TW201406760A - Amino-substituted imidazopyridazines - Google Patents

Abstract

The present invention relates to amino-substituted imidazopyridazine compounds of general formula (I): in which A, R1, R3 and n are as defined in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.

Description

Amine substituted imidazolium

The present invention relates to an amine substituted imidazolium oxime of the general formula (I) as described and defined herein. Compounds; methods of preparing such compounds; pharmaceutical compositions and combinations comprising such compounds; the use of such compounds for the manufacture of a pharmaceutical composition for treating or preventing a disease, particularly a hyperproliferative and/or angiogenic condition; And intermediate compounds suitable for the preparation of such compounds.

The present invention relates to compounds which inhibit MKNK1 kinase (also known as MAP kinase interacting kinase Mnk1) and MKNK2 kinase (also known as MAP kinase interacting kinase Mnk2). Human MKNK contains a group of four proteins encoded by two genes (gene symbols: MKNK1 and MKNK2) by alternative splicing. The b form lacks the MAP kinase binding domain at the C-terminus. 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) in other protein kinases and indicates altered ATP binding [Jauch Et al., Structure 13, 1559-1568, 2005 and Jauch et al., EMBO J25, 4020-4032, 2006]. MKNK1a binds to ERK and p38 MAP kinase and is activated by ERK and p38 MAP kinase but not by JNK1. MKNK2a binds to ERK and is only activated by ERK. MKNK1b has low activity under all conditions and MKNK2b has a fundamental activity independent of ERK or p38 MAP kinase [Buxade M et al, Frontiers in Bioscience 5359-5374, May 1, 2008].

MKNK has been shown to enable eukaryotic initiation factor 4E (eIF4E), heterogeneous nuclear ribonucleic acid Binding protein A1 (hnRNP A1), polypyrimidine tract binding protein-associated splicing factor (PSF), cytosolic phospholipase A2 (cPLA2) and Sprouty 2 (hSPRY2) phosphorylation [Buxade M et al., Frontiers in Bioscience 5359- 5374, May 1, 2008].

eIF4E is an oncogene that is amplified in many cancers and phosphorylated only by MKNK protein as 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]. eIF4E plays a key role in enabling translation of cellular mRNA. eIF4E binds to the 7-methylguanosine cap at the 5' end of the cellular mRNA and delivers it to the ribosome as part of the eIF4F complex, which also contains eIF4G and eIF4A. Although all capped mRNAs require eIF4E for translation, the mRNA pool is subject to elevated eIF4E translational activity. These so-called "weak mRNAs" are usually not translated efficiently due to their long and complex 5' UTR regions, and they encode proteins that play a significant role in all aspects of malignant diseases, including VEGF, FGF-2, c. - Myc, cyclin D1, survivin, BCL-2, MCL-1, MMP-9, heparinase, and the like. The performance and function of eIF4E is elevated in a variety of human cancers and is directly related to disease progression [Konicek et al, Cell Cycle 7: 16, 2466-2471, 2008].

MKNK1 and MKNK2 are the only kinases known to phosphorylate eIF4E at Ser209. The overall translation ratio was not affected by eIF4E phosphorylation, but it has been shown that eIF4E phosphorylation contributes to the more efficient translation of polymorphic ribosomes (ie multiple ribosomes on a single mRNA) [Buxade M] [Buxade M Etc. Frontiers in Bioscience 5359-5374, May 1, 2008]. Alternatively, phosphorylation of eIF4E by MKNK protein may contribute to 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 Clin Oncol .8(5): 280-91, 2011]. Therefore, increased eIF4E phosphorylation in patients with non-small cell lung cancer predicts a poor prognosis [Yoshizawa et al, Clin Cancer Res. 16(1): 240-8, 2010]. Further information indicates that MKNK1 has a functional role in carcinogenesis due to the overexpression of constitutively active MKNK1 but not kinase-independent MKNK1, which has a functional role in carcinogenesis [Chrestensen CA et al., Genes Cells 12, 1133- 1140, 2007]. Furthermore, increased phosphorylation and activity of MKNK proteins is associated with overexpression of HER2 in breast cancer [Chrestensen, CA et al, J. Biol. Chem. 282, 4243-4252, 2007]. Constitutive activity, but not kinase-independent MKNK1 also accelerates tumor growth in mice using Eμ - Myc transgenic hematopoietic stem cells to produce tumors in mice. When analyzing eIF4E carrying the S209D mutation, a comparable result was achieved. The S209D mutation mimics the phosphorylation at the MKNK1 phosphorylation site. In contrast, the non-phosphorylated form of eIF4E reduces tumor growth [Wendel HG et al, Genes Dev. 21 (24): 3232-7, 2007]. Selective MKNK inhibitors that block eIF4E phosphorylation induce apoptosis in cancer cells in vitro and inhibit proliferation and soft agar growth. This inhibitor also inhibits the excessive growth of experimental B16 melanoma lung metastasis 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 conclusion, eIF4E phosphorylation via MKNK protein activity promotes cell proliferation and survival and is critical for malignant transformation. Inhibition of MKNK activity provides an easily controlled cancer treatment.

WO 2007/025540 A2 (Bayer Schering Pharma AG) relates to substituted imidazo[1,2- b ]indole as a kinase inhibitor, in particular a PKC (protein kinase C) inhibitor, in particular a PKC θ inhibitor .

WO 2007/025090 A2 (Kalypsis, Inc.) relates to heterocyclic compounds useful as inhibitors of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (Erk) kinase (abbreviated as "MEK"). In particular, WO 2007/025090 A2 relates in particular to imidazo[1,2- b ]嗒 .

WO 2007/013673 A1 (Astellas Pharma Inc.) relates to a fused heterocyclic ring which is an inhibitor of lymphocyte protein tyrosine kinase (abbreviated as "LCK"). In particular, WO 2007/013673 A1 relates in particular to imidazo[1,2- b ]嗒 .

WO 2007/147646 A1 (Bayer Schering Pharma AG) relates to the substitution of imidazo[1,2- b ]indole as a kinase inhibitor, in particular a PKC (protein kinase C) inhibitor, in particular a PKC θ inhibitor .

WO 2008/025822 A1 (Cellzome (UK) Ltd.) relates to a diazolodiazine derivative as a kinase inhibitor. In particular, WO 2008/025822 A1 relates in particular to imidazo[1,2- b ]indole as a kinase inhibitor, in particular an inhibitor of T cell kinase (abbreviated as "Itk"). .

WO 2008/030579 A2 (Biogen Idec MA Inc.) relates to a modulator of interleukin-1 (IL-1) receptor-associated kinase (abbreviated as "IRAK"). In particular, WO 2008/030579 A2 relates in particular to imidazo[1,2- b ]嗒 .

WO 2008/058126 A2 (Supergen, Inc.) relates in particular to imidazo[1,2- b ]indole as a protein kinase inhibitor, in particular a PIM kinase inhibitor derivative.

WO 2009/060197 A1 (Centro Nacional de Investigaciones Oncologicas (CNIO)) relates to imidazolium as a protein kinase inhibitor (such as the PIM family kinase) .

US 4,408,047 (Merck & Co., Inc., in particular) relates to imidazolium having a 3-amino-2-OR-propoxy substituent having beta-adrenergic blocking activity. .

WO 03/018020 A1 (Takeda Chemical Industries, Ltd.) relates to an inhibitor against c-Jun N-terminal kinase, which comprises especially imidazo[1,2- b ]-oxime Compound.

WO 2008/052734 A1 (Novartis AG) relates to heterocyclic compounds as anti-inflammatory agents. In particular, these compounds are especially imidazo[1,2- b ]嗒 . These compounds are useful in the treatment of diseases mediated by the ALK-5 and/or ALK-4 receptors and are also useful in the treatment of 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 having an effect of inhibiting the production of TNF-α and exerting an effect in a pathological model of an inflammatory disease and/or an autoimmune disease. ]despair derivative.

WO 2008/079880 A1 (Alcon Research, Ltd.) relates to 6-aminomidazo[1,2- b ]pyrene as a p-kinase inhibitor for the treatment of glaucoma and ocular hypertension analog.

WO 2009/091374 A2 (Amgen Inc.) relates to fused heterocyclic derivatives. Selected compounds are effective in preventing and treating diseases such as hepatocyte growth factor ("HGF") diseases.

J. Med. Chem., 2005, 48 , 7604-7614, the paper entitled "Structural Basis of Inhibitor Specificity of the Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (PIM-1) Kinase", and in particular disclosed as The imidazo[1,2- b ]嗒 of the inhibitor structure in the study described therein .

J. Med. Chem., 2010, 53 , 6618-6628 is a paper entitled "Discovery of Mitogen-Activated Protein Kinase-Interacting Kinase 1 Inhibitors by a Comprehensive Fragment-Oriented Virtual Screening Approach", and in particular disclosed in Table 1. Some specific imidazo[1,2- b ]嗒 as a compound identified as an MKNK-1 inhibitor .

Cancer Res March 1, 2011, 71 , 1849-1857, entitled "Therapeutic inhibition of MAP kinase interactions eukaryotic initiation factor 4E phosphorylation and suppresses outgrowth of experimental lung mestastases", and in particular discloses known antifungal agents Cercosporamide is an MKNK1 inhibitor.

However, the current state of the art described above does not describe the specific amine substituted imidazolium of the formula (I) of the present invention as defined herein. Compound, ie imidazo[1,2- b ]嗒 a base moiety carrying: - at its 3 position, a benzo[ b ]furanyl group having the following structure: Wherein * indicates the point of attachment of the benzo[ b ]furanyl group to the rest of the molecule, i.e., the 2 position of the benzo[ b ]furanyl group; and at the 6 position thereof, a group having the following structure: Wherein * indicates the point of attachment of the group to the rest of the molecule, and wherein R1 represents a linear C ₂ -C ₆ alkyl-, branched C ₃ -C ₆ alkyl group as defined herein, optionally substituted C ₃ -C ₆ cycloalkyl-; or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or mixtures thereof, as described and defined herein and As hereinafter referred to as "the compound of the present invention"; or its pharmacological activity.

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

In particular, it has been surprisingly found that such compounds of the invention are effective in inhibiting MKNK-1 kinase and are therefore useful in the treatment or prevention of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses or inappropriate cellular inflammatory responses. Or diseases associated with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly where uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses are caused by MKNK-1 kinase mediated, such as hematological tumors, solid tumors and / or its metastasis, such as leukemia and myelodysplastic syndromes, malignant lymphoma, head and neck tumors (including brain tumors and brain metastases), chest tumors (including non-small cells) 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 their metastases.

According to a first aspect, the invention encompasses a compound of formula (I):

Wherein: R1 represents a linear C ₂ -C ₆ alkyl-, a linear C ₁ -C ₆ alkyl-O-straight C ₁ -C ₆ alkyl-, a branched C ₃ -C ₆ alkyl-, C _3- C ₆ cycloalkyl-, linear C ₁ -C ₆ alkyl-C ₃ -C ₆ cycloalkyl- or C ₃ -C ₆ cycloalkyl-linear C ₁ -C ₆ alkyl-, Alternately, one or more substituents are optionally substituted with one another selected from the group consisting of: a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl -, C ₂ -C ₆ alkynyl-, optionally C ₃ -C ₁₀ cycloalkyl-, optionally 3 to 10 membered heterocycloalkyl, aryl-, optionally independently attached to each other In the case where one or more aryl groups, heteroaryl groups are substituted by R, and independently, one or more heteroaryl groups, -C(=O)NH ₂ , -C(= O) N(H)R', -C(=O)N(R')R", -C(=O)OH, -C(=O)OR', -NH ₂ , -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) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R ')R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC( =O)NHR', -OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R"group; Indicates: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and R3 represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl -, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, -C(=O)R', -C(=O)NH ₂ , -C(=O)N(H)R' , -C(=O)N(R')R", -NH ₂ , -NHR', -N(R')R", -N(H)C(=O)R', -N(R' ) C(=O)R', -N(H)C(=O)NH ₂ , -N(H)C(=O)NHR', -N(H)C(=O)N(R') R", -N(R')C(=O)NH ₂ , -N(R')C(=O)NHR', -N(R')C(=O)N(R')R", -N(H)C(=O)OR', -N(R')C(=O)OR', -NO ₂ , -N(H)S(-O)R', -N(R') S(=O)R', -N(H)S(=O) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R ", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -SH, C ₁ -C ₆ alkyl-S-, - S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R') R", -S(=O)(=NR')R"group; R represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ halo -C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₃ -C ₁₀ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, aryl-, heteroaryl-, -C (= O) R ', - C (= O) NH 2, -C (= O) N (H) R', - C (= O) N (R ') R " -C (= O) OR ', - NH 2, -NHR', - N (R ') R ", - N (H) C (= O) R', - N (R ') C (= O) R', -N(H)C(=O)NH ₂ , -N(H)C(=O)NHR', -N(H)C(=O)N(R')R", -N( R')C(=O)NH ₂ , -N(R')C(=O)NHR', -N(R')C(=O)N(R')R", -N(H)C (=O)OR', -N(R')C(=O)OR', -NO ₂ , -N(H)S(=O)R', -N(R')S(=O)R ', -N(H)S(=O) ₂ R', -N(R')S(=O) ₂ R', - N=S(=O)(R')R", -OH, C _1- C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', -OC( =O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R", -S(=O)(=NR')R"group;R' and R" Substituents independently selected from each other are: C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-; n represents an integer of 0, ₁ , 2, 3, 4 or 5; A conformation, tautomer, N-oxide, hydrate, solvate or salt or mixture thereof.

According to one embodiment of the first aspect, the invention encompasses a compound of formula (Ia):

Wherein: R1 represents a linear C ₂ -C ₆ alkyl-, branched C ₃ -C ₆ alkyl- or C ₃ -C ₆ cycloalkyl group, which, independently of one another, is optionally substituted with a substituent selected from the group consisting of Or multiple times: halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₃ - C ₁₀ cycloalkyl, aryl-, -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N(R')R", -C(= O) OH, -C(=O)OR', -NH ₂ , -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) ₂ R', -N (R')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy -, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', -OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(= O) ₂ N(R')R"group; R2 means: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and independently of each other, the R3 substituent is optionally substituted once, twice, three times, four times or five times; R3 represents a substituent selected from the group consisting of : halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, -C(=O) R', -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N(R')R", -NH ₂ , -NHR', -N( R')R", -N(H)C(=O)R', -N(R')C(=O)R', -N(H)C(=O)NH ₂ , -N(H C(=O)NHR', -N(H)C(=O)N(R')R", -N(R')C(=O)NH ₂ , -N(R')C(= O) NHR', -N(R')C(=O)N(R')R", -N(H)C(=O)OR', -N(R')C(=O)OR' , -NO ₂ , -N(H)S(=O)R', -N(R')S(=O)R', -N(H)S(=O) ₂ R', -N(R ')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R", -S(=O)(=NR')R"groups;R' and R" are independent of each other represents a substituent selected from the group: C ₁ -C ₆ alkyl -, C ₁ -C ₆ haloalkyl -; or a stereoisomer, tautomer, N- oxide, hydrate, Agent or salts thereof, or mixtures thereof.

According to one embodiment of the first aspect, the invention encompasses a compound of the formula (Ib):

Wherein: R1 represents a linear C ₂ -C ₆ alkyl-, branched C ₃ -C ₆ alkyl- or C ₃ -C ₆ cycloalkyl group: which: - independently of one another, is substituted with a substituent selected from the group consisting of Or multiple times: -aryl-, which are substituted one or more times by R substituents independently of each other; -heteroaryl-, which, independently of one another, are substituted one or more times by R substituents; and: - Alternately, one or more substituents are optionally substituted with a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl- , C ₂ -C ₆ alkynyl-, C ₃ -C ₁₀ cycloalkyl, aryl-, -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O N(R')R", -C(=O)OH, -C(=O)OR', -NH ₂ , -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) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C ₁ -C ₆ alkane Oxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', -OC(=O)N( R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ ,- S(=O) ₂ NHR', -S(=O) ₂ N(R')R"groups; R2 means: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and independently of each other, the R3 substituent is optionally substituted once, twice, three times, four times or five times; R3 represents a substituent selected from the group consisting of : halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, -C(=O) R', -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N(R')R", -NH ₂ , -NHR', -N( R')R", -N(H)C(=O)R', -N(R')C(=O)R', -N(H)C(=O)NH ₂ , -N(H C(=O)NHR', -N(H)C(=O)N(R')R", -N(R')C(=O)NH ₂ , -N(R')C(= O) NHR', -N(R')C(=O)N(R')R", -N(H)C(=O)OR', -N(R')C(=O)OR' , -NO ₂ , -N(H)S(=O)R', -N(R')S(=O)R', -N(H)S(=O) ₂ R', -N(R ')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R", -S(=O)(=NR')R"groups; R represents a substitution selected from Base: halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₃ -C ₁₀ Cycloalkyl-, 3 to 10 members Cycloalkyl -, aryl -, heteroaryl -, - C (= O) NH 2, -C (= O) N (H) R ', - C (= O) N (R') R ", -C(=O)OR', -NH ₂ , -NHR', -N(R')R", -N(H)C(=O)R', -N(R')C(=O) R', -N(H)C(=O)NH ₂ , -N(H)C(=O)NHR', -N(H)C(=O)N(R')R", -N( R')C(=O)NH ₂ , -N(R')C(=O)NHR', -N(R')C(=O)N(R')R", -N(H)C (=O)OR', -N(R')C(=O)OR', -NO ₂ , -N(H)S(=O)R', -N(R')S(=O)R ', -N(H)S(=O) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C _1- C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', -OC( =O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R", -S(=O)(=NR')R"group;R' and R" Substituents independently selected from each other are: C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-; or a stereoisomer, tautomer, N-oxide, hydrate thereof, Solvate or salt or a mixture thereof.

The terms mentioned herein preferably have the following meanings:

The terms "halogen atom", "halo-" or "Hal-" are understood to mean a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine, bromine or iodine atom. According to an embodiment, the terms "halogen atom", "halo-" or "Hal-" are understood to mean a fluorine atom. According to an embodiment, the terms "halogen atom", "halo-" or "Hal-" are understood to mean a chlorine atom.

The term "C ₁ -C ₆ alkyl" is understood to preferably mean a straight or branched chain saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl or propyl. Base, butyl, pentyl, hexyl, isopropyl, isobutyl, second butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethyl Propyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1- Methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2 , 3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl or an isomer thereof. In particular, the group has 1, 2, 3 or 4 carbon atoms ("C ₁ -C ₄ alkyl"), such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl The second butyl group, the third butyl group, more particularly has 1, 2 or 3 carbon atoms ("C ₁ -C ₃ alkyl group"), such as methyl, ethyl, n-propyl or isopropyl.

The term "linear C ₂ -C ₆ 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. Base, n-pentyl or n-hexyl. Specific words, the group having 4 or 5 carbon atoms ( "linear C ₂ -C ₅ alkyl") such as ethyl, n-propyl, n-butyl or n-pentyl. Alternatively, the group having 3 or 4 carbon atoms ( "linear C ₂ -C ₄ alkyl"), such as ethyl, n-propyl or n-butyl. Alternatively, the group having 2 or 3 carbon atoms ( "linear C ₂ -C ₃ alkyl"), for example, ethyl or n-propyl.

The term "branched chain C ₃ -C ₆ alkyl-" is understood to mean preferably a branched chain saturated monovalent hydrocarbon radical having 3, 4, 5 or 6 carbon atoms, such as isopropyl, isobutyl, second butyl. Base, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1- Dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3, 3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1, 2-dimethylbutyl or an isomer thereof. In particular, the group has 3, 4 or 5 carbon atoms ("branched chain C ₃ -C ₅ alkyl"), such as isopropyl, isobutyl, second butyl, tert-butyl, iso Butyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl. In particular, the group has 3 or 4 carbon atoms ("branched chain C ₃ -C ₄ alkyl"), such as isopropyl, isobutyl, t-butyl, t-butyl, more particularly Three carbon atoms (branched chain "C ₃ alkyl"), such as isopropyl.

The term "halo-C ₁ -C ₆ alkyl" is understood to preferably mean a straight-chain or branched-chain saturated monovalent hydrocarbon radical, wherein the term "C ₁ -C ₆ alkyl" is defined above, and one or more of them The hydrogen atoms are replaced by halogen atoms in the same or different manner, that is, one halogen atom is independent of the other halogen atom. According to an embodiment, the halogen atom is F. The halo-C ₁ -C ₆ alkyl group is, for example, -CF ₃ , -CHF ₂ , -CH ₂ F, -CF ₂ CF ₃ or -CH ₂ CF ₃ . According to an embodiment, the halogen atom is Cl. The halo-C ₁ -C ₆ alkyl group is, for example, -CCl ₃ , -CCl ₂ CCl ₃ or -CH ₂ CCl ₃ .

The term "C ₁ -C ₆ alkoxy" is understood to preferably mean a straight-chain, branched-chain or cyclic saturated monovalent hydrocarbon radical of the formula -O-alkyl, wherein the term "alkyl" is defined above, for example Methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, isobutoxy, tert-butoxy, second butoxy, cyclobutoxy, A pentyloxy group, an isopentyloxy group or a n-hexyloxy group or an isomer thereof.

The term "halo-C ₁ -C ₆ alkoxy" is understood to preferably mean a straight-chain or branched-chain saturated monovalent C ₁ -C ₆ alkoxy group as defined above, wherein one or more hydrogen atoms are the same Or replaced by a halogen atom in different ways. Specifically, the halogen atom is F. The halo-C ₁ -C ₆ alkoxy group is, for example, -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -OCF ₂ CF ₃ or -OCH ₂ CF ₃ .

The term "C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl" is understood to preferably mean a straight-chain or branched-chain saturated monovalent alkyl group as defined above, wherein one or more hydrogen atoms are the same or Different ways are substituted by a C ₁ -C ₆ alkoxy group as defined above, for example methoxyalkyl, ethoxyalkyl, propoxyalkyl, isopropoxyalkyl, butoxyalkyl, iso butoxy group, tert-butoxy group, butoxy group, pentyloxy group, iso-pentyloxy group, hexyloxy group, wherein the term "C ₁ -C ₆ alkyl The base is as defined above, or an isomer thereof.

The term "halo-C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl" is understood to preferably mean a linear or branched saturated monovalent C ₁ -C ₆ alkoxy-C as defined above. ₁ -C ₆ alkyl, wherein one or more hydrogen atoms are replaced by a halogen atom in the same or different manner. Specifically, the halogen atom is F. The halo-C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl group is, for example, -CH ₂ CH ₂ OCF ₃ , -CH ₂ CH ₂ OCHF ₂ , -CH ₂ CH ₂ OCH ₂ F, -CH ₂ CH ₂ OCF ₂ CF ₃ or -CH ₂ CH ₂ OCH ₂ CF ₃ .

The term "C ₂ -C ₆ alkenyl" is understood to preferably mean a straight-chain or branched-chain 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 -C ₃ alkenyl"), it is understood that where the alkenyl group contains more than one double bond, the double bonds may be isolated or conjugated to each other. The alkenyl group is, for example, a vinyl group, an allyl group, (E)-2-methylvinyl group, (Z)-2-methylvinyl group, homoallyl group, (E)-but-2-enyl group, (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)-pentyl 1-enyl, hex-5-alkenyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)- Hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl , isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1- Alkenyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl , 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methyl But-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-ene , (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z) -1-methylbut-1-enyl, 1,1-dimethylprop-2-ene , 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-A Pent-3-enyl, (Z)-1-methylpent-3-enyl, (E)-4-methylpent-2-enyl, (Z)-4-methylpent-2- Alkenyl, (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-A Pent-1-enyl, (Z)-4-methylpent-1-enyl, (E)-3-methylpent-1-enyl, (Z)-3-methylpent-1- Alkenyl, (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-ethyl -2-alkenyl, (E)-1-ethylbut-2-enyl, (Z)-1-ethylbutyl -2-alkenyl, (E)-3-ethylbut-1-enyl, (Z)-3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E) 1-ethylbuten-1-enyl, (Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2 -isopropylpropan-2-enyl, 1-isopropylprop-2-enyl, (E)-2-propylprop-1-enyl, (Z)-2-propylprop-1- Alkenyl, (E)-1-propylprop-1-enyl, (Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1-enyl, ( Z)-2-isopropylpropan-1-enyl, (E)-1-isopropylpropan-1-enyl, (Z)-1-isopropylpropan-1-enyl, (E) -3,3-dimethylprop-1-enyl, (Z)-3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)vinyl, butyl - 1,3-dienyl, pentane-1,4-dienyl, hex-1,5-dienyl or methylhexadienyl. In particular, the group is a vinyl or allyl group.

The term "C ₂ -C ₆ alkynyl" is understood to preferably mean a straight-chain or branched-chain monovalent hydrocarbon radical which contains one or more reference bonds and which contains 2, 3, 4, 5 or 6 carbon atoms, in particular 2 or 3 carbon atoms ("C ₂ -C ₃ alkynyl"). The C ₂ -C ₆ alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pentane- 1-alkynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4 - alkynyl, hex-5-alkynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbutyl- 2-Alkynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1 -methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpentan-2 - alkynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1- Ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1- Dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethyl-but-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

The term "C ₃ -C ₁₀ cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms ("C ₃ - C ₁₀ cycloalkyl"). The C ₃ -C ₁₀ cycloalkyl group is, for example, a monocyclic hydrocarbon ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl or cyclodecyl; or bicyclic A hydrocarbon ring, such as a perhydropentalenylene or decahydronaphthalene ring. In particular, the group has 3, 4, 5 or 6 carbon atoms ("C ₃ -C ₆ cycloalkyl"), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. In particular, the group has 4, 5 or 6 carbon atoms ("C ₄ -C ₆ cycloalkyl"), such as cyclobutyl, cyclopentyl, cyclohexyl.

