HK1157782B - 3-(3-pyrimidin-2-yl-benzyl)-[1,2,4]triazolo[4,3-b]pyridazine derivatives as met kinase inhibitors - Google Patents

Description

3- (3-pyrimidin-2-ylbenzyl) -1,2, 4-triazolo [4,3-b ] pyridazine derivatives as MET kinase inhibitors

Background

The object of the present invention was to find new compounds with valuable properties, in particular those which can be used for the preparation of medicaments.

The present invention relates to compounds and the use of compounds in which the inhibition, regulation and/or modulation of signal transduction by kinases, in particular tyrosine kinases and/or serine/threonine kinases, plays a role, to pharmaceutical compositions comprising these compounds and to the use of these compounds in the treatment of kinase-induced diseases.

In particular, the present invention relates to compounds and uses of compounds in which inhibition, regulation and/or modulation of signal transduction by Met kinase plays a role.

One of the major mechanisms for achieving cellular regulation is through transmembrane extracellular signal transduction, which in turn further regulates the biochemical pathways within the cell. Protein phosphorylation represents a process by which intracellular signals propagate from molecule to molecule, ultimately leading to a cellular response. These signal transduction cascades are highly regulated and often overlap, as can be seen by the presence of multiple protein kinases as well as phosphatases. Protein phosphorylation occurs primarily at serine, threonine or tyrosine residues, and protein kinases have therefore been classified by the specificity of their phosphorylation sites, i.e., serine/threonine kinases and tyrosine kinases. Since phosphorylation is a ubiquitous process within cells and cellular phenotypes are largely influenced by the activity of these pathways, it is currently believed that many disease states and/or diseases can be attributed to aberrant activation or functional mutations of molecular components of the kinase cascade. Therefore, much attention has been devoted to the characterization of these proteins and compounds capable of modulating their activity (for a review see: Weinstein-Oppenheimer et al, Pharma. &. Therap., 2000, 88, 229-279).

Berthou et al describe the role of receptor tyrosine kinase Met in human neoplasia and the possibility of inhibiting HGF (hepatocyte growth factor) -dependent Met activation in Oncogene, Vol.23, No. 31, p.5387-5393 (2004). The inhibitor described therein SU11274 (a pyrrole-indoline compound) may be useful against cancer.

Christensen et al describe another Met kinase inhibitor for Cancer therapy in Cancer Res.2003, 63(21), 7345-55.

Hov et al, Clinical Cancer Research, Vol.10, 6686-6694(2004), reported another tyrosine kinase inhibitor for use against Cancer. The compound PHA-665752 (an indole derivative) acts against the HGF receptor c-Met. In addition, HGF and Met have been reported to have a large effect on the malignant process of various forms of cancer, such as multiple myeloma.

Therefore, it is desirable to synthesize small compounds that specifically inhibit, regulate and/or modulate signal transduction of tyrosine kinases and/or serine/threonine kinases, particularly Met kinase, which is an object of the present invention.

The compounds of the invention and their salts have been found to possess very valuable pharmacological properties while being well tolerated.

The invention relates in particular to compounds of formula I which inhibit, modulate and/or modulate Met kinase signal transduction, compositions comprising these compounds and methods of their use in mammals for the treatment of Met kinase-induced diseases and disorders (complaints) such as angiogenesis, cancer, neoplasia, growth and spread, arteriosclerosis, ocular diseases such as age-induced macular degeneration, choroidal neovascularization and diabetic retinopathy, inflammatory diseases, arthritis, thrombosis, fibrosis, glomerulonephritis, neurodegeneration, psoriasis, restenosis, wound healing, graft rejection, metabolic diseases and diseases of the immune system, but also autoimmune diseases, cirrhosis, diabetes and vascular diseases, but also instability (instability) and permeability (persistence), and the like.

Solid tumors, particularly rapidly growing tumors, can be treated with Met kinase inhibitors. These solid tumors include monocytic leukemia, brain cancer, genitourinary tract cancer, lymphatic system cancer, stomach cancer, laryngeal cancer, and lung disorders, including lung adenocarcinoma and small cell lung cancer.

The present invention relates to methods of modulating, modulating or inhibiting Met kinase for the prevention and/or treatment of diseases associated with deregulated or disturbed Met kinase activity. In particular, the compounds of formula I can also be used to treat certain forms of cancer. The compounds of formula I may also be used to provide additive or synergistic effects in certain existing cancer chemotherapies, and/or can be used to restore the efficacy of certain existing cancer chemotherapies and radiation therapies.

The compounds of formula I can also be used to isolate and study Met kinase activity or expression. Furthermore, they are particularly suitable for use in diagnostic methods for diseases associated with disregulation or disturbance of Met kinase activity.

The compounds of the invention have been shown to have an antiproliferative effect in vivo in a xenograft tumor model. The compounds of the present invention are administered to a patient with a hyperproliferative disease, thereby inhibiting tumor growth, reducing inflammation associated with lymphoproliferative diseases, inhibiting graft rejection or nerve damage due to tissue repair, for example. The compounds of the invention are suitable for prophylactic or therapeutic purposes. The term "treatment" as used herein refers to both prevention of disease and treatment of an already existing condition. Prevention of proliferation, e.g., prevention of tumor growth, prevention of metastatic growth, reduction of restenosis associated with cardiovascular surgery, etc., is achieved by administering a compound of the invention before an apparent disease develops. Alternatively, the compounds are used to treat an ongoing disease by stabilizing or ameliorating the clinical symptoms of the patient.

The host or patient may include any mammalian species, for example primates, particularly humans; rodents, including mice, rats, and hamsters; a rabbit; horses, cattle, dogs, cats, etc. Experimental studies have focused on animal models that provide a model for the treatment of human diseases.

The sensitivity of a particular cell to treatment with a compound of the invention can be determined by in vitro assays. Typically, the cell culture is mixed with various concentrations of the compounds of the invention for a period of time sufficient for the active agent to induce cell death or inhibit migration, usually about 1 hour to 1 week. In vitro testing may be performed with cultured cells from a biopsy sample. The remaining viable cells after treatment were then counted.

The dosage will vary depending on the particular compound used, the particular disease, the patient's condition, and the like. The therapeutic dose is typically sufficient to significantly reduce the undesirable cell population in the target tissue while maintaining the viability of the patient. Treatment is generally continued until a significant reduction occurs, e.g., a reduction in cell burden (cell garden) of at least about 50%, and may be continued until substantially no more undesired cells are detected in the body.

In order to identify signal transduction pathways and to detect interactions between multiple signal transduction pathways, various scientists have developed suitable models or model systems, such as cell culture models (e.g., Khwaria et al, EMBO, 1997, 16, 2783-93) and transgenic animal models (e.g., White et al, Oncogene, 2001, 20, 7064-. To determine certain stages in the signal transduction cascade, interacting compounds may be utilized in order to modulate the signal (e.g., Stephens et al, Biochemical j., 2000, 351, 95-105). The compounds of the invention may also be used as reagents for testing kinase-dependent signal transduction pathways in animal and/or cell culture models or in the clinical conditions mentioned in the present application.

The determination of kinase activity is a technique well known to those skilled in the art. General test systems for determining kinase activity using substrates such as histones (e.g.Alessi et al, FEBS Lett.1996, 399, 3, 333-338 pages) or basic myelin proteins are described in the literature (e.g.Campos-Gonz-lez, R. and Glenney, Jr., J.R.1992, J.biol.chem.267, 14535).

For the identification of kinase inhibitors, a variety of assay systems are available. Gamma ATP is used to measure the radioactive phosphorylation of proteins or peptides as substrates in both the scintillation proximity assay (Sorg et al, j.of. biomolecular Screening, 2002, 7, 11-19) and the flash plate assay. In the presence of the inhibitory compound, a reduced radioactive signal or no radioactive signal at all can be detected. Furthermore, uniform time-resolved fluorescence resonance energy transfer (HTR-FRET) and Fluorescence Polarization (FP) techniques are also suitable for use as assay methods (Sills et al, J.of Biomolecular Screening, 2002, 191-214).

Other non-radioactive ELISA assays employ specific phospho-antibodies (phospho-AB). phospho-AB binds only phosphorylated substrates. This binding can be detected by chemiluminescence using peroxidase-conjugated anti-sheep secondary antibodies (Ross et al, 2002, biochem.j.).

There are many diseases associated with dysregulation of cell proliferation and cell death (apoptosis). Disorders of interest include, but are not limited to, those below. The compounds of the invention are suitable for use in the treatment of a variety of conditions in which there is proliferation and/or migration of smooth muscle cells and/or inflammatory cells into the vascular lining resulting in restricted blood flow through the vessel, for example in the case of neointimal occlusive lesions. Occlusive graft vascular diseases of interest include atherosclerosis, post-transplant coronary vascular disease, venous graft stenosis, peri-anastomotic restenosis (peri-arterial restenosis), restenosis following angioplasty or stent placement, and the like.

Prior Art

Other triazolopyridazine derivatives as Met kinase inhibitors are described in WO 2007/064797, WO 2007/075567, WO 2007/138472, WO2008/008539, WO 2008/051805.

Summary of The Invention

The present invention relates to compounds of formula I and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios:

wherein

R¹Represents Ar, Het or A,

R²represents H, A, Hal, OR⁵、N(R⁵)₂、N＝CR⁵N(R⁵)₂、SR⁵、NO₂、CN、COOR⁵、CON(R⁵)₂、NR⁵COA、NR⁵SO₂A、SO₂N(R⁵)₂、S(O)_mA、Het、-[C(R⁵)₂]_nN(R⁵)₂、-[C(R⁵)₂]_nHet、O[C(R⁵)₂]_nN(R⁵)₂、O[C(R⁵)₂]_nHet、S[C(R⁵)₂]_nN(R⁵)₂、S[C(R⁵)₂]_nHet、-NR⁵[C(R⁵)₂]_nN(R⁵)₂、-NR⁵[C(R⁵)₂]_nHet、NHCON(R⁵)₂、NHCONH[C(R⁵)₂]_nN(R⁵)₂、NHCONH[C(R⁵)₂]_nHet、NHCO[C(R⁵)₂]_nN(R⁵)₂、NHCO[C(R⁵)₂]_nHet、CON(R⁵)₂、CONR⁵[C(R⁵)₂]_nN(R⁵)₂、CONR⁵[C(R⁵)₂]_nHet, COhet or COA,

R³、R³' each independently represents H, F or A,

together also denotes alkylene having 2 to 5C atoms,

R⁴the representation H, A or Hal is,

R⁵represents a group of a compound represented by the formula H or A,

a represents an unbranched or branched alkyl group having 1 to 10C atoms,

wherein 1 to 7H atoms may be replaced by OH, F, Cl and/or Br,

and/or one or two of CH₂The radicals being selected from the group consisting of O, NH, S, SO₂And/or CH ═ CH groups,

or

A cyclic alkyl group having 3 to 7C atoms,

ar represents phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di-or trisubstituted with: hal, A, OR⁵、N(R⁵)₂、SR⁵、NO₂、CN、COOR⁵、CON(R⁵)₂、NR⁵COA、NR⁵SO₂A、SO₂N(R⁵)₂And/or S (O)_mA，

Het represents a mono-, bi-or tricyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be unsubstituted or mono-, bi-or trisubstituted by: hal, A, OR⁵、N(R⁵)₂、SR⁵、NO₂、CN、COOR⁵、CON(R⁵)₂、NR⁵COA、NR⁵SO₂A、SO₂N(R⁵)₂、S(O)_mA、CO-Het¹、Het¹、[C(R⁵)₂]_nN(R⁵)₂、[C(R⁵)₂]_nHet¹、O[C(R⁵)₂]_nN(R⁵)₂、O[C(R⁵)₂]_nHet¹、NHCOOA、NHCON(R⁵)₂、NHCOO[C(R⁵)₂]_nN(R⁵)₂、NHCOO[C(R⁵)₂]_nHet¹、NHCONH[C(R⁵)₂]_nN(R⁵)₂、NHCONH[C(R⁵)₂]_nHet¹、OCONH[C(R⁵)₂]_nN(R⁵)₂、OCONH[C(R⁵)₂]_nHet¹、CO-Het¹CHO, COA, ═ S, ═ NH, ═ NA and/or ═ O (carbonyl oxygen),

Het¹represents a monocyclic saturated heterocycle having 1 to 2N and/or O atoms, which may be mono-or disubstituted by: A. OA, OH, Hal and/or ═ O (carbonyl oxygen),

hal represents F, Cl, Br or I,

m represents 0, 1 or 2,

n represents 1,2, 3 or 4.

