HK1221719B - Arylquinazolines - Google Patents

Description

Aryl quinazolines

The invention relates to compounds of formula (I),

wherein

X is CH, CF, S or N,

y is CH, S or N,

z is a group selected from the group consisting of C and N,

-when Z = C, together with a single bond, a double bond is formed,

when Z = N, is absent,

n is 1 or 2, wherein

When n = 1, X = S,

and when N =2, two X = CH, or X connected to the pyrimidine ring is CF and X not connected to the pyrimidine ring is CH, or one X is CH and the other X is N;

m is 1 or 2, wherein

When m = 1, Y = S,

and when m =2, two Y = CH, or one Y is CH and the other Y is N;

R¹、R²、R³、R⁴independently of one another, H, Hal, CN, OH, CONH₂CONH (LA) or LA;

R⁵is H, Hal, CN or C ≡ CH;

cyc is phenyl which may be unsubstituted or mono-or doubly and independently of one another by R⁶Substitution; or is Het¹；

Het¹Is mono-or bicyclic and has 1 to 3N atoms, O atoms and/or S atoms or 1 to 4N atomsIs unsubstituted or mono-, bi-or triply independently of one another by R⁶Substituted or may be singly substituted by Het²Substitution;

R⁶is Hal, LA, oxo, CN or NH₂；

LA is an unbranched or branched alkyl radical having 1 to 5C atoms, which may be saturated or partially unsaturated, where 1 to 3H atoms may be Hal and/or one H atom may be CN or Het²And/or one or two CH₂The radicals-may be substituted by O, NH₂、N(CH₃) Or CO substitution;

Het²is a 3-5 membered aliphatic carbon-or heterocyclic ring having 0, 1,2 or 3N atoms, O atoms and/or S atoms, which is unsubstituted;

hal is F, Cl, Br or I;

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

The compounds of formula (I) are useful for inhibiting serine/threonine protein kinases and for sensitizing cancer cells to anticancer agents and/or ionizing radiation. The invention also relates to the use of a compound of formula (I) in the prevention, treatment or process control of cancer, tumors or metastases, in combination with radiotherapy and/or an anti-cancer agent. The invention furthermore relates to a process for the preparation of compounds of the formula (I) by reacting compounds of the formulae (IV) and (V) and optionally converting the base or acid of the compound of the formula (I) into a salt thereof.

DNA-dependent protein kinases (DNA-PKs) are serine/threonine protein kinases that are activated by binding to DNA. Biochemical and genetic data show that DNA-PK consists of: (a) a catalytic subunit, which is called DNA-PKcs, and (b) two regulatory components (Ku70 and Ku 80). Functionally, DNA-PK is a key component for the repair of DNA Double Strand Breaks (DSB) on the one hand and somatic cells or V (D) J recombination on the other hand. In addition, DNA-PK and its components are associated with a variety of other physiological processes, including the regulation of chromatin structure and telomere maintenance (Smith and Jackson (1999) Genesand Dev 13: 916; Goytisolo et al (2001) mol. cell. biol. 21: 3642; Williams et al (2009) Cancer Res. 69: 2100).

Human genetic material in the form of DNA is constantly subject to attack by Reactive Oxygen Species (ROS), which are formed primarily as byproducts of oxidative metabolism. ROS can cause DNA damage in the form of single strand breaks. Double strand breaks can be caused if a previous single strand break occurs in the immediate vicinity. In addition, single-and double-strand breaks can be caused if DNA replication forks encounter a damaged base pattern (basemulter). In addition, exogenous influences such as ionizing radiation (e.g., gamma or heavy particle radiation) and certain anticancer drugs (e.g., bleomycin) can cause DNA double strand breaks. DSBs can furthermore occur as intermediates for somatic recombination, a process important for the development of a functional immune system in all vertebrates. If a DNA double strand break is not repaired or incorrectly repaired, mutations and/or chromosomal aberrations can occur, which can thus lead to cell death. To cope with the serious risks posed by DNA double strand breaks, eukaryotic cells have developed various mechanisms to repair them. Higher eukaryotes mainly use so-called nonhomologous end joining, in which DNA-dependent protein kinases play a critical role. Biochemical studies have shown that DNA-PK is most efficiently activated by the development of DNA-DSB. Cell lines whose DNA-PK components have been mutated and are non-functional have been shown to be sensitive to radiation (Smith and Jackson, 1999).

