HK1183031A

HK1183031A - Bipyridyl derivatives useful for the treatment of kinase - induced diseases

Info

Publication number: HK1183031A
Application number: HK13110431.1A
Authority: HK
Inventors: Guenter Hoelzemann; Dieter Dorsch; Alfred Jonczyk; Christiane Amendt; Frank Zenke
Original assignee: Merck Patent Gmbh
Priority date: 2010-07-05
Filing date: 2011-06-07
Publication date: 2013-12-13

Description

Bipyridine derivatives for the treatment of kinase-induced diseases

Description

Technical Field

The present invention relates to novel bipyridine derivatives, to the use of said compounds in the inhibition, regulation and/or modulation of signal transduction by ATP consuming proteins, such as kinases, in particular to inhibitors of TGF-beta receptor kinases, and to the use of said compounds for the treatment of kinase induced diseases.

Prior Art

Many kinds of proteins that bind to ATP and use its energy to change conformation, phosphorylate substrates, and initiate signaling cascades are known, such as kinases, phosphatases, chaperones, or isomerases. ATP-binding proteins can be enriched using specific tools and techniques.

Tyrosine kinase and serine threonine kinase subfamilies have been identified from the large family of protein kinases, a partial list including cAbl, Akt, ALK1 and family members thereof such as ALK1 and ALK5, Axl, Aurora a and B, Btk, Dyrk2, EGFR, Erk, Ephrin (Ephrin) receptors such as EphA2, FAK, FGF receptors such as FGFR3, insulin receptor IR and insulin-like growth factor receptor IGF1R, IKK2, Jak2, JNK3, cKit, LimK, VEGF receptors 1,2 and 3, Mek1, Met, P70s6K, PDGFR, PDK1, PI3K, Plk1, PKD1, bRaf, RSK1, Src and family members thereof, TAK1, TrkA, B, C, Zap 70. The different kinases can be described by multiple synonyms, well known to those skilled in the art, reports of genes and proteins and links to alternative names, classes, gene annotations, sequences and gene structures, and pdb3D structural information can be found in databases such as Kinweb. Similarly, proteomics servers allow access to information for many genes and proteins (including kinases) as well as analytical and predictive tools.

As part of the mechanism of cancer markers, Ser/Thr kinases and Receptor Tyrosine Kinases (RTKs) are required phosphorylases in cell signaling. Cell cycle, survival, proliferation and cell death are all cellular processes that are regulated by cellular signaling, allowing tissue growth, regeneration and maintenance of homeostasis or regression. Thus, some kinases are keen targets for mammalian therapy.

Among the different families of kinases that are part of the human kinase group (kineme), the receptor tyrosine kinase KDR (also known as VEGF receptor 2) can stimulate the survival and proliferation of endothelial cells if it is extracellularly linked by VEGF. Ligand binding then leads to intracellular phosphorylation events, signaling cascades, and ultimately to proliferation. Various treatments attempt to inhibit the delivery of the KDR signal.

Other kinases and ligands important to the function of endothelial cells are TIE2 kinase and angiogenin, PDGF receptors and PDGF and PIGF, ephrin receptor kinase and ephrin, especially EphB4 and ephrin-B2. In addition, the ligand TGF β and its receptor TGF β R (i.e., Alk1/Alk5) play an important role in maintaining vascular integrity. By binding to the TGF β II receptor, TGF β can activate 2 different type I receptors in endothelial cells, namely EC-localized ALK1 and widely expressed ALK5, which have opposite effects on the behavior of EC. ALK1 stimulates EC proliferation and migration via Smad1/5 transcription factors, and ALK5 inhibits these functions via Smad2/3 transcription factors. An example of an Alk5 kinase inhibitor that contributes to EC proliferation and layer formation is SB-431542. Inhibition of ligand binding may be another method of modulating TGF receptor signaling also present in angiogenesis. This has been demonstrated with 2 peptides and also discussed in terms of soluble TGF receptor T β R-Fc. The use of anti-TGF β antibodies, and even TGF β capture agents, would be another strategy to inhibit TGF β signaling.

TGF-beta proteins include a family of conserved dimeric proteins with molecular weights of 25kDa, which are ubiquitously expressed and secreted in an inactive form. Local proteolysis in response to appropriate stimuli results in active TGF ligand. TGF β signaling is involved in a number of conditions and diseases, including cancer, cardiovascular disease, bone disease, CNS disease, PNS disease, inflammatory disease, and neurodegenerative disease.

In epithelial cells, TGF β inhibits cell proliferation. The transition from normal epithelial cells to cancer cells is accompanied by a down-regulation in response to growth inhibition by TGF β, thereby allowing the cells to evade autocrine tumor suppressor activity of TGF β signaling. The increase in TGF β production by cancer cells promotes cancer cell invasion and metastatic behavior. TGF β can induce epithelial to mesenchymal transition (EMT), which makes cells invasive and migratory. Furthermore, the increase in TGF β production exerts an effect on stromal cells and immune cells, providing a favorable microenvironment for cancer progression. TGF-beta proteins signal through T-beta R-I/II receptor kinases and their Smad substrates, but may also be Smad independent signaling, such as ERK MAP kinase, PI3 kinase, Rho-like GTPase, protein phosphatase 2A and Par 6. Activated type I T β R kinases enhance cell survival and can accelerate pathological cell progression.

Type I and type II TGF β receptors (T β R I, T β R II) are single channel transmembrane intracellular serine/threonine kinases that provide binding receptors for extracellular ligands (TGF β). Intracellular signaling occurs through autophosphorylation, transphosphorylation and substrate phosphorylation, resulting in modulation of target gene expression. The cloning and genomic organization of the T β R protein is well known. The T β R sequence is deposited at www.uniprot.org under accession number P36897 as TGFR1_ human and under accession number P37173 as TGF β R2_ human. At the protein level, type I tsr is described as containing a Gly and Ser rich region (GS domain) followed by a receptor kinase domain. T β R II is a constitutively active kinase in its autophosphorylation/phosphorylation state, which binds to type I receptors and phosphorylates them in the GS domain.

The tsr receptor is a tetrameric complex of 2 tss R I and 2 tss R II units, to which the ligand TGF β binds (activated), phosphorylates smads (Smad2 and Smad3) as substrates at their C-terminal SSXS motifs, which in turn bind to Smad 4/are bound by Smad4 to be translocated to the nucleus where they regulate TGF β responsive genes. Different domains that regulate the formation of homomeric and heteromeric complexes in type I and type II T β rs are known. Mutations in the GS domain of T β R I may be constitutively active. The kinase inactivating mutation of type I T β R was found to be K232R and the kinase inactivating mutation of type II T β R was found to be K277R. Inactivating or attenuating mutations of type I and type II T β R genes are found in a variety of cancers. In addition, signaling of tsr is regulated by phosphorylation and dephosphorylation mechanisms, ubiquitination (ubiquitination) and sumoylation (sumoylation), and by endocytosis and TACE-mediated shedding of the extracellular domain of type I, but not type II receptor TACE (akaADAM-17), which mediates shedding of cytokines, GF receptors and adhesion proteins and is highly expressed in cancer.

The X-ray co-crystal (co-crystal) structures of T β R I and FKBP12 have been described, and the kinase activation process has also been discussed. Meanwhile, a variety of crystal structures can be found in the PDB database: 1B6C, 1IAS, 1PY5, 1RW8, 1VJY, 2PJY and model 1 TBI. For T β R II, only X-ray studies of extracellular ligand binding domains are known: 1KTZ, 1M9Z and 1plo (nmr), but no kinase domain.

TGF β signalling involves the sole substrate for Smad-type I T β R receptor kinase. The human genome encodes eight Smads from 3 subfamilies (R-, Co-, I-Smad), which are ubiquitously expressed throughout developmental processes and adult tissues. Smads are not only phosphorylated by TGF β type I receptor kinases, but they are also regulated by oligomerization, ubiquitination and degradation, and nuclear shuttling.

VEGF release has been shown to be regulated by ALK1 and ALK5, whereas TGF β enhances VEGF expression and BMP-9 inhibits VEGF expression.

Studies with the truncated isoform of ALK4 show that this type I kinase is involved in the growth and development of pituitary tumors through dominant negative inhibition of activin signaling. Spatiotemporal window studies of the role of ALK4 in embryonic development, regulation of mesoderm induction, primitive streak formation, gastrulation, major axis formation, and left-right axis determination have not yet elucidated the role of ALK4 in adults.

In a large-scale human candidate screen, the dominant negative ALK2 allele was found to be associated with congenital heart disease such as inappropriate atrioventricular compartment development.

ALK1 binds to T β R-II and endoglin/CD 105/T β R-III and phosphorylates SMAD-1 and SMAD-5. The role of endoglin, particularly the differential regulation of TGF signaling by the two variants (L-and S-endoglin), has been demonstrated. ALK1 functions in vascular remodeling and is found to balance the activation state of the endothelium in inflamed tissues, wounds, and tumors, along with ALK 5. ALK1 is expressed in the lungs, placenta, and other highly vascularized tissues and is selectively found in ECs. ALK1 was also detected on neurons.

Loss of type II T β R expression is associated with high tumor levels of human breast cancer, suggesting that it promotes breast cancer progression. Tumor growth may be characterized by unregulated, i.e., autonomous, cell growth due to disruption of RTK signaling by mutations or other genetic changes. Of the 32000 human coding genes involved in signal transduction, more than 520 protein kinases and 130 protein phosphatases exert tight, reversible control over protein phosphorylation. Selectivity was found for tyrosine and serine/threonine phosphorylation. There are more than 90 known PTK genes in the human genome, more than 50 encoding transmembrane RPTK distributed in 20 subfamilies, and 32 non-receptor PTKs encoding cytoplasm in 10 subfamilies. For example, Trk a plays an important role in thyroid cancer and neuroblastoma, EphB2 and B4 are overexpressed in cancer, Axl and Lck are overexpressed in leukemia.

TGF β inhibitors have been reviewed for use in the treatment of cancer. There are additional indications and pathologies that are indirectly targeted to cancer, wound healing and inflammation through anti-angiogenesis, vascular formation, stabilization, maintenance and degeneration.

Angiogenesis (the development of new blood vessels from pre-existing vessels) is critical in vascular development in embryogenesis, organogenesis and wound healing. In addition to these physiological processes, angiogenesis is important for tumor growth, metastasis and inflammation, leading to diseases such as tumors of the breast, cervix, uterus (endometrium), ovary, lung, bronchi, liver, kidney, skin, oral cavity and pharynx, prostate, pancreas, bladder, blood cells, colon, rectum, bone, brain, central and peripheral nervous system, e.g., breast cancer, colorectal cancer, glioma, lymphoma, etc., as well as inflammatory diseases such as rheumatoid arthritis and psoriasis, or ocular diseases such as macular degeneration and diabetic retinopathy. The molecular mechanisms of the angiogenic switch in angiogenesis and tumorigenesis have been recently discussed. Angiogenesis is regulated by Eph receptor tyrosine kinases and ephrin ligands (e.g., ephrin-B2 signaling by Eph B4 and Eph B1). EphB4 controls vascular morphogenesis during postnatal angiogenesis. Maturation of neovasculature formed by angiogenesis or vasculogenesis requires the production of mural cells (pericytes, smooth muscle cells), extracellular matrix and specialization of the vessel wall for structural support and regulation of vessel function. The regulation of these processes and the interaction between endothelial cells and their parietal cells involve a variety of ligand kinase pairs, such as VEGF/VEGFR1, VEGFR2, ephrin B2/EphB4, PDGFR/PDGFR β, angiopoietin/TIE 2, TGF β/TGF β R-ALK1/ALK 5. Vascular assembly, capillary formation, sprouting, stabilization and destabilization, and even regression, are regulated by the functional balance of these kinases and ligands. Lymphangiogenesis (lymphangiogenesis) is regulated by VEGF receptor 3 and its ligands VEGF C and D and TIE2 and its ligand angiopoietins 1, 2. Inhibition of VEGFR3 and/or TIE2 signaling, and thus inhibition of lymphatic vessel formation, may be one means of stopping tumor cell metastasis. The overall information on pathological angiogenesis led to the hypothesis that: inhibition of angiogenesis is a promising strategy for the treatment of cancer and other disorders.

The importance of TGF β receptors for the angiogenic process was shown by Alk1, endoglin, Alk5, and T β RII KO mice, which exhibit an embryonic lethal phenotype due to vascular defects. Furthermore, in EC, TGF β ligands can stimulate two pathways, namely Smad1/5/8 phosphorylation downstream of Alk1 and Smad2/3 phosphorylation downstream of Alk 5. The two paths interfere with each other. Alk5 knock-in mice with the L45 loop mutation showed defective Smad activation. In EC, TGF β/Alk5 signaling is antagonized by ALK 1.

TGF β exists in at least five isoforms (TGF β 1-5), all of which are unrelated to TGF α, TGF β 1 being a prevalent form. TGF β is a ubiquitous, essential regulator of cellular and physiological processes including proliferation, differentiation, migration, cell survival, angiogenesis and immune surveillance.

Since cancer cells express tumor-specific antigens, they are generally recognized by the immune system and destroyed. During tumorigenesis, cancer cells acquire the ability to evade this immune surveillance through a variety of mechanisms. One major mechanism is cancer cell-mediated immunosuppression by secretion of TGF β, a potent immunosuppressive cytokine. TGF β has the potential to convert from tumor suppressors to tumor promoters and prometastatic factors. The function of TGF β is transmitted by a tetrameric receptor complex consisting of two sets of transmembrane serine-threonine kinase receptors, termed type I and type II receptors, which are activated upon engagement of members of the TGF β superfamily of ligands (which are divided into 2 groups, TGF β/activin and BMP/GDF branches). TGF-beta 1,2, and 3 belong to the TGF-beta/activin ligand branch. These binding events detail downstream responses that are differentially regulated in different cell types.

The importance of fibroblasts in the mesenchymal-epithelial cell interaction of the skin during wound repair is described in the postnatal TGF β RII deletion inducible in skin fibroblasts. During wound repair, the expression of the ligand TGF β and its receptors type RI and RII is regulated both temporally and spatially. CD109 (a GPI-linked cell surface antigen expressed by CD34+ acute myeloid leukemia cell line, EC, activated platelets and T cells) is part of the T β R system in human keratinocytes. Hair Follicle Stem Cells (FSCs) in the hair follicle bulge region can give rise to multiple lineages during the hair cycle and during wound healing. Smad4 (a common mediator of TGF β signaling) is part of FSC maintenance. Smad4KO studies in mouse skin showed the formation of hair follicle defects and squamous cell carcinoma. Potential TGF β inhibition delays the hair growth metaphase process in the hair follicle. The role of TGF β in keratinocyte apoptosis during catagen, which has been well described, may involve specific follicular components of anagen, which are also involved in co-localized T β R and T β RII.

Abnormal activity of TGF β in fibrosis of various organs such as skin, kidney, heart and liver is known, which is the rationale for the use of T β R inhibitors in fibrotic diseases. Systemic sclerosis (scleroderma), a complex disorder of connective tissue leading to fibrosis of the skin and internal organs, has been shown to be TGF β/receptor RI dependent. Pulmonary Arterial Hypertension (PAH) is a potential treatment disorder with ALK5 inhibitors, as abnormal proliferation of peripheral arterial smooth muscle cells is driven by activated TGF β receptors. Treatment with SB525334 was successful in rats. Benefits were also shown with IN-1233 IN rats. Renal fibrosis can lead to diabetes.

The beneficial side effects of TbetaR kinase inhibitor derivatives and the link between TGF signaling and Hepatitis C Virus (HCV) replication are known. TGF signaling is discussed as an emerging stem cell target in metastatic breast cancer. TGF β 1,2,3 and their receptors are expressed in neurons, astrocytes and microglia. TGF signaling modulators can be expected to improve pathological outcomes. The TGF β superfamily in cardiovascular diseases such as atherosclerosis, myocardial ischemia and cardiac remodeling is the focus of cardiovascular research issues.

