US20150005288A1 - Substituted phenylimidazopyrazoles and use thereof - Google Patents

Substituted phenylimidazopyrazoles and use thereof Download PDF

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US20150005288A1
US20150005288A1 US14/372,917 US201314372917A US2015005288A1 US 20150005288 A1 US20150005288 A1 US 20150005288A1 US 201314372917 A US201314372917 A US 201314372917A US 2015005288 A1 US2015005288 A1 US 2015005288A1
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methyl
fluorine
mmol
group
hydroxy
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Frank Süssmeier
Mario Lobell
Sylvia GRÜNEWALD
Michael Härter
Bernd Buchmann
Joachim Telser
Hannah Jörissen
Melanie HEROULT
Antje Kahnert
Klemens Lustig
Niels LINDNER
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Bayer Pharma AG
Bayer Intellectual Property GmbH
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Bayer Intellectual Property GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present application relates to novel 1-phenyl-1H-imidazo[1,2-b]pyrazole derivatives, to processes for their preparation, to their use for the treatment and/or prevention of diseases and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular angiogenic disorders and hyperproliferative disorders, where neovascularization plays a role, such as, for example, neoplastic disorders and tumour disorders.
  • Such treatments can be carried out as monotherapy or else in combination with other medicaments or further therapeutic measures.
  • angiogenesis i.e. the formation of new blood vessels from existing vessels [W. Risau, Nature 386, 671 (1997); R. K. Jain, Nat. Med. 9, 685 (2003)], is relatively rare in adult organisms (wound healing, ovarian cycle); it does, however, play an important role in pathological processes, in particular in tumour disorders including haemangiomas and haemangioblastomas, and also in inflammatory diseases and autoimmune disorders, cardiovascular disorders, kidney disorders, eye disorders and endometriosis with dysregulated angiogenesis.
  • Neoplastic disorders are the result of uncontrolled cell growth of various tissues. In many cases, the new cells penetrate into existing tissues (invasive growth), or they metastasize into remote organs. Neoplastic disorders occur in various organs and their progression is often tissue-specific. Accordingly, the term neoplastic disorder describes a large group of defined disorders of various organs, tissues and cell types.
  • nascent tumours are not vascularized. Pre-condition for further growth exceeding a volume of a few mm 3 is the formation of new blood vessels to provide the tumour with oxygen and nutrients.
  • This induction of angiogenesis also referred to as angiogenic switch, is one of the characterizing features of the development of cancer [Hanahan and Weinberg, Cell 100, 57 (2000)].
  • intratumoural neovascularization increases the probability that tumour cells enter the systemic circulation, and strong vascularization therefore increases the potential of metastasization.
  • tumours The dependency of the tumours on neovascularization led to the inhibition of angiogenesis as a novel treatment principle in cancer therapy [Ferrara et al., Nature 438, 967 (2005); Carmeliet, Nature 438, 932 (2005)].
  • the supply of the growing tumour is restricted by inhibiting the even concomitant growth of the vascular system.
  • the status quo is stabilized and the tumour even regresses.
  • One of the most important pro angiogenesis factors is the vascular endothelial growth factor VEGF.
  • VEGFR kinase inhibitors such as sorafenib, sunitinib or pazopanib show positive results in the treatment of renal cell carcinomas, liver carcinomas and advanced stages of gastrointestinal stromal tumours (GIST).
  • GIST gastrointestinal stromal tumours
  • angiopoietin-Tie2 signal transduction system is one of the most endothelial cell-selective and most important signal generators for vascular stabilization and, together with VEGF, for the initiation of vascular growth.
  • the human angiopoietin-Tie signal transduction system consists of the two Type I receptor tyrosine kinases Tie1 and Tie2 (Tyr kinase with Ig and EGF homology domains) and the three secreted glycoprotein ligands angiopoietin 1 (Ang1), angiopoietin 2 (Ang2) and angiopoietin 4 (Ang4). These three ligands bind to Tie2, whereas hitherto no endogenous ligands have been identified for Tie1. Tie1 interacts with Tie2 and regulates its activity [Huang et al., Nat. Rev. Cancer 10, 575-585 (2010)].
  • Ang1 acts as Tie2 receptor agonist and induces, both in vitro and in vivo, multimerization and autophosphorylation of Tie2 at tyrosine residues in the intracellular C-terminal region of the receptor, which allows docking of various effectors such as, for example, DOKR (downstream of tyrosine kinase-related protein), GRB2 (growth factor receptor-bound protein 2), the p85 subunit of PI3K or SHP2 (SH2 domain-containing phosphatase) and results in the activation of several signal cascades downstream.
  • DOKR downstream of tyrosine kinase-related protein
  • GRB2 growth factor receptor-bound protein 2
  • SHP2 SH2 domain-containing phosphatase
  • the DOKR signal transduction cascade and various PI3K signal transduction cascades mediate Ang1-induced migration, tube formation and sprouting of endothelial cells, whereas the activated MAPK and PI3K-AKT signal paths have anti-apoptotic action and contribute to the survival of the endothelial cells [Eklund and Olsen, Exp. Cell Res. 312, 630-641 (2006)].
  • Ang2 was initially identified as Ang1 antagonist [Maisonpierre et al., Science 277, 55-60 (1997)] which inhibits the Ang1-stimulated Tie2 phosphorylation.
  • Ang2 is capable in its own right to induce, under certain conditions in the absence of Ang1, Tie2 phosphorylation, and therefore acts like a partial agonist, depending on the experimental conditions.
  • the significance of the angiopoietin-Tie system for the development and maintenance of the vascular system is confirmed by knock-out and transgenic animal studies.
  • the phenotypes of Tie2-deficient and Ang1-deficient mice are embryonally lethal and in a comparable manner characterized by incompletely formed, partially expanded vessels which lack the branched networks and the peri-endothelial support cells.
  • Analysis of Tie2-deficient murine embryos further showed an important role for Tie2 in haematopoesis and the development of the endocardium.
  • Tie1-deficient murine embryos die of oedema and bleedings which are a consequence of the poor structural state of the endothelial cells of the microvasculature.
  • Ang2-deficient mice are viable and display no serious impairment of embryonal vascular development. There are, however, defects where postnatal vascular restructuring and angiogenesis take place, for example in the retina. In contrast, transgenic overexpression of Ang2 results in an impaired embryonal vessel formation with an embryonally lethal phenotype similar to Tie2- or Ang1-knock-out. The conditional overexpression of Ang2 in endothelial cells leads to complete inhibition of Tie2 phosphorylation in vivo, which supports the view of Ang2 as an Ang1 antagonist.