Due to its catalytic domain (which is located at about 500 amino acids)CIn the terminal catalytic subunit (DNA-PKcs), DNA-PK belongs toPhosphatidylinositol-3-kinase-related kinases (PIKK)wherein the DNA-PK is not a lipid kinase (Hartley et al (1995) Cell 82: 849; Smith and Jackson (1999) Genes and Dev 13: 916; Lempi ä inen and Halazonetis (2009) EMBO J. 28: 3067).

Izzard et al (1999) Cancer Res.59: 2581 have described that the PI3 kinase inhibitor LY294002 inhibits the function of DNA-PK in vitro experiments. IC (integrated circuit)₅₀The value (concentration at which 50% of the enzyme activity is inhibited) is relatively ineffective1.25 μ M (5.0 mM ATP). Although evidence that the inhibitor LY294002 renders mammalian cells more sensitive to radiation (i.e. increased cytotoxicity of ionizing radiation) suggests in principle for use in irradiation therapy of, for example, solid cancer tumors, only a slight increase in sensitivity to ionizing radiation has been demonstrated in cellular terms for LY294002 (Rosenzweig et al (1999) clin. cancer res. 3: 1149). KuDOS Pharmaceuticals Ltd. the guide structure LY294002 has been optimized and various DNA-PK inhibitors have been improved. Introduction of Dibenzothienyl production inhibitor NU-7441, which is IC₅₀ATP-competitive compounds with a value of 20.0 nM (Hardcastle et al (2005) J. Med. chem. 48: 7829). KU-0060648 combines the inhibitory properties for DNA-PK with improved solubility characteristics in aqueous media, but the PI3K isozyme family of kinases are also effectively inhibited by KU-0060648. Thus, to date there has been an unmet need for effective and selective DNA-PK inhibitors.

The present invention is based on the object of overcoming the disadvantages represented in the prior art and of developing effective DNA-PK inhibitors which are selective for the related kinases of the PIKK family and have a low molecular size, in particular for effective administration in cancer therapy as radiosensitizers and chemosensitizers, with the aim of improving the efficacy and at the same time reducing the side effects.

The object of the invention is achieved according to the independent claims. The dependent claims contain preferred embodiments. According to the present invention, there is provided a compound of formula (I).

Surprisingly, it has been found that the compounds of the invention have inhibitory properties on serine/threonine protein kinases. The compounds of formula (I) are designed to allow effective and selective inhibition of DNA-PK. The compounds of the invention thus open up entirely new possibilities with regard to the anticancer effect of anticancer agents. In the present invention, the compounds of formula (I) act as radiosensitizers and chemosensitizers in the treatment of cancer by specifically inhibiting the repair of DNA double strand breaks (non-homologous end joining).

To date, 2, 4-diaminoquinazoline derivatives are known from WO 1992/07844 as potentiators of chemotherapeutic agents in the treatment of cancer. These derivatives solve the multidrug resistance of tumor cells as a result of overexpression of mdr1 gene, and the gene product of the P glycoprotein efflux pump of mdr1 gene maintains low intracellular active substance concentration. Physicochemical or pharmacological data are neither disclosed nor known are commercially available drugs. Further quinazoline derivatives are disclosed as DNA-PK inhibitors in WO 2011/113512.

The present invention provides a new generation of DNA-PK inhibitors that can not only be used for specific inhibition, which occurs especially in cell assays. They are also characterized by the absence of frequently observed undesired inhibition of cardiac ion channels, particularly Kv1.11hERG, whose blockade can lead to life-threatening arrhythmias.

The compounds of the invention and their salts therefore have valuable pharmacological properties as well as good compatibility.

Within the scope of the present invention, the compounds of formula (I) are defined such that they are also used to represent pharmaceutically usable derivatives, salts, solvates of salts, precursors, tautomers and optically active forms (e.g. stereoisomers, diastereomers, enantiomers, racemates) of the compounds. By solvate of a compound is meant the addition of an inert solvent molecule to the compound, which is formed due to their mutual attraction. Solvates are for example mono-or dihydrate or alcoholates. Pharmaceutically usable derivatives are used to indicate, for example, the salts of the compounds of the invention and the so-called precursors of these compounds. By precursor is meant a compound of formula (I) modified, for example by means of an alkyl or acyl group, a sugar or an oligopeptide, which dissociates rapidly in an organism to give an effective compound of the invention. These also include biodegradable polymer derivatives of the compounds of the invention, which are described, for example, in int. j. pharm. 115, 61-67 (1995). Any compound that can be converted in vivo into a biologically active agent (i.e. a compound of formula (I)) is a precursor in the sense of the present invention. Any biologically active compound resulting from the in vivo metabolism of a compound of the invention is a metabolite in the sense of the present invention. The compounds of formula (I) may have one or more chiral centers and thus occur in various stereoisomeric forms. Formula (I) includes all of these forms.