The compounds of the formula I are also hydrates and solvates of these compounds, which are furthermore referred to as pharmaceutically acceptable derivatives.

The invention also relates to optically active forms (stereoisomers), enantiomers, racemates, diastereomers and hydrates and solvates of these compounds. Solvates of a compound means that inert solvent molecules are adducted to the compound, which are formed due to their mutual attraction. Solvates are, for example, mono-or di-hydrates or alcoholates.

Pharmaceutically acceptable derivatives mean, for example, salts of the compounds of the invention and also the so-called prodrug compounds.

Prodrug derivatives mean compounds of the formula I which are modified with, for example, alkyl or acyl groups, sugars or oligopeptides and are capable of rapid cleavage in vivo to form the active compounds of the invention.

These also include biodegradable polymer derivatives of the compounds of the invention, such as, for example, int.j.pharm.11561-67 (1995).

The expression "effective amount" means the amount of a drug or pharmaceutically active ingredient that produces a biological or medical response in a tissue, system, animal or human that is, for example, sought or desired by a researcher or physician.

Furthermore, the expression "therapeutically effective amount" denotes an amount which produces the following effect compared to the corresponding individual not receiving this amount:

improved treatment, healing, prevention or elimination of a disease, syndrome, condition, disorder, or side effect, or alternatively, reduced progression of a disease, disorder, or condition.

The term "therapeutically effective amount" also includes amounts that are effective in terms of enhancing normal physiological function.

The invention also relates to the use of mixtures of compounds of the formula I, for example mixtures of two diastereomers in a ratio of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000.

Mixtures of the stereoisomeric compounds are particularly preferred.

The present invention relates to compounds of formula I and salts thereof, to a process for the preparation of compounds of formula I according to claims 1 to 12 and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, characterized in that:

a) reacting a compound of formula II

Wherein R is¹、R³、R³' and R⁴Has the meaning indicated in claim 1 and L represents a boronic acid or a boronic ester group,

with compounds of the formula III

Wherein R is²Having the meaning indicated in claim 1,

or

b) By replacing the halogen atom by an amino, alkoxy or aryl group²With another radical R²Instead of this, the user can,

converting a base or acid of formula I into one of its salts.

Unless expressly stated otherwise, the radicals R in the context¹、R²、R³、R³' and R⁴Have the meaning indicated in formula I.

A represents alkyl, which is unbranched (linear) or branched and has 1,2, 3, 4, 5, 6, 7, 8, 9 or 10C atoms. A preferably represents methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore pentyl, 1-, 2-or 3-methylbutyl, 1-, 1, 2-or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3-or 4-methylpentyl, 1-, 1, 2-, 1, 3-, 2, 2-, 2, 3-or 3, 3-dimethylbutyl, 1-or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 2-or 1,2, 2-trimethylpropyl, furthermore preferably, for example, trifluoromethyl.

A very particularly preferably represents alkyl having 1,2, 3, 4, 5 or 6C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1, 1, 1-trifluoroethyl.

Cyclic alkyl (cycloalkyl) preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

R¹Particularly preferably represents thiazolyl, thienyl, furyl, pyrrolyl,Azolyl radical, isoAzolyl group,Oxadiazolyl, pyrazolyl, imidazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, pyridyl or pyrimidinyl,

wherein the radicals may also be mono-, di-or trisubstituted by: hal, [ C (R) ]⁵)₂]_nOR⁵And/or a,

or

Phenyl, which is mono-, di-or trisubstituted with the following groups: hal and/or CN

Or

A。

R²Preferably represents H, OH, OA, O [ C (R)⁵)₂]_nOR⁵、Hal、Het、-[C(R⁵)₂]_nHet or O [ C (R)⁵)₂]_nHet。

R⁴Preferably represents H.

Ar denotes, for example, phenyl, o-, m-or p-tolyl, o-, m-or p-ethylphenyl, o-, m-or p-propylphenyl, o-, m-or p-isopropylphenyl, o-, m-or p-tert-butylphenyl, o-, m-or p-hydroxyphenyl, o-, m-or p-nitrophenyl, o-, m-or p-aminophenyl, o-, m-or p- (N-methylamino) phenyl, o-, m-or p- (N-methylaminocarbonyl) phenyl, o-, m-or p-acetylaminophenyl, o-, m-or p-methoxyphenyl, o-, m-or p-ethoxyphenyl, o-, m-or p-ethoxycarbonylphenyl, o-, m-or p- (N, N-dimethylamino) phenyl, o-, m-or p- (N, N-dimethylaminocarbonyl) phenyl, o-, m-or p- (N-ethylamino) phenyl, o-, m-or p- (N, N-diethylamino) phenyl, o-, m-or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m-or p-chlorophenyl, o-, m-or p- (methylsulfonylamino) phenyl, o-, m-or p- (methylsulfonyl) phenyl, o-, m-or p-methylsulfanylphenyl, o-, m-or p-cyanophenyl, o-, m-or p-carboxyphenyl, o-, m-or p-methoxycarbonylphenyl, o-, m-or p-aminosulfonylphenyl, further preferably 2, 3-, 2,4-, 2, 5-, 2, 6-, 3, 4-or 3, 5-difluorophenyl, 2, 3-, 2,4-, 2, 5-, 2, 6-, 3, 4-or 3, 5-dichlorophenyl, 2, 3-, 2,4-, 2, 5-, 2, 6-, 3, 4-or 3, 5-dibromophenyl, 2, 4-or 2, 5-dinitrophenyl, 2, 5-or 3, 4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro-or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino-or 3-nitro-4-N, N-dimethylaminophenyl, 2, 3-diaminophenyl, 2, 3, 4-, 2, 3, 5-, 2, 3, 6-, 2,4, 6-or 3, 4, 5-trichlorophenyl, 2,4, 6-trimethoxyphenyl, 2-hydroxy-3, 5-dichlorophenyl, p-iodophenyl, 3, 6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2, 5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2, 5-dimethyl-4-chlorophenyl.

Ar particularly preferably represents phenyl, which is unsubstituted or mono-, di-or trisubstituted by: hal and/or CN.

Het represents, regardless of the additional substitution, for example 2-or 3-furyl, 2-or 3-thienyl, 1-, 2-or 3-pyrrolyl, 1-, 2-, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-Azolyl, 3-, 4-or 5-isoOxazolyl, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidinyl, furthermore preferably 1,2, 3-triazol-1-, -4-or 5-yl, 1,2, 4-triazol-1-, -3-or 5-yl, 1-or 5-tetrazolyl, 1,2, 3-Oxadiazol-4-or-5-yl, 1,2,4-Oxadiazol-3-or-5-yl, 1, 3, 4-thiadiazol-2-or-5-yl, 1,2, 4-thiadiazol-3-or-5-yl, 1,2, 3-thiadiazol-4-or-5-yl, 3-or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 4-or 5-isoindolyl, indazolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzo.Azolyl, 3-, 4-, 5-, 6-or 7-benzisoxazoAzolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 4-, 5-, 6-or 7-benzo-2, 1, 3-Oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7-or 8-quinazolinyl, 5-or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7-or 8-2H-benzo-1, 4-Oxazinyl, more preferably 1, 3-benzodioxol-5-yl, 1, 4-benzodiAlk-6-yl, 2, 1, 3-benzothiadiazol-4-or-5-yl, 2, 1, 3-benzoOxadiazol-5-yl or dibenzofuranyl.

The heterocyclic group may also be partially or fully hydrogenated.

Het may therefore also represent, for example, 2, 3-dihydro-2-, -3-, -4-or-5-furyl, 2, 5-dihydro-2-, -3-, -4-or 5-furyl, tetrahydro-2-or-3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2-or-3-thienyl, 2, 3-dihydro-1-, -2-, -3-, -4-or-5-pyrrolyl, 2, 5-dihydro-1-, -2-, -3-, -4-or-5-pyrrolyl, irrespective of the further substitution, 1-, 2-or 3-pyrrolidinyl, tetrahydro-1-, 2-or 4-imidazolyl, 2, 3-dihydro-1-, -2-, -3-, -4-or 5-pyrazolyl, tetrahydro-1-, -3-or 4-pyrazolyl, 1, 4-dihydro-1-, -2-, -3-or 4-pyridyl, 1,2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-or 6-pyridyl, 1-, 2-, 3-or 4-piperidyl, 2-, 3-or 4-morpholinyl, tetrahydro-2-, -3-or 4-pyranyl, 1, 4-diylAlkyl, 1, 3-diAlk-2-, -4-or-5-yl, hexahydro-1-, -3-or-4-pyridazinyl, hexahydro-1-, -2-, -4-or-5-pyrimidinyl, 1-, 2-or 3-piperazinyl, 1,2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or-8-quinolinyl, 1,2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or-8-isoquinolinyl, 2-, 3-, 5-, 6-, 7-or 8-3, 4-dihydro-2H-benzo-1, 4-Oxazinyl, further preferably 2, 3-methylenedioxyphenyl, 3, 4-methylenedioxyphenyl, 2, 3-ethylenedioxyphenyl, 3, 4- (difluoromethylenedioxy) phenyl, 2, 3-dihydrobenzofuran-5-or 6-yl, 2, 3- (2-oxomethylenedioxy) phenyl or also 3, 4-dihydro-2H-1, 5-benzodioxepin-6-or-7-yl, furthermore preferably 2, 3-dihydrobenzofuranyl, 2, 3-dihydro-2-oxofuranyl, 3, 4-dihydro-2-oxo-1H-quinazolinyl, 2, 3-dihydrobenzoAzolyl, 2-oxo-2, 3-dihydrobenzoAzolyl, 2-3-dihydrobenzimidazolyl, 1, 3-indoline, 2-oxo-1, 3-indoline or 2-oxo-2, 3-dihydrobenzimidazolyl.

Het particularly preferably represents a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be unsubstituted or mono-, di-or trisubstituted by: A. [ C (R)⁵)₂]_nOR⁵And/or [ C (R)⁵)₂]_nHet¹。

Het very particularly preferably represents piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl,Oxazolidinyl, pyrazolyl, pyridinyl, pyrimidinyl, furanyl, thienyl,Azolyl group,Oxadiazolyl, imidazolyl, pyrrolyl, isoxazolylOxazolyl or imidazolidinyl, wherein this radical may also be mono-or disubstituted by: A. [ C (R)⁵)₂]_nOR⁵And/or [ C (R)⁵)₂]_nHet¹。

Het¹Preferably represents piperidyl, pyrrolidinyl, morpholinyl, piperazinyl,Oxazolidinyl or imidazolidinyl, where the radical may also be mono-or disubstituted by:o and/or a.

Hal preferably denotes F, Cl or Br, but may also be I, particularly preferably F or Cl.

In the present invention, all groups occurring more than once may be the same or different, i.e. independent of each other.

The compounds of formula I may have one or more chiral centers and may therefore occur in a variety of stereoisomeric forms. Formula I encompasses all of these forms.