  • Ang1 Overexpression of Ang1 reduces the increased vascular permeability caused by inflammatory cytokines and systemic treatment with Ang1 couteracts the vascular permeability caused by VEGF [Marchin et al., Nat. Rev. Mol. Cell Biol. 10, 165-177 (2009)].
  • Ang1-Tie2 signal transduction for maintaining vascular integrity and endothelial barrier.
  • Ang1 is secreted constitutively by pericytes and activates the Tie2 receptor localized on the endothelial cells. This constitutive activation is controlled dynamically by Tie1 and in particular by autocrine-acting Ang2.
  • Expression of Ang2 in endothelial cells is induced transcriptionally by cytokines, in particular VEGF, and hypoxia and is increased in tissues where angiogenesis and/or restructuring of vessels takes place.
  • Ang2 stored in endothelial Weibel-Palade bodies can be released very rapidly, resulting in the displacement of the Ang1 bound to Tie2 and suppression of the Ang1-mediated signal transduction. This leads to the dissociation of the pericytes from the endothelial cells and reduced endothelial cell-cell contacts and thus to destabilization of the vessels with concomitant degradation of the basal membrane. In the absence of VEGF, this process leads to the apoptosis of the endothelial cells and vascular regression.
  • VEGF tissue concentrations are sufficiently high, for example as a result of hypoxic induction of the expression in the tumour, the endothelial cells are, depending on their localization in the destabilized vessel, stimulated to proliferate or migrate and in the end to form new vascular sprouts.
  • Tie2 is expressed on a subpopulation of tumor-infiltrated CD11b + myeloid cells, the Tie2-expressing monocytes (TEMs).
  • TEMs monocytes
  • the circulating TEMs promote tumour angiogenesis with their pro-angiogenic properties which are enhanced by increased Ang2 [Coffelt et al., Cancer Res. 70, 5270-5280 (2010)].
  • Tie2 receptors In the pathological processes associated with anomal neovascularization, angiogenic growth factors and the receptors thereof are frequently increasingly expressed. Increased expression of Tie2 receptors was observed, for example, in the endothelium of metastasizing melanomas [Kaipainen et al., Cancer Res. 54, 6571-6577 (1994)], in breast cancer [Salven et al., Br. J. Cancer 74, 69-72 (1996)], in recurrent papillary thyroid cancer [Hsueh et al., J. Surg. Oncol. 103, 395-399 (2011)], in large liver tumours [Dhar et al., Anticancer Res.
  • soluble angiopoietin-neutralizing Tie2 variants consisting of the Fc-fused extracellular ligand-binding Tie2 domain were used in xenograft tumour models for blocking angiopoietin-Tie2 signal transduction, and an inhibition of the growth and the vascularization of the experimental tumours was shown [Lin et al., J. Clin. Invest. 103, 159-165 (1999); Sieffle et al., Cancer Res. 59, 3185-3191 (1999)].
  • angiopoietin-Tie2 system In vitro and in vivo studies demonstrate the great significance of the angiopoietin-Tie2 system for tumour angiogenesis and persistent tumour growth and also involvement in lymphangiogenesis, metastasization and inflammatory processes [Huang et al., Nat. Rev. Cancer 10, 575-585 (2010)].
  • the angiopoietin-Tie2 system is increasingly the target of therapeutic strategies. These include, firstly, biological molecules directed against angiopoietins and, secondly, low-molecular-weight compounds inhibiting Tie2 kinase activity.
  • AMG-386 (Amgen) and CVX-060 (Pfizer) are dual peptide fusion proteins which neutralize Ang1 and Ang2 and just Ang2, respectively, and which are in clinical development phase III and II, respectively.
  • the dual Tie2/VEGFR-inhibitor CEP-11981 (Cephalon) is in phase I of clinical development.
  • WO 2008/042639-A1 describes N-phenylpyrimidinylpyrazolamines as multikinase inhibitors for the treatment of proliferative disorders.
  • EP 2 327 704-A1 and WO 2010/125799-A1 disclose ureido-substituted fused azole derivatives, amongst others 1-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazoles, as PI3K inhibitors for the treatment of various disorders.
  • the present invention provides compounds of the general formula (I)
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, the compounds included in the formula (I) of the formulae mentioned in the following and their salts, solvates and solvates of the salts, and the compounds included in the formula (I) and mentioned in the following as working examples and their salts, solvates and solvates of the salts, where the compounds included in the formula (I) and mentioned in the following are not already salts, solvates and solvates of the salts.
  • the compounds according to the invention can exist in different stereoisomeric forms depending on their structure, i.e. in the form of configuration isomers or optionally also as conformation isomers (enantiomers and/or diastereomers, including those in the case of atropisomers).
  • the present invention therefore includes the enantiomers and diastereomers and their particular mixtures.
  • the stereoisomerically uniform constituents can be isolated from such mixtures of enantiomers and/or diastereomers in a known manner; chromatography processes are preferably used for this, in particular HPLC chromatography on an achiral or chiral phase.
  • the present invention includes all the tautomeric forms.
  • the present invention also encompasses all suitable isotopic variants of the compounds according to the invention.
  • An isotopic variant of a compound according to the invention is understood here to mean a compound in which at least one atom within the compound according to the invention has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound according to the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I.
  • Particular isotopic variants of a compound according to the invention may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body; due to comparatively easy preparability and detectability, especially compounds labelled with 3 H or 14 C isotopes are suitable for this purpose.
  • the incorporation of isotopes, for example of deuterium can lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required; such modifications of the compounds according to the invention may therefore in some cases also constitute a preferred embodiment of the present invention.
  • Isotopic variants of the compounds according to the invention can be prepared by generally used processes known to those skilled in the art, for example by the methods described below and the methods described in the working examples, by using corresponding isotopic modifications of the particular reagents and/or starting compounds therein.
  • Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Salts which are not themselves suitable for pharmaceutical uses but can be used, for example, for isolation or purification of the compounds according to the invention are also included.
  • Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • Physiologically acceptable salts of the compounds according to the invention also include salts of conventional bases, such as, by way of example and preferably, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, N,N-diisopropylethylamine, monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol, diethylaminoethanol, procaine, dicyclohexylamine, dibenzylamine, N-methylmorpholine, N-methylpiperidine, arginine, lysine and 1,2-ethylenediamine.
  • alkali metal salts for example sodium and potassium salts
  • alkaline earth metal salts for example calcium and magnesium salts
  • Solvates in the context of the invention are described as those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of solvates, in which the coordination takes place with water. Hydrates are preferred solvates in the context of the present invention.
  • N-oxides of pyridyl rings and tertiary cyclic amine groupings contained in compounds according to the invention are similarly included in the present invention.