The invention also relates to the use of a mixture of compounds of formula (I), for example a mixture of two diastereomers, for example in a ratio of 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1: 1000. Mixtures of stereoisomeric compounds are particularly preferred here.

Unless expressly stated otherwise, groups X, Y, R in the context¹、R²、R³、R⁴、R⁵、R⁶、LA、Cyc、Het¹、Het²And Hal and m and n have the meanings given for formula (I). If a single radical is present multiple times within a compound or radical, these radicals, independently of one another, have the meanings given, unless expressly stated otherwise. The names used herein to define compounds are generally based on the IUPAC organization rules for compounds, particularly organic compounds. Unless otherwise indicated in the specification or claims, the names of the above-mentioned compounds used to explain the present invention always have the following meanings.

In the present invention, "LA" denotes a saturated or partially unsaturated hydrocarbon group which is unbranched (straight-chain) or branched and has 1,2, 3, 4 or 5C atoms. Examples of LA are methyl, ethyl, propyl, isopropyl, 1-, 1, 2-or 2, 2-dimethylpropyl, 1-ethylpropyl, butyl, isobutyl, sec-butyl, tert-butyl. These hydrocarbon radicals may also be substituted, where 1 to 3H atoms may be Hal, and/or one H atom may be CN or Het²And/or one or two CH₂The radical-may be substituted by O, NH, N (CH)₃) Or CO substitution. Examples of this are methoxy, methylthio (Methylsulfanyl), ethoxy, cyanomethoxy, 2-propionyloxy, oxetan-3-yloxy, N-methylaminocarbonyl, carboxamido, 2-methoxy-ethoxy, 2,2, 2-trifluoro-ethoxy or 2-hydroxy-ethoxy.

In the present invention, "Het¹"means having3. Mono-or bicyclic, aliphatic or aromatic, hydrocarbon-heterocycles of 4,5, 6, 7, 8, 9 or 10C atoms and 0, 1,2 or 3N-, O-and/or S atoms, which may be substituted. Examples of suitable "Cyc" are phenyl, pyridine, pyrazine, pyridazine, pyrazolo [1,5-a ]]Pyrimidinyl or imidazo [1,2-b ]]A pyridazinyl group.

In the present invention, "Het²"denotes a 3-to 5-membered aliphatic carbon-or heterocycle having 0, 1,2 or 3N-, O-and/or S-atoms. Het²Examples of (a) are oxetane, pyrrolidine or cyclopropyl.

In a preferred embodiment of the invention, there are provided arylquinazoline-derivatives of the formula (Ia),

wherein

X, Y are each independently CH, S or N,

z is a group selected from the group consisting of C and N,

-when Z = C, together with a single bond, a double bond is formed,

when Z = N, is absent,

n is 1 or 2, wherein

When n = 1, X = S,

and when N =2, two X = CH or X connected to the pyrimidine ring is CH and X not connected to the pyrimidine ring is N;

m is 1 or 2, wherein

When m = 1, Y = S,

and when m =2, two Y = CH or one Y is CH and the other Y is N;

R¹、R²、R³、R⁴independently of one another, H, Hal, CN, OH, CONH₂Or LA;

R⁵is H, Hal, CN or C ≡ CH;

cyc is phenyl which may be unsubstituted or mono-or doubly and independently of one another by R⁶Substitution; or is Het¹；

Het¹Is a monocyclic or bicyclic 5-to 10-membered heterocycle having 1 to 3N-, O-and/or S-atoms which may be unsubstituted or substituted independently of one another by R⁶Mono-or double substitution;

R⁶is Hal, LA, oxo, CN, NH₂Or Het²；

LA is an unbranched or branched alkyl radical having 1 to 5C atoms, which may be saturated or partially unsaturated, where 1 to 3H atoms may be Hal and/or one H atom may be CN or Het²And/or one or two CH₂The radicals-may be substituted by O, NH₂、N(CH₃) Or CO substitution;