Further details regarding the biological activity of TGF β are disclosed in WO2009/004753, which is incorporated by reference in its entirety into the present invention.

Furthermore, RON kinase is a valuable target in tumor biology (Wagh et al (2008) Adv Cancer Res.100: 1-33). The Met-related receptor tyrosine kinase RON is involved in tumor growth and metastasis. RON receptors are members of the Met family of cell surface receptor tyrosine kinases and are expressed primarily on epithelial cells and macrophages. The biological response of RON is mediated by the binding of its ligand, hepatocyte growth factor-like protein/macrophage stimulating protein (HGFL). HGFL is synthesized and secreted from hepatocytes, mainly in the form of an inactive precursor, and is activated on the cell surface. Binding of HGFL to RON activates RON and leads to the induction of various intracellular signaling cascades leading to cell growth, motility and invasion. Recent studies have demonstrated the overexpression of RON in a variety of human cancers including breast, colon, liver, pancreas and bladder cancers. In addition, clinical studies have shown that RON overexpression is associated with poor prognosis and metastasis in patients. Forced overexpression of RON in transgenic mice leads to tumorigenesis in the lungs and mammary glands and is associated with metastatic spread. Although overexpression of RON appears to be a hallmark of many human cancers, the mechanism by which RON induces tumorigenesis and metastasis remains unclear. Several strategies are currently being undertaken to inhibit RON as a potential therapeutic target; current strategies include the use of RON blocking proteins, small interfering rnas (sirnas), monoclonal antibodies, and small inhibitors. Overall, these data suggest that RON is a key factor in tumorigenesis and that inhibition of this protein alone or in combination with other current therapies may prove beneficial in the treatment of cancer patients.

Furthermore, TAK1 or CHK2 are valuable targets in the immune and Cell damage response pathways (Delaney & Mlodzik (2006) Cell Cycle5(24):2852-5, a new insight describing the various roles of TGF- β activated kinase-1 and TAK1 in development and immunity. many recent publications have examined the role of TAK1 in model systems from flies to mice. TAK1 appears to play a role in signaling nodes responding to various upstream signals (including inflammatory molecules and developmental cues) rather than following a well-defined linear molecular pathway. then TAK1 affects many downstream processes from innate immune response to patterning and differentiation through JNK, NF κ B and TCF β -catenin signaling. these functional differences are not simply a matter of Cell type. Depending on the nature of the activation signal. Interestingly, the multitasking function of TAK1 is conserved among vertebrates and invertebrates. The study of TAK1 in various experimental systems has the potential to reveal more roles of this kinase, and to elucidate the mechanism by which other signaling molecules fulfill different signaling roles.

Furthermore, checkpoint kinases Chk1 and Chk2 are Ser/Thr protein kinases that function as key regulatory kinases in cellular DNA damage response pathways, limiting cell cycle progression in the presence of DNA damage. The development of checkpoint kinase inhibitors for the treatment of cancer is a major goal of drug development in the past decade, as demonstrated by three checkpoint kinase inhibitors that have entered clinical trials since the last 2005. A number of chemically diverse inhibitors of Chk1 and Chk2 kinase have been described in recent patent literature. Common structural motifs for checkpoint kinase inhibitors have been identified. Currently there are three checkpoint kinase inhibitors in clinical development, which is a continuing effort by the pharmaceutical industry to identify new structural scaffolds for checkpoint kinase inhibition (Janetka & Ashwell (2009) expertOpin Ther paper.200919 (2): 165-97).

Further prior art documents are as follows:

WO2004/014891 discusses pyridazine derivatives as ligands for GABA receptors. The international application does not disclose bipyridine derivatives.

WO2004/084824 describes biaryl substituted 6-membered heterocycles as sodium channel blockers. The international application does not disclose bipyridine derivatives.

WO2004/089286 discloses pyridine derivatives as protein kinase inhibitors. The international application does not disclose bipyridine derivatives.

WO2006/071960 relates to antiproliferative compounds as tyrosine kinase inhibitors. The international application does not disclose bipyridine derivatives.

US2006/270686 relates to heteroaryl derivatives as anti-cancer agents. The us application does not disclose bipyridine derivatives.

US2007/191371 describes substituted heterocyclic compounds as modulators of peroxisome proliferator-activated receptor PPAR. The us application does not disclose bipyridine derivatives.

WO2008/002676 and WO2008/127728 discuss biaryl derivatives and methods for modulating a kinase cascade. These international applications do not disclose bipyridine derivatives.

WO2008/008059 relates to heteroatom-containing compounds as anticancer agents. The international application does not disclose bipyridine derivatives.

US2008/280891 discloses old and new aromatic compounds useful for the treatment of proliferative retinopathy, diabetic retinopathy, macular degeneration and cancer. The us application does not disclose bipyridine derivatives.

WO2009/011850 relates to novel tri (hetero) aryl substituted sulphonamide, amide or sulphide derivatives useful for the treatment of e.g. rheumatoid arthritis, asthma, sepsis, psoriasis, inflammatory bowel disease, Chrohn's disease, multiple sclerosis, pain and cancer. The international application does not disclose bipyridine derivatives.

WO2009/024825 relates to 2-pyrazinylbenzimidazole derivatives as receptor tyrosine kinase inhibitors. The international application does not disclose bipyridine derivatives.

Citation of any reference in this application is not an admission that such reference is pertinent prior art to the present application.

Detailed Description

It is an object of the present invention to provide novel bipyridine derivatives.

In one aspect, the object of the present invention has surprisingly been solved by providing compounds of formula (I):

wherein:

W₁、W₂、W₃independently of one another, N or CR³，

R¹Denotes monocyclic aryl having 5,6, 7,8, 9 or 10C atoms or monocyclic heteroaryl having 5,6, 7,8, 9, 10, 11, 12, 13 or 14C atoms and 1,2,3,4 or 5N, O and/or S atoms, which may each, independently of one another, be substituted by at least one radical chosen from Y, Hal, CN, CF₃And a substituent of OY,

R²represents Ar, Het¹、Het²、NY-Het¹Or NY-Het²Preferably Ar, Het¹Or Het²Each of which may be independently of the other by R⁴The substitution is carried out by the following steps,

R³denotes H, NYY or NY-COY,

R⁴representing Hal, A, - (CYY)_n-OY、-(CYY)_n-NYY、(CYY)_n-Het³、(CYY)_n-O-Het³、SY、NO₂、CF₃、CN、COOY、-CO-NYY、-NY-COA、-NY-SO₂A、-SO₂-NYY、S(O)_mA、-CO-Het³、-O(CYY)_n-NYY、-O(CYY)_n-Het³、-NH-COOA、-NH-CO-NYY、-NH-COO-(CYY)_n-NYY、-NH-COO-(CYY)_n-Het³、-NH-CO-NH-(CYY)_n-NYY、-NH-CO-NH(CYY)_n-Het³、-OCO-NH-(CYY)_n-NYY、-OCO-NH-(CYY)_n-Het³、CHO、COA、=S、=NY、=O，

Y represents H or A, and Y represents hydrogen or A,

a represents an unbranched or branched hydrocarbon radical having 1,2,3,4, 5,6, 7,8, 9 or 10C atoms, wherein 1,2,3,4, 5,6 or 7H atoms may be replaced independently of one another by Hal andor one or two of CH₂The radicals may be independently of one another substituted by O, S, SO₂-CY = CY-group and/or-C ≡ C-group,

ar represents a saturated, unsaturated or aromatic, monocyclic or bicyclic carbocyclic ring having 5,6, 7,8, 9 or 10C atoms,

Het¹represents a saturated or unsaturated monocyclic, bicyclic or tricyclic heterocycle having 3,4,5,6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20C atoms and 1,2,3,4 or 5N, O and/or S atoms,

Het²represents a monocyclic, bicyclic or tricyclic heteroaryl group having 3,4,5,6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20C atoms and 1,2,3,4 or 5N, O and/or S atoms,

Het³denotes a saturated or unsaturated monocyclic, bicyclic or tricyclic heterocycle having 3,4,5,6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20C atoms and 1,2,3,4 or 5N, O and/or S atoms, which may be substituted independently of one another by at least one radical chosen from Hal, A, - (CYY)_n-OY、-(CYY)_n-NYY、SY、NO₂、CN、CF₃、COOY、-CO-NYY、-NY-COA、-NY-SO₂A、-SO₂-NYY、S(O)_mA. -NH-COOA, -NH-CO-NYY, CHO, COA, = S, = NY, = O,

hal represents F, Cl, Br or I,

m represents 0,1 or 2,

n represents 0,1, 2,3 or 4,

and physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

In a preferred embodiment, there is provided a compound of formula (I) wherein:

W₁、W₂、W₃represents CR³，

Or

W₁、W₂Represents CR³And is and

W₃the expression N is used to represent the number of the N,

In a preferred embodiment, there are provided compounds of formula (I) and the above embodiments, wherein:

R¹represents a monocyclic aryl group having 5,6, 7,8, 9 or 10C atoms, preferably phenyl, which may be independently substituted by at least one substituent selected from Y, Hal, CN, CF₃Or a substituent of OY,

R²represents Ar, Het²Or NY-Het²Preferably represents Het²Which may be independently of one another by R⁴The substitution is carried out by the following steps,

R⁴representation A, CF₃、Hal、-(CYY)_n-OY、-(CYY)_n-NYY、(CYY)_n-Het³Preferably represents- (CYY)_n-OY、-(CYY)_n-NYY、(CYY)_n-Het³，

Het³represents a saturated monocyclic heterocycle having 4 or 5C atoms and 1 or 2N and/or O atoms, which may be independently substituted by at least one atom chosen from Hal, A, - (CYY)_n-OY、-(CYY)_n-NYY、SY、NO₂、CN、CF₃、COOY、-CO-NYY、-NY-COA、-NY-SO₂A、-SO₂-NYY、S(O)_mA. -NH-COOA, -NH-CO-NYY, CHO, COA, = S, = NY, = O,

In another aspect, the object of the present invention has surprisingly been solved by providing a compound selected from the group consisting of:

For the avoidance of doubt, if the chemical name and chemical structure of the above compound do not correspond due to the wrong two, the chemical structure is deemed to unambiguously define the compound.

All compounds disclosed generally or explicitly above, including preferred subsets/embodiments of formula (I) and compounds 1 to 45 disclosed herein, are hereinafter referred to as compounds of the invention.

The nomenclature used herein to define compounds, especially the compounds of the invention, is generally based on the rules of the IUPAC organization for compounds, and especially organic compounds.

Unless otherwise indicated in the specification or claims, the terms used to explain the above-mentioned compounds of the invention are to be understood as having the following meanings:

the term "unsubstituted" means that the corresponding radical, group or moiety is free of substituents.

The term "substituted" means that the corresponding radical, group or moiety has one or more substituents. In the case where the atomic group has a plurality of substituents and a plurality of substituents which can be selected are given, the substituents are selected independently of each other and are not necessarily the same.

The term "hydrocarbon radical" or "A" and other radicals having the prefix "hydrocarbon radical" refer for the purposes of the present invention to acyclic, saturated or unsaturated hydrocarbon radicals which may be branched or straight-chain and preferably have from 1 to 10 carbon atoms, i.e.C₁-C₁₀Alkyl radical, C₂-C₁₀-alkenyl and C₂-C₁₀-alkynyl. Alkenyl has at least one C-C double bond and alkynyl has at least one C-C triple bond. The alkynyl group may additionally have at least one C-C double bond. Examples of suitable hydrocarbon radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl (tert-pentyl), 2-or 3-methyl-pentyl, n-hexyl, 2-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl, n-docosyl, vinyl (ethenyl), propenyl (-CH), n-dodecyl (-NH-H-)₂CH=CH₂；-CH=CH-CH₃、-C(=CH₂)-CH₃) Butenyl, pentenyl, hexenyl, heptenyl, octenyl, octadienyl, octadecenyl, octadecen-9-enyl, eicosenyl, eicosa-11-enyl, (Z) -eicosa-11-enyl, docosenyl, docosen-13-enyl, (Z) -docosen-13-enyl, ethynyl, propynyl (-CH)₂-C≡CH、-C≡C-CH₃) Butynyl, pentynyl, hexynyl, heptynyl, octynyl. Particularly preferred is C_1-4-a hydrocarbon radical. C_1-4Hydrocarbon radicals are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl.

The term "cycloalkyl" for the purposes of the present invention refers to saturated and partially unsaturated non-aromatic cyclic hydrocarbon radicals having from 1 to 3 rings, which contain from 3 to 20, preferably from 3 to 12, most preferably from 3 to 8, carbon atoms per radical. The cycloalkyl group may also be part of a bicyclic or polycyclic ring system, wherein for example the cycloalkyl group is bonded to the ring systemThe aryl, heteroaryl or heterocyclyl groups defined herein are fused via any possible and desired ring member. The bonding to the compounds of the general formula (I) can be effected via any possible ring member of the cyclic hydrocarbon radical. Examples of suitable cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl and cyclooctadienyl. Particularly preferred is C₃-C₉-cycloalkyl radical and C₄-C₈-a cyclic hydrocarbon radical. C₄-C₈Cycloalkyl is, for example, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

The term "heterocyclyl" or "heterocycle" for the purposes of the present invention means a mono-or polycyclic ring system of 3 to 20, preferably 5 or 6 to 14, ring atoms comprising carbon atoms and 1,2,3,4 or 5 heteroatoms, in particular nitrogen, oxygen and/or sulfur, where the heteroatoms are identical or different. The ring system may be saturated, monounsaturated or polyunsaturated, but may not be aromatic. In the case of a ring system consisting of at least two rings, the rings may be fused or spiro or otherwise connected. Such "heterocyclyl" groups may be attached through any ring member. The term "heterocyclyl" also includes systems in which the heterocyclic ring is part of a bicyclic or polycyclic saturated, partially unsaturated, and/or aromatic system, for example, in which the heterocyclic ring is fused to "aryl", "cycloalkyl", "heteroaryl", or "heterocyclyl" as defined herein, through any desired and possible ring members of the heterocyclic group. The bonding to the compounds of the general formula (I) can be effected via any of the possible ring members of the heterocyclic radical. Examples of suitable "heterocyclyl" groups are pyrrolidinyl, thiapyrrolidinyl (pyrrolidinyl), piperidinyl, piperazinyl, oxapiperazinyl (oxapiperazinyl), oxapiperidinyl (oxapiperadinyl),Oxadiazolyl, tetrahydrofuryl, imidazolidinyl, thiazolidinyl, tetrahydropyranyl, morpholinyl, tetrahydrothienyl, dihydropyranyl, indolinyl, indolinylmethyl, imidazolidinyl, 2-aza-bicyclo [2.2 ] methyl.2]And (4) octyl.

The term "aryl" for the purposes of the present invention means a monocyclic or polycyclic aromatic hydrocarbon system having from 3 to 14, preferably from 5 to 14, more preferably from 5 to 10, carbon atoms. The term "aryl" also includes systems in which the aromatic ring is part of a bicyclic or polycyclic saturated, partially unsaturated, and/or aromatic system, for example, in which the aromatic ring is fused to "aryl", "cycloalkyl", "heteroaryl", or "heterocyclyl" as defined herein, through any desired and possible ring members of the aromatic group. The bonding to the compounds of the general formula (I) can be effected via any of the possible ring members of the aryl group. Examples of suitable "aryl" are phenyl, biphenyl, naphthyl, 1-naphthyl, 2-naphthyl and anthracenyl, but also indanyl, indenyl or 1,2,3, 4-tetrahydronaphthyl. The most preferred aryl group is phenyl.