  • the present invention moreover also includes prodrugs of the compounds according to the invention.
  • prodrugs here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their dwell time in the body.
  • (C 1 -C 6 )-Alkyl, (C 1 -C 4 )-alkyl and (C 2 -C 4 )-alkyl in the context of the invention represent a straight-chain or branched alkyl radical having 1 to 6, 1 to 4 and 2 to 4 carbon atoms, respectively.
  • (C 1 -C 4 )-Alkylsulphonyl in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms which is attached via a sulphonyl group [—S( ⁇ O) 2 -] to the remainder of the molecule.
  • a sulphonyl group [—S( ⁇ O) 2 -] to the remainder of the molecule.
  • (C 1 -C 6 )-Alkoxy, (C 1 -C 4 )-alkoxy and (C 2 -C 4 )-alkoxy in the context of the invention represent a straight-chain or branched alkoxy radical having 1 to 6, 1 to 4 and 2 to 4 carbon atoms, respectively.
  • (C 3 -C 6 )-Cycloalkyl in the context of the invention represents a monocyclic saturated cycloalkyl group having 3 to 6 ring carbon atoms. There may be mentioned by way of example and preferably: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • a 4- to 6-membered heterocycle in the context of the invention represents a monocyclic saturated heterocycle having a total of 4 to 6 ring atoms which contains one or two identical or different ring heteroatoms from the group consisting of N, O and S and is attached via a ring carbon atom or a ring nitrogen atom. Preference is given to a 4- to 6-membered heterocycle having one or two ring heteroatoms from the group consisting of N and O.
  • azetidinyl Preference is given to azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl and morpholinyl. Particular preference is given to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.
  • R 10 represents a monocyclic aromatic heterocycle (heteroaromatic) having a total of 5 and 6 ring atoms, respectively, which contains up to three identical or different ring heteroatoms from the group consisting of N, O and S and is attached via a ring carbon atom or a ring nitrogen atom.
  • furyl pyrrolyl, thienyl, pyrazolyl, imidazolyl, 1,2-oxazolyl (isoxazolyl), 1,3-oxazolyl, 1,2-thiazolyl (isothiazolyl), 1,3-thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl and 1,3,5-triazinyl.
  • 5-membered heteroaryl which contains a ring nitrogen atom
  • azaheteroaryl may additionally contain a further ring heteroatom from the group consisting of N, O and S, such as pyrrolyl, pyrazolyl, imidazolyl, 1,2-oxazolyl, 1,3-oxazolyl, 1,2-thiazolyl and 1,3-thiazolyl.
  • An oxo substituent in the context of the invention represents an oxygen atom, which is bonded to a carbon atom or a sulphur atom via a double bond.
  • radicals which occur more than once are defined independently of one another. If radicals in the compounds according to the invention are substituted, the radicals may be mono- or polysubstituted, unless specified otherwise. Substitution by one, two or three identical or different substituents is preferred. Particular preference is given to substitution by one or two identical or different substituents. Very particular preference is given to substitution by one substituent.
  • a certain embodiment of the present invention comprises compounds of the formula (I) in which
  • a further preferred embodiment of the present invention comprises compounds of the formula (I) in which
  • a particular embodiment of the present invention relates to compounds of the formula (I) in which
  • a further particular embodiment of the present invention relates to compounds of the formula (I) in which
  • a further particular embodiment of the present invention relates to compounds of the formula (I) in which
  • a further particular embodiment of the present invention relates to compounds of the formula (I) in which
  • a further particular embodiment of the present invention relates to compounds of the formula (I) in which
  • a further particular embodiment of the present invention relates to compounds of the formula (I) in which
  • a further particular embodiment of the present invention relates to compounds of the formula (I) in which
  • a further particularly preferred embodiment of the present invention relates to compounds of the formula (I) in which
  • a further very particularly preferred embodiment of the present invention relates to compounds of the formula (I) in which
  • radicals indicated specifically in the respective combinations or preferred combinations of radicals are replaced as desired irrespective of the particular combinations indicated for the radicals also by definitions of radicals of other combinations. Combinations of two or more of the abovementioned preferred ranges are very particularly preferred.
  • the present invention furthermore provides a process for preparing the compounds of the formula (I) according to the invention, characterized in that either
  • group Ar N in formula (I) represents 5-membered azaheteroaryl of the structures shown above and ring member Y in this structure represents NH
  • a protective group PG Suitable for this purpose are known amino protective groups such as, in particular, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl or tetrahydro-2H-pyran-2-yl (THP).
  • THP tetrahydro-2H-pyran-2-yl
  • Inert solvent for process step [A] (II)+(III) ⁇ (IV) [amide coupling] are, for example, ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis(2-methoxyethyl) ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichlorothane, trichloroethylene or chlorobenzene, or dipolar aprotic solvents such as acetone, acetonitrile, ethyl acetate, pyridine, dimethyl sulphoxide (DMSO), N,N-di
  • Suitable condensing agents for these coupling reactions are, for example, carbodiimides such as N,N′-diethyl-, N,N′-dipropyl-, N,N′-diisopropyl-, N,N′-dicyclohexylcarbodiimide (DCC) or N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as N,N′-carbonyldiimidazole (CDI) or isobutyl chloroformate, 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulphate or 2-tert-butyl 5-methylisoxazolium perchlorate, acyl-amino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, ⁇ -chloroenamines such as 1-
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate
  • the reaction [A] (II)+(III) ⁇ (IV) is generally carried out in a temperature range of from ⁇ 20° C. to +60° C., preferably at from 0° C. to +40° C.
  • the reaction can be carried out at atmospheric, at elevated or at reduced pressure (for example from 0.5 to 5 bar); in general, the reaction is carried out at atmospheric pressure.
  • the coupling reaction [B] (V)+(VI) ⁇ (IV) is carried out with the aid of a copper(I) catalyst such as copper(I) oxide, copper(I) bromide or copper(I) iodide, in the presence of a copper ligand such as 8-hydroxyquinoline or 1,10-phenanthroline, and an inorganic or organic carbonate base such as potassium carbonate, caesium carbonate or bis(tetraethylammonium) carbonate.
  • a copper(I) catalyst such as copper(I) oxide, copper(I) bromide or copper(I) iodide
  • a copper ligand such as 8-hydroxyquinoline or 1,10-phenanthroline
  • an inorganic or organic carbonate base such as potassium carbonate, caesium carbonate or bis(tetraethylammonium) carbonate.
  • Suitable inert solvents for this reaction are in particular toluene, xylene, 1,4-dioxane, acetonitrile, dimethyl sulphoxide (DMSO), N,N-dimethylformamide (DMF) or mixtures thereof, if appropriate with addition of water.