The present invention therefore relates in particular to compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Certain preferred groups of compounds may be represented by the following subformulae Ia to Ij, which conform to formula I and in which the radicals not specified in more detail have the meanings given for formula I, but wherein:

in Ia, R²Represents H, OH, OA, O [ C (R)⁵)₂]_nOR⁵、Hal、Het、-[C(R⁵)₂]_nHet or O [ C (R)⁵)₂]_nHet；

In Ib, Ar represents phenyl, which is mono-, di-or trisubstituted with the following groups: hal and/or CN;

in Ic, A represents an unbranched or branched alkyl group having 1 to 6C atoms;

in Id, R⁴Represents H;

in Ie, R¹Represents thiazolyl, thienyl, furyl, pyrrolyl,Azolyl radical, isoAzolyl group,Diazolyl, pyrazolyl, imidazolyl, thiadiazoleA pyridyl, pyridazinyl, pyrazinyl, pyridyl or pyrimidinyl group,

wherein the group may also be mono-, di-or trisubstituted with: hal, [ C (R) ]⁵)₂]_nOR⁵And/or a,

or

Phenyl, which is mono-, di-or trisubstituted with the following groups: hal and/or CN

Or

A；

In If, Het represents a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be unsubstituted or mono-, di-or trisubstituted by: A. [ C (R)⁵)₂]_nOR⁵And/or [ C (R)⁵)₂]_nHet¹；

In Ig, Het represents piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl,Oxazolidinyl, pyrazolyl, pyridinyl, pyrimidinyl, furanyl, thienyl,Azolyl group,Oxadiazolyl, imidazolyl, pyrrolyl, isoxazolylOxazolyl or imidazolidinyl, wherein this radical may also be mono-or disubstituted by: A. [ C (R)⁵)₂]_nOR⁵And/or [ C (R)⁵)₂]_nHet¹；

In Ih, Het¹Represents piperidyl, pyrrolidinyl, morpholinyl, piperazinyl,Oxazolidinyl or imidazolidinyl, where the radical may also be mono-or disubstituted by: o and/or a;

in Ii, R¹Represents Ar, Het or A,

R²represents H, OH, OA, O [ C (R)⁵)₂]_nOR⁵、Hal、Het、[C(R⁵)₂]_nHet or O [ C (R)⁵)₂]_nHet，

R³、R³' each independently represents H, F or A,

together also denotes alkylene having 2 to 5C atoms,

R⁴the expression "H" is used to indicate the formula,

R⁵represents a group of a compound represented by the formula H or A,

a represents an unbranched or branched alkyl group having 1 to 6C atoms,

ar represents phenyl, which is mono-, di-or trisubstituted with the following groups: the Hal and/or the CN is,

het represents a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be unsubstituted or mono-, di-or trisubstituted by: A. [ C (R)⁵)₂]_nOR⁵And/or [ C (R)³)₂]_nHet¹，

Het¹Represents piperidyl, pyrrolidinyl, morpholinyl, piperazinyl,Oxazolidinyl or imidazolidinyl, where the radical may also be mono-or disubstituted by: either O and/or a is/are,

hal represents F, Cl, Br or I,

n represents 1,2, 3 or 4;

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

Furthermore, the compounds of the formula I and the starting materials for their preparation are prepared by well-known methods, such as, for example, the methods described in the literature (for example, standard textbooks such as Houben-Weyl, Methoden der organischen Chemie [ methods of organic chemistry ], Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditions which are known and suitable for the reaction in question. Well-known variants which are not mentioned in more detail herein can also be applied.

The compounds of formula I can preferably be prepared by reacting a compound of formula II with a compound of formula III.

The reaction is carried out under the conditions of a Suzuki reaction known to the person skilled in the art.

The starting compounds of the formulae (II) and (III) are generally known. However, if they are new, they can be prepared by a well-known method.

In the compounds of the formula II, L preferably represents

The reaction was carried out under standard conditions for Suzuki coupling.

Depending on the conditions applied, the reaction time is from a few minutes to 14 days and the reaction temperature is from about-30 ℃ to 140 ℃, usually from 0 ℃ to 100 ℃, in particular from about 60 ℃ to about 90 ℃.

Suitable inert solvents are, for example, hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, e.g. methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanolButanol; ethers, e.g. diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or diAn alkane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or Dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of said solvents.

Ethanol, toluene, dimethoxyethane are particularly preferred.

In addition, the compounds of the formula I can be prepared preferably by reacting the compounds with another radical R²In place of the radical R²And then obtaining the compound. Preferably, the halogen atom is replaced with an amino group, an alkoxy group or an aryl group. The reaction is preferably carried out under the conditions of a Suzuki coupling.

In addition, it is possible to convert a compound of the formula I into another compound of the formula I by converting the radical R²Conversion to another group R²For example by reduction of the nitro group to an amino group (for example by hydrogenation on Raney nickel or Pd/carbon in an inert solvent such as methanol or ethanol).

In addition, the free amino group can be acylated in a conventional manner using acid chlorides or anhydrides or alkylated using unsubstituted or substituted alkyl halides, advantageously in an inert solvent, such as dichloromethane or THF, and/or in the presence of a base, such as triethylamine or pyridine, at temperatures between-60 and +30 ℃.

The compounds of formula I may also be obtained by solvolysis, in particular hydrolysis, or by liberation from their functional derivatives by hydrogenolysis.

Preferred starting materials for the solvolysis or hydrogenolysis are those which contain the corresponding protected amino group andinstead of one or more free amino and/or hydroxyl groups, starting materials are preferably those which carry an amino-protecting group other than the H atom bound to the N atom, for example those corresponding to formula I but which contain a NHR 'group (wherein R' is an amino-protecting group, e.g. BOC or CBZ) instead of NH₂Starting from a radical.

Also preferred are starting materials which carry a hydroxy-protecting group other than the H atom of a hydroxy group, for example those corresponding to formula I but which contain an R 'O-phenyl group (where R' is a hydroxy-protecting group) other than a hydroxyphenyl group.

In the starting molecule, there may also be a plurality of (identical or different) protected amino and/or hydroxyl groups. If the protecting groups present are different from one another, they can be cleaved off selectively in many cases.

The term "amino-protecting group" is known as a generic term and refers to a group suitable for protecting (blocking) an amino group from chemical reactions, but which is easily removed after the desired chemical reaction at other positions in the molecule has taken place. Typical of such radicals are in particular unsubstituted or substituted acyl, aryl, aralkyloxymethyl or aralkyl radicals. Since the amino-protecting groups are removed after the desired reaction (or reaction sequence), their type and size are not particularly important; however, those having 1 to 20, in particular 1 to 8, carbon atoms are preferred. In the present process, the term "acyl" is to be understood in its broadest sense. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, especially alkoxycarbonyl, aryloxycarbonyl, and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl groups such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl groups such as benzoyl and toluoyl (tolyl); aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, BOC and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, and FMOC; and arylsulfonyl groups such as Mtr, Pbf, and Pmc. Preferred amino-protecting groups are BOC and Mtr, and also include CBZ, Fmoc, benzyl and acetyl.

The term "hydroxy-protecting group" is also a known generic term and refers to a group that is suitable for protecting a hydroxy group from chemical reactions, but which is readily removable after the desired chemical reaction at other locations in the molecule has taken place. Typical such groups are the above unsubstituted or substituted aryl, aralkyl or acyl groups, also including alkyl groups. The nature and size of the hydroxy-protecting groups are not particularly critical, as they are removed after the desired chemical reaction or reaction sequence has been carried out; preference is given to radicals having from 1 to 20, in particular from 1 to 10, carbon atoms. In addition, examples of the hydroxy-protecting group are t-butoxycarbonyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl, t-butyl and acetyl, with benzyl and t-butyl being particularly preferred. The COOH groups in aspartic and glutamic acids are preferably protected in the form of their tert-butyl esters (e.g., Asp (OBut)).

The compounds of the formula I can be liberated from their functional derivatives (depending on the protective group used), for example using strong acids, advantageously TFA or perchloric acid, but also other strong inorganic acids, for example hydrochloric acid or sulfuric acid, strong organic carboxylic acids, for example trichloroacetic acid, or sulfonic acids, for example benzenesulfonic acid or p-toluenesulfonic acid. Other inert solvents may be present, but are not always necessary. Suitable inert solvents are preferably organic solvents, such as carboxylic acids, for example acetic acid; ethers, e.g. tetrahydrofuran or diAn alkane; amides, such as DMF; halogenated hydrocarbons such as dichloromethane; and also alcohols, such as methanol, ethanol or isopropanol; and water. Mixtures of the above solvents are also suitable. Preferably, TFA is used in excess without the addition of further solvents, and the perchloric acid is preferably used as a 9: 1 mixture of acetic acid and 70% perchloric acid. The reaction temperature for the cleavage is advantageously between about 0 and about 50 c, preferably between 15 and 30 c (room temperature).

The BOC, OBut, Pbf, Pmc and Mtr groups may beFor example preferably using TFA in dichloromethane or using about 3 to 5N HCl in bisThe alkane is cleaved at 15-30 ℃ to remove the FMOC group, and the FMOC group can be cleaved at 15-30 ℃ using about 5-50% DMF solution of dimethylamine, diethylamine or piperidine.

Trityl groups are used to protect the amino acids histidine, asparagine, glutamine and cysteine. Depending on the desired end product, they are cleaved off using TFA/10% thiophenol, the trityl group being cleaved off from all the above amino acids; when TFA/anisole or TFA/thioanisole is used, only the trityl group of His, Asn and Gln is cleaved off, while it remains on the Cys side chain.

Pbf (pentamethylbenzofuranyl) is used to protect Arg. It is removed by cleavage with TFA, for example in dichloromethane.

The hydrogenolytically removable protecting group (e.g. CBZ or benzyl) can be cleaved off, for example, by treatment with hydrogen in the presence of a catalyst (e.g. a noble metal catalyst, e.g. palladium, advantageously on a support, e.g. on carbon). Suitable solvents herein are those indicated above, for example alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is generally carried out at a temperature of between about 0 and 100 ℃ and at a pressure of between about 1 and 200bar, preferably between 20 and 30 ℃ and 1 and 10 bar. Hydrogenolysis of the CBZ group is carried out, for example, on 5 to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30 ℃ with high success rates.

Pharmaceutically acceptable salts and other forms

The compounds of the invention described may be used in their final non-salt form. In another aspect, the invention also includes the use of these compounds in the form of pharmaceutically acceptable salts, which can be derived from a variety of organic and inorganic acids and bases by methods known in the art. The pharmaceutically acceptable salt forms of the compounds of formula I are in large part prepared by conventional methods. If a compound of formula I contains a carboxyl group, one of its suitable salts may be formed by reacting the compound with a suitable base to yield the corresponding base addition salt. Such bases are, for example: alkali metal hydroxides including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal alkoxides such as potassium ethoxide and sodium propoxide; and various organic bases such as piperidine, diethanolamine and N-methyl-glutamine. Also included are aluminum salts of the compounds of formula I. In the case of certain compounds of formula I, acid addition salts may be formed by treating these compounds with pharmaceutically acceptable organic and inorganic acids, for example hydrohalides, such as hydrochloric acid, hydrogen bromide or hydrogen iodide; other inorganic acids and their corresponding salts, such as sulfates, nitrates or phosphates, and the like; and alkyl-and monoaryl sulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts, such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate, and the like. Thus, pharmaceutically acceptable acid addition salts of the compounds of formula I include the following salts: acetate, adipate, alginate, arginine, aspartate, benzoate, benzenesulfonate (phenylsulfonate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galactarate (from mucic acid), galacturonate, glucoheptonate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, levulinate, salicylate, dihydrogensulfonate, dihydrogensulfate, isovalerate, fumarate, dihydrogenphosphate, dihydrogensulfate, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, or mixtures thereof, Maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate (palmoate), pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not intended to be limiting.

Further, the base salt of the compound of the present invention includes aluminum salt, ammonium salt, calcium salt, copper salt, iron (III) salt, iron (II) salt, lithium salt, magnesium salt, manganese (III) salt, manganese (II) salt, potassium salt, sodium salt and zinc salt, but this is not meant to be limiting. Among the above salts, ammonium salts are preferred; alkali metal salt sodium and potassium salts, and alkaline earth metal salt calcium and magnesium salts. Salts of the compounds of formula I derived from pharmaceutically acceptable organic non-toxic bases include salts of: primary, secondary and tertiary amines, substituted amines, and also naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, chloroprocaine, choline, N' -dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine, and tris (hydroxymethyl) methylamine (tromethamine), but this is not meant to be limiting.

The compounds of the present invention containing basic nitrogen-containing groups may be quaternized with, for example: (C)₁-C₄) Alkyl halides such as methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; sulfuric acid di (C)₁-C₄) Alkyl esters such as dimethyl, diethyl and diamyl sulfate; (C)₁₀-C₁₈) Alkyl halides such as decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl (C)₁-C₄) Alkyl halides, such as benzyl chloride and phenethyl bromide. The salts can be used to prepare water-soluble and oil-soluble compounds of the invention.

Preferred pharmaceutically acceptable salts include, but are not limited to, acetate, trifluoroacetate, benzenesulfonate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine.

Particularly preferred are the hydrochloride, dihydrochloride, hydrobromide, maleate, methanesulfonate, phosphate, sulfate and succinate salts.

Acid addition salts of basic compounds of formula I are prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in a conventional manner. The free base can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. The free base form differs from its corresponding salt form in some respects with respect to certain physical properties, such as solubility in polar solvents; however, for the purposes of the present invention, salts are otherwise comparable to their respective free base forms.

As mentioned above, pharmaceutically acceptable base addition salts of compounds of formula I are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base addition salts of the acidic compounds of the present invention are prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner. The free acid may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid form differs from its corresponding salt form in some way with respect to certain physical properties, such as solubility in polar solvents; however, for the purposes of the present invention, salts are otherwise comparable to their respective free acid forms.