The term "heteroaryl" for the purposes of the present invention means a 3 to 15-membered, preferably 5 to 14-membered, more preferably 5-, 6-or 7-membered, mono-or polycyclic, aromatic hydrocarbon radical which comprises at least 1, if appropriate 2,3,4 or 5 heteroatoms, preferably nitrogen, oxygen and/or sulfur, where the heteroatoms are identical or different. The number of nitrogen atoms is preferably 0,1, 2 or 3, and the number of oxygen and sulfur atoms is independently 0 or 1. The term "heteroaryl" also includes systems in which the aromatic ring is part of a bicyclic or polycyclic saturated, partially unsaturated, and/or aromatic system, for example, in which the aromatic ring is fused to "aryl", "cycloalkyl", "heteroaryl", or "heterocyclyl" as defined herein, through any desired and possible ring members of the heteroaryl. The bonding to the compounds of the general formula (I) can be effected via any of the possible ring members of the heteroaryl radical. Examples of suitable "heteroaryl" groups are acridinyl, benzodiazepineAlkenyl, benzimidazolyl, benzisoxazoleAzolyl, benzodioxolyl, benzofuranyl, benzothiadiazolyl, benzoxadiazolylThiazolyl, benzothienyl, benzoOxazolyl, carbazolyl, cinnolinyl, dibenzofuranyl, dihydrobenzothienyl, furanyl, furazanyl, furanyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, isobenzylfuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoindolylAzolyl, naphthyridinyl,A diazolyl group,Azolyl, phenazinyl, phenothiazinyl, phenoOxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl.

For the purposes of the present invention, the terms "alkyl-cycloalkyl", "cycloalkylalkyl", "alkyl-heterocyclyl", "heterocyclylalkyl", "alkyl-aryl", "arylalkyl", "alkyl-heteroaryl" and "heteroarylalkyl" mean that the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are each as defined above and that the cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are each defined above by an alkyl radical, preferably C₁-C₈-hydrocarbyl, more preferably C₁-C₄-the hydrocarbon group is attached to the compound of formula (la).

The term "hydrocarbyloxy" or "hydrocarbyloxy" for the purposes of this invention refers to a hydrocarbyl group as defined above attached to an oxygen atom. The connection of which with a compound of the formulaThrough an oxygen atom. Examples are methoxy, ethoxy and n-propoxy, isopropoxy. Preference is given to "C" having the indicated number of carbon atoms₁-C₄-an alkoxy group.

The term "cycloalkyloxy" or "cycloalkyloxy" for the purposes of the present invention means a cycloalkyl group as defined above attached to an oxygen atom. The bond to the compound of formula (I) is through an oxygen atom. Examples are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy. Preference is given to "C" having the indicated number of carbon atoms₃-C₉A cycloalkyloxy group ".

The term "heterocyclyloxy" for the purposes of the present invention refers to a heterocyclyl group as defined above which is attached to an oxygen atom. The bond to the compound of formula (I) is through an oxygen atom. Examples are pyrrolidinyloxy, thiapyrrolidinyloxy, piperidinyl oxy, piperazinyl oxy.

The term "aryloxy" for the purposes of the present invention means an aryl radical as defined above which is bonded to an oxygen atom. The bond to the compound of formula (I) is through an oxygen atom. Examples are phenyloxy, 2-naphthyloxy, 1-naphthyloxy, biphenyloxy, indanyloxy. Preferred is a phenoxy group.

The term "heteroaryloxy" for the purposes of the present invention means a heteroaryl group as defined above attached to an oxygen atom. The bond to the compound of formula (I) is through an oxygen atom. Examples are pyrrolyloxy, thiophenyloxy, furanyloxy, imidazolyloxy, thiazolyloxy.

The term "carbonyl" or "carbonyl moiety" for the purposes of the present invention refers to the group-C (O) -.

The term "hydrocarbyl carbonyl" for purposes of this invention refers to a "hydrocarbyl-c (o) -group, wherein hydrocarbyl is as defined herein.

The term "hydrocarbyloxycarbonyl" or "hydrocarbyloxycarbonyl" for purposes of this invention refers to a "hydrocarbyl-O-c (O) -group, wherein hydrocarbyl is as defined herein.

The term "hydrocarbyloxyhydrocarbyl" for purposes of this invention refers to a "hydrocarbyl-O-hydrocarbyl-" group, wherein hydrocarbyl is as defined herein.

The term "halohydrocarbyl" for the purposes of the present invention refers to a hydrocarbyl group, as defined herein, which contains at least one carbon atom substituted with at least one halogen, as defined herein.

The terms "halogen", "halogen atom", "halogen substituent" or "Hal" mean, for the purposes of the present invention, one or, where appropriate, a plurality of fluorine (F, fluoro), bromine (Br, bromo), chlorine (Cl, chloro) or iodine (I, iodo) atoms. The designations "dihalogen", "trihalogen" and "perhalogen" refer to two, three or four substituents, respectively, wherein each substituent may be independently selected from fluorine, chlorine, bromine, iodine. "halogen" preferably means a fluorine, chlorine or bromine atom. When halogen is a substituent on a hydrocarbyl group (halohydrocarbyl) or a hydrocarbyloxy group, most preferred is fluorine (e.g., CF)₃And CF₃O)。

The term "hydroxyl" or "hydroxy" means an OH group.

The term "composition" (e.g., a "composition" in a pharmaceutical composition) for purposes of this invention includes a product comprising one or more active ingredients and one or more inert ingredients that constitute a carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from separation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention include any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

It is to be understood that the term "administration" or "administering" of a compound means providing a compound of the invention or a prodrug of a compound of the invention to an individual in need thereof.

The term "effective amount" as used herein refers to any amount of a drug or pharmaceutical substance that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for example, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount that results in an improved treatment, cure, prevention or amelioration of a disease, disorder or side effect or a reduction in the rate of progression of a disease or disorder as compared to a corresponding individual not receiving that amount. The term also includes within its scope an amount effective to enhance normal physiological function.

The present invention includes all stereoisomers of the compounds of the invention in admixture or in pure or substantially pure form. The compounds of the present invention may have asymmetric centers on any carbon atom. They may therefore be present in the form of their racemates, in the form of pure enantiomers and/or diastereomers or in the form of mixtures of these enantiomers and/or diastereomers. The mixture may have any desired mixture ratio of stereoisomers.

Thus, for example, the compounds of the invention which have one or more chiral centers and are present in the form of racemates or diastereomeric mixtures can be separated into their optically pure isomers, i.e. enantiomers or diastereomers, by methods known per se. The compounds of the invention can be isolated by column separation on chiral or achiral phases or by recrystallization from solvents optionally optically active or from optically active acids or bases or by derivatization with optically active reagents, for example optically active alcohols, and subsequent removal of the radicals.

The compounds of the invention may exist as "pure" E or Z isomers in the form of their double bond isomers, or as mixtures of these double bond isomers.

Where possible, the compounds of the invention may be in tautomeric form, for example keto-enol tautomers.

The compounds of the invention may also be in the form of any desired prodrug, for example an ester, carbonate, carbamate, urea, amide or phosphate ester, in which case the actual biologically active form can only be released metabolically. Any compound that can be converted in vivo to provide a biologically active agent (i.e., a compound of the invention) is a prodrug within the scope and spirit of the invention.

Prodrugs in various forms are well known in the art and are described, for example, in the following references:

(i) wermuth CG et al, Chapter 31 671-696, The Practice of medicinal chemistry, academic Press 1996;

(ii) bundgaard H, Design of Prodrugs, Elsevier 1985; and

(iii) bundgaard H, Chapter 5: 131-.

The references are incorporated herein by reference.

It is also known that chemical substances are converted in vivo into metabolites, which may also cause the desired biological effect-in some cases even in more pronounced forms-in appropriate cases.

Any biologically active compound that is converted in vivo by metabolism from any of the compounds of the invention is a metabolite within the scope and spirit of the invention.

If they have sufficiently basic groups, for example secondary or tertiary amines, the compounds of the invention can be converted into salts with inorganic or organic acids. The pharmaceutically acceptable salts of the compounds of the present invention are preferably formed with hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic, carbonic, formic, acetic, sulfoacetic, trifluoroacetic, oxalic, malonic, maleic, succinic, tartaric, racemic, malic, pamoic, mandelic, fumaric, lactic, citric, taurocholic, glutaric, stearic, glutamic or aspartic acid. Salts formed are, in particular, the hydrochloride, chloride, hydrobromide, bromide, iodide, sulfate, phosphate, methanesulfonate, toluenesulfonate, carbonate, bicarbonate, formate, acetate, sulfoacetate, trifluoromethanesulfonic acid, oxalate, malonate, maleate, succinate, tartrate, malate, pamoate, mandelate, fumarate, lactate, citrate, glutarate, stearate, aspartate and glutamate salts. Furthermore, the stoichiometry of a salt formed from a compound of the invention can be an integer multiple or a non-integer multiple of one.

If they contain sufficiently acidic groups, for example carboxyl, sulfonic acid, phosphoric acid or phenolic groups, the compounds of the invention can be converted into their physiologically tolerated salts with inorganic or organic bases. Examples of suitable inorganic bases are ammonium, sodium hydroxide, potassium hydroxide, calcium hydroxide, and examples of organic bases are ethanolamine, diethanolamine, triethanolamine, ethylenediamine, t-butylamine, t-octylamine, dehydroabietylamine, cyclohexylamine, dibenzylethylenediamine, and lysine. Furthermore, the stoichiometry of the salt formed by the compounds of the invention may be an integer multiple or a non-integer multiple of one

The compounds of the invention may also be in the form of their solvates, in particular hydrates, which may be obtained, for example, by crystallization from a solvent or from an aqueous solution. In addition, one, two, three, or any number of solvent or water molecules may be combined with the compounds of the present invention to give solvates and hydrates.

The term "solvate" means a hydrate, alcoholate or other solvate of crystallization.

It is known that chemical substances form solids which exist in different sequential states, which are referred to as polymorphs or polymorphic modifications. The various variants of polymorphic substances may differ greatly in their physical properties. The compounds of the invention may exist in various polymorphic forms, and in addition certain variants may be metastable. All such polymorphs of the compounds are considered to be within the scope of the present invention.

Surprisingly, the compounds of the invention are characterized by potent and/or selective inhibition of ATP consuming proteins, preferably tyrosine kinases and serine/threonine kinases, more preferably TGF- β, RON, TAK1, CHK2, PDK1, Met, PKD1, MINK1, SAPK2- α, SAPK2- β, MKK1, GCK, HER4, ALK1, ALK2, ALK4, ALK5 and TbR type II. More preferably, serine/threonine kinase is inhibited. The most preferred inhibited kinases are TGF-beta receptor kinases, RON, TAK1, PKD1, MINK1, SAPK 2-alpha, SAPK 2-beta and/or CHK2, with TGF-beta receptor kinases being highly preferred.

Due to its surprisingly potent and/or selective enzyme inhibition, the compounds of the present invention can advantageously be administered at lower doses than other inhibitors of the art having lower efficacy or selectivity, while still achieving an equivalent or even better desired biological effect. Furthermore, such a dose reduction may advantageously result in fewer or even no medical side effects. In addition, it is understood from the high inhibitory selectivity of the compounds of the invention that the unwanted side effects themselves are reduced regardless of the dosage applied.

In general, compounds of the invention that are inhibitors of ATP consuming proteins have an inhibition constant IC of less than about 10 μ M, preferably less than about 1 μ M₅₀。

The compounds of the present invention preferably exhibit advantageous biological activities that can be readily demonstrated in enzyme-based assays, such as the assays of the examples described herein. In the enzyme-based assay, the compounds of the invention preferably show and cause an inhibitory effect, typically by an IC in the appropriate range, preferably in the micromolar range, more preferably in the nanomolar range₅₀The value proves.

As discussed herein, these signaling pathways are associated with a variety of diseases. Accordingly, the compounds of the present invention are useful in the prevention and/or treatment of diseases that rely on one or more of said signalling pathways by interacting with said signalling pathways. Accordingly, the present invention relates to compounds of the invention as promoters or inhibitors, preferably as inhibitors, of the signaling pathways described herein, in particular of the TGF- β signaling pathway.

In another aspect, the objects of the invention have surprisingly been solved by providing the use of a compound of the invention for inhibiting an ATP consuming protein, preferably TGF-beta receptor kinase, RON, TAK1, PKD1, MINK1, SAPK 2-a, SAPK2- β and/or CHK 2.

The term "inhibit and/or prevent" for the purposes of the present invention is intended to mean: "partially or completely inhibit and/or prevent". In this case, it is within the expertise of the person skilled in the art to measure and determine such inhibitory and/or inhibitory effects by means of customary measurement and determination methods. Thus, for example, partial inhibition and/or inhibition may be measured and determined relative to complete inhibition and/or inhibition.

In another aspect, the object of the present invention has surprisingly been solved by providing a process for the preparation of a compound of the present invention, comprising the steps of:

(a) reacting a compound of formula (II)

Wherein

R⁵Denotes Hal or B (OH)₂And is and

R¹and Hal has the meaning defined above,

with a compound of the formula (III),

wherein

R⁶Represents Hal, boric acid or a borate, and

R²、W₁、W₂、W₃and Hal has the meaning defined above,

to obtain the compound of the formula (I),

wherein

R¹、R²、W₁、W₂And W₃Having the meaning as defined above, and which,

and optionally R as defined above¹And/or R²Conversion of a group to another R¹And/or R²Groups, for example by cleavage of protecting groups and/or introduction of hydrocarbon groups,

or

(b) Reacting a compound of formula (IV)

Wherein

R⁷Represents Hal, boric acid or a borate, and

R²、W₁、W₂、W₃and Hal has the meaning defined above,

with a compound of the formula (V),

R⁸-R¹ (V)

wherein

R⁸Denotes Hal or B (OH)₂And is and

R¹and Hal has the meaning defined above,

to give a compound of the formula (I)

Wherein

R¹、R²、W₁、W₂And W₃Having the meaning as defined above, and which,

or

(c) Reacting a compound of formula (VI)

Wherein

R⁹Denotes Hal or B (OH)₂And is and

R¹、W₁、W₂、W₃and Hal has the meaning defined above,

with a compound of the formula (VII),

R¹⁰-R² (VII)

wherein

R¹⁰Represents Hal, boric acid or a borate, and

R²and Hal has the meaning defined above,

to obtain the compound of the formula (I),

wherein

R¹、R²、W₁、W₂And W₃Having the meaning as defined above, and which,

and optionally

(d) Converting a base or acid of the compound of formula (I) into a salt thereof.

Some of the crude products were subjected to standard chromatographic treatments using solvent mixtures containing methanol, ethanol, isopropanol, n-hexane, cyclohexane, dichloromethane, n-heptane or petroleum ether, respectively.

For a more detailed description of the preparation, please also refer to the examples and the following general description of the preferred conditions.

Physiologically acceptable salts of the compounds of the invention can also be obtained by isolating and/or treating the compounds of the invention obtained by said reaction with an acid or a base.

The compounds of the invention and the starting materials for their preparation are prepared by the methods described in the examples or by methods known per se, such as those described in the literature (for example, standard works, such as Houben-Weyl, Methoden der Organischen Chemie [ methods of Organic chemistry ], Georg Thieme Verlag, Stuttgart; Organic Reaction, John Wiley & Sons, Inc., New York), to be precise under Reaction conditions which are known and suitable for the Reaction. It is also possible to use process variants which are known per se but are not described in greater detail here.

If desired, the starting materials of the claimed process can also be formed in situ, without separating them from the reaction mixture, but directly converting them further into the compounds of the invention. On the other hand, the reaction may be carried out stepwise.

