HK1199732B

HK1199732B - Amino-substituted imidazopyridazines

Info

Publication number: HK1199732B
Application number: HK15100198.3A
Authority: HK
Inventors: K.艾斯; F.普勒; L.措恩; A.肖尔茨; P.利瑙; M.J.格诺特; U.伯默; J.京特; M.希契科克
Original assignee: 拜耳知识产权有限责任公司
Priority date: 2011-09-06
Filing date: 2012-09-05
Publication date: 2018-02-02

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 pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, and to intermediate compounds useful for manufacturing said compounds.

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 Bioscience 5359-5374, 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 Bioscience 5359-5374,2008, 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 MKNK1 in 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.,2010,536618-6628 is a paper entitled "Discovery of Mitogen-Activated Protein Kinase-Interacting Kinase 1Inhibitors by a comprehensive fragment-organic Screening Approach" and some specific imidazo [1,2-b ] compounds identified as Inhibitors of MKNK-1 are disclosed in particular in Table 1 ]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 factor4 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 amino-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:

-a structure having a benzo [ b ] furanyl group in its 3-position:

wherein denotes the point of attachment of said benzo [ b ] furanyl group to the rest of the molecule, i.e. in position 2 of said benzo [ b ] furanyl group;

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

wherein represents the point of attachment of said group to the rest of the molecule, and wherein R1 represents a linear C optionally substituted as defined herein ₂-C₆-alkyl-, branched C₃-C₆-alkyl-or C₃-C₆-a cycloalkyl group.

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:

r1 represents linear C₂-C₆-alkyl-, linear C₁-C₆Linear C of-alkyl-O-)₁-C₆-alkyl-, branched C₃-C₆-alkyl-, C₃-C₆Cycloalkyl, linear C₁-C₆-alkyl-C₃-C₆-cycloalkyl-or C₃-C₆Cycloalkyl-linear C₁-C₆-alkyl-, which is optionally substituted one or more times independently from each other with substituents selected from the group consisting of:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C optionally linked in spiro form₃-C₁₀-cycloalkyl-, 3-to 10-membered heterocycloalkyl optionally linked in spiro form, aryl-, aryl optionally substituted once or more times independently of each other by R, heteroaryl-, heteroaryl optionally substituted once or more times independently of each other by R substituents-, -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”；

Represents:

a group;

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

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”；

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-, C₁-C₆-haloalkyl-;

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

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

wherein:

r1 represents linear C₂-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-, C ₁-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 group;

Which is optionally substituted once by a substituent R3 or, independently of one another, twice, three times, four times or five times;

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”；

C₁-C₆-alkyl-, C₁-C₆-haloalkyl-.

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

wherein:

r1 represents linear C₂-C₆-alkyl-, branched C₃-C₆-alkyl-or C₃-C₆-a cycloalkyl group which:

-substituted once or more independently of each other with a substituent selected from:

-aryl-substituted once or more independently of each other with R substituents;

-heteroaryl optionally substituted once or more times independently of each other with an R substituent;

and which:

-optionally substituted once or more times independently of 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 group;

r3 represents a substituent selected from:

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) NH ₂、-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”；

C₁-C₆-alkyl-, C₁-C₆-haloalkyl-.

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. According to one embodiment, the terms "halogen atom", "halo-" or "halogen-" are understood to mean a fluorine atom. According to one embodiment, the terms "halogen atom", "halo-" or "halogen-" are understood to mean a chlorine 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-C₃Alkyl), such as methyl, ethyl, n-propyl or isopropyl。

The term "linear C₂-C₆-alkyl- "is understood to preferably mean a linear, saturated, monovalent hydrocarbon radical having 2,3, 4, 5 or 6 carbon atoms, such as ethyl, n-propyl, n-butyl, n-pentyl or n-hexyl. In particular, the radicals have 2,3, 4 or 5 carbon atoms ("linear C₂-C₅-alkyl "), such as ethyl, n-propyl, n-butyl or n-pentyl. Alternatively, the group has 2,3 or 4 carbon atoms ("linear C₂-C₄-alkyl "), such as ethyl, n-propyl or n-butyl. Alternatively, the group has 2 or 3 carbon atoms ("linear C₂-C₃-alkyl "), such as ethyl or n-propyl.

The term "branched C₃-C₆Alkyl "is understood as preferably meaning a branched, saturated, monovalent hydrocarbon radical having 3, 4, 5 or 6 carbon atoms, such as 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 3, 4 or 5 carbon atoms ("branched C ₃-C₅Alkyl groups), such as isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl. In particular, the radicals have 3 or 4 carbon atoms ("branched C₃-C₄-alkyl "), such as isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly said group having 3 carbon atoms (" branched C₃-alkyl "), such as isopropyl.

The term "halo-C₁-C₆Alkyl is understood to preferably mean in which one or more hydrogen atoms are present in the same or different mannerLinear or branched, saturated monovalent hydrocarbon radicals substituted by (i.e. independent of) halogen atoms, wherein the term "C" refers to₁-C₆-alkyl "is as defined above. According to one embodiment, the halogen atom is F. Said halo-C₁-C₆Alkyl is, for example, -CF₃、-CHF₂、-CH₂F、-CF₂CF₃or-CH₂CF₃. According to one embodiment, the halogen atom is Cl. Said halo-C₁-C₆Alkyl is, for example, -CCl₃、-CCl₂CCl₃or-CH₂CCl₃。

The term "C₁-C₆Alkoxy is to be understood as preferably meaning a linear, branched or cyclic, saturated monovalent hydrocarbon radical of the formula-O-alkyl, where the term "alkyl" is as defined above, for example methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, isobutoxy, t-butoxy, sec-butoxy, cyclobutoxy, pentyloxy, isopentyloxy or n-hexyloxy, 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 in which 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, isopentoxyalkyl, hexyloxyalkyl.

The term "halo-C₁-C₆-alkoxy-C₁-C₆Alkyl is understood to preferably mean a linear or branched, saturated, monovalent-C radical 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-C ₁-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-methyl.But-3-enyl, 3-methylbut-2-enyl, (E) -2-methylbut-2-enyl, (Z) -2-methylbut-2-enyl, (E) -1-methylbut-2-enyl, (Z) -1-methylbut-2-enyl, (E) -3-methylbut-1-enyl, (Z) -3-methylbut-1-enyl, (E) -2-methylbut-1-enyl, (Z) -2-methylbut-1-enyl, (E) -1-methylbut-1-enyl, (Z) -1-methylbut-1-enyl, 1, 1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl, 4-methylpent-3-enyl, (E) -3-methylpent-3-enyl, (Z) -3-methylpent-3-enyl, (E) -2-methylpent-3-enyl, (Z) -2-methylpent-3-enyl, (E) -1-methylpent-3-enyl, methyl-1-propenyl, methyl-4-enyl, methyl-3-enyl, methyl-2-pentenyl, ethyl-, (Z) -1-methylpent-3-enyl, (E) -4-methylpent-2-enyl, (Z) -4-methylpent-2-enyl, (E) -3-methylpent-2-enyl, (Z) -3-methylpent-2-enyl, (E) -2-methylpent-2-enyl, (Z) -2-methylpent-2-enyl, (E) -1-methylpent-2-enyl, (Z) -1-methylpent-2-enyl, (E) -4-methylpent-1-enyl, (Z) -4-methylpent-1-enyl, (E) -3-methylpent-1-enyl, (Z) -3-methylpent-1-enyl, (E) -2-methylpent-1-enyl, (Z) -2-methylpent-1-enyl, (E) -1-methylpent-1-enyl, (Z) -1-methylpent-1-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl, 1-ethylbut-3-enyl, (E) -3-ethylbut-2-enyl, (Z) -3-ethylbut-2-enyl, (E) -2-ethylbut-2-enyl, (Z) -2-ethylbut-2-enyl, (E) -1-ethylbut-2-enyl, (Z) -1-ethylbut-2-enyl, (E) -3-ethylbut-1-enyl, (Z) -3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E) -1-ethylbut-1-enyl, (Z) -1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E) -2-propylprop-1-enyl, (Z) -2-propylprop-1-enyl, (E) -1-propylprop-1-enyl, (Z) -1-propylprop-1-enyl, (E) -2-isopropylprop-1-enyl, (Z) -2-isopropylprop-1-enyl, (E) -1-isopropylprop-1-enyl, (Z) -1-isopropylprop-1-enyl, (E) -3, 3-dimethylprop-1-enyl, (Z) -3, 3-dimethylprop-1-enyl, 1- (1, 1-dimethylethyl) 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-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, prop-2-ynyl, but-3-methylbut-1-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, 1-isopropylprop-2-ynyl, 2-dimethylbut-3-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-1-ynyl, 3-methylpent-1-, 1, 1-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 radicals having 3, 4, 5 or 6 carbon atoms ("C)₃-C₆-cycloalkyl "), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. In particular the radicals having 4, 5 or 6 carbon atoms ("C)₄-C₆-cycloalkyl "), such as cyclobutyl, cyclopentyl, cyclohexyl.

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 more groups 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 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); a 5-membered ring such as tetrahydrofuranyl group, dioxolyl (dioxolinyl), pyrrolidinyl group, pyrrolidonyl group, imidazolidinyl group, pyrazolidinyl group, pyrrolinyl group; 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 a 5,5 membered ring, such as a hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl ring, or a 5,6 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, a 2, 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, 8 or 9 carbon atoms and one or more substituents selected from the group consisting of 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 "aryl" is understood to mean preferably a mono-, bi-or tricyclic hydrocarbon ring having a monovalent aromatic or partially aromatic character with 6, 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 is a ring having 9 carbon atoms ("C₉-aryl radical") for example indanyl or indenyl, or a ring having 10 carbon atoms (" C)₁₀Aryl), 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, 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 comprises 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 a hydrocarbon radical 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 meaning 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-C₆Alkyl group "" linear C₂-C₆-alkyl- "," C ₂-C₆-alkenyl "and" C₂-C₆The term "C" as used in the context of the definition of-alkynyl₂-C₆"is understood to mean a hydrocarbon radical having a limited number of carbon atoms from 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 subrange therein, e.g. C₂-C₆、C₃-C₅、C₃-C₄、C₂-C₃、C₂-C₄、C₂-C₅(ii) a In particular C₂-C₃。

Further, as used herein, throughout this document, for example, in "branched C₃-C₆-alkyl group "," C₃-C₆The term "C" as used in the context of the definition of-cycloalkyl₃-C₆"is understood to mean a hydrocarbon radical having a limited number of carbon atoms 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 subrange therein, e.g. 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.

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.

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 invention also includes all suitable isotopic variations of the compounds of the invention. Isotopic variations of a compound of the present invention are defined as those in which at least one atom is substituted with a compound having the same atomic number but an atomic mass different from what is common or predominant in natureNow atoms of atomic mass are substituted. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as²H (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 detectability ¹⁴C) 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 (1, 3-dioxolen-2-onylmethyl) (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:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C optionally linked in spiro form₃-C₁₀-cycloalkyl-, 3-to 10-membered heterocycloalkyl optionally linked in spiro form, aryl-, aryl optionally substituted once or more than once by R, heteroaryl-, -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”；

Represents:

a group;

R3 represents a substituent selected from:

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

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”；

C₁-C₆-alkyl-, C₁-C₆-haloalkyl-;

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

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

halogen atom, -CN, C ₁-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 group;

r3 represents a substituent selected from:

C₁-C₆-alkyl-, C₁-C₆-haloalkyl-.

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

-aryl-substituted once or more independently of each other with R substituents;

and which:

R2 represents:

a group;

r3 represents a substituent selected from:

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) 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”；

C₁-C₆-alkyl-, C₁-C₆-haloalkyl-.

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:

r1 represents linear C₂-C₅-alkyl-, linear C₁-C₅Linear C of-alkyl-O-)₁-C₅-alkyl-, branched C₃-C₅-alkyl-, C₄-C₆Cycloalkyl, linear C₁-C₆-alkyl-C₄-C₆-cycloalkyl-or C₄-C₆Cycloalkyl-linear C₁-C₆-alkyl-, which is optionally substituted one or more times independently from each other with substituents selected from the group consisting of:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C optionally linked in spiro form₃-C₁₀-cycloalkyl-, 3-to 10-membered heterocycloalkyl optionally linked in spiro form, aryl-, aryl optionally substituted once or more than once by R, heteroaryl-, -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”；

Represents:

a group;

R3 represents a substituent selected from:

halogen atom, -CN, C ₁-C₆-alkyl-, C₁-C₆-haloalkyl-, -OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-;

r represents a substituent selected from the group consisting of:

C₁-C₆-alkyl-, C₁-C₆-haloalkyl-;

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

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

r1 represents linear C₂-C₅-alkyl-, branched C₃-C₅-alkyl-or C₄-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) NH ₂、-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 group;

r3 represents a substituent selected from:

C₁-C₆-alkyl-, C₁-C₆-haloalkyl-.