If the compounds of the present invention contain more than one group capable of forming such pharmaceutically acceptable salts, the present invention also includes multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, meglumine, diphosphate, disodium salt, and trihydrochloride, although this is not intended to be limiting.

In the light of the above, it can be seen that the expression "pharmaceutically acceptable salt" in this context is intended to mean an active ingredient comprising a compound of formula I in one of its salt forms, in particular if this salt form confers improved pharmacokinetic properties on the active ingredient compared to the free form of the active ingredient or any other salt form of the active ingredient used earlier. The pharmaceutically acceptable salt form of the active ingredient may also provide the active ingredient for the first time with desirable pharmacokinetic properties not previously possessed by it, and may even have a positive effect on the pharmacodynamics of the active ingredient in terms of its in vivo therapeutic effect.

The invention also relates to medicaments comprising at least one compound of the formula I and/or pharmaceutically acceptable salts and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or adjuvants.

The pharmaceutical preparations may be administered in dosage units containing a predetermined amount of the active ingredient per dosage unit. Such units may contain, for example, from 0.5mg to 1g, preferably from 1mg to 700mg, particularly preferably from 5mg to 100mg, of a compound according to the invention, depending on the condition to be treated, the method of administration and the age, weight and condition of the patient, or pharmaceutical preparations may be administered in dosage units containing a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those containing the above-described daily dose or partial dose or a fraction thereof of the active ingredient. In addition, such pharmaceutical preparations may be prepared using methods widely known in the pharmaceutical field.

The pharmaceutical formulations may be adapted for administration by any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations may be prepared using all methods known in the art of pharmacy, for example by mixing the active ingredient with excipients or adjuvants.

Pharmaceutical formulations adapted for oral administration may be administered in the form of discrete units such as capsules or tablets; powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foamed foods; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

Thus, for example, in the case of oral administration in the form of tablets or capsules, the active ingredient component can be mixed with an oral, non-toxic, pharmaceutically acceptable inert excipient such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitably fine size and mixing it with a similarly comminuted pharmaceutical excipient such as an edible carbohydrate, for example starch or mannitol. Flavoring, preservative, dispersing and coloring agents may also be present.

Capsules can be prepared by preparing a powder mixture as described above and filling into shaped gelatin capsule shells. Glidants and lubricants, for example highly disperse silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation. Disintegrating or solubilizing agents, such as agar-agar, calcium carbonate or sodium carbonate, may also be added to improve the availability of the drug after ingestion of the capsule.

In addition, if desired or necessary, suitable binders, lubricants and disintegrants and also dyes can be added to the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners made from corn, natural and synthetic gums (e.g., acacia, tragacanth or sodium alginate), carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Tablets are prepared, for example, by preparing a powder mixture, granulating or dry-pressing the mixture, adding a lubricant and a disintegrant, and pressing the entire mixture into tablets. The powder mixture is prepared by mixing the compound, comminuted in a suitable manner, with the above-mentioned diluents or bases and optionally with binders (for example carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone), dissolution retarders such as paraffin, absorption accelerators such as quaternary salts and/or absorbents (for example bentonite, kaolin or dicalcium phosphate). The powder mixture may be granulated by wetting with a binder (e.g. syrup, starch paste, acadia mucilage or solutions of cellulose or polymeric materials) and sieving. As an alternative to granulation, the powder mixture may be passed through a tablet press to obtain a non-uniformly shaped mass which is broken up to form granules. The granules may be lubricated by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet mould. The lubricated mixture is then compressed into tablets. The compounds of the present invention may also be mixed with free-flowing inert excipients and then compressed directly into tablets without a granulation or dry compression step. There may be a transparent or opaque protective layer comprising a shellac barrier layer, a sugar or polymer material layer and a glossy layer of wax. Dyes may be added to these coatings to enable differentiation between different dosage units.

Oral liquids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution with a suitable flavoring agent, while elixirs can be prepared using a non-toxic alcoholic medium. Suspensions may be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like may also be added.

Dosage unit formulations for oral administration may be encapsulated in microcapsules, if desired. The formulations may also be prepared in a form in which the release is extended or delayed, for example by coating or embedding the particulate material with a polymer, wax or the like.

The compounds of formula I and salts thereof may also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of formula I and salts thereof may also be delivered using a monoclonal antibody as a separate carrier, wherein the compound molecule is conjugated to the monoclonal antibody. The compounds may also be coupled to soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenol, or polyoxyethylene polylysine, which is substituted with palmitoyl groups. The compounds may also be coupled to a class of biodegradable polymers suitable for achieving controlled release of a drug, such as polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, and cross-linked or amphiphilic block copolymer hydrogels.

Pharmaceutical formulations adapted for transdermal administration may be administered as a stand-alone plaster in intimate contact with the epidermis of the recipient for an extended period of time. Thus, for example, the active ingredient may be delivered from a plaster by iontophoresis, as described in general terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissues (e.g. oral cavity and skin), the formulations are preferably applied in the form of a topical ointment or cream. In the case of formulating an ointment, the active ingredient may be applied with a paraffinic or water-miscible cream base. Alternatively, the active ingredient may be formulated as a cream in an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations suitable for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouth include lozenges, pastilles and mouthwashes.

Pharmaceutical preparations suitable for rectal administration may be administered in the form of suppositories or enemas.

Pharmaceutical preparations suitable for nasal administration in which the carrier substance is a solid comprise a coarse powder having a particle size of, for example, 20 to 500 microns, which is administered by sniffing, i.e. rapid inhalation from a powder-containing container near the nose via the nasal passage. Suitable formulations for administration as nasal sprays or nasal drops containing a liquid as carrier material comprise solutions of the active ingredient in water or oil.

Pharmaceutical formulations adapted for administration by inhalation comprise a fine particulate powder or mist which may be generated by various types of aerosol-containing pressurised dispensers, nebulisers or insufflators.

Pharmaceutical formulations adapted for vaginal administration may be administered in the form of pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient to be treated; aqueous and non-aqueous sterile suspensions, which may contain suspending media and thickening agents. The formulations may be administered in unit-dose or multi-dose containers, for example sealed ampoules and vials, and stored in a freeze-dried (lyophilized) state, so that only the addition of the sterile carrier liquid, for example water for injections, is required immediately prior to use. Injection solutions and suspensions prepared according to the prescription can be prepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the components specifically mentioned above, the formulations may also comprise other substances applicable in the art for this particular type of formulation; thus, for example, formulations suitable for oral administration may contain flavouring agents.

The therapeutically effective amount of a compound of formula I will depend on a number of factors including, for example, the age and weight of the animal, the precise condition to be treated and its severity, the nature of the formulation and the method of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. However, an effective amount of a compound of the invention for treating tumor growth, e.g., colon or breast cancer, is generally from 0.1 to 100mg/kg of recipient (mammal) body weight per day, and particularly typically from 1 to 10mg/kg of body weight per day. Thus, for an adult mammal weighing 70kg, the actual amount per day is typically 70 to 700mg, wherein the amount may be administered as a single dose per day or typically in multiple divided doses per day (e.g. two, three, four, five or six divided doses) such that the total daily dose is the same. An effective amount of a salt or solvate or physiologically functional derivative thereof may be determined as a fraction of the effective amount of the compound of the invention per se. It is believed that similar dosages are suitable for the treatment of the other conditions mentioned above.

The invention also relates to medicaments comprising at least one compound of the formula I and/or pharmaceutically acceptable salts and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further pharmaceutically active ingredient.

The present invention also relates to a kit (kit) comprising the following individual packages:

(a) an effective amount of a compound of formula I and/or pharmaceutically acceptable salts and stereoisomers thereof, including mixtures thereof in all ratios;

and

(b) an effective amount of a further pharmaceutically active ingredient.

The kit comprises a suitable container, such as a box, individual bottle, pouch or ampoule. The kit may comprise, for example, separate ampoules, each containing an effective amount of a compound of formula I and/or pharmaceutically acceptable salts and stereoisomers thereof, including mixtures thereof in all ratios,

and an effective amount of a further pharmaceutically active ingredient in dissolved or lyophilized form.

Applications of

The compounds of the present invention are suitable as pharmaceutical active ingredients for mammals, particularly humans, for the treatment of tyrosine kinase induced diseases. These diseases include tumor cell proliferation, pathological neovascularization (or angiogenesis) that promotes the growth of solid tumors, ocular neovascularization (diabetic retinopathy, age-induced macular degeneration, etc.), and inflammation (psoriasis, rheumatoid arthritis, etc.).

The invention comprises the use of a compound of formula I and/or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of cancer. Preferred cancers to be treated are cancers derived from brain, genitourinary tract, lymphatic system, stomach, larynx and lung cancers. A further group of preferred cancer forms are monocytic leukaemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic carcinoma, glioblastoma and breast cancer.

Also included is the use of a compound of the invention according to claim 1 and/or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of diseases in which angiogenesis is involved.

Such diseases in which angiogenesis is involved are ocular diseases such as retinal vascularization, diabetic retinopathy, age-induced macular degeneration and the like.

The use of the compounds of the formula I and/or their physiologically acceptable salts and solvates for the preparation of a medicament for the treatment or prophylaxis of inflammatory diseases also lies within the scope of the present invention. Examples of such inflammatory diseases include rheumatoid arthritis, psoriasis, contact dermatitis, delayed type hypersensitivity reactions, and the like.

Also included is the use of a compound of formula I and/or a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a tyrosine kinase-induced disease or a tyrosine kinase-induced disorder in a mammal, wherein for the method a therapeutically effective amount of a compound of the invention is administered to a mammal in need of such treatment. The amount of treatment will vary depending on the particular disease and can be determined by one skilled in the art without undue experimentation.

The invention also comprises the use of a compound of formula I and/or physiologically acceptable salts and solvates thereof in the manufacture of a medicament for the treatment or prevention of retinal vascularization.

Methods for treating or preventing ocular diseases, such as diabetic retinopathy and age-induced macular degeneration are also part of the invention. The use for the treatment or prevention of inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity and the use for the treatment or prevention of bone diseases derived from osteosarcoma, osteoarthritis and rickets also belong to the scope of the present invention.

The expression "tyrosine kinase-induced disease or condition" refers to a pathological condition which depends on the activity of one or more tyrosine kinases. Tyrosine kinases are involved directly or indirectly in signal transduction pathways for a variety of cellular activities, including proliferation, adhesion and migration, and differentiation. Diseases associated with tyrosine kinase activity include tumor cell proliferation, pathological neovascularization that promotes the growth of solid tumors, ocular neovascularization (diabetic retinopathy, age-induced macular degeneration, etc.), and inflammation (psoriasis, rheumatoid arthritis, etc.).

The compounds of formula I may be administered to a patient to treat cancer, particularly rapidly growing tumors.

The invention therefore relates to the use of compounds of the formula I and of their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all ratios, for the preparation of medicaments for the treatment of diseases in which inhibition, regulation and/or modulation of kinase signal transduction plays a role.

Preferred herein is Met kinase.

The use of preferred compounds of the formula I and their pharmaceutically acceptable salts and stereoisomers, including mixtures thereof in all ratios, for the preparation of medicaments for the treatment of diseases in which inhibition of tyrosine kinases by the compounds of claim 1 has an effect.

Particularly preferred is the use for the preparation of a medicament for the treatment of diseases in which inhibition of Met kinase by a compound according to claim 1 has an effect.

Particularly preferred is the use for the treatment of a disease, wherein the disease is a solid tumor.

The solid tumor is preferably selected from tumors of the lung, squamous epithelium, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate, genito-urinary tract, lymphatic system, stomach and/or larynx.

The solid tumor is further preferably selected from lung adenocarcinoma, small cell lung carcinoma, pancreatic carcinoma, glioblastoma, colon carcinoma and breast carcinoma.

Also preferred is the use for the treatment of tumours of the blood and immune system, preferably for the treatment of tumours selected from acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia.

The disclosed compounds of formula I may be administered in combination with other known therapeutic agents, including anticancer agents. The term "anti-cancer agent" as used herein refers to any substance that is administered to a cancer patient for the purpose of treating cancer.