  • DMSO dimethyl sulphoxide
  • DMF N,N-dimethylformamide
  • the reaction is generally carried out in a temperature range of from +100° C. to +200° C., advantageously using a microwave oven.
  • Suitable palladium catalysts for the coupling reaction [C] (VII)+(VI) ⁇ (VIII) are, for example, palladium(II) acetate, palladium(II) chloride, bis(triphenylphosphine)palladium(II) chloride, bis(acetonitrile)palladium(II) chloride, tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, in each case in combination with a suitable phosphine ligand such as, for example, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos), 2-dicyclohexylphosphino
  • the coupling reaction [C] (VII)+(VI) ⁇ (VIII) is generally carried out in the presence of a base.
  • Suitable bases are in particular alkali metal carbonates such as sodium carbonate, potassium carbonate or caesium carbonate, alkali metal phosphates such as sodium phosphate or potassium phosphate, alkali metal fluorides such as potassium fluoride or caesium fluoride, or alkali metal tert-butoxides such as sodium tert-butoxide or potassium tert-butoxide.
  • the reaction is carried out in an inert solvent such as, for example, toluene, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, dimethyl sulphoxide (DMSO), N,N-dimethylformamid (DMF), N,N-dimethylacetamide (DMA) or mixtures thereof in a temperature range of from +80° C. to +200° C., where here, too, heating by means of a microwave apparatus may be advantageous.
  • an inert solvent such as, for example, toluene, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, dimethyl sulphoxide (DMSO), N,N-dimethylformamid (DMF), N,N-dimethylacetamide (DMA) or mixtures thereof in a temperature range of from +80° C. to +200° C., where here, too, heating by means of a microwave apparatus
  • a catalyst/ligand/base system consisting of palladium(II) acetate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) and caesium carbonate, and 1,4-dioxane as solvent.
  • the cyclization [C] (VIII) ⁇ (IV) is preferably carried out by heating the acetal (VIII) with an aqueous acid such as, for example, sulphuric acid in an alcoholic solvent such as methanol or ethanol, where once more carrying out the reaction with microwave irradiation may be advantageous.
  • an aqueous acid such as, for example, sulphuric acid in an alcoholic solvent such as methanol or ethanol
  • conversions are carried out by customary methods familiar to the person skilled in the art and include, for example, reactions such as nucleophilic or electrophilic substitution reactions, transition metal-catalyzed coupling reactions (for example Ullmann reaction, Buchwald-Hartwig reaction, Suzuki coupling, Negishi coupling), addition reactions of organometallic compounds (for example Grignard compounds or organilithium compounds) on carbonyl compounds, oxidation and reduction reactions, hydrogenation, alkylation, acylation, sulphonylation, amination, hydroxylation, the formation of nitriles, carboxylic esters, carboxamides and sulfonamides, ester cleavage and hydrolysis and also introduction and removal of temporary protective groups.
  • reactions such as nucleophilic or electrophilic substitution reactions, transition metal-catalyzed coupling reactions (for example Ullmann reaction, Buchwald-Hartwig reaction, Suzuki coupling, Negishi coupling), addition reactions of organometallic compounds (for example Grignard compounds or organilith
  • aminopyrazole intermediate of the formula (VII) from process route [C] can be prepared by acid-catalyzed condensation of a cyanoenamine or -enol of the formula (IX)
  • R 2 , R 3 and R 15 have the meanings given above.
  • the reaction is preferably carried out in an alcoholic solvent such as methanol or ethanol in a temperature range of from +60° C. to +120° C., the use of a microwave oven being advantageous.
  • a particularly suitable acid catalyst is aqueous hydrochloric acid.
  • enolate salts such as, for example, lithium enolates, sodium enolates or potassium enolates, for the reaction.
  • aniline intermediate of the formula (II) from process route [A] can be obtained by (i) palladium-catalyzed coupling of (VII) with a meta-nitrophenyl bromide of the formula (XI)
  • the reduction of the nitro group to the amine in process step (XIII) ⁇ (II) can be carried out, for example, with the aid of tin(II) chloride or by catalytical hydrogenation with gaseous hydrogen or, in the sense of a transfer hydrogenation, in the presence of hydrogen donors such as ammonium formate, cyclohexene or cyclohexadiene.
  • the preferred method is the palladium(0)-catalyzed hydrogenation with ammonium formate.
  • the reaction is preferably carried out in an alcoholic solvent such as methanol or ethanol, if appropriate with addition of water, in a temperature range of from +20° C. to +100° C.
  • R 4A , R 4B , R 5 and R 6 have the meanings given above, with a carboxylic acid of the formula (III) or a corresponding carbonyl chloride of the formula (XV)
  • the carboxylic acid amidation (XIV)+(III) ⁇ (VI) is carried out by customary methods with the aid of a condensing agent under reaction conditions similar to those described above for the analogous reaction [A] (II)+(III) ⁇ (IV).
  • the condensing agent used is O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and the base is N,N-diisopropylethylamine.
  • a customary organic auxiliary base such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, pyridine, 2,6-lutidine, 4-N,N-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • DBN 1,5-diazabicyclo[4.3.0]non-5-ene
  • the compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of disorders in humans and animals.
  • the compounds according to the invention are highly potent inhibitors of Tie2 receptor kinase and can be administered orally. By virtue of this activity profile, the compounds according to the invention are suitable in particular for the treatment of angiogenic disorders in humans and mammals in general.
  • angiogenic disorders include in particular neoplastic disorders and tumour disorders which, in the context of the present invention, is to be understood as meaning in particular the following disorders, but without being limited thereto: breast carcinomas and breast tumours (mammary carcinomas including ductal and lobular forms, also in situ), tumours of the respiratory tract (small-cell and non-small-cell lung carcinoma, bronchial carcinomas), brain tumours (for example of the brain stem and of the hypothalamus, astrocytoma, ependymoma, glioblastoma, glioma, medullo-blastoma, meningioma and neuro-ectodermal and pineal tumours), tumours of the digestive organs (oesophagus, stomach, gall bladder, small intestine, large intestine, rectum and anal carcinomas), liver tumours (inter alia hepatocellular carcinoma, cholangiocellular carcinoma and mixed hepatocellular and cholangiocellular carcinomas),
  • lymphomas include proliferative disorders of the blood, the lymph system and the spinal cord, in solid form and as circulating cells, such as leukaemias, lymphomas and myeloproliferative diseases, for example acute myeloid, acute lymphoblastic, chronic myeloic, chronic lymphocytic and hair cell leukaemia, multiple myeloma (plasmocytoma) and AIDS-correlated lymphomas, Hodgkin's lymphomas, non-Hodgkin's lymphomas, cutaneous T cell lymphomas, Burkitt's lymphomas and lymphomas in the central nervous system.