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

r1 represents linear C₂-C₅-alkyl-, branched C₃-C₅-alkyl-or C₄-C₆-a cycloalkyl group which:

-aryl-substituted once or more independently of each other with R substituents;

and is

-optionally substituted once or more times independently of each other with substituents selected from: halogen atom, -CN, C ₁-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 group;

r3 represents a substituent selected from:

r represents a substituent selected from the group consisting of:

C₁-C₆-alkyl-, C₁-C₆-haloalkyl-.

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:

R1 represents linear C₂-C₅-alkyl-, linear C₁-C₅Linear C of-alkyl-O-)₁-C₅-alkyl-, branched C₃-C₅-alkyl-, C₄-C₆Cycloalkyl, linear C₁-C₆-alkyl-C₄-C₆-cycloalkyl-or C₄-C₆-cycloalkyl-C₁-C₆-alkyl-, which is optionally substituted one or more times independently from each other with substituents selected from the group consisting of:

-NH₂、C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C optionally linked in spiro form₃-C₁₀-cycloalkyl-, 3-to 10-membered heterocycloalkyl optionally linked in spiro form, aryl-, aryl optionally substituted once or several times independently of each other by R, or heteroaryl-;

represents:

a group;

R3 represents a substituent selected from:

r represents a substituent selected from the group consisting of:

C₁-C₆-alkyl-, C₁-C₆-haloalkyl-;

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

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

C₁-C₆-alkyl-or aryl;

r2 represents:

a group;

r3 represents a substituent selected from:

C₁-C₆-alkyl-, C₁-C₆-haloalkyl-.

-aryl-substituted once or more independently of each other with R substituents;

r2 represents:

a group;

r3 represents a substituent selected from:

r represents a substituent selected from the group consisting of:

C₁-C₆-alkyl-, C₁-C₆-haloalkyl-.

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:

-NH₂、C₂-C₆-alkenyl-, C optionally linked in spiro form₃-C₁₀-cycloalkyl-, 3-to 10-membered heterocycloalkyl optionally linked in spiro form, aryl optionally substituted once or more times independently of each other by R, or heteroaryl-;

represents:

a group;

R3 represents a substituent selected from:

halogen atom, C₁-C₆-alkoxy-, C₁-C₆-alkyl-;

r represents a substituent selected from the group consisting of:

a halogen atom;

n represents an integer of 0 or 1.

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

An aryl group;

r2 represents:

a group;

Optionally substituted once with an R3 substituent;

r3 represents a substituent selected from:

halogen atom, C₁-C₆-alkoxy groups.

-aryl-substituted once or more independently of each other with R substituents;

r2 represents:

a group;

Optionally substituted once with an R3 substituent;

r3 represents a substituent selected from:

halogen atom, C₁-C₆-an alkoxy group;

r represents a substituent selected from the group consisting of:

halogen atom, C₁-C₆-haloalkyl-, C₁-C₆-alkoxy-.

In another embodiment, the present invention encompasses compounds of formula (I) above wherein:

halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C optionally linked in spiro form₃-C₁₀-cycloalkyl-, 3-to 10-membered heterocycloalkyl optionally linked in spiro form, aryl-, aryl optionally substituted once or more than once by R, heteroaryl-, -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”。

represents:

a group;

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

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) NH ₂、-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”。

C₁-C₆-alkyl-, C₁-C₆-haloalkyl-.

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

r3 represents a substituent selected from:

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

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 represents a substituent selected from the group consisting of:

a halogen atom.

-NH₂、C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C optionally linked in spiro form₃-C₁₀-cycloalkyl-, 3-to 10-membered heterocycloalkyl which is optionally linked in spiro form, aryl-, aryl which is optionally substituted once or several times independently of one another by R, or heterolepticAryl-.

-NH₂、C₂-C₆-alkenyl-, C optionally linked in spiro form₃-C₁₀-cycloalkyl-, 3-to 10-membered heterocycloalkyl optionally linked in spiro form, aryl-, aryl optionally substituted once or several times independently of one another by R, or heteroaryl-.

r3 represents a substituent selected from:

halogen atom, C₁-C₆-alkoxy-, C₁-C₆-alkyl-.

n represents an integer of 0 or 1.

In another embodiment, the present invention encompasses compounds of formula (I) or formula (Ia) above:

wherein:

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”。

wherein:

r1 represents linear C₂-C₆-an alkyl group, optionally substituted once or more times independently from each other with substituents selected from:

wherein:

r1 represents 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”。

In another embodiment, the invention encompasses compounds of general formula (Ia):

wherein:

r2 represents:

a group;

Which is optionally substituted once by a substituent R3 or, independently of one another, twice, three times, four times or five times.

wherein:

r3 represents a substituent selected from:

C₁-C₆-alkyl-, C₁-C₆-haloalkyl-.

wherein:

r3 represents a substituent selected from:

halogen atom, -CN, C ₁-C₆-alkyl-, C₁-C₆-haloalkyl-, -OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-.

wherein:

C₁-C₆-alkyl-or aryl.

wherein:

And (4) an aryl group.

wherein:

r2 represents:

a group;

Which is optionally substituted once with a R3 substituent.

wherein:

r3 represents a substituent selected from:

halogen atom, C₁-C₆-alkoxy groups.

In another embodiment, the present invention encompasses compounds of formula (I) or formula (Ia) as described above according to any of the above embodiments:

in the form of stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or in the form of mixtures thereof.

In another embodiment, the invention encompasses compounds of general formula (Ib):

wherein:

-aryl-substituted once or more independently of each other with R substituents;

and which:

-optionally substituted once or more times independently of each other with substituents selected from: halogen atom, -CN, C ₁-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”。

wherein:

r2 represents:

a group;

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”。

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) NH ₂、-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”。

wherein:

C₁-C₆-alkyl-, C₁-C₆-haloalkyl-.

wherein:

r3 represents a substituent selected from:

wherein:

-aryl-substituted once or more independently of each other with R substituents;

and is

-optionally substituted once or more times independently of each other with substituents selected from: halogen atom, -CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C ₃-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”。

wherein:

-aryl-substituted once or more independently of each other with R substituents;

-heteroaryl-optionally substituted once or more times independently of each other by an R substituent.

wherein:

r3 represents a substituent selected from:

halogen atom, C₁-C₆-alkoxy groups.

wherein:

r represents a substituent selected from the group consisting of:

halogen atom, C₁-C₆-haloalkyl-, C₁-C₆-alkoxy-.

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.

It will also be appreciated that the present invention relates to any subcombination within any embodiment or aspect of compounds of formula (I) or formula (Ia) 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 process for the preparation of a compound of general formula (I) according to the invention, comprising the steps described in the experimental section herein.

According to one embodiment, the invention encompasses a process for the preparation of a compound of general formula (I) of the invention, said process comprising reacting an intermediate compound of general formula (V):

wherein A, R3 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 or a nonafluorobutylsulfonate group),

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

wherein R1 is as defined above for the compound of formula (I),

to obtain a compound of general formula (I):

wherein A, R1, R3 and n are as defined above for the compound of formula (I).

According to one embodiment, the invention encompasses a process for the preparation of a compound of general formula (Ia) of the invention, said process comprising reacting an intermediate compound of general formula (Va):

wherein R2 is as defined above for the compound of formula (Ia) 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,

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

wherein R1 is as defined above for the compound of formula (Ia),

to obtain a compound of formula (Ia):

wherein R1 and R2 are as defined above for the compound of formula (Ia).

According to one embodiment, the invention encompasses a process for the preparation of a compound of general formula (Ib) according to the invention, comprising reacting an intermediate compound of general formula (Vb):

wherein R2 is 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 or a nonafluorobutylsulfonate group),

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

wherein R1 is as defined above for the compound of formula (I),

to obtain a compound of formula (Ib):

wherein R1 and R2 are as defined above for the compounds of formula (Ib).

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

-a compound of general formula (V):

And

-a compound of general formula (Va):

wherein R2 is as defined above for the compound of formula (Ia) 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),

and

-a compound of general formula (Vb):

wherein R2 is as defined above for the compound of formula (Ib), 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).

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

wherein A, R3 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 (Va) for the preparation of a compound of general formula (Ia) as defined above:

wherein R2 is as defined above for the compound of formula (Ia) 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).

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

Experimental part

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

Abbreviations	Means of
		BINAP	(+/-) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthalene
DMF	N, N-dimethylformamide
		DMSO	Dimethyl sulfoxide
THF	Tetrahydrofuran (THF)
		NaO^tBu	Sodium tert-butoxide
H	Hour(s)
		min	Minute (min)
Rt	At room temperature
		NMR	Nuclear magnetic resonance
MS	Mass spectrometry
		R_t	Retention time
NMP	N-methyl pyrrolidone
		HPLC,LC	High performance liquid chromatography

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 and R2 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 R1, R3, a and n are as defined above for the compound of formula (I), and X and Y represent 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).

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 diacetals or bromoacetaldehyde diacetals to give bicyclic ring systems [ 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 to introduce a variety of side chains comprising alcohol functionality, which leads to the imidazopyridazine-ethers of formula F. 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 in which functional groups that may interfere with the desired reaction are modified with suitable protecting groups.

The fourth and fifth steps of the described steps may also be interchanged.

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 and R3 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 or a nonafluorobutylsulfonate group),

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

wherein R1 is as defined above for the compound of formula (I),

to obtain a compound of general formula (I):

wherein R1, R3, A 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

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% strength 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 column chromatography on silica gel, 4.17g (70%) of the desired product were isolated in the form of an amorphous white solid.

¹H-NMR(CDCl₃Stored in molecular sieves) [ ppm]＝7.06(1H)；7.79(1H)；7.92,(1H)；7.96(1H)ppm.

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(CDCl₃Stored in molecular sieves) [ ppm]＝7.12(1H)；7.79(1H)；7.90,(1H)ppm.

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 19.0g (179mmol) of 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 in 40mL of a mixture of dichloromethane and methanol (8:2) (digest), filtered 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 intermediate 2, starting from 1.68g (7.22mmol) of intermediate 1, 6-chloro-3- (4-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine is prepared to yield 43% of a solid substance.

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 intermediate 2, starting from 1.74g (7.5mmol) of intermediate 1, 6-chloro-3- (5-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine is prepared to give a solid substance of 45%.

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

In analogy to intermediate 2, starting from 1.68g (7.2mmol) of intermediate 1, 6-chloro-3- (6-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine is prepared to give 53% solid substance.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝3.84(3H),6.95(1H),7.29(1H),7.51(1H),7.55(1H),7.66(1H),8.31(1H),8.38(1H).

LCMS (method 1) R_t＝1.30min；MS(ESIpos)m/z＝300[M+H]⁺.

Intermediate 6

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

In analogy to intermediate 2, starting from 174mg (0.75mmol) of intermediate 1, 6-chloro-3- (3-methyl-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine is prepared to give a 24% solid substance.

LCMS (method 1) R_t＝1.30min；MS(ESIpos)m/z＝300[M+H]⁺.

Intermediate 7

6-chloro-3- (7-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine

A mixture of 500mg (3.38mmol) of 7-methoxy-1-benzofuran in dry THF (30mL) is cooled to-78 ℃. 3.2mL (5mmol) of a 1.6M solution of n-butyllithium in hexane were added, and the resulting mixture was stirred at-78 ℃ for 1 hour. 1.37mL (5mmol) of tributyltin chloride was added. The reaction was stirred at room temperature overnight.

Methanol was carefully added and the solvent was evaporated. The residue obtained was purified by flash chromatography to give 1.3g of the corresponding crude 2-stannylbenzofuran, which was used without further purification.

506mg (2.2mmol) of intermediate 1, 1g (2.3mmol) of crude 2-stannylbenzofuran, 41mg (0.22mmol) of copper (I) iodide and 76mg (0.11mmol) of bis (triphenylphosphine) palladium (II) chloride in 18mL of THF are stirred in a sealed pressure tube at 85 ℃ overnight under an inert atmosphere. The solvent was evaporated, the obtained solid was impregnated in methanol and filtered. The solid residue was subjected to flash column chromatography to give 282mg (39%) of the title compound as a solid substance.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝3.99(3H),7.02(1H),7.23(1H),7.35(1H),7.55(1H),7.62(1H),8.37-8.43(6H).

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

Intermediate 10

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

In analogy to intermediate 7, starting from 513mg (2.21mmol) of intermediate 1, 6-chloro-3- (5-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine is prepared to a solid substance.

LCMS (method 2) R_t＝1.34min；MS(ESIpos)m/z＝288[M+H]⁺.

Intermediate 11

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

Analogously to intermediate 7, starting from 219mg (0.94mmol) of intermediate 1, 6-chloro-3- (3-chloro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine is prepared as a 62% solid.

LCMS (method 2) R_t＝1.38min；MS(ESIpos)m/z＝304[M+H]⁺.

Intermediate 12

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

Analogously to intermediate 7, starting from 921mg (3.96mmol) of intermediate 1, 6-chloro-3- (4-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine is prepared to yield 929mg of a solid substance, which is used in the form of a 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 ] +.

Intermediate 13

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

In analogy to intermediate 7, starting from 2.34g (10.1mmol) of intermediate 1, 6-chloro-3- (5-chloro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine is prepared to yield 2.73g of a solid substance which is used in the form of a crude product.