The anti-cancer treatments defined herein may be applied as monotherapy or may include conventional surgery or radiotherapy or chemotherapy in addition to the compounds of the invention. Such chemotherapy may include one or more of the following classes of antineoplastic agents:

(i) antiproliferative/antineoplastic/DNA-damaging agents and combinations thereof for medical oncology, such as alkylating agents (e.g., cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, and nitrosoureas); antimetabolites (e.g., antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, hydroxyurea, and gemcitabine); antitumor antibiotics (e.g., anthracyclines such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxanes such as taxol and taxotere); topoisomerase inhibitors (e.g. epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, irinotecan and camptothecin) and cell differentiating agents (e.g. all-trans retinoic acid, 13-cis-retinoic acid and fenretinide);

(ii) cytostatics, such as antiestrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene, and iodoxyfene), estrogen receptor downregulators (e.g., fulvestrant), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide, and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorozole, and exemestane), and 5 α -reductase inhibitors such as finasteride;

(iii) substances that inhibit cancer cell invasion (e.g., metalloproteinase inhibitors such as marimastat and urokinase-plasminogen activator receptor function inhibitors);

(iv) inhibitors of growth factor function, e.g., such inhibitors include growth factor antibodies, growth factor receptor antibodies (e.g., anti-erbb 2 antibody trastuzumab [ Herceptin ]^TM]And the anti-erbb 1 antibody cetuximab [ C225]) Farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for exampleSuch as inhibitors of the epidermal growth factor family (e.g. EGFR family tyrosine kinase inhibitors, e.g.N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, AZD1839),N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) quinazolin-4-amine (Cl 1033)), for example an inhibitor of the platelet derived growth factor family and for example an inhibitor of the hepatocyte growth factor family;

(v) anti-angiogenic agents, e.g., those that inhibit the action of vascular endothelial growth factor (e.g., anti-vascular endothelial growth factor antibody bevacizumab [ Avastin)^TM]Such as those disclosed in published international patent applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that act by other mechanisms (e.g., inoxamine, inhibitors of integrin- α v β 3 function and angiostatin);

(vi) vascular damaging agents, such as combretastatin a4 and compounds disclosed in international patent applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) antisense therapies, e.g., those directed against the above targets, such as ISIS 2503, anti-Ras antisense;

(viii) gene therapy methods, including, for example, methods of replacing abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA 2; GDEPT (gene-directed enzyme prodrug therapy) approaches such as those employing cytosine deaminase, thymidine kinase, or bacterial nitroreductase; and methods of increasing the patient's tolerance to chemotherapy or radiation therapy, such as multi-drug resistance gene therapy; and

(ix) immunotherapeutic approaches, including, for example, ex vivo and in vivo approaches to increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4, or granulocyte-macrophage colony stimulating factor; methods of reducing T-cell anergy; methods of using transfected immune cells such as cytokine-transfected dendritic cells; methods of using cytokine transfected tumor cell lines; and methods of using anti-atopic antibodies.

Preferably the drugs in table 1 below (but not exclusively) are used in combination with a compound of formula I.

Such combination therapy can be achieved by means of simultaneous, sequential or separate administration of the individual components of the treatment. Combinations of this type employ the compounds of the present invention.

Measurement method

The compounds of formula I described in the examples were tested by the assays described below and found to have kinase inhibitory activity. Other assays are known In the literature and can be readily performed by those skilled In the art (see, e.g., Dhanabal et al, Cancer Res.59: 189-197; Xin et al, J.biol.chem.274: 9116-9121; Sheu et al, Anticancer Res.18: 4435-4441; Ausprunk et al, Dev.biol.38: 237-248; Gimbron et al, J.Natl.cancer Inst.52: 413-427; Nicosia et al, In Vitro 18: 538-549).

Determination of Met kinase Activity

According to the manufacturer's data (Met, activity, Upstate, cat # 14-526), Met kinase was expressed with the aim of producing the protein in insect cells (Sf 21; Spodoptera frugiperda), followed by affinity chromatography purification in the form of an "N-terminal 6 His-tagged" recombinant human protein in a baculovirus expression vector.

A variety of available assay systems can be used to determine kinase activity. Radiolabeled ATP is used in scintillation proximity assays (Sorg et al, J.of. biomolecular Screening, 2002, 7, 11-19), flash plate methods, or filter binding assays (II)³²P-ATP，³³P-ATP) to measure the radioactive phosphorylation of proteins or peptides as substrates. In the presence of the inhibitory compound, a reduced or no radioactive signal is detected. In addition, homogeneous time-resolved fluorescence resonance energy transfer (HTR-FRET) and Fluorescence Polarization (FP) techniques can also be used as assay methods (Sills et al, J.of Biomolecular Screening, 2002, 191-214).

Other non-radioactive ELISA assays use specific phospho-antibodies (phospho-AB). Phosphoantibodies bind only phosphorylated substrates. This binding can be detected by chemiluminescence using a peroxidase-conjugated secondary antibody (Ross et al, 2002, biochem.j.).

Flash plate method (Met kinase)

The test plate used was a 96-well Flashplate from Perkin Eimer^RMicroplate (catalog number SMP 200). The components of the kinase reaction described below were pipetted into the assay plate. Met kinase and substrate poly Ala-Glu-Lys-Tyr (pAGLT, 6: 2: 5: 1) are reacted with radiolabeled³³P-ATP was incubated together in a total volume of 100. mu.L for 3 hours at room temperature in the presence and absence of the experiment. The reaction was stopped using 150. mu.L of 60mM EDTA solution. After a further incubation for 30 minutes at room temperature, the supernatant was filtered off with suction and the wells were washed three times with 200. mu.L of 0.9% NaCl solution each time. Bound radioactivity was determined by scintillation spectrometry (Topcount NXT, Perkin-Elmer).

The full value used is the kinase response without inhibitor. This should be between about 6000 and 9000 cpm. The pharmacological zero value used was staurosporine at a final concentration of 0.1 mM. The inhibition value (IC50) was determined using the RS1_ MTS program.

Kinase reaction conditions in each well:

30 μ L assay buffer

10 μ L of test substance in assay buffer containing 10% DMSO

10 μ L ATP (1 μ M cold, 0.35 μ Ci final concentration)³³P-ATP)

50 μ L of Met kinase/substrate mixture in assay buffer;

(10ng enzyme/well, 50ng pAGLT/well)

The solutions used were:

-assay buffer:

50mM HEPES

3mM magnesium chloride

3 μ M sodium orthovanadate

3mM manganese (II) chloride

1mM Dithiothreitol (DTT)

pH 7.5 (set with sodium hydroxide)

-a stop solution:

60mM Titriplex III(EDTA)

-³³P-ATP：Perkin-Elmer；

-Met kinase: upstate, catalog number 14-526, stock 1 μ g/10 μ L; specific activity 954U/mg;

-poly-Ala-Glu-Lys-Tyr, 6: 2: 5: 1: sigma catalog number P1152

In vivo experiments

Experimental methods: female Balb/C mice (breeder: Charles River Wiga) arrived 5 weeks old. The animals were acclimated to the experimental breeding environment for 7 days. 400 million TPR-Met/NIH3T3 cells in 100 μ L PBS (without Ca + + and Mg + +) were then injected subcutaneously into the pelvic region of each mouse. After 5 days, the animals were randomly divided into 3 groups, and the average tumor volume of 9 mice per group was 110. mu.L (range: 55-165). The control group was administered 100. mu.L of vehicle (0.25% methylcellulose/100 mM acetate buffer, pH 5.5) daily, and the treatment group was administered 200mg/kg of either "A56" or "A91" daily, both administered via gastric tube, dissolved in vehicle (volume likewise 100. mu.L/animal). After 9 days, the mean volume of the control group was 1530. mu.L, and the experiment was discontinued.

Determination of tumor volume: the length (L) and width (B) were measured using vernier calipers, and the tumor volume was calculated using the formula L.times.BxB/2.

Feeding conditions: animals were fed with commercial mouse chow (Sniff) 4 or 5 per cage.

In this context, all temperatures are expressed in degrees Celsius. In the following examples, "conventional treatment" means: if necessary, adding water; if necessary, the pH is adjusted to 2-10, depending on the constitution of the final product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or by crystallization. Rf value on silica gel; eluent: ethyl acetate/methanol 9: 1.

Mass Spectrum (MS): EI (Electron impact ionization) M⁺

FAB (Rapid atom bombardment) (M + H)⁺

ESI (electrospray ionization) (M + H)⁺

APCI-MS (atmospheric pressure chemical ionization-mass spectrometry) (M + H)⁺。

m.p. melting point [ ° c ].

HPLC method:

the method A comprises the following steps: gradient: 4.5 min/flow rate: 3 mL/min 99: 01-0: 100

Water + 0.1% by volume of TFA: acetonitrile + 0.1% by volume of TFA

0.0 to 0.5 minutes: 99: 01

0.5 to 3.5 minutes: 99: 01- - -0: 100

3.5 to 4.5 minutes: 0: 100

Column: chromolith SpeedROD RP18e 50-4.6

Wavelength: 220nm

The method B comprises the following steps: gradient: 4.2 min/flow rate: 2 mL/min 99: 01-0: 100

Water + 0.1% by volume of TFA: acetonitrile + 0.1% by volume of TFA

0.0 to 0.2 minutes: 99: 01

0.2 to 3.8 minutes: 99: 01- - -0: 100

3.8 to 4.2 minutes: 0: 100

Column: chromolith Performance RP18 e; the length of the glass is 100mm,

inner diameter of 3mm

Wavelength: 220nm

Retention time Rt., calculated in minutes min.

Example 1

Preparation of 3- [3- (5-bromopyrimidin-2-yl) benzyl ] -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine ("A1") was carried out in analogy to the following scheme

1.1: 2.70kg (18.0mol) of sodium iodide were added portionwise at room temperature to a mixture of 5.0L of water and 11.3L of 57% aqueous hydroiodic acid solution (75.2 mol). 2.00kg (13.4mol) of 3, 6-dichloropyridazine were subsequently added in portions to the solution which was maintained at 20 ℃. The reaction mixture was stirred at 20 ℃ for 18 hours. 10L of tert-butyl methyl ether and 4L of water were added to the reaction mixture. The organic phase is separated and washed with water and aqueous sodium sulfite solution. The organic phase is evaporated, heptane is added, and the resulting solid is filtered off with suction and washed with heptane. The residue was dried in vacuo: 3-chloro-6-iodopyridazine as colorless foliate crystals; ESI 241.

1.2: 705g (3.39mol) of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 1.44kg of tripotassium phosphate trihydrate were added to a solution of 815g (3.39mol) of 3-chloro-6-iodopyridazine in 3.8L of 1, 2-dimethoxyethane. The resulting suspension was heated to 80 ℃ under nitrogen and stirring, and 59.5g (85mmol) of bis (triphenylphosphine) palladium (II) chloride were added. The reaction mixture was stirred at 80 ℃ for 3 hours. The mixture was cooled to room temperature and 9L of water was added. The resulting precipitate was filtered off with suction, washed with water and dried in vacuo: 3-chloro-6- (1-methyl-1H-pyrazol-4-yl) pyridazine, as brown crystals; ESI 195.

1.3: 4.86mL (100mmol) of hydrogen was oxidizedTo a solution of 11.5g (50.0mmol) of methyl 3-bromophenylacetate in 35mL of 1-butanol was added, and the mixture was heated at boiling for 90 minutes. The reaction mixture was cooled to room temperature. The resulting precipitate was filtered off with suction, washed with petroleum ether and dried in vacuo: (3-bromophenyl) acethydrazide in the form of colorless fine needles; ESI 229, 231.

1.4: a suspension of 3.89g (20.0mmol) 3-chloro-6- (1-methyl-1H-pyrazol-4-yl) pyridazine and 4.58g (20.0mmol) (3-bromophenyl) acethydrazide in 40mL 1-butanol was heated at 130 ℃ for 18 hours. The reaction mixture was cooled and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a column of silica gel with dichloromethane/tert-butyl methyl ether/methanol as eluent: 3- (3-bromobenzyl) -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine as beige crystals; ESI 369, 371.

1.5: 1.57mg (16.0mmol) of potassium acetate are added to a solution of 2.10g (5.35mmol) of 3- (3-bromobenzyl) -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine and 1.77g (6.95mmol) of bis (pinacolato) diboron in 11mL of DMF and the mixture is heated to 80 ℃ under nitrogen. 118mg (0.16mmol) of 1, 1-bis (diphenylphosphino) ferrocene palladium (II) dichloride are then added and the mixture is stirred at 80 ℃ for 3 hours. The reaction mixture was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue is heated with tert-butyl methyl ether, cooled and filtered with suction and washed with tert-butyl methyl ether and dried in vacuo: 6- (1-methyl-1H-pyrazol-4-yl) -3- [3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan (dioxaborolan) -2-yl) benzyl ] -1,2, 4-triazolo [4,3-b ] pyridazine as gray crystals; the ESI 417.