Preferably, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, e.g. diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or diAn alkane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, Dimethylformamide (DMF) or N-methylpyrrolidone (NMP); nitriles such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of said solvents or mixtures with water. In general, polar solvents are preferred. Examples of suitable polar solvents are chlorinated hydrocarbons, alcohols, glycol ethers, nitriles, amides and sulfoxides or mixtures thereof. More preferred are amides, especially Dimethylformamide (DMF).

As noted above, the reaction temperature is between about-100 ℃ and 300 ℃, depending on the reaction step and the conditions used.

The reaction time is generally in the range of several minutes to several days, depending on the reactivity of the respective compound and the respective reaction conditions. Suitable reaction times can be readily determined by methods known in the art, such as reaction monitoring. Suitable reaction times are generally in the range of from 10 minutes to 48 hours, based on the reaction times given above.

The base of the compounds of the invention can be converted with an acid into the relevant acid addition salt, for example by reacting equal amounts of base and acid in a preferably inert solvent (e.g. ethanol), any evaporation. Suitable acids for this reaction are in particular those which give rise to physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, sulfurous acid, dithionic acid, nitric acid, hydrohalic acids, for example hydrochloric acid or hydrobromic acid, phosphoric acids, for example orthophosphoric acid, sulfamic acid, and furthermore organic acids, in particular aliphatic, cycloaliphatic, araliphatic (araliphatic), aromatic or heterocyclic mono-or polybasic carboxylic acids, sulfonic acids or sulfuric acids, for example formic acid, acetic acid, propionic acid, caproic acid, caprylic acid, capric acid, palmitic acid, octadecanoic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, trimethoxybenzoic acid, adamantanecarboxylic acid, p-toluenesulfonic acid, glycolic acid, pamoic acid, chlorophenoxyacetic acid, aspartic acid, nicotinic, Glutamic acid, proline, glyoxylic acid, palmitic acid, p-chlorophenoxyisobutyric acid, cyclohexanecarboxylic acid, glucose 1-phosphate, naphthalene monosulfonic acid or naphthalene disulfonic acid, or dodecylsulfuric acid.

Salts with physiologically unacceptable acids, such as picrates, can be used to isolate and/or purify the compounds of the invention.

On the other hand, the compounds of the invention can be converted into the corresponding metal salts, in particular alkali metal salts or alkaline earth metal salts, or into the corresponding ammonium salts, with bases such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate. Suitable salts are, furthermore, substituted ammonium salts, such as dimethyl-, diethyl-and diisopropyl-ammonium salts, monoethanol-, diethanol-and diisopropyl-ammonium salts, cyclohexyl-and dicyclohexyl-ammonium salts, dibenzylethylenediamine salts, and also salts formed, for example, with arginine or lysine.

If desired, the free bases of the compounds of the invention can be liberated from their salts by treatment with strong bases, such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, provided that no further acidic groups are present in the molecule. In the case of compounds of the invention having a free acid, salt formation can also be achieved by treatment with a base. Suitable bases are alkali metal hydroxides, alkaline earth metal hydroxides or organic bases in the form of primary, secondary or tertiary amines.

Each of the reaction steps described herein may optionally be followed by one or more work-up operations and/or separation operations. Suitable such procedures are known in the art, for example from standard works such as Houben-Weyl, Methoden der organischen Chemie [ methods of organic chemistry ], Georg-Thieme-Verlag, Stuttgart. Examples of such operations include, but are not limited to, evaporation of solvent, distillation, crystallization, fractional crystallization, extraction operations, washing operations, digestion operations, filtration operations, chromatography, HPLC chromatography, and drying operations, particularly drying operations conducted under vacuum and/or at elevated temperatures.

In another aspect, the object of the present invention has surprisingly been solved by providing a medicament comprising at least one compound of the present invention.

In another aspect, the object of the present invention has surprisingly been solved by providing a medicament comprising at least one compound of the invention for the treatment and/or prevention of a physiological and/or pathophysiological condition selected from the group consisting of: "cancer, tumor, malignant tumor, benign tumor, solid tumor, sarcoma, carcinoma, hyperproliferative disorder, carcinoid, Ewing's sarcoma, Kaposi's sarcoma, brain tumor, tumor derived from the brain and/or nervous system and/or meninges, glioma, glioblastoma, neuroblastoma, gastric cancer, renal cell carcinoma, prostate cancer, connective tissue tumor, soft tissue sarcoma, pancreatic tumor, liver tumor, head tumor, neck tumor, larynx cancer, esophageal cancer, thyroid cancer, osteosarcoma, retinoblastoma, thymoma, testicular cancer, lung adenocarcinoma, small cell lung cancer, bronchial cancer, breast cancer, intestinal cancer, colorectal tumor, colon cancer, rectal cancer, gynecological tumor, ovarian tumor, uterine cancer, cervical cancer, uterine body cancer, Endometrial cancer, bladder cancer, cancer of the genitourinary tract, bladder cancer, skin cancer, epithelial tumors, squamous epithelial cancer, basal cell carcinoma, acanthocyte cancer (spinoalioma), melanoma, intraocular melanoma, leukemia, monocytic leukemia, chronic myelogenous leukemia (myelogenous leukemia), chronic lymphocytic leukemia, acute myelogenous leukemia, acute lymphocytic leukemia, lymphoma, ophthalmic diseases, choroidal neovascularization, diabetic retinopathy, inflammatory diseases, arthritis, neurodegeneration, graft rejection, metastatic growth, fibrosis, restenosis, HIV infection, atherosclerosis, inflammation and wound healing, angiogenesis, cardiovascular system, bone, CNS and/or PNS disorders. The invention encompasses the corresponding use for the preparation of a medicament for the treatment and/or prophylaxis of the above-mentioned conditions. The invention also includes corresponding methods of treatment by administering to a patient in need thereof at least one compound of the invention.

The compounds of the present invention may be used in combination with one or more other active substances (ingredients, drugs) for the treatment, prevention, inhibition or amelioration of diseases or conditions for which the compounds of the present invention or said other substances have a functional effect. Typically, a combination of drugs is safer or more effective than either drug alone in the combination, or a combination of drugs is safer or more effective than would be expected based on the additive properties of the drugs. The other drug or drugs may be administered by a route commonly used, either simultaneously or sequentially with the compound of the present invention in an amount commonly used. When the compound of the present invention is used simultaneously with one or more other drugs, a combination product containing the one or more other drugs and the compound of the present invention is preferable. However, combination therapy also includes therapies in which a compound of the invention and one or more other drugs are administered in different staggered regimens. When used in combination with other active ingredients, the compounds of the present invention or other active ingredients or both may be effectively used at lower doses than when each is used alone. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients in addition to the compounds of the present invention.

Examples of other active substances (ingredients, drugs) that may be administered in combination (separately or in the same pharmaceutical composition) with a compound of the invention include, but are not limited to, the classes of compounds and specific compounds listed in table 1:

in a preferred embodiment, the compounds of the invention are administered in combination with one or more known antineoplastic agents, such as the following antineoplastic agents: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxins, antiproliferative agents, prenyl protein transferase (prenyl transferase) inhibitors, HMG-CoA-reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors. The compounds of the invention are particularly suitable for administration simultaneously with radiotherapy.

The compounds of the invention are particularly well suited for administration in combination with radiotherapy. The synergistic effect of VEGF inhibition in combination with radiotherapy is known to the person skilled in the art (WO 00/61186).

In the present invention, the term "estrogen receptor modulator" refers to a compound that interferes with or inhibits the binding of estrogen to the estrogen receptor-regardless of the mode of action. Non-limiting examples of estrogen receptor modulators are tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4- [7- (2, 2-dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1-piperidinyl) ethoxy ] phenyl ] -2H-1-benzopyran-3-yl ] phenyl-2, 2-dimethyl-propionate, 4' -dihydroxybenzophenone-2, 4-dinitrophenylhydrazone, and SH 646.

In the present invention, the term "androgen receptor modulator" refers to a compound that interferes with or inhibits the binding of androgens to the androgen receptor-regardless of the mode of action. Non-limiting examples of androgen receptor modulators are finasteride and other 5 α -reductase inhibitors, nilutamide, flutamide, bicalutamide, liazole and abiraterone acetate.

In the present invention, the term "retinoid receptor modulator" refers to compounds that interfere with or inhibit the binding of retinoids to retinoid receptors-regardless of the mode of action. Non-limiting examples of retinoid receptor modulators are bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α -difluoromethylornithine, ILX23-7553, trans-N- (4' -hydroxyphenyl) tretinoin, and N-4-carboxyphenyltretinoin.

In the present invention, the term "cytotoxin" refers to a compound that mainly causes cell death by directly acting on cell functions or a compound that interferes with or inhibits cell meiosis, such as alkylating agents, tumor necrosis factors, intercalating agents, microtubule inhibitors and topoisomerase inhibitors. Non-limiting examples of cytotoxins are tirapazimin, sertenef, cachectin, ifosfamide, tasolinamine, lonidamine, carboplatin, hexamethaminem, prednimustine, dibromodulcitol, ramustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin (heptaplatin), estramustine, enkephalin tosylate, trofosfamide, nimustine, dibromospiro ammonium chloride, pyrimipide, lobaplatin, satraplatin, mitomycin, cisplatin, irofumevin, dexifosfamide, cis-aminodichloro (2-methylpyridine) platinum (cis-aminodichloro (2-methylpyridine) platine), benzylguanine, glufosfamide, GPX100, (trans ) -bis- μ - (hexane-1, 6-diamine) - μ -diamine (II) bis- [ II (tetrachloro) chloride) ] (II) platinum (tetrachloro), platinum (II) chloride (tetrachloro), and mixtures thereof, Diazopyridinylspermine (Diarizidinylspermine), arsenic trioxide, 1- (11-dodecylamino-10-hydroxyundecyl) -3, 7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, naproxen-free, valrubicin, amrubicin, antineoplastic, 3 '-deamino-3' -morpholino-13-deoxo-10-hydroxycarminomycin, anamycin, calicheacin, eletrinder, MEN10755 and 4-demethoxy-3-deamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (WO 00/50032).

Non-limiting examples of microtubule inhibitors are paclitaxel, vindesine sulfate, 3',4' -didehydro-4 '-deoxy-8' -norvinblastine, docetaxel, rhizomycin, dolastatin, mitobutrine-isethionate, auristatin, cimadrol, RPR109881, BMS184476, vinflunine, cryptophycine, 2,3,4,5, 6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) -benzenesulfonamide, vinblastine dehydrate, N-dimethyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-tert-butylamide, TDX258 and BMS 188797.

Non-limiting examples of topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ',4' -O-exo-benzylidene-tebucin (chartreusine), 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4, 5-kl-]Acridine-2- (6H) propylamine, 1-amino-9-ethyl-5-fluoro-2, 3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo- [ de]Pyrano- [3',4': b,7]Indolizino [1,2b ]]Quinoline-10, 13(9H,15H) -dione, lurtotecan, 7- [2- (N-isopropylamino) ethyl]- (20S) camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzosin, 2 '-dimethylamino-2' -deoxy-etoposide, GL331, N- [2- (dimethylamino) ethyl ] etoposide]-9-hydroxy-5, 6-dimethyl-6H-pyrido [4,3-b]Carbazole-1-carboxamide, asularnine, (5a,5aB,8aa,9b) -9- [2- [ N- [2- (dimethylamino) ethyl group]-N-methylamino radical]Ethyl radical]-5- [ 4-hydroxy-3, 5-dimethoxyphenyl group]-5,5a,6,8,8a, 9-hexahydrofuro (3',4':6,7) naphtho (2,3-d) -1, 3-dioxol-6-one, 2,3- (methylenedioxy) -5-methyl-7-hydroxy-8-methoxybenzo [ c ]]Phenanthridines6, 9-bis [ (2-aminoethyl) amino group]-benzo [ g ]]Isoquinoline-5, 10-dione, 5- (3-aminopropylamino) -7, 10-dihydroxy-2- (2-hydroxyethylaminomethyl) -6H-pyrazolo [4,5,1-de]-acridin-6-one, N- [1- [2 (diethylamino) ethylamino]-7-methoxy-9-oxo-9H-thia-neAlk-then-4-ylmethyl]Formamide, N- (2- (dimethyl-amino) -ethyl) acridine-4-carboxamide, 6- [ [2- (dimethylamino) -ethyl ] carbonyl]Amino group]-3-hydroxy-7H-indeno [2,1-c]Quinolin-7-one and dimesna.

Non-limiting examples of antiproliferative agents are antisense RNA-and antisense DNA-oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001 and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, deoxyfluorouridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine octadecyl sodium phosphate (cytarabine-ocfosfate), fosetadine sodium hydrate, raltitrexed, pacitexide, ethirimol, thiazoline, decitabine, nolatrexed, pemetrexed, lagitabine, 2' -deoxy-2 ' -methylenecytidine, 2' -fluoromethylene-2 ' -deoxycytidine, N- [5- (2, 3-dihydrobenzofuranyl) sulfonyl ] -N ' - (3, 4-dichlorophenyl) urea, N6- [ 4-deoxy-4- [ N2- [2(E),4(E) -Tetradecadienoyl ] glycylamino ] -L-glycero-B-L-manno-heptopyranosyl (heptopyranosyl) ] adenine, aplidine, ecteinascidin, troxacitabine, 4- [ 2-amino-4-oxo-4, 6,7, 8-tetrahydro-3H-pyrimido [5,4-B ] [1,4] thiazin-6-yl- (S) -ethyl ] -2, 5-thiophenoyl-L-glutamic acid, aminopterin, 5-fluorouracil, aragonin, 11-acetyl-8- (carbamoyloxymethyl) -4-formyl-6-methoxy-14-oxa-1, 11-diaza-tetracyclo- (7.4.1.0.0) -tetradec-2, 4, 6-trien-9-yl acetate, octahydroindolizinetriol, lometrexol, dexrazoxane, methioninase (methioninase), 2 '-cyano-2' -deoxy-N4-palmitoyl-1-B-D-arabinofuranosyl cytosine and 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone.

"antiproliferative agents" also include monoclonal antibodies against growth factors such as trastuzumab and tumor suppressor genes such as p53, which are not listed under "angiogenesis inhibitors".

In a further aspect of the invention, there is provided a medicament according to the above aspects and embodiments, wherein at least one additional pharmacologically active substance (drug, ingredient) is comprised in the medicament.

In a preferred embodiment, the at least one pharmacologically active substance is a substance as described herein.

In a further aspect of the invention there is provided a medicament according to the above aspects and embodiments, wherein the medicament is applied before and/or during and/or after treatment with at least one further pharmacologically active substance.

In another aspect of the invention, pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of the invention are provided.

In a preferred embodiment, the pharmaceutical composition contains at least one further compound selected from the group consisting of physiologically acceptable excipients, adjuvants, diluents, carriers and/or further pharmacologically active substances which are not compounds of the invention.

In another aspect of the invention, pharmaceutical compositions are disclosed comprising at least one compound of the invention, at least one pharmacologically active agent described herein which is not a compound of the invention; and a pharmaceutically acceptable carrier.

Another embodiment of the invention is a process for the preparation of said pharmaceutical compositions, characterized in that one or more compounds of the invention and one or more compounds selected from the group consisting of solid, fluid or semi-liquid excipients, adjuvants, diluents, carriers and pharmaceutically active agents other than the compounds of the invention are converted into suitable dosage forms.

In another aspect of the invention, a kit is provided comprising a therapeutically effective amount of at least one compound of the invention and/or at least one pharmaceutical composition as described herein and a therapeutically effective amount of at least one additional pharmacologically active substance which is not a compound of the invention.