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

Intermediate 14

6-chloro-3- (7-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine

In analogy to intermediate 7, starting from 1.0g (4.31mmol) of intermediate 1, 6-chloro-3- (7-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine is prepared to yield 918mg of a solid substance, which is used in the form of a crude product.

LCMS (method 3) R_t＝1.39min；MS(ESIpos)m/z＝288[M+H]⁺.

Intermediate 15

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

In analogy to intermediate 7, starting from 2.7g (11.6mmol) of intermediate 1, 6-chloro-3- (5-methyl-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine is prepared to yield 2.61g of a solid substance which is used in the form of a crude product.

LCMS (method 2) R_t＝1.45min；MS(ESIpos)m/z＝284[M+H]+.

Example 1

4- { [3- (4-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } butan-1-amine

14.1mg (0.352mmol) of sodium hydride (60%, dispersed in mineral oil) are dispersed in 2.7mL of anhydrous THF in an ice bath. 36.4mg (0.40mmol) of 4-amino-butan-1-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 60.0mg (0.20mmol) of intermediate 3 was added, the ice bath was removed and the resulting mixture was stirred at room temperature for 72 hours.

The reaction mixture was carefully poured into saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated.

The crude product was purified by HPLC to give 50mg of the title compound as a solid.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.61-1.76(2H),1.81-1.97(2H),2.78(2H),3.92(3H),4.48(2H),6.83(1H),6.99(1H),7.19-7.33(2H),7.51(1H),8.08-8.19(2H),8.41(1H).

LC-MS (method 3) R_t＝0.80min；MS(ESIpos)m/z＝353[M+H]⁺.

Example 2

Trans-3- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclobutylamine

In an ice bath, 44.5mg (1.12mmol) of sodium hydride (60%, dispersed in mineral oil) were dispersed in 5mL of anhydrous THF. 91.6mg (0.742mmol) of trans-3-aminocyclobutan-1-ol (hydrochloride) are slowly added. Stirring was continued for 15 minutes at 0 ℃. 100mg (0.371mmol) of intermediate 2 was added, the ice bath was removed and the resulting mixture was stirred at 40 ℃ for 5 days.

The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated.

The crude product was purified by HPLC to give the title compound as a solid substance 32 mg.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝2.49-2.57(2H),3.72(2H),5.53(1H),7.01(1H),7.31(2H),7.58-7.67(2H),7.71-7.77(1H),8.11-8.19(2H).

LC-MS (method 3) R_t＝0.73min；MS(ESIpos)m/z＝321[M+H]⁺.

Example 3

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

18.2mg (0.457mmol) of sodium hydride (60%, dispersed in mineral oil) are dispersed in 4.3mL of anhydrous THF in an ice bath. 64.2mg (0.519mmol) of cis-3-aminocyclobutan-1-ol (hydrochloride) are slowly added. Stirring was continued for 15 minutes at 0 ℃. 70mg (0.260mmol) of intermediate 2 was added, the ice bath was removed and the resulting mixture was stirred at 40 ℃ for 16 hours.

The crude product was purified by flash chromatography to give 36mg of the title compound as a solid.

¹H-NMR(300MHz,DMSO-d6),[ppm]＝1.85(3H),1.96(2H),2.90(2H),3.19-3.32(1H),4.99(1H),6.99(1H),7.30(2H),7.56-7.67(2H),7.71-7.80(1H),8.09-8.21(1H).

LC-MS (method 3) R_t＝0.72min；MS(ESIpos)m/z＝321[M+H]⁺.

Example 4

3- { [3- (4-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } propan-1-amine

16.4mg (0.41mmol) of sodium hydride (60%, dispersed in mineral oil) are dispersed in 1.6mL of anhydrous THF in an ice bath. 35.8mg (0.467mmol) of 3-amino-propan-1-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 70.0mg (0.234mmol) of intermediate 3 was added, the ice bath was removed and the resulting mixture was stirred at room temperature for 96 hours.

The crude product was purified by HPLC to give 54mg of the title compound as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝2.00-2.14(2H),2.92(2H),3.92(3H),4.55(2H),6.83(1H),7.02(1H),7.19-7.33(2H),7.52(1H),8.09-8.20(2H),8.37(1H).

LC-MS (method 2) R_t＝0.74min；MS(ESIpos)m/z＝339[M+H]⁺.

Example 5

2- { [3- (4-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } ethanamine

16.4mg (0.41mmol) of sodium hydride (60%, dispersed in mineral oil) are dispersed in 3.1mL of anhydrous THF in an ice bath. 29.1mg (0.467mmol) 2-amino-ethan-1-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 70.0mg (0.234mmol) of intermediate 3 was added, the ice bath was removed and the resulting mixture was stirred at room temperature for 96 hours.

The crude product was purified by HPLC to give 49mg of the title compound as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝3.15(2H),3.91(3H),4.50(2H),6.83(1H),7.00(1H),7.20-7.31(2H),7.49(1H),8.09-8.20(2H),8.29(1H).

LC-MS (method 2) R_t＝0.73min；MS(ESIpos)m/z＝325[M+H]⁺.

Example 6

2- { [3- (5-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } ethanamine

16.4mg (0.41mmol) of sodium hydride (60%, dispersed in mineral oil) are dispersed in 3.1mL of anhydrous THF in an ice bath. 29.1mg (0.467mmol) 2-amino-ethan-1-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 70.0mg (0.234mmol) of intermediate 4 was added, the ice bath was removed and the resulting mixture was stirred at 35 ℃ for 17 hours.

The crude product was purified by HPLC to give 14mg of the title compound as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝3.05(2H),3.78(3H),4.46(2H),6.89(1H),7.01(1H),7.23(1H),7.46-7.59(2H),8.08-8.18(2H).

LC-MS (method 2) R_t＝1.02min；MS(ESIpos)m/z＝325[M+H]⁺.

Example 7

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

In an ice bath, 48.2mg (1.21mmol) of sodium hydride (60%, dispersed in mineral oil) were dispersed in 5mL of anhydrous THF. 97.4mg (1.3mmol) of (S) -2-amino-propan-1-ol are slowly added. Stirring was continued for 15 minutes at 0 ℃. 250mg (0.0.927mmol) of intermediate 2 was added, the ice bath was removed and the resulting mixture was stirred at 40 ℃ for 16 hours.

The reaction mixture was carefully poured into saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated.

The crude product was purified by HPLC to give 77mg of the title compound as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.21(3H),3.38-3.53(1H),4.34-4.41(2H),7.01(1H),7.22-7.37(2H),7.56-7.65(2H),7.68-7.75(1H),8.11-8.19(2H).

LC-MS (method 3) R_t＝0.75min；MS(ESIpos)m/z＝309[M+H]⁺.

Example 8

4- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } butan-1-amine

18.3mg (0.457mmol) of sodium hydride (60%, dispersed in mineral oil) are dispersed in 3.5mL of THF in an ice bath. 47.2mg (0.519mmol) of 4-amino-butan-1-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 70.0mg (0.26mmol) of intermediate 2 was added, the ice bath was removed and the resulting mixture was stirred at room temperature for 16 hours.

The crude product was purified by HPLC to give 73mg of the title compound as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.66-1.81(2H),1.81-1.97(2H),2.83(2H),4.50(2H),6.98(1H),7.22-7.38(2H),7.57-7.64(2H),7.71(1H),8.07-8.16(2H),8.38(5H).

LC-MS (method 2) R_t＝0.79min；MS(ESIpos)m/z＝323[M+H]⁺.

Example 9

3- { [3- (5-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } propan-1-amine

16.4mg (0.41mmol) of sodium hydride (60%, dispersed in mineral oil) are dispersed in 3.1mL of anhydrous THF in an ice bath. 35.8mg (0.467mmol) of 3-amino-propan-1-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 70.0mg (0.234mmol) of intermediate 4 was added, the ice bath was removed and the resulting mixture was stirred at 35 ℃ for 17 hours.

The crude product was purified by HPLC to give 47mg of the title compound as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.99-2.13(2H),2.92(2H),3.78(3H),4.56(2H),6.89(1H),7.01(1H),7.23(1H),7.47-7.63(2H),8.07-8.19(2H),8.39(1H).

LC-MS (method 2) R_t＝1.08min；MS(ESIpos)m/z＝339[M+H]⁺.

Example 10

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

26.1mg (0.653mmol) of sodium hydride (60%, dispersed in mineral oil) are dispersed in 5mL of anhydrous THF in an ice bath. 78.1mg (0.742mmol) of 4-amino-2-methylbutan-2-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 100.0mg (0.371mmol) of intermediate 2 was added, the ice bath was removed, and the resulting mixture was stirred at room temperature for 96 hours.

The crude product was purified by HPLC to give 2mg of the title compound as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.20(6H),1.72-1.83(2H),3.39-3.53(2H),6.73(1H),7.17-7.34(3H),7.54-7.64(2H),7.68(1H),7.78(1H),7.89(1H).

LC-MS (method 2) R_t＝0.98min；MS(ESIpos)m/z＝337[M+H]⁺.

Example 11

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

18.3mg (0.457mmol) of sodium hydride (60%, dispersed in mineral oil) are dispersed in 3.5mL of anhydrous THF in an ice bath. 39.8mg (0.519mmol) of 3-amino-propan-1-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 70.0mg (0.26mmol) of intermediate 2 was added, the ice bath was removed and the resulting mixture was stirred at room temperature for 18 hours.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝2.12(2H),2.99(2H),4.56(2H),7.01(1H),7.22-7.38(2H),7.56-7.66(2H),7.67-7.75(1H),8.07-8.18(2H),8.36(1H).

LC-MS (method 1) R_t＝0.75min；MS(ESIpos)m/z＝309[M+H]⁺.

Example 12

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

In an ice bath, 10.4mg (0.261mmol) of sodium hydride (60%, dispersed in mineral oil) was dispersed in 2mL of anhydrous THF. 18.5mg (0.297mmol) of 2-aminoethan-1-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 40.0mg (0.148mmol) of intermediate 2 was added, the ice bath was removed and the resulting mixture was stirred at room temperature for 17 hours.

The reaction mixture was carefully poured into saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate/methanol (9: 1). The combined organic layers were dried over magnesium sulfate and concentrated.

The crude product (90mg) was dissolved in dichloromethane and a trace of methanol was added. The mixture was extracted with water, dried over magnesium sulfate and concentrated to give 45mg of the title compound as a solid.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝2.98(2H),4.43(2H),7.00(1H),7.21-7.36(2H),7.56-7.64(2H),7.71(1H),8.06-8.16(2H).

LC-MS (method 1) R_t＝0.72min；MS(ESIpos)m/z＝295[M+H]⁺.

Example 13

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

479mg (12mmol) of sodium hydride (60%, dispersed in mineral oil) was dispersed in 75mL of anhydrous THF in an ice bath. 600mg (8mmol) of (2R) -1-aminopropan-2-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 1.08g (4mmol) of intermediate 2 was added, the ice bath was removed and the resulting mixture was stirred at 40 ℃ for 16 hours.

The reaction mixture was carefully poured into half-saturated saline solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated.

The crude product was purified by flash chromatography to give 387mg of the title compound as a solid.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝1.48(3H),3.06-3.23(2H),5.44(1H),6.95(1H),7.22-7.35(2H),7.55(1H),7.61(1H),7.70(1H),8.12-8.19(2H),8.34(1H).

LC-MS (method 3) R_t＝0.76min；MS(ESIpos)m/z＝309[M+H]⁺.

Example 14

4- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -2-methylbutan-2-amine

26.1mg (0.653mmol) of sodium hydride (60%, dispersed in mineral oil) are dispersed in 5mL of anhydrous THF in an ice bath. 78.1mg (0.742mmol) of 3-amino-3-methylbutan-1-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 100.0mg (0.371mmol) of intermediate 2 was added, the ice bath was removed, and the resulting mixture was stirred at room temperature for 17 hours.

The crude product was purified by flash chromatography to give 81mg of the title compound as a solid.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.12(6H),1.87(2H),4.62(2H),6.98(1H),7.22-7.37(2H),7.59-7.70(3H),8.10-8.16(2H).

LC-MS (method 2) R_t＝0.81min；MS(ESIpos)m/z＝337[M+H]⁺.

Example 15

(2R) -2- { [3- (5-chloro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -propan-1-amine

12.4mg (0.518mmol) of sodium hydride (60%, dispersed in mineral oil) are dispersed in 4mL of anhydrous THF in an ice bath. 29.2mg (0.388mmol) of (2R) -1-aminopropan-2-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 105.0mg (0.259mmol) of intermediate 13 was added, the ice bath was removed and the resulting mixture was stirred at 40 ℃ for 16 hours.

The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated.

The crude product was purified by HPLC to give 43mg of the title compound as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.42(3H),2.78-2.97(2H),5.08-5.24(1H),6.99(1H),7.33(1H),7.55(1H),7.65(1H),7.82(1H),8.09-8.19(2H).

LC-MS (method 3) R_t＝0.86min；MS(ESIpos)m/z＝343[M+H]⁺.