1.6: 581mg (5.48mmol) of sodium carbonate in 2.7mL of water are added to a suspension of 1.14g (2.74mmol) of 6- (1-methyl-1H-pyrazol-4-yl) -3- [3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl ] -1,2, 4-triazolo [4,3-b ] pyridazine in 2.7mL of toluene and 5.4mL of ethanol, and the mixture is heated to 80 ℃ under nitrogen. 780mg (2.74mmol) of 5-bromo-2-iodopyrimidine and 38.4mg (0.06mmol) of bis (triphenylphosphine) palladium (II) chloride were then added and the reaction mixture was stirred at 80 ℃ under nitrogen for 18 h. The reaction mixture was partitioned between water and dichloromethane. The organic phase was evaporated and the residue was chromatographed on silica gel column using petroleum ether/dichloromethane/methanol as eluent: 3- [3- (5-bromopyrimidin-2-yl) benzyl ] -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine ("a 1") as colorless crystals; ESI 447/449;

¹H-NMR(d₆-DMSO)：δ[ppm]＝3.93(s，3H)，4.63(s，2H)，7.50(t，J＝7.8Hz，1H)，7.63(dt，J₁＝7.5Hz，J₂＝1.5Hz，1H)，7.66(d，J＝9.3Hz，1H)，8.20(s，1H)，8.23(dt，J₁＝7.4Hz，J₂＝1.3Hz，1H)，8.32(d，J＝9.6Hz，1H)，8.48(t，J＝1.5Hz，1H)，8.51(s，1H)，9.06(s，2H)。

example 2

Preparation of 6- (1-methyl-1H-pyrazol-4-yl) -3- (3- {5- [1- (2-pyrrolidin-1-yl-ethyl) -1H-pyrazol-4-yl ] pyrimidin-2-yl } benzyl) -1,2, 4-triazolo [4,3-b ] pyridazine ("A2") was carried out in analogy to the following scheme

2.1: 17.5g (101mmol) of N- (2-chloroethyl) pyrrolidine hydrochloride and 49.4g (152mmol) of cesium carbonate are added to a solution of 10.0g (50.5mmol) of pyrazole-4-boronic acid pinacol ester in 100mL of acetonitrile. The resulting suspension was stirred at room temperature for 18 hours. The reaction mixture was filtered with suction and washed with acetonitrile. The filtrate was evaporated and partitioned between ethyl acetate and saturated sodium chloride solution. The organic phase was dried over sodium sulfate and evaporated: 1- (2-pyrrolidin-1-ylethyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole. As a light orange oil, which gradually crystallized;

¹H-NMR(d₆-DMSO)：δ[ppm]＝1.25(s，12H)，1.65(m，4H)，2.44(m，4H)，2.79(t，J＝6.8Hz，2H)，4.21(t，J＝6.8Hz，2H)，7.56(s，1H)，7.93(s，1H)。

2.2: a suspension of 112mg (0.25mmol)3- [3- (5-bromopyrimidin-2-yl) benzyl ] -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine, 100mg (0.30mmol)1- (2-pyrrolidin-1-ylethyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole and 106mg (0.50mmol) tripotassium phosphate trihydrate in 2mL 1, 2-dimethoxyethane was heated to 80 ℃ under nitrogen. Then 14mg (20. mu. mol) bis (triphenylphosphine) palladium (II) chloride and 1 drop triethylamine were added and the mixture was stirred at 80 ℃ for 6 hours. The reaction mixture was cooled 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: 6- (1-methyl-1H-pyrazol-4-yl) -3- (3- {5- [1- (2-pyrrolidin-1-ylethyl) -1H-pyrazol-4-yl ] pyrimidin-2-yl } benzyl) -1,2, 4-triazolo [4,3-b ] pyridazine ("a 2") as colorless crystals; ESI 532;

¹H-NMR(d₆-DMSO)：δ[ppm]＝1.67(m，4H)，2.48(m，4H)，2.87(t，J＝6.6Hz，2H)，3.93(s，3H)，4.27(t，J＝6.6Hz，2H)，4.64(s，2H)，7.48(t，J＝8Hz，1H)，7.57(d，J＝8Hz，1H)，7.67(d，J＝9.6Hz，1H)，8.09(s，1H)，8.20(s，1H)，8.26(d，J＝7.8Hz，1H)，8.33(d，J＝9.6Hz，1H)，8.44(s，1H)，8.50(bs，1H)，8.52(s，1H)，9.12(s，2H)。

example 3

Preparation of 3- { [3- (5-bromopyrimidin-2-yl) phenyl ] difluoromethyl } -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine ("A3") was carried out in analogy of the following scheme

3.1: 12.3mL (253mmol) of hydrogen hydroxideTo a solution of 15.0g (50.5mmol) of ethyl (3-bromophenyl) difluoroacetate (prepared according to WO 2007/014454) in 200mL of methanol was added, and the mixture was stirred at 45 ℃ for 10 minutes. The reaction mixture was evaporated. The residue was dissolved in dichloromethane and filtered. The residue was dissolved in water, filtered, washed with water and dried in vacuo: (3-bromophenyl) difluoroacethydrazide as pale yellow crystals; ESI 265/267.

3.2: a suspension of 4.18g (20.0mmol) 3-chloro-6- (1-methyl-1H-pyrazol-4-yl) pyridazine and 5.46g (20.0mmol) (3-bromophenyl) difluoroacetohydrazide in 87mL 1-butanol was heated at 30 ℃ for 18 hours. The reaction mixture was cooled and stirred at room temperature for 4 days. The resulting precipitate was filtered with suction and the residue was chromatographed on silica gel column with dichloromethane/methanol as eluent: 3- [ (3-bromophenyl) difluoromethyl ] -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine as a colorless solid; ESI 405/407.

¹H-NMR(d₆-DMSO)：δ[ppm]＝3.95(s，3H)，7.55(t，J＝7.8Hz，1H)，7.76(d，J＝8.4Hz，1H)，7.83(d，J＝8.4Hz，1H)，7.86(d，J＝9.5Hz，1H)，7.97(s，1H)，8.09(s，1H)，8.49(d，J＝9.5Hz，1H)，8.51(s，1H)。

3.3: 2.45g (25.0mmol) of potassium acetate are added to a solution of 3.38g (8.33mmol) of 3- [ (3-bromophenyl) difluoromethyl ] -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine and 2.65g (10.4mmol) of bis (pinacol) diboron in 17mL of DMF and the mixture is heated to 80 ℃ under nitrogen. 175mg (0.25mmol) of bis (triphenylphosphine) palladium (II) chloride were then added and the mixture was stirred at 80 ℃ for 18 h. The reaction mixture was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue is heated with tert-butyl methyl ether, cooled and filtered with suction and washed with tert-butyl methyl ether and dried in vacuo: 3- { difluoro- [3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] methyl } -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine as colorless crystals; ESI 453.

3.4: 1.07g (10.1mmol) of sodium carbonate in 5mL of water was added to a suspension of 2.31g (5.06mmol) of 3- { difluoro- [3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] methyl } -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine in 5mL of toluene and 10mL of ethanol, and the mixture was heated to 80 ℃ under nitrogen. Then 1.44g (5.06mmol) of 5-bromo-2-iodopyrimidine and 71mg (0.10mmol) of bis (triphenylphosphine) palladium (II) chloride were added and the reaction mixture was stirred at 80 ℃ under nitrogen for 18 h. The reaction mixture was cooled to room temperature, water was added, and the mixture was filtered with suction. The residue was dissolved in ethanol, stirred for a few minutes and filtered again with suction. The residue was dried in vacuo: 3- { [3- (5-bromopyrimidin-2-yl) phenyl ] difluoromethyl } -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine as a beige powder; ESI483, 485;

¹H-NMR(d₆-DMSO)：δ[ppm]＝3.92(s，3H)，7.76(t，J＝7.8Hz，1H)，7.83(d，J＝9.9Hz，1H)，7.95(d，J＝7.8Hz，1H)，8.11(s，2H)，8.46(s，2H)，8.47(d，J＝9.8Hz，1H)，8.58(d，J＝7.5Hz，1H)，8.80(bs，1H)，9.18(s，2H)。

the compound 3- (3- { [3- (5-bromopyrimidin-2-yl) phenyl ] difluoromethyl } -1,2, 4-triazolo [4,3-b ] pyridazin-6-yl) benzonitrile ("A3 a")

ESI 504/506。

Example 4

In analogy to preparation "A1", starting from methyl 1- (3-bromophenyl) cyclopentanecarboxylate the compound "A4" was obtained "

Example 5

Preparation of 3- {3- [3- (5-bromopyrimidin-2-yl) benzyl ] -1,2, 4-triazolo [4,3-b ] pyridazin-6-yl } benzonitrile ("A5") was carried out in analogy to the following scheme

5.1: a50 mL aqueous solution of 10.6g (100mmol) of sodium carbonate was added to a solution of 7.34g (50.0mol) of 3-cyanophenylboronic acid and 12.0g (50.0mmol) of 3-chloro-6-iodopyridazine in 100mL of ethanol and 50mL of toluene, and the mixture was heated to 80 ℃ under nitrogen. 351mg (0.50mmol) of bis (triphenylphosphine) palladium (II) chloride were then added. The reaction mixture was stirred at 80 ℃ for 18 hours. The mixture was cooled to room temperature, and the resulting precipitate was filtered with suction and washed with water. The residue was recrystallized from 2-propanol: 3- (6-chloropyridazin-3-yl) benzonitrile as brown crystals; ESI 216.

5.2: a suspension of 3.33g (15.0mmol) 3-chloro-6- (3-cyanophenyl) pyridazine and 3.47g (15.0mmol) (3-bromophenyl) acethydrazide in 30mL 1-butanol was heated at 130 ℃ for 18 h. The reaction mixture was cooled and ethyl acetate and water were added. The resulting precipitate was filtered off with suction, washed thoroughly with water and dried in vacuo: 3- [3- (3-bromobenzyl) -1,2, 4-triazolo [4,3-b ] pyridazin-6-yl ] benzonitrile as brown crystals; ESI 390/392.

5.3: further as prepared "A3".

3- {3- [3- (5-bromopyrimidin-2-yl) benzyl ] -1,2, 4-triazolo [4,3-b ] pyridazin-6-yl } benzonitrile ("A5"), ESI 468/470 was obtained.

Example 6

In analogy to preparation "A1", starting from 1-chloro-4-methylpyridazine (prepared according to EP 1422218) the compound "A6" is obtained "

Example 7

The following compounds were obtained in analogy to preparation "A2

Example 8

Preparation of 6- (1-methyl-1H-pyrazol-4-yl) -3- [3- (5-morpholin-4-yl-pyrimidin-2-yl) benzyl ] -1,2, 4-triazolo [4,3-b ] pyridazine ("A10") was carried out in analogy to the following scheme

Example 8a

Preparation of the compound 3- {3- [5- (4-methylpiperazin-1-yl) pyrimidin-2-yl ] benzyl } -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine ("A11") in analogy to the following scheme

546mg (1.22mmol) of 3- [3- (5-bromopyrimidin-2-yl) benzyl]-6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b]A suspension of pyridazine and 366mg (2.44mmol) of sodium iodide in 6mL of DMF was heated to 80 ℃ under nitrogen. 26mg (0.18mmol) of trans-N, N' -dimethyl-1, 2-cyclohexanediamine, 18.6mg (0.100mmol) of copper (I) iodide and 6mL of bis (methylene chloride) were then addedAlkane and the resulting suspension was stirred at a temperature of 95 ℃ under nitrogen 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 with dichloromethane/methanol as eluent: 3- [3- (5-iodopyrimidin-2-yl) benzyl]-6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b]Pyridazine as brown crystals; the ESI 495.