The term "C ₄ -C ₁₀ cycloalkenyl" is understood to preferably mean a monovalent monocyclic or bicyclic hydrocarbon ring containing 4, 5, 6, 7, 8, 9 or 10 carbon atoms and one or two, Three or four double bonds which are allowed to be conjugated or non-conjugated by the size of the cycloalkenyl ring. The C ₄ -C ₁₀ cycloalkenyl group is, for example, a monocyclic hydrocarbon ring such as a cyclobutenyl group, a cyclopentenyl group or a cyclohexenyl group; or a bicyclic hydrocarbon group, for example:

The term "3 to 10 membered heterocycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one or more ^a hetero atom-containing group selected from C(=O), O, S, S(=O), S(=O) ₂ , NR ^a wherein R ^a represents a hydrogen atom or a C ₁ -C ₆ alkyl group- Or halo-C ₁ -C ₆ alkyl-; the heterocycloalkyl group may be attached to the remainder of the molecule via any carbon atom or, if present, a nitrogen atom.

In particular, the 3 to 10 membered heterocycloalkyl group may contain 2, 3, 4 or 5 carbon atoms and one or more of the above mentioned hetero atom-containing groups ("3 to 6 membered heterocycloalkyl" More particularly, the heterocycloalkyl group may contain 4 or 5 carbon atoms and one or more of the above-mentioned hetero atom-containing groups ("5 to 6 membered heterocycloalkyl").

In particular, but not limited to, the heterocycloalkyl group can be a 4-membered ring, such as azetidinyl, oxetanyl; or a 5-membered ring, such as tetrahydrofuranyl, dioxolanyl, Pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thio? Orolinyl, piperazinyl or trithiaalkyl; or a 7-membered ring, such as a diazepanyl ring. The heterocycloalkyl group may optionally be benzofused.

The heterocyclic group may be a bicyclic ring such as, but not limited to, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring; or a 5,6-membered bicyclic ring, For example, hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring.

As mentioned above, the ring containing a nitrogen atom may be partially unsaturated, that is, it may contain one or more double bonds such as, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[ 1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl ring, or it may be benzofused, such as, but not limited to, dihydroiso Quinoline ring.

The term "4 to 10 membered heterocycloalkenyl" is understood to mean an unsaturated monovalent monocyclic or bicyclic hydrocarbon ring containing 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one or more selected ^a hetero atom-containing group derived from C(=O), O, S, S(=O), S(=O) ₂ , NR ^a wherein R ^a represents a hydrogen atom or a C ₁ -C ₆ alkyl group or Halo-C ₁ -C ₆ alkyl-; the heterocycloalkenyl group is attached to the remainder of the molecule via any carbon atom or, if present, a nitrogen atom. Examples of the heterocycloalkenyl group may contain one or more double bonds, such as 4H-piperidyl, 2H-piperidyl, 3H-diazapropenyl, 2,5-dihydro-1H-pyrrolyl, [1,3]dioxolyl, 4H-[1,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5- Dihydrothienyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzofused.

The term "aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic or bicyclic or tricyclic hydrocarbon ring having 6, 9, 10, 11, 12, 13 or 14 carbon atoms ("C ₆ -C ₁₄ aryl"), especially a ring having 6 carbon atoms ("C ₆ aryl"), such as phenyl; or biphenyl; or a ring having 9 carbon atoms ("C ₉ aryl") , for example, indanyl or fluorenyl; or a ring having 10 carbon atoms ("C ₁₀ aryl"), such as a naphthyl, dihydronaphthyl or naphthyl group; or a ring having 13 carbon atoms ("C ₁₃ aryl"), such as fluorenyl; or a ring having 14 carbon atoms ("C ₁₄ aryl"), such as fluorenyl.

The term "heteroaryl" is understood to preferably mean a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms ("5 Up to 14 members heteroaryl"), especially 5 or 6 or 9 or 10 atoms, and which contain at least one hetero atom which may be the same or different, such as oxygen, nitrogen or sulfur, and additionally in each case It can be benzofused. In particular, the heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl , thiadiazolyl, thia-4H-pyrazolyl and the like and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, Benzotriazole, carbazolyl, fluorenyl, isodecyl, etc.; or pyridyl, anthracene a pyrimidyl group, a pyrazinyl group, a triazinyl group, etc., and a benzo derivative thereof, such as a quinolyl group, a quinazolinyl group, an isoquinolyl group, etc.; or an indomethacin group, a pyridazinyl group, a fluorenyl group, etc. And its benzo derivative; or Lolinyl, pyridazinyl, quinazolinyl, quinoxalinyl, naphthylpyridyl, acridinyl, oxazolyl, acridinyl, phenazinyl, phenothiazine, phenoxazinyl, Base or oxo group.

In general and unless otherwise stated, a heteroaryl group or a heteroaryl group includes All possible isomeric forms, such as their positional isomers. Thus, for some illustrative, non-limiting examples, the term pyridyl or extended pyridyl includes pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridine-4 - and pyridyl-4-yl; or the term thienyl or thienyl includes thiophen-2-yl, thiophen-2-yl, thiophen-3-yl and thiophen-3-yl.

As used throughout this text, for example, "C ₁ -C ₆ alkyl", "C ₁ -C ₆ haloalkyl", "C ₁ -C ₆ alkoxy" or "C ₁ -C ₆ haloalkoxy" In the case of the definition, the term "C ₁ -C ₆ " is understood to mean a finite number of carbon atoms having from 1 to 6, ie 1, 2, 3, 4, 5 or 6 carbon atoms. Hydrocarbyl group. It should also be understood that the term "C ₁ -C ₆ " should be interpreted as any subrange contained therein, such as C ₁ -C ₆ , C ₂ -C ₅ , C ₃ -C ₄ , C ₁ -C ₂ , C ₁ -C ₃ , C ₁ -C ₄ , C ₁ -C ₅ ; especially C ₁ -C ₂ , C ₁ -C ₃ , C ₁ -C ₄ , C ₁ -C ₅ , C ₁ -C ₆ ; C ₁ -C ₄ ; in the case of "C ₁ -C ₆ haloalkyl" or "C ₁ -C ₆ haloalkoxy", more particularly C ₁ -C ₂ .

Similarly, as used herein, as used throughout the text, for example, "C ₂ -C ₆ alkyl-", "linear C ₂ -C ₆ alkyl-", "C ₂ -C ₆ alkenyl", and In the case of the definition of "C ₂ -C ₆ alkynyl", the term "C ₂ -C ₆ " is understood to mean having 2 to 6, ie 2, 3, 4, 5 or 6 carbon atoms. A hydrocarbon group of a limited number of carbon atoms. It should also be understood that the term "C ₂ -C ₆ " should be interpreted as any subrange contained therein, such as C ₂ -C ₆ , C ₃ -C ₅ , C ₃ -C ₄ , C ₂ -C ₃ , C ₂ -C ₄ , C ₂ -C ₅ ; especially C ₂ -C ₃ .

Further, as used herein, as used throughout the text, for example, in the context of the definition of "branched chain C ₃ -C ₆ alkyl-", "C ₃ -C ₆ cycloalkyl", the term "C ₃ -C" ₆ ′′ is understood to mean a hydrocarbon group having a finite number of carbon atoms having 3 to 6, ie 3, 4, 5 or 6 carbon atoms. It should also be understood that the term "C ₃ -C ₆ " should be interpreted as any subrange contained therein, such as C ₃ -C ₆ , C ₄ -C ₅ , C ₃ -C ₅ , C ₃ -C ₄ , C ₄ - C ₆ , C ₅ - C ₆ ; especially C ₃ - C ₆ .

The term "substituted" means that one or more hydrogens on a given atom are selected by a self-indicating group. The group substitution is such that, in the prior case, it does not exceed the normal valence of the specified atom, and the substitution can result in a stable compound. Combinations may be permitted only if the combination of substituents and/or variables results in a stable compound.

The term "optionally substituted" means replaced by a group/radical or a partial condition.

As used herein, for example, in the definition of a substituent of a compound of the formula of the present invention, the term "one or more" is understood to mean "1, 2, 3, 4 or 5 times; especially 1, 2, 3" Or 4 times; more especially 1, 2 or 3 times; more especially 1 or 2 times."

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

The invention also includes all suitable isotopic variations of the compounds of the invention. An isotopic variation of a compound of the invention is defined as a variant of an atom having at least one atom that has the same atomic number but differs in atomic weight from the atomic mass normally or predominantly found in nature. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H(氘), ³ H(氚), ¹³ C, respectively. , ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I. Certain isotopic variations of the compounds of the invention, for example, isotopic variations of one or more radioisotopes (such as ³ H or ¹⁴ C), are useful for drug and/or matrix distribution studies. Deuterated and carbon 14 (i.e., ¹⁴ C) isotopes are particularly preferred due to their ease of preparation and detectability. In addition, substitution by isotopes such as hydrazine may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and thus may be preferred in some circumstances. Isotopic variants of the compounds of the invention can generally be prepared by the use of suitable isotopic variations of suitable reagents, such as by descriptive methods or by the methods described in the examples below, which are known to those skilled in the art. .

When used herein, the words compound, salt, polymorph, hydrate, solvate In the plural form of the analogs thereof, they also mean a single compound, a salt, a polymorph, an isomer, a hydrate, a solvate or the like.

"Stable compound" or "stable structure" means a sufficiently robust compound that can be isolated from the reaction mixture to a useful degree of purity and formulated into an effective therapeutic agent.

Depending on the location and nature of the various substituents desired, the compounds of the invention may contain one or more asymmetric centers. Asymmetric carbon atoms may be present in the (R) or (S) configuration, producing a racemic mixture in the case of a single asymmetric center, and producing a mixture of diastereomers in the case of multiple asymmetric centers. In some cases, asymmetry may also be present by limited rotation about a specified bond (eg, a central bond connecting two substituted aromatic rings of a particular compound).

The compounds of the invention may contain asymmetric sulfur atoms such as asymmetric hydrazine or sulfonium imine groups having, for example, the following structure: Where * indicates the atom to which the remainder of the molecule can bind.

Substituents on the ring may also exist in cis or trans form. All such configurations, including enantiomers and diastereomers, are contemplated as being within the scope of the invention.

Preferred compounds are those which 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 separation of such materials can be accomplished by standard techniques known in the art.

Optical isomers can be obtained according to conventional procedures by resolution of the racemic mixture (for example, by formation of diastereomeric salts using optically active acids or bases, or formation of covalent diastereomers). Examples of suitable acids are tartaric acid, diethyl tartaric acid, and xylene mercapto Stone acid and camphorsulfonic acid. Mixtures of diastereomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example by chromatography or fractional crystallization. . The optically active base or acid is subsequently released from the separated diastereomeric salt. Different processes for isolating optical isomers involve the use of palm chromatography, which is optimally selected to maximize separation of the enantiomers, with or without the use of conventional derivatization methods (eg, for palm chromatography HPLC columns) ). Suitable for palm-shaped HPLC column lines manufactured by Diacel, such as Chiracel OD and Chiracel OJ, etc., which can be selected conventionally. Enzymatic separation with or without derivatization is also applicable. The optically active compounds of the invention can likewise be obtained by the palmitic synthesis using optically active starting materials.

To limit the different types of isomers to each other, refer to IUPAC Guidelines Part E (Pure Appl Chem 45, 11-30, 1976).

The invention includes all possible stereoisomers of the compounds of the invention, either in the form of a single stereoisomer or in any ratio of such stereoisomers (eg, R or S isomers or E or Z isomers). Any form of mixture. Separation of a single stereoisomer (e.g., a single enantiomer or a single diastereomer) of a compound of the invention may be by any suitable state of the art method (such as chromatography, especially for example, for the palm layer) Analytical method) to achieve.

Additionally, the compounds of the invention may exist in the form of tautomers. For example, any compound of the invention containing a pyrazole moiety as a heteroaryl group can exist, for example, as a 1H tautomer or a 2H tautomer or even a mixture of two tautomers in any amount, or Any of the compounds of the invention wherein the triazole moiety is a heteroaryl group may, for example, be a 1H tautomer, a 2H tautomer or a 4H tautomer or even a mixture of such 1H, 2H and 4H tautomers in any amount. The form exists, namely:

The invention includes all possible tautomers of the compounds of the invention, either as a single tautomeric form or as a mixture of any ratio of such tautomers.

Additionally, the compounds of the invention may exist in the form of N-oxides which are defined as oxidation of at least one nitrogen of the compounds of the invention. The invention includes all such possible N-oxides.

The invention also relates to suitable forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts (especially pharmaceutically acceptable salts) and coprecipitates.

The compound of the present invention may exist in the form of a hydrate or a solvate wherein the compound of the present invention contains a polar solvent (especially, for example, water, methanol or ethanol) as a structural element of the crystal lattice of the compound. The amount of polar solvent, especially water, can be present in stoichiometric or non-stoichiometric ratios. In the case of stoichiometric solvates (eg hydrates), it may be a hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvate, respectively. Or hydrate. The invention includes all such hydrates or solvates.

Additionally, the compounds of the invention may exist in free form (for example in the form of the free base or the free acid or zwitterionic) or may exist in the form of a salt. The salt may be any salt, may be an organic or inorganic addition salt, and in particular may be any pharmaceutically acceptable organic or inorganic addition salt conventionally used in pharmacy.

The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the invention. See, for example, SM Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977 , 66, 1-19.

Suitable pharmaceutically acceptable salts of the compounds of the invention may, for example, be, for example, acid addition salts of the compounds of the invention having a nitrogen atom in their chain or ring, which are sufficiently basic, such as An acid addition salt formed by an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, bisulfuric acid, phosphoric acid or nitric acid; or an acid addition salt formed with an organic acid, Organic acids such as formic acid, acetic acid, acetamidineacetic acid, acetone Acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzhydryl)-benzoic acid, camphoric acid ( Camphoric acid), cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfate , 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, amine sulfonic acid, trifluoromethanesulfonic acid, ten Dialkylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalene disulfonic 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), glucose heptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.

Further, another suitable pharmaceutically acceptable salt of the compound of the present invention which is sufficiently acidic is an alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; an ammonium salt or a physiological agent A salt formed from an acceptable organic base of a cation, for example, a salt formed with N-methyl-glucosamine, dimethyl-glucosamine, ethyl-glucosamine, lysine, dicyclohexyl Amine, 1,6-hexanediamine, ethanolamine, glucosamine, sarcosine, silkamine, cis-hydroxy-methyl-aminomethane, alanine propylene glycol, sowak-base, 1- Amino-2,3,4-butanetriol. In addition, basic nitrogen-containing groups can be quaternized by four reagents such as lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; dialkyl sulfate Such as dimethyl sulfate, diethyl sulfate and dibutyl sulfate and diamyl sulfate; long chain halides such as sulfhydryl, lauryl, myristyl and stearyl chloride, bromide and iodide; Aralkyl halides such as benzyl and phenethyl bromide.

It will be further appreciated by those skilled in the art that the acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable mineral or organic acid by any of a variety of known methods. Alternatively, the alkali metal salt and the alkaline earth metal salt of the acidic compound of the present invention can be borrowed It is prepared by reacting a compound of the invention with a suitable base by a variety of known methods.

The invention includes all possible salts of the compounds of the invention, either in the form of a single salt or in any mixture of any ratio of such salts.

As used herein, the term "in vivo hydrolyzable ester" is understood to mean an in vivo hydrolysable ester of a compound of the invention containing a carboxy or hydroxy group, for example, pharmaceutically acceptable in the hydrolysis of a human or parent alcohol in a human or animal body. Accepted ester. Suitable pharmaceutically acceptable esters of carboxy include, for example, alkyl esters, cycloalkyl esters and optionally substituted phenylalkyl esters, especially benzyl esters, C ₁ -C ₆ alkoxymethyl esters (eg methoxy groups) Methyl ester), C ₁ -C ₆ alkyl alkoxymethyl ester (for example, p-amyloxymethyl ester), decyl ester, C ₃ -C ₈ cycloalkoxy-carbonyloxy-C ₁ -C ₆ alkyl ester (eg 1-cyclohexylcarbonyloxyethyl ester); 1,3-dioxol-2-one methyl ester, for example 5-methyl-1,3-dioxol-2- Ketomethyl ester; and C ₁ -C ₆ alkoxycarbonyloxyethyl ester, for example 1-methoxycarbonyloxyethyl ester, and may be formed at any of the carboxyl groups in the compounds of the invention.

In vivo hydrolysable esters of the compounds of the invention containing a hydroxy group include inorganic esters such as phosphates and [α]-nonoxyalkyl ethers and related compounds which are produced by the in vivo hydrolysis degradation of the ester to release the parent hydroxyl group. Examples of the [α]-nonoxyalkyl ether include an ethoxymethoxymethoxy group and a 2,2-dimethylpropoxymethoxy group. The choice of in vivo hydrolyzable ester forming a hydroxyl group includes an alkyl fluorenyl group, a benzamidine group, a phenyl ethane group, a substituted benzamyl group, a phenylethyl group, an alkoxycarbonyl group (to produce an alkyl carbonate) Ester), dialkylamine methyl sulfhydryl and N-(dialkylaminoethyl)-N-alkylamine carbaryl (to produce urethane), dialkylaminoethyl hydrazide and Carboxyethyl group. The present invention covers all such esters.

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

According to a second embodiment of the first aspect, the invention encompasses a compound of the above formula (I), wherein: R1 represents a linear C ₂ -C ₆ alkyl-, straight-chain C ₁ -C ₆ alkyl-O- straight Chain C ₁ -C ₆ alkyl-, branched C ₃ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, linear C ₁ -C ₆ alkyl-C ₃ -C ₆ cycloalkyl- Or a C ₃ -C ₆ cycloalkyl-linear C ₁ -C ₆ alkyl- group which, independently of one another, is optionally substituted one or more times with a substituent selected from the group consisting of: halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, optionally C ₃ -C ₁₀ cycloalkyl-linked as spiro The case is a 3- to 10-membered heterocycloalkyl group, an aryl group, an aryl group, a heteroaryl group, a -C(=O)NH ₂ , a -C, which are independently substituted by R, as the case may be. (=O)N(H)R', -C(=O)N(R')R", -C(=O)OH, -C(=O)OR', -NH ₂ , -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) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O) (R')R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ ,- OC(=O)NHR', -OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O) R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R"group; Indicates: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and R3 represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl -, -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-; R represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl -, C ₂ -C ₆ alkenyl -, C ₂ - C ₆ alkynyl -, C ₃ -C ₁₀ cycloalkyl -, 3-10 heterocycloalkyl -, aryl -,heteroaryl-, -C(=O)R', -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N(R')R ", -C(=O)OR', -NH ₂ , -NHR', -N(R')R", -N(H)C(=O)R', -N(R')C(= O) R', -N(H)C(=O)NH ₂ , -N(H)C(=O)NHR', -N(H)C(=O)N(R')R",- N(R')C(=O)NH ₂ , -N(R')C(=O)NHR', -N(R')C(=O)N(R')R", -N(H ) C(=O)OR', -N(R')C(=O)OR', -NO ₂ , -N(H)S(=O)R', -N(R')S(=O R', -N(H)S(=O) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH , C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', - OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(= O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R", -S(= O) (=NR')R"group;R' and R" independently of each other represent a substituent selected from C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-; n represents 0 An integer of 1, 2, 3, 4 or 5; or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof or a mixture thereof.

According to a variant of the second embodiment of the first aspect, the invention encompasses a compound of the formula (Ia):

R1 represents a linear C ₂ -C ₆ alkyl-, branched C ₃ -C ₆ alkyl- or C ₃ -C ₆ cycloalkyl group, which, independently of one another, is optionally substituted by one or more substituents selected from the group consisting of views: a halogen atom, -CN, C ₁ -C ₆ alkyl -, C ₁ -C ₆ haloalkyl -, C ₂ -C ₆ alkenyl -, C ₂ - C ₆ alkynyl -, C ₃ -C ₁₀ Cycloalkyl, aryl-, -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N(R')R", -C(=O) OH, -C(=O)OR', -NH ₂ , -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) ₂ R', -N(R ')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', -OC(=O)N(R')R", -SH, C ₁ -C ₆ alkane Base -S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R"group; R2 means: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and independently of each other, the R3 substituent is optionally substituted once, twice, three times, four times or five times; R3 represents a substituent selected from the group consisting of : a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-; R' and R" independently of each other represent a substituent selected from C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-; or a stereoisomer, tautomer, N-oxidation thereof a hydrate, a solvate or a salt or a mixture thereof.

According to a variant of the second embodiment of the first aspect, the invention encompasses a compound of the formula (Ib):

R1 represents a linear C ₂ -C ₆ alkyl-, branched C ₃ -C ₆ alkyl- or C ₃ -C ₆ cycloalkyl group which: - independently of one another, is substituted one or more substituents selected from the group consisting of Sub: -aryl-, which are substituted one or more times independently of one another by an R substituent; -heteroaryl-, which, independently of one another, are optionally substituted one or more times by an R substituent; and: - independently of each other Substituting one or more substituents with a substituent selected from the group consisting of: a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₃ -C ₁₀ cycloalkyl, aryl-, -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N (R')R", -C(=O)OH, -C(=O)OR', -NH ₂ , -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) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C ₁ -C ₆ alkoxy -, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', -OC(=O)N(R'R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S( =O) ₂ NHR', -S(=O) ₂ N(R')R"groups; R2 means: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and independently of each other, the R3 substituent is optionally substituted once, twice, three times, four times or five times; R3 represents a substituent selected from the group consisting of : a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-; R represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl -, C ₃ -C ₁₀ 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', -NH ₂ , -NHR', -N(R')R", -N(H)C( =O)R', -N(R')C(=O)R', -N(H)C(=O)NH ₂ , -N(H)C(=O)NHR', -N(H C(=O)N(R')R", -N(R')C(=O)NH ₂ , -N(R')C(=O)NHR', -N(R')C( =O)N(R')R", -N(H)C(=O)OR', -N(R')C(=O)OR', -NO ₂ , -N(H)S(= O) R', -N(R')S(=O)R', -N(H)S(=O) ₂ R', -N(R')S(=O) ₂ R', -N =S(=O)(R')R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(= O) NH ₂ , -OC(=O)NHR', -OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, - S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R') R", -S(=O)(=NR')R"groups;R' and R" independently of each other represent a substituent selected from C ₁ -C ₆ alkyl-, C ₁ -C ₆ halo Alkyl-; or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof or a mixture thereof.

According to a third embodiment of the first aspect, the invention encompasses a compound of the above formula (I), wherein: R1 represents a linear C ₂ -C ₅ alkyl-, straight-chain C ₁ -C ₅ alkyl-O- straight Chain C ₁ -C ₅ alkyl-, branched C ₃ -C ₅ alkyl-, C ₄ -C ₆ cycloalkyl-, linear C ₁ -C ₆ alkyl-C ₄ -C ₆ cycloalkyl- Or a C ₄ -C ₆ cycloalkyl-linear C ₁ -C ₆ alkyl- group which, independently of one another, is optionally substituted one or more times with a substituent selected from the group consisting of: halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, optionally C ₃ -C ₁₀ cycloalkyl-linked as spiro The case is a 3- to 10-membered heterocycloalkyl group, an aryl group, an aryl group, a heteroaryl group, a -C(=O)NH ₂ , a -C, which are independently substituted by R, as the case may be. (=O)N(H)R', -C(=O)N(R')R", -C(=O)OH, -C(=O)OR', -NH ₂ , -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) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O) (R')R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ ,- OC(=O)NHR', -OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R"group; Indicates: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and R3 represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl -, -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-; R represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₃ -C ₁₀ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, aryl -,heteroaryl-, -C(=O)R', -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N(R')R ", -C(=O)OR', -NH ₂ , -NHR', -N(R')R", -N(H)C(=O)R', - N(R')C(= O) R', -N(H)C(=O)NH ₂ , -N(H)C(=O)NHR', -N(H)C(=O)N(R')R",- N(R')C(=O)NH ₂ , -N(R')C(=O)NHR', -N(R')C(=O)N(R')R", -N(H ) C(=O)OR', -N(R')C(=O)OR', -NO ₂ , -N(H)S(=O)R', -N(R')S(=O R', -N(H)S(=O) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH , C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', - OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(= O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R", -S(= O) (=NR')R"group;R' and R" independently of each other represent a substituent selected from C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-; n represents 0 An integer of 1, 2, 3, 4 or 5; or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof or a mixture thereof.

According to a variant of the third embodiment of the first aspect, the invention encompasses a compound of the formula (Ia):

R1 represents a linear C ₂ -C ₅ alkyl-, branched C ₃ -C ₅ alkyl- or C ₄ -C ₆ cycloalkyl group, which, independently of one another, is optionally substituted by one or more substituents selected from the group consisting of Secondary: halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₃ -C ₁₀ Cycloalkyl, aryl-, -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N(R')R", -C(=O) OH, -C(=O)OR', -NH ₂ , -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) ₂ R', -N(R ')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', -OC(=O)N(R')R", -SH, C ₁ -C ₆ alkane Base -S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R"group; R2 means: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and independently of each other, the R3 substituent is optionally substituted once, twice, three times, four times or five times; R3 represents a substituent selected from the group consisting of : a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-; R' and R" independently of each other represent a substituent selected from C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-; or a stereoisomer, tautomer, N-oxidation thereof a hydrate, a solvate or a salt or a mixture thereof.

According to a variant of the third embodiment of the first aspect, the invention encompasses a compound of the formula (Ib):

R1 represents a linear C ₂ -C ₅ alkyl-, branched C ₃ -C ₅ alkyl- or C ₄ -C ₆ cycloalkyl group which: - independently of one another, is substituted one or more substituents selected from the group consisting of Sub:-aryl-, which are substituted one or more times by R substituents independently of one another; -heteroaryl-, independently of one another, substituted one or more times by R substituents; and - independently of each other, as appropriate Substituted one or more times by a substituent selected from the group consisting of: a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ - C ₆ alkynyl-, C ₃ -C ₁₀ cycloalkyl, aryl-, -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N(R ')R", -C(=O)OH, -C(=O)OR', -NH ₂ , -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) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', -OC(=O)N(R')R ", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O ₂ NHR', -S(=O) ₂ N(R')R"group; R2 means: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and independently of each other, the R3 substituent is optionally substituted once, twice, three times, four times or five times; R3 represents a substituent selected from the group consisting of : a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-; R represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl -, C ₃ -C ₁₀ 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', -NH ₂ , -NHR', -N(R')R", -N(H)C( =O)R', -N(R')C(=O)R', -N(H)C(=O)NH ₂ , -N(H)C(=O)NHR', -N(H C(=O)N(R')R", -N(R')C(=O)NH ₂ , -N(R')C(=O)NHR', -N(R')C( =O)N(R')R", -N(H)C(=O)OR', -N(R')C(=O)OR', -NO ₂ , -N(H)S(= O) R', -N(R')S(=O)R', -N(H)S(=O) ₂ R', -N(R')S(=O) ₂ R', -N =S(=O)(R')R", -OH, C ₁ -C ₆ alkoxy-C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O NH ₂ , -OC(=O)NHR', -OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S( =O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R" , -S(=O)(=NR')R"group;R' and R" independently of each other represent a substituent selected from C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl Or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof or a mixture thereof.