Het²is a 3-5 membered aliphatic carbon-or heterocyclic ring having 0, 1,2 or 3N atoms, O atoms and/or S atoms, which is unsubstituted;

hal is F, Cl, Br or I;

more preferred arylquinazoline-derivatives correspond to formula (Ib),

wherein all substituents have the meaning given for formula (I) or (Ia);

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

In another preferred embodiment of the invention, there are provided arylquinazoline-derivatives of the formula (II),

wherein

R³Is Hal, CN, OH, CONH₂CONH (LA) or LA;

R^6'、R^6''independently of one another H, Hal, LA, oxo, CN, NH₂Or Het²；

Q¹、Q²Independently of one another, CH, N or NH and are in each case unsubstituted;

represents the presence or absence of a double bond on Cyc;

and the remaining substituents have the meanings given for formula (I);

and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios. [0021]That is, it has been found that when R is³The activity of the compounds of the invention is particularly high when Q has no substituent, as shown in formula (II).

In another preferred embodiment of the invention, there are provided arylquinazoline-derivatives of the formula (III),

wherein

R³Is Hal, CN, OH, CONH₂CONH (LA) or LA;

R⁶is Hal, LA, oxo, CN, NH₂Or Het²；

R^6''Is H, Hal, LA, oxo, CN, NH₂Or Het²；

Represents the presence or absence of a double bond on Cyc;

and the remaining substituents have the meanings given for formula (I);

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

That is, it has been found that when R is³Is as shown in formula (III) and Cyc is substituted with R in the ortho position⁶When substituted, the activity of the compounds of the invention is particularly high.

Very particular preference is given to the sub-formulae (IIa), (IIb), (IIIa) and (IIIb) in formulae (II) and (III):

wherein

R²、R³Independently of one another Hal, CN, OH, CONH₂CON (LA) or LA;

R^6'、R^6''independently of one another H, Hal, LA, oxo, CN, NH₂Or Het²；

Q¹、Q²Independently of one another, CH, N or NH and are in each case unsubstituted;

X¹is CH, CF or N;

X²is a group of one of the groups CH or N,

wherein X¹、X²Not N at the same time;

y is CH or N;

represents the presence or absence of a double bond on Cyc;

and the remaining substituents have the meanings given for formula (I);

and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios;

wherein

R²、R³Independently of one another Hal, CN, OH, CONH₂CON (LA) or LA;

R^6'、R^6''independently of one another H, Hal, LA, oxo, CN, NH₂Or Het²；

Q¹、Q²Independently of one another, CH, N or NH and are in each case unsubstituted;

y is a group of the formula CH or N,

represents the presence or absence of a double bond on Cyc;

and all the remaining substituents have the meanings given for formula (I);

and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios;

wherein

R³Is Hal, CN, OH, CONH₂CON (LA) or LA;

R⁶is Hal, LA, oxo, CN, NH₂Or Het²；

R^6''Is H, Hal, LA, oxo, CN, NH₂Or Het²；

X¹Is CH, CF or N;

X²is a group of one of the groups CH or N,

wherein X¹、X²Not N at the same time;

y is CH or N;

represents the presence or absence of a double bond on Cyc;

and the remaining substituents have the meanings given for formula (I);

and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios;

wherein

R³Is Hal, CN, OH, CONH₂CON (LA) or LA;

R⁶is Hal, LA, oxo, CN, NH₂Or Het²；

R^6''Is H, Hal, LA, oxo, CN, NH₂Or Het²；

Y is a group of the formula CH or N,

represents the presence or absence of a double bond on Cyc;

and all the remaining substituents have the meanings given for formula (I);

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

A more preferred subgroup of compounds of formula (IIa) may be represented as follows: the following sub-formulae (IIa-A) to (IIa-O) corresponding to formula (IIa), but wherein

For the sub-formula (IIa-A)

X¹Is a group of atoms selected from the group consisting of CH,

R¹is a compound of formula (I) or (II),

R²is a compound of formula (I) or (II),

for the sub-formula (IIa-B)

R¹Is a compound of formula (I) wherein F,

R²is a compound of formula (I) or (II),

for the sub-formula (IIa-C)

X¹、X²Is a group of atoms selected from the group consisting of CH,

for the sub-formula (IIa-D)

X¹Is a group of atoms selected from the group consisting of CH,

R⁵is a compound of formula (I) wherein the compound is H,

for the sub-formula (IIa-E)