A suspension of 288mg (0.582mmol)3- [3- (5-iodopyrimidin-2-yl) benzyl ] -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine in 1.5mL toluene was heated to 110 ℃ under nitrogen and cooled to room temperature. 178mg (0.815mmol) of tripotassium phosphate, 97. mu.L (0.874mmol) of 1-methylpiperazine, 19.7mg (0.047mmol) of 2-dicyclohexylphosphino-2 ', 6' -dimethoxybiphenyl and 10.7mmol (0.012mmol) of tris (dibenzylideneacetone) dipalladium are then added, and the resulting suspension is stirred at 110 ℃ for 18 hours under nitrogen. The reaction mixture was cooled to room temperature, and ethyl acetate was added. The resulting precipitate was filtered with suction and the residue was chromatographed on silica gel column with dichloromethane/methanol as eluent: 3- {3- [5- (4-methylpiperazin-1-yl) pyrimidin-2-yl ] benzyl } -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine as beige crystals; ESI 467;

¹H-NMR(d₆-DMSO)：δ[ppm]＝2.31(s，3H)，2.58(m，4H)，3.34(m，4H)，3.94(s，3H)，4.61(s，2H)，7.42(t，J＝7.7Hz，1H)，7.63(d，J＝7.3Hz，1H)，7.67(d，J＝9.8Hz，1H)，8.14(d，J＝7.4Hz，1H)，8.20(s，1H)，8.32(d，J＝9.6Hz，1H)，8.39(bs，1H)，8.51(s，1H)，8.58(s，2H)。

the following compounds were obtained analogously

Example 9

Preparation of 3- (difluoro- {3- [5- (2-morpholin-4-ylethoxy) pyrimidin-2-yl ] phenyl } methyl) -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine ("A12") and 3- [ difluoro- (3-pyrimidin-2-ylphenyl) methyl ] -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine ("A26") was carried out in analogy to the following scheme

20mg (0.105mmol) of copper (I) iodide and 25. mu.L (0.16mmol) of trans-N, N' -dimethyl-1, 2-cyclohexanediamine were added to 700mg (1.41mmol) of 3-porting maintained under argon[3- (5-Bromopyrimidin-2-yl) phenyl]Difluoromethyl } -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b]Pyridazine and 449mg (2.93mmol) sodium iodide in 3mL portionsIn an alkane, and the mixture was stirred at 110 ℃ for 18 hours. The reaction mixture was cooled to room temperature, water was added, and the resulting precipitate was filtered with suction. The residue was stirred with acetonitrile, filtered with suction, and the residue was dried in vacuo: 3- { difluoro- [3- (5-iodopyrimidin-2-yl) phenyl]Methyl } -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b]Pyridazine, beige crystal; ESI 531.

mu.L (1.68mmol) of 2-morpholinoethanol is added to a suspension of 593mg (1.12mmol) of 3- { difluoro- [3- (5-iodopyrimidin-2-yl) phenyl ] methyl } -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine, 547mg (1.68mmol) of cesium carbonate, 21.3mg (0.11mmol) of copper (I) iodide and 53mg (0.22mmol) of 3, 4, 7, 8-tetramethyl-1, 10-phenanthroline in 4mL of toluene, maintained under argon, and the mixture is stirred at 100 ℃ for 18 hours. The reaction mixture was cooled to room temperature, water and dichloromethane were added, and the mixture was filtered through kieselguhr with suction. The organic phase was separated, washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed on a column of silica gel with dichloromethane/methanol as eluent to give two products:

3- (difluoro- {3- [5- (2-morpholin-4-ylethoxy) pyrimidin-2-yl]Phenyl } methyl) -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b]Pyridazine, as colorless crystals; ESI 534;¹H-NMR(d₆-DMSO)：δ[ppm]2.50(m, 4H), 2.75(t, J ═ 5.6Hz, 2H), 3.59(m, 4H), 3.92(s, 3H), 4.34(t, J ═ 5.6Hz, 2H), 7.71(t, J ═ 7.7Hz, 1H), 7.83(d, J ═ 9.6Hz, 1H), 7.85(d, J ═ 7.5Hz, 1H), 8.13(s, 1H), 8.48(d, J ═ 9.6Hz, 1H), 8.50(d, J ═ 7.7Hz, 1H), 8.71(s, 2H), 8.73(bs, 1H) and

3- [ difluoro- (3-pyrimidin-2-ylphenyl) methyl]-6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b]Pyridazine, as colorless crystals; ESI 406;¹H-NMR(d₆-DMSO)：δ[ppm]＝3.90(s，3H)，7.52(t，J＝4.8Hz，1H)，7.74(t，J＝7.8Hz，1H)，7.82(d，J＝9.7Hz，1H)，7.91(d，J＝7.5Hz，1H)，8.13(s，1H)，8.46(d，J＝9.7Hz，1H)，8.47(s，1H)，8.59(d，J＝7.7Hz，1H)，8.85(bs，1H)，8.96(d，J＝4.7Hz，2H)。

the related documents are: altman et al, j.org.chem.73, page 284 (2008).

The following compounds were obtained analogously

Example 10

The compound 3- {1- [3- (5-bromopyrimidin-2-yl) phenyl ] ethyl } -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine ("A18" was obtained in analogy to the preparation of "A4" starting from methyl 2- (3-bromophenyl) propionate

ESI 462。

Example 11

The following compounds were obtained in analogy to preparation "A7

Example 12

Preparation of 3- { [3- (5-bromopyrimidin-2-yl) phenyl ] difluoromethyl } -6-methyl-1, 2, 4-triazolo [4,3-b ] pyridazine ("A27") was carried out in analogy of the following scheme

1: 29.4g (300mmol) of potassium acetate are added to a solution of 27.9g (100mmol) of ethyl (3-bromophenyl) difluoroacetate (prepared according to WO 2007/014454) and 31.7g (125mmol) of bis (pinacol) diboron in 200mL of THF, which is maintained under nitrogen, and the mixture is heated to 80 ℃. Then 2.11g (3.00mmol) bis (triphenylphosphine) palladium (II) chloride was added and the mixture was stirred at 90 ℃ for 42 h. The reaction mixture was cooled to room temperature and saturated sodium chloride solution was added. The organic phase was separated, dried over sodium sulfate and evaporated: crude difluoro- [3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetic acid ethyl ester (ESI 327) as an orange-brown oil, which was used in the subsequent reaction without further purification.

2: a100 mL aqueous solution of 21g (198mmol) of sodium carbonate is added to a solution of 54.7g (about 99mmol) of ethyl difluoro- [3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan 2-yl) phenyl ] acetate in 100mL of toluene and 200mL of ethanol, which is maintained under nitrogen, and the mixture is heated to 80 ℃. 33.8g (119mmol) of 5-bromo-2-iodopyrimidine and 1.39g (1.98mmol) of bis (triphenylphosphine) palladium (II) chloride were then added and the reaction mixture was stirred at 80 ℃ under nitrogen for 66 hours. The reaction mixture was evaporated and partitioned between THF and saturated sodium chloride solution. The organic phase was evaporated and the residue was stirred with 2-propanol: 3- (5-bromopyrimidin-2-yl) phenyl ] difluoroacetic acid as beige crystals; ESI 329/331.

Similar preparation starting from methyl [3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetate, prepared according to j.med.chem.50(6), 1101-:

3- (5-Bromopyrimidin-2-yl) phenyl ] acetic acid (m.p. 211 ℃. 213 ℃)

3: 15.2mL trimethyl orthoformate and 1.8mL concentrated sulfuric acid were added to a 45mL methanol suspension of 15.2g (46.2mmol)3- (5-bromopyrimidin-2-yl) phenyl ] difluoroacetic acid, and the mixture was stirred at 35 ℃ for 24 hours. Water was added to the reaction mixture. The resulting precipitate was filtered off with suction, washed with water and dried in vacuo: methyl [3- (5-bromopyrimidin-2-yl) phenyl ] difluoroacetate as beige crystals; ESI 343/345.

The following were prepared analogously:

4: 12.1g (35.2mmol) of [3- (5-bromopyrimidin-2-yl) phenyl]A suspension of methyl difluoroacetate in 140mL of methanol was warmed to 45 ℃ and 8.57mL (176mmol) of hydrogen hydroxide was addedA clear solution initially formed and then precipitated again. After stirring the reaction mixture at 45 ℃ for 18 hours, water was added, the precipitate was filtered off with suction, washed with water and dried in vacuo: [3- (5-Bromopyrimidin-2-yl) phenyl]Difluoroacetohydrazide as brown crystals; ESI 343, 345;

¹H-NMR(d₆-DMSO)：δ[ppm]＝4.58(bs，2H)，7.71(t，J＝7.8Hz，1H)，7.78(d，J＝7.8Hz，1H)，8.52(d，J＝7.8Hz，1H)，8.58(s，1H)，9.13(s，2H)，10.4(bs，1H)。

the following was prepared analogously (reaction temperature 70 ℃):

[3- (5-bromopyrimidin-2-yl) phenyl ] acethydrazide; ESI 307/309; m.p.229-231 ℃.

5: a solution of 900mg (7.0mmol) of 3-chloro-6-methylpyridazine and 2.40g (7.00mmol) of [3- (5-bromopyrimidin-2-yl) phenyl ] difluoroacetohydrazide in 28mL of 1-butanol is heated at 130 ℃ for 18 hours. The reaction mixture was cooled to room temperature. The resulting precipitate was filtered off with suction, washed with 2-propanol and dried in vacuo: 3- { [3- (5-bromopyrimidin-2-yl) phenyl ] difluoromethyl } -6-methyl-1, 2, 4-triazolo [4,3-b ] pyridazine as gray crystals; ESI 417/419;

¹H-NMR(d₆-DMSO)：δ[ppm]＝2.64(s，3H)，7.51(d，J＝9.6Hz，1H)，7.82(t，J＝7.8Hz，1H)，7.95(d，J＝7.8Hz，1H)，8.46(d，J＝9.3Hz，1H)，8.63(d，J＝7.9Hz，1H)，8.76(bs，1H)，9.19(s，2H)。

the following were prepared analogously by this method:

3- [3- (5-bromopyrimidin-2-yl) benzyl ] -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine ("A1") and

3- { [3- (5-bromopyrimidin-2-yl) phenyl ] difluoromethyl } -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine ("A3").

Example 13

Preparation of 3- (difluoro- {3- [5- (2-morpholin-4-ylethoxy) pyrimidin-2-yl ] phenyl } methyl) -6-methyl-1, 2, 4-triazolo [4,3-b ] pyridazine ("A28") was carried out in analogy to the following scheme

1: 827mg (8.43mmol) of potassium acetate are added to a solution of 1.17g (2.81mmol) of 3- { [3- (5-bromopyrimidin-2-yl) phenyl ] difluoromethyl } -6-methyl-1, 2, 4-triazolo [4,3-b ] pyridazine and 892mg (3.51mmol) of bis (pinacol) diboron in 6mL of THF which is kept under nitrogen, and the mixture is heated to 80 ℃. Then 30mg (0.056mmol) bis (triphenylphosphine) palladium (II) chloride were added and the mixture was stirred at 80 ℃ for 18 hours. The reaction mixture was cooled to room temperature, filtered and washed with a small amount of THF. 10mL of water and 476mg (3.09mmol) of sodium perborate tetrahydrate were added to the filtrate, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was acidified with 1N HCl and THF was removed in vacuo. The resulting precipitate was filtered off with suction, washed with water and dried in vacuo: 2- {3- [ difluoro (6-methyl-1, 2, 4-triazolo [4,3-b ] pyridazin-3-yl) methyl ] phenyl } pyrimidin-5-ol as brown crystals; ESI 355.

The following were prepared analogously:

2- (3- { difluoro- [6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazin-3-yl ] methyl } phenyl) pyrimidin-5-ol ("a 29"); colorless crystals, ESI 421;

2- {3- [6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazin-3-ylmethyl ] phenyl } pyrimidin-5-ol ("a 30"); colorless crystals, ESI 385.

