM dithiothreitol, 0.01% (v/v) Triton-X100(Sigma),0.5mM EGTA, and 5mM β -glycerophosphate ], and the mixture was incubated at 22 ℃ for 15min to pre-bind the test compound to the enzyme prior to starting the kinase reaction. The kinase reaction was then started by adding 3 μ L of a solution of adenosine triphosphate (ATP,16.7 μ M ═ 10 μ M final concentration in 5 μ L assay volume) and substrate (1.67 μ M ═ 1 μ M final concentration in 5 μ L assay volume) in assay buffer and the resulting mixture was incubated at 22 ℃ for a reaction time of 45 min. The Flt4 concentration in the assay was adjusted according to the activity of the enzyme batch and was chosen appropriately to bring the assay in the linear range, with typical enzyme concentrations ranging from about 120pg/μ L (final concentration in a5 μ L assay volume). The reaction was stopped by adding 5. mu.L of HTRF detection reagent (200nM streptavidin-XL 665[ Cis Biointernational ] and 1nM PT 66-Tb-cryptate (terbium-cryptate labeled anti-phosphotyrosine antibody from Cisbio Bioassays (Codolet, France)) in aqueous EDTA (50mM EDTA, 0.2% (w/v) bovine serum albumin in 50mM HEPES pH 7.5).

The resulting mixture was incubated at 22 ℃ for 1h to allow conjugation of biotinylated phosphorylated peptides to streptavidin-XL 665 and PT 66-Tb-cryptateAnd (6) mixing. The amount of phosphorylated substrate was then assessed by measuring the resonance energy transfer from PT 66-Tb-cryptate to streptavidin-XL 665. Thus, fluorescence emissions at 620nm and 665nm after excitation at 350nm were measured using an HTRF reader, such as Rubystar (BMGLAbtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and 622nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor 0% inhibition with all other assay components without enzyme 100% inhibition). Typically, test compounds are tested at 10 different concentrations on the same microtiter plate, two values are tested for each concentration, and IC is calculated using 4-parameter fitting₅₀Values, the concentration was 20. mu.M to 0.1nM (20. mu.M, 6.7. mu.M, 2.2. mu.M, 0.74. mu.M, 0.25. mu.M, 82nM, 27nM, 9.2nM, 3.1nM and 1nM, the dilution series prepared separately by 1:3 serial dilutions at the level of 100-fold concentrated stock solution prior to assay).

TrkA kinase assay

TrkA inhibitory activity of the compounds of the present invention was quantified using the TrkA HTRF assay as described in the following paragraphs.

As kinase, GST-His fusion protein containing the C-terminal fragment of human TrkA (amino acid 443-796) purchased from Proqinase [ Freiburg i.Brsg., Germany ], which was expressed in insect cells [ SF9] and purified by affinity chromatography was used. Biotinylated poly-Glu, Tyr (4:1) copolymer (#61GT0BLA) from Cis biointentation (Marcoule, France) was used as a substrate for the kinase reaction.

For the assay, 50nL of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μ L of TrkA in aqueous assay buffer [8mM MOPS/hcl pH 7.0,10mM magnesium chloride, 1mM dithiothreitol, 0.01% (v/v) NP-40(Sigma),0.2mM edta ] was added, and the mixture was incubated at 22 ℃ for 15min to pre-bind the test compound to the enzyme before starting the kinase reaction. Then, the kinase reaction was started by adding 3 μ L of a solution of adenosine triphosphate (ATP,16.7 μ M ═ 10 μ M final concentration in 5 μ L assay volume) and substrate (2.27 μ g/mL ═ 1.36 μ g/mL [ about 30nM ] final concentration in 5 μ L assay volume) in assay buffer, and the resulting mixture was incubated at 22 ℃ for a reaction time of 60 min. The TrkA concentration in the assay is adjusted according to the activity of the enzyme batch and is chosen appropriately to bring the assay in the linear range, typical enzyme concentrations being in the range of about 20pg/μ L (final concentration in a5 μ L assay volume). The reaction was stopped by adding 5. mu.L of HTRF detection reagent (30nM streptavidin-XL 665[ Cis Biointernational ] and 1.4nM PT 66-Eu-chelate (europium-chelate labeled anti-phosphotyrosine antibody from Perkin Elmer [ PT 66-Tb-cryptate from Cis Biointernational can also be used instead of PT 66-Eu-chelate ]) in aqueous EDTA solution (100mM EDTA, 0.2% (w/v) bovine serum albumin in 50mM HEPES/sodium hydroxide pH 7.5).