According to a fourth embodiment of the first aspect, the invention encompasses a compound of the above formula (I), wherein: R1 represents a linear C ₂ -C ₅ alkyl-, straight-chain C ₁ -C ₅ alkyl-O- straight Chain C ₁ -C ₅ alkyl-, branched C ₃ -C ₅ alkyl-, C ₄ -C ₆ cycloalkyl-, linear C ₁ -C ₆ alkyl-C ₄ -C ₆ cycloalkyl- Or a C ₄ -C ₆ cycloalkyl-C ₁ -C ₆ alkyl- group, which, independently of one another, is optionally substituted one or more times with a substituent selected from the group consisting of -NH ₂ , C ₁ -C ₆ alkyl- , C ₂ -C ₆ alkenyl-, optionally as a spiro C ₃ -C ₁₀ cycloalkyl-, optionally as a spiro 3 to 10 membered heterocycloalkyl, aryl-, independently of each other, as appropriate One or more aryl or heteroaryl groups substituted by R; Indicates: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and R3 represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl -, -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-; R represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₃ -C ₁₀ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, aryl -,heteroaryl-, -C(=O)R', -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N(R')R ", -C(=O)OR', -NH ₂ , -NHR', -N(R')R", -N(H)C(=O)R', -N(R')C(= O) R', -N(H)C(=O)NH ₂ , -N(H)C(=O)NHR', -N(H)C(=O)N(R')R",- N(R')C(=O)NH ₂ , -N(R')C(=O)NHR', -N(R')C(=O)N(R')R", -N(H ) C(=O)OR', -N(R')C(=O)OR', -NO ₂ , -N(H)S(=O)R', -N(R')S(=O R', -N(H)S(=O) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH , C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', - OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(= O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R", -S(=O (=NR')R"group;R' and R" independently of each other represent a substituent selected from C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-; n represents 0, An integer of 1, 2, 3, 4 or 5; or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof or a mixture thereof.

According to a variant of the fourth embodiment of the first aspect, the invention encompasses a compound of the formula (Ia):

R1 represents a linear C ₂ -C ₅ alkyl-, branched C ₃ -C ₅ alkyl- or C ₄ -C ₆ cycloalkyl group, which, independently of one another, is optionally substituted by one or more substituents selected from the group consisting of Secondary: C ₁ -C ₆ alkyl- or aryl-; R2 means: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and independently of each other, the R3 substituent is optionally substituted once, twice, three times, four times or five times; R3 represents a substituent selected from the group consisting of : a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-; R' and R" independently of each other represent a substituent selected from C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-; or a stereoisomer thereof, tautomer, N-oxidation thereof a hydrate, a solvate or a salt or a mixture thereof.

According to a variant of the fourth embodiment of the first aspect, the invention encompasses a compound of the formula (Ia):

R1 represents a linear C ₂ -C ₅ alkyl-, branched C ₃ -C ₅ alkyl- or C ₄ -C ₆ cycloalkyl group which: - independently of one another, is substituted one or more substituents selected from the group consisting of Sub: -aryl-, which are substituted one or more times independently of each other by an R substituent; -heteroaryl-, which, independently of one another, are optionally substituted one or more times by an R substituent; R2 represents: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and independently of each other, the R3 substituent is optionally substituted once, twice, three times, four times or five times; R3 represents a substituent selected from the group consisting of : a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-; R represents a substituent selected from the group: a halogen atom, -CN, C ₁ -C ₆ alkyl -, C ₁ -C ₆ haloalkyl -, C ₂ -C ₆ alkenyl -, C ₂ - C ₆ alkynyl group -, C ₃ -C ₁₀ 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', -NH ₂ , -NHR', -N(R')R", -N(H)C( =O)R', -N(R')C(=O)R', -N(H)C(=O)NH ₂ , -N(H)C(=O)NHR', -N(H C(=O)N(R')R", -N(R')C(=O)NH ₂ , -N(R')C(=O)NHR', -N(R')C( =O)N(R')R", -N(H)C(=O)OR', -N(R')C(=O)OR', -NO ₂ , -N(H)S(= O) R', -N(R')S(=O)R', -N(H)S(=O) ₂ R', -N(R')S(=O) ₂ R', -N =S(=O)(R')R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(= O) NH ₂ , -OC(=O)NHR', -OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R'R",-S(=O)(=NR')R"groups;R' and R" independently of each other represent a substituent selected from C ₁ -C ₆ alkyl-, C ₁ -C ₆ Haloalkyl-; or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof or a mixture thereof.

According to a fifth embodiment of the first aspect, the invention encompasses a compound of the above formula (I), wherein: R1 represents a linear C ₂ -C ₅ alkyl-, straight-chain C ₁ -C ₅ alkyl-O- straight Chain C ₁ -C ₅ alkyl-, branched C ₃ -C ₅ alkyl-, C ₄ -C ₆ cycloalkyl-, linear C ₁ -C ₆ alkyl-C ₄ -C ₆ cycloalkyl- Or a C ₄ -C ₆ cycloalkyl-C ₁ -C ₆ alkyl- group which, independently of one another, is optionally substituted one or more times with a substituent selected from the group consisting of -NH ₂ , C ₂ -C ₆ alkenyl- , optionally, C ₃ -C ₁₀ cycloalkyl-, optionally 3 to 10 membered heterocycloalkyl, aryl-, optionally substituted by R, one or more times, depending on the case Base or heteroaryl-; Indicates: a group; wherein * indicates a point of attachment of the group to the rest of the molecule; and R3 represents a substituent selected from the group consisting of a halogen atom, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkyl group; Substituents selected from the group consisting of halogen atoms; n represents an integer of 0 or 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof or a mixture thereof.

According to a variant of the fifth embodiment of the first aspect, the invention encompasses a compound of the formula (Ia):

R1 represents a linear C ₂ -C ₅ alkyl-, branched C ₃ -C ₅ alkyl- or C ₄ -C ₆ cycloalkyl group, which, independently of one another, is optionally substituted by one or more substituents selected from the group consisting of Times: aryl-; R2 means: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and it is optionally substituted once by the R3 substituent; R3 represents a substituent selected from the group consisting of a halogen atom, a C ₁ -C ₆ alkoxy group; Its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts or mixtures thereof.

According to a variant of the fifth embodiment of the first aspect, the invention encompasses a compound of the formula (Ia): R1 represents a linear C ₂ -C ₅ alkyl-, branched C ₃ -C ₅ alkyl- or C ₄ -C ₆ cycloalkyl group which: - independently of one another, is substituted one or more substituents selected from the group consisting of Sub: -aryl-, which are substituted one or more times independently of each other by an R substituent; -heteroaryl-, which, independently of one another, are optionally substituted one or more times by an R substituent; R2 represents: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and it is optionally substituted once by the R3 substituent; R3 represents a substituent selected from the group consisting of a halogen atom, a C ₁ -C ₆ alkoxy group; Represents a substituent selected from the group consisting of: a halogen atom, a C ₁ -C ₆ haloalkyl-, a C ₁ -C ₆ alkoxy group; or a stereoisomer, tautomer, N-oxide, hydrate thereof , solvates or salts or mixtures thereof.

In another embodiment, the invention encompasses a compound of the above formula (I) wherein: R1 represents a linear C ₂ -C ₆ alkyl-, linear C ₁ -C ₆ alkyl-O-straight C ₁ - C ₆ alkyl-, branched C ₃ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl-, linear C ₁ -C ₆ alkyl-C ₃ -C ₆ cycloalkyl- or C ₃ - C ₆ cycloalkyl-linear C ₁ -C ₆ alkyl-, which, independently of one another, is optionally substituted one or more times with a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl- , C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, optionally as a spiro C ₃ -C ₁₀ cycloalkyl-, optionally linked to a snail 3 to 10 membered heterocycloalkyl, aryl-, aryl, heteroaryl-, -C(=O)NH ₂ , -C(=O), which are substituted one or more times by R, as the case may be. N(H)R', -C(=O)N(R')R", -C(=O)OH, -C(=O)OR', -NH ₂ , -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) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R') R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O NHR', -OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R ', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R" group.

In another embodiment, the invention encompasses a compound of the above formula (I) wherein: Indicates: a group; wherein * indicates the point of attachment of the group to the rest of the molecule.

In another embodiment, the present invention encompasses a compound of the formula (the I), wherein: R3 represents a substituent selected from the group: a halogen atom, -CN, C ₁ -C ₆ alkyl -, C ₁ -C ₆ halo Alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, -C(=O)R', -C(=O)NH ₂ , -C(=O)N(H) R', -C(=O)N(R')R", -NH ₂ , -NHR', -N(R')R", -N(H)C(=O)R', -N( R')C(=O)R', -N(H)C(=O)NH ₂ , -N(H)C(=O)NHR', -N(H)C(=O)N(R ')R", -N(R')C(=O)NH ₂ , -N(R')C(=O)NHR', -N(R')C(=O)N(R')R ", -N(H)C(=O)OR', -N(R')C(=O)OR', -NO ₂ , -N(H)S(=O)R', -N(R ')S(=O)R', -N(H)S(=O) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R'R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -SH, C ₁ -C ₆ alkyl-S- , -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R ') R", -S(=O)(=NR')R" groups.

In another embodiment, the invention encompasses a compound of the above formula (I), wherein: R' and R" independently of one another represent a substituent selected from C ₁ -C ₆ alkyl-, C ₁ -C ₆ Haloalkyl-.

In another embodiment, the invention encompasses a compound of the above formula (I) wherein: n represents an integer of 0, 1, 2, 3, 4 or 5.

In another embodiment, the present invention encompasses a compound of the formula (the I), wherein: R3 represents a substituent selected from the group: a halogen atom, -CN, C ₁ -C ₆ alkyl -, C ₁ -C ₆ halo alkyl _{-, - OH, C 1 -C} 6 alkoxy -, C ₁ -C ₆ haloalkoxy -.

In another embodiment, the present invention encompasses a compound of the formula (the I), wherein: R represents a substituent selected from the group: a halogen atom, -CN, C ₁ -C ₆ alkyl -, C ₁ -C ₆ halo Alkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₃ -C ₁₀ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, aryl-, heteroaryl- , -C(=O)R', -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N(R')R", -C(= O) OR', -NH ₂ , -NHR', -N(R')R", -N(H)C(=O)R', -N(R')C(=O)R',- N(H)C(=O)NH ₂ , -N(H)C(=O)NHR', -N(H)C(=O)N(R')R", -N(R')C (=O)NH ₂ , -N(R')C(=O)NHR', -N(R')C(=O)N(R')R", -N(H)C(=O) OR', -N(R')C(=O)OR', -NO ₂ , -N(H)S(=O)R', -N(R')S(=O)R', -N (H)S(=O) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C ₁ -C ₆ Alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', -OC(=O)N (R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R", -S(=O)(=NR')R" groups.

In another embodiment, the invention encompasses a compound of the above formula (I), wherein: R represents a substituent selected from the group consisting of halogen atoms.

In another embodiment, the invention encompasses a compound of the above formula (I) wherein: R1 represents a linear C ₂ -C ₅ alkyl-, linear C ₁ -C ₅ alkyl-O-straight C ₁ - C ₅ alkyl-, branched C ₃ -C ₅ alkyl-, C ₄ -C ₆ cycloalkyl-, linear C ₁ -C ₆ alkyl-C ₄ -C ₆ cycloalkyl- or C ₄ - C ₆ cycloalkyl-linear C ₁ -C ₆ alkyl-, which, independently of one another, is optionally substituted one or more times with a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl- , C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, optionally as a spiro C ₃ -C ₁₀ cycloalkyl-, optionally linked to a snail 3 to 10 membered heterocycloalkyl, aryl-, aryl, heteroaryl-, -C(=O)NH ₂ , -C(=O), which are substituted one or more times by R, as the case may be. N(H)R', -C(=O)N(R')R", -C(=O)OH, -C(=O)OR', -NH ₂ , -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) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R') R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O NHR', -OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R" group.

In another embodiment, the invention encompasses a compound of the above formula (I) wherein: R1 represents a linear C ₂ -C ₅ alkyl-, linear C ₁ -C ₅ alkyl-O-straight C ₁ - C ₅ alkyl-, branched C ₃ -C ₅ alkyl-, C ₄ -C ₆ cycloalkyl-, linear C ₁ -C ₆ alkyl-C ₄ -C ₆ cycloalkyl- or C ₄ - C ₆ cycloalkyl-C ₁ -C ₆ alkyl-, which, independently of one another, is optionally substituted one or more times with a substituent selected from the group consisting of -NH ₂ , C ₁ -C ₆ alkyl-, C ₂ - C ₆ alkenyl-, optionally C ₃ -C ₁₀ cycloalkyl-, optionally 3 to 10 membered heterocycloalkyl, aryl-, optionally substituted by R, independently of each other Or multiple aryl or heteroaryl-.

In another embodiment, the invention encompasses a compound of the above formula (I) wherein: R1 represents a linear C ₂ -C ₅ alkyl-, linear C ₁ -C ₅ alkyl-O-straight C ₁ - C ₅ alkyl-, branched C ₃ -C ₅ alkyl-, C ₄ -C ₆ cycloalkyl-, linear C ₁ -C ₆ alkyl-C ₄ -C ₆ cycloalkyl- or C ₄ - C ₆ cycloalkyl-C ₁ -C ₆ alkyl-, which, independently of one another, is optionally substituted one or more times with a substituent selected from the group consisting of -NH ₂ , C ₂ -C ₆ alkenyl-, optionally linked a C ₃ -C ₁₀ cycloalkyl-, optionally, 3 to 10 membered heterocycloalkyl, aryl-, optionally substituted aryl or heteroaryl, as the case may be, substituted by R, one or more times. base-.

In another embodiment, the invention encompasses a compound of the above formula (I), wherein: R3 represents a substituent selected from the group consisting of a halogen atom, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkyl group - .

In another embodiment, the invention encompasses a compound of formula (I) above, wherein: n represents an integer of 0 or 1.

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

Wherein: R1 represents a linear C ₂ -C ₆ alkyl-, branched C ₃ -C ₆ alkyl- or C ₃ -C ₆ cycloalkyl group, which, independently of one another, is optionally substituted with a substituent selected from the group consisting of Or multiple times: halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₃ - C ₁₀ cycloalkyl, aryl-, -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N(R')R", -C(= O) OH, -C(=O)OR', -NH ₂ , -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) ₂ R', -N (R')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy -, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', -OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(= O) ₂ N(R')R" group.

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

Wherein: R1 represents a linear C ₂ -C ₆ alkyl- group which, independently of one another, is optionally substituted one or more times with a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C _1- C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₃ -C ₁₀ cycloalkyl, aryl-, -C(=O)NH ₂ ,- C(=O)N(H)R', -C(=O)N(R')R", -C(=O)OH, -C(=O)OR', -NH ₂ , -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) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O (R')R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', -OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(= O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R" group.

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

Wherein: R1 represents a C ₃ -C ₆ cycloalkyl group which, independently of one another, is optionally substituted one or more times with a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ - C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₃ -C ₁₀ cycloalkyl, aryl-, -C(=O)NH ₂ , -C( =O)N(H)R', -C(=O)N(R')R", -C(=O)OH, -C(=O)OR', -NH ₂ , -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) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)( R')R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC (=O)NHR', -OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R" group.

In another embodiment, the invention encompasses a compound of formula (Ia):

Where: R2 means: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and independently of one another, the R3 substituent is optionally substituted once, twice, three times, four times or five times.

In another embodiment, the invention encompasses a compound of formula (Ia):

Wherein: R3 represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ Alkynyl-, -C(=O)R', -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N(R')R",- NH ₂ , -NHR', -N(R')R", -N(H)C(=O)R', -N(R')C(=O)R', -N(H)C( =O)NH ₂ , -N(H)C(=O)NHR', -N(H)C(=O)N(R')R", -N(R')C(=O)NH ₂ , -N(R')C(=O)NHR', -N(R')C(=O)N(R')R", - N(H)C(=O)OR', -N( R')C(=O)OR', -NO ₂ , -N(H)S(=O)R', -N(R')S(=O)R', -N(H)S(= O) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C ₁ -C ₆ alkoxy-, C _1- C ₆ haloalkoxy-, -OC(=O)R', -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R ', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R", -S(=O)(=NR')R" The groups; R' and R" independently of each other represent a substituent selected from C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-.

In another embodiment, the invention encompasses a compound of formula (Ia):

Wherein: R3 represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, -OH, C ₁ -C ₆ alkoxy-, C _1- C ₆ haloalkoxy-.

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

Wherein: R1 represents a linear C ₂ -C ₅ alkyl-, branched C ₃ -C ₅ alkyl- or C ₄ -C ₆ cycloalkyl group, which, independently of one another, is optionally substituted with a substituent selected from the group consisting of Or multiple times: halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₃ - C ₁₀ cycloalkyl, aryl-, -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N(R')R", -C(= O) OH, -C(=O)OR', -NH ₂ , -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) ₂ R', -N (R')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy -, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', -OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(= O) ₂ N(R')R" group.

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

Wherein: R1 represents a linear C ₂ -C ₅ alkyl-, branched C ₃ -C ₅ alkyl- or C ₄ -C ₆ cycloalkyl group, which, independently of one another, is optionally substituted with a substituent selected from the group consisting of Or multiple times: C ₁ -C ₆ alkyl- or aryl-.

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

Wherein: R1 represents a linear C ₂ -C ₅ alkyl-, branched C ₃ -C ₅ alkyl- or C ₄ -C ₆ cycloalkyl group, which, independently of one another, is optionally substituted with a substituent selected from the group consisting of Or multiple times: aryl-.

In another embodiment, the invention encompasses a compound of formula (Ia):

Where: R2 means: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and it is optionally substituted once with the R3 substituent.

In another embodiment, the invention encompasses a compound of formula (Ia):

Wherein: R3 represents a substituent selected from the group consisting of a halogen atom and a C ₁ -C ₆ alkoxy group.

In another embodiment, the invention encompasses a compound of the above formula (I) or formula (Ia) according to any of the above mentioned examples:

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

In another embodiment, the invention encompasses a compound of formula (Ib):

Wherein: R1 represents a linear C ₂ -C ₆ alkyl-, branched C ₃ -C ₆ alkyl- or C ₃ -C ₆ cycloalkyl group: which: - independently of one another, is substituted with a substituent selected from the group consisting of Or multiple times: -aryl-, which are substituted one or more times by R substituents independently of each other; -heteroaryl-, which, independently of one another, are substituted one or more times by R substituents; and: - Alternately, one or more substituents are optionally substituted with a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl- , C ₂ -C ₆ alkynyl-, C ₃ -C ₁₀ cycloalkyl, aryl-, -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O N(R')R", -C(=O)OH, -C(=O)OR', -NH ₂ , -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) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C ₁ -C ₆ alkane Oxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', -OC(=O)N( R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ ,- S(=O) ₂ NHR', -S(=O) ₂ N(R')R" groups.

In another embodiment, the invention encompasses a compound of formula (Ib):

Where: R2 means: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and independently of one another, the R3 substituent is optionally substituted once, twice, three times, four times or five times.

In another embodiment, the invention encompasses a compound of formula (Ib):

Wherein: R3 represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ Alkynyl-, -C(=O)R', -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N(R')R",- NH ₂ , -NHR', -N(R')R", -N(H)C(=O)R', -N(R')C(=O)R', -N(H)C( =O)NH ₂ , -N(H)C(=O)NHR', -N(H)C(=O)N(R')R", -N(R')C(=O)NH ₂ , -N(R')C(=O)NHR', -N(R')C(=O)N(R')R", -N(H)C(=O)OR', -N( R')C(=O)OR', -NO ₂ , -N(H)S(=O)R', -N(R')S(=O)R', -N(H)S(= O) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C ₁ -C ₆ alkoxy-, C _1- C ₆ haloalkoxy-, -OC(=O)R', -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R ', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R", -S(=O)(=NR')R" Group.

In another embodiment, the invention encompasses a compound of formula (Ib):

Wherein: R represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ Alkynyl-, C ₃ -C ₁₆ 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', -NH ₂ , -NHR', -N(R')R", -N(H) C(=O)R', -N(R')C(=O)R', -N(H)C(=O)NH ₂ , -N(H)C(=O)NHR', -N (H)C(=O)N(R')R", -N(R')C(=O)NH ₂ , -N(R')C(=O)NHR', -N(R') C(=O)N(R')R", -N(H)C(=O)OR', -N(R')C(=O)OR', -NO ₂ , -N(H)S (=O)R', -N(R')S(=O)R', -N(H)S(=O) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC (=O)NH ₂ , -OC(=O)NHR', -OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O) R', -S(=O) ₂ R', - S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R", -S (=O)(=NR')R" group.

In another embodiment, the invention encompasses a compound of formula (Ib):

Wherein: R' and R" independently of each other represent a substituent selected from the group consisting of C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-.

In another embodiment, the invention encompasses a compound of formula (Ib):

Wherein: R3 represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, -OH, C ₁ -C ₆ alkoxy-, C _1- C ₆ haloalkoxy-.

In another embodiment, the invention encompasses a compound of formula (Ib):

Wherein: R1 represents a linear C ₂ -C ₅ alkyl-, branched C ₃ -C ₅ alkyl- or C ₄ -C ₆ cycloalkyl group, which: - is independently substituted with one another selected from the group consisting of the following substituents Or multiple times: -aryl-, which are substituted one or more times by R substituents independently of each other; -heteroaryl-, independently of one another, optionally substituted by R substituents one or more times; and - independently of each other Substituting one or more substituents with a substituent selected from the group consisting of: a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₃ -C ₁₀ cycloalkyl, aryl-, -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N (R')R", -C(=O)OH, -C(=O)OR', -NH ₂ , -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) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C ₁ -C ₆ alkoxy -, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', -OC(=O)N(R'R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S( =O) ₂ NHR', -S(=O) ₂ N(R')R" groups.

In another embodiment, the invention encompasses a compound of formula (Ib):

Wherein: R1 represents a linear C ₂ -C ₅ alkyl-, branched C ₃ -C ₅ alkyl- or C ₄ -C ₆ cycloalkyl group: which: - independently of one another, is substituted with a substituent selected from the group consisting of Or multiple times: -aryl-, which are substituted one or more times independently of one another by an R substituent; -heteroaryl-, which, independently of one another, are optionally substituted one or more times with an R substituent.

In another embodiment, the invention encompasses a compound of formula (Ib):

Wherein: R3 represents a substituent selected from the group consisting of a halogen atom and a C ₁ -C ₆ alkoxy group.

In another embodiment, the invention encompasses a compound of formula (Ib):

Wherein: R represents a substituent selected from the group consisting of a halogen atom, a C ₁ -C ₆ haloalkyl-, a C ₁ -C ₆ alkoxy group.

It will be understood that the invention relates to any subcombination of any of the embodiments or aspects of the invention of the above formula (I).

It is further understood that the present invention relates to any subcombination of any of the embodiments or aspects of the invention of the above formula (I) or formula (Ia).

More specifically, the invention encompasses compounds of formula (I) as disclosed herein below in the Examples section.

According to another aspect, the invention encompasses methods of preparing the compounds of formula (I) of the invention, which comprise the steps as described in the experimental section herein.

According to an embodiment, the invention encompasses a process for the preparation of a compound of the formula (I) according to the invention, which process comprises the step of bringing an intermediate compound of the 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 such as a chlorine, bromine or iodine atom; or a perfluoroalkyl sulfonate group such as trifluoro a methylsulfonate group or a nonafluorobutyl sulfonate group, reacted with a compound of the formula (III): Wherein R1 is as defined above for the compound of formula (I), whereby a compound of formula (I) is obtained:

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

According to an embodiment, the invention encompasses a process for the preparation of a compound of the formula (Ia) according to the invention, which comprises the step of bringing an intermediate compound of the 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, such as a chlorine, bromine or iodine atom; or a perfluoroalkyl sulfonate group, such as trifluoromethanesulfonic acid An ester group or a nonafluorobutyl sulfonate group, reacted with a compound of the formula (III): Wherein R1 is as defined above for the compound of formula (Ia), whereby a compound of formula (Ia) is obtained:

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

According to an embodiment, the invention encompasses a process for the preparation of a compound of the formula (Ib) according to the invention, which comprises the step of bringing an intermediate compound of the 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, such as a chlorine, bromine or iodine atom; or a perfluoroalkyl sulfonate group, such as trifluoromethanesulfonic acid Ester group or nonafluorobutyl sulfonate group, reacted with a compound of the formula (IIIb): Wherein R1 is as defined above for the compound of formula (I), whereby a compound of formula (Ib) is obtained:

Wherein R1 and R2 are as defined above for the compound of formula (Ib).

According to another aspect, the invention encompasses intermediate compounds which are suitable for use in the preparation of the compounds of the invention of formula (I) or formula (Ia), especially for use in the methods described herein. In particular, the invention encompasses a compound of 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 such as a chlorine, bromine or iodine atom; or a perfluoroalkyl sulfonate group such as trifluoro a methylsulfonate group or a nonafluorobutyl sulfonate group, and a compound of the 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, such as a chlorine, bromine or iodine atom; or a perfluoroalkyl sulfonate group, such as trifluoromethanesulfonic acid Ester group, and - compound of the 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, such as a chlorine, bromine or iodine atom; or a perfluoroalkyl sulfonate group, such as trifluoromethanesulfonic acid Ester group.