The pharmaceutical compositions of the present invention may be administered by any method that achieves their intended purpose. For example, administration can be by oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intra-articular, intraspinal, transtracheal, ocular, subcutaneous, intraperitoneal, transdermal, or buccal routes. Alternatively or concurrently, administration may be by the oral route. The dose administered will depend on the age, health and weight of the recipient, and on the type of concurrent treatment, if any, the frequency of the treatment, and the nature of the effect desired. Parenteral administration is preferred. Oral administration is particularly preferred.

Suitable dosage forms include, but are not limited to, capsules, tablets, pellets, dragees, semi-solid formulations, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, poultices, gels, tape (tape), eye drops, solutions, syrups, aerosols, suspensions, emulsions, which can be prepared according to methods known in the art, for example as described below:

and (3) tablet preparation: the active ingredient is mixed with the auxiliaries, the mixture is compressed into tablets (direct compression), and optionally part of the mixture is granulated before compression.

And (3) capsule preparation: mixing one or more active ingredients with adjuvants to obtain a flowable powder, optionally granulating the powder, filling the powder/granules into an open capsule, and capping the capsule.

Semisolid preparation (ointment, gel, cream): dissolving/dispersing one or more active ingredients in an aqueous or fatty carrier; the aqueous/fat phase is then mixed with the complementary fat/aqueous phase and homogenized (for cream only).

Suppositories (rectal and vaginal): the active ingredient(s) is/are dissolved/dispersed in a carrier material which is liquefied by heating (rectal suppository: the carrier material is usually a wax; pessary: the carrier material is usually a solution of a heated gelling agent), the mixture is poured into suppository moulds, annealed and the suppositories are removed from the moulds.

Aerosol: one or more active agents are dispersed/dissolved in a propellant and the mixture is charged to a nebulizer.

In general, non-chemical routes for preparing pharmaceutical compositions and/or pharmaceutical formulations include processing steps performed on suitable mechanical means known in the art to convert one or more compounds of the present invention into a dosage form suitable for administration to a patient in need of such treatment. Typically, converting one or more compounds of the invention into such dosage forms comprises adding one or more compounds selected from the group consisting of: carriers, excipients, adjuvants and pharmaceutically active ingredients which are not compounds of the present invention. Suitable processing steps include, but are not limited to, combining, milling, mixing, granulating, dissolving, dispersing, homogenizing, molding, and/or compressing the respective active and inactive ingredients. Mechanical tools for carrying out said process steps are known in the art, for example from Ullmann's Encyclopedia of Industrial chemistry, fifth edition. In this respect, the active ingredients are preferably at least one compound of the invention and one or more additional pharmaceutically active agents which are not compounds of the invention, preferably those disclosed herein which are not compounds of the invention, which exhibit valuable pharmaceutical properties.

Particularly suitable for oral use are tablets, pills, coated tablets, capsules, powders, granules, syrups, juices (juice) or drops, for rectal use are suppositories, for parenteral use are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, for topical use are ointments, creams or powders. The compounds of the invention may also be lyophilized, the resulting lyophilizates being used, for example, for the preparation of injectable preparations. The given formulations can be sterilized and/or contain adjuvants (assistant), such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for varying the osmotic pressure, buffer substances, dyes, flavorings and/or a multiplicity of further active ingredients, for example one or more vitamins.

Suitable excipients are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical administration and do not react with the compounds of the invention, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, triacetin, gelatin, carbohydrates such as lactose, sucrose, mannitol, sorbitol or starch (corn starch, wheat starch, rice starch, potato starch), cellulose preparations and/or calcium phosphate salts such as tricalcium phosphate or calcium hydrogen phosphate, magnesium stearate, talc, gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and/or vaseline.

If desired, disintegrating agents can be added, such as the starches mentioned above as well as carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate. Adjuvants include, without limitation, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, a film-coating solution (lacquer solution) and suitable organic solvents or solvent mixtures. To prepare coatings resistant to gastric juices or to provide dosage forms with the advantage of a long-lasting effect, tablets, dragees or pills can comprise an inner dosage component and an outer dosage component, the latter enclosing the former in the form of a shell. The two components may be separated by an enteric layer which serves to resist disintegration in the stomach and allows the inner component to pass intact through the stomach into the duodenum or to be delayed in release. A variety of materials may be used for such enteric layers or coatings, such materials including a number of polymeric acids and solutions of polymeric acids with such materials as shellac, acetyl alcohol (acetyl alcohol), suitable cellulosics such as acetyl cellulose phthalate, cellulose acetate or hydroxypropylmethyl cellulose phthalate. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to identify active compound dosage combinations.

Suitable carrier substances are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral or topical application and which do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petrolatum. In particular, tablets, coated tablets, capsules, syrups, suspensions, drops or suppositories are used for enteral administration, solutions, preferably oily or aqueous solutions, also suspensions, emulsions or implants are used for parenteral administration, ointments, creams or powders are used for topical application. The compounds of the invention may also be lyophilized and the resulting lyophilizates may be used, for example, for the preparation of injectable preparations.

The given formulations may be sterilized and/or may contain excipients such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing osmotic pressure, buffer substances, colorants, flavors and/or fragrances. They may also, if desired, contain one or more further active compounds, for example one or more vitamins.

Other pharmaceutical preparations which can be used orally include push-fit (push-fit) capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules can contain the active compounds in the form of granules which can be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin. In addition, stabilizers may be added.

Liquid forms in which the novel compositions of the present invention may be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical media. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions. Additionally, suspensions of the active compounds may be administered, such as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).

Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran, and may also optionally contain stabilizers.

For administration in the form of an inhalation spray, use may be made of a spray in which the active ingredient is dissolved or suspended in a propellant gas or propellant gas mixture (for example CO)₂Or chlorofluorocarbons). The active ingredient is advantageously used here in micronized form, in which case one or more further physiologically acceptable solvents, for example ethanol, may be present. The inhalation solution can be administered by means of a conventional inhaler.

Possible pharmaceutical preparations which can be used rectally include, for example, suppositories which consist of a combination of one or more active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides or paraffin hydrocarbons. In addition, gelatin rectal capsules may also be used, which consist of a combination of the active compound with a base. Possible matrix materials include, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

For medical use, the compounds of the invention will be in the form of pharmaceutically acceptable salts. However, other salts may be useful in preparing the compounds of the present invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of the invention include acid addition salts which may be formed, for example, by mixing a compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic group, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, for example sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts with suitable organic bases, such as quaternary ammonium salts.

The pharmaceutical preparations can be used as medicaments in human and veterinary medicine. The term "effective amount" as used herein means an amount of a drug or pharmaceutical substance that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for example, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount that results in an improved treatment, cure, prevention or amelioration of a disease, disorder or side effect or a reduction in the rate of progression of a disease or disorder as compared to a corresponding individual not receiving that amount. The term also includes within its scope an amount effective to enhance normal physiological function. The therapeutically effective amount of the one or more compounds of the invention is known to those skilled in the art or can be readily determined by standard methods known in the art.

The compounds of the invention and the further active substances are generally applied analogously to the commercial preparations. In general, suitable dosages for therapeutic effectiveness lie in the range from 0.0005mg to 1000mg, preferably from 0.005mg to 500mg, in particular from 0.5mg to 100mg per dosage unit. The daily dosage is preferably between about 0.001mg/kg body weight and 10mg/kg body weight.

One skilled in the art will readily appreciate that dosage levels may vary depending on the particular compound, the severity of the symptoms, and the individual's susceptibility to side effects. Some specific compounds are more effective than others. Preferred dosages for a given compound can be readily determined by one skilled in the art using a variety of methods. One preferred method is to determine the physiological potency of a given compound.

For the purposes of the present invention, all mammalian species are included. In a preferred embodiment, the mammal is selected from the group consisting of "primate, human, rodent, equine, bovine, canine, feline, farm animal, bovine, livestock, pet, cow, sheep, pig, goat, horse, pony (pony), donkey, mule, horse mule, rabbit, cat, dog, guinea pig, hamster, rat, mouse". More preferably, the mammal is a human. Animal models are important for experimental studies, providing a model for the treatment of human disease.

However, the specific dose for each individual patient depends on numerous factors, such as the potency of the specific compound used, the age, body weight, general health, sex, dietary type, time and route of administration, rate of excretion, type and dosage form of administration, drug combination and the severity of the particular disorder involved in the treatment. The specific therapeutically effective amount for each patient can be readily determined by routine experimentation, for example, by the physician or physician providing the advice and charge for treatment.

In the case of many disorders, the susceptibility of a particular cell to treatment with a subject compound may be determined by in vitro assays. Typically, cell cultures are mixed with varying concentrations of the subject compounds for a period of time sufficient for the active agents to exhibit a relevant response, usually about 1 hour to one week. For in vitro assays, cultured cells of a biopsy sample may be used.

Those skilled in the art will be able to utilize the above description to its fullest extent, even if not in any further detail. The preferred embodiments are therefore to be considered in all respects as illustrative and not restrictive.

Above and below, all temperatures are given in ° C. In the following examples, "conventional workup" means removal of the solvent if necessary, addition of water if necessary, adjustment of the pH to a value of between 2 and 10 if necessary, depending on the constitution of the end product, extraction of the mixture with ethyl acetate or dichloromethane, separation of the phases, separation of the organic layer with saturated NaHCO₃The solution is washed, if desired with water and saturated NaCl solution, dried over sodium sulfate, filtered and evaporated, and the product is purified by chromatography on silica gel, preparative HPLC and/or crystallization. If desired, the purified compound is lyophilized.

Retention time R_t[min]The determination of (b) was performed by HPLC:

column Chromolith speedROD RP-18e, 50X 4.6mm²

Gradient A: B =96:4 to 0:100

Flow rate of 2.4ml/min

Eluent A of water and 0.05% formic acid

Eluent B acetonitrile +0.04% formic acid

Wavelength of 220nm

Mass Spectrometry (MS) ESI (electrospray ionization) (M + H)⁺

List of abbreviations and acronyms:

AcOH acetic acid, anh Anhydrous, atm atmospheric pressure, BOC t-butoxycarbonyl, CDI1,1' -carbonyldiimidazole, conc concentrated/concentrated, d days, dec decomposition, DIAD diisopropyl azodicarboxylate, DMAC NN-dimethylacetamide, DMPU1, 3-dimethyl-3, 4,5, 6-tetrahydro-2 (IH) -pyrimidinone, DMF NN-dimethylformamide, DMSO dimethyl formamideSulfoxide, DPPA Diphenyl azidophosphate, EDCI1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, EtOAc ethyl acetate, EtOH ethanol (100%), Et₂O diethyl ether, Et₃N triethylamine, h, MeOH methanol, pet. ether petroleum ether (boiling range 30-60 ℃), PPh₃Triphenylphosphine, temp. THF tetrahydrofuran, TFA trifluoro AcOH, Tf triflyl.

The contents of all cited references are incorporated herein by reference in their entirety. The following examples illustrate the present invention in more detail, but the present invention is not limited to these examples.

Examples

I. Synthesis of selected Compounds of the invention

The following compounds were synthesized and characterized. However, it is within the skill of the person skilled in the art to prepare and characterize these compounds in different ways.

I.1 Synthesis of pyridine intermediates

EXAMPLE 1 Synthesis of 2- (5-chloro-2-fluoro-phenyl) -pyridine-4-boronic acid

1. A solution of 2.96g (20.0mmol)2, 4-dichloropyridine, 3.49g (20.0mmol) 5-chloro-2-fluorobenzeneboronic acid and 2.02g (20.0mmol) sodium bicarbonate in 40ml DMF and 20ml water was heated to 80 ℃ under nitrogen. 281mg (0.40mmol) of bis- (triphenylphosphine) -palladium (II) chloride were added and the mixture was stirred at 80 ℃ for 16 h. Water was added to the reaction mixture, and the resulting precipitate was filtered off and washed well with water. The residue was dried under vacuum to give 4-chloro-2- (5-chloro-2-fluoro-phenyl) -pyridine as a pink solid; HPLC-MS 2.75min, [ M + H ] 242.

2. 4.68g (19.3mmol) 4-chloro-2- (5-chloro-2-fluoro-phenyl) -pyridine are dissolved in 60ml THF, 10ml4N hydrochloric acid in twoSolution in an alkane. The solution was evaporated and the residue was dried under vacuum. A slurry of this solid in 200ml acetonitrile was treated with 29.0g (193mmol) sodium iodide and heated to 80 ℃ with stirring. After 24h the reaction mixture was cooled to room temperature and 60ml of an aqueous solution containing 10% potassium carbonate and 5% sodium bisulfite were added. The mixture was extracted several times with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated. Subjecting the residue to silica gel column chromatography using petroleum ether/ethyl acetate as eluent to give 2- (5-chloro-2-fluoro-phenyl) -4-iodo-pyridine in the form of colorless crystals; HPLC-MS 2.83min, [ M + H ]]334。

¹H NMR(400MHz，DMSO)δ＝8.43(d，J＝5.1，1H)，8.21(s，1H)，7.91(m，2H)，7.59(ddd，J＝8.8，4.2，2.8，1H)，7.43(dd，J＝10.8，8.8，1H).

3. A slurry of 2.00g (6.00mmol)2- (5-chloro-2-fluoro-phenyl) -4-iodo-pyridine, 1.98g (7.8mmol) bis (pinacolato) diboron and 1.77g (18.0mmol) potassium acetate in 20ml THF was heated to 80 ℃ under nitrogen. 840mg (0.12mmol) of bis- (triphenylphosphine) -palladium (II) chloride are then added and the reaction mixture is stirred at 80 ℃ for 24 hours. The mixture was cooled to room temperature and partitioned between saturated sodium chloride solution and THF. The combined organic layers were dried over sodium sulfate and evaporated to give crude 2- (5-chloro-2-fluoro-phenyl) -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyridine as a brown oil. The oil was dissolved in 20ml THF. 3ml of 25% aqueous hydrochloric acid were added and the mixture was stirred at room temperature for 5 h. The resulting precipitate was filtered off, washed with water and THF and dried under vacuum to give 2- (5-chloro-2-fluoro-phenyl) -pyridine-4-boronic acid as a grey solid; HPLC-MS 2.30min, [ M + H ]259

EXAMPLE 2 Synthesis of 5-bromo-2 '-chloro- [3,4' ] bipyridinyl

A solution of 9.63g (33.9mmol) 3-bromo-5-iodopyridine, 4.85g (30.8mmol) 2-chloro-pyridine-4-boronic acid and 3.11g (37.0mmol) sodium bicarbonate in 120ml DMF and 30ml water was heated to 80 ℃ under nitrogen. 433mg (0.616mmol) bis- (triphenylphosphine) -palladium (II) chloride were added and the mixture was stirred at 80 ℃ for 4 h. Water was added to the reaction mixture, and the resulting precipitate was filtered off and washed thoroughly with water. The residue was dried under vacuum and recrystallized from 2-propanol to give 5-bromo-2 '-chloro- [3,4' ] bipyridinyl as brown crystals; HPLC-MS 2.16min, [ M + H ] 271.

¹H NMR(400MHz，DMSO)δ＝9.06(d，J＝2.0，1H)，8.83(d，J＝2.1，1H)，8.60(t，J＝2.1，1H)，8.53(d，J＝5.2，1H)，8.04(d，J＝1.6，1H)，7.89(dd，J＝5.2，1.6，1H).