The resulting mixture was incubated at 22 ℃ for 1h to bind biotinylated phosphorylated peptides to streptavidin-XL 665 and PT 66-Eu-chelate. The amount of phosphorylated substrate was subsequently evaluated by measuring the resonance energy transfer from PT 66-Eu-chelate to streptavidin-XL 665. Thus, fluorescence emissions at 620nm and 665nm after excitation at 350nm were measured using an HTRF reader, such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and 622nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor 0% inhibition with all other assay components without enzyme 100% inhibition). Typically, test compounds are tested at 10 different concentrations on the same microtiter plate, two values are tested for each concentration, and IC is calculated using 4-parameter fitting₅₀Values, the concentration was 20. mu.M to 0.1nM (20. mu.M, 6.7. mu.M, 2.2. mu.M, 0.74. mu.M, 0.25. mu.M, 82nM, 27nM, 9.2nM, 3.1nM and 1nM, the dilution series prepared separately by 1:3 serial dilutions at the level of 100-fold concentrated stock solution prior to assay).

AlphaScreen Surefire eIF4E Ser209 phosphorylation assay

The AlphaScreen SureFire eIF4E Ser209 phosphorylation assay was used to measure the phosphorylation of endogenous eIF4E in cell lysates. The AlphaScreen SureFire technique enables the determination of phosphorylated proteins in cell lysates. In this assay, sandwich antibody complexes formed only in the presence of the analyte (p-eIF4E Ser209) were captured in close proximity by AlphaScreen donor and acceptor microbeads. Excitation of the donor bead causes the release of singlet oxygen atoms, which triggers an energy transfer cascade in the acceptor bead, producing light emission at 520-620 nm.

Surefire EIF4e Alphascreen stimulated with 20% FCS in A549 cells

For the assay, the AlphaScreen SureFire p-eIF4E Ser20910K assay kit and the AlphaScreen protein A kit (for 10K assay sites), both from Perkin Elmer, were used.

On the first day, 50.000A549 cells in growth medium (DMEM/Hams' F12 with stabilized glutamine, 10% FCS) were seeded at 100. mu.L per well in 96-well plates and incubated at 37 ℃. After cell attachment, the medium was changed to starvation medium (DMEM, 0.1% FCS, no glucose, with glutamine, supplemented with 5g/L maltose). On the next day, the test compounds were serially diluted in 50 μ L of starvation medium and the final DMSO concentration was 1% and added to a549 cells in the test plate at a final concentration range of 10 μ M up to 10nM low depending on the concentration of test compound. The treated cells were incubated at 37 ℃ for 2 h. To wells 37 μ L FCS was added (20% final FCS concentration) for 20 min. The medium was then removed and the cells were lysed by adding 50 μ Ι _ of cell lysis buffer. Then, the plate was shaken on a plate shaker for 10 min. After 10min cell lysis time, 4 μ L of lysate was transferred to 384 well plates (proxoplate, from PerkinElmer) and 5 μ L of reaction buffer containing AlphaScreen receptor microbeads plus activation buffer mix was added. Plates were sealed with TopSeal-A adhesive film and gently shaken on a plate shaker at room temperature for 2 h. Thereafter, 2 μ L of dilution buffer with AlphaScreen donor beads was added under soft light and plates were sealed again with TopSeal-a glue film and covered with foil. Incubate for another 2h and shake gently at room temperature. The plates were then measured in an EnVision reader (Perkin Elmer) with AlphaScreen program. Each data point (compound dilution) was measured in triplicate.