According to another aspect, the invention encompasses the use of an intermediate compound of formula (V):

Wherein A, R3 and n are as defined above for the compound of formula (I) and X represents the departure a group such as a halogen atom such as a chlorine, bromine or iodine atom; or a perfluoroalkyl sulfonate group such as a trifluoromethylsulfonate group or a nonafluorobutyl sulfonate group, which is used for the preparation as described above A compound of the formula (I) as defined.

According to another aspect, the invention encompasses the use of an intermediate compound of 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, such as a chlorine, bromine or iodine atom; or a perfluoroalkyl sulfonate group, such as trifluoromethanesulfonic acid An ester group which is used to prepare a compound of the formula (Ia) as defined above.

According to another aspect, the invention encompasses the use of an intermediate compound of the 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, such as a chlorine, bromine or iodine atom; or a perfluoroalkyl sulfonate group, such as trifluoromethanesulfonic acid An ester group which is used to prepare a compound of formula (I) as defined above.

Experimental part

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

Synthesis of compounds (review):

The compounds of the invention can be prepared as described in the following sections. Scheme 1 and procedures described below illustrate the general synthetic route of the compounds of formula (I) of the present invention and are not intended to be limiting. It will be apparent to those skilled in the art that the order of transformation as exemplified in Scheme 1 can be adjusted in a number of ways. Therefore, the order of transformations exemplified in Scheme 1 is not intended to be limiting. Additionally, the interconversion of any of the substituents R1 and R2 can be achieved before and/or after the exemplified conversion. Such modifications may be, for example, introduction of a protecting group, cleavage of a protecting group, exchange, reduction or oxidation of a functional group, halogenation, metallation, substitution or other reaction known to those skilled in the art. Such transformations include the introduction of a conversion of a functional group that allows for further interconversion of the substituents. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, T. W. Greene and P. G. M. Wuts, Protective Groups in Organic). Synthesis, 3rd edition, Wiley 1999). Specific examples are described in subsequent paragraphs. Additionally, as is well known to those skilled in the art, two or more consecutive steps may be performed without processing between such steps, such as a "one pot" reaction.

Wherein R1, R3, A and n are as defined above for the compound of formula (I), and X and Y represent a leaving group such as a halogen atom, such as a chlorine, bromine or iodine atom; or a perfluoroalkyl sulfonate group. For example, a trifluoromethylsulfonate group or a nonafluorobutyl sulfonate group.

In the first step, a compound of formula A (i.e., a dichloropurine carrying a substituent suitable for X) ) Aqueous ammonia may be reacted at elevated temperature and pressure to give the compound of general formula B. [Similar to WO200733080, which is hereby incorporated by reference in its entirety herein.

In a second step, a compound of the formula B is reacted, for example, with a chloro-acetaldehyde diacetal or a bromo-acetaldehyde diacetal to give a bicyclic system C [similar to DE 10 2006 029 447, which is hereby incorporated by reference in its entirety. in].

The bicyclic ring system of 3 to give the activated D of the compound of the formula may be, for example, by separately using N- bromo - iodo butylene or N- (PEI) - butadiene (PEI) reacting a compound of general formula C brominating or iodinating to realise.

In a fourth step, the introduction of residue A-[R3] _n can be carried out using a suitably catalyzed cross-coupling reaction, for example This is achieved by an acid or a stannane which produces a compound of the formula E.

The compound of formula E acts as a central intermediate for the introduction of a plurality of side chains containing an alcohol functional group which produces an imidazolium of the formula F. Ether. The 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 operate these reactions at elevated temperatures. It may also be desirable to introduce a side chain decorated with a suitable protecting group on the functional group that can interfere with the desired reaction.

The fourth and fifth steps of the sequence are also interchangeable.

According to an embodiment, the invention also relates to a process for the preparation of a compound of the formula (I) as defined above, which process comprises the step of: bringing an intermediate compound of the 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, such as a chlorine, bromine or iodine atom; or a perfluoroalkyl sulfonate group, such as a trifluoromethyl group. a sulfonate group, a nonafluorobutyl sulfonate group, reacted with a compound of the formula (III): Wherein R1 is as defined above for the compound of formula (I), whereby a compound of formula (I) is obtained:

Wherein R1, R3, A and n are as defined above.

General part

Chemical names were generated using ACD/Name Batch version 12.01.

HPLC method: method 1:

Apparatus: Waters Acquity UPLCMS ZQ4000; Column: Acquity UPLC BEH C18 1.7 μm, 50 x 2.1 mm; Dissolve A: Water + 0.05 vol% formic acid, Eluent B: Acetonitrile + 0.05 vol% formic acid, Gradient: 0-1.6 min 1-99% B, 1.6-2.0 minutes 99% B; flow rate: 0.8 ml/min; temperature: 60 ° C; injection: 2 μL; DAD scan: 210-400 nm; ELSD

Method 2:

Apparatus: Waters Acquity UPLCMS SQD 3001; Column: Acquity UPLC BEH C18 1.7 μm, 50 x 2.1 mm; Eluent A: Water + 0.1% by volume formic acid (95%), Eluent B: Acetonitrile, Gradient: 0-1.6 min 1-99% B, 1.6-2.0 minutes 99% B; flow rate: 0.8 ml/min; temperature: 60 ° C; injection: 2 μL; DAD scan: 210-400 nm; ELSD

Method 3:

Apparatus: Waters Acquity UPLCMS SQD; Column: Acquity UPLC BEH C18 1.7 μm, 50 x 2.1 mm; Eluent A: Water + 0.05 vol% formic acid (95%), Eluent B: Acetonitrile + 0.05 vol% formic acid (95%) ), gradient: 0-1.6 minutes 1-99% B, 1.6-2.0 minutes 99% B; flow rate: 0.8 ml/min; temperature: 60 ° C; injection: 2 μL; DAD scan: 210-400 nm; ELSD

Intermediate Intermediate 1

3-bromo-6-chloro-imidazo[1,2- b ]嗒

3-bromo-6-chloro-imidazo[1,2- b ]嗒 It is synthesized as described, for example, in WO 2007/147646 or DE 10 2006 029447, for example as follows:

Step 1: Preparation of 6-chloroimidazo[1,2- b ]嗒 :

5.0 g (38.6 mmol) of 3-amino-6-chloropurine in 15 mL of n-butanol at 120 °C Heated with 4.7 mL (40 mmol) of chloroacetaldehyde (55% strength in water) for a period of 5 days. After the reaction was completed, the reaction mixture was added to a saturated aqueous sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with a saturated sodium chloride solution and dried over sodium sulfate and solvent was evaporated in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70%) of the desired product was isolated as an amorphous white solid.

¹ H-NMR (CDCl ₃ , stored on molecular sieves): δ [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 ]嗒

478 mg (3.11 mmol) of 6-chloroimidazo[1,2-b]嗒 under argon It was introduced into 10 mL of chloroform and simultaneously cooled in ice, and 664 mg (3.73 mmol) of N -bromosuccinimide was added. After the addition was completed, the reaction mixture was stirred at room temperature overnight. The reaction mixture was then mixed with water and ethyl acetate, and after addition of saturated sodium bicarbonate solution, the phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were then washed with a saturated sodium chloride solution and dried over sodium sulfate. The desired product, in the form of an amorphous white solid, which was used in the subsequent reaction without purification by further chromatography, was isolated in a quantitative yield.

¹ H-NMR (CDCl ₃ , stored on molecular sieves): δ [ppm] = 7.12 (1H); 7.79 (1H); 7.90, (1H) ppm.

Intermediate 2

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

13.9 g (59.8 mmol) of 3-bromo-6-chloro-imidazo[1,2-b]indole Suspended in 508 mL of 1,4-dioxane. Add 10.1 g (62.8 mmol) of 2-benzofuranyl Acid, 2.76 g (2.29 mmol) of ruthenium (triphenylphosphine) palladium- (0) and 19.0 g (179 mmol) of sodium carbonate. The resulting mixture was heated to 100 ° C for 24 hours.

Add 400 mL of saturated aqueous ammonium chloride solution. The obtained mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. After evaporating the solvent, the obtained solid material was taken in a 40 mL mixture of dichloromethane and methanol (8:2), filtered, and dried in vacuo to give 5.42 g (44%) Compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [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 = 1.35 minutes; MS (ESI +) m / z = 270 [M + H] +.

Intermediate 3

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

6-chloro-3-(4-methoxy-1-benzofuran-2-yl)imidazo[1,2- b ]嗒 Prepared analogously to Intermediate 2 with 1.68 g (7.22 mmol) of Intermediate 1 to afford 43% solid.

¹ H-NMR (300 MHz, DMSO-d6), δ [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 = 1.31 minutes; MS (ESI +) m / z = 300 [M + H] +.

Intermediate 4

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

6-chloro-3-(5-methoxy-1-benzofuran-2-yl)imidazo[1,2- b ]嗒 Prepared analogously to Intermediate 2 with 1.74 g (7.5 mmol) of Intermediate 1 to afford 45% solid material.

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 1.29 minutes; MS (ESI +) m / z = 300 [M + H] +.

Intermediate 5

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

6-chloro-3-(6-methoxy-1-benzofuran-2-yl)imidazo[1,2-b]indole Prepared analogously to Intermediate 2 using 1.68 g (7.2 mmol) Intermediate 1 to afford 53% solid material.

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 1.30 minutes; MS (ESI +) m / z = 300 [M + H] +.

Intermediate 6

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

6-chloro-3-(3-methyl-1-benzofuran-2-yl)imidazo[1,2- b ]indole Prepared analogous to Intermediate 2 with 174 mg (0.75 mmol) Intermediate 1 as a starting material to afford 24% solid material.

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 1.30 minutes; MS (ESI +) m / z = 300 [M + H] +.

Intermediate 7

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

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

Carefully add methanol and evaporate the solvent. The residue obtained was purified by flash chromatography eluting elut elut elut elut

In an inert atmosphere, stir 506 mg (2.2 mmol) of intermediate 1 in 1 mL of THF at 85 ° C in a sealed pressure tube, 1 g (2.3 mmol) of crude 2-stannylbenzofuran, 41 mg (0.22) Methyl) copper (I) iodide and 76 mg (0.11 mmol) of bis(triphenylphosphine)palladium(II) chloride overnight. The solvent was evaporated, and the obtained solid was taken up in methanol and filtered. The solid residue was subjected to flash chromatography to give 289 mg (39%)

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ [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 = 1.29 minutes; MS (ESI +) m / z = 300 [M + H] +.

Intermediate 10

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

6-chloro-3-(5-fluoro-1-benzofuran-2-yl)imidazo[1,2- b ]indole Prepared analogously to intermediate 7 using 513 mg (2.21 mmol) of Intermediate 1 to afford a solid material.

LCMS (Method 2): R _t = 1.34 minutes; MS (ESI +) m / z = 288 [M + H] +.

Intermediate 11

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

6-chloro-3-(3-chloro-1-benzofuran-2-yl)imidazo[1,2- b ]嗒 Prepared analogously to intermediate 7 using 219 mg (0.94 mmol) Intermediate 1 to afford 62% solid material.

LCMS (Method 2): R _t = 1.38 minutes; MS (ESI +) m / z = 304 [M + H] +.

Intermediate 12

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

6-chloro-3-(4-fluoro-1-benzofuran-2-yl)imidazo[1,2- b ]indole Prepared analogously to intermediate 7 using 921 mg (3.96 mmol) of Intermediate 1 to afford 929 mg of material as crude material.

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [ppm] = 7.09-7.23 (1H), 7.32 - 7.45 (1H), 7.55 (3H), 8.41 (2H).

LCMS (Method 3): R _t = 1.42 minutes; MS (ESI +) m / z = 288 [M + H] +.

Intermediate 13

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

6-chloro-3-(5-chloro-1-benzofuran-2-yl)imidazo[1,2- b ]嗒 Prepared analogously to intermediate 7 using 2.34 g (10.1 mmol) of Intermediate 1 to afford 2.73 g of solid material which was used as crude material.

LCMS (Method 3): R _t = 1.00 minutes; MS (ESI +) m / z = 304 [M + H] +.

Intermediate 14

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

6-chloro-3-(7-fluoro-1-benzofuran-2-yl)imidazo[1,2- b ]嗒 Prepared analogously to intermediate 7 using 1.0 g (4.31 mmol) of Intermediate 1 to afford 918 mg of solid material which was used as crude material.

LCMS (Method 3): R _t = 1.39 minutes; MS (ESI +) m / z = 288 [M + H] +.

Intermediate 15

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

6-chloro-3-(5-methyl-1-benzofuran-2-yl)imidazo[1,2-b]indole Prepared analogously to intermediate 7 using 2.7 g (11.6 mmol) of Intermediate 1 to afford 2.61 g of solid material which was used as crude material.

LCMS (Method 2): R _t = 1.45 minutes; MS (ESI +) m / z = 284 [M + H] +.

Instance Example 1

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

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

The reaction mixture was carefully poured into a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated.

The crude product was purified by HPLC to afford 50 mg of titled

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.80 minutes; MS (ESI +) m / z = 353 [M + H] +.

Example 2

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

44.5 mg (1.12 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 5 mL of anhydrous THF in an ice bath. 91.6 mg (0.742 mmol) of trans- 3-aminocyclobutan-1-ol (hydrochloride) was added slowly. Stirring was continued for 15 minutes at 0 °C. 100 mg (0.371 mmol) of Intermediate 2 was added , the ice bath was removed, and the resulting mixture was stirred at 40 ° C 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 with MgSO4 and evaporated.

The crude product was purified by HPLC to give 32 mg of titled

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.73 minutes; MS (ESI +) m / z = 321 [M + H] +.

Example 3

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

In an ice bath, 18.2 mg (0.457 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 4.3 mL of anhydrous THF. 64.2 mg (0.519 mmol) of cis- 3-aminocyclobutan-1-ol (hydrochloride) was added slowly. Stirring was continued for 15 minutes at 0 °C. 70 mg (0.260 mmol) of Intermediate 2 was added , the ice bath was removed, and the mixture was stirred at 40 ° C 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 with MgSO4 and evaporated.

The crude product was purified by flash chromatography to give 36 mg as a solid material. Compound.

¹ H-NMR (300 MHz, DMSO-d6), δ [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 = 0.72 minutes; MS (ESI +) m / z = 321 [M + H] +.

Example 4

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

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

The reaction mixture was carefully poured into a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated.

The crude product was purified by HPLC to give 54 mg, m.

^t H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.74 minutes; MS (ESI +) m / z = 339 [M + H] +.

Example 5

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

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

The reaction mixture was carefully poured into a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated.

The crude product was purified by HPLC to afford 49 mg of the title material.

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.73 minutes; MS (ESI +) m / z = 325 [M + H] +.

Example 6

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

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

The reaction mixture was carefully poured into a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated.

The crude product was purified by HPLC to give 14 mg of title titled

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 1.02 minutes; MS (ESI +) m / z = 325 [M + H] +.

Example 7

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

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

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

The crude product was purified by EtOAc to afford titled:

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.75 minutes; MS (ESI +) m / z = 309 [M + H] +.

Example 8

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

In an ice bath, 18.3 mg (0.457 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 3.5 mL THF. 47.2 mg (0.519 mmol) of 4-amino-butan-1-ol was added slowly. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. 70.0 mg (0.26 mmol) of Intermediate 2 was added , the ice bath was removed, and the mixture was stirred at room temperature for 16 hours.

The reaction mixture was carefully poured into a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated.

The crude product was purified by EtOAc (EtOAc):

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.79 minutes; MS (ESI +) m / z = 323 [M + H] +.

Example 9

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

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

The reaction mixture was carefully poured into a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated.

The crude product was purified by HPLC to afford 47 mg of titled

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 1.08 minutes; MS (ESI +) m / z = 339 [M + H] +.

Example 10

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

In an ice bath, 26.1 mg (0.653 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 5 mL anhydrous THF. 78.1 mg (0.742 mmol) of 4-amino-2-methylbutan-2-ol was added slowly. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. 100.0 mg (0.371 mmol) of Intermediate 2 was added , the ice bath was removed, and the mixture was stirred at room temperature for 96 hours.

The reaction mixture was carefully poured into a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated.

The crude product was purified by HPLC to afford 2 mg of title titled

^t H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.98 minutes; MS (ESI +) m / z = 337 [M + H] +.

Example 11

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

In an ice bath, 18.3 mg (0.457 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 3.5 mL of anhydrous THF. 39.8 mg (0.519 mmol) of 3-amino-propan-1-ol was added slowly. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. 70.0 mg (0.26 mmol) of Intermediate 2 was added , the ice bath was removed, and the mixture was stirred at room temperature for 18 hours.

The reaction mixture was carefully poured into a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated.

The crude product was purified by HPLC to give 54 mg, m.

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.75 minutes; MS (ESI +) m / z = 309 [M + H] +.

Example 12

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

10.4 mg (0.261 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 2 mL of anhydrous THF in an ice bath. 18.5 mg (0.297 mmol) of 2-aminoethyl-1-ol was added slowly. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. 40.0 mg (0.148 mmol) of Intermediate 2 was added , the ice bath was removed, and the mixture was stirred at room temperature for 17 hours.

The reaction mixture was carefully poured into a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate/methanol (9:1). The combined organic layers were dried with MgSO4 and evaporated.

The crude product (90 mg) was dissolved in dichloromethane and a trace of methanol was added. The mixture was extracted with water, dried over magnesium sulfate and evaporated

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.72 minutes; MS (ESI +) m / z = 295 [M + H] +.

Example 13

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

In an ice bath, 479 mg (12 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 75 mL of anhydrous THF. 600 mg (8 mmol) of ( 2R )-1-aminopropan-2-ol was added slowly. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. 1.08 g (4 mmol) of Intermediate 2 was added , the ice bath was removed, and the mixture was stirred at 40 ° C for 16 hours.

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

The crude product was purified by flash chromatography to afford 387 mg of titled

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ [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 = 0.76 minutes; MS (ESI +) m / z = 309 [M + H] +.

Example 14

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

In an ice bath, 26.1 mg (0.653 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 5 mL anhydrous THF. 78.1 mg (0.742 mmol) of 3-amino-3-methylbutan-1-ol was added slowly. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. 100.0 mg (0.371 mmol) of Intermediate 2 was added , the ice bath was removed, and the mixture was stirred at room temperature for 17 hours.

The reaction mixture was carefully poured into a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated.

The crude product was purified by flash chromatography to afford titled:

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [ppm] = 1.12 (6H), 1.87 (2H), 4.62 (2H), 6.98 (1H), 7.22-7.37 (2H), 7.59-7. 3H), 8.10-8.16 (2H).

LC-MS (Method 2): R _t = 0.81 minutes; MS (ESI +) m / z = 337 [M + H] +.

Example 15

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

12.4 mg (0.518 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 4 mL of anhydrous THF in an ice bath. 29.2 mg (0.388 mmol) of ( 2R )-1-aminopropan-2-ol was slowly added. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. 105.0 mg (0.259 mmol) of intermediate 13 was added , the ice bath was removed, and the mixture was stirred at 40 ° C 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 with sodium sulfate and evaporated.

The crude product was purified by HPLC to give 43 mg of titled

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.86 minutes; MS (ESI +) m / z = 343 [M + H] +.

Example 16

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

Add 102 mg (0.74 mmol) of (1 R )-2-amino-1-phenylethanol to 5 mL of 30 mg (0.75 mmol) sodium hydride (60% in mineral oil) at 0-5 °C In anhydrous DMF. After stirring for 15 minutes on an ice bath, 100 mg (0.37 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]indole was 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 and extracted four times with ethyl acetate. The combined organic phases were washed with brine. The brine phase was made basic and extracted twice with chloroform. The organic phases were combined, dried over magnesium sulfate and evaporated. The residue was purified by HPLC to give 39.8 mg (30%).

¹ H-NMR (300 MHz, chloroform-d), δ [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 = 0.90 minutes; MS (ESI +) m / z = 371 [M + H] +.

Example 17

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

48.2 mg (1.21 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 5 mL of anhydrous THF in an ice bath. 178 mg (1.3 mmol) of ( S )-2-phenylglycolamine was added slowly. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. 250 mg (0.927 mmol) of Intermediate 2 was added , the ice bath was removed, and the mixture was stirred at room temperature for 16 hours.

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

The crude product was purified by HPLC to afford title titled:

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.88 minutes; MS (ESI +) m / z = 371 [M + H] +.

Example 18

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

48.2 mg (1.21 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 5 mL of anhydrous THF in an ice bath. 178 mg (1.3 mmol) of ( R )-2-phenylglycolamine was added slowly. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. 250 mg (0.927 mmol) of Intermediate 2 was added , the ice bath was removed, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was carefully poured into a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate

The crude product was purified by HPLC to afford 192 mg of titled

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.89 minutes; MS (ESI +) m / z = 371 [M + H] +.

Example 19

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

20.7 mg (0.52 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 4 mL of anhydrous THF in an ice bath. 71 mg (0.52 mmol) of ( S )-2-phenylglycolamine was added slowly. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. 105 mg (0.259 mmol) of intermediate 13 was added , the ice bath was removed, and the mixture was stirred at 40 ° C 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 with sodium sulfate and evaporated.

The crude product was purified by HPLC to afford 41 mg of titled

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ [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 = 0.96 minutes; MS (ESI +) m / z = 405 [M + H] +.

Example 20

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

153 mg (1.11 mmol) of trans- 3-(aminomethyl)cyclobutanol hydrochloride was added to 89 mg (2.23 mmol) of sodium hydride (60% in mineral oil) at 0-5 °C. 7.5 mL of anhydrous DMF. After stirring for 5 minutes on an ice bath, 150 mg (0.56 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]indole was added. . The ice bath was removed and it was stirred overnight at room temperature. 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 The residue was purified by HPLC to give 114 mg (61%).

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ [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 = 0.75 minutes; MS (ESI +) m / z = 335 [M + H] +.

Example 21

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

117 mg (1.11 mmol) of 2-(2-aminoethoxy)ethanol was added to 7.5 mL of anhydrous DMF containing 44.5 mg (1.11 mmol) of sodium hydride (60% in mineral oil) at 0-5 °C. in. After stirring for 5 minutes on an ice bath, 150 mg (0.56 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]indole was added. . The ice bath was removed and it was stirred overnight at room temperature. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted four times with ethyl acetate. The combined organic phases were washed twice with brine, dried over magnesium sulfate The residue was purified by HPLC to afford 138 mg (73%).

¹ H-NMR (300 MHz, METHANOL-d ₄ ), δ [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 = 0.75 minutes; MS (ESI +) m / z = 339 [M + H] +.

Example 22

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

153 mg (1.11 mmol) of ( trans- 3-aminocyclobutyl)methanol hydrochloride was added to 7.5 mg (2.23 mmol) of sodium hydride (60% in mineral oil) at 0-5 °C. mL of anhydrous DMF. After stirring for 5 minutes on an ice bath, 150 mg (0.56 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]indole was added. . The ice bath was removed and it was stirred overnight at room temperature. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted four times with ethyl acetate. The combined organic phases were washed twice with brine, dried over magnesium sulfate The residue was purified by HPLC to give &lt

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.78 minutes; MS (ESI +) m / z = 335 [M + H] +.

Example 23

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

168.7 mg (1.11 mmol) of (1 R , 2 R )-2-aminocyclohexanol hydrochloride was added to 89 mg (2.23 mmol) of sodium hydride (60% in mineral oil) at 0-5 °C. ) in 7.5 mL of anhydrous DMF. After stirring for 5 minutes on an ice bath, 150 mg (0.56 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]indole was added. . The ice bath was removed and it was stirred overnight at room temperature. The reaction mixture was concentrated and purified by HPLC to afford &lt

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.96 minutes; MS (ESI +) m / z = 349 [M + H] +.

Example 24

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

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

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ [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 = 0.82 minutes; MS (ESI +) m / z = 335 [M + H] +.

Example 25

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

153 mg (1.11 mmol) of (1 S , 2 R )-2-aminocyclopentanol hydrochloride was added to 89 mg (2.23 mmol) of sodium hydride (60% in mineral oil) at 0-5 °C. ) in 7.5 mL of anhydrous DMF. After stirring for 5 minutes on an ice bath, 150 mg (0.56 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]indole was added. . The ice bath was removed and it was stirred overnight at room temperature. The reaction mixture was poured into a half-saturated ammonium chloride solution and extracted four times with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium The residue was purified by HPLC to give &lt

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.84 minutes; MS (ESI +) m / z = 335 [M + H] +.

Example 26

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

209 mg (1.11 mmol) of 1-amino-3-phenylpropan-2-ol hydrochloride was added to 89 mg (2.23 mmol) of sodium hydride (60% in mineral oil) at 0-5 °C 7.5 mL of anhydrous DMF. After stirring for 5 minutes on an ice bath, 150 mg (0.56 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]indole was added. . The ice bath was removed and it was stirred overnight at room temperature. The reaction mixture was poured into a half-saturated ammonium chloride solution and extracted four times with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate The residue was purified by HPLC to give 105 mg (44%).

¹ H-NMR (600 MHz, DMSO-d ₆ ), δ [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 = 0.96 minutes; MS (ESI +) m / z = 385 [M + H] +.

Example 27

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

112.5 mg (1.11 mmol) of (1-aminocyclobutyl)methanol was added to 7.5 mL of anhydrous DMF containing 44.5 mg (1.11 mmol) of sodium hydride (60% in mineral oil) at 0-5 °C. After stirring for 5 minutes on an ice bath, 150 mg (0.56 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]indole was added. . The ice bath was removed and stirred at room temperature for 2 hours. Stir at 50 ° C overnight. The reaction mixture was poured into a half-saturated ammonium chloride solution and extracted four times with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate The residue was purified by HPLC to give 53 mg (28%).

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ [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 = 0.83 minutes; MS (ESI +) m / z = 335 [M + H] +.