  • leukaemias for example acute myeloid, acute lymphoblastic, chronic myeloic, chronic lymphocytic and hair cell leukaemia, multiple myeloma (plasmocytoma) and AIDS-correlated lymphomas, Hodgkin's lymphomas, non-Hodgkin's lymphomas, cutaneous T cell lymphomas, Burkitt'
  • the treatment of the neoplastic disorders mentioned above may comprise both a treatment of the solid tumours and a treatment of metastasizing or circulating forms thereof.
  • the compounds according to the invention are particularly suitable for the treatment of breast, colorectal, liver, kidney and ovarial carcinomas, glioblastomas, acute myeloic leukaemia (AML), chronic myeloic leukaemia (CML) and multiple myeloma.
  • AML acute myeloic leukaemia
  • CML chronic myeloic leukaemia
  • the compounds of the present invention can be used for treating blood vessel malformations such as haemangiomas, haemangioblastomas, cavernomas and lymphangiomas, and further disorders associated with excessive or anormal angiogenesis.
  • blood vessel malformations such as haemangiomas, haemangioblastomas, cavernomas and lymphangiomas, and further disorders associated with excessive or anormal angiogenesis.
  • these include, inter alia, diabetic retinopathy, ischaemic retinal vene occlusion and retinopathy of prematurity, age-related macular degeneration, neovascular glaucoma, psoriasis, retrolental fibroplasia, angiofibroma, inflammation, rheumatic arthritis, restenosis, in-stent restenosis and restenosis after vessel implantation, endometriosis, kidney disorders (for example glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis) and
  • treatment includes the inhibition, delay, arrest, amelioration, attenuation, limitation, reduction, suppression, reversal or cure of a disease, a condition, a disorder, an injury and a health impairment, of the development, course or the progression of such states and/or the symptoms of such states.
  • therapy is understood to be synonymous with the term “treatment”.
  • prevention In the context of the present invention, the terms “prevention”, “prophylaxis” or “precaution” are used synonymously and refer to the avoidance or reduction of the risk to get, to contract, to suffer from or to have a disease, a condition, a disorder, an injury or a health impairment, a development or a progression of such states and/or the symptoms of such states.
  • the treatment or the prevention of a disease, a condition, a disorder, an injury or a health impairment may take place partially or completely.
  • the invention furthermore provides the use of the compounds according to the invention for the treatment and/or prevention of disorders, in particular the disorders mentioned above.
  • the present invention furthermore provides the use of the compounds according to the invention for preparing a medicament for the treatment and/or prevention of disorders, in particular the disorders mentioned above.
  • the present invention furthermore provides the use of the compounds according to the invention in a method for the treatment and/or prevention of disorders, in particular the disorders mentioned above.
  • the present invention furthermore provides a method for the treatment and/or prevention of disorders, in particular the disorders mentioned above, using an effective amount of at least one of the compounds according to the invention.
  • the compounds according to the invention can be employed by themselves or, if required, in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesirable and unacceptable side effects. Accordingly, the present invention furthermore provides medicaments comprising at least one of the compounds according to the invention and one or more further active compounds, in particular for the treatment and/or prevention of the abovementioned diseases.
  • the compounds of the present invention can be combined with known anti-angiogenic, anti-hyperproliferative, cytostatic or cytotoxic substances for the treatment of neoplastic disorders.
  • Suitable active compounds in the combination which may be mentioned by way of example are:
  • the compounds according to the invention can moreover also be employed in combination with radiotherapy and/or surgical intervention.
  • the present invention furthermore provides medicaments which comprise at least one compound according to the invention, conventionally together with one or more inert, non-toxic, pharmaceutically suitable auxiliary substances, and the use thereof for the abovementioned purposes.
  • the compounds according to the invention can act systemically and/or locally. They can be administered in a suitable manner for this purpose, such as e.g. orally, parenterally, pulmonally, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms for these administration routes.
  • Administration forms which function according to the prior art, release the compounds according to the invention rapidly and/or in a modified manner and contain the compounds according to the invention in crystalline and/or amorphized and/or dissolved form are suitable for oral administration, such as e.g. tablets (non-coated or coated tablets, for example with coatings which are resistant to gastric juice or dissolve in a delayed manner or are insoluble and control the release of the compound according to the invention), tablets or films/oblates, films/lyophilisates or capsules which disintegrate rapidly in the oral cavity (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions, are suitable for oral administration.
  • tablets non-coated or coated tablets, for example with coatings which are resistant to gastric juice or dissolve in a delayed manner or are insoluble and control the release of the compound according to the invention
  • Parenteral administration can be effected with bypassing of an absorption step (e.g. intravenously, intraarterially, intracardially, intraspinally or intralumbally) or with inclusion of an absorption (e.g. intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally).
  • Administration forms which are suitable for parenteral administration are, inter alia, injection and infusion formulations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • inhalation medicament forms inter alia powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • tablets films/oblates or capsules for lingual, sublingual or buccal administration
  • suppositories e.g. suppositories
  • ear or eye preparations vaginal capsules
  • aqueous suspensions e.g. aqueous suspensions (lotions, shaking mixtures)
  • lipophilic suspensions ointments
  • creams e.g. patches
  • transdermal therapeutic systems e.g. patches
  • milk pastes, foams, sprinkling powders, implants or stents
  • implants or stents are suitable.
  • Oral or parenteral administration is preferred, in particular oral and intravenous administration.
  • auxiliary substances include inter alia carrier substances (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecyl sulphate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants, such as, for example, ascorbic acid), dyestuffs (e.g. inorganic pigments, such as, for example, iron oxides) and flavour and/or smell correctants.
  • carrier substances for example microcrystalline cellulose, lactose, mannitol
  • solvents e.g. liquid polyethylene glycols
  • emulsifiers and dispersing or wetting agents for example sodium dodecyl sulphate, polyoxysorbitan oleate
  • binders for example polyvinylpyrrolidone
  • parenteral administration amounts of from about 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg of body weight to achieve effective results.
  • the dosage is about 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and very particularly preferably 0.1 to 10 mg/kg of body weight.
  • Instrument Micromass Quattro Premier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9 ⁇ m, 50 mm ⁇ 1 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A ⁇ 0.1 min 90% A ⁇ 1.5 min 10% A ⁇ 2.2 min 10% A; flow rate: 0.33 ml/min; temperature: 50° C.; UV detection: 210 nm.