Example 16

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

102mg (0.74mmol) of (1R) -2-amino-1-phenylethanol are added at 0-5 ℃ to 30mg (0.75mmol) of sodium hydride (60% in mineral oil) in 5mL of anhydrous DMF. Stirring is carried out in an ice bath for 15 minutes, then 100mg (0.37mmol) 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 2 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. The brine phase was basified and extracted twice with chloroform. The organic phases were combined, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 39.8mg (30%) of the product.

¹H-NMR (300MHz, chloroform-d), [ ppm [ (] ppm ]]＝3.19-3.36(2H),5.96(1H),6.91(1H),7.13(1H),7.23-7.35(3H),7.41(2H),7.51(3H),7.63(1H),7.90(1H),8.10(1H).

LC-MS (method 2) R_t＝0.90min；MS(ESIpos)m/z＝371[M+H]⁺.

Example 17

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

In an ice bath, 48.2mg (1.21mmol) of sodium hydride (60%, dispersed in mineral oil) were dispersed in 5mL of anhydrous THF. 178mg (1.3mmol) of (S) -2-phenylglycinol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 250mg (0.927mmol) of intermediate 2 was added, the ice bath was removed, and the resulting mixture was stirred at room temperature for 16 hours.

The crude product was purified by HPLC to give 200mg of the title compound as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝4.35-4.44(1H),4.45-4.53(1H),4.56-4.64(1H),6.96(1H),7.21-7.38(5H),7.47-7.57(3H),7.59-7.67(2H),8.08-8.15(2H).

LC-MS (method 3) R_t＝0.88min；MS(ESIpos)m/z＝371[M+H]⁺.

Example 18

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

In an ice bath, 48.2mg (1.21mmol) of sodium hydride (60%, dispersed in mineral oil) were dispersed in 5mL of anhydrous THF. 178mg (1.3mmol) of (R) -2-phenylglycinol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 250mg (0.927mmol) of intermediate 2 was added, the ice bath was removed, and the resulting mixture was stirred at room temperature for 16 hours.

The crude product was purified by HPLC to give 192mg of the title compound as a solid substance.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝4.37-4.44(1H),4.45-4.54(1H),4.56-4.65(1H),6.97(1H),7.21-7.39(5H),7.47-7.57(3H),7.59-7.68(2H),8.09-8.15(2H).

LC-MS (method 3) R_t＝0.89min；MS(ESIpos)m/z＝371[M+H]⁺.

Example 19

(1S) -2- { [3- (5-chloro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -1-phenylethylamine

In an ice bath, 20.7mg (0.52mmol) of sodium hydride (60%, dispersed in mineral oil) were dispersed in 4mL of anhydrous THF. 71mg (0.52mmol) of (S) -2-phenylglycinol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 105mg (0.259mmol) of intermediate 13 were added, the ice bath was removed and the resulting mixture was stirred at 40 ℃ for 16 hours.

The crude product was purified by HPLC to give 41mg of the title compound as a solid material.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝4.38-4.44(1H),4.51-4.63(2H),7.01(1H),7.24-7.31(1H),7.36(3H),7.49-7.57(3H),7.65-7.70(1H),7.73(1H),8.13-8.18(2H).

LC-MS (method 3) R_t＝0.96min；MS(ESIpos)m/z＝405[M+H]⁺.

Example 20

1- (trans-3- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclobutyl) methylamine

153mg (1.11mmol) of trans-3- (aminomethyl) cyclobutanol hydrochloride are added to 89mg (2.23mmol) of sodium hydride (60% in mineral oil) in 7.5mL of anhydrous DMF at 0-5 ℃. Stirring is carried out for 5 minutes on an ice bath, then 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 overnight. The reaction mixture was poured into a saturated ammonium chloride solution. It was extracted four times with ethyl acetate. The combined organic phases were washed twice with brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 114mg (61%) of the product.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝2.21-2.44(5H),2.77(2H),5.36-5.44(1H),7.01(1H),7.25-7.36(2H),7.59(1H),7.62(1H),7.70-7.75(1H),7.71-7.75(1H),8.11-8.17(2H).

LC-MS (method 2) R_t＝0.75min；MS(ESIpos)m/z＝335[M+H]⁺.

Example 21

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

117mg (1.11mmol) of 2- (2-aminoethoxy) ethanol are added to 44.5mg (1.11mmol) of sodium hydride (60% in mineral oil) in 7.5mL of anhydrous DMF at 0-5 ℃. Stirring is carried out for 5 minutes on an ice bath, then 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 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 residue was purified by HPLC to give 138mg (73%) of the product.

¹H-NMR (300MHz, methanol-d)₄),[ppm]＝2.84(2H),3.63(2H),3.95-4.01(2H),4.67-4.73(2H),7.00(1H),7.22-7.36(2H),7.51-7.56(1H),7.60(1H),7.63-7.69(1H),7.98(1H),8.09(1H).

LC-MS (method 2) R_t＝0.75min；MS(ESIpos)m/z＝339[M+H]⁺.

Example 22

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

153mg (1.11mmol) of (trans-3-aminocyclobutyl) methanol hydrochloride are added to 89mg (2.23mmol) of sodium hydride (60% in mineral oil) in 7.5mL of anhydrous DMF at 0-5 ℃. Stirring is carried out for 5 minutes on an ice bath, then 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 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 residue was purified by HPLC to give 77mg (41%) of the product.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.79-1.92(2H),2.11-2.22(2H),2.58-2.69(1H),3.46-3.59(1H),4.49(2H),7.02(1H),7.23-7.36(2H),7.57-7.66(2H),7.71-7.77(1H),8.14(2H).

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

Example 23

(1R,2R) -2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclohexylamine

168.7mg (1.11mmol) of (1R,2R) -2-aminocyclohexanol hydrochloride were added to 89mg (2.23mmol) of sodium hydride (60% in mineral oil) in 7.5mL of anhydrous DMF at 0-5 ℃. Stirring is carried out for 5 minutes on an ice bath, then 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 overnight. The reaction mixture was concentrated and purified by HPLC to give 113mg (58%) of the product.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.26-1.59(4H),1.63-1.94(3H),2.81-2.91(1H),4.66-4.77(1H),7.01(1H),7.23-7.37(2H),7.52(1H),7.61(1H),7.68-7.73(1H),8.11-8.19(2H).

LC-MS (method 2) R_t＝0.96min；MS(ESIpos)m/z＝349[M+H]⁺.

Example 24

(1S,2S) -2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclopentylamine

204mg (1.48mmol) ((1S,2S) -2-aminocyclopentanol hydrochloride is added to 118.6mg (2.97mmol) sodium hydride (60% in mineral oil) in 10mL anhydrous DMF at 0-5 ℃ stirring on an ice bath for 5 minutes, then 200mg (0.74mmol)3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine is added, the ice bath is removed and it is stirred at room temperature overnight, the reaction mixture is poured into half-saturated ammonium chloride solution and extracted four times with ethyl acetate, the combined organic phases are washed with brine, dried over magnesium sulfate and concentrated, the residue is dissolved in DMF, the insoluble matter is filtered and washed with methanol, the filtrate is purified by HPLC to give 66.7mg (27%) of the product.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝1.45(1H),1.63-1.87(3H),1.90-2.01(1H),2.30-2.41(1H),3.41-3.47(1H),5.07-5.14(1H),6.97(1H),7.23-7.36(2H),7.59-7.66(2H),7.72(1H),8.09-8.16(2H).

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

Example 25

(1S,2R) -2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclopentylamine formate salt

153mg (1.11mmol) of (1S,2R) -2-aminocyclopentanol hydrochloride are added to 89mg (2.23mmol) of sodium hydride (60% in mineral oil) in 7.5mL of anhydrous DMF at 0-5 ℃. Stirring is carried out for 5 minutes on an ice bath, then 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 overnight. 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 78mg (37%) of the product.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.54-1.87(3H),1.92-2.05(2H),2.18-2.32(1H),3.49-3.58(1H),5.28-5.35(1H),7.03(1H),7.23-7.37(2H),7.57(1H),7.59-7.65(1H),7.70-7.76(1H),8.12-8.19(2H),8.24(1H).

LC-MS (method 2) R_t＝0.84min；MS(ESIpos)m/z＝335[M+H]⁺.

Example 26

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -3-phenylpropan-1-amine formate salt

209mg (1.11mmol) of 1-amino-3-phenylpropan-2-ol hydrochloride are added to 89mg (2.23mmol) of sodium hydride (60% in mineral oil) in 7.5mL of anhydrous DMF at 0-5 ℃. Stirring is carried out for 5 minutes on an ice bath, then 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 overnight. 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 (44%) of the product.

¹H-NMR(600MHz,DMSO-d₆),[ppm]＝2.96-3.05(2H),3.12-3.17(1H),3.18-3.23(1H),5.45-5.51(1H),7.01(1H),7.18-7.22(1H),7.26(2H),7.32-7.40(4H),7.60(1H),7.66-7.69(1H),7.70-7.73(1H),8.16-8.19(2H),8.25(1H).

LC-MS (method 2) R_t＝0.96min；MS(ESIpos)m/z＝385[M+H]⁺.

Example 27

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

112.5mg (1.11mmol) of (1-aminocyclobutyl) methanol are added at 0-5 ℃ to 44.5mg (1.11mmol) of sodium hydride (60% in mineral oil) in 7.5mL of anhydrous DMF. Stirring is carried out for 5 minutes on an ice bath, then 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 2 hours. It was stirred at 50 ℃ overnight. 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 53mg (28%) of the product.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝1.74-1.85(2H),1.99(2H),2.16-2.24(2H),4.45(2H),7.04(1H),7.25-7.35(2H),7.61-7.66(2H),7.74(1H),8.13-8.19(2H).

LC-MS (method 2) R_t＝0.83min；MS(ESIpos)m/z＝335[M+H]⁺.

Example 28

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } hex-5-en-1-amine

Step 1: some small crystals of iodine were added to 458mg (18.85mmol) of magnesium turnings in 5mL of anhydrous THF. A solution of 2.544g (18.85mmol) of (bromomethyl) cyclopropane in 5mL of anhydrous THF was added. It was stirred for 10 minutes and the reaction was cooled to room temperature. This solution was slowly added to 1g (6.28mmol) of tert-butyl (2-oxoethyl) carbamate in 10mL of anhydrous THF with cooling. It was stirred at room temperature for 2 hours. Saturated ammonium chloride solution was added, the layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated. The residue was purified on silica gel (hexane/ethyl acetate gradient 1:1) to give 363mg (27%) of the product.

¹H-NMR (300MHz, chlorine)Imitation-d), [ ppm]＝1.44(9H),1.49-1.58(2H),2.05-2.30(2H),2.37(1H),2.97-3.03(1H),3.23-3.37(1H),3.66-3.79(1H),4.90(1H),4.98(1H),5.05(1H),5.83(1H).

Step 2: 2.09mL (8.36mmol) of hydrochloric acid solution (4M in 1, 4-dioxane) was slowly added to 0.36g (1.67mmol) of tert-butyl (2-hydroxyhex-5-en-1-yl) carbamate in 3.6mL of 1, 4-dioxane. It was stirred at room temperature overnight. It was concentrated on a rotary evaporator. The solid residue was triturated with ether twice to give 190mg (67%) of the product as the hydrochloride salt.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.32-1.52(2H),1.93-2.18(2H),2.51-2.65(1H),2.74-2.88(1H),3.57-3.68(1H),4.93(1H),5.00(1H),5.21(1H),5.78(1H),7.90(3H).

And step 3: 168.7mg (1.11mmol) of 1-aminohex-5-en-2-ol hydrochloride are added to 89mg (2.23mmol) of sodium hydride (60% in mineral oil) in 7.5mL of anhydrous DMF at 0-5 ℃. Stirring is carried out for 5 minutes on an ice bath, then 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 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 residue was purified by HPLC to give 92mg (47%) of the product.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝1.86-1.94(2H),2.11-2.27(2H),2.87-2.98(2H),4.90-4.95(1H),4.97-5.05(1H),5.11-5.18(1H),5.79-5.91(1H),6.99(1H),7.25-7.36(2H),7.57(1H),7.63(1H),7.68-7.73(1H),8.13(2H).

LC-MS (method 2) R_t＝0.88min；MS(ESIpos)m/z＝349[M+H]⁺.

Example 29

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

132.2mg (1.48mmol) of 2-amino-2-methylpropan-1-ol are added to 59mg (1.48mmol) of sodium hydride (60% in mineral oil) in 7.5mL of anhydrous DMF at 0-5 ℃. After stirring for 5 minutes on an ice bath, 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 a half-saturated ammonium chloride solution. 20mL of ethyl acetate was added and the layers were separated. The solid in the aqueous phase was filtered, washed twice with water and twice with n-hexane. The solid was dried at 40 ℃ in vacuo to give 133mg (56%) of the product.

¹H-NMR(600MHz,DMSO-d₆),[ppm]＝0.50-0.55(1H),0.56-0.67(3H),1.23-1.30(1H),3.08-3.13(1H),3.14-3.18(1H),4.82-4.87(1H),7.04(1H),7.31(1H),7.34-7.39(1H),7.54(1H),7.64-7.67(1H),7.74-7.77(1H),8.16-8.19(2H).