Example 28

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

Step 1: Some small iodine crystals were added to 5 mL of anhydrous THF containing 458 mg (18.85 mmol) of magnesium turnings. A solution of 2.544 g (18.85 mmol) of (bromomethyl)cyclopropane in 5 mL of dry THF was added. Stir for 10 minutes and cool the reaction to room temperature. This solution was slowly added under cooling to 10 g of anhydrous THF containing 1 g (6.28 mmol) of (2-ethyloxyethyl)aminocarbamic acid tert-butyl ester. It was stirred at room temperature for 2 hours. A 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 with MgSO4 and evaporated. The residue was purified on EtOAc (EtOAc:EtOAc:EtOAc

¹ H-NMR (300 MHz, chloroform-d), δ [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: Slowly add 2.09 mL (8.36 mmol) of hydrogen chloride solution (4 M in 1,4-dioxane) to 0.36 g (1.67 mmol) of (2-hydroxyhex-5-en-1-yl)amine. 3.6 mL of 1,4-dioxane in tert-butyl carboxylic acid. It was stirred overnight at room temperature. It was concentrated on a rotary evaporator. The solid residue was triturated twice with diethyl ether to give 190 mg (yield: 67%).

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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).

Step 3: Add 168.7 mg (1.11 mmol) of 1-aminohex-5-en-2-ol hydrochloride to 89 mg (2.23 mmol) of sodium hydride (60% in mineral oil) at 0-5 °C Medium) in 7.5 mL of anhydrous DMF. After stirring for 5 minutes on an ice bath, 150 mg (0.56 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]indole was added. . The ice bath was removed and it was stirred overnight at room temperature. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted four times with ethyl acetate. The combined organic phases were washed twice with brine, dried over magnesium sulfate The residue was purified by EtOAc to afford (EtOAc)

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ [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 = 0.88 minutes; MS (ESI +) m / z = 349 [M + H] +.

Example 29

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

Add 132.2 mg (1.48 mmol) of 2-amino-2-methylpropan-1-ol to 7.5 mL of 59 mg (1.48 mmol) of sodium hydride (60% in mineral oil) at 0-5 °C In anhydrous DMF. After stirring for 5 minutes on an ice bath, 200 mg (0.74 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]indole was 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. 20 mL 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 hexane. The solid was dried in vacuo at 40 ° C to afford 133 mg (56%).

¹ H-NMR (600 MHz, DMSO-d ₆ ), δ [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 = 0.83 minutes; MS (ESI +) m / z = 335 [M + H] +.

Example 30

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

150 mg (1.48 mmol) of 2-amino-1-cyclopropylethanol was added to 10 mL of anhydrous DMF containing 59.3 mg (1.48 mmol) of sodium hydride (60% in mineral oil) at 0-5 °C. . After stirring for 5 minutes on an ice bath, 200 mg (0.74 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]indole was 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 The residue was purified by EtOAc to afford &lt

¹ H-NMR (600 MHz, DMSO-d ₆ ), δ [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 = 0.87 minutes; MS (ESI +) m / z = 335 [M + H] +.

Example 31

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

278.4 mg (1.11 mmol) of 1-amino-3-(morpholin-4-yl)propan-2-ol oxalate (1:1) was added to contain 144.6 mg (3.62) at 0-5 °C. Methyl) sodium hydride (60% in mineral oil) in 7.5 mL anhydrous DMF. After stirring for 5 minutes on an ice bath, 150 mg (0.56 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]indole was added. . The ice bath was removed and stirred at room temperature for 2 hours. 26.7 mg (1.11 mmol) of sodium hydride (60% in mineral oil) was added. It was stirred overnight at room temperature. 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 The residue was purified by HPLC to afford 145 mg (66%).

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.71 minutes; MS (ESI +) m / z = 394 [M + H] +.

Example 32

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

107 mg (0.74 mmol) of 2-amino-2-(tetrahydro-2 H -piperidin-4-yl)ethanol was added to 29.7 mg (0.74 mmol) of sodium hydride (60%) at 0-5 °C. In mineral oil, washed with hexane in 5 mL of anhydrous DMF. After stirring for 5 minutes on an ice bath, 100 mg (0.37 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]indole was 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 The residue was purified by HPLC to give &lt

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ [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 = 0.82 minutes; MS (ESI +) m / z = 379 [M + H] +.

Example 33

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

Add 173.8 mg (1.48 mmol) of 1-amino-4-methylpentan-2-ol to 10 mL of 59.3 mg (1.48 mmol) of sodium hydride (60% in mineral oil) at 0-5 °C In anhydrous DMF. After stirring for 5 minutes on an ice bath, 200 mg (0.74 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]indole was 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 The residue was purified by HPLC to afford 135 mg (52%).

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ [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 = 1.01 minutes; MS (ESI +) m / z = 351 [M + H] +.

Example 34

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

100 mg (1.11 mmol) of 1,3-diaminopropan-2-ol was added to 7.5 mL of anhydrous DMF containing 44.5 mg (1.11 mmol) of sodium hydride (60% in mineral oil) at 0-5 °C. in. After stirring for 5 minutes on an ice bath, 150 mg (0.56 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]indole was added. . The ice bath was removed and it was stirred overnight at room temperature. 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 The residue was taken up in DMF, and the insoluble product was filtered and dried in vacuo to give 18.5 g (10%). The filtrate was purified by HPLC to give an additional 35 mg (17%) of product.

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ [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 = 0.53 minutes; MS (ESI +) m / z = 324 [M + H] +.

Example 35

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

186.5 mg (1.11 mmol) of 2-amino-1-(tetrahydrofuran-3-yl)ethanol hydrochloride was added to 89 mg (2.23 mmol) of sodium hydride (60% in mineral oil) at 0-5 °C. ) in 7.5 mL of anhydrous DMF. After stirring for 5 minutes on an ice bath, 150 mg (0.56 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]indole was added. . The ice bath was removed and it was stirred overnight at room temperature. 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 The residue was purified by HPLC to afford 60 mg (30%)

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.76 minutes; MS (ESI +) m / z = 365 [M + H] +.

Example 36

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

Step 1: 17.4 mg (0.434 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 4 mL anhydrous THF in an ice bath. Was slowly added 81.3 mg (0.434 mmol) (trans-3-hydroxy-cyclobutyl) -carbamic acid tert-butyl ester. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. Add 73.5 mg (0.217 mmol) of 6-chloro-3-(4-fluoro-1-benzofuran-2-yl)imidazo[1,2- b ]嗒 The ice bath was removed and the resulting mixture was stirred at 40 ° C 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 a crude material. One step of purification is used in step 2.

Step 2: Add 2 mL of trifluoroacetic acid to 95 mg of the crude product from Step 1 in 4 mL of dichloromethane. The mixture was stirred at room temperature for 30 minutes. 2 mL of an aqueous ammonia solution (30% by volume aqueous ammonia solution) 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 with MgSO4 and evaporated.

The crude product was purified by HPLC to afford 28 mg of titled

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.74 minutes; MS (ESI +) m / z = 339 [M + H] +.

Example 37

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

33.5 mg (0.838 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 2 mL anhydrous THF in an ice bath. A 21:1 1:1 mixture of anhydrous DMF containing 69.1 mg (0.559 mmol) of trans- 3-aminocyclobutanol hydrochloride and anhydrous THF was slowly added. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. Add 100 mg (0.279 mmol) of 6-chloro-3-(5-chloro-1-benzofuran-2-yl)imidazo[1,2- b ]嗒 The ice bath was removed and the resulting mixture was stirred at 40 ° C for 72 hours.

The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated.

The crude product was purified by HPLC to give 44 mg of titled

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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) (The methylene group on the cyclobutyl moiety is not visible and may be hidden under the DMSO peak).

LC-MS (Method 3): R _t = 0.83 minutes; MS (ESI +) m / z = 355 [M + H] +.

Example 38

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

25.4 mg (0.635 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 2 mL of anhydrous THF in an ice bath. A 21:1 1:1 mixture of anhydrous DMF containing 52.9 mg (0.43 mmol) of trans- 3-aminocyclobutanol hydrochloride and anhydrous THF was slowly added. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. Add 100 mg (0.287 mmol) of 6-chloro-3-(5-methoxy-1-benzofuran-2-yl)imidazo[1,2- b ]嗒 The ice bath was removed and the resulting mixture was stirred at 40 ° C for 72 hours.

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

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

The crude product was purified by HPLC to give 54 mg, m.

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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): R _t = 0.76 minutes; MS (ESI +) m / z = 351 [M + H] +.

Example 39

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

Step 1: 11.5 mg (0.288 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 4 mL anhydrous THF in an ice bath. Was slowly added 53.9 mg (0.288 mmol) (trans-3-hydroxy-cyclobutyl) -carbamic acid tert-butyl ester. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. Add 69 mg (0.144 mmol) of 6-chloro-3-(5-fluoro-1-benzofuran-2-yl)imidazo[1,2- b ]嗒 The ice bath was removed and the resulting mixture was stirred at 40 ° C 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 with EtOAc (EtOAc m.

Step 2: To a crude product from Step 1 was added 2 mL of trifluoroacetic acid to 4 mL of dichloromethane. The mixture was stirred at room temperature for 30 minutes. Add 2 mL of ammonia water (30% by volume aqueous ammonia solution). Water was added and the mixture was extracted with a mixture of dichloromethane and methanol (95: 5 vol%). The organic layer was dried with MgSO4 and evaporated.

The crude product was purified by HPLC to give 18 mg of titled

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ [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): R _t = 0.74 minutes; MS (ESI +) m / z = 339 [M + H] +.

Example 40

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

44.5 mg (1.11 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 8 mL of anhydrous THF in an ice bath. 99.2 mg (1.11 mmol) of 3-amino-2-methyl-propan-1-ol was added slowly. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. Add 150 mg (0.556 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]嗒 The ice bath was removed and the resulting mixture was stirred at 40 ° C for 72 hours.

The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated.

The crude product was purified by HPLC to afford 147 mg of titled

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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): R _t = 0.76 minutes; MS (ESI +) m / z = 323 [M + H] +.

Example 41

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

In an ice bath, 32 mg (0.8 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 3 mL anhydrous THF. 73.5 mg (0.534 mmol) of 2-amino-2-cyclopropylethanol hydrochloride and 1 mL of anhydrous DMF were added slowly. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. Add 80 mg (0.267 mmol) of 6-chloro-3-(4-methoxy-1-benzofuran-2-yl)imidazo[1,2- b ]嗒 The ice bath was removed and the resulting mixture was stirred at room temperature for 20 hours.

The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated.

The crude product was purified by HPLC to afford 52 mg of titled

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.82 minutes; MS (ESI +) m / z = 365 [M + H] +.

Example 42

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

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

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

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ [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 = 0.78 minutes; MS (ESI +) m / z = 309 [M + H] +.

Example 43

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

21 mg (0.526 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 3.5 mL of anhydrous THF in an ice bath. 39.5 mg (0.526 mmol) of ( R )-2-amino-propan-1-ol was added slowly. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. Add 94.1 mg (0.263 mmol) of 6-chloro-3-(5-chloro-1-benzofuran-2-yl)imidazo[1,2- b ]嗒 The ice bath was removed and the resulting mixture was stirred at 40 ° C 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 with MgSO4 and evaporated.

The crude product was purified by HPLC to afford titled:

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.91 minutes; MS (ESI +) m / z = 343 [M + H] +.

Example 44

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

23.7 mg (0.593 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 4.8 mL of anhydrous THF in an ice bath. 69.5 mg (0.593 mmol) ([3-(Aminomethyl)oxetan-3-yl]methanol was added slowly. After the addition was completed, stirring was continued for 15 minutes at 0 ° C. Add 80 mg (0.297 mmol) 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2-b]indole The ice bath was removed and the resulting mixture was stirred at 40 ° C for 72 hours.

The reaction mixture was carefully poured into water. The aqueous layer was extracted with EtOAc.

The crude product was purified by HPLC to afford titled:

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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): R _t = 0.76 minutes; MS (ESI +) m / z = 351 [M + H] +.

Example 45

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

21.2 mg (0.532 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 4 mL anhydrous THF in an ice bath. 39.9 mg (0.532 mmol) of ( S )-2-aminopropan-1-ol was added slowly. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. Add 90 mg (0.266 mmol) of 6-chloro-3-(4-fluoro-1-benzofuran-2-yl)imidazo[1,2- b ]嗒 The ice bath was removed, and the resulting mixture was stirred at 40 ° C for 23 hours.

The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated.

The crude product was purified by HPLC to afford 41 mg of titled

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ [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 = 0.85 minutes; MS (ESI +) m / z = 327 [M + H] +.

Example 46

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

21.2 mg (0.532 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 4 mL anhydrous THF in an ice bath. 73 mg (0.532 mmol) of ( S )-2-phenylglycolamine was added slowly. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. Add 90 mg (0.266 mmol) of 6-chloro-3-(4-fluoro-1-benzofuran-2-yl)imidazo[1,2- b ]嗒 The ice bath was removed, and the resulting mixture was stirred at 40 ° C for 23 hours.

The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated.

The crude product was purified by HPLC to afford 41 mg of titled

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ [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 = 0.95 minutes; MS (ESI +) m / z = 389 [M + H] +.

Example 47

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

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

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

The crude product was taken up in EtOAc (m.)

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.76 minutes; MS (ESI +) m / z = 309 [M + H] +.

Example 48

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

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

The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated.

The crude product was purified by HPLC to afford 58 mg of titled

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ [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 = 0.83 minutes; MS (ESI +) m / z = 327 [M + H] +.

Example 49

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

20.6 mg (0.515 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 4 mL of anhydrous THF in an ice bath. 38.7 mg (0.515 mmol) of ( R )-1-amino-propan-2-ol was added slowly. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. Add 100.0 mg (0.257 mmol) of 6-chloro-3-(5-methyl-1-benzofuran-2-yl)imidazo[1,2-b]indole The ice bath was removed and the resulting mixture was stirred at 40 ° C for 48 hours.

The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated.

The crude product was purified by HPLC to afford 46 mg of titled

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.84 minutes; MS (ESI +) m / z = 323 [M + H] +.

Example 50

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

29.7 mg (0.742 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 5 mL of anhydrous THF in an ice bath. 112 mg (0.742 mmol) of ( 2S )-2-amino-3-phenylpropan-1-ol was added slowly. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. Add 60.0 mg (0.20 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]嗒 The ice bath was removed, and the resulting mixture was stirred at 40 ° C for 17 hours.

The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated.

The crude product was purified by HPLC to give 117 mg of titled

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ [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 = 0.92 minutes; MS (ESI +) m / z = 385 [M + H] +.

Example 51

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

20.4 mg (0.512 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 4 mL of anhydrous THF in an ice bath. 44.6 mg (0.512 mmol) of (1-aminocyclopropyl)methanol dissolved in a mixture of 2 mL of anhydrous THF and 2 mL of anhydrous DMF was slowly added. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. Add 100 mg (0.371 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]嗒 The ice bath was removed and the resulting mixture was stirred at 40 ° C for 72 hours.

20 mg (0.23 mmol) of (1-aminocyclopropyl)methanol dissolved in 1 mL of dry THF was treated with 9.2 mg (0.23 mmol) of sodium hydride (60% of a mineral oil dispersion) at 0 ° C for 15 min. The resulting mixture was then added to the reaction flask and the reaction was stirred at 40 °C. hour.

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

The crude product was purified by HPLC to give 14 mg of title titled

^{1 H-NMR (500MHz, DMSO} -d 6): δ [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 = 0.79 minutes; MS (ESI +) m / z = 321 [M + H] +.

Example 52

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

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

The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated.

The crude product was purified by HPLC to afford 149 mg of titled

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ [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 = 0.86 minutes; MS (ESI +) m / z = 385 [M + H] +.

Example 53

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

Step 1: Some small iodine crystals were added to 25 mL of anhydrous ether containing 1.145 g (47.1 mmol) of magnesium turnings. A solution of 8.906 g (47.1 mmol) of 1-(bromomethyl)-4-fluorobenzene in 20 mL of dry diethyl ether was added. Stir under reflux for 1 hour and cool the reaction to room temperature. This solution was slowly added to 25 mL of anhydrous THF containing 2.5 g (15.7 mmol) of (3-ethyloxyethyl)aminocarbamic acid formate under ice-cooling. It was stirred overnight at room temperature. A 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 The residue was purified on EtOAc (EtOAc:EtOAc:

¹ H-NMR (300 MHz, chloroform-d), δ [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: Slowly add 1.62 mL (6.50 mmol) of hydrogen chloride solution (4 M in 1,4-dioxane) to 0.35 g (1.30 mmol) of [3-(4-fluorophenyl)-2-hydroxypropane. Base 2.8 mL of butyl carbamic acid in 1,4-dioxane. It was stirred overnight at room temperature. It was concentrated on a rotary evaporator. The solid residue was triturated twice with ether and triturated three times with toluene. The solid was dried under vacuum at 45 ° C to give 240 mg (90%) of product as hydrogen chloride.

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [ppm] = 2.51-2.84 (4H), 3.78-3.90 (1H), 7.03-7.13 (2H), 7.19-7.28 (2H), 7.95 (3H) ).

Step 3: Add 240 mg (1.17 mmol) of 1-amino-3-(4-fluorophenyl)propan-2-ol hydrochloride to 93.3 mg (2.33 mmol) of sodium hydride at 0-5 °C. (60% in mineral oil) in 7.5 mL of anhydrous DMF. After stirring for 5 minutes on an ice bath, 157.4 mg (0.58 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]indole was added. . The ice bath was removed and it was stirred overnight at room temperature. 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 The residue was purified by HPLC to give 18 mg (8%).

¹ H-NMR (600 MHz, DMSO-d ₆ ), δ [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 = 1.27 minutes; MS (ESI +) m / z = 403 [M + H] +.

Example 54

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

269.5 mg (1.11 mmol) of 1-amino-3-(pyridin-4-yl)propan-2-ol oxalate (1:1) (dissolved in 4 mL of anhydrous DMF) at 0-5 °C And dried by 0.3 nm molecular sieve for 96 hours) was added to 4 mL of anhydrous DMF containing 133.5 mg (3.34 mmol) of sodium hydride (60% in mineral oil). After stirring for 5 minutes on an ice bath, 150 mg (0.56 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2- b ]indole was added. . The ice bath was removed and it was stirred overnight at room temperature. 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 The residue was purified by HPLC to give 26 mg (12%).

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.63 minutes; MS (ESI +) m / z = 386 [M + H] +.

Example 55, Method A

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

157 mg (0.74 mmol) of (1R)-2-amino-1-(pyridin-3-yl)ethanol dihydrochloride was added to a solution containing 89 mg (2.23 mmol) of sodium hydride at 0-5 °C. % in mineral oil) in 5 mL of anhydrous DMF. After stirring for 15 minutes on an ice bath, 100 mg (0.37 mmol) of 3-(1-benzofuran-2-yl)-6-chloroimidazo[1,2-b]indole was 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 and extracted four times with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate The residue was purified by HPLC. The HPLC solution was adjusted to an alkaline pH and concentrated. The residue was dissolved in chloroform, washed twice with water, dried over magnesium sulfate.

¹ H-NMR (600 MHz, DMSO-d ₆ ), δ [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 = 0.74 minutes; MS (ESI +) m / z = 372 [M + H] +.

The examples in Table 2 were prepared analogously to Method A.

Example 61

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

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

The reaction mixture was carefully poured into water. The mixture was extracted with ethyl acetate. The organic layer was dried with MgSO4 and evaporated.

The crude product was purified by HPLC to afford titled:

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ [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 = 0.92 minutes; MS (ESI +) m / z = 389 [M + H] +.

Example 62

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

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

The reaction mixture was carefully poured into water. The mixture was extracted with ethyl acetate. The organic layer was dried with MgSO4 and evaporated.

The crude product was purified by HPLC to afford 65 mg of titled

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ [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 = 0.96 minutes; MS (ESI +) m / z = 405 [M + H] +.

Example 63

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

119 mg (2.97 mmol) of sodium hydride (60% dispersion in mineral oil) was partitioned into 20 mL of tetrahydrofuran in an ice bath. 410 mg (2.97 mmol) of 2-amino-3-pyridylethanol was added slowly. After the addition was completed, stirring was continued at 0 ° C for 15 minutes. 400 mg (1.48 mmol) of Intermediate 2 was added , the ice bath was removed, and the mixture was stirred at 40 ° C for 18 hours.

The reaction mixture was carefully poured into water. The mixture was extracted with ethyl acetate. The organic layer was dried with MgSO4 and evaporated.

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

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 0.74 minutes; MS (ESI +) m / z = 372 [M + H] +.

Example 64

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

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

The reaction mixture was carefully poured into water. The mixture was extracted with ethyl acetate. The organic layer was dried with MgSO4 and evaporated.

The crude product was purified by HPLC to afford 27 mg of titled

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ [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 = 1.0 minutes; MS (ESI +) m / z = 403 [M + H] +.

Additionally, the compounds of formula (I) of the present invention can be converted to 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 can be converted to a free compound by any method known to those skilled in the art.

Pharmaceutical composition of the compound of the present invention

The invention also relates to pharmaceutical compositions containing one or more compounds of the invention. Such compositions can be used to achieve the desired pharmacological effect by administering to a patient in need thereof. A patient suitable for the purposes of the present invention is a mammal, including a human, in need of treatment for a particular condition or disease. Accordingly, the invention includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the invention or a salt thereof. The pharmaceutically acceptable carrier is preferably a downloading agent which is relatively non-toxic and non-toxic to the patient at a concentration consistent with the effective activity of the active ingredient so that any side effects attributable to the carrier do not impair the active ingredient. Beneficial effect. The pharmaceutically effective amount of the compound is preferably an amount that produces an effect or exerts an effect on the particular condition being treated. The compounds of the present invention can be administered orally, parenterally, in any effective conventional unit dosage form, including immediate release, sustained release and extended release formulations, together with pharmaceutically acceptable carriers well known in the art. Topical, nasal, ophthalmically, transocular, sublingual, transrectal, transvaginal and the like.

For oral administration, the compound may be formulated into a solid or liquid preparation, such as a capsule, a pill, a lozenge, a dragee, a lozenge, a melt, a powder, a solution, a suspension or an emulsion, and may be according to the art. It is known to prepare a method for producing a pharmaceutical composition. The solid unit dosage form can be a capsule which can be a conventional hard or soft shell gelatin type capsule containing, for example, a surfactant, a lubricant, and an inert filler such as lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, a compound of the invention may be combined with a conventional lozenge matrix (such as lactose, sucrose, and corn starch) in the form of a tablet: a binder, such as acacia, corn starch. Or gelatin; a disintegrant intended to aid in the decomposition and dissolution of the tablet after administration, such as potato starch, alginic acid, corn starch, and guar (guar) Gum), tragacanth, gum arabic; a lubricant intended to improve the flowability of tablet particles and prevent the tablet material from sticking to the tablet mold and the surface of the punch, such as talc, stearic acid or magnesium stearate, Calcium stearate or zinc stearate; a dye, coloring agent, and flavoring agent such as peppermint, wintergreen or cherry flavoring that is intended to enhance the aesthetic qualities of the tablet and render it 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 a pharmaceutically acceptable surfactant, Suspending agent or emulsifier. Various other materials may be present in the form of a coating or otherwise alter the physical form of the dosage unit. For example, a lozenge, pill or capsule may be coated with shellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of aqueous suspensions. It provides a mixture of the active ingredient with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by the reagents already mentioned above. Other excipients as described above, such as such sweeteners, flavoring agents, and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil (such as liquid paraffin) or a mixture of vegetable oils. Suitable emulsifiers can be (1) naturally occurring gums such as acacia and tragacanth; (2) naturally occurring phospholipids such as soy and lecithin; (3) esters derived from fatty acids and hexitol anhydrides or Partial esters, such as sorbitan monooleate; (4) condensation products of such partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The lotion may also contain sweeteners and flavoring agents.

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

Syrups and tinctures can be sweeteners such as glycerin, propylene glycol, sorbitol or sucrose To deploy. These formulations may also contain a demulcent and preservative (such as methylparaben and propylparaben) as well as flavoring and coloring agents.

The compounds of the present invention may also be administered in a parenteral form (i.e., subcutaneously, intravenously, intraocularly, intrasynovally, intramuscularly or peritoneally in an injectable form in a physiologically acceptable diluent and a pharmaceutical carrier). Internally, the pharmaceutical carrier may be added with or without the addition of a pharmaceutically acceptable surfactant (such as soap or detergent), a suspending agent (such as gum, carbomer, methylcellulose) , hydroxypropylmethylcellulose or carboxymethylcellulose) or a sterile liquid or liquid mixture of an emulsifier and other pharmaceutical adjuvants such as water, physiological saline, aqueous dextrose and related sugar solutions; Such as ethanol, isopropanol or cetyl alcohol; glycols such as propylene glycol or polyethylene glycol; glycerol ketals such as 2,2-dimethyl-1,1-dioxolan-4-methanol; ether Such as poly(ethylene glycol) 400; oil, fatty acid, fatty acid ester or fatty acid glyceride or acetylated fatty acid glyceride.

Illustrative oils useful in parenteral formulations of the invention are oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, paraffin oil, 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 alkali metal salts, ammonium salts and triethanolamine salts of fatty acids, and suitable cleaning agents include cationic detergents such as dimethyldialkylammonium halide, alkylhalide pyridinium and alkylamine acetate; anions Type cleaners such as alkyl, aryl and alkene sulfonates, alkyl, olefin, ether and monoglyceride sulfates, and sulfosuccinates; nonionic detergents such as fatty amine oxides, Fatty acid alkanolamine and poly(oxyethylene-oxypropylene), or ethylene oxide or propylene oxide copolymer; and amphoteric detergents such as alkyl-β-aminopropionate and 2-alkylimidazoline a quaternary ammonium salt; and a mixture.

The parenteral compositions of the present invention typically comprise from about 0.5% to about 25% by weight of active ingredient in solution. Preservatives and buffers may also be advantageously employed. To minimize or eliminate irritation of the injection site, the compositions may contain a hydrophilic lipophilic having from about 12 to about 17, preferably from about 12 to about 17. Balanced value (HLB) nonionic surfactant. The amount of surfactant in the formulation is preferably in the range of from about 5% by weight 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.