  • MS instrument Waters SQD
  • HPLC instrument Waters UPLC
  • column Zorbax SB-Aq (Agilent), 50 mm ⁇ 2.1 mm, 1.8 ⁇ m
  • mobile phase A water+0.025% formic acid
  • mobile phase B acetonitrile+0.025% formic acid
  • gradient 0.0 min 98% A ⁇ 0.9 min 25% A ⁇ 1.0 min 5%
  • a ⁇ 1.41 min 98% A ⁇ 1.5 min 98% A oven: 40° C.
  • flow rate 0.60 ml/min
  • the reaction was carried out in a 3 litre three-necked flask with internal thermometer under argon. 50 g (537 mmol) of 1H-pyrazole-4-carbonitrile were suspended in 1.66 litre of methylene chloride and, after 3 h, cooled to 3° C. using an ice bath. At this temperature, 10.2 g (53.7 mmol) of 4-toluenesulphonic acid monohydrate were added. At 3° to 6° C., 58.8 ml (54.2 g, 644 mmol) of 3,4 dihydro-2H-pyran were then added dropwise over a period of 30 min. The reaction was then stirred at RT overnight.
  • Step 3 1-(2,2-Diethoxyethyl)-1′-(tetrahydro-2H-pyran-2-yl)-1H,1′H-3,4′-bipyrazole-5-amine
  • Step 3 1-(2,2-Diethoxyethyl)-1′-(4-methoxybenzyl)-1H,1′H-3,4′-bipyrazol-5-amine
  • Step 2 1-(1,1-Dimethoxypropan-2-yl)-1′-(4-methoxybenzyl)-1H,1′H-3,4′-bipyrazole-5-amine
  • Step 1 1-(2,2-Diethoxyethyl)-N-(2-methyl-5-nitrophenyl)-3-(pyridin-3-yl)-1H-pyrazole-5-amine
  • the crude product obtained in this manner was purified by filtration with suction through silica gel (mobile phase gradient ethyl acetate/petroleum ether 4:1 ⁇ 100% ethyl acetate). The product fractions were combined and freed from the solvent on a rotary evaporator. Trituration with diisopropyl ether at RT, removal of the solid by filtration with suction and drying under high vacuum gave 195 g (84% of theory) of the title compound.
  • Step 1 1-(2,2-Diethoxyethyl)-N-(2-methyl-5-nitrophenyl)-1′-(tetrahydro-2H-pyran-2-yl)-1H,1′H-3,4′-bipyrazole-5-amine
  • Example 7A/Step 1 The compound from Example 7A/Step 1 (5.5 g, 11.3 mmol) was dissolved in 80 ml of ethanol, and 17 ml of 2 M sulphuric acid were added. The reaction was then divided into five 20 ml-microwave reactor vessels, and each batch was heated in a single-mode microwave reactor (Biotage Emrys Optimizer) at 120° C. for 15 min. The batches were then combined again, poured into dilute aqueous sodium bicarbonate solution and extracted twice with methylene chloride. The combined organic phases were dried over sodium sulphate, filtered and concentrated. In four portions, the residue was purified by preparative HPLC (Method 25). This gave 2.1 g (86% pure, 52% of theory) of the title compound.
  • Step 3 4-Methyl-3-[6-(1H-pyrazol-4-yl)-1H-imidazo[1,2-b]pyrazol-1-yl]aniline
  • Step 1 1-(2,2-Diethoxyethyl)-1′-(4-methoxybenzyl)-N-(2-methyl-5-nitrophenyl)-1H,1′H-3,4′-bipyrazole-5-amine
  • Step 2 6-[1-(4-Methoxybenzyl)-1H-pyrazol-4-yl]-1-(2-methyl-5-nitrophenyl)-1H-imidazo-[1,2-b]pyrazole
  • Step 3 3- ⁇ 6-[1-(4-Methoxybenzyl)-1H-pyrazol-4-yl]-1H-imidazo[1,2-b]pyrazol-1-yl ⁇ -4-methylaniline trifluoroacetate
  • Step 1 1-(1,1-Dimethoxypropan-2-yl)-1′-(4-methoxybenzyl)-N-(2-methyl-5-nitrophenyl)-1H,1′H-3,4′-bipyrazole-5-amine
  • Step 2 6-[1-(4-Methoxybenzyl)-1H-pyrazol-4-yl]-3-methyl-1-(2-methyl-5-nitrophenyl)-1H-imidazo[1,2-b]pyrazole
  • Step 3 3- ⁇ 6-[1-(4-Methoxybenzyl)-1H-pyrazol-4-yl]-3-methyl-1H-imidazo[1,2-b]pyrazol-1-yl ⁇ -4-methylaniline
  • Step 1 1-(2,2-Diethoxyethyl)-N-(2-methoxy-5-nitrophenyl)-3-(pyridin-3-yl)-1H-pyrazole-5-amine
  • Step 1 1-(2,2-Diethoxyethyl)-N-(2,4-dimethyl-5-nitrophenyl)-3-(pyridin-3-yl)-1H-pyrazole-5-amine
  • a solution of 4.17 g (9.81 mmol) of the compound of Example 11A/Step 1 in 42 ml of ethanol and 9.8 ml (19.6 mmol) of 2 M sulphuric acid was divided into four microwave reaction vessels which were then each heated in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 130° C. for 15 min. The contents of the four reaction vessels were then stirred into about 100 ml of water. By addition of saturated aqueous sodium bicarbonate solution the aqueous phase was adjusted to a neutral pH. The mixture was then extracted repeatedly with ethyl acetate.
  • Example 11A/Step 2 135 mg (85% pure, 0.34 mmol) of the compound of Example 11A/Step 2 were converted analogously to the procedure of Example 10A/Step 3 into 110 mg (87% pure, 92% of theory) of the title compound.
  • Step 2 1-(2,2-Diethoxyethyl)-N-(4-fluoro-2-methyl-5-nitrophenyl)-3-(pyridin-3-yl)-1H-pyrazole-5-amine
  • Example 12A/Step 3 80 mg (0.23 mmol) of the compound of Example 12A/Step 3 were reacted analogously to the procedure of Example 10A/Step 3 to give 65 mg (94% pure, 84% of theory) of the title compound.
  • the mixture was stirred under reflux for 30 min (instead of 15 min)
  • Step 1 1-(2,2-Diethoxyethyl)-N-(2-fluoro-5-nitrophenyl)-3-(pyridin-3-yl)-1H-pyrazole-5-amine
  • Step 3 4-Fluoro-3-[6-(pyridin-3-yl)-1H-imidazo[1,2-b]pyrazol-1-yl]aniline
  • Step 1 1-(2,2-Diethoxyethyl)-N-(4-methyl-3-nitrophenyl)-3-(pyridin-3-yl)-1H-pyrazole-5-amine
  • Example 14A/Step 1 Analogously to Example 13A/Step 2, a test reaction of 841 mg (2.04 mmol) and the main reaction of 1.1 g (2.67 mmol) of the compound of Example 14A/Step 1 gave a crude product which was initially purified on a Biotage system (100 g Snap column; mobile phase gradient hexane/ethyl acetate, from 0% ethyl acetate increasing steadily to 100% ethyl acetate, then ethyl acetate/methanol, from 0% methanol increasing slowly to 80% methanol). This gave 623 mg (69% of theory) of the title compound and material which was still impure.