Determination of IC by 4-parameter fitting₅₀The value is obtained.

It will be apparent to those skilled in the art that other MKNK-1 kinase assays may be similarly performed using suitable reagents.

Accordingly, the compounds of the present invention are effective in inhibiting one or more MKNK-1 kinases and are therefore suitable for the treatment or prevention of diseases caused by uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, particularly wherein said uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is mediated by MKNK-1, more particularly wherein said diseases caused by uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response are hematological tumors, solid tumors, and/or metastases thereof, such as leukemias and myelodysplastic syndromes, malignant lymphomas, head and neck tumors including brain tumors and brain metastases, head and neck tumors, and head and neck tumors including brain tumors and brain metastases, Breast, gastrointestinal, endocrine, breast and other gynaecological tumours including non-small cell and small cell lung tumours, urological tumours including renal, bladder and prostate tumours, skin tumours and sarcomas, and/or metastases thereof.

Claims (21)

1. A compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a mixture of same:

wherein:

represents:

a group;

wherein denotes the point of attachment of the group to the rest of the molecule; and is

R1 represents linear-C₁-C₆-alkyl-, branched-C₃-C₆-alkyl-or-C₃-C₆-cycloalkyl-, which is optionally substituted once or more times independently from each other with substituents selected from the group consisting of:

halogen atom, -CN, C₁-C₆-alkyl-, aryl-, -OH, C₁-C₆-alkoxy-;

r2 represents a hydrogen atom;

r3 represents a substituent selected from:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, -OH, C₁-C₆-alkoxy-;

r4 represents a substituent selected from:

a hydrogen atom;

r5 represents:

or:

-a substituent selected from: c₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₃-C₁₀-cycloalkyl-, C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-;

or:

-forms together with the nitrogen atom to which it is attached and the carbon atom of R1 a 3-to 7-membered cyclic secondary amine group,

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

2. A compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or mixture thereof, wherein:

represents:

a group;

wherein denotes the point of attachment of the group to the rest of the molecule; and is

R1 represents linear-C₁-C₆-alkyl-, branched-C₃-C₆-alkyl-or-C₃-C₆-cycloalkyl-, which is optionally substituted once or more times independently from each other with substituents selected from the group consisting of:

C₁-C₆-alkyl-, aryl-, -OH, C₁-C₆-alkoxy-;

r2 represents a hydrogen atom;

r3 represents a substituent selected from:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, -OH, C₁-C₆-alkoxy-;

r4 represents a substituent selected from:

a hydrogen atom;

r5 represents:

or:

-a substituent selected from: c₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₃-C₁₀-cycloalkyl-, C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-;

or:

-forms together with the nitrogen atom to which it is attached and the carbon atom of R1 a 3-to 7-membered cyclic secondary amine group,

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

3. A compound of claim 1 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or mixture thereof wherein:

represents:

a group;

wherein denotes the point of attachment of the group to the rest of the molecule; and is

R1 represents linear-C₁-C₆-alkyl-or branched-C₃-C₆-alkyl-, which is optionally substituted one or more times independently from each other with substituents selected from the group consisting of:

C₁-C₆-alkyl-, aryl-, -OH, C₁-C₆-alkoxy-;

r2 represents a hydrogen atom;

r3 represents a substituent selected from:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, -OH, C₁-C₆-alkoxy-;

r4 represents a substituent selected from:

a hydrogen atom;

r5 represents:

or:

-a substituent selected from: c₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₃-C₁₀-cycloalkyl-, C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-;

or:

-together with the nitrogen atom to which it is attached and the carbon atom of R1 form a 3-to 7-membered cyclic secondary amine group;

n represents an integer of 0 or 1.