Illustrative surfactants for use in parenteral formulations are polyethylene sorbitan fatty acid esters (eg, sorbitan monooleate) and ethylene oxide condensed with propylene oxide and propylene glycol. A high molecular weight adduct of the hydrophobic matrix formed.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous suspension. These suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate , polyvinylpyrrolidone, tragacanth and acacia, dispersing or wetting agents may be naturally occurring phospholipids, such as lecithin; condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate; epoxy a condensation product of ethane with a long chain aliphatic alcohol, such as heptahexylethylhexadecanol; a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyoxyethylene sorbitol a monooleate; or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, such as a polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectable solution or suspension 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 suspension medium. Any mild, fixed oil including synthetic mono- or diglycerides can be used for this purpose. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compositions of the invention may also be administered in the form of suppositories for rectal administration of the drug. Such 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 thus melts in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycol.

Another formulation used in the method of the invention will use a transdermal delivery device ("Paste sheet"). These transdermal patches can be used to continuously or discontinuously infuse a controlled amount of a compound of the invention. The construction and use of a transdermal patch for the delivery of a pharmaceutical agent is well known in the art (see, for example, U.S. Patent No. 5,023,252, issued Jun. The patches can be configured for continuous, pulsed or on-demand delivery of a pharmaceutical agent.

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

It may be necessary or necessary to introduce a pharmaceutical composition into a patient via a mechanical delivery device. The construction and use of mechanical delivery devices for delivering pharmaceutical agents are well known in the art. For example, direct techniques for 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 a medicament to a particular anatomical region of the body is described in U.S. Patent No. 5,011,472 (issued Apr. 30, 1991).

The compositions of the present invention may also contain other conventional pharmaceutically acceptable compounding ingredients (commonly referred to as carriers or diluents) as needed or desired. Conventional procedures for preparing such compositions into suitable dosage forms can be used. Such components and procedures include the ingredients and procedures described in the following references, each of which is incorporated herein by reference: Powell, MF et al., "Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998 , 52(5), 238-311; Strickley, RG "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1" PDA Journal of Pharmaceutical Science & Technology 1999 , 53(6), 324-349; and Nema, S. et al., "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical Science & Technology 1997 , 51(4), 166-171.

Common pharmaceutical ingredients that may be used to formulate compositions suitable for the intended route of administration, as appropriate, include: acidulants (examples include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalizing agents (examples) Including, but not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, 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, CCl ₂ F ₂ , F ₂ ClC-CClF ₂ and CClF ₃ ); venting 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 p-hydroxybenzoate, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzene Sodium formate); 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 (thimerosal); antioxidant Agents (examples include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxymethoxybenzene, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate , sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); bonding materials (examples include (but not limited to) block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, polyfluorenes Oxygen, polyoxyalkylene and styrene-butadiene copolymers; buffers (examples include, but are not limited to, potassium metaphosphate, dipotassium hydrogen phosphate, sodium acetate, anhydrous sodium citrate, and sodium citrate dihydrate) Carrier (examples include, but are not limited to, gum arabic syrup, aromatic syrup, aromatic tincture, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection Liquid and bacteriostatic water for injection); chelating agents (examples include (but not limited to) disodium edetate and ethylenediaminetetraacetic acid); colorants (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 Iron Oxide Red; clarifying agents (examples include, but not limited to, bentonite); emulsifiers (examples include (but are not limited to) gum arabic, polycetitol ( Cetomacrogol), cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate; capsule encapsulant (examples include (but not limited to) gelatin And cellulose acetate phthalate); flavoring agents (examples include (but not limited to) anise oil, cinnamon oil, cocoa beans, menthol, orange oil, peppermint oil and vanillin); humectants (examples include (but Not limited to) glycerin, propylene glycol and sorbitol); research agents (examples include, but not limited to, mineral oil and glycerin); oils (examples include (but are not limited to) peanut oil, mineral oil, olive oil, peanut oil, sesame oil and Vegetable oil); ointment base (examples include (but not limited to) lanolin, hydrophilic ointment, polyethylene glycol ointment, paraffin oil, hydrophilic paraffin oil, white ointment, yellow ointment and rose water ointment); penetration enhancer ( transdermal delivery) (examples include (but are not limited to) monohydric or polyhydric alcohols, Valuable or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phospholipid derivatives, cephalins, guanidines, guanamines, ethers, ketones and ureas Plasticizers (examples include, but are not limited to, diethyl phthalate and glycerin); solvents (examples include, but are not limited to) ethanol, corn oil, cottonseed oil, glycerin, isopropanol, mineral oil, Oleic acid, peanut oil, purified water, water for injection, sterile water for injection and water for aseptic perfusion); hardener (examples include but not limited to cetyl alcohol, cetyl alcohol wax, microcrystalline wax, paraffin wax, stearyl alcohol) , white wax and yellow wax); suppository base (examples include, but not limited to, cocoa butter and polyethylene glycol (mixture)); surfactants (examples include, but are not limited to, benzalkonium chloride, nonoxynol ether 10, octetyl alcohol 9 (oxtoxynol 9), polysorbate 80, sodium lauryl sulfate and sorbitan monopalmitate); suspending agent (examples include (but not limited to) agar, bentonite, card Pom, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl fiber , kaolin, methylcellulose, tragacanth and veegum; sweeteners (examples include (but are not limited to) aspartame, dextrose, glycerol, mannitol , propylene glycol, sodium saccharin, sorbitol, and sucrose); lozenge anti-adhesives (examples include, but are not limited to, magnesium stearate and talc); lozenge binders (examples include (but are not limited to) gum arabic, brown algae Acid, sodium carboxymethylcellulose, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone and pregelatinized starch; tablets and capsule diluents (examples include (but are not limited to) calcium hydrogen phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); lozenges package Coating agents (examples include, but are not limited to) liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate phthalate and shellac); lozenges direct compression excipients (examples include (but are not limited to) calcium hydrogen phosphate); Disintegrating agents (examples include (but are not limited to) alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, potassium mooring pull succinylcholine (polacrillin potassium), crosslinked polyvinylpyrrolidone, sodium alginate, ethanol Sodium starch and starch); lozenge slips (examples include, but are not limited to, colloidal cerium oxide, corn starch and talc); lozenge lubricants (examples include (but are not limited to) calcium stearate, stearic acid Magnesium, mineral, stearic, and zinc stearate; lozenge/capsule opacifiers (examples include, but are not limited to, titanium dioxide); lozenge polishes (examples include, but are not limited to, carnauba wax (carnuba) Wax) and white wax); thickeners (examples include, but are not limited to, beeswax, cetyl alcohol and paraffin); tonicity agents (examples include, but are not limited to, dextrose and sodium chloride); tackifiers ( Examples include, but are not limited to, alginic acid, bentonite, carbomer, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium alginate, and tragacanth; and humectants (examples include But not limited to) seventeen extension ethyloxyhexadecanol, lecithin, sorbitol monooleate, polyoxyethylene sorbitan monooleic acid Ester and polyoxyethylene stearate).

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

Sterile Intravenous Solution : A 5 mg/mL solution of the compound of the invention to be used can be prepared using sterile injectable water and adjusted if necessary. The solution was diluted to 1-2 mg/mL with sterile 5% dextrose for administration and administered by intravenous infusion over about 60 minutes.

Lyophilized powder for intravenous administration : Sterile preparations can be prepared by (i) 100-1000 mg of the compound of the invention in the form of a lyophilized powder, (ii) 32-327 mg/mL sodium citrate, and (iii) 300-3000 mg of dextran 40. The formulation is reconstituted to a concentration of 10 to 20 mg/mL by sterile injectable physiological saline or 5% dextrose, and further diluted to 0.2-0.4 mg/mL and 15-60 by physiological saline or 5% dextrose. Minutes are administered by intravenous bolus or intravenous infusion.

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

50 mg/mL of water-insoluble compounds required by the present invention

5 mg/mL sodium carboxymethylcellulose

4 mg/mL TWEEN 80

9 mg/mL sodium chloride

9 mg/mL benzyl alcohol

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

Soft gelatin capsules : prepare a mixture of the active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil and inject it into molten gelatin by means of a positive displacement pump to form a soft gelatin capsule containing 100 mg of active ingredient. . Wash and dry the capsules. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water-miscible pharmaceutical mixture.

Lozenges : A large number of tablets are prepared by conventional procedures such that the dosage unit is 100 mg active ingredient, 0.2 mg colloidal cerium oxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg. lactose. Appropriate aqueous and non-aqueous coatings can be applied to increase palatability, improve aesthetics and stability, or delay absorption.

Immediate Release Lozenges/Capsules : These dosage forms are solid oral dosage forms made by conventional and novel processes. These units can be administered orally in the absence of water for rapid dissolution and delivery of the drug. The active ingredient is incorporated into a liquid containing ingredients such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The pharmaceutical compound can be compressed with a viscoelastic and thermoelastic sugar and polymer or foaming component to produce a porous matrix intended for immediate release without the need for water.

Combination therapy

The compounds of the invention may be administered in the form of a single pharmaceutical agent or in combination with one or more other pharmaceutical agents, wherein the combination does not cause unacceptable adverse effects. The invention also relates to such combinations. For example, the compounds of the invention may be combined with known anti-hyperproliferative agents or other indication agents and their analogs, as well as mixtures and combinations thereof. Other indications include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, antimetabolites, DNA-intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors , topoisomerase inhibitors, biological response modifiers or anti-hormones.

According to an embodiment, the invention relates to a pharmaceutical combination comprising: - one or more first active ingredients selected from the group consisting of the compounds of formula (I) as defined above; and - one or more selected from the group consisting of chemotherapeutic anti-cancer The second active ingredient of the agent.

The term "chemotherapeutic anticancer agent" includes, but is not limited to, 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, Alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole (anastrozole), arglabin, arsenic trioxide, aspartate, azacitidine, basiliximab, BAY 80-6946, BAY 1000394, BAY 86-9766 ( RDEA 119), belototecan, bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene ), bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, calcium leucovorin, calcium leucovorin, cape Capectabine, carboplatin, carmofur, carmustine, cattozumab (catum) Axomab), celecoxib, celmoleukin, cetuximab, chlorambucil (chlorambucil), chlormadinone, chlormethine, cisplatin, cladribine, clodronic acid, clofarabine, cretinase (crisantaspase), cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, Dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, de Deslorelin, dibrospidium chloride, docetaxel, doxifluridine, doxorubicin, doxorubicin + estrone, AI Eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, table Epirubicin, epitiostanol, alpha ebertin (epoetin alfa), beta epoetin ( Epoetin beta), eptaplatin, eribulin, erlotinib, estradiol, estramustine, etoposide, euvita Everyone, exemestane, fadrozole, filgrastim, fludarabine, fluorouracil, flutamide, and formamide Formestane), fotemustin, fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine, jitozhu Monoclonal antibody (gemtuzumab), oxidized glutoxim, goserelin, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 particles, Iban Ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod, acetaminophen Improsulfan, interferon alpha, interferon beta, interferon gamma, ipilimumab (ipilimumab), irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide, lenograstim, Lentinan, letrozole, leuprorelin, levamisole, lisuride, lobaplatin, lomustine, chlorine Lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan, mepitiostane, mercaptopurine, Methotrexate, methoxsalen, methyl aminolevulinate, methyltestosterone, mifamurtide, miltefosine , miiplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotan, mitoxantrone (mitoxantrone), nedaplatin, neelarabine, nilotinib (nilo) Tinib), nilutamide, nimotuzumab, nimustine, nitracrine, umvazumab (ofatumumab), omeprazole (omeprazole), oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium 103 particles, pamidronic acid ), panitumumab, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-β epoetin) , pegfilgrastim, pegylated glutamate, pemetrexed, pentazocine, pentostatin, and pilomycin (peplomycin), perfosfamide, picibanil, pirarubicin, plerixafor, plicamycin, pigolusam ), estradiol polyphosphate, polysaccharide-K, porfimer sodium, prajic (pralatrexate), prednimustine, procarbazine, quinagolide, raloxifene, raltitrexed, ranimustine , razoxane, regorafenib, risedronic acid, rituximab, romidepsin, romiposttim, sand Sargramostim, sipuleucel-T, sizofiran, sobuzuxane, sodium glycididazole, sorafenib , streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tasonermin , for teceleukin, tegafur, fluridine + gimeracil + oteracil, temoporfin, temozolomide, Tamsirolimus, teniposide, testosterone, tetrofosmin, thalidomide (tha) Lidomide), thiotepa, thymalfasin, tioguanine, tocilizumab, topotecan, toremifene, tosi Tositumomab, trobectedin, trastuzumab, treosulfan, tretinoin, trilostane, triptorelin (triptorelin), trofosfamide, tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, vitamin Vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, volt Vorozole, 钇90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin or a combination thereof.

Other pharmaceutical agents may be afinitor, adiponectin, alendronate (alendronic acid), alfaffinone, alitretinoin, allopurinol, aloprim, aloxi, hexamethylene melamine, amine rumimi Amifostine, amrubicin, ampicillin, anastrozole, anzmet, afarep, alagabin, arsenic trioxide, arnobiotic (aromasin), 5-azacytidine, azathioprine, BAY 80-6946, BCG or tice BCG, bestatin, betamethasone acetate, doubling Betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan, calcitonin (calcitonin), campas, capecitabine, carboplatin, cassodex, cefesone, simmeine, cerubidine, styrene Acid mustard, cisplatin, cladribine, clodronic acid, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin lipid (DaunoXome), decadron, decadron phosphate, delestrogen, denistin, depo-medrol, de Sherylin, dexrazoxane, diethylstilbestrol, diflucan, docetaxel, deoxyfluorouridine, doxorubicin, dronabinol, DW-166HC, Ai Eligard, elitek, ellence, emend, epirubicin, alpha epoetin, epogen, ibine, erji Igamisol, estrace, estradiol, estramustine phosphate sodium, ethinyl estradiol, ethymol, etidronic acid ), etopophos, etoposide, fartrexazole, farston, filgrastim, finasteride, furgrastim, fluorosis Floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluorohydroxymethyl ketone (fluoxymes) Terone), flutamide (flutamide), formestane, fosteabine, fotemustine, fulvestrant, gammagard, gemcitabine, gemtuzumab , Gleevec, gliadel, goserelin, granisetron HCl, histamine, and hycamtin, hydrocortone, erythro-hydroxyl Adenine, hydroxyurea, tiimumab, idarubicin, ifosfamide, interferon alpha, interferon alpha 2, interferon alpha-2A, interferon alpha-2B, interferon alpha-n1, interference Α-n3, interferon beta, interferon gamma-1a, interleukin-2, intron A, iressa, irinotecan, kytril, lapatinib , lentinan sulphate, letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, levobonine calcium salt Levofolinic acid calcium salt), levothroid, levoxyl, lomustine, lonidamine, marinol, dichloromethane Mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogen (menest), 6-巯基嘌呤, Mesna, methotrexate, metvix, miltefosine, minocycline, mitomycin C, rice Mittane, mitoxantrone, Modrenal, Myocet, nedaplatin, neulasta, neumega , neupogen, nilutamide, nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCl, europ Orapred, oxaliplatin, paclitaxel, pediapred, pemonase, Pegasys, pentastatin, picibanil, pico Pilocarpine HCl, pirarubicin, plicamycin, porfimer sodium, prednistatin, prednisolone (pred) Nisolone), prednisone (prednisone), premarin, precarbamate, procrit, raltitrexed, RDEA 119, rebif, etidronate-186 (rhenium-186) Etidronate), rituximab, roferon-A, romurtide, salagen, sandostatin, sagstatin, semustine ), cilostazol, sobutazo, solu-medrol, sparfosic acid, stem cell therapy, streptozocin, strontium chloride-89, snijod (synthroid), tamoxifen, tamsulosin, tasonermin, testolactone, taxotere, tetansin, temozolomide, Tenoside, testosterone propionate, testred, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, Toremifene, tosimozumab, trastuzumab, troxulfan, retinoic acid, trexall, trimethyl melamine, trimethoate (trimet) Rexate), triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, Vincristine, vindesine, vinorelbine, virulizin, zinecard, netstatin, zofran, ABI-007, acolbifene, Interferon γ-1b (actimmune), affinitak, aminopterin, arzoxifene, asoprisnil, atamestane, aqu Astrasentan, sorafenib (BAY 43-9006), avastin (avistin), CCI-779, CDC-501, celebrex, cetuximab, cetuximab, Crisnatol, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, Aidol Kangrui Edotecarin), eflornithine, exatecan, fenretinide, histamine dihydrochloride, implanted histamine lining hydrogel (histreli) n hydrogel implant), 鈥- 166DOTMP, Ibandronic acid, interferon gamma, tron-PEG (intron-PEG), ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide Lanreotide), lasofoxifene, libra, lonafarnib, miproxifene, minodronate, MS-209, liposome MTP -PE, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS , Osidem, paclitaxel polyglutamate, pamidronate disodium, PN-401, QS-21, quazepam, R-1549, Raloxifene, ranpirnase, 13-cis-retinoic acid, satraplatin, seocalcitol, T-138067, tarceva, he Taxoprexin, thymosin alpha 1, tiazofurine, tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-10 7R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic acid or a combination thereof.

Optionally, an anti-hyper-proliferative agent that can be added to the composition includes, but is not limited to, the Cancer Chemotherapy Drug Program in the Merck Index, (1996) 11th Edition, which is incorporated herein by reference. Listed compounds, such as aspartate, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, Dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, epothilone, eplesone derivatives, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, formazan tetrahydrofolate, lomustine, dichloromethyldiethylamine, 6-mercaptopurine, mesto Sodium, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozotocin, tamoxifen, sulphur bird 嘌呤, Topotecan, vinblastine, vincristine and vindesine.

Other anti-hyperproliferative agents suitable for use in the compositions of the present invention include, but are not limited to, Goodman and Gilman's The Pharmacological Basis of Therapeutics (ninth edition), edited by Molinoff et al., issued by McGraw-Hill, pp. 1225-1287, (1996). (This document is incorporated herein by reference) for use in the treatment of compounds for the treatment of neoplastic diseases, such as amine lutite, L-aspartate, azathioprine, 5-azacytidine, carat Qubin, busulfan, diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel, erythrohydroxy adenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxygenation Uridine monophosphate, fludarabine phosphate, fluorohydroxymethyl ketone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate , megestrol acetate, melphalan, mitoxantrone, paclitaxel, pentastatin, N-phosphonium-L-aspartate (PALA), pucamycin, semustine , teniposide, propionate propionate, thiotepa, trimethyl melamine, uridine and vinorelbine.

Other anti-hyper-proliferative agents suitable for use in the compositions of the present invention include, but are not limited to, other anti-cancer agents such as epsilon 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 in the compositions of the invention include, but are not limited to, interferon (e.g., interferon alpha, interferon beta or interferon gamma) super agonistic monoclonal antibodies , Tuebingen, TRP-1 protein vaccine, colostrin, anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab, trastuzum Monoclonal antibody, dinisin, rituximab, thymosin alpha 1, bevacizumab, mecasermin, mecasermin rinfabate, oprisermin rinfabate Integrin, natalizumab, rhMBL, MFE-CP1+ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-35, MT-103, Lin Feipei, AS-1402, B43-stain wood B43-genistein, L-19-based radioimmunotherapy, AC- 9301, NY-ESO-1 vaccine, IMC-1C11, CT-322, rhCC10, r(m)CRP, MORAb-009, aviscurin (aviscumine), MDX-1307, Her-2 vaccine, APC-8024, NGR-hTNF, rhH1.3, IGN-311, endostatin, volociximab, PRO-1762, lexatumumab, SGN-40, pertuzumab , EMD-273063, L19-IL-2 fusion protein, PRX-321, CNTO-328, MDX-214, tigapotide, CAT-3888, labetuzumab, alpha-particle emission Radioisotope-linked leptuzumab, EM-1421, HyperAcute vaccine, turkuzumab-tucotuzumab celmoleukin, plus Galiximab, HPV-16-E7, Javelin-prostate cancer, Javelin-melanoma, NY-ESO-1 vaccine, EGF vaccine, CYT-004 -MelQbG10, WT1 peptide, orgoviromab, oratumumab, zalutumumab, cintredekin besudotox, WX-G250 Interferon albumin (Albuferon), aflibercept (aflibercept), denosumab (denosumab), vaccines, CTP-37, Eve ancient mAb (efungumab) or 131I-chTNT-1 / B. Monoclonal antibodies suitable for use as protein therapeutics include, but are not limited to, morozumab-CD3 (muromonab-CD3), abciximab, edrezumab, daclizumab, true Gentuzumab, alemtuzumab, temimumab, cetuximab, bevicizumab, efalizumab, adalimumab ( Adalimumab), omalizumab, muramomab-CD3, rituximab, daclizumab, trastuzumab, palivizumab, Baltiximab and infliximab.

The compounds of the invention may also be combined with biotherapeutic agents such as antibodies (e.g., Avastin, rituxan, erbitux, herceptin) or recombinant proteins.

According to an embodiment, the invention relates to a pharmaceutical combination comprising: one or more compounds of the above formula (I) or a stereoisomer, tautomer, N-oxide, hydrate, solvate thereof Or a salt (especially a pharmaceutically acceptable salt thereof) or a mixture thereof; and one or more agents selected from the group consisting of taxanes, such as docetaxel, paclitaxel, pull Patinib, sunitinib or paclitaxel (Taxol); Epsilon, such as Ixabepilone, Patugilone or Sagopilone; Mitoxantrone Prednisone (Predinisolone); Dexamethasone; Estramustin; Vinblastin; Vincristin; Doxorubicin; Doxorubicin (Adriamycin); Idarubicin; Daunorubicin; Bleomycin; Etoposide; Cyclophosphamide; Ifosfamide ); Procarbazine; Melphalan; 5-fluorouracil (5-Fluo) Rouracil); 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 anti-angiogenic agents such as Avastin, axitinib, DAST, centrein, sorafenib or sunitinib. . Combinations with proteasome inhibitors or mTOR inhibitors or anti-hormone or steroid metabolic enzyme inhibitors are also possible.

In general, the use of a cytotoxic agent and/or a cytostatic agent in combination with a compound or composition of the invention will be used to: (1) produce better efficacy in reducing tumor growth or even as compared to administration of only any one agent; Eliminate tumors; (2) administer less chemotherapeutic agents; (3) provide chemotherapeutic treatments that are well tolerated by patients with less harmful pharmacological complications than with single agent chemotherapy And observation of certain other combination therapies; (4) treating a variety of different cancer types in mammals, particularly humans; (5) providing a higher response rate in the treated patients; (6) among the patients treated, Provides longer survival times than standard chemotherapy treatments; (7) provides longer tumor development time; and/or (8) compared to other cancer agents in combination with known conditions that produce antagonistic effects, resulting in at least The same good efficacy and tolerability results.

Method of making cells sensitive to radiation

In a unique embodiment of the invention, the compounds of the invention are useful for sensitizing cells to radiation. That is, treatment of cells with a compound of the invention prior to irradiation treatment of the cells results in the cells being more susceptible to DNA damage and cell death than if the cells were not treated with any of the compounds of the invention. In one aspect, the cells are 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 a cell in combination with conventional radiation therapy.

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

In one embodiment, the cells are killed by treating the cells with at least one DNA damaging agent. That is, after treating the cells with one or more compounds of the invention such that the cells are susceptible to cell death, the cells are treated with at least one DNA damaging agent to kill the cells. DNA damaging agents suitable for use in the present invention include, but are not limited to, chemotherapeutic agents (e.g., cisplatin), ionizing radiation (X-rays, ultraviolet radiation), carcinogens, and mutagens.

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 cell signaling pathway that, upon activation, causes DNA damage; inhibits a cellular signaling pathway that, when inhibited, causes DNA damage; and induces biochemical changes in the cell , where the change causes DNA damage. By way of non-limiting example, DNA repair pathways in cells can be inhibited, thereby preventing repair of DNA damage and causing abnormal accumulation of DNA damage in the cells.

In one aspect of the invention, a compound of the invention is administered to the cell prior to inducing DNA damage in the cell by radiation or otherwise. In another aspect of the invention, a compound of the invention is administered to the cell while it is being irradiated or otherwise induced to cause DNA damage in the cell. In another aspect of the invention, a compound of the invention is administered to the cell immediately after it has begun to induce or otherwise induce DNA damage in the cell.

In another aspect, the cells are in vitro. In another embodiment, the cells are in vivo.

As mentioned above, it has been surprisingly found that the compounds of the invention are effective for inhibiting MKNK-1 and are therefore useful for treating or preventing diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses or inappropriate cellular inflammatory responses; Or diseases associated with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly where uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses are caused by MKNK -1 mediated, such as hematological tumors, solid tumors and/or their turn Migration, such as leukemia and myelodysplastic syndromes, malignant lymphoma, head and neck tumors (including brain tumors and brain metastases), chest tumors (including non-small cell lung tumors and small cell lung tumors), gastrointestinal tumors, endocrine tumors, breast tumors And other gynecological tumors, urinary tumors (including kidney tumors, bladder tumors and prostate tumors), skin tumors and sarcomas and/or their metastases.

Thus, according to another aspect, the invention encompasses a compound of formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, as described and defined herein. (especially a pharmaceutically acceptable salt thereof) or a mixture thereof for use in the treatment or prevention of a disease as mentioned above.

Thus, another particular aspect of the invention is a compound of formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, as described above (especially Use of a pharmaceutically acceptable salt) or a mixture thereof for the prevention or treatment of a disease.

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

The diseases mentioned in the first two paragraphs are diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response; or accompanied by uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response Or a disease in which the cell is inflammatory, especially where uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cell inflammatory response is mediated by MKNK-1, such as hematological tumors, solid tumors and/or Metastasis, such as leukemia and myelodysplastic syndromes, malignant lymphoma, head and neck tumors (including brain tumors and brain metastases), chest tumors (including non-small cell lung tumors and small cell lung tumors), gastrointestinal tumors, endocrine tumors, breast tumors And other gynecological tumors, urinary tumors (including kidney tumors, bladder tumors and prostate tumors), skin tumors and sarcomas and/or their metastases.

As used herein, the term "improper" is used in the context of the present invention, especially In the case of a cellular immune response or an inflammatory response to an inappropriate cell, it is understood that preferably the response is below normal or above normal, and associated with the disease of the disease, causing or causing a lesion of the disease.

Preferably, the use is for the treatment or prevention of diseases wherein the diseases are hematological tumors, solid tumors and/or metastases thereof.