  • a Biotage system 100 g Snap column; mobile phase gradient hexane/ethyl acetate, from 0% ethyl acetate increasing steadily to 100% ethyl acetate, then ethyl acetate/methanol, from 0% methanol increasing slowly to 80%
  • the impure material was purified once more by chromatography on a Biotage system (25 g Snap column; mobile phase gradient ethyl acetate/methanol, from 0% methanol increasing slowly to 80% methanol). This gave a further 225 mg (25% of theory) of the title compound.
  • Example 13A/Step 3 Analogously to Example 13A/Step 3, a test reaction of 225 mg (0.71 mmol) and the main reaction of 622 mg (1.95 mmol) of the compound of Example 14A/Step 2 gave a crude product of the title compound (730 mg, 95% of theory) which was reacted further without additional purification.
  • the reaction was stirred in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 130° C. for 30 min.
  • the reaction was then stirred into 10 ml of saturated aqueous sodium chloride solution and extracted twice with in each case 30 ml of ethyl acetate.
  • the organic phase was washed with pH 4 buffer solution, dried over sodium sulphate and concentrated on a rotary evaporator.
  • the residue was dissolved in 5 ml of tert-butyl methyl ether, and 10 ml of pentane were added.
  • the precipitate formed was filtered off and dried. This gave 1.04 g (68% of theory) of the title compound.
  • Example 19A Analogously to the procedure for Example 19A, 250 mg (0.76 mmol) of the compound of Example 15A and 0.25 ml (1.15 mmol) of tert-butyl 3-oxoazetidine-1-carboxylate gave, after purification by preparative HPLC (Method 27), 65 mg (20% of theory) of the title compound.
  • reaction mixture was stirred in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 130° C. for 30 min.
  • the reaction was then filtered whilst still hot and the residue was washed thoroughly with toluene.
  • the combined filtrates were concentrated under reduced pressure and the residue was purified by preparative HPLC (Method 13). This gave 255 mg (34% of theory) of the title compound.
  • Step 1 3- ⁇ [3-(Dimethylamino)propyl](methyl)amino ⁇ -5-(trifluoromethyl)benzonitrile
  • the reaction was then concentrated to a volume of about 5 ml under reduced pressure and stirred into 100 ml of 0.1 M aqueous sodium hydroxide solution.
  • the solid formed was filtered off, the filtrate was adjusted to pH 1 with concentrated hydrochloric acid and the precipitate formed was filtered off again.
  • the filtrate was extracted twice with in each case 50 ml of tert-butyl methyl ether, and the combined organic phases were washed with water and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure.
  • the product was isolated by preparative HPLC (Method 20). Evaporation of the product fractions and drying of the residue under high vacuum gave 75 mg (92% pure, 4% of theory) of the title compound.
  • Example 16A The compound from Example 16A (320 mg, 0.74 mmol) was dissolved in 2.3 ml of DMF, HATU (309 mg, 0.81 mmol) and then 4-methylmorpholine (0.32 ml) were added, and the mixture was stirred at RT for 30 min. At ⁇ 5° C., the compound of Example 7A (103 mg, 0.37 mmol) was then added and the mixture was stirred at RT for 16 h. A few millilitres of concentrated aqueous ammonia solution were then added. The mixture was stirred at RT for 15 min and then extracted with ethyl acetate. The organic phase was washed with conc. sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (Method 28). This gave 210 mg (purity 61%, 50% of theory) of the title compound which was used without further purification for the next synthesis step.
  • Example 8A 60 mg (0.12 mmol) of the compound of Example 8A and 31.6 mg (0.12 mmol) of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid [lit.: WO 2004/005281-A1, Example 91b] were reacted and worked up analogously to the procedure of Example 48A. This gave 61 mg (77% of theory) of the title compound.
  • Step 1 3-tert-Butyl-N-(3- ⁇ [1-(2,2-diethoxyethyl)-1′-(4-methoxybenzyl)-1H,1′H-3,4′-bipyrazol-5-yl]amino ⁇ -4-methylphenyl)benzamide
  • Step 2 3-tert-Butyl-N-(3- ⁇ 6-[1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-1H-imidazo[1,2-b]-pyrazol-1-yl ⁇ -4-methylphenyl)benzamide
  • Example 8A 70 mg (0.14 mmol) of the compound of Example 8A and 51 mg (0.14 mmol) of the compound of Example 22A were reacted analogously to the procedure of Example 48A. This gave 83 mg (88% pure, 83% of theory) of the title compound.
  • Example 9A 70 mg (0.17 mmol) of the compound of Example 9A and 78 mg (0.17 mmol) of the compound of Example 17A were reacted and worked up analogously to the procedure of Example 48A. This gave 125 mg (95% of theory) of the title compound.
  • Step 1 Sodium 2-cyano-1-(pyrazin-2-yl)ethenolate
  • Example 8A/Step 2 490 mg (1.14 mmol) of the compound of Example 8A/Step 2 were reacted and worked up analogously to Example 9A/Step 3. In this case, the reaction was heated under reflux for 30 min (instead of 1.5 h). This gave 436 mg (77% of theory, 80% pure) of the title compound.
  • Step 1 1-(2,2-Diethoxyethyl)-N-(2,4-dimethyl-5-nitrophenyl)-1′-(4-methoxybenzyl)-1H,1′H-3,4′-bipyrazole-5-amine
  • Example 61A/Step 2 200 mg (0.45 mmol) of the compound of Example 61A/Step 2 were reacted analogously to Example 61A. After the reaction had ended, the mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was separated into its components by preparative HPLC (Method 21). The product-containing fractions were combined, concentrated almost completely under reduced pressure and made alkaline with a little saturated aqueous sodium bicarbonate solution. The resulting precipitate was filtered off, washed with water and dried under high vacuum. This gave 120 mg (64% of theory) of the title compound.
  • Step 1 1-(2,2-Diethoxyethyl)-N-(3-nitrophenyl)-3-(pyridin-3-yl)-1H-pyrazole-5-amine
  • Example 9A/Step 3 855 mg (2.80 mmol) of the compound of Example 62A/Step 2 gave 760 mg (98% of theory) of the title compound. In this case, the reaction time was 30 minutes.