I.2 Synthesis of the Final Compounds

EXAMPLE 3 Synthesis of 2'- (5-chloro-2-fluoro-phenyl) -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) - [3,4' ] bipyridinyl and 2'- (5-chloro-2-fluoro-phenyl) -5- [1- (1-methyl-piperidin-4-yl) -1H-pyrazol-4-yl ] - [3,4' ] bipyridinyl

1. A slurry of 2.50g (8.81mmol) 3-bromo-5-iodo-pyridine, 3.66g (9.7mmol)4- [4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyrazol-1-yl ] -piperidine-1-carboxylic acid tert-butyl ester, the synthesis of which is described in WO2007/066187, and 3.74g (17.6mmol) tripotassium phosphate trihydrate in 30ml1, 2-dimethoxyethane was heated to 80 ℃ under nitrogen. Then 618mg (0.88mmol) of bis- (triphenylphosphine) -palladium (II) chloride were added. The reaction mixture was stirred at 80 ℃ for 16 hours. The reaction mixture was partitioned between THF and brine. The organic phase was dried over sodium sulfate and evaporated to give 4- [4- (5-bromo-pyridin-3-yl) -pyrazol-1-yl ] -piperidine-1-carboxylic acid tert-butyl ester as light yellow crystals; HPLC-MS:2.28min, [ M + H ] 407/409.

2. A slurry of 367mg (0.90mmol) of 4- [4- (5-bromo-pyridin-3-yl) -pyrazol-1-yl ] -piperidine-1-carboxylic acid tert-butyl ester, 249mg (0.99mmol) of 2- (5-chloro-2-fluoro-phenyl) -pyridine-4-boronic acid and 90.7mg (1.08mmol) of sodium bicarbonate in 2ml of DMF and 1ml of water was heated to 80 ℃ under nitrogen. Then 12.6mg (0.018mmol) bis- (triphenylphosphine) -palladium (II) chloride were added. The reaction mixture was stirred at 80 ℃ for 18 hours. The reaction mixture was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column using dichloromethane/methanol as eluent to give 4- {4- [2'- (5-chloro-2-fluoro-phenyl) - [3,4' ] bipyridinyl-5-yl ] -pyrazol-1-yl } -piperidine-1-carboxylic acid tert-butyl ester as a yellow oil; HPLC-MS:2.73min, [ M + H ] 534.

3. 389mg (0.729mmol)4- {4- [2'- (5-chloro-2-fluoro-phenyl) - [3,4']Bipyridin-5-yl]-pyrazol-1-yl } -piperidine-1-carboxylic acid tert-butyl ester in 1ml4N HCl in bisThe slurry in the alkane was treated with one drop of methanol. The solution thus formed was left at room temperature for 3 hours. The precipitate formed is filtered off and purified with IIThe alkane and tert-butyl methyl ether were washed and dried under vacuum to give 2'- (5-chloro-2-fluoro-phenyl) -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) - [3,4']Bipyridine dihydrochloride; HPLC-MS 1.74min, [ M + H ]]434。

¹H NMR(500MHz，DMSO)δ＝9.25(d，J＝10.1，1H)，9.18(d，J＝1.7，1H)，9.09(m，2H)，8.91(d，J＝5.2，1H)，8.88(s，1H)，8.68(s，1H)，8.32(s，2H)，8.03(dd，J＝5.2，1.6，1H)，8.00(dd，J＝6.6，2.7，1H)，7.62(ddd，J＝8.7，4.0，2.9，1H)，7.48(dd，J＝10.4，8.9，1H)，4.57(ddd，J＝14.8，10.7，4.1，1H)，3.40(d，J＝12.9，2H)，3.11(q，J＝12.2，2H)，2.22(m，4H).

4. A slurry of 210mg (0.414mmol) of 2'- (5-chloro-2-fluoro-phenyl) -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) - [3,4' ] bipyridinyl dihydrochloride in 1ml of water is treated with 2N aqueous sodium hydroxide solution with vigorous stirring until a pH of 14 is reached. The mixture was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated to give crude 2'- (5-chloro-2-fluoro-phenyl) -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) - [3,4' ] bipyridine as a colorless solid. The solid was dissolved in 2ml of formic acid and treated with 55mg (0.69mmol) of 35% aqueous formaldehyde. The reaction mixture was stirred at 80 ℃ for 2 hours. The volume of the reaction mixture was reduced under vacuum. The residue was strongly basified with 2N aqueous NaOH and then partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated to give 2'- (5-chloro-2-fluoro-phenyl) -5- [1- (1-methyl-piperidin-4-yl) -1H-pyrazol-4-yl ] - [3,4' ] bipyridinyl as colorless crystals. HPLC/MS 1.72min, [ M + H ] 533.

¹H NMR(400MHz，DMSO)δ＝8.97(d，J＝2.1，1H)，8.87(d，J＝2.2，1H)，8.85(d，J＝5.2，1H)，8.52(s，1H)，8.45(t，J＝2.1，1H)，8.21(s，1H)，8.14(s，1H)，7.99(dd，J＝6.7，2.8，1H)，7.92(dd，J＝5.2，1.7，1H)，7.60(ddd，J＝8.8，4.2，2.8，1H)，7.46(dd，J＝10.5，8.8，1H)，4.15(m，1H)，2.88(d，J＝11.4，2H)，2.22(s，3H)，2.01(m，6H).

EXAMPLE 4 Synthesis of 2'- (2, 5-difluoro-phenyl) -5- [1- (1-methyl-piperidin-4-yl) -1H-pyrazol-4-yl ] - [3,4' ] bipyridinyl

1. A slurry of 760mg (2.82mmol) 5-bromo-2 '-chloro- [3,4' ] bipyridinyl, 1.17g (3.10mmol) tert-butyl 4- [4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyrazol-1-yl ] -piperidine-1-carboxylate and 2.00g (5.64mmol) tripotassium phosphate trihydrate in 12ml1, 2-dimethoxyethane is heated to 80 ℃ under nitrogen. Then 100mg (0.14mmol) bis- (triphenylphosphine) -palladium (II) chloride and one drop of triethylamine were added. The reaction mixture was stirred at 80 ℃ for 2 hours. The reaction mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. Subjecting the residue to silica gel column chromatography with dichloromethane/methanol as eluent to give tert-butyl 4- [4- (2 '-chloro- [3,4' ] bipyridinyl-5-yl) -pyrazol-1-yl ] -piperidine-1-carboxylate in the form of pale yellow crystals; HPLC-MS:2.34min, [ M + H ] 440.

2. A solution of 513mg (1.17mmol) of tert-butyl 4- [4- (2 '-chloro- [3,4' ] bipyridinyl-5-yl) -pyrazol-1-yl ] -piperidine-1-carboxylate, 221mg (1.40mmol) of 2, 5-difluorophenylboronic acid and 147mg (1.75mmol) of sodium bicarbonate in 3ml of DMF and 1.5ml of water is heated to 80 ℃ under nitrogen. Then 16.4mg (0.023mmol) of bis- (triphenylphosphine) -palladium (II) chloride were added. The reaction mixture was stirred at 80 ℃ for 18 hours. The reaction mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent to give 4- {4- [2'- (2, 5-difluoro-phenyl) - [3,4' ] bipyridinyl-5-yl ] -pyrazol-1-yl } -piperidine-1-carboxylic acid tert-butyl ester as a dark oil; HPLC-MS:2.63min, [ M + H ] 518.

3. A solution of 439g (0.85mmol) of tert-butyl 4- {4- [2'- (2, 5-difluoro-phenyl) - [3,4' ] bipyridinyl-5-yl ] -pyrazol-1-yl } -piperidine-1-carboxylate in 2.8ml of formic acid was treated with 202. mu.l (2.55mmol) of 35% aqueous formaldehyde. The reaction mixture was stirred at 80 ℃ for 18 hours. The volume of the reaction mixture was reduced under vacuum. The residue was strongly basified with 2N aqueous NaOH and then partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was dissolved under mild heating in 7.4ml of a 0.1M solution of hydrochloric acid in isopropanol. The solution was cooled to room temperature and tert-butyl methyl ether was added. The precipitate thus formed was filtered off, washed with tert-butyl methyl ether and dried under vacuum to give 2'- (2, 5-difluoro-phenyl) -5- [1- (1-methyl-piperidin-4-yl) -1H-pyrazol-4-yl ] - [3,4' ] bipyridinium hydrochloride in the form of colorless crystals. HPLC/MS 1.61min, [ M + H ] 432.

¹H NMR(400MHz，DMSO)δ＝10.04(s，1H)，9.00(d，J＝1.7，1H)，8.89(d，J＝2.1，1H)，8.86(d，J＝5.2，1H)，8.53(s，1H)，8.47(t，J＝2.1，1H)，8.22(m，2H)，7.92(dd，J＝5.2，1.7，1H)，7.78(ddd，J＝9.2，6.0，3.2，1H)，7.43(m，2H)，4.49(m，1H)，3.57(d，J＝11.8，2H)，3.18(m，2H)，2.81(s，3H)，2.28(m，4H).

The following compounds were prepared analogously using the procedure of example 4:

2'- (2-fluoro-5-trifluoromethyl-phenyl) -5- [1- (1-methyl-piperidin-4-yl) -1H-pyrazol-4-yl ] - [3,4' ] bipyridinyl; HPLC/MS 1.76min, [ M + H ] 482.

2'- (2-fluoro-phenyl) -5- (1-piperidin-4-yl-1H-pyrazol-4-yl) - [3,4' ] bipyridinyl; HPLC/MS 1.54min, [ M + H ] 400.

¹H NMR(400MHz，DMSO)δ9.34(d,J＝1.8，1H)，9.33(d，J＝1.6，1H)，9.23(t，1H)，9.08(d，J＝5.6，1H)，8.74(s，1H)，8.55(s，1H)，8.40(s，1H)，8.34-8.23(m，1H)，7.99(td，J＝7.5，1.9，1H)，7.71-7.60(m，1H)，7.51-7.41(m，2H)，4.63(tt，J＝10.8，4.0，1H)，3.48(dt，J＝13.1，3.5，3.1，2H)，3.18(td，J＝12.6，3.1，2H)，2.44-2.11(m，4H).

2'- (2-fluoro-phenyl) -5- [1- (1-methyl-piperidin-4-yl) -1H-pyrazol-4-yl ] - [3,4' ] bipyridinyl; HPLC/MS 1.49min, [ M + H ]414

¹H NMR(400MHz，DMSO)δ9.40-9.23(m，3H)，9.10(d，J＝6.0，1H)，8.70(s，1H)，8.63(s，1H)，8.45(dd，J＝5.9，1.8，1H)，8.31(s，1H)，7.90(td，J＝7.7，1.7，1H)，7.63(tdd，J＝8.2，5.2，1.7，1H)，7.46-7.34(m，2H)，4.68-4.45(m，1H)，3.58(d，J＝12.3，2H)，3.20(td，J＝12.6，3.4，2H)，2.81(s，3H)，2.26(dt，J＝12.6，7.1，4H).

EXAMPLE 5 Synthesis of 2- {4- [2'- (2-fluoro-phenyl) - [3,4' ] bipyridinyl-5-yl ] -pyrazol-1-yl } -ethanol

1. To 15ml of 1, 2-dimethoxyethane were added 1.0g of 5-bromo-2 '-chloro- [3,4' ] bipyridinyl (example 2) and 1.58g of 1- [2- (tetrahydropyran-2-yloxy) -ethyl ] -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazole (prepared according to WO 2009/091374). 1.52g of tripotassium phosphate trihydrate were added and the mixture was heated to 80 ℃ under nitrogen. 125mg of bis- (triphenylphosphine) -palladium (II) chloride and one drop of triethylamine are then added. The reaction mixture was stirred at 80 ℃ for 3 hours.

For work-up, the solvent was evaporated and the resulting mixture was partitioned between water and dichloromethane. The organic phase was separated and dried. The product was purified by chromatography to give 850mg of 2 '-chloro-5- {1- [2- (tetrahydro-pyran-2-yloxy) -ethyl ] -1H-pyrazol-4-yl } - [3,4' ] bipyridinyl as a viscous oil. HPLC-MS 2.05min, [ M + H ]385

2. To 4ml of dimethylformamide and 2ml of water were added 250mg of the compound prepared above, 111mg of 2-fluoro-phenylboronic acid and 81mg of sodium bicarbonate. The mixture was heated to 80 ℃. 9.1mg of bis (triphenylphosphine) -palladium (II) chloride were then added to the reaction. The reaction mixture was stirred for 2 h. After cooling, the solvent was evaporated and the residue was partitioned between dichloromethane and water. The organic phase was dried and chromatographed after evaporation, eluting with ethyl acetate and methanol, to give 248mg2'- (2-fluoro-phenyl) -5- {1- [2- (tetrahydro-pyran-2-yloxy) -ethyl ] -1H-pyrazol-4-yl } - [3,4' ] bipyridinyl. HPLC-MS 2.24min, [ M + H ]445

3. 198mg of the product prepared aboveThe material was dissolved in 4ml of dichloromethane. Add 450. mu.l HCl/bisAlkane (about 4 mol/l). The mixture was stirred for 1 h. The resulting precipitate was filtered off and washed with dichloromethane. To yield 156mg2- {4- [2'- (2-fluoro-phenyl) - [3,4']Bipyridin-5-yl]-pyrazol-1-yl } -ethanol. HPLC-MS 1.74min, [ M + H ]]361

¹H NMR(500MHz，DMSO)δ8.95(d，J＝2.0，1H)，8.85(d，J＝2.1，1H)，8.83(d，J＝5.1，1H)，8.43(t，J＝2.1，1H)，8.41(s，1H)，8.17(s，1H)，8.13(s，1H)，8.00-7.92(m，1H)，7.87(dd，J＝5.2，1.7，1H)，7.58-7.49(m，1H)，7.41-7.33(m，2H)，4.94(s，1H)，4.19(t，J＝5.6，2H)，3.79(t，J＝5.6，2H).

Using the same procedure and 5-chloro-2-fluoro-phenylboronic acid we obtained 2- {4- [2'- (5-chloro-2-fluoro-phenyl) - [3,4' ] bipyridinyl-5-yl ] -pyrazol-1-yl } -ethanol

HPLC-MS:2.02min,[M+H]395

¹H NMR(500MHz，DMSO)δ8.95(d，J＝2.0，1H)，8.87(d，J＝2.1，1H)，8.84(d，J＝5.1，1H)，8.43(t，J＝2.1，1H)，8.41(s，1H)，8.21(s，1H)，8.13(s，1H)，7.99(dd，J＝6.6，2.7，1H)，7.92(dd，J＝5.1，1.6，1H)，7.64-7.55(m，1H)，7.46(dd，J＝10.5，8.9，1H)，4.95(s，1H)，4.19(t，J＝5.6，2H)，3.79(t，J＝5.6，2H).

Using the same procedure and 2, 5-difluoro-phenylboronic acid we obtained 2- {4- [2'- (2, 5-difluoro-phenyl) - [3,4' ] bipyridinyl-5-yl ] -pyrazol-1-yl } -ethanol

HPLC-MS:1.88min,[M+H]379

¹H NMR(500MHz，DMSO)δ8.95(d，J＝2.0，1H)，8.86(d，J＝2.1，1H)，8.84(d，J＝5.1，1H)，8.43(t，J＝2.1，1H)，8.41(s，1H)，8.21(s，1H)，8.13(s，1H)，7.91(dd，J＝5.1，1.6，1H)，7.82-7.73(m，1H)，7.50-7.41(m，1H)，7.41-7.33(m，1H)，4.96(s，0H)，4.19(t，J＝5.6，2H)，3.79(t，J＝5.6，2H).

Using the same procedure and 5-trifluoromethyl-2-fluoro-phenylboronic acid we obtained 2- {4- [2'- (2-fluoro-5-trifluoromethyl-phenyl) - [3,4' ] bipyridinyl-5-yl ] -pyrazol-1-yl } -ethanol

HPLC-MS：2.11min，[M+H]429

¹H NMR(400MHz，DMSO)δ8.96(d，J＝2.0，1H)，8.90-8.85(m，1H)，8.45(t，J＝2.1，1H)，8.42(s，1H)，8.31(dd，J＝6.8，2.0，1H)，8.28(s，1H)，8.13(s，1H)，7.99-7.89(m，2H)，7.66(t，J＝9.8，1H)，4.95(t，J＝5.3，1H)，4.19(t，J＝5.6，2H)，3.78(q，J＝5.5，2H).