Method of treating hyperproliferative disorders

The present invention relates to a method of treating a hyperproliferative disorder in a mammal using the compounds of the invention and compositions thereof. The compounds are useful for inhibiting, blocking, reducing, reducing, etc., and/or producing apoptosis of cell proliferation and/or cell division. The method comprises administering a compound of the invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, in an amount effective to treat the condition, Mammals, including humans. Hyperproliferative disorders include, but are not limited to, for example, psoriasis, keloids, and other hyperplasia affecting the skin; benign prostatic hyperplasia (BPH); solid tumors such as breast cancer, respiratory cancer, brain cancer, genital cancer, digestive tract cancer, urinary tract Cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and their distant metastasis. These conditions also include lymphoma, sarcoma and leukemia.

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

Examples of respiratory cancer include, but are not limited to, small cell lung cancer and non-small cell lung cancer, as well as bronchial adenomas and pleural pulmonary blastomas.

Examples of brain cancer include, but are not limited to, brainstem and hypothalamic gliomas, cerebellum and cerebral astrocytoma, chorioblastoma, ependymoma, and neuroectoderm and pineal tumors.

Male reproductive organ tumors include, but are not limited to, prostate cancer and testicular cancer. Tumors of the female reproductive organs include, but are not limited to, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer and vulvar cancer, and uterine sarcoma.

Gastrointestinal tumors include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small bowel cancer, and salivary gland cancer.

Urinary tract tumors include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvic cancer, ureteral cancer, urethral cancer, and human papillary renal cancer.

Eye cancer includes, but is not limited to, intraocular melanoma and retinoblastoma.

Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar variation), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocyte 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 cancer includes, but is not limited to, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip and oral cancer, and squamous cell carcinoma. Lymphomas include, but are not limited to, AIDS-associated lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's Disease) and lymphoma of the central nervous system.

Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

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

Such conditions have been well characterized in humans and are also present in similar pathogens in other mammals and can be treated by administration of the pharmaceutical compositions of the invention.

The term "treating/treatment" as used throughout the text is used in the conventional sense, for example to manage or care for an individual to achieve a condition that counters, reduces, reduces, alleviates, ameliorates a disease or condition, such as a cancer. Etc.

Method of treating a kinase disorder

The invention also provides a treatment for diseases associated with abnormal extracellular mitogenic factor extracellular kinase activity Symptoms, including but not limited to stroke, heart failure, hepatomegaly, cardiac hypertrophy, diabetes, Alzheimer's disease, cystic fibrosis, symptoms of xenograft rejection, Septic shock or asthma.

An effective amount of a compound of the invention can be used to treat such conditions, including those diseases (e.g., cancer) as mentioned in the [Prior Art] section above. Nonetheless, regardless of the mechanism of action and/or the relationship between the kinase and the condition, such cancers and other diseases can be treated with the compounds of the invention.

The phrase "abnormal kinase activity" or "abnormal tyrosine kinase activity" includes any abnormal expression or activity of a gene encoding a kinase or a polypeptide encoded by the gene. Examples of such aberrant activities include, but are not limited to, overexpression of a gene or polypeptide; gene amplification; mutations that produce constitutively active or hyperactive kinase activity; gene mutations, deletions, substitutions, additions, and the like.

The invention also provides methods of inhibiting kinase activity, particularly mitogen extracellular kinase activity, comprising administering an effective amount of a compound of the invention, including salts, polymorphs, metabolites, hydrates, solvates thereof, Prodrugs (eg, esters) and their diastereomeric forms. It is possible to inhibit kinase activity in cells (e.g., in vitro) or in mammalian individuals, particularly in human patients in need of treatment.

Method of treating angiogenic disorders

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

Improper angiogenesis and ectopic performance can be harmful to organisms. A large number of pathological conditions are associated with the growth of additional blood vessels. Such conditions 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. Opththalmol. Vis. Sci. 1996 , 37, 855], neovascular glaucoma, psoriasis, posterior fibrous hyperplasia, angiofibroma, inflammation, rheumatoid arthritis (RA) ), restenosis, restenosis within the vascular stent, restenosis of the vascular graft, and the like. In addition, increased blood supply associated with cancerous and neoplastic tissue promotes growth, leading to rapid tumor expansion and metastasis. In addition, the growth of new blood vessels and lymphatic vessels in tumors provides escape pathways to rebel cells, thereby promoting the metastasis of cancer and the resulting spread. Thus, the compounds of the invention may be used, for example, by inhibiting and/or reducing angiogenesis; by inhibiting, blocking, reducing, reducing, etc., endothelial cells, or other types involved in angiogenesis, and cells that cause such cell types Death or apoptosis to treat and/or prevent any of the aforementioned angiogenic conditions.

Dosage and administration

Based on standard laboratory techniques known for assessing compounds useful in the treatment of hyperproliferative disorders and angiogenic disorders, standard toxicity testing and standard pharmacology for the treatment of conditions identified above mammals The analysis, and the comparison of such results with the results of known agents for treating such conditions, can readily determine the effective dosage of a compound of the invention for use in treating various contemplated indications. The amount of active ingredient administered to treat one of these conditions can vary greatly depending on, for example, the particular compound and dosage unit employed, the mode of administration, the treatment period, the age and sex of the patient being treated, and The nature and extent of the condition being treated.

The total amount of active ingredient to be administered will generally range from about 0.001 mg to about 200 mg per kilogram of body weight per day and preferably from about 0.01 mg to about 20 mg per kilogram of body weight per day. Clinically useful dosing schedules range from one to three times a day to once every four weeks. In addition, "drug holidays" (where the drug is not administered to a patient for a certain period of time) may be beneficial to the overall balance between pharmacological effects and tolerance. A unit dose may contain from about 0.5 mg to about 1500 mg of the active ingredient and may be administered one or more times a day or less than once a day. The daily average dose administered by injection (including intravenous, intramuscular, subcutaneous and parenteral injection) and by infusion techniques is preferably from 0.01 to 200 mg per kg of total body weight. The average daily rectal dosage regimen is preferably from 0.01 to 200 mg per kg of total body weight. Average daily vaginal dose Preferably, the total weight is from 0.01 to 200 mg per kg. The average daily topical dosage regimen is preferably from 0.1 to 200 mg and the number of administrations per day is between one and four times. The transdermal concentration is preferably a concentration required to maintain a daily dose of 0.01 to 200 mg/kg. The average daily inhaled dosage regimen is preferably from 0.01 to 100 mg per kg of total weight.

Of course, the specific initial and continuous dosing regimen for each patient will be based on the nature and severity of the condition as determined by the attending physician, the activity of the particular compound employed, the age and general condition of the patient, the time of administration, the route of administration, the rate of drug excretion, The drug combination and its similar factors vary. The number of doses of the desired mode of treatment and the compound of the invention or a pharmaceutically acceptable salt or ester or composition thereof can be determined by those skilled in the art using conventional therapeutic tests.

The disease of the method is preferably a blood tumor, a solid tumor and/or a metastasis thereof.

In particular, the compounds of the invention are useful in the treatment and prevention of tumor growth and metastasis, particularly for solid tumors where all indications and stages of tumor growth are pre-treated or not previously treated.

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

The example test experiments described herein are illustrative of the invention and the invention is not limited to the examples given.

Biological analysis:

Test the example one or more times in the selected bioanalytical. When more than one test is performed, the data is reported as an average or median, where: • The average (also known as the arithmetic mean) represents the sum of the values obtained divided by the number of tests, and • the median is expressed in increments or The middle number of the value group in descending order. If data The number of values in the set is odd, and the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two intermediate values.

The examples are synthesized one or more times. When more than one synthesis is performed, the data from the bioanalysis represents the average or median calculated using the data set obtained by testing one or more synthetic batches.

MKNK1 kinase assay

The MKNK1 inhibitory activity of the compounds of the invention was quantified using the MKNK1 TR-FRET assay as described in the following paragraphs.

Glutathione-S-transferase (GST, N-terminus) and human full-length MKNK1 (amino acid 1-424) expressed in insect cells using a baculovirus expression system and purified via glutathione agarose affinity chromatography The recombinant fusion protein of Accession No. BAA 19885.1, T344D) was purchased from Carna Biosciences (Product No. 02-145) and used as an enzyme. As a substrate for the kinase reaction, biotin-labeled peptide biotin-Ahx-IKKRKLTRRKSLKG (C-terminal of the guanamine form), which is commercially available, for example, from Biosyntan (Berlin-Buch, Germany), is used.

In the assay, 50 nL of the test compound in 100 times concentrated solution in DMSO was pipetted into a black low volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and 2 μL of MKNK1 was added for aqueous analysis. a solution of buffer [50 mM HEPES pH 7.5, 5 mM magnesium chloride, 1.0 mM dithiothreitol, 0.005% (v/v) Nonide-P40 (Sigma)], and the mixture was incubated at 22 ° C for 15 minutes to The test compound is pre-bound to the enzyme prior to the start of the kinase reaction. This was followed by the addition of 3 μL of adenosine triphosphate (ATP, 16.7 μM = >5 μL final concentration in the assay volume of 10 μM) and the substrate (0.1 μM = >5 μL final concentration in the assay volume of 0.06 μM) in the assay buffer The solution was started to initiate the kinase reaction, and the resulting mixture was incubated at 22 ° C for a reaction time of 45 minutes. The concentration of MKNK1 is adjusted depending on the activity of the enzyme lot and is selected to allow the analysis to be in the linear range, typically in the range of 0.05 μg/ml. By adding 5 μL of TR-FRET detection reagent (5 nM streptavidin-XL665 [Cisbio Bioassays, Codolet, France] and 1 nM anti-ribosomal protein S6 (pSer236) antibody from Invitrogen [# 44921G] and 1 nM LANCE EU-W1024 labeled protein G [Perkin-Elmer, product number AD0071]) in aqueous EDTA (100 mM EDTA) A solution of 0.1% (w/v) bovine serum albumin in 50 mM HEPES pH 7.5) was stopped.

The resulting mixture was incubated at 22 ° C for 1 hour to form a complex between the phosphorylated biotin-labeled peptide and the detection reagent. Subsequently, the amount of phosphorylated host was assessed by measuring the resonance energy transfer of the Eu chelating agent to streptavidin-XL. Therefore, the amount of fluorescence emission at 620 nm and 665 nm after excitation at 350 nm was measured with a TR-HTRF reader (for example, Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer)). The ratio of the emission at 665 nm to the emission at 622 nm is considered a measure of the amount of phosphorylation. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other analysis components except enzyme = 100% inhibition). Typically, 11 different concentrations (20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33) in the range of 20 μM to 0.1 nM on the same microtiter plate. Test compounds were tested at nM and 0.1 nM by serial dilutions of 100-fold concentrated solution in DMSO prior to analysis (diluted values for each concentration) And the IC ₅₀ value was calculated by a 4-parameter fit.

High ATP analysis of MKNK1 kinase

MKNK1 inhibitory activity at high ATP after pre-incubation of a compound of the invention with MKNK1 using a TR-FRET-based MKNK1 high ATP assay as described in the following paragraphs To quantify.

Glutathione-S-transferase (GST, N-terminus) and human full-length MKNK1 (amino acid 1-424) expressed in insect cells using a baculovirus expression system and purified via glutathione agarose affinity chromatography The recombinant fusion protein of Accession No. BAA 19885.1, T344D) was purchased from Carna Biosciences (Product No. 02-145) and used as an enzyme. As a substrate for the kinase reaction, biotin-labeled peptide biotin-Ahx-IKKRKLTRRKSLKG (C-terminal of the guanamine form), which is commercially available, for example, from Biosyntan (Berlin-Buch, Germany), is used.

In the assay, 50 nL of the test compound in 100 times concentrated solution in DMSO was pipetted into a black low volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and 2 μL of MKNK1 was added for aqueous analysis. a solution of buffer [50 mM HEPES pH 7.5, 5 mM magnesium chloride, 1.0 mM dithiothreitol, 0.005% (v/v) Nonide-P40 (Sigma)], and the mixture was incubated at 22 ° C for 15 minutes to The test compound is pre-bound to the enzyme prior to the start of the kinase reaction. This was followed by the addition of 3 μL of adenosine triphosphate (ATP, 3.3 mM =>5 μL of final concentration in the assay volume of 2 mM) and the substrate (0.1 μM = >5 μL of final concentration in the assay volume of 0.06 μM) in the assay buffer. The solution was started to initiate the kinase reaction, and the resulting mixture was incubated at 22 ° C for a reaction time of 30 minutes. The concentration of MKNK1 is adjusted depending on the activity of the enzyme lot and is selected to allow the analysis to be in the linear range, typically in the range of 0.003 μg/ml. By adding 5 μL of TR-FRET detection reagent (5 nM streptavidin-XL665 [Cisbio Bioassays, Codolet, France] and 1 nM anti-ribosomal protein S6 (pSer236) antibody from Invitrogen [# 44921G] and 1 nM LANCE EU-W1024 labeled protein G [Perkin-Elmer, product number AD0071] was stopped in a solution of aqueous EDTA (100 mM EDTA, 0.1% (w/v) bovine serum albumin in 50 mM HEPES pH 7.5). reaction.

The resulting mixture was incubated at 22 ° C for 1 hour to form a complex between the phosphorylated biotin-labeled peptide and the detection reagent. Subsequently, the amount of phosphorylated host was assessed by measuring the resonance energy transfer of the Eu chelating agent to streptavidin-XL. Therefore, the amount of fluorescence emission at 620 nm and 665 nm after excitation at 350 nm was measured with a TR-FRET reader (for example, Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer)). The ratio of the emission at 665 nm to the emission at 622 nm is considered a measure of the amount of phosphorylation. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other analysis components except enzyme = 100% inhibition). Typically, 11 different concentrations in the range of 20 μM to 0.1 nM on the same microtiter plate (eg 20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1 nM, tested for test compounds by serial dilution of the separately prepared dilution series at the level of 100 times concentrated solution in DMSO, the exact concentration depending on the pipette used) Get two duplicate values for each concentration), and by 4 parameter fit ₅₀ values _were calculated IC.

CDK2/CycE kinase analysis

The CDK2/CycE inhibitory activity of the compounds of the invention is quantified using a CDK2/CycE TR-FRET assay as described in the following paragraphs.

A recombinant fusion protein of GST expressed in insect cells (Sf9) and purified by glutathione-agarose affinity chromatography and human CDK2 and GST and human CycE was purchased from ProQinase GmbH (Freiburg, Germany). As a substrate for the kinase reaction, biotin-labeled peptide biotin-Ttds-YISPLKSPYKISEG (C-terminal of the guanamine form), which is commercially available, for example, from JERINI Peptide Technology (Berlin, Germany), is used.

In the assay, 50 nL of the test compound in 100 times concentrated solution in DMSO was pipetted into a black low volume 384-well microtiter plate (Greiner Bio-One, In Frickenhausen, Germany), add 2 μL of CDK2/CycE to aqueous assay buffer [50 mM Tris/HCl pH 8.0, 10 mM magnesium chloride, 1.0 mM dithiothreitol, 0.1 mM sodium orthovanadate, 0.01% (v/) v) A solution in Nonidet-P40 (Sigma)] and the mixture was incubated at 22 °C for 15 minutes to allow the test compound to pre-adhere to the enzyme prior to the start of the kinase reaction. This was followed by the addition of 3 μL of adenosine triphosphate (ATP, 16.7 μM = >5 μL final concentration in the assay volume of 10 μM) and the substrate (1.25 μM = >5 μL final concentration in the assay volume of 0.75 μM) in the assay buffer The solution was started to initiate the kinase reaction, and the resulting mixture was incubated at 22 ° C for a reaction time of 25 minutes. The concentration of CDK2/CycE is adjusted depending on the activity of the enzyme batch and is selected to allow the analysis to be in the linear range, typically in the range of 130 ng/ml. By adding 5 μL of TR-FRET detection reagent (0.2 μM streptavidin-XL665 [Cisbio Bioassays, Codolet, France] and 1 nM anti-RB (pSer807/pSer811) antibody from BD Pharmingen [# 558389] and 1.2 nM LANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer, product number AD0077, as an alternative to the use of a cryptate-like anti-mouse IgG antibody from Cisbio Bioassays]) in aqueous EDTA (100 mM EDTA, 0.2 A solution of % (w/v) bovine serum albumin in 100 mM HEPES/NaOH pH 7.0) was stopped.

The resulting mixture was incubated at 22 ° C for 1 hour to form a complex between the phosphorylated biotin-labeled peptide and the detection reagent. Subsequently, the amount of phosphorylated host was assessed by measuring the resonance energy transfer of the Eu chelating agent to streptavidin-XL. Therefore, the amount of fluorescence emission at 620 nm and 665 nm after excitation at 350 nm was measured with a TR-FRET reader (for example, Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer)). The ratio of the emission at 665 nm to the emission at 622 nm is considered a measure of the amount of phosphorylation. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other analysis components except enzyme = 100% inhibition). Typically, 11 different concentrations (20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33) in the range of 20 μM to 0.1 nM on the same microtiter plate. Test compounds were tested at nM and 0.1 nM by serial dilutions of 100-fold concentrated solution in DMSO prior to analysis (diluted values for each concentration) And the IC ₅₀ value was calculated by a 4-parameter fit.

PDGFRß kinase analysis

The PDGFRß inhibitory activity of the compounds of the invention is quantified using the PDGFRß HTRF assay as described in the following paragraphs.

As a kinase, GST containing a C-terminal fragment of human PDGFRß (amino acid 561-1106), which was obtained from Proqinase [Freiburg i. Brsg., Germany], expressed in insect cells [SF9] and purified by affinity chromatography, was used. -His fusion protein. As a substrate for the kinase reaction, a biotin-labeled poly Glu, Tyr (4:1) copolymer (#61GT0BLA) from Cis Biointernational (Marcoule, France) was used.

In the assay, 50 nL of the test compound in 100 times concentrated solution in DMSO was pipetted into a black low volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and 2 μL of PDGFRß was added for aqueous analysis. A solution of buffer [50 mM HEPES/NaOH pH 7.5, 10 mM magnesium chloride, 2.5 mM dithiothreitol, 0.01% (v/v) Triton-X100 (Sigma)], and the mixture was incubated at 22 ° C for 15 minutes. So that the test compound is pre-bound to the enzyme prior to the start of the kinase reaction. Subsequent addition of 3 μL of adenosine triphosphate (ATP, 16.7 μM = >5 μL final concentration in the assay volume of 10 μM) and substrate (2.27 μg/ml => 5 μL of the final concentration in the assay volume was 1.36 μg/ml [ Approximately 30 nM]) The solution in the assay buffer was used to initiate the kinase reaction and the resulting mixture was incubated at 22 ° C for a reaction time of 25 minutes. The concentration of PDGFRß in the assay was adjusted depending on the activity of the enzyme lot and was chosen to allow the assay to be in the linear range, with typical enzyme concentrations ranging from about 125 pg/μL (the final concentration in the 5 μL assay volume). Anti-phospho-tyrosine antibody labeled with Perkin Elmer chelating agent by adding 5 μL of HTRF detection reagent (200 nM streptavidin-XLent [Cis Biointernational]; and 1.4 nM PT66-Eu chelating agent) [Alternative to PT66-Eu chelating agent, can also be used The PT66-Tb cryptate from Cis Biointernational]) was stopped in a solution of aqueous EDTA (100 mM EDTA, 0.2% (w/v) bovine serum albumin in 50 mM HEPES/NaOH pH 7.5).

The resulting mixture was incubated at 22 ° C for 1 hour to allow the biotin-labeled phosphorylated peptide to bind to the streptavidin-XLent and PT66-Eu chelating agents. The amount of phosphorylated host was then assessed by measuring the resonance energy transfer of the PT66-Eu chelating agent to streptavidin-XLent. Therefore, the amount of fluorescence emission at 620 nm and 665 nm after excitation at 350 nm was measured with an HTRF reader (for example, Rubystar (BMG Labtechnologies, offenburg, Germany) or Viewlux (Perkin-Elmer)). The ratio of the emission at 665 nm to the emission at 622 nm is considered a measure of the amount of phosphorylation. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other analysis components except enzyme = 100% inhibition). Typically, 10 different concentrations (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1) in the range of 20 μM to 1 nM on the same microtiter plate nM, test compounds were tested by serial dilutions of 1:3 dilutions at the level of 100 times concentrated stock solution (two replicates were obtained for each concentration) and were prepared by 4 parameters Combine to calculate the IC ₅₀ value.

Fyn kinase analysis

The C-terminal His6-tagged human recombinant kinase domain (purchased from Invitrogen, P3042) of human T-Fyn expressed in baculovirus-infected insect cells was used as a kinase. As a substrate for the kinase reaction, the biotin-labeled peptide biotin-KVEKIGEGTYGVV (C-terminal of the guanamine form), which is commercially available, for example, from Biosynthan GmbH (Berlin-Buch, Germany), is used.

In the analysis, 50 nL of the test compound in 100 times concentrated solution in DMSO was pipetted into a black low volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and 2 μL of LT-Fyn was added to the aqueous solution. Assay buffer [25 mM Tris/HCl pH 7.2, 25 mM magnesium chloride, 2 mM dithiothreitol, 0.1% (w/v) bovine serum albumin, 0.03% (v/v) Nonidet-P40 (Sigma)] Solution in, and in The mixture was incubated at 22 ° C for 15 minutes to allow the test compound to pre-adhere to the enzyme prior to the start of the kinase reaction. The assay buffer was then added by adding 3 μL of adenosine triphosphate (ATP, 16.7 μM = >5 μL final concentration in the assay volume of 10 μM) and the substrate (2 μM = >5 μL final concentration in the assay volume of 1.2 μM) The solution was started to initiate the kinase reaction, and the resulting mixture was incubated at 22 ° C for a reaction time of 60 minutes. The concentration of Fyn is adjusted depending on the activity of the enzyme batch and is selected to allow the analysis to be in the linear range, typically at a concentration of 0.13 nM. By adding 5 μL of HTRF detection reagent (0.2 μM streptavidin-XL [Cisbio Bioassays, Codolet, France]; and 0.66 nM PT66-Eu chelating agent, anti-phosphate group labeled by Perkin Elmer chelating agent- Tyrosine antibody [in place of PT66-Eu chelating agent, PT66-Tb cryptate from Cisbio Bioassays] can also be used in aqueous EDTA (125 mM EDTA, 0.2% (w/v) bovine serum albumin at 50 mM HEPES /NaOH in pH 7.0) to stop the reaction.

The resulting mixture was incubated at 22 ° C for 1 hour to allow the biotin-labeled phosphorylated peptide to bind to the streptavidin-XL and PT66-Eu chelating agents. The amount of phosphorylated host was then assessed by measuring the resonance energy transfer of PT66-Eu chelating agent to streptavidin-XL. Therefore, the amount of fluorescence emission at 620 nm and 665 nm after excitation at 350 nm was measured with an HTRF reader (for example, Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer)). The ratio of the emission at 665 nm to the emission at 622 nm is considered a measure of the amount of phosphorylation. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other analysis components except enzyme = 100% inhibition). Typically, 10 different concentrations (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and in the range of 20 μM to 1 nM on the same microtiter plate) 1 nM, test compounds were tested by serial dilutions of 1:3 dilutions at a concentration of 100 times concentrated stock (two replicates were obtained for each concentration) and by 4 parameters Fit to calculate the IC ₅₀ value.

Flt4 kinase analysis

The Flt4 inhibitory activity of the compounds of the invention is quantified using the Flt4 TR-FRET assay as described in the following paragraphs.

As a kinase, GST containing a human Clt fragment of human Flt4 (amino acid 799-1298), which was obtained from Proqinase [Freiburg i. Brsg., Germany], expressed in insect cells [SF9] and purified by affinity chromatography, was used. -His fusion protein. As a substrate for the kinase reaction, the biotin-labeled peptide biotin-Ahx-GGEEEEYFELVKKKK (C-terminal of the guanamine form, available from Biosyntan, Berlin-Buch, Germany) was used.

In the assay, 50 nL of the test compound in 100 times concentrated solution in DMSO was pipetted into a black low volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and 2 μL of Flt4 was added for aqueous analysis. Buffer [25 mM HEPES pH 7.5, 10 mM magnesium chloride, 2 mM dithiothreitol, 0.01% (v/v) Triton-X100 (Sigma), 0.5 mM EGTA, and 5 mM ß-phosphate-glycerol] The solution was incubated and the mixture was incubated at 22 °C for 15 minutes to allow the test compound to pre-adhere to the enzyme prior to the start of the kinase reaction. The assay buffer was then added by adding 3 μL of adenosine triphosphate (ATP, 16.7 μM = >5 μL final concentration in the assay volume of 10 μM) and the substrate (1,7 μM in a 1.67 μM => 5 μL assay volume) The solution was started to initiate the kinase reaction, and the resulting mixture was incubated at 22 ° C for a reaction time of 45 minutes. The concentration of Flt4 in the assay is adjusted depending on the activity of the enzyme batch and is selected to be such that the assay is in the linear range, with a typical enzyme concentration in the range of about 120 pg/μL (the final concentration in the 5 μL assay volume). Anti-chick compound resistance from Cisbio Bioassays (Codolet, France) by adding 5 μL of HTRF detection reagent (200 nM streptavidin-XL665 [Cis Biointernational]; and 1 nM PT66-Tb cryptate) The phosphate-tyrosine antibody) was stopped in a solution of aqueous EDTA (50 mM EDTA, 0.2% (w/v) bovine serum albumin in 50 mM HEPES pH 7.5).

The resulting mixture was incubated at 22 ° C for 1 hour to allow the biotin-labeled phosphorylated peptide to bind to the streptavidin-XL665 and PT66-Tb cryptate. The amount of phosphorylated host was then assessed by measuring the resonance energy transfer of PT66-Tb cryptate to streptavidin-XL665. Therefore, the amount of fluorescence emission at 620 nm and 665 nm after excitation at 350 nm was measured with an HTRF reader (for example, Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer)). The ratio of the emission at 665 nm to the emission at 622 nm is considered a measure of the amount of phosphorylation. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other analysis components except enzyme = 100% inhibition). Typically, 10 different concentrations (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and in the range of 20 μM to 1 nM on the same microtiter plate) 1 nM, test compounds were tested by serial dilutions of 1:3 dilutions at a concentration of 100 times concentrated stock (two replicates were obtained for each concentration) and by 4 parameters Fit to calculate the IC ₅₀ value.