  • Step 1 1-(2,2-Diethoxyethyl)-N-[5-nitro-2-(trifluoromethyl)phenyl]-3-(pyridin-3-yl)-1H-pyrazole-5-amine
  • Step 2 1-[5-Nitro-2-(trifluoromethyl)phenyl]-6-(pyridin-3-yl)-1H-imidazo[1,2-b]pyrazole
  • Example 13A/Step 2 Analogously to Example 13A/Step 2, 2.03 g (4.36 mmol) of the compound of Example 63A/Step 1 gave a crude product which was purified by single chromatography on a Biotage system (50 g Snap column; mobile phase gradient dichloromethane/methanol, from 2% methanol increasing steadily to 8% methanol). This gave 1.17 g (65% of theory) of the title compound.
  • Step 1 N-(2-Chloro-5-nitrophenyl)-1-(2,2-diethoxyethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-amine
  • Example 9A/Step 3 310 mg (0.912 mmol) of the compound of Example 64A/Step 2 gave, after a reaction time of 60 minutes, 267 mg (73% pure, 68% of theory) of a mixture which consisted of the title compound and the compound from Example 62A in a ratio of 73:27. This mixture was used without further purification for subsequent reactions.
  • Step 1 1-(2,2-Diethoxyethyl)-N-(2,3-dimethyl-5-nitrophenyl)-3-(pyridin-3-yl)-1H-pyrazole-5-amine
  • Example 65A/Step 1 Analogously to Example 13A/Step 2, 1.31 g (3.08 mmol) of the compound of Example 65A/Step 1 gave a crude product which was purified by single chromatography on a Biotage system (50 g Snap column; mobile phase gradient dichloromethane/methanol, from 0% methanol increasing steadily to 10% methanol). This gave 670 mg (63% of theory) of the title compound.
  • Example 13A/Step 3 Analogously to Example 13A/Step 3, 670 mg (2.01 mmol) of the compound of Example 65A/Step 2 gave 524 mg (86% of theory) of the title compound.
  • Step 1 N-(3-Fluoro-2-methyl-5-nitrophenyl)-1-(2,2-diethoxyethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-amine
  • Example 13A/Step 2 1.19 g (2.77 mmol) of the compound of Example 66A/Step 1 gave a crude product which was purified by single chromatography on a Biotage system (25 g Snap column; mobile phase gradient hexane/ethyl acetate, from 0% ethyl acetate increasing steadily to 100% ethyl acetate, then ethyl acetate/methanol, proportion of methanol increasing slowly from 0 to 80%). This gave 587 mg (60% of theory) of the title compound.
  • Example 13A/Step 3 Analogously to Example 13A/Step 3, 570 mg (1.69 mmol) of the compound of Example 66A/Step 2 gave 520 mg (100% of theory) of the title compound.
  • Step 1 N-(3-Chloro-2-methyl-5-nitrophenyl)-1-(2,2-diethoxyethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-amine
  • Example 13A/Step 1 Analogously to Example 13A/Step 1, 1.0 g (3.62 mmol) of the compound of Example 4A and 1.0 g (3.98 mmol) of 1-bromo-3-chloro-2-methyl-5-nitrobenzene gave 670 mg (42% of theory) of the title compound.
  • the starting material 1-bromo-3-chloro-2-methyl-5-nitrobenzene can be prepared from 2-chloro-1-methyl-4-nitrobenzene by a process described in U.S. Pat. No. 5,877,191 for the preparation of 3-bromo-5-fluoro-4-methyl-1-nitrobenzene.
  • Example 13A/Step 2 670 mg (1.50 mmol) of the compound of Example 67A/Step 1 gave a crude product which was purified by single chromatography on a Biotage system (25 g Snap column; mobile phase gradient hexane/ethyl acetate, from 0% ethyl acetate increasing steadily to 100% ethyl acetate, then ethyl acetate/methanol, proportion of methanol increasing slowly from 0 to 80%). This gave 309 mg (52% of theory) of the title compound.
  • Step 1 1-(2,2-Diethoxyethyl)-N-(2,6-dimethyl-3-nitrophenyl)-3-(pyridin-3-yl)-1H-pyrazole-5-amine
  • Example 13A/Step 1 Analogously to Example 13A/Step 1, a test reaction with 1.0 g (3.62 mmol) and the main reaction with 2.0 g (7.24 mmol), respectively, of the compound of Example 4A and 916 mg (3.98 mmol) and 1.83 g (7.96 mmol), respectively, of 4-bromo-1,3-dimethyl-2-nitrobenzene gave a total of 3.15 g (75% of theory) of the title compound.
  • Example 13A/Step 3 Analogously to Example 13A/Step 3, 530 mg (1.59 mmol) of the compound of Example 68A/Step 2 gave 507 mg (99% of theory) of the title compound.
  • Step 1 1-(2,2-Diethoxyethyl)-N-(2-methyl-3-nitrophenyl)-3-(pyridin-3-yl)-1H-pyrazole-5-amine
  • Example 9A/Step 3 Analogously to the process described in Example 9A/Step 3, 1.08 g (3.38 mmol) of the compound of Example 69A/Step 2 gave 940 mg (93% of theory, 97% pure) of the title compound. In this case, the reaction time was 30 minutes.
  • Step 1 1-(2,2-Diethoxyethyl)-N-(2-fluoro-3-nitrophenyl)-3-(pyridin-3-yl)-1H-pyrazole-5-amine
  • Example 69A/Step 2 1.10 g (2.65 mmol) of the compound of Example 70A/Step 1 gave 570 mg (63% of theory) of the title compound.
  • the product was then triturated with a little acetonitrile at RT.
  • Example 64A/Step 1 Analogously to the process described in Example 64A/Step 1, 1.0 g (3.62 mmol) of the compound of Example 4A and 1.23 g (3.98 mmol) of the compound of Example 71A/Step 1 gave 1.44 g of the title compound (63% of theory, content 80%, contamination: debenzylated product).
  • chromatographic purification was carried out using the mobile phase cyclohexane/ethyl acetate 1:1.
  • Variant B Preparation Starting with the Compound from Example 71A/Step 4:
  • Example 9A/Step 3 Analogously to the process described in Example 9A/Step 3, 260 mg (0.632 mmol) of the compound of Example 71A/Step 4 gave 200 mg (86% of theory, 80% pure) of the title compound. In this case, the reaction time was 1 h.
  • Step 1 1-(2,2-Diethoxyethyl)-N-(2-methyl-5-nitrophenyl)-3-(pyrazin-2-yl)-1H-pyrazole-5-amine

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