LC-MS (method 2) R_t＝0.83min；MS(ESIpos)m/z＝335[M+H]⁺.

Example 30

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

150mg (1.48mmol) of 2-amino-1-cyclopropylethanol are added at 0-5 ℃ to 59.3mg (1.48mmol) of sodium hydride (60% in mineral oil) in 10mL of anhydrous DMF. After stirring for 5 minutes on an ice bath, 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 2 hours. The reaction mixture was poured into a half-saturated ammonium chloride solution. It was extracted four times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 89mg (36%) of the product.

LC-MS (method 2) R_t＝0.87min；MS(ESIpos)m/z＝335[M+H]⁺.

Example 31

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -3- (morpholin-4-yl) propan-1-amine

278.4mg (1.11mmol) of 1-amino-3- (morpholin-4-yl) propan-2-ol oxalate (1:1) was added to 144.6mg (3.62mmol) of sodium hydride (60% in mineral oil) in 7.5mL of anhydrous DMF at 0-5 ℃. Stirring is carried out for 5 minutes on an ice bath, then 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 2 hours. 26.7mg (1.11mmol) of sodium hydride (60% in mineral oil) are added. It was stirred at room temperature overnight. The reaction mixture was poured into a half-saturated ammonium chloride solution. It was extracted four times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 145mg (66%) of the product.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝2.70(2H),2.96-3.05(1H),3.08-3.17(1H),3.38-3.53(4H),5.38-5.48(1H),6.98(1H),7.24-7-37(2H),7.60-7.70(3H),8.11-8.18(2H).

LC-MS (method 2) R_t＝0.71min；MS(ESIpos)m/z＝394[M+H]⁺.

Example 32

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -1- (tetrahydro-2H-pyran-4-yl) ethanamine

107mg (0.74mmol) of 2-amino-2- (tetrahydro-2H-pyran-4-yl) -ethanol are added to 29.7mg (0.74mmol) of sodium hydride (60% in mineral oil) in 5mL of anhydrous DMF at 0-5 ℃. Stirring is carried out in an ice bath for 5 minutes, then 100mg (0.37mmol) 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 2 hours. The reaction mixture was poured into a half-saturated ammonium chloride solution. Ethyl acetate was added and the layers were separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 85mg (61%) of the product.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝1.30-1.52(2H),1.55-1.62(1H),1.68-1.82(2H),3.04(1H),3.28(2H),3.84-3.92(2H),4.37(1H),4.56(1H),7.02(1H),7.25-7.36(2H),7.60(1H),7.61-7.64(1H),7.67-7.71(1H),8.13-8.18(2H).

LC-MS (method 2) R_t＝0.82min；MS(ESIpos)m/z＝379[M+H]⁺.

Example 33

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -4-methylpent-1-amine

173.8mg (1.48mmol) of 1-amino-4-methylpent-2-ol are added to 59.3mg (1.48mmol) of sodium hydride (60% in mineral oil) in 10mL of anhydrous DMF at 0-5 ℃. After stirring for 5 minutes on an ice bath, 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 a half-saturated ammonium chloride solution. It was extracted four times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 135mg (52%) of the product.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝0.89(3H),0.98(3H),1.55-1.65(1H),1.68-1.80(2H),2.97(1H),3.03(1H),5.36(1H),6.97(1H),7.25-7.36(2H),7.60-7.69(3H),8.11-8.16(2H).

LC-MS (method 2) R_t＝1.01min；MS(ESIpos)m/z＝351[M+H]⁺.

Example 34

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } propane-1, 3-diamine

100mg (1.11mmol) of 1, 3-diaminopropan-2-ol are added to 44.5mg (1.11mmol) of sodium hydride (60% in mineral oil) in 7.5mL of anhydrous DMF at 0-5 ℃. Stirring is carried out for 5 minutes on an ice bath, then 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 overnight. The reaction mixture was poured into a half-saturated ammonium chloride solution. It was extracted four times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The residue was treated with DMF and the insolubles were filtered off and dried in vacuo to yield 18.5mg (10%) of product. The filtrate was purified by HPLC to give an additional 35mg (17%) of the product as formate salt.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝2.90-3.02(4H),5.02(1H),6.99(1H),7.24-7.35(2H),7.58-7.64(2H),7.72(1H),8.10-8.15(2H).

LC-MS (method 2) R_t＝0.53min；MS(ESIpos)m/z＝324[M+H]⁺.

Example 35

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -2- (tetrahydrofuran-3-yl) ethanamine

186.5mg (1.11mmol) of 2-amino-1- (tetrahydrofuran-3-yl) ethanolic hydrochloride are added to 89mg (2.23mmol) of sodium hydride (60% in mineral oil) in 7.5mL of anhydrous DMF at 0-5 ℃. Stirring is carried out for 5 minutes on an ice bath, then 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 overnight. The reaction mixture was poured into a saturated ammonium chloride solution. It was extracted four times with ethyl acetate. The combined organic layers were washed twice with brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 60mg (30%) of the product as a mixture of diastereomers.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.51-1.92(3H),1.93-2.09(1H),2.73-3.11(3H),3.53-3.69(2H),3.69-3.85(2H),5.14-5.22(1H),6.97-7.04(1H),7.24-7.36(2H),7.55-7.66(2H),7.70-7.75(1H),8.13(2H).

LC-MS (method 2) R_t＝0.76min；MS(ESIpos)m/z＝365[M+H]⁺.

Example 36

Trans-3- { [3- (4-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclobutylamine

Step 1: in an ice bath, 17.4mg (0.434mmol) of sodium hydride (60%, dispersed in mineral oil) were dispersed in 4mL of anhydrous THF. 81.3mg (0.434mmol) of tert-butyl (trans-3-hydroxycyclobutyl) carbamate are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 73.5mg (0.217mmol) of 6-chloro-3- (4-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine are added, the ice bath is removed and the resulting mixture is stirred at 40 ℃ for 18 hours.

The reaction mixture was carefully poured into half-saturated brine. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to give the crude product, which was used in step 2 without further purification.

Step 2: to 95mg of the crude product from step 1 in 4mL of dichloromethane was added 2mL of trifluoroacetic acid. The mixture was stirred at room temperature for 30 minutes. 2mL of aqueous ammonia (30% by volume ammonia in water) was added. Water was added and the mixture was extracted with a mixture of dichloromethane and methanol (95:5 vol%). The organic layer was dried over magnesium sulfate and concentrated.

The crude product was purified by HPLC to give 28mg of the title compound as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝2.40-2.48(2H),2.54(3H),3.71-3.82(1H),5.43-5.53(1H),7.07(1H),7.16(1H),7.38(1H),7.52-7.61(2H),8.19-8.33(2H).

LC-MS (method 3) R_t＝0.74min；MS(ESIpos)m/z＝339[M+H]⁺.

Example 37

Trans-3- { [3- (5-chloro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclobutylamine

33.5mg (0.838mmol) of sodium hydride (60%, dispersed in mineral oil) are dispersed in 2mL of anhydrous THF in an ice bath. Slowly add to 69.1mg (0.559mmol) of trans-3-aminocyclobutanol hydrochloride in 2mL of a mixture of anhydrous DMF and anhydrous THF 1: 1. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 100mg (0.279mmol) of 6-chloro-3- (5-chloro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine are added, the ice bath is removed and the resulting mixture is stirred at 40 ℃ for 72 hours.

The crude product was purified by HPLC to give 44mg of the title compound as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]3.65-3.80(1H),5.46-5.58(1H),7.03(1H),7.30-7.38(1H),7.60(1H),7.63-7.70(1H),7.81(1H),8.12-8.20(1H) (methylene on cyclobutyl is not visible, and appears to be hidden in the DMSO peak).

LC-MS (method 3) R_t＝0.83min；MS(ESIpos)m/z＝355[M+H]⁺.

Example 38

Trans-3- { [3- (5-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclobutylamine

In an ice bath, 25.4mg (0.635mmol) of sodium hydride (60%, dispersed in mineral oil) are dispersed in 2mL of anhydrous THF. Slowly add to 52.9mg (0.43mmol) of trans-3-aminocyclobutanol hydrochloride in 2mL of a mixture of anhydrous DMF and anhydrous THF 1: 1. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 100mg (0.287mmol) of 6-chloro-3- (5-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine are added, the ice bath is removed and the resulting mixture is stirred at 40 ℃ for 72 hours.

The reaction mixture was cooled to room temperature and a freshly prepared mixture of 9mg (0.225mmol) sodium hydride (60% dispersed in mineral oil) and 18mg (0.146mmol) trans-3-aminocyclobutanol hydrochloride in 1mL of a 1:1 mixture of anhydrous DMF and anhydrous THF was added to the reaction mixture. Stirring was continued at 40 ℃ for 18 hours.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝2.53(4H),3.68-3.77(1H),3.79(3H),5.47-5.58(1H),6.90(1H),7.00(1H),7.26(1H),7.48-7.57(2H),8.09-8.17(2H).

LC-MS (method 3) with Rt 0.76 min; ms (esipos) M/z 351[ M + H ] +.

Example 39

Trans-3- { [3- (5-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclobutylamine

Step 1: in an ice bath, 11.5mg (0.288mmol) of sodium hydride (60%, dispersed in mineral oil) were dispersed in 4mL of anhydrous THF. 53.9mg (0.288mmol) of tert-butyl (trans-3-hydroxycyclobutyl) carbamate are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 69mg (0.144mmol) of 6-chloro-3- (5-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine are added, the ice bath is removed and the resulting mixture is stirred at 40 ℃ for 18 hours.

Step 2: to 63mg of the crude product from step 1 in 4mL of dichloromethane was added 2mL of trifluoroacetic acid. The mixture was stirred at room temperature for 30 minutes, and 2mL of aqueous ammonia (30 vol% ammonia in water) was added. Water was added and the mixture was extracted with a mixture of dichloromethane and methanol (95:5 vol%). The organic layer was dried over magnesium sulfate and concentrated.

The crude product was purified by HPLC to give 18mg of the title compound as a solid material.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝2.56-2.63(4H),3.78-3.87(1H),5.53-5.62(1H),7.07(1H),7.16-7.24(1H),7.48-7.53(1H),7.62(1H),7.67-7.72(1H),8.17-8.25(2H).

LC-MS (method 3) with Rt 0.74 min; ms (esipos) M/z 339[ M + H ] +.

Example 40

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

In an ice bath, 44.5mg (1.11mmol) of sodium hydride (60%, dispersed in mineral oil) were dispersed in 8mL of anhydrous THF. 99.2mg (1.11mmol) of 3-amino-2-methylpropan-1-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 150mg (0.556mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added, the ice bath is removed and the resulting mixture is stirred at 40 ℃ for 72 hours.

The crude product was purified by HPLC to give 147mg of the title compound as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.12(3H),2.22-2.32(1H),2.74-2.82(1H),2.87-2.96(1H),4.40-4.54(2H),7.03-7.11(1H),7.26-7.42(2H),7.68(2H),7.73-7.80(1H),8.16-8.23(2H).

LC-MS (method 3) with Rt 0.76 min; ms (esipos) M/z 323[ M + H ] +.

EXAMPLE 41

1-cyclopropyl-2- { [3- (4-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } ethanamine

32mg (0.8mmol) of sodium hydride (60%, dispersed in mineral oil) are dispersed in 3mL of anhydrous THF in an ice bath. 73.5mg (0.534mmol) of 2-amino-2-cyclopropylethanol hydrochloride and 1mL of anhydrous DMF are added slowly. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 80mg (0.267mmol) of 6-chloro-3- (4-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine are added, the ice bath is removed and the resulting mixture is stirred at room temperature for 20 hours.

The crude product was purified by HPLC to give 52mg of the title compound as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝0.44(4H),0.80-0.97(1H),2.63-2.71(1H),3.91(3H),4.25-4.33(1H),4.53-4.62(1H),6.83(1H),7.01(1H),7.19-7.32(2H),7.53(1H),8.09-8.18(2H).

LC-MS (method 3) R_t＝0.82min；MS(ESIpos)m/z＝365[M+H]⁺.

Example 42

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

57.8mg (1.44mmol) of sodium hydride (60%, dispersed in mineral oil) are dispersed in 6mL of anhydrous THF in an ice bath. 117mg (1.56mmol) of (R) -2-amino-propan-1-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 300mg (1.11mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added, the ice bath is removed and the resulting mixture is stirred at room temperature for 18 hours.

The reaction mixture was carefully poured into saturated aqueous ammonium chloride solution. The precipitate was filtered and subjected to flash chromatography to give 23mg of the title compound as a solid substance.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝1.16(3H),1.70-1.75(1H),4.28(2H),7.06(1H),7.30(2H),7.62(1H),7.64(1H),7.73-7.77(1H),8.15-8.20(2H).

LC-MS (method 3) R_t＝0.78min；MS(ESIpos)m/z＝309[M+H]⁺.

Example 43

(2R) -1- { [3- (5-chloro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -propan-2-amine

In an ice bath, 21mg (0.526mmol) of sodium hydride (60%, dispersed in mineral oil) was dispersed in 3.5mL of anhydrous THF. 39.5mg (0.526mmol) of (R) -2-amino-propan-1-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 94.1mg (0.263mmol) of 6-chloro-3- (5-chloro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine are added, the ice bath is removed and the resulting mixture is stirred at 40 ℃ for 16 hours.