2: mu.L (0.60mmol) of diisopropyl azodicarboxylate are slowly added dropwise with stirring to a suspension of 177mg (0.50mmol) of 2- {3- [ difluoro- (6-methyl-1, 2, 4-triazolo [4,3-b ] pyridazin-3-yl) methyl ] phenyl } pyrimidin-5-ol, 80.4. mu.L (0.65mmol) of 2-morpholinoethanol and 157mg (0.60mmol) of triphenylphosphine in 1mL of THF. The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was evaporated and chromatographed on silica gel column with dichloromethane/methanol as eluent: 3- (difluoro- {3- [5- (2-morpholin-4-ylethoxy) pyrimidin-2-yl ] phenyl } methyl) -6-methyl-1, 2, 4-triazolo [4,3-b ] pyridazine as colorless crystals; ESI 468;

¹H-NMR(d₆-DMSO)：δ[ppm]＝2.51(m，4H)，2.57(s，3H)，2.75(t，J＝5.4Hz，2H)，3.58(m，4H)，4.33(t，J＝5.4Hz，2H)，7.44(d，J＝9.5Hz，1H)，7.70(t，J＝7.8Hz，1H)，7.79(d，J＝7.6Hz，1H)，8.39(d，J＝9.5Hz，1H)，8.51(d，J＝7.7Hz，1H)，8.63(bs，1H)，8.69(s，2H)。

the preparation is similar as follows

3- (difluoro- {3- [5- (2-methoxyethoxy) pyrimidin-2-yl ] phenyl } methyl) -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine ("A31")

ESI 479；

2- [2- (3- { difluoro- [6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazin-3-yl ] methyl } phenyl) pyrimidin-5-yloxy ] ethanol ("A32") (hydrolysis of the ester by 2-acetoxyethoxy derivatives and application of sodium hydroxide/methanol)

ESI 465；

3- {3- [5- (2-methoxyethoxy) pyrimidin-2-yl ] benzyl } -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine ("A33")

ESI 443；

2- (2- {3- [6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazin-3-ylmethyl ] phenyl } pyrimidin-5-yloxy) ethanol ("A34") (hydrolysis of the ester by 2-acetoxyethoxy derivatives and application of sodium hydroxide/methanol)

ESI 429；

3- [3- (5-Methoxypyrimidin-2-yl) benzyl ] -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine ("A35")

ESI 399；

3- {3- [5- (3-Methoxypropoxy) pyrimidin-2-yl ] benzyl } -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine ("A36")

ESI 457；

3- (3- {5- [2- (4-methylpiperazin-1-yl) ethoxy ] pyrimidin-2-yl } benzyl) -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine ("A37")

ESI 511；

(hydrolysis of the ester by 3-acetoxypropoxy derivatives and using sodium hydroxide/methanol);

example 14

Preparation of 3- (difluoro- {3- [5- (1-methylpiperidin-4-ylmethoxy) pyrimidin-2-yl ] phenyl } methyl) -6-methyl-1, 2, 4-triazolo [4,3-b ] pyridazine ("A41") was carried out in analogy to the following scheme

1: mu.L (0.55mmol) of diisopropyl azocarboxylate are slowly added dropwise with stirring to a suspension of 177mg (0.50mmol) of 2- {3- [ difluoro (6-methyl-1, 2, 4-triazolo [4,3-b ] pyridazin-3-yl) methyl ] phenyl } pyrimidin-5-ol, 129mg (0.60mmol) of tert-butyl 4-hydroxymethylpiperidine-1-carboxylate and 144mg (0.55mmol) of triphenylphosphine in 1mL of THF, and the reaction mixture is stirred at room temperature for 18 h. The reaction mixture was diluted with 2-propanol and cooled to 0 ℃. The resulting precipitate was filtered off with suction, washed with 2-propanol and dried in vacuo: 4- (2- {3- [ difluoro- (6-methyl-1, 2, 4-triazolo [4,3-b ] pyridazin-3-yl) methyl ] phenyl } pyrimidin-5-yloxymethyl) piperidine-1-carboxylic acid tert-butyl ester as beige crystals; the ESI 552.

2: 20mg of paraformaldehyde in 1mL of formic acid was stirred at 80 ℃ for 1 hour, cooled to room temperature, and then added dropwise to 195mg (0.353mmol) of 4- (2- {3- [ difluoro- (6-methyl-1, 2, 4-triazolo [4,3-b ] maintained at 80 ℃ C]Pyridazin-3-yl) methyl]1mL Di-butyl phenyl } pyrimidin-5-yloxymethyl) piperidine-1-carboxylateIn an alkane suspension. The reaction mixture was stirred at 80 ℃ for 18 hours. The reaction mixture was cooled to room temperature and THF, saturated sodium chloride solution and 1.7mL of 50% sodium hydroxide solution were added. The organic phase was separated, dried over sodium sulfate and evaporated. The residue was purified by preparative HPLC: 3- (difluoro- {3- [5- (1-methylpiperidin-4-ylmethoxy) pyrimidin-2-yl]Phenyl } methyl) -6-methyl-1, 2, 4-triazolo [4,3-b]Pyridazine, trifluoroacetate, as colorless crystals; ESI 466;

¹H-NMR(d₆-DMSO)：δ[ppm]＝1.53(m，2H)，2.01(m，2H)，2.07(m，1H)，2.57(s，3H)，2.78(s，3H)，2.99(m，2H)，3.49(m，2H)，4.12(d，J＝5.9Hz，2H)，7.44(d，J＝9.6Hz，1H)，7.71(t，J＝7.8Hz，1H)，7.79(d，J＝7.8Hz，1H)，8.40(d，J＝9.6Hz，1H)，8.51(d，J＝7.8Hz，1H)，8.63(bs，1H)，8.69(s，2H)，9.49(bs，1H)。

the compound 3- (difluoro- {3- [5- (1-methylpiperidin-4-ylmethoxy) pyrimidin-2-yl ] phenyl } methyl) -6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ] pyridazine ("A42")

Colorless crystals, ESI 532;

¹H-NMR(d₆-DMSO)：δ[ppm]＝1.32(m，2H)，1.74(m，3H)，1.85(t，J＝11Hz，2H)，2.15(s，3H)，2.78(d，J＝11Hz，2H)，3.91(s，3H)，4.06(d，J＝5.5Hz，2H)，7.70(t，J＝7.8Hz，1H)，7.83(m，2H)，8.11(s，1H)，8.47(m，3H)，8.67(s，2H)，8.73(s，1H)。

example 15

Preparation of 2- (4- {3- [3- (5-bromopyrimidin-2-yl) benzyl ] -1,2, 4-triazolo [4,3-b ] pyridazin-6-yl } pyrazol-1-yl) ethanol ("A43") and 2- (4- {3- [3- (5-methylpyrimidin-2-yl) benzyl ] -1,2, 4-triazolo [4,3-b ] pyridazin-6-yl } pyrazol-1-yl) ethanol ("A44") was carried out analogously to the following scheme

1: 2.93g (9.09mmol)1- [2- (tetrahydropyran-2-yloxy) ethyl ] -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (prepared by reacting 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole and 2- (2-bromoethoxy) tetrahydropyran with cesium carbonate in acetonitrile) and 4.25g (20.0mmol) tripotassium phosphate trihydrate were added to a solution of 2.40g (10.0mmol) 3-chloro-6-iodopyridazine in 12mL 1, 2-dimethoxyethane. The resulting suspension was heated to 80 ℃ under nitrogen and stirring, and 210mg (0.30mmol) of bis (triphenylphosphine) palladium (II) chloride were added. The reaction mixture was stirred at 80 ℃ for 18 hours. The mixture was cooled to room temperature and 60mL of water and 30mL of dichloromethane were added. The organic phase was separated, washed with water, dried over sodium sulfate and evaporated: 3-chloro-6- {1- [2- (tetrahydropyran-2-yloxy) ethyl ] -1H-pyrazol-4-yl } pyridazine as a brown waxy solid; ESI 309.

2: a suspension of 1.02g (3.26mmol) 3-chloro-6- {1- [2- (tetrahydropyran-2-yloxy) ethyl ] -1H-pyrazol-4-yl } pyridazine, 1.00g [3- (5-bromopyrimidin-2-yl) phenyl ] acethydrazide and 54mg (0.33mmol) potassium iodide in 18mL 1-butanol was heated to reflux during which time a clear solution formed. The reaction mixture was kept at reflux for 20 hours and then cooled to room temperature. The resulting precipitate was filtered off with suction, washed with acetone and dried in vacuo: 2- (4- {3- [3- (5-bromopyrimidin-2-yl) benzyl ] -1,2, 4-triazolo [4,3-b ] pyridazin-6-yl } pyrazol-1-yl) ethanol as brown crystals; ESI 477/479; m.p.237-239 ℃.

3: 630. mu.L (1.26mmol) of a 2M solution of trimethylaluminum in toluene and 50mg (0.04mmol) of tetrakis (triphenylphosphine) palladium are added to a solution of 300mg (0.63mmol) of 2- (4- {3- [3- (5-bromopyrimidin-2-yl) benzyl ] -1,2, 4-triazolo [4,3-b ] pyridazin-6-yl } pyrazol-1-yl) ethanol in 6mL of THF, and the mixture is heated at the boil for 16 hours. The reaction mixture was cooled to room temperature, methanol was added, and the mixture was evaporated. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent: 2- (4- {3- [3- (5-methylpyrimidin-2-yl) benzyl ] -1,2, 4-triazolo [4,3-b ] pyridazin-6-yl } pyrazol-1-yl) ethanol as colorless crystals; ESI 413; m.p.204-206 ℃;

¹H-NMR(d₆-DMSO)：δ[ppm]＝2.31(s，3H)，3.78(m，2H)，4.22(t，J＝5.5Hz，2H)，4.63(s，2H)，4.95(bs，1H)，7.46(t，J＝7.7Hz，1H)，7.56(d，J＝7.9Hz，1H)，7.69(d，J＝9.8Hz，1H)，8.23(m，2H)，8.31(d，J＝9.8Hz，1H)，8.51(bs，1H)，8.52(s，1H)，8.74(s，2H)。

pharmacological data

Met kinase inhibition

TABLE 1

IC₅₀：1nM-0.1μM＝A

0.1μM-10μM＝B

＞10μM＝C

The following examples relate to pharmaceuticals:

example A: injection vial

A solution of 100g of the active ingredient of the formula I and 5g of disodium hydrogen phosphate in 3L of bidistilled water is adjusted to pH 6.5 using 2N hydrochloric acid, sterile-filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contained 5mg of active ingredient.

Example B: suppository

A mixture of 20g of active ingredient of the formula I with 100g of soya lecithin and 1400g of cocoa butter is melted, poured into moulds and allowed to cool. Each suppository contains 20mg of active ingredient.

Example C: solution preparation

Preparation of 1g of active ingredient of the formula I, 9.38g of NaH₂PO₄·2H₂O、28.48g Na₂HPO₄·12H₂A solution of O and 0.1g benzalkonium chloride in 940mL of double distilled water. The pH was adjusted to 6.8 and the solution was made up to 1L and sterilized by irradiation. The solution can be applied in the form of eye drops.

Example D: ointment formulation

500mg of active ingredient of the formula I are mixed with 99.5g of vaseline under sterile conditions.

Example E: tablet formulation

A mixture of 1kg of active ingredient of the formula I, 4kg of lactose, 1.2kg of potato starch, 0.2kg of talc and 0.1kg of magnesium stearate is compressed in the conventional manner to tablets, so that each tablet contains 10mg of active ingredient.

Example F: dragee (dragee)

Tablets were compressed in a similar manner to example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

Example G: capsule preparation

2kg of active ingredient of formula I are filled into hard gelatin capsules in a conventional manner so that each capsule contains 20mg of active ingredient.

Example H: ampoule agent

A solution of 1kg of the active ingredient of the formula I in 60L of bidistilled water is sterile-filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10mg of active ingredient.

Claims (12)

1. A compound selected from

And pharmaceutically acceptable salts thereof.

2. A medicament comprising at least one compound according to claim 1 and/or a pharmaceutically acceptable salt thereof, and optionally an excipient and/or adjuvant.

3. The use of a compound of claim 1, and pharmaceutically acceptable salts thereof, for the manufacture of medicaments for the treatment of diseases in which inhibition, modulation and/or modulation of kinase signal transduction plays a role.

4. The use according to claim 3 for the preparation of a medicament for the treatment of diseases in which inhibition of Met kinase by the compounds according to claim 1 has an effect.

5. The use according to claim 3 or 4, wherein the disease to be treated is a solid tumor.

6. Use according to claim 5, wherein the solid tumor originates from a tumor of the squamous epithelium, bladder, stomach, kidney, head and neck, esophagus, thyroid, intestine, liver, brain, genito-urinary tract, lymphatic system, larynx and/or lung.

7. The use of claim 5, wherein the solid tumor is derived from cervical and prostate tumors.

8. The use of claim 5, wherein the solid tumor is derived from lung adenocarcinoma, small cell lung carcinoma, pancreatic carcinoma, glioblastoma, colon carcinoma and breast carcinoma.

9. The use according to claim 3 or 4, wherein the diseases to be treated are tumors of the blood and immune system.

10. Use according to claim 9, wherein the tumour is derived from monocytic leukaemia, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia.

11. A medicament comprising at least one compound according to claim 1 and/or a pharmaceutically acceptable salt thereof, and at least one further pharmaceutically active ingredient.

12. Kit comprising the following individual packages

(a) An effective amount of a compound of claim 1 and/or a pharmaceutically acceptable salt thereof;

and

(b) an effective amount of an additional pharmaceutically active ingredient.