R³Is at a value of H, OH which is,

for the sub-formula (IIa-F)

X¹Is a group of atoms selected from the group consisting of CH,

R³is an OH group, and is a hydroxyl group,

for the sub-formula (IIa-G)

X¹Is a group of atoms selected from the group consisting of CH,

y is a radical of the formula CH,

for the sub-formula (IIa-H)

X¹Is a group of atoms selected from the group consisting of CH,

cyc is pyridine, pyrazine or pyridazine, or pyrazolo [1,5-a ] pyrimidinyl or imidazo [1,2-b ] pyridazinyl,

for the sub-formula (IIa-J)

Cyc is pyridine, pyrazine, pyridazine, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-b ]]Pyridazinyl, furo [2,3-c ]]Pyridyl, furo [2,3-d ]]Pyridazinyl, thieno [2,3-d ]]Pyridazinyl, thieno [2,3-d ]]Pyrimidinyl or imidazo [4, 5-c)]Pyridyl, which may each be unsubstituted or may be substituted by methoxy, methyl, oxo, Cl or CHF₂O mono-or double extractionInstead of the first generation,

for the sub-formula (IIa-K)

R¹Is a compound of formula (I) or (II),

R²is a compound of formula (I) or (II),

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

X¹、X²is a group of atoms selected from the group consisting of CH,

for the sub-formula (IIa-L)

R¹Is a compound of formula (I) wherein F,

R²is a compound of formula (I) or (II),

R³is a compound of formula (I) which is H or OH,

R⁵is a compound of formula (I) wherein the compound is H,

for the sub-formula (IIa-M)

R¹Is a compound of formula (I) or (II),

R²is a compound of formula (I) or (II),

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

X¹、X²is a group of atoms selected from the group consisting of CH,

cyc is pyridine, pyrazine or pyridazine, or pyrazolo [1,5-a ] pyrimidinyl or imidazo [1,2-b ] pyridazinyl,

for the sub-formula (IIa-N)

R¹Is a compound of formula (I) wherein F,

R²is a compound of formula (I) or (II),

R³is a compound of formula (I) which is H or OH,

R⁵is a compound of formula (I) wherein the compound is H,

cyc is pyridine, pyrazine, pyridazine, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-b ]]Pyridazinyl, furo [2,3-c ]]Pyridyl radicalFuro [2,3-d ]]Pyridazinyl, thieno [2,3-d ]]Pyridazinyl, thieno [2,3-d ]]Pyrimidinyl or imidazo [4, 5-c)]Pyridyl, which may each be unsubstituted or may be substituted by methoxy, methyl, oxo, Cl or CHF₂O is mono-or doubly substituted,

for the sub-formula (IIa-O)

R¹Is a compound of formula (I) wherein F,

R²is a compound of formula (I) or (II),

R³is a compound of formula (I) which is H or OH,

R⁵is a compound of formula (I) wherein the compound is H,

cyc is 5-methoxy-pyridazin-3-yl, imidazo [1,2-b ] pyridazin-6-yl, 3-chloro-6-methoxy-pyrazin-2-yl, 3-chloro-pyrazin-2-yl, pyridazin-4-yl, 3-methoxy-pyrazin-2-yl, 6-methoxy-pyridazin-3-yl, 3-difluoromethoxy-pyridin-2-yl, 3-methyl-pyrazin-2-yl, thieno [2,3-d ] pyrimidin-4-yl, 1-methyl-1H-pyridin-2-one-6-yl, 1H-pyridazin-6-one-3-yl, furo [2,3-d ] pyridazin-7-yl, thieno [2,3-d ] pyridazin-7-yl, 3, 5-dimethyl-pyrazin-2-yl, furo [2,3-d ] pyrimidin-4-yl, 3-methyl-3H-imidazo [4,5-c ] pyridin-4-yl;

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

A more preferred subgroup of compounds of formula (IIIa) may be represented as follows: the following sub-formulae (IIIa-B) to (IIIa-O) corresponding to formula (IIIa), but wherein

For the sub-formula (IIIa-B)

R¹Is a compound of formula (I) wherein F,

for the sub-formula (IIIa-C)

X¹、X²Is a group of atoms selected from the group consisting of CH,

for the sub-formula (IIIa-D)

X¹Is a group of atoms selected from the group consisting of CH,

R⁵is a compound of formula (I) wherein the compound is H,

for the subformula IIIa- (E)