The crude product was purified by HPLC to give 72mg of the title compound as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.20(3H),3.43(1H),4.29-4.41(2H),7.03(1H),7.33(1H),7.56(1H),7.65(1H),7.79(1H),8.13-8.20(2H).

LC-MS (method 3) R_t＝0.91min；MS(ESIpos)m/z＝343[M+H]⁺.

Example 44

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

In an ice bath, 23.7mg (0.593mmol) of sodium hydride (60%, dispersed in mineral oil) were dispersed in 4.8mL of anhydrous THF. 69.5mg (0.593mmol) of ((3- (aminomethyl) oxetan-3-yl) methanol) are slowly added after the addition is complete, stirring is continued at 0 ℃ for 15 minutes, 80mg (0.297mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added, the ice bath is removed and the resulting mixture is stirred at 40 ℃ for 72 hours.

The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate and concentrated.

The crude product was purified by HPLC to give 64mg of the title compound as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝3.12(2H),3.82-3.91(2H),4.49(2H),4.58(2H),4.76(2H),7.07(1H),7.27-7.40(2H),7.66(1H),7.73-7.80(2H),8.19(2H).

LC-MS (method 3) with Rt 0.76 min; ms (esipos) M/z 351[ M + H ] +.

Example 45

(2S) -1- { [3- (4-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -propan-2-amine

In an ice bath, 21.2mg (0.532mmol) of sodium hydride (60%, dispersed in mineral oil) were dispersed in 4mL of anhydrous THF. 39.9mg (0.532mmol) of (S) -2-aminopropan-1-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 90mg (0.266mmol) of 6-chloro-3- (4-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine are added, the ice bath is removed and the resulting mixture is stirred at 40 ℃ for 23 hours.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝1.12(3H),1.63-1.98(1H),4.23(2H),7.04(1H),7.12(1H),7.34(1H),7.49-7.55(2H),8.12-8.17(2H).

LC-MS (method 3) R_t＝0.85min；MS(ESIpos)m/z＝327[M+H]⁺.

Example 46

(1S) -2- { [3- (4-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -1-phenylethylamine

In an ice bath, 21.2mg (0.532mmol) of sodium hydride (60%, dispersed in mineral oil) were dispersed in 4mL of anhydrous THF. 73mg (0.532mmol) of (S) -2-phenylglycinol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 90mg (0.266mmol) of 6-chloro-3- (4-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine are added, the ice bath is removed and the resulting mixture is stirred at 40 ℃ for 23 hours.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝4.42(2H),4.59(1H),7.00(1H),7.07-7.15(1H),7.22-7.29(1H),7.30-7.38(3H),7.48-7.56(4H),8.11-8.18(2H).

LC-MS (method 3) R_t＝0.95min；MS(ESIpos)m/z＝389[M+H]⁺.

Example 47

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

In an ice bath, 3.91g (97.9mmol) of sodium hydride (60%, dispersed in mineral oil) were dispersed in 616mL of anhydrous THF. 5g (65.2mmol) of (S) -1-amino-propan-2-ol were slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 8.78g (32.6mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added, the ice bath is removed and the resulting mixture is stirred at room temperature for 12 hours.

The reaction mixture was carefully poured into 500mL of half-saturated brine. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated.

The crude product was impregnated with methyl t-butyl ether to obtain 5.5g of the title compound as a solid.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.18(3H),3.28-3.43(2H),3.94-4.08(1H),4.81(1H),6.85(1H),7.19-7.33(3H),7.54(1H),7.59(1H),7.64-7.70(1H),7.79(1H),7.90(1H).

LC-MS (method 3) R_t＝0.76min；MS(ESIpos)m/z＝309[M+H]⁺.

Example 48

(2R) -2- { [3- (7-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -propan-1-amine

In an ice bath, 21.3mg (0.532mmol) of sodium hydride (60%, dispersed in mineral oil) were dispersed in 4mL of anhydrous THF. 39.9mg (0.532mmol) of (R) -1-amino-propan-2-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 90mg (0.266mmol) of 6-chloro-3- (7-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine are added, the ice bath is removed and the resulting mixture is stirred at room temperature for 18 hours.

The crude product was purified by HPLC to give 58mg of the title compound as a solid.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝1.46(3H),2.96(2H),5.18-5.31(1H),7.02(1H),7.21-7.37(2H),7.55-7.73(2H),8.12-8.27(2H).

LC-MS (method 3) R_t＝0.83min；MS(ESIpos)m/z＝327[M+H]⁺.

Example 49

(2R) -2- { [3- (5-methyl-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } propan-1-amine

In an ice bath, 20.6mg (0.515mmol) of sodium hydride (60%, dispersed in mineral oil) were dispersed in 4mL of anhydrous THF. 38.7mg (0.515mmol) of (R) -1-amino-propan-2-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 100.0mg (0.257mmol) of 6-chloro-3- (5-methyl-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazine are added, the ice bath is removed and the resulting mixture is stirred at 40 ℃ for 48 hours.

The crude product was purified by HPLC to give 46mg of the title compound as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝1.42(3H),2.38(3H),2.87(2H),5.15(1H),6.96(1H),7.08-7.15(1H),7.46-7.53(3H),8.07-8.16(2H).

LC-MS (method 3) R_t＝0.84min；MS(ESIpos)m/z＝323[M+H]⁺.

Example 50

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

In an ice bath, 29.7mg (0.742mmol) of sodium hydride (60%, dispersed in mineral oil) were dispersed in 5mL of anhydrous THF. 112mg (0.742mmol) of (2S) -2-amino-3-phenylpropan-1-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 60.0mg (0.20mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added, the ice bath is removed and the resulting mixture is stirred at 40 ℃ for 17 hours.

The crude product was purified by HPLC to give 117mg of the title compound as a solid material.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝2.74-2.82(1H),2.92(1H),3.45-3.52(1H),4.27(1H),4.40(1H),7.03(1H),7.18(1H),7.23-7.37(6H),7.50(1H),7.62(1H),7.71(1H),8.11-8.18(2H).

LC-MS (method 3) R_t＝0.92min；MS(ESIpos)m/z＝385[M+H]⁺.

Example 51

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

In an ice bath, 20.4mg (0.512mmol) of sodium hydride (60%, dispersed in mineral oil) were dispersed in 4mL of anhydrous THF. 44.6mg (0.512mmol) of (1-aminocyclopropyl) methanol dissolved in 2mL of anhydrous THF and 2mL of anhydrous DMF are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 100mg (0.371mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added, the ice bath is removed and the resulting mixture is stirred at 40 ℃ for 72 hours.

20mg (0.23mmol) of (1-aminocyclopropyl) -methanol dissolved in 1mL of anhydrous THF are treated with 9.2mg (0.23mmol) of sodium hydride (60%, dispersed in mineral oil) at 0 ℃ for 15 minutes. The resulting mixture was then added to the reaction flask and the reaction was stirred at 40 ℃ for 48 hours.

¹H-NMR(500MHz,DMSO-d₆):[ppm]＝0.60-0.67(m,2H),0.72-0.79(m,2H),4.43(s,2H),7.10(d,1H),7.29-7.32(m,1H),7.34-7.38(m,1H),7.62(s,1H),7.64-7.68(m,1H),7.75-7.78(m,1H),8.16(s,1H),8.19(d,1H).

LC-MS (method 3) R_t＝0.79min；MS(ESIpos)m/z＝321[M+H]⁺.

Example 52

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

89mg (2.23mmol) of sodium hydride (60%, dispersed in mineral oil) are dispersed in a mixture of 4mL of anhydrous THF and 4mL of anhydrous DMF in an ice bath. 209mg (1.11mmol) of 3-amino-2-phenylpropan-1-ol hydrochloride are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 150mg (0.556mmol) of 3- (1-benzofuran-2-yl) -6-chloroimidazo [1,2-b ] pyridazine are added, the ice bath is removed and the resulting mixture is stirred at 40 ℃ for 72 hours.

The crude product was purified by HPLC to give 149mg of the title compound as a solid material.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝2.99-3.07(1H),3.13-3.21(1H),3.34-3.43(1H),4.70-4.85(2H),6.97(1H),7.23-7.42(7H),7.60-7.68(3H),8.09-8.16(2H),8.27(1H).

LC-MS (method 3) R_t＝0.86min；MS(ESIpos)m/z＝385[M+H]⁺.

Example 53

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -3- (4-fluorophenyl) propan-1-amine

Step 1: some small crystals of iodine were added to 1.145g (47.1mmol) of magnesium turnings in 25mL of anhydrous ether. A solution of 8.906g (47.1mmol)1- (bromomethyl) -4-fluorobenzene in 20mL dry ether was added. It was stirred at reflux for 1 hour and the reaction was cooled to room temperature. The solution was slowly added to 2.5g (15.7mmol) of tert-butyl (2-oxoethyl) carbamate in 25mL of anhydrous THF with cooling in an ice bath. It was stirred at room temperature overnight. Saturated ammonium chloride solution was added, the layers were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed twice with water, dried over magnesium sulfate and concentrated. The residue was purified on silica gel (hexane/ethyl acetate gradient 1:1) to give 1.72g (41%) of product.

¹H-NMR (300MHz, chloroform-d), [ ppm [ (] ppm ]]＝1.45(9H),2.64-2.82(2H),3.00-3.13(1H),3.28-3.41(1H),3.85-3.95(1H),4.81-4.99(1H),6.95-7.04(2H),7.18(2H).

Step 2: 1.62mL (6.50mmol) of hydrochloric acid solution (4M in 1, 4-dioxane) was added slowly to 0.35g (1.30mmol) of tert-butyl [3- (4-fluorophenyl) -2-hydroxypropyl ] carbamate in 2.8mL of 1, 4-dioxane. It was stirred at room temperature overnight. It was concentrated on a rotary evaporator. The solid residue was triturated with ether twice and with toluene three times. The solid was dried at 45 ℃ in vacuo to yield 240mg (90%) of the product as the hydrochloride salt.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝2.51-2.84(4H),3.78-3.90(1H),7.03-7.13(2H),7.19-7.28(2H),7.95(3H).

And step 3: 240mg (1.17mmol) of 1-amino-3- (4-fluorophenyl) propan-2-ol hydrochloride are added to 93.3mg (2.33mmol) of sodium hydride (60% in mineral oil) in 7.5mL of anhydrous DMF at 0-5 ℃. Stirring is carried out for 5 minutes on an ice bath, then 157.4mg (0.58mmol) 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. It was extracted four times with ethyl acetate. The combined organic layers were washed twice with brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 18mg (8%) of the product.

¹H-NMR(600MHz,DMSO-d₆),[ppm]＝2.93(2H),3.11-3.20(2H),5.33-5.39(1H),7.01(1H),7.07(2H),7.32-7.40(4H),7.57(1H),7.66-7.69(1H),7.75(1H),8.16(2H).

LC-MS (method 2) R_t＝1.27min；MS(ESIpos)m/z＝403[M+H]⁺.

Example 54

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -3- (pyridin-4-yl) propan-1-amine

269.5mg (1.11mmol) of the oxalate salt of 1-amino-3- (pyridin-4-yl) propan-2-ol (1:1) (dissolved in 4mL of anhydrous DMF and dried over 0.3nm molecular sieves for 96 h) was added to 133.5mg (3.34mmol) of sodium hydride (60% in mineral oil) in 4mL of anhydrous DMF at 0-5 ℃. Stirring is carried out for 5 minutes on an ice bath, then 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 overnight. The reaction mixture was poured into a saturated ammonium chloride solution. It was extracted four times with ethyl acetate. The combined organic phases were washed twice with brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to give 26mg (12%) of the product.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝2.93-3.10(2H),3.11-3.26(2H),5.47-5.59(1H),6.96(1H),7.26-7.39(4H),7.52(1H),7.60-7.72(2H),8.10-8.18(2H),8.38(2H).

LC-MS (method 2) R_t＝0.63min；MS(ESIpos)m/z＝386[M+H]⁺.

Example 55, method A

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

157mg (0.74mmol) of (1R) -2-amino-1- (pyridin-3-yl) ethanol dihydrochloride was added to 89mg (2.23mmol) of sodium hydride (60% in mineral oil) in 5mL of anhydrous DMF at 0-5 ℃. Stirring is carried out in an ice bath for 15 minutes, then 100mg (0.37mmol) 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 2 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. The HPLC solution was adjusted to basic pH and concentrated. The residue was dissolved in chloroform, washed twice with water, dried over magnesium sulfate and concentrated to give 95mg (68%) of the product.

¹H-NMR(600MHz,DMSO-d₆),[ppm]＝3.04-3.08(1H),3.12-3.17(1H),6.01-6.05(1H),7.18(1H),7.25(1H),7.34(2H),7.40-7.43(1H),7.62-7.65(1H),7.76-7.79(1H),7.95-7.98(1H),8.12(1H),8.21(1H),8.47-8.50(1H),8.83(1H).