TrkA kinase assay

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

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

In the assay, 50 nL of the test compound in 100 times concentrated solution in DMSO was pipetted into a black low volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany) and 2 μL of TrkA was added for aqueous analysis. a solution of buffer [8 mM MOPS/HCl pH 7.0, 10 mM magnesium chloride, 1 mM dithiothreitol, 0.01% (v/v) NP-40 (Sigma), 0.2 mM EDTA] at 22 ° C The mixture was incubated for 15 minutes to allow the test compound to pre-adhere to the enzyme prior to the start of the kinase reaction. Subsequently, by adding 3 μL of adenosine triphosphate (ATP, 16.7 μM => 5 μL, the final concentration in the assay volume is Start the kinase reaction with 10 μM) and the solution (1.27 μg/ml =>5 μL final concentration in the assay volume of 1.36 μg/ml [about 30 nM]) in assay buffer and incubate at 22 °C The resulting mixture was reacted for 60 minutes. The concentration of TrkA in the assay is adjusted depending on the activity of the enzyme lot and is selected to be such that the assay is in the linear range, with typical enzyme concentrations ranging from about 20 pg/μL (the final concentration in the 5 μL assay volume). Anti-phospho-tyrosine antibody labeled with Perkin Elmer chelating agent by adding 5 μL of HTRF detection reagent (30 nM streptavidin-XL665 [Cis Biointernational]; and 1.4 nM PT66-Eu chelating agent) [Alternative to PT66-Eu chelating agent, PT66-Tb cryptate from Cis Biointernational can also be used] in aqueous EDTA (100 mM EDTA, 0.2% (w/v) bovine serum albumin at 50 mM HEPES/NaOH pH 7.5 The solution in medium) stops the reaction.

The resulting mixture was incubated at 22 ° C for 1 hour to allow the biotin-labeled phosphorylated peptide to bind to the streptavidin-XL665 and PT66-Eu chelating agents. The amount of phosphorylated host was then assessed by measuring the resonance energy transfer of the PT66-Eu chelating agent to streptavidin-XL665. Therefore, the amount of fluorescence emission at 620 nm and 665 nm after excitation at 350 nm was measured with an HTRF reader (for example, Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer)). The ratio of the emission at 665 nm to the emission at 622 nm is considered a measure of the amount of phosphorylation. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other analysis components except enzyme = 100% inhibition). Typically, 10 different concentrations (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and in the range of 20 μM to 1 nM on the same microtiter plate) 1 nM, test compounds were tested by serial dilutions of 1:3 dilutions at a concentration of 100 times concentrated stock (two replicates were obtained for each concentration) and by 4 parameters Fit to calculate the IC ₅₀ value.

AlphaScreen SureFire eIF4E Ser209 Phosphorylation Analysis

AlphaScreen SureFire eIF4E Ser209 phosphorylation assay was used to measure phosphorylation of endogenous eIF4E in cell lysates. AlphaScreen SureFire technology allows detection of cells Phosphorylated protein in lysates. In this assay, the sandwich antibody complex formed only in the presence of the analyte (p-eIF4E Ser209) was captured by the AlphaScreen donor and acceptor beads, bringing them in close proximity. Excitation of the donor beads causes the release of unimodal oxygen molecules that trigger an energy transfer cascade in the acceptor beads, resulting in light emission at 520-620 nm.

Surefire EIF4e Alphascreen in A549 cells stimulated by 20% FCS

In the analysis, the AlphaScreen SureFire p-eIF4E Ser209 10K assay kit and the AlphaScreen ProteinA kit (for 10K assay points) were used , all from Perkin Elmer.

On the first day, 50,000 A549 cells were plated in 96-well plates in 100 μL per well in growth medium (DMEM/Hams' F12 with stable glutamic acid, 10% FCS) and incubated at 37 °C. . After the cells were attached, the medium was changed to starvation medium (DMEM, 0.1% FCS, no glucose, glutamic acid, supplemented with 5 g/L maltose). The next day, the test compound was serially diluted in 50 μL of starvation medium to a final DMSO concentration of 1%, and added to the test at a final concentration ranging from 10 μM to as low as 10 nM depending on the activity of the test compound. In the A549 cells in the plate. The treated cells were incubated for 2 hours at 37 °C. Add 37 ul of FCS to the well (= final FCS concentration 20%) and hold for 20 minutes. The medium was subsequently removed and the cells were lysed by the addition of 50 μL of lysis buffer. The plate was then agitated on a plate shaker for 10 minutes. After a 10 minute dissolution time, 4 μL of the lysate was transferred to a 384-well plate (Proxiplate from Perkin Elmer) and 5 μL of reaction buffer containing AlphaScreen acceptor beads plus activation buffer mixture was added. The plates were sealed with a TopSeal-A adhesive film and gently agitated on a plate shaker for 2 hours at room temperature. Subsequently, 2 μL of the dilution buffer with AlphaScreen donor beads was added under soft light, and the plate was again sealed with a TopSeal-A adhesive film and covered with a foil. Incubation was carried out for 2 hours at room temperature with gentle agitation. The plate was then measured using the AlphaScreen program in the EnVision reader (Perkin Elmer). Each data point (compound dilution) was measured in triplicate.

IC ₅₀ values were determined by means of a 4 parameter fit.

It will be apparent to those skilled in the art that other reagents can be similarly used for the analysis of other MKNK-1 kinases.

Thus, the compounds of the invention are effective for inhibiting one or more MKNK-1 kinases and are therefore suitable for treating or preventing diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses or inappropriate cellular inflammatory responses, particularly where runaway cell growth , proliferation and/or survival, inappropriate cellular immune response or inappropriate cell inflammatory response mediated by MKNK-1, more particularly diseases in which uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response are Hematological tumors, solid tumors and/or their metastases, such as leukemia and myelodysplastic syndromes, malignant lymphomas, head and neck tumors (including brain tumors and brain metastases), chest tumors (including non-small cell lung tumors and small cell lung tumors) Gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, urinary tumors (including kidney tumors, bladder tumors and prostate tumors), skin tumors and sarcomas and/or their metastases.

Claims (15)

a compound of the formula (I), Or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein: R1 represents a linear C ₂ -C ₆ alkyl-, linear C ₁ - C ₆ alkyl-O-straight C ₁ -C ₆ alkyl-, branched C ₃ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl, linear C ₁ -C ₆ alkyl-C ₃ a -C ₆ cycloalkyl- or C ₃ -C ₆ cycloalkyl-linear C ₁ -C ₆ alkyl- group, which, independently of one another, is optionally substituted one or more times with a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, optionally C ₃ -C ₁₀ cycloalkyl-, optionally 3 to 10 membered heterocycloalkyl, aryl-, aryl, heteroaryl-substituted, independently of one another, optionally substituted by R, independently of each other In the case where one or more of the heteroaryl-, -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N(R')R", -C(=O)OH, -C(=O)OR', -NH ₂ , -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) ₂ R ', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ Haloalkoxy-, -OC (=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', -OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl- S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N (R')R"group; Indicates: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and R3 represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl -, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, -C(=O)R', -C(=O)NH ₂ , -C(=O)N(H)R' , -C(=O)N(R')R", -NH ₂ , -NHR', -N(R')R", -N(H)C(=O)R', -N(R' ) C(=O)R', -N(H)C(=O)NH ₂ , -N(H)C(=O)NHR', -N(H)C(=O)N(R') R", -N(R')C(=O)NH ₂ , -N(R')C(=O)NHR', -N(R')C(=O)N(R')R", -N(H)C(=O)OR', -N(R')C(=O)OR', -NO ₂ , -N(H)S(=O)R', -N(R') S(=O)R', -N(H)S(=O) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R ", -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -SH, C ₁ -C ₆ alkyl-S-, - S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R') R", -S(=O)(=NR')R"group; R represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ halo -C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₃ -C ₁₀ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, aryl-, heteroaryl-, -C (= O) R ', - C (= O) NH 2, -C (= O) N (H) R', - C (= O) N (R ') R " -C (= O) OR ', - NH 2, -NHR', - N (R ') R ", - N (H) C (= O) R', - N (R ') C (= O) R', -N(H)C(=O)NH ₂ , -N(H)C(=O)NHR', -N(H)C(=O)N(R')R", -N( R')C(=O)NH ₂ , -N(R')C(=O)NHR', -N(R')C(=O)N(R')R", -N(H)C (=O)OR', -N(R')C(=O)OR', - NO ₂ , -N(H)S(=O)R', -N(R')S(=O)R ', -N(H)S(=O) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C _1- C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', -OC( =O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R", -S(=O)(=NR')R"group;R' and R" Substituents independently selected from each other are represented by C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-; n represents an integer of 0, ₁ , 2, 3, 4 or 5. The compound of the requested item 1, or a stereoisomer, tautomer, N- oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein: R1 represents a linear C ₂ -C ₆ alkyl - a linear C ₁ -C ₆ alkyl-O-straight C ₁ -C ₆ alkyl-, branched C ₃ -C ₆ alkyl-, C ₃ -C ₆ cycloalkyl, linear C ₁ - C ₆ alkyl-C ₃ -C ₆ cycloalkyl- or C ₃ -C ₆ cycloalkyl-linear C ₁ -C ₆ alkyl-, which, independently of one another, is optionally substituted with a substituent selected from the group consisting of Or multiple times: halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, optionally connected C ₃ -C ₁₀ cycloalkyl-, which is optionally a 3 to 10 membered heterocycloalkyl group, aryl group, optionally substituted aryl, heteroaryl, and optionally substituted by R, as the case may be. Substituent, independently of each other, substituted by one or more heteroaryl-, -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N (R')R", -C(=O)OH, -C(=O)OR', -NH ₂ , -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) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C ₁ -C ₆ alkoxy - C ₁ -C ₆ haloalkoxy -, - OC (= O) R ', - OC (= O) NH 2, -OC (= O) NHR', - OC (= O) N (R ') R ", -SH, C ₁ -C ₆ alkyl-S-, - S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S(=O ₂ NHR', -S(=O) ₂ N(R')R"group; Indicates: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and R3 represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl -, -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-; R represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₃ -C ₁₀ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, aryl -,heteroaryl-, -C(=O)R', -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N(R')R ", -C(=O)OR', -NH ₂ , -NHR', -N(R')R", -N(H)C(=O)R', -N(R')C(= O) R', -N(H)C(=O)NH ₂ , -N(H)C(=O)NHR', -N(H)C(=O)N(R')R",- N(R')C(=O)NH ₂ , -N(R')C(=O)NHR', -N(R')C(=O)N(R')R", -N(H ) C(=O)OR', -N(R')C(=O)OR', -NO ₂ , -N(H)S(=O)R', -N(R')S(=O R', -N(H)S(=O) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH , C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', - OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(= O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R", -S(=O (=NR')R"group;R' and R" independently of each other represent a substituent selected from the group consisting of C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-; n represents 0, An integer of 1, 2, 3, 4 or 5. The compound of claim 1 or 2, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein: R1 represents a linear C ₂ -C ₅ Alkyl-, linear C ₁ -C ₅ alkyl-O-straight C ₁ -C ₅ alkyl-, branched C ₃ -C ₅ alkyl-, C ₄ -C ₆ cycloalkyl, straight chain C _1- C ₆ alkyl-C ₄ -C ₆ cycloalkyl- or C ₄ -C ₆ cycloalkyl-linear C ₁ -C ₆ alkyl-, independently of each other, optionally substituted with a substituent selected from Substituted one or more times: halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, a C ₃ -C ₁₀ cycloalkyl- group which is a spiro group, optionally a 3 to 10 membered heterocycloalkyl group, an aryl group, optionally substituted with one or more aryl groups, optionally substituted by R, Heteroaryl-, heteroaryl-, -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O, substituted one or more times by R independently, as the case may be. N(R')R", -C(=O)OH, -C(=O)OR', -NH ₂ , -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) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH, C ₁ -C ₆ alkane oxygen -, C ₁ -C ₆ haloalkoxy -, - OC (= O) R ', - OC (= O) NH 2, -OC (= O) NHR', - OC (= O) N (R 'R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(=O) ₂ NH ₂ , -S( =O) ₂ NHR', -S(=O) ₂ N(R')R"groups; Indicates: a group; wherein * indicates a point of attachment of the group to the rest of the molecule; and R3 represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl -, -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-; R represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₃ -C ₁₀ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, aryl -,heteroaryl-, -C(=O)R', -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N(R')R ", -C(=O)OR', -NH ₂ , -NHR', -N(R')R", -N(H)C(=O)R', -N(R')C(= O) R', -N(H)C(=O)NH ₂ , -N(H)C(=O)NHR', -N(H)C(=O)N(R')R",- N(R')C(=O)NH ₂ , -N(R')C(=O)NHR', -N(R')C(=O)N(R')R", -N(H ) C(=O)OR', -N(R')C(=O)OR', -NO ₂ , -N(H)S(=O)R', -N(R')S(=O R', -N(H)S(=O) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH , C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', - OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(= O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R", -S(= O) (=NR')R"group;R' and R" independently of each other represent a substituent selected from C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-; n represents 0 An integer of 1, 2, 3, 4 or 5. The compound of any one of claims 1, 2 or 3, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein: R1 represents straight Chain C ₂ -C ₅ alkyl-, linear C ₁ -C ₅ alkyl-O-straight C ₁ -C ₅ alkyl-, branched C ₃ -C ₅ alkyl-, C ₄ -C ₆ ring An alkyl group, a linear C ₁ -C ₆ alkyl-C ₄ -C ₆ cycloalkyl group or a C ₄ -C ₆ cycloalkyl-C ₁ -C ₆ alkyl group, which, independently of one another, is optionally selected from Substituting one or more of the following substituents: -NH ₂ , C ₁ -C ₆ alkyl-, C ₂ -C ₆ alkenyl-, optionally as a spiro C ₃ -C ₁₀ cycloalkyl-, as appropriate 3 to 10 membered heterocycloalkyl, aryl-, aryl, heteroaryl-substituted, or optionally substituted by R, independently of one another, or independently, optionally substituted by R, one or more times. Heteroaryl-; Indicates: a group; wherein * indicates the point of attachment of the group to the rest of the molecule; and R3 represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl -, -OH, C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-; R represents a substituent selected from the group consisting of a halogen atom, -CN, C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-, C ₂ -C ₆ alkenyl-, C ₂ -C ₆ alkynyl-, C ₃ -C ₁₀ cycloalkyl-, 3 to 10 membered heterocycloalkyl-, aryl -,heteroaryl-, -C(=O)R', -C(=O)NH ₂ , -C(=O)N(H)R', -C(=O)N(R')R ", -C(=O)OR', -NH ₂ , -NHR', -N(R')R", -N(H)C(=O)R', -N(R')C(= O) R', -N(H)C(=O)NH ₂ , -N(H)C(=O)NHR', -N(H)C(=O)N(R')R",- N(R')C(=O)NH ₂ , -N(R')C(=O)NHR', -N(R')C(=O)N(R')R", -N(H ) C(=O)OR', -N(R')C(=O)OR', -NO ₂ , -N(H)S(=O)R', -N(R')S(=O R', -N(H)S(=O) ₂ R', -N(R')S(=O) ₂ R', -N=S(=O)(R')R", -OH , C ₁ -C ₆ alkoxy-, C ₁ -C ₆ haloalkoxy-, -OC(=O)R', -OC(=O)NH ₂ , -OC(=O)NHR', - OC(=O)N(R')R", -SH, C ₁ -C ₆ alkyl-S-, -S(=O)R', -S(=O) ₂ R', -S(= O) ₂ NH ₂ , -S(=O) ₂ NHR', -S(=O) ₂ N(R')R", -S(= O) (=NR')R"group;R' and R" independently of each other represent a substituent selected from C ₁ -C ₆ alkyl-, C ₁ -C ₆ haloalkyl-; n represents 0 An integer of 1, 2, 3, 4 or 5. The compound of any one of claims 1 to 4, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein: R1 represents a linear C _2- C ₅ alkyl-, linear C ₁ -C ₅ alkyl-O-straight C ₁ -C ₅ alkyl-, branched C ₃ -C ₅ alkyl-, C ₄ -C ₆ cycloalkyl a linear C ₁ -C ₆ alkyl-C ₄ -C ₆ cycloalkyl- or C ₄ -C ₆ cycloalkyl-C ₁ -C ₆ alkyl- group, independently of each other, optionally selected from the group consisting of Substituent substitution of one or more substituents: -NH ₂ , C ₂ -C ₆ alkenyl-, optionally C ₃ -C ₁₀ cycloalkyl-, optionally as a spiro, 3 to 10 membered heterocycloalkane a aryl group, an aryl group, an aryl group, a heteroaryl group, or a heteroaryl group, which is optionally substituted one or more times by an R substituent, as the case may be, independently of one another; Indicates: a group; wherein * indicates a point of attachment of the group to the rest of the molecule; and R3 represents a substituent selected from the group consisting of a halogen atom, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkyl group; Represents a substituent selected from the group consisting of a halogen atom, a C ₁ -C ₆ haloalkyl-, a C ₁ -C ₆ alkoxy group; n represents an integer of 0 or 1. The compound according to any one of claims 1 to 5, which is selected from the group consisting of 4-{[3-(4-methoxy-1-benzofuran-2-yl)imidazo[1, 2- b ]嗒 -6-yl]oxy}butan-1-amine; trans- 3-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}cyclobutylamine; cis -3-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}cyclobutylamine; 3-{[3-(4-methoxy-1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}propan-1-amine; 2-{[3-(4-methoxy-1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}ethylamine; 2-{[3-(5-methoxy-1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}ethylamine; ( 2S )-1-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}propan-2-amine; 4-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}butan-1-amine; 3-{[3-(5-methoxy-1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}propan-1-amine; 3-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}-3-methylbutan-1-amine; 3-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}propan-1-amine; 2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}ethylamine; ( 2R )-2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]嗒 -6-yl]oxy}propan-1-amine; 4-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}-2-methylbutan-2-amine; ( 2R )-2-{[3-(5-chloro-1-benzofuran-2-yl)imidazo[1, 2- b ]嗒 -6-yl]oxy}propan-1-amine; ( 2R )-2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}-2-phenylethylamine; (1 S )-2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}-1-phenethylamine; (1 R )-2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}-1-phenethylamine; (1 S )-2-{[3-(5-chloro-1-benzofuran-2-yl)imidazo[1,2- b ] despair -6-yl]oxy}-1-phenethylamine; 1-( trans- 3-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}cyclobutyl)-methylamine; 2-(2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]fluorene -6-yl]oxy}ethoxy)ethylamine; trans- 3-({[3-(1-benzofuran-2-yl)imidazo[1,2- b ]嗒 -6-yl]oxy}methyl)cyclobutylamine; (1 R , 2 R )-2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]嗒 -6-yl]oxy}cyclohexylamine; (1 S , 2 S )-2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]嗒 -6-yl]oxy}cyclopentylamine; (1 S , 2 R )-2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]嗒 Formate of 6-yl]-oxy}cyclopentylamine; 2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole Formate of 6-yl]oxy}-3-phenylpropan-1-amine; 1-({[3-(1-benzofuran-2-yl)imidazo[1,2- b ] despair -6-yl]oxy}methyl)cyclobutylamine; 2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}hex-5-en-1-amine; 1-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}-2-methylpropan-2-amine; 2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}-2-cyclopropylethylamine; 2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}-3-(morpholin-4-yl)-propan-1-amine; 2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]嗒 -6-yl]oxy}-1-(tetrahydro- 2H -pyran-4-yl)ethylamine; 2-{[3-(1-benzofuran-2-yl)imidazo[1,2 - b ]嗒 -6-yl]oxy}-4-methylpentan-1-amine; 2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}propane-1,3-diamine; 2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}-2-(tetrahydrofuran-3-yl)-ethylamine; trans- 3-{[3-(4-fluoro-1-benzofuran-2-yl)imidazo[1, 2- b ]嗒 -6-yl]oxy}cyclobutylamine; trans- 3-{[3-(5-chloro-1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}cyclobutylamine; trans- 3-{[3-(5-methoxy-1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}cyclobutylamine; trans- 3-{[3-(5-fluoro-1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}cyclobutylamine; 3-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}-2-methylpropan-1-amine; 1-cyclopropyl-2-{[3-(4-methoxy-1-benzofuran-2-yl)imidazolium [1,2- b ]嗒 -6-yl]oxy}ethylamine; ( 2R )-1-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]嗒 -6-yl]oxy}propan-2-amine; ( 2R )-1-{[3-(5-chloro-1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}propan-2-amine; 1-[3-({[3-(1-benzofuran-2-yl)imidazo[1,2- b ]嗒 -6-yl]oxy}methyl)oxetan-3-yl]-methylamine; ( 2S )-1-{[3-(4-fluoro-1-benzofuran-2-yl) Imidazo[1,2- b ]嗒 -6-yl]oxy}propan-2-amine; (1 S )-2-{[3-(4-fluoro-1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}-1-phenethylamine; ( 2S )-2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole (6- R )-2-{[3-(7-fluoro-1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}propan-1-amine; ( 2R )-2-{[3-(5-methyl-1-benzofuran-2-yl)imidazo[1,2- b ] despair -6-yl]oxy}propan-1-amine; (2 S )-1-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]嗒 -6-yl]oxy}-3-phenylpropan-2-amine; 1-({[3-(1-benzofuran-2-yl)imidazo[1,2- b ]嗒 -6-yl]oxy}methyl)cyclopropylamine; 3-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}-2-phenylpropan-1-amine; 2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ]indole -6-yl]oxy}-3-(4-fluorophenyl)propan-1-amine; 2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b ] despair -6-yl]oxy}-3-(pyridin-4-yl)propan-1-amine; (2R)-2-{[3-(1-benzofuran-2-yl)imidazo[1, 2-b]嗒 -6-yl]oxy}-2-(pyridin-3-yl)ethylamine; 2-{[3-(1-benzofuran-2-yl)imidazo[1,2-b]indole -6-yl]oxy}-2-(4-fluorophenyl)ethylamine; 2-{[3-(1-benzofuran-2-yl)imidazo[1,2-b]indole -6-yl]oxy}-2-(pyridin-2-yl)ethylamine; 2-{[3-(1-benzofuran-2-yl)imidazo[1,2-b]indole -6-yl]oxy}-2-(3-isopropoxyphenyl)ethylamine; 2-{[3-(1-benzofuran-2-yl)imidazo[1,2-b] despair -6-yl]oxy}-2-[3-(trifluoromethyl)phenyl]ethylamine; 2-{[3-(1-benzofuran-2-yl)imidazo[1,2- b]嗒 -6-yl]oxy}-2-(2,4-difluorophenyl)ethylamine; (1S)-2-{[3-(1-benzofuran-2-yl)imidazo[1, 2-b]嗒 -6-yl]oxy}-1-(4-fluorophenyl)ethylamine; (1S)-2-{[3-(1-benzofuran-2-yl)imidazo[1,2-b ]despair -6-yl]oxy}-1-(4-chlorophenyl)ethylamine; 2-{[3-(1-benzofuran-2-yl)imidazo[1,2-b]indole -6-yl]oxy}-1-(pyridin-3-yl)ethylamine; and 2-{[3-(1-benzofuran-2-yl)imidazo[1,2-b]indole -6-yl]oxy}-1-(pyridin-3-yl)ethylamine. A process for the preparation of a compound of the formula (I) according to any one of claims 1 to 6, which comprises the step of: bringing the intermediate compound of the formula (V): Wherein A, R3 and n are as defined for the compound of the formula (I) according to any one of claims 1 to 6, and X represents a leaving group such as a halogen atom such as a chlorine, bromine or iodine atom; or perfluoro An alkyl sulfonate group, such as a triflate group or a nonafluorobutyl sulfonate group, is reacted with a compound of 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 the compound of the formula (I) according to any one of claims 1 to 6. A compound of the formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, according to any one of claims 1 to 6 (particularly pharmaceutically Accepted salt) or a mixture thereof for use in the treatment or prevention of a disease. A pharmaceutical composition comprising a compound of the formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, according to any one of claims 1 to 6 ( In particular, a pharmaceutically acceptable salt thereof or a mixture thereof; and a pharmaceutically acceptable diluent or carrier. A pharmaceutical combination comprising: one or more first active ingredients selected from the compounds of formula (I) according to any one of claims 1 to 6; and one or more second active ingredients selected from the group consisting of chemotherapeutic anticancer agents . A compound of the formula (I) according to any one of claims 1 to 6, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof (particularly in medicinal form thereof) Use of an acceptable salt) or a mixture thereof for preventing or treating a disease. A compound of the formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, according to any one of claims 1 to 6 (especially pharmaceutically The use of a salt or a mixture thereof for the preparation of a medicament for the prevention or treatment of a disease. The use of claim 8, 11, or 12, wherein the disease is a disease of growth, proliferation and/or survival of an uncontrolled cell, an inappropriate cellular immune response, or an inflammatory reaction of an inappropriate cell, particularly wherein the uncontrolled cell grows, proliferates, and / or survival, inappropriate cellular immune response or inappropriate cell inflammatory response is mediated by the MKNK-1 pathway, more particularly the growth, proliferation and / or survival of uncontrolled cells, inappropriate cellular immune responses or inappropriate cellular inflammatory responses The disease is a hematological tumor, a solid tumor and/or its metastasis, such as leukemia and myelodysplastic syndrome, malignant lymphoma, head and neck tumors (including brain tumors and brain metastases), chest tumors (including non-small cell lung tumors and small). Cell lung tumors), gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, urinary tumors (including kidney tumors, bladder tumors and prostate tumors), skin tumors and sarcomas and/or their metastases. a compound of the formula (V), Wherein A, R3 and n are as defined for the compound of the formula (I) according to any one of claims 1 to 6, and X represents a leaving group such as a halogen atom such as a chlorine, bromine or iodine atom; or perfluoro An alkyl sulfonate group such as a trifluoromethylsulfonate group or a nonafluorobutyl sulfonate group. A use of a compound of claim 14 for the preparation of a compound of formula (I) according to any one of claims 1 to 6.