Using 1- [2- (tetrahydro-pyran-2-yloxy) -propyl ] -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazole and 2-fluoro-phenylboronic acid we obtained 3- {4- [2'- (2-fluoro-phenyl) - [3,4' ] bipyridinyl-5-yl ] -pyrazol-1-yl } -propan-1-ol

HPLC-MS：1.80min，[M+H]375

¹H NMR(400MHz，DMSO)δ8.94(d，J＝2.1，1H)，8.85(d，J＝2.2，1H)，8.83(dd，J＝5.2，0.6，1H)，8.45-8.39(m，2H)，8.16(s，1H)，8.12(d，J＝0.6，1H)，8.01-7.92(m，2H)，7.87(dd，J＝5.2，1.7，1H)，7.59-7.48(m，1H)，7.42-7.31(m，2H)，4.58(t，J＝5.0，1H)，4.21(t，J＝7.1，3H)，3.43(M，J＝11.3，6.0，3H)，2.05-1.88(m，3H).

Example 6 Synthesis of (3- {4- [2'- (2-fluoro-phenyl) - [3,4' ] bipyridinyl-5-yl ] -pyrazol-1-yl } -propyl) -dimethyl-amine

Dimethyl- {3- [4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyrazol-1-yl ] -propyl } -amine was synthesized according to Bioorganic & Medicinal Chemistry Letters18(2008) 5299-one 5302.

The following compounds were obtained using the procedure of the above-mentioned example:

(3- {4- [2'- (5-chloro-2-fluoro-phenyl) - [3,4' ] bipyridinyl-5-yl ] -pyrazol-1-yl } -propyl) -dimethylamine

HPLC-MS：1.63min，[M+H]436

¹H NMR(400MHz，DMSO)δ8.98(d，J＝2.1，1H)，8.90(d，J＝2.2，1H)，8.86(dd，J＝5.2，0.6，1H)，8.49-8.42(m，2H)，8.25-8.18(m，2H)，7.99(dd，1H)，7.92(dd，1H)，7.61(m，1H)，7.47(dd，1)，4.26(t，J＝6.7，2H)，3.20-3.01(m，2H)，2.79(s，3H)，2.78(s，3H)，2.31-1.99(m，2H).

(3- {4- [2'- (2-fluoro-phenyl) - [3,4' ] bipyridinyl-5-yl ] -pyrazol-1-yl } -propyl) -dimethyl-amine

HPLC-MS：1.46min，[M+H]402

¹H NMR(400MHz，DMSO)δ9.18(d，J＝1.9，1H)，9.13(d，J＝2.0，1H)，8.94(d，J＝5.2，1H)，8.91(t，1H)，8.67(s，1H)，8.34(s，1H)，8.30(s，1H)，8.07(dd，J＝5.3，1.7，1H)，7.97(td，J＝7.7，1.6，1H)，7.65-7.54(m，1H)，7.53-7.38(m，2H)，4.31(t，J＝6.8，2H)，3.18-3.00(m，2H)，2.75(s，3H)，2.74(s，3H)，2.37-2.19(m，2H).

(3- {4- [2'- (2, 5-difluoro-phenyl) - [3,4' ] bipyridinyl-5-yl ] -pyrazol-1-yl } -propyl) -dimethylamine

HPLC-MS:1.54min,[M+H]420

¹H NMR(500MHz，DMSO)δ8.95(d，1H)，8.86(d，J＝2.1，2H)，8.84(d，J＝5.1，1H)，8.43(s，2H)，8.21(s，1H)，8.13(s，1H)，7.91(dd，J＝5.1，1.6，1H)，7.82-7.73(m，1H)，7.51-7.43(m，1H)，7.43-7.35(m，1H)，4.17(t，J＝7.0，3H)，2.20(t，J＝6.9，3H)，2.13(s，6H)，1.95(m，3H).

Example Synthesis of 2 '' - (2-fluoro-phenyl) -6-piperazin-1-yl- [3,3';5',4'' ] terpyridine and 2 '' - (2-fluoro-phenyl) -6- (4-methyl-piperazin-1-yl) - [3,3';5',4'' ] terpyridine

Using the same procedures and tert-butyl 4- [5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyridin-2-yl ] -piperazine-1-carboxylate as described in the above example, the following compound was obtained:

2 '' - (2-fluoro-phenyl) -6-piperazin-1-yl- [3,3';5',4'' ] terpyridyl

HPLC-MS:1.56min,[M+H]412

¹H NMR(400MHz，DMSO)δ9.11(t，J＝1.7，2H)，8.89(dd，J＝5.2，0.6，1H)，8.75(d，J＝2.3，1H)，8.73(t，J＝1.9，1H)，8.31(s，1H)，8.25(dd，J＝9.0，2.6，1H)，8.02(dd，J＝5.3，1.7，1H)，7.96(td，J＝7.9，1.9，1H)，7.68-7.51(m，1H)，7.44-7.34(m，2H)，7.13(d，J＝9.0，1H)，3.94-3.81(m，4H)，3.35-3.07(m，4H).

2 '' - (2-fluoro-phenyl) -6- (4-methyl-piperazin-1-yl) - [3,3';5',4'' ] terpyridines

HPLC-MS：1.54min，[M+H]426

¹H NMR(400MHz，DMSO)δ8.97(d，J＝2.2，1H)，8.96(d，J＝2.1，1H)，8.83(dd，J＝5.2，0.6，1H)，8.65(d，J＝2.4，1H)，8.46(t，J＝2.2，1H)，8.21(s，1H)，8.08(dd，J＝8.9，2.6，1H)，7.95(td，J＝8.0，1.9，1H)，7.90(dd，J＝5.2，1.7，1H)，7.58-7.48(m，1H)，7.42-7.32(m，2H)，6.97(d，J＝9.0，1H)，3.59(m，4H)，2.45(m，4H)，2.26(s，3H).

Example 8 Synthesis of-2 '- (2-fluoro-phenyl) -5- {1- [3- (4-methyl-piperazin-1-yl) -propyl ] -1H-pyrazol-4-yl } - [3,4' ] bipyridinyl

2- (2-fluoro-phenyl) -pyridine-4-boronic acid was prepared using the procedure and operation of example 1; HPLC-MS 0.96min, [ M + H ]218

1. To 1.78g of sodium bicarbonate in 300ml of DMF and 150ml of water were added 5g of 3-bromo-5-iodopyridine and 5.4g of 4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyrazole-1-carboxylic acid tert-butyl ester. The mixture was heated to 80 ℃ under nitrogen and then 1.11g of bis (triphenylphosphine) -palladium (II) chloride was added. The mixture was stirred overnight. After cooling, the reaction mixture was evaporated. The residue was partitioned between ethyl acetate and water. The organic phase was dried, filtered and evaporated. The product was purified by chromatography. 2.55g 3-bromo-5- (1H-pyrazol-4-yl) -pyridine are obtained;

HPLC-MS:1.63min,[M+H]226

2. 500mg of 3-bromo-5- (1H-pyrazol-4-yl) -pyridine, 850mg of 3- (N-methylpiperazine) -propan-1-ol and 1.69g of triphenylphosphine were dissolved in dimethylformamide. To the reaction was added 1.28ml of diisopropyl azodicarboxylate. The mixture was stirred at room temperature overnight. For work-up, the mixture is evaporated and dichloromethane is added. The organic phase was washed with dilute HCl. The acidic aqueous phase was neutralized and extracted with dichloromethane. After drying, filtration and evaporation, the product is purified by chromatography, eluting with ethyl acetate and methanol. To give 472mg of 1- {3- [4- (5-bromo-pyridin-3-yl) -pyrazol-1-yl ] -propyl } -4-methyl-piperazine;

HPLC-MS:1.23min,[M+H]366

3. in the same procedure as described in example 3, 240mg1- {3- [4- (5-bromo-pyridin-3-yl) -pyrazol-1-yl ] -propyl } -4-methyl-piperazine and 462mg2- (2-fluoro-phenyl) -pyridine-4-boronic acid were used. After purification 43mg2'- (2-fluoro-phenyl) -5- {1- [3- (4-methyl-piperazin-1-yl) -propyl ] -1H-pyrazol-4-yl } - [3,4' ] bipyridinyl was obtained.

HPLC-MS:1.49min,[M+H]457

Using the same procedure and using 3-morpholin-4-yl-propan-1-ol instead of 3- (N-methylpiperazine) -propan-1-ol, 2'- (2-fluoro-phenyl) -5- [1- (3-morpholin-4-yl-propyl) -1H-pyrazol-4-yl ] - [3,4' ] bipyridinyl was obtained.

HPLC-MS：1.50min，[M+H]444

¹H NMR(500MHz，DMSO)δ8.97(d，J＝1.9，1H)，8.88(s，1H)，884(d，J＝5.1，1H)，8.48(s，1H)，8.44(t，J＝2，1，1H)，8.21(s，1H)，8.17(s，1H)，7.96(td，J＝7.8，1.7，1H)，7.88(dd，J＝5.2，1.7，1H)，7.58-7.49(m，1H)，7.43-7.34(m，2H)，4.27(s，2H)，3.97(d，J＝11.4，2H)，3.71-3.55(m，2H)，3.45(m，2H)，3.21-2.96(m，2H)，2.27(m，2H)，1.43-1.05(m，2H).

EXAMPLE 9 Synthesis of 2'- (2-fluoro-phenyl) -5-quinolin-3-yl- [3,4' ] bipyridinyl

1. To 8ml of 1, 2-dimethoxyethane were added 500mg of 5-bromo-2 '-chloro- [3,4' ] bipyridinyl, 350mg of 3-quinolineboronic acid and 758mg of tripotassium phosphate trihydrate. The mixture was stirred and heated to 80 ℃ under nitrogen. 63mg of bis- (triphenylphosphine) -palladium (II) chloride and 25. mu.l of triethylamine are added immediately. The mixture was stirred for 3 h. The solvent was evaporated and the residue partitioned between dichloromethane and water. The organic phase was dried, filtered and evaporated. The product was purified by chromatography with ethyl acetate and methanol. 117mg2 '-chloro-5-quinolin-3-yl- [3,4' ] bipyridinyl were obtained.

HPLC-MS[M+H]318

2. To 6ml of dimethylformamide and 3ml of water were added 117mg of 2 '-chloro-5-quinolin-3-yl- [3,4' ] bipyridinyl, 56mg of 2-fluorophenylboronic acid and 41mg of sodium bicarbonate. The mixture was heated to 80 ℃ under nitrogen. 4.6mg of bis- (triphenylphosphine) -palladium (II) chloride were immediately added. The mixture was stirred for 3 h. For work-up, the reaction mixture was evaporated and the residue partitioned between dichloromethane and water. After drying, filtration and evaporation, the product was purified by chromatography using ethyl acetate and methanol. 78mg of 2'- (2-fluoro-phenyl) -5-quinolin-3-yl- [3,4' ] bipyridinyl are obtained.

HPLC-MS：1.50min，[M+H]444

¹H NMR(500MHz，DMSO)δ9.46(d，J＝2.3，1H)，9.24(d，J＝2.1，1H)，9.15(d，J＝2.1，1H)，8.93(d，J＝2.1，1H)，8.87(d，J＝5.1，1H)，8.78(t，J＝2.1，1H)，8.29(s，1H)，8.10(t，J＝8.5，2H)，8.02-7.91(m，2H)，7.87-7.79(m，1H)，7.74-7.66(m，1H)，7.59-7.49(m，1H)，7.43-7.34(m，2H).

EXAMPLE 10 Synthesis of 2- (4- {6- [2- (2-fluoro-phenyl) -pyridin-4-yl ] -pyrazin-2-yl } -pyrazol-1-yl) -ethanol

1. 5.0g2- (2-fluoro-phenyl) -4-pyridineboronic acid, 3.6g2, 6-dichloropyrazine and 1.6g sodium bicarbonate were suspended in 80ml dimethylformamide and 20ml water. The mixture was heated to 80 ℃ and 226mg of bis- (triphenylphosphine) -palladium (II) chloride were added. After 7h at 80 ℃, the mixture was cooled to room temperature and poured onto ice. The mixture was extracted with dichloromethane. The organic phase was dried, filtered and evaporated. The product was purified by chromatography using petroleum ether and ethyl acetate. 1.09g 2-chloro-6- [2- (2-fluoro-phenyl) -pyridin-4-yl ] -pyrazine was obtained.

HPLC-MS[M+H]286

2. 500mg of 2-chloro-6- [2- (2-fluoro-phenyl) -pyridin-4-yl ] -pyrazine prepared above, 775mg1- [2- (tetrahydro-pyran-2-yloxy) -ethyl ] -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazole (prepared according to WO 2009/091374) and 932mg of tripotassium phosphate trihydrate were suspended in 10ml of 1, 2-dimethoxyethane and heated to 80 ℃ under nitrogen. After 1h the reaction mixture was cooled and evaporated. The residue was partitioned between dichloromethane and water. After drying, filtration and evaporation, the product is purified by chromatography. 680mg2- [2- (2-fluoro-phenyl) -pyridin-4-yl ] -6- {1- [2- (tetrahydro-pyran-2-yloxy) -ethyl ] -1H-pyrazol-4-yl } -pyrazine were obtained.

HPLC-MS[M+H]446

3. 680mg of 2- [2- (2-fluoro-phenyl) -pyridin-4-yl prepared above are added]-6- {1- [2- (tetrahydro-pyran-2-yloxy) -ethyl]-1H-pyrazol-4-yl } -pyrazine in 12ml of a solutionIn an alkane. 1.1l of HCl are added in twoSolution in alkane (4 mol/l). The product precipitated out of solution and was filtered off. 147mg of 2- (4- {6- [2- (2-fluoro-phenyl) -pyridin-4-yl) were obtained]-pyrazin-2-yl } -pyrazol-1-yl) -ethanol.

HPLC-MS[M+H]362

¹H NMR(500MHz，DMSO)δ＝9.20(s，1H)，9.09(s，1H)，8.90(d，J＝5.1，1H)，8.55(d，J＝8.2，2H)，8.26(s，1H)，8.20(dd，J＝5.1，1.6，1H)，7.99(td，J＝7.9，1.6，1H)，7.55(m，1H)，7.44-7.35(m，2H)，4.98(s，1H，OH)，4.24(t，J＝5.5，2H)，3.80(t，J＝5.4，2H).

EXAMPLE 11 Synthesis of 2'- (2-fluoro-phenyl) -5-pyrazol-1-yl- [3,4' ] bipyridinyl

The title compound was obtained using the method in step 1 of example 1.

HPLC-MS：2.19min，[M+H]317.

1H NMR(500MHz，DMSO)δ＝9.24(d，J＝2.4，1H)，9.01(d，J＝1.9，1H)，8.86(d，J＝5.1，1H)，8.77(d，J＝2.5，1H)，8.66(t，J＝2.2，1H)，8.22(s，0H)，7.99-7.91(m，2H)，7.88(d，J＝1.6，1H)，7.57-7.51(m，1H)，7.42-7.36(m，2H)，6.69-6.64(m，1H).

EXAMPLE 12 Synthesis of 2'- (2-fluoro-phenyl) -5- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) - [3,4' ] bipyridinyl

Step 1:

250mg of 5-bromo-2-trifluoromethyl-1H-pyrrolo [2,3-b ]]Pyridine was dissolved in 2ml under nitrogenTo the alkane, 360mg of KOAc and 328mg of bis (pinacolato) bis were addedBoron, 15mg1,1 '-bis (diphenylphosphino) ferrocene and 23mg (1,1' -bis (diphenylphosphino) ferrocene) -palladium (II) chloride dichloromethane adduct. The mixture was stirred under microwave at 140 ℃ for 1 hour 30 minutes.