LC-MS (method 2) R_t＝0.74min；MS(ESIpos)m/z＝372[M+H]⁺.

The examples in table 2 were prepared in a similar manner to method a.

TABLE 2

Example 61

(1S) -2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -1- (4-fluorophenyl) ethylamine

In an ice bath, 45mg (1.11mmol) of sodium hydride (60%, dispersed in mineral oil) were dispersed in 5mL of tetrahydrofuran. 142mg (0.742mmol) of (2S) -2-amino-2- (4-fluorophenyl) ethanol hydrochloride are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 100mg (0.371mmol) of intermediate 2 was added, the ice bath was removed and the resulting mixture was stirred at 40 ℃ for 120 hours.

The reaction mixture was carefully poured into water. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated.

The crude product was purified by HPLC to give 96mg of the title compound as a solid material.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝2.51-2.55(2H),4.48(1H),4.58(2H),7.00(1H),7.20(2H),7.31(2H),7.53-7.62(3H),7.63-7.73(2H),8.11-8.23(2H).

LC-MS (method 2) R_t＝0.92min；MS(ESIpos)m/z＝389[M+H]⁺.

Example 62

(1S) -2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -1- (4-chlorophenyl) ethanamine

In an ice bath, 45mg (1.11mmol) of sodium hydride (60%, dispersed in mineral oil) were dispersed in 5mL of tetrahydrofuran. 154mg (0.742mmol) of (2S) -2-amino-2- (4-chlorophenyl) ethanol hydrochloride are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 100mg (0.371mmol) of intermediate 2 was added, the ice bath was removed and the resulting mixture was stirred at 40 ℃ for 120 hours.

The crude product was purified by HPLC to give 65mg of the title compound as a solid material.

¹H-NMR(400MHz,DMSO-d₆),[ppm]＝2.51-2.55(2H),4.46(1H),4.58(2H),6.99(1H),7.31(2H),7.42(2H),7.53-7.60(3H),7.67(2H),8.12-8.22(2H).

LC-MS (method 2) R_t＝0.96min；MS(ESIpos)m/z＝405[M+H]⁺.

Example 63

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

119mg (2.97mmol) of sodium hydride (60%, dispersed in mineral oil) are dispersed in 20mL of tetrahydrofuran in an ice bath. 410mg (2.97mmol) of 2-amino-3-pyridylethanol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 400mg (1.48mmol) of intermediate 2 was added, the ice bath was removed and the resulting mixture was stirred at 40 ℃ for 18 hours.

The crude product was purified by HPLC to give 356mg of the title compound as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝4.44-4.51(1H),4.58-4.69(2H),7.01(1H),7.36(3H),7.62(3H),7.93-8.00(1H),8.12-8.23(2H),8.46-8.53(1H),8.73(1H).

LC-MS (method 3) R_t＝0.74min；MS(ESIpos)m/z＝372[M+H]⁺.

Example 64

3- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -3- (4-fluorophenyl) propan-1-amine

18mg (0.741mmol) of sodium hydride (60%, dispersed in mineral oil) are dispersed in 11mL of tetrahydrofuran in an ice bath. 94mg (0.556mmol) of 3-amino-1- (4-fluorophenyl) propan-1-ol are slowly added. After the addition was complete, stirring was continued at 0 ℃ for 15 minutes. 100mg (0.371mmol) of intermediate 2 was added, the ice bath was removed and the resulting mixture was stirred at 40 ℃ for 17 hours.

The crude product was purified by HPLC to give 27mg of the title compound as a solid material.

¹H-NMR(300MHz,DMSO-d₆),[ppm]＝2.05-2.19(1H),2.20-2.34(1H),2.85-2.94(2H),6.16-6.23(1H),7.15(1H),7.21-7.39(5H),7.63(3H),7.75-7.81(1H),8.11(1H),8.19(1H),8.38(1H).

LC-MS (method 2) R_t＝1.0min；MS(ESIpos)m/z＝403[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 an amount 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 compounds can be tableted with viscoelastic and thermoelastic sugars and polymers or effervescent ingredients to make a tablet that does not require water A porous matrix that is immediate release under conditions.

Combination therapy

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 may be combined with known agents and the like that are resistant to hyperproliferative diseases or other indications, as well as 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.

According to one embodiment, the present invention relates to a pharmaceutical combination comprising:

-one or more first active ingredients selected from the compounds of general formula (I) defined above, and

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

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, Neat stastatin, neat stastatin ester, zoledronic acid, zorubicin, or combinations thereof.

The additional agent may be afinitor, aldesleukin, alendronic acid, alpha-interferon (alfaferone), alitretinoin, allopurinol (alprimem), palonosetron hydrochloride injection (aloxi), altretamine, aminoglutethimide, amifostine, amsacrine, anastrozole, dolasetron tablet (anzmet), alfa bestatin injection (aranesp), arglabin, arsenic trioxide, exemestane tablet, 5-azacytidine, azathioprine, BAY 80-6946, BCG or tide, ubenimex, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, uridine bromide, bortezomib, busulfan, calcitonin, alemtin (cantimah), capecitabine, carboplatin, bipenemelamine, bicine, clindamycin butyrate, clindamycin hydrochloride, chlorambucil, meconium, mechlorethamine, berlin, berrubicin, clindamycin hydrochloride, clotrimycin hydrochloride, Cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin liposome citrate (DaunoXome), dexamethasone sodium phosphate, estradiol valerate, dinil interleukin 2, methylprednisolone, deslorelin, dexrazine, diethylstilbestrol, fluconazole capsule, docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166, leuprorelin, labyrine injection (elitek), epirubicin hydrochloride injection (ellence), aprepitant capsule (emid), epirubicin, erythropoietin alpha, recombinant human erythropoietin (epigen), cisplatin, levamisole, estradiol (estrace), estradiol, estramustine sodium phosphate, ethinylestradiol, amifostine, etidronic acid, etoposide injection, etoposide, fadrozole, farstonin, filgrastim, finasteride, filgrastimras, flugium, flugisitagliptin, fluvastatin, fludroxyfotema, doxime, fludroxydim, doxine, fludroxydim-2, fludroxyme, flu, Fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, fosetabine, fotemustine, fulvestrant, gamma-globulin (gamma-tagard), gemcitabine, gemtuzumab ozogamicin, gleevec, carmustine wafer capsule (gliadel), goserelin, granisetron hydrochloride, histrelin, and metin (hycamtin), hydrocortisone, erythroxylynonyadenine (eyrthro-hydroxyynyladenine), hydroxyurea, ibritumomab, idarubicin, ifosfamide, alpha interferon, alpha 2 interferon, alpha-2A interferon, alpha-2B interferon, alpha-n 1 interferon, alpha-n 3 interferon, beta interferon, gamma-1 a interferon, interleukin-2, interferon alpha (introl), interferon alpha (introl a), interferon alfa (gefitinib a), gefitinib (gefitinib a), gemcitabine (gamma-d) Irinotecan, ketrey, lapatinib, lentinan sulfate, letrozole, leucovorin, leuprorelin acetate, levamisole, calcium levofolinate (levofolinic acid calcium salt), levothyroxine sodium (levothroid), levothyroxine sodium (levoxyl), lomustine, lonidamine, dronabinol, mechlorethamine, mecobalamin acetate, megestrol acetate, melphalan, esterified estrol tablets (menest), 6-mercaptopurine, mesna, methotrexate, metivke, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, trilostane, Myocet, nedaplatin, filgrastimatin (nelasta), recombinant human interleukin 11 (neumesta), feugegen (neogenin), nilutamide, talufen, NSE 3543, NStrexadiol, cefatrine, cefatrix (oxepididn), cefatriptan hydrochloride (oxtretin), and indomethacin hydrochloride (oxtretin), Oxaliplatin, paclitaxel, prednisone sodium phosphate (pidiapred), pemetrexed, pyroxin, pentostatin, bicincarnib, pilocarpine hydrochloride, pirarubicin, plicamycin, porfimer sodium, prednimustine, prednisolone, prednisone, bemeili, procarbazine, recombinant human erythropoietin alpha, raltitrexed, RDEA 119, recombinant human interferon beta 1a injection (rebif), rhenium-186 hydroxyethylphosphonate, rituximab, roscovitine (roferon-A), romopeptide, pilocarpine hydrochloride tablet (salagen), shanin, sargrastim, semustine, sisofuran, sobuzolve, methylprednisolone, foscarnet acid, stem cell therapy, streptozocin, strontium chloride 89, sunitinib, levothyroxine sodium, tamoxifen, tamicine, tamicin, tacrine, testolactone (docetaxel), and docetaxel injection (docetaxel), Temozine, temozolomide, teniposide, testosterone propionate, methyltestosterone, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, troosulfan, tretinoin, methotrexate (trexall), trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, prolide, uridine, valrubicin, vesnarinone, vinblastine, vindesine, vinorelbine, vilizine, dexpropinimine (zinecard), setastatin, pinine, ABI-007, arbifen, interferon gamma-1 b (actammu), affiniak, aminopterin, azoxifene, axolinib, actamertant, atrasentan, sorafenib (BAY 43-9006), avastin, CCI-779, CDC 501, CDC, altretamine, trexate, altretamine, trimetrexate, triptorelbine, triptorexin, doxamide, triptolide, and, Cetuximab, clinostat, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, eltrexinol, eflorelin, efavirenz, isoxatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implants, holmium-166 DOTMP, ibandronic acid, gamma interferon, pegylated interferon alpha-2 b (intron-PEG), ixabepilone, keyhole limpet hemocyanin (keyhole limpheochrocyanin), L-651582, lanreotide, lasofoxifene, libra, clonafarnib, mirpiroxifene, minodronate, MS-209, MTP-PE liposomes, MX-6, nafarelin, neviracin, neovastat, nolamexane, oncho-TCS, osetron, polysufenol, paclitaxel, disodium 15421-qua-401, diazepam-R-401, diazepam, dox, doxycycline, and doxycycline, Raloxifene, ranpirnase, 13-cis-tretinoin, satraplatin, seocalcitol, T-138067, erlotinib hydrochloride tablets (tarceva), taxoprexin, alpha-1 thymosin, thiazolufrine, tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, pentosacoda, vapreotide, valcanib, verteporfin, vinflunine, Z-100, zoledronic acid, or combinations thereof.

Optional anti-hyperproliferative agents that may be added to the compositions include, but are not limited to, compounds listed in the cancer chemotherapeutic regimen of the Merck index 11 edition (1996) to which reference is made, e.g., asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, asparaginase (colaspase), cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin, doxorubicin (adriamycin), epirubicin, epothilone derivatives, etoposide, 5-fluorouracil, altretamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, nitrogen mustard, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, and mechlorethamine, Streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine.

Other anti-hyperproliferative agents suitable for use with The compositions of The present invention include, but are not limited to, those compounds recognized for use in The treatment of neoplastic diseases in Goodmann and Gilman's The pharmaceutical basic of Therapeutics (9 th edition), edited by Molinoff et al, McGraw-Hill, pages 1225-1287 (1996), to which reference is made, such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2' -difluorodeoxycytidine, docetaxel, red hydroxynonyladenine, ethinyl estradiol, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoromethanesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, medroxyprogesterone acetate, Paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine.

Other anti-hyperproliferative agents suitable for use with the compositions of the present invention include, but are not limited to, other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifene and topotecan.

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.

The compounds of the invention may also be combined with biological therapeutic agents such as antibodies (e.g., avastin, B-cell monoclonal antibodies (rituxan), erbitux, herceptin) or recombinant proteins.

-one or more compounds of general formula (I) 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;

and

-one or more agents selected from the group consisting of: a taxane, such as docetaxel, paclitaxel, lapatinib, sunitinib, or taxol; epothilones, such as ixabepilone, patupilone, or salgopilone; mitoxantrone; prednisolone (Predinisolone); dexamethasone; estramustin; vinblastine; vincristine; doxorubicin; doxorubicin hydrochloride for injection (Adriamycin); idarubicin; daunorubicin; bleomycin; etoposide; cyclophosphamide; ifosfamide; procarbazine; melphalan; 5-fluorouracil; capecitabine; fludarabine; cytarabine; Ara-C; 2-chloro-2' -deoxyadenosine; thioguanine; antiandrogens, such as flutamide, cyproterone acetate or bicalutamide; bortezomib; platinum derivatives, such as cisplatin or carboplatin; chlorambucil; methotrexate and rituximab.

The compounds of the invention may also be combined with an anti-angiogenic agent, for example with avastin, axitinib, DAST, recentin, sorafenib or sunitinib). It may also be combined with proteasome inhibitors, mTOR inhibitors, or anti-hormonal or steroidal metabolic enzyme inhibitors.

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:

The 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 set of values of the digits 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 MKNK1 in 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, 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).

Table 1: MKNK1IC₅₀

Examples	MKNK1IC₅₀[nM]
		1	3
2	5

3	4
		4	5
5	6
		6	6
7	7
		8	7
9	7
		10	8
11	8
		12	10
13	14
		14	20
15	36
		16	26
17	6
		18	22
19	25
		20	4
22	6
		24	10
25	7
		26	15
29	17
		30	41
33	32
		34	39
35	32

36	1
		37	4
38	3
		39	3
40	9
		41	12
42	15
		43	33
44	52
		45	17
46	36
		47	39
48	71
		49	88
50	27
		51	29
52	17
		55	16
56	40
		57	94
58	20
		59	37
60	39
		61	29
62	31
		63	54

64

57

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.