R³Is at a value of H, OH which is,

for the sub-formula (IIIa-F)

X¹Is a group of atoms selected from the group consisting of CH,

R³is an OH group, and is a hydroxyl group,

for the sub-formula (IIIa-G)

X¹Is a group of atoms selected from the group consisting of CH,

y is a radical of the formula CH,

for the sub-formula (IIIa-H)

X¹Is a group of atoms selected from the group consisting of CH,

cyc is pyridine, pyrazine or pyridazine, or pyrazolo [1,5-a ] pyrimidinyl or imidazo [1,2-b ] pyridazinyl,

for the sub-formula (IIIa-J)

Cyc is pyridine, pyrazine, pyridazine, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-b ]]Pyridazinyl, furo [2,3-c ]]Pyridyl, furo [2,3-d ]]Pyridazinyl, thieno [2,3-d ]]Pyridazinyl, thieno [2,3-d ]]Pyrimidinyl or imidazo [4, 5-c)]Pyridyl, which may each be unsubstituted or may be substituted by methoxy, methyl, oxo, Cl or CHF₂O is mono-or doubly substituted,

for the sub-formula (IIIa-K)

R¹Is a compound of formula (I) or (II),

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

X¹、X²is a group of atoms selected from the group consisting of CH,

for the sub-formula (IIIa-L)

R¹Is a compound of formula (I) wherein F,

R³is a compound of formula (I) which is H or OH,

R⁵is a compound of formula (I) wherein the compound is H,

for the sub-formula (IIIa-M)

R¹Is a compound of formula (I) or (II),

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

X¹、X²is a group of atoms selected from the group consisting of CH,

cyc is pyridine, pyrazine or pyridazine, or pyrazolo [1,5-a ] pyrimidinyl or imidazo [1,2-b ] pyridazinyl,

for the sub-formula (IIIa-N)

R¹Is a compound of formula (I) wherein F,

R³is a compound of formula (I) which is H or OH,

R⁵is a compound of formula (I) wherein the compound is H,

cyc is pyridine, pyrazine, pyridazine, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-b ]]Pyridazinyl, furo [2,3-c ]]Pyridyl, furo [2,3-d ]]Pyridazinyl, thieno [2,3-d ]]Pyridazinyl, thieno [2,3-d ]]Pyrimidinyl or imidazo [4, 5-c)]Pyridyl, which may each be unsubstituted or may be substituted by methoxy, methyl, oxo, Cl or CHF₂O is mono-or doubly substituted,

for the sub-formula (IIIa-O)

R¹Is a compound of formula (I) wherein F,

R³is a compound of formula (I) which is H or OH,

R⁵is a compound of formula (I) wherein the compound is H,

cyc is 5-methoxy-pyridazin-3-yl, imidazo [1,2-b ] pyridazin-6-yl, 3-chloro-6-methoxy-pyrazin-2-yl, 3-chloro-pyrazin-2-yl, pyridazin-4-yl, 3-methoxy-pyrazin-2-yl, 6-methoxy-pyridazin-3-yl, 3-difluoromethoxy-pyridin-2-yl, 3-methyl-pyrazin-2-yl, thieno [2,3-d ] pyrimidin-4-yl, 1-methyl-1H-pyridin-2-one-6-yl, 1H-pyridazin-6-one-3-yl, furo [2,3-d ] pyridazin-7-yl, thieno [2,3-d ] pyridazin-7-yl, 3, 5-dimethyl-pyrazin-2-yl, furo [2,3-d ] pyrimidin-4-yl, 3-methyl-3H-imidazo [4,5-c ] pyridin-4-yl;

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

A more preferred subgroup of compounds of formula (IIb) may be represented as follows: the following sub-formulae (IIb-Q) to (IIb-U) corresponding to the formula (IIb), but wherein

For the sub-formula (IIb-Q)

R¹Is a compound of formula (I) or (II),

R²is a compound of formula (I) or (II),

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

y is a radical of the formula CH,

for the sub-formula (IIb-R)

R¹Is a compound of formula (I) wherein F,

R²is a compound of formula (I) or (II),

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

y is a radical of the formula CH,

for the sub-formula (IIb-S)

Cyc is pyridine, pyrazine or pyridazine,

for the sub-formula (IIb-T)

R¹Is a compound of formula (I) or (II),

R²is a compound of formula (I) or (II),

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

cyc is pyridine, pyrazine or pyridazine,

for sub-formula (IIb-U)