4. A compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or mixture thereof, wherein:

represents:

a group;

wherein denotes the point of attachment of the group to the rest of the molecule; and is

R1 represents linear-C₁-C₅-alkyl-or branched-C₃-C₅-alkyl-, which is optionally substituted one or more times independently from each other with substituents selected from the group consisting of:

C₁-C₆-alkyl-or aryl-;

r2 represents a hydrogen atom;

r3 represents a substituent selected from:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, -OH, C₁-C₆-alkoxy-;

r4 represents a substituent selected from:

a hydrogen atom;

r5 represents:

or:

-a substituent selected from: c₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₃-C₁₀-cycloalkyl-, C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-;

or:

-together with the nitrogen atom to which it is attached and the carbon atom of R1 form a 3-to 7-membered cyclic secondary amine group;

n represents an integer of 0 or 1.

5. A compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or mixture thereof, wherein:

represents:

a group;

wherein denotes the point of attachment of the group to the rest of the molecule; and is

R1 represents linear-C₁-C₅-alkyl-, optionally substituted once with substituents which are:

aryl-;

r2 represents a hydrogen atom;

r3 represents a substituent selected from:

halogen atom, C₁-C₆-alkoxy-;

r4 represents a hydrogen atom;

r5 represents:

or:

-a substituent selected from: c₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-, C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-;

or:

-together with the nitrogen atom to which it is attached and the carbon atom of R1 form a 3-to 7-membered cyclic secondary amine group;

n represents an integer of 0 or 1.

6. A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or mixture thereof, selected from the group consisting of:

3- (1-benzofuran-2-yl) -6- [2- (morpholin-2-yl) ethoxy ] imidazo [1,2-b ] pyridazine;

3- (4-methoxy-1-benzofuran-2-yl) -6- [ (2R) -morpholin-2-ylmethoxy ] imidazo [1,2-b ] pyridazine;

3- (1-benzofuran-2-yl) -6- (morpholin-2-ylmethoxy) imidazo [1,2-b ] pyridazine;

n- (3- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } propyl) -2, 2-dimethylpropan-1-amine;

3- (5-methoxy-1-benzofuran-2-yl) -6- [ (2R) -morpholin-2-ylmethoxy ] imidazo [1,2-b ] pyridazine;

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -N- (cyclopropylmethyl) ethylamine;

3- (1-benzofuran-2-yl) -6- [ (2R) -morpholin-2-ylmethoxy ] imidazo [1,2-b ] pyridazine;

3- (1-benzofuran-2-yl) -6- {2- [ (3R) -morpholin-3-yl ] ethoxy } imidazo [1,2-b ] pyridazine;

3- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -N- (propan-2-yl) propan-1-amine;

n- (2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } ethyl) propan-2-amine;

3- (1-benzofuran-2-yl) -6- [ (2S) -morpholin-2-ylmethoxy ] imidazo [1,2-b ] pyridazine;

n- (2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } ethyl) -2, 2-dimethylpropan-1-amine;

3- (1-benzofuran-2-yl) -6- {2- [ (3S) -morpholin-3-yl ] ethoxy } imidazo [1,2-b ] pyridazine;

6- (azetidin-3-ylmethoxy) -3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine;

3- (1-benzofuran-2-yl) -6- {2- [ (2S) -pyrrolidin-2-yl ] ethoxy } imidazo [1,2-b ] pyridazine;

3- (1-benzofuran-2-yl) -6- (piperidin-2-ylmethoxy) imidazo [1,2-b ] pyridazine;

n- (2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } ethyl) cyclopropylamine;

n- (2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } ethyl) -2-methylpropan-2-amine;

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -N- (propan-2-yl) propan-1-amine;

3- (5-chloro-1-benzofuran-2-yl) -6- [ (2R) -morpholin-2-ylmethoxy ] imidazo [1,2-b ] pyridazine;

3- (1-benzofuran-2-yl) -6- [ (2R) -pyrrolidin-2-ylmethoxy ] imidazo [1,2-b ] pyridazine;

3- (1-benzofuran-2-yl) -6- (piperidin-3-yloxy) imidazo [1,2-b ] pyridazine;

3- (1-benzofuran-2-yl) -6- [ (2S) -pyrrolidin-2-ylmethoxy ] imidazo [1,2-b ] pyridazine;

1- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -N-methylpropan-2-amine;