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 MKNK1 in 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, using TR-FRET readers, e.g. Rubystar (BMG L)abtechnologies, offburg, Germany) or Viewlux (Perkin-Elmer) to measure fluorescence emission at 620nm and 665nm after excitation at 350 nm. 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

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/NaOH 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 (inhibitor-free enzyme reaction)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 to a solution in aqueous assay buffer [50mM HEPES/NaOH 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 a 5 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/NaOH 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, 0.2% (w/v) bovine serum albumin in 50mM HEPES/NaOH pH 7.0).

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 is 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 being prepared separately by a 1:3 dilution series at 100-fold level of the concentrated stock solution before the 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 a 5 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 binding of biotinylated phosphorylated peptides to streptavidin-XL 665 and PT 66-Tb-cryptate. 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 a solution 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 a 5 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/NaOH 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, said concentrations being 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 1 nM), the dilution series being prepared separately by 1:3 serial dilutions at the level of 100-fold concentrated stock solution before the 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-eIF4ESer20910K 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

1. A compound of formula (I) or a stereoisomer or salt thereof, or a mixture thereof:

wherein:

r1 represents linear C₂-C₆-alkyl-, linear C₁-C₆Linear C of-alkyl-O-)₁-C₆Alkyl, branched C₃-C₆-alkyl-、C₃-C₆Cycloalkyl, linear C₁-C₆-alkyl-C₃-C₆-cycloalkyl-or C₃-C₆Cycloalkyl-linear C₁-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-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C optionally linked in spiro form₃-C₁₀-cycloalkyl-, 3-to 10-membered heterocycloalkyl optionally linked in spiro form, aryl-, aryl optionally substituted once or more than once independently of one another by R, heteroaryl-, -NH₂、C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-;

represents:

a group;

R3 represents a substituent selected from:

r represents a substituent selected from the group consisting of:

n represents an integer of 0 or 1.

2. The compound of claim 1 or a stereoisomer or salt thereof, or a mixture thereof, wherein:

R1 represents linear C₂-C₅-alkyl-, linear C₁-C₅Linear C of-alkyl-O-)₁-C₅Alkyl, branched C₃-C₅-alkyl-, C₄-C₆Cycloalkyl, linear C₁-C₆-alkyl-C₄-C₆-cycloalkyl-or C₄-C₆Cycloalkyl-linear C₁-C₆-alkyl-, which is optionally substituted one or more times independently from each other with substituents selected from the group consisting of:

represents:

a group;

R3 represents a substituent selected from:

r represents a substituent selected from the group consisting of:

n represents an integer of 0 or 1.

3. The compound of claim 1 or a stereoisomer or salt thereof, or a mixture thereof, wherein:

r1 represents linear C ₂-C₅-alkyl-, linear C₁-C₅Linear C of-alkyl-O-)₁-C₅Alkyl, branched C₃-C₅-alkyl-, C₄-C₆Cycloalkyl, linear C₁-C₆-alkyl-C₄-C₆-cycloalkyl-or C₄-C₆-cycloalkyl-C₁-C₆-alkyl-, which is optionally substituted one or more times independently from each other with substituents selected from the group consisting of:

-NH₂、C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C optionally linked in spiro form₃-C₁₀-cycloalkyl-, 3-to 10-membered heterocycloalkyl optionally linked in spiro form, aryl-, aryl optionally substituted once or several times independently of each other by R, heteroaryl-;

represents:

a group;

R3 represents a substituent selected from:

r represents a substituent selected from the group consisting of:

n represents an integer of 0 or 1.

4. The compound of claim 1 or a stereoisomer or salt thereof, or a mixture thereof, wherein:

r1 represents linear C₂-C₅-alkyl-, linear C₁-C₅Linear C of-alkyl-O-)₁-C₅Alkyl, branched C₃-C₅-alkyl-, C ₄-C₆Cycloalkyl, linear C₁-C₆-alkyl-C₄-C₆-cycloalkyl-or C₄-C₆-cycloalkyl-C₁-C₆-alkyl-, which is optionally substituted one or more times independently from each other with substituents selected from the group consisting of:

-NH₂、C₂-C₆-alkenyl-, C optionally linked in spiro form₃-C₁₀-cycloalkyl-, 3-to 10-membered heterocycloalkyl optionally linked in spiro form, aryl optionally substituted once or more times independently of each other by R, heteroaryl-;

represents:

a group;

R3 represents a substituent selected from:

halogen atom, C₁-C₆-alkoxy-, C₁-C₆-alkyl-;

r represents a substituent selected from the group consisting of:

halogen atom, C₁-C₆-haloalkyl-, C₁-C₆-alkoxy-;

n represents an integer of 0 or 1.

5. A compound according to claim 1, or a stereoisomer or a salt thereof, or a mixture thereof, which is selected from:

4- { [3- (4-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } butan-1-amine;

trans-3- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclobutylamine;

cis-3- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclobutylamine;

3- { [3- (4-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } propan-1-amine;

2- { [3- (4-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } ethanamine;

2- { [3- (5-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } ethanamine;

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

4- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } butan-1-amine;

3- { [3- (5-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } propan-1-amine;

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

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

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

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

4- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -2-methylbutan-2-amine;

(2R) -2- { [3- (5-chloro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } propan-1-amine;

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

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

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

(1S) -2- { [3- (5-chloro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -1-phenylethylamine;

1- (trans-3- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclobutyl) methylamine;

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

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

(1R,2R) -2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclohexylamine;

(1S,2S) -2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclopentylamine;

(1S,2R) -2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclopentylamine formate;

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

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

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } hex-5-en-1-amine;

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

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

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -3- (morpholin-4-yl) propan-1-amine;

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -1- (tetrahydro-2H-pyran-4-yl) ethylamine;

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -4-methylpent-1-amine;

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } propane-1, 3-diamine;

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

trans-3- { [3- (4-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclobutylamine;

trans-3- { [3- (5-chloro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclobutylamine;

trans-3- { [3- (5-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclobutylamine;

trans-3- { [3- (5-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclobutylamine;

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

1-cyclopropyl-2- { [3- (4-methoxy-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } ethanamine;

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

(2R) -1- { [3- (5-chloro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } propan-2-amine;

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

(2S) -1- { [3- (4-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } propan-2-amine;

(1S) -2- { [3- (4-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -1-phenylethylamine;

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

(2R) -2- { [3- (7-fluoro-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } propan-1-amine;

(2R) -2- { [3- (5-methyl-1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } propan-1-amine;

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

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

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

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -3- (4-fluorophenyl) propan-1-amine;

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -3- (pyridin-4-yl) propan-1-amine;

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

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -2- (4-fluorophenyl) ethylamine;

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

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

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -2- [3- (trifluoromethyl) phenyl ] ethanamine;

2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -2- (2, 4-difluorophenyl) ethylamine;

(1S) -2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -1- (4-fluorophenyl) ethylamine;

(1S) -2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -1- (4-chlorophenyl) ethylamine;

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

3- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -3- (4-fluorophenyl) propan-1-amine.

6. The compound of claim 5 or a stereoisomer or salt thereof, or a mixture of thereof, wherein the salt is a pharmaceutically acceptable salt.

7. The compound of claim 1 which is trans-3- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclobutylamine or a stereoisomer or salt thereof, or a mixture thereof.

8. The compound of claim 7 or a stereoisomer or salt thereof, or a mixture of thereof, wherein the salt is a pharmaceutically acceptable salt.

9. The compound of claim 1 which is (2S) -1- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } propan-2-amine or a stereoisomer or salt thereof, or a mixture thereof.

10. A compound according to claim 9 or a stereoisomer or a salt thereof, or a mixture of same, wherein the salt is a pharmaceutically acceptable salt.

11. The compound of claim 1 which is 3- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -3-methylbutan-1-amine or a stereoisomer or salt thereof, or a mixture of same.

12. A compound according to claim 11 or a stereoisomer or a salt thereof, or a mixture of same, wherein the salt is a pharmaceutically acceptable salt.

13. The compound of claim 1 which is (2R) -2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } propan-1-amine or a stereoisomer or salt thereof, or a mixture thereof.

14. A compound according to claim 13 or a stereoisomer or a salt thereof, or a mixture of same, wherein the salt is a pharmaceutically acceptable salt.

15. The compound of claim 1 which is (1S) -2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -1-phenylethylamine or a stereoisomer or salt thereof, or a mixture thereof.

16. The compound of claim 15 or a stereoisomer or salt thereof, or a mixture of thereof, wherein the salt is a pharmaceutically acceptable salt.

17. The compound of claim 1 which is trans-3- ({ [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } methyl) cyclobutylamine or a stereoisomer or salt thereof, or a mixture thereof.

18. A compound according to claim 17 or a stereoisomer or salt thereof, or a mixture of same, wherein the salt is a pharmaceutically acceptable salt.

19. The compound of claim 1 which is (1S,2S) -2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } cyclopentylamine or a stereoisomer or salt thereof, or a mixture thereof.

20. The compound of claim 19 or a stereoisomer or salt thereof, or a mixture of thereof, wherein the salt is a pharmaceutically acceptable salt.

21. The compound of claim 1 which is 2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -4-methylpent-1-amine or a stereoisomer or salt thereof, or a mixture of thereof.

22. The compound of claim 21, or a stereoisomer or salt thereof, or a mixture thereof, wherein the salt is a pharmaceutically acceptable salt.

23. The compound of claim 1 which is 3- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -2-methylpropan-1-amine or a stereoisomer or salt thereof, or a mixture thereof.

24. The compound of claim 23 or a stereoisomer or salt thereof, or a mixture of thereof, wherein the salt is a pharmaceutically acceptable salt.

25. The compound of claim 1 which is (2R) -2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -2- (pyridin-3-yl) ethylamine or a stereoisomer or salt thereof, or a mixture thereof.

26. The compound of claim 25 or a stereoisomer or salt thereof, or a mixture of thereof, wherein the salt is a pharmaceutically acceptable salt.

27. The compound of claim 1 which is (1S) -2- { [3- (1-benzofuran-2-yl) imidazo [1,2-b ] pyridazin-6-yl ] oxy } -1- (4-fluorophenyl) ethylamine or a stereoisomer or salt thereof, or a mixture thereof.

28. The compound of claim 27 or a stereoisomer or salt thereof, or a mixture of thereof, wherein the salt is a pharmaceutically acceptable salt.

29. A process for the preparation of a compound of formula (I) as defined in any one of claims 1 to 28, which process comprises reacting an intermediate compound of formula (V):

wherein A, R3 and n are as defined for a compound of general formula (I) in any one of claims 1 to 28, and X represents a leaving group,

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

wherein R1 is as defined above for the compound of formula (I),

thereby obtaining a compound of formula (I):

wherein A, R1, R3 and n are as defined for a compound of general formula (I) in any one of claims 1 to 28.

30. The method of claim 29, wherein the leaving group is a halogen atom or a perfluoroalkylsulfonate group.

31. The method of claim 30, wherein the halogen atom is a chlorine atom, a bromine atom, or an iodine atom.

32. The method of claim 30, wherein the perfluoroalkylsulfonate group is a trifluoromethylsulfonate group or a nonafluorobutylsulfonate group.

33. A pharmaceutical composition comprising a compound of general formula (I) or a stereoisomer or a salt thereof, or a mixture thereof, according to any one of claims 1 to 28, in association with a pharmaceutically-acceptable diluent or carrier.

34. The pharmaceutical composition of claim 33, wherein the salt is a pharmaceutically acceptable salt.

35. A pharmaceutical combination comprising:

-one or more first active ingredients selected from compounds of general formula (I) according to any of claims 1 to 28, and

36. Use of a compound of general formula (I) or a stereoisomer or a salt thereof, or a mixture of same, according to any one of claims 1 to 28, for the preparation of a medicament for the prophylaxis or treatment of a disease.

37. The use of claim 36, wherein the salt is a pharmaceutically acceptable salt.

38. The use of claim 36 or 37, 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.

39. The use of claim 38, 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.

40. The use of claim 38, 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.

41. The use of claim 40, wherein the hematological tumors, solid tumors and/or metastases thereof are selected from leukemia and myelodysplastic syndrome, malignant lymphoma, 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, endocrine tumors, breast tumors and other gynecological tumors, urological tumors including kidney tumors, bladder tumors and prostate tumors, skin tumors and sarcomas, and/or metastases thereof.

42. A compound of the general formula (V):

wherein A, R3 and n are as defined for a compound of general formula (I) in any one of claims 1 to 28, and X representsPerfluoroalkanes Alkylsulfonate radical。

43. The compound of claim 42, wherein the perfluoroalkylsulfonate group is a trifluoromethylsulfonate group or a nonafluorobutylsulfonate group.

44. Use of a compound according to any one of claims 42 to 43 for the preparation of a compound of general formula (I) according to any one of claims 1 to 28.