R¹Is a compound of formula (I) wherein F,

R²is a compound of formula (I) or (II),

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

cyc is pyridine, pyrazine, pyridazine or 3-methyl-pyrazin-2-yl;

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

A more preferred subgroup of compounds of formula (IIIb) can be represented as follows: the following sub-formulae (IIIb-Q) to (IIIb-U) corresponding to formula (IIIb), but wherein

For the sub-formula (IIIb-Q)

R¹Is a compound of formula (I) or (II),

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

y is a radical of the formula CH,

for the sub-formula (IIIb-R)

R¹Is a compound of formula (I) wherein F,

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

y is a radical of the formula CH,

for the sub-formula (IIIb-S)

Cyc is pyridine, pyrazine or pyridazine,

for the sub-formula (IIIb-T)

R¹Is a compound of formula (I) or (II),

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

cyc is pyridine, pyrazine or pyridazine,

for the sub-formula (IIIb-U)

R¹Is a compound of formula (I) wherein F,

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

cyc is pyridine, pyrazine, pyridazine or 3-methyl-pyrazin-2-yl;

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

Very particular preference is given to those compounds of the formula (I) and its subformulae, and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios, which are summarized in tables 1 to 8.

The compounds of the formula (I) and the starting materials for their preparation are prepared by methods known per se and under reaction conditions known and suitable for this reaction, which are described, for example, in the literature (for example in standard works, such as Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart) and/or are known to the person skilled in the art. Variants known per se, which are not mentioned here in more detail, can also be used here.

Depending on the conditions used, the reaction time is from a few minutes to 14 days and the reaction temperature is from-70 ℃ to 150 ℃, usually from-50 ℃ to 100 ℃ and particularly preferably from-10 ℃ to 70 ℃.

The reaction is carried out in an inert solvent and is generally carried out in the presence of an acid-binding agent, preferably in the presence of an organic base, such as DIPEA, triethylamine, dimethylaniline, pyridine, quinoline, piperidine or diethanolamine. It may also be advantageous to add a hydroxide, carbonate or bicarbonate of an alkali or alkaline earth metal or another salt of a weak acid of these alkali or alkaline earth metals, preferably potassium, sodium, calcium or cesium. Suitable bases are metal oxides such as alumina, alkali metal hydroxides (including potassium hydroxide, sodium hydroxide and lithium hydroxide), alkaline earth metal hydroxides (such as barium hydroxide and calcium hydroxide) and alkali metal alkoxides (such as potassium ethoxide and sodium propoxide).

Suitable inert solvents are, in particular, hydrocarbons, such as cyclohexane, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, Tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl ether or monoethyl ether (methyl glycol or ethyl glycol), 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. Particular preference is given to DMF, methanol, dichloromethane, THF, acetic acid and acetonitrile.

The process and the subsequent work-up of the reaction mixture can be carried out essentially as a batch reaction or in a continuous reaction. Continuous reaction means include, for example, reactions in continuous stirred tank reactors, stirred tank cascades, loop or cross-flow reactors, flow tubes or in microreactors. The reaction mixture is optionally worked up as required by: by filtration of the solid phase, chromatography, separation between immiscible phases (e.g. extraction), adsorption on a solid support, removal of the solvent and/or azeotropic mixture by distillation, selective distillation, sublimation, crystallization, co-crystallization or by nanofiltration on a membrane.

The compounds of formula (I) can preferably be obtained by reacting compounds of formulae (V) and (VI). The present invention therefore also relates to a process for preparing compounds of the formula (I) and its subformulae and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios, having the following steps:

(a) reacting a compound of formula (V) with a compound of formula (IV) to obtain a compound of formula (I),

where LG is a common leaving group, such as Hal,

wherein A is a boronic acid or a boronic ester,

and optionally

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

The starting compounds are generally known. If they are novel, they can be prepared by methods known per se. The compounds of the formulae (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV) and (V) can be prepared by known methods. If desired, the starting materials may be formed in situ so that they are not isolated from the reaction mixture but immediately converted further to the compounds of the invention. The reaction can likewise be carried out stepwise.

The compounds of the invention 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 their pharmaceutically acceptable salts, which salts can be derived from various organic and inorganic acids and bases by procedures known in the art. The pharmaceutically acceptable salt forms of the compounds of formula (I) and subformulae thereof are prepared in large part by conventional methods. If these compounds contain a carboxyl group, one