3- (5-chloro-1-benzofuran-2-yl) -6- {2- [ (2S) -pyrrolidin-2-yl ] ethoxy } imidazo [1,2-b ] pyridazine;

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -N-methylpropan-1-amine;

formic acid-N- (2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -2-phenylethyl) propan-2-amine;

2-methyl-N- (2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -2-phenylethyl) -2-methylpropan-1-amine;

(-) -2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -N-methyl-2-phenylethylamine;

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -2-phenylethyl) -2, 2-dimethylpropan-1-amine;

3- (1-benzofuran-2-yl) -6- [ (3R) -pyrrolidin-3-yloxy ] imidazo [1,2-b ] pyridazine;

3- (1-benzofuran-2-yl) -6- [ (3R) -piperidin-3-yloxy ] imidazo [1,2-b ] pyridazine;

3- (4-fluoro-1-benzofuran-2-yl) -6- [ (2R) -morpholin-2-ylmethoxy ] imidazo [1,2-b ] pyridazine;

and

3- (5-fluoro-1-benzofuran-2-yl) -6- [ (2R) -morpholin-2-ylmethoxy ] imidazo [1,2-b ] pyridazine.

7. A process for the preparation of a compound of general formula (I) according to any one of claims 1 to 6, which comprises reacting an intermediate compound of general formula (V):

wherein A, R2, R3, R4 and n are as defined for the compound of general formula (I) in any one of claims 1 to 6 and X represents a leaving group,

a step of reacting with a compound of the general formula (III):

wherein R1 and R5 are as defined for the compounds of the general formula (I) in any one of claims 1 to 6,

thereby obtaining a compound of formula (I):

wherein A, R1, R2, R3, R4, R5 and n are as defined for the compounds of the general formula (I) in any one of claims 1 to 6.

8. The process of claim 7, wherein the leaving group is a halogen atom or a perfluoroalkylsulfonate group.

9. The method of claim 8, wherein the halogen atom is a chlorine atom, a bromine atom, or an iodine atom.

10. The method of claim 8, wherein the perfluoroalkylsulfonate group is a trifluoromethylsulfonate group or a nonafluorobutylsulfonate group.

11. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 6 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a mixture of same, in association with a pharmaceutically acceptable diluent or carrier.

12. A pharmaceutical combination comprising:

-one or more first active ingredients selected from compounds of general formula (I) according to any of claims 1 to 6, and

-one or more second active ingredients selected from chemotherapeutic anti-cancer agents.

13. Use of a compound of general formula (I) according to any one of claims 1 to 6 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a mixture of same, for the preparation of a medicament for the prophylaxis or treatment of a disease.

14. The use of claim 13, wherein the disease is a disease caused by uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response.

15. The use of claim 14, wherein the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is mediated by the MKNK-1 pathway.

16. The use of claim 14, wherein the disease caused by uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses or inappropriate cellular inflammatory responses is a hematological tumor, a solid tumor and/or metastases thereof.

17. Use according to claim 14, wherein the disease caused by uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response or an inappropriate cellular inflammatory response is selected from the group consisting of leukaemia and myelodysplastic syndrome, malignant lymphoma, head and neck tumours including brain tumours and brain metastases, breast tumours including non-small cell lung tumours and small cell lung tumours, gastrointestinal tumours, endocrine tumours, breast tumours and other gynaecological tumours, tumours of the urinary system including kidney, bladder and prostate tumours, skin tumours and sarcomas, and/or metastases thereof.

18. Use of a compound of formula (V) for the preparation of a compound of formula (I) according to any one of claims 1 to 6:

wherein A, R2, R3, R4 and n are as defined for the compound of general formula (I) in any one of claims 1 to 6 and X represents a leaving group.

19. Use according to claim 18, wherein the leaving group is a halogen atom or a perfluoroalkylsulfonate group.

20. The use according to claim 19, wherein the halogen atom is a chlorine atom, a bromine atom or an iodine atom.

21. Use according to claim 19, wherein the perfluoroalkylsulfonate group is a trifluoromethylsulfonate group or a nonafluorobutylsulfonate group.