288mg of 5-bromo-2 ' -chloro- [3,4' are added to the mixture ']Bipyridine (see example 2) and dipyridyl in 1.6mlAlkane and Na₂CO₃20mg of dichlorobis (tricyclohexylphosphine) palladium (II) diluted in solution (3N), the reaction mixture was stirred in a microwave at 140 ℃ for 3 h.

The product was extracted with dichloromethane and dried over anhydrous Na₂SO₄Dried, filtered and concentrated under vacuum to give a black-red oil.

The crude product was purified by flash chromatography (AcOEt/petroleum ether: 60/40) to give 200mg of 2 '-chloro-5- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) - [3,4' ] bipyridinyl.

HPLC-MS：2.24min，[M+H]375.

¹H NMR(400MHz，DMSO)δ9.10(d，J＝2.1，1H)，9.08(d，J＝2.2，1H)，8.97(d，J＝2.2，1H)，8.66(d，J＝2.2，1H)，8.65(t，J＝2.2，1H)，8.55(dd，J＝0.47，5.22，1H)，8.18(d，J＝1.0，1H)，8.01(dd，J＝5.2，1.6，1H)，7.14(s，1H).

Step 2:

200mg of 2' -chloro-5- (2-trifluoromethyl-1H-pyrrolo [2,3-b ]]Pyridin-5-yl) - [3,4']Bipyridine and 149mg 2-fluoro-phenylboronic acid were dissolved in DMF under nitrogen, and 112mg NaHCO was added₃And 1.5ml of water. The mixture was heated at 80 ℃. Then, 7.5mg of bis (triphenylphosphine) -palladium (II) chloride were added and the mixture was stirred at 80 ℃ overnight.

The mixture was cooled to room temperature, concentrated and combined with CH₂Cl₂And (4) extracting. The organic layer was washed with Na₂SO₄Dried and concentrated to give an orange solid.The solid was treated with methanol and acetonitrile to give 95mg of the desired end product.

HPLC-MS：2.43min，[M+H]435.

¹H NMR(500MHz，DMSO)δ13.12(s，1H)，9.09(d，J＝2.1，1H)，9.08(d，J＝2.1，1H)，8.96(d，J＝2.1，1H)，8.85(d，J＝5.1，1H)，8.65(d，J＝2.1，1H)，8.63(t，J＝2.1，1H)，8.27(s，1H)，7.95(m，J＝5.1，1.7，2H)，7.53(m，1H)，7.38(m，2H)，7.14(s，1H).

Example 13 Synthesis of (2-ethoxy-pyridin-4-yl) - [2'- (2-fluoro-phenyl) - [3,4' ] bipyridinyl-5-yl ] -amine, [2'- (2-fluoro-phenyl) - [3,4' ] bipyridinyl-5-yl ] - (6-methoxy-pyridin-3-yl) -amine and (5-ethoxymethyl-2-methyl-pyrimidin-4-yl) - [2'- (2-fluoro-phenyl) - [3,4' ] bipyridinyl-5-yl ] -amine

The title compound (2-ethoxy-pyridin-4-yl) - [2'- (2-fluoro-phenyl) - [3,4' ] bipyridin-5-yl ] -amine was obtained using the procedure described in step 2 of the synthesis of (2 '-chloro- [3,4' ] bipyridin-5-yl) - (2-ethoxy-pyridin-4-yl) -amine and 2-fluoro-phenylboronic acid and 2'- (2-fluoro-phenyl) -5- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) - [3,4' ] bipyridine (vide supra).

HPLC-MS:1.57min,[M+H]387。

The title compound [2'- (2-fluoro-phenyl) - [3,4' ] bipyridin-5-yl ] - (6-methoxy-pyridin-3-yl) -amine was obtained using the procedure described in step 2 (above) for the synthesis of (2 '-chloro- [3,4' ] bipyridin-5-yl) - (6-methoxy-pyridin-3-yl) -amine and 2-fluoro-phenylboronic acid and 2'- (2-fluoro-phenyl) -5- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) - [3,4' ] bipyridine.

HPLC-MS：1.93min，[M+H]373.

1H NMR(500MHz，DMSO)δ＝8.78(d，J＝5.1，1H)，8.39(d，J＝1.9，1H)，8.37(s，1H)，8.31(d，J＝2.6，1H)，8.09(d，J＝2.8，1H)，8.00(s，1H)，7.96(td，J＝7.9，1.7，1H)，7.70(dd，J＝5.1，1.7，1H)，7.66(dd，J＝8.8，2.9，1H)，7.56(t，J＝2.3，1H)，7.55-7.48(m，1H)，7.40-7.32(m，2H)，6.83(d，J＝8.8，1H)，3.84(s，3H).

The title compound (5-ethoxymethyl-2-methyl-pyrimidin-4-yl) - [2'- (2-fluoro-phenyl) - [3,4' ] bipyridin-5-yl ] -amine was obtained using the procedure described in step 2 (above) for the synthesis of (2 '-chloro- [3,4' ] bipyridin-5-yl) - (5-ethoxymethyl-2-methyl-pyrimidin-4-yl) -amine and 2-fluoro-phenylboronic acid and 2'- (2-fluoro-phenyl) -5- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) - [3,4' ] bipyridinyl.

HPLC-MS：1.67min，[M+H]416.

1H NMR(500MHz，DMSO)δ＝9.02(d，J＝2.4，1H)，8.84(d，J＝5.2，1H)，8.73(d，J＝1.9，2H)，8.70(t，J＝2.2，1H)，8.26(s，1H)，8.11(s，1H)，8.00(tt，J＝9.0，4.4，1H)，7.95(s，1H)，7.81(dd，J＝5.2，1.7，1H)，7.54(tdd，J＝7.6，6.1，2.5，1H)，7.38(ddd，J＝8.6，2.4，1.4，2H)，4.57(s，2H)，3.56(q，J＝6.99，2H)，2.48(s，3H)，1.19(t，J＝6.99，3H).

Assay method

Example 14: cellular assays for detecting TGF-beta receptor I kinase inhibitors

As an example, the ability of the inhibitor to abrogate TGF- β mediated growth inhibition was tested. The lung epithelial cell line cells Mv1Lu were seeded at a defined cell density in 96-well microtiter plates and cultured overnight under standard conditions. The following day, the medium was replaced with a medium containing 0.5% FCS and 1ng/ml TGF-. beta.and the test substance (typically 5-fold serial dilutions) was added at the determined concentration. The concentration of the solvent DMSO was constant at 0.5%. After a further two days, crystal violet staining of the cells was performed. After extraction of crystal violet from the fixed cells, the absorbance was measured spectrophotometrically at 550 nm. It can be used as a quantitative measure of the presence of adherent cells and thus of the proliferation of cells during the culture.

Example 15: inhibition of Smad2/3 phosphorylation of Mv1Lu cells by TGF-beta receptor I kinase inhibitors

This assay was used to determine the inhibitory potency of compounds on TGF- β mediated phosphorylation of Smad2(Ser465/467) and Smad3(Ser 423/425). Mv1-Lu cells (lung epithelial cell line, from mine Mustella vison; ATCC No. CCL-64) were seeded in 24-well or 96-well plates (24-well plates: 1.5X 10. sup. th. the cell density was determined in DMEM (Invitrogen) supplemented with 10% fetal bovine serum (PanBiotech)⁵Individual cells/well; 96-well plate: 4X 10⁴Individual cells/well). Cell cultures were grown in DMEM at 37 ℃ and 10% CO₂And (4) incubating. The following day, the medium was replaced and the cells were serum starved for 16-20 hours. The following day, serial dilutions of the compound were added to each well, preincubated for 1.5 hours, and recombinant TGF-. beta.1 ligand (final concentration 5ng/ml; R)&Dsystems). After 1 hour of ligand stimulation, lysates were prepared and analyzed using an enzyme-linked immunoassay Kit (PathScan phosphor-Smad 2Kit, Cell Signaling Technologies). ELISA detects phosphorylated Smad2 and phosphorylated Smad3 using phospho-specific antibodies. TGF- β stimulated and unstimulated cells were used as positive and recessive controls (100% and background controls). The concentration of medium DMSO was kept constant at 0.2% (v/v) in all wells. Dose-response relationships were fitted using a curve fitting algorithm of the RS1 Statistical software package (Brooks Automation Inc. RS/1-Statistical Tools handbook. Release6.2) to determine the concentration at which half-maximal inhibition of Smad2/3 phosphorylation was achieved (IC 2/3 phosphorylation)₅₀)。

Example 16: in vitro (enzymatic) assay for determining the efficacy of inhibitors to inhibit TGF-beta-mediated effects

The kinase assay was performed using a 384 well scintillation plate assay. 31.2nM GST-ALK5, 439nM GST-SMAD2 and 3mM ATP (with 0.3. mu. Ci)³³P-ATP/well) In a total volume of 35. mu.l (20mM HEPES, 10mM MgCl)₂，5mM MnCl₂1mM DTT, 0.1% BSA, pH7.4) in the presence or absence of test substance (5-10 concentrations) at 30 ℃ for 45 minutes. The reaction was stopped with 25. mu.l of 200mM EDTA solution, suction filtered at room temperature after 30 minutes and the wells were washed 3 times with 100. mu.l of 0.9% NaCl solution. Radioactivity was measured using a TopCount. Computing IC using RS1₅₀The value is obtained. The results are given in table 2.

TABLE 2

Claims

1. A compound of the formula (I),

wherein:

W₁、W₂、W₃independently of one another, N or CR³，

R¹Represents a monocyclic aryl group having 5,6, 7,8, 9 or 10C atoms or a monocyclic aryl group having 5,6, 7,8, 9, 10. Monocyclic heteroaryl of 11, 12, 13 or 14C atoms and 1,2,3,4 or 5N, O and/or S atoms, which may each, independently of one another, be substituted by at least one radical chosen from Y, Hal, CN, CF₃And a substituent of OY,

R³denotes H, NYY or NY-COY,

Y represents H or A, and Y represents hydrogen or A,

a represents an unbranched or branched hydrocarbon radical having 1,2,3,4, 5,6, 7,8, 9 or 10C atoms, wherein 1,2,3,4, 5,6 or 7H atoms may be replaced independently of one another by Hal and/or wherein one or two CH groups₂The radicals may be independently of one another substituted by O, S, SO₂-CY = CY-group and/or-C ≡ C-group,

Het²indicating toolMonocyclic, bicyclic or tricyclic heteroaryl having 3,4,5,6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20C atoms and 1,2,3,4 or 5N, O and/or S atoms,

hal represents F, Cl, Br or I,

m represents 0,1 or 2,

n represents 0,1, 2,3 or 4,

2. The compound of claim 1, wherein

W₁、W₂、W₃Represents CR³，

Or

W₁、W₂Represents CR³And is and

W₃the expression N is used to represent the number of the N,

3. A compound according to claim 1 or 2, wherein

4. A compound according to any one of claims 1 to 3, wherein

R²Represents Ar, Het²Or NY-Het²Which may be independently of one another by R⁴Substitutions, and physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

5. A compound according to any one of claims 1 to 4, wherein

R⁴Representation A, CF₃、Hal、-(CYY)_n-OY、-(CYY)_n-NYY、(CYY)_n-Het³，

6. A compound according to any one of claims 1 to 5, wherein

7. The compound according to any one of claims 1 to 6, selected from:

8. A process for preparing a compound of formula (I) comprising the steps of:

(a) reacting a compound of formula (II)

Wherein

R⁵Denotes Hal or B (OH)₂And is and

R¹and Hal has the meaning indicated aboveThe meaning of (A) is,

with a compound of the formula (III),

wherein

R⁶Represents Hal, boric acid or a borate, and

R²、W₁、W₂、W₃and Hal has the meaning defined above,

to obtain the compound of the formula (I),

wherein

R¹、R²、W₁、W₂And W₃Having the meaning as defined above, and which,

or

(b) Reacting a compound of formula (IV)

Wherein

R⁷Represents Hal, boric acid or a borate, and

R²、W₁、W₂、W₃and Hal has the meaning defined above,

with a compound of the formula (V),

R⁸-R¹ (V)

wherein

R⁸Denotes Hal or B (OH)₂And is and

R¹and Hal has the meaning defined above,

to give a compound of the formula (I)

Wherein

R¹、R²、W₁、W₂And W₃Having the meaning as defined above, and which,

or

(c) Reacting a compound of formula (VI)

Wherein

R⁹Denotes Hal or B (OH)₂And is and

R¹、W₁、W₂、W₃and Hal has the meaning defined above,

with a compound of the formula (VII),

R¹⁰-R² (VII)

wherein

R¹⁰Represents Hal, boric acid or a borate, and

R²and Hal has the meaning defined above,

to obtain the compound of the formula (I),

wherein

R¹、R²、W₁、W₂And W₃Having the meaning as defined above, and which,

and optionally

9. Use of a compound according to any one of claims 1 to 7 for inhibiting an ATP consuming protein, preferably TGF-beta receptor kinase, RON, TAK1, PKD1, MINK1, SAPK 2-a, SAPK2- β and/or CHK 2.

10. A medicament comprising at least one compound according to any one of claims 1 to 7.

11. Medicament comprising at least one compound according to any one of claims 1 to 7 for the treatment and/or prophylaxis of physiological and/or pathophysiological conditions selected from the group consisting of: "cancer, tumor, malignant tumor, benign tumor, solid tumor, sarcoma, carcinoma, hyperproliferative disorder, carcinoid, Ewing's sarcoma, Kaposi's sarcoma, brain tumor, tumor derived from the brain and/or nervous system and/or meninges, glioma, glioblastoma, neuroblastoma, gastric cancer, renal cell carcinoma, prostate cancer, connective tissue tumor, soft tissue sarcoma, pancreatic tumor, liver tumor, head tumor, neck tumor, larynx cancer, esophageal cancer, thyroid cancer, osteosarcoma, retinoblastoma, thymoma, testicular cancer, lung adenocarcinoma, small cell lung cancer, bronchial cancer, breast cancer, intestinal cancer, colorectal tumor, colon cancer, rectal cancer, gynecological tumor, ovarian tumor, uterine cancer, cervical cancer, uterine body cancer, Endometrial cancer, bladder cancer, genitourinary tract cancer, bladder cancer, skin cancer, epithelial tumors, squamous epithelial cancer, basal cell carcinoma, echinocyte cancer, melanoma, intraocular melanoma, leukemia, monocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, acute lymphocytic leukemia, lymphoma, ophthalmic diseases, choroidal neovascularization, diabetic retinopathy, inflammatory diseases, arthritis, neurodegeneration, graft rejection, metastatic growth, fibrosis, restenosis, HIV infection, atherosclerosis, inflammation and wound healing, angiogenesis, cardiovascular system, bone, CNS and/or PNS disorders. "

12. The medicament according to any one of claims 10 to 11, wherein at least one further pharmacologically active substance is contained in the medicament.

13. The medicament according to any one of claims 10 to 11, wherein the medicament is applied before and/or during and/or after treatment with at least one further pharmacologically active substance.

14. Pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any one of claims 1 to 7, and optionally further comprising at least one additional compound selected from the group consisting of physiologically acceptable excipients, adjuvants, diluents, carriers and/or additional pharmaceutically active substances which are not compounds according to any one of claims 1 to 7.

15. A kit comprising a therapeutically effective amount of at least one compound according to any one of claims 1 to 7 and/or at least one pharmaceutical composition according to claim 14 and a therapeutically effective amount of at least one further pharmacologically active substance which is not a compound according to any one of claims 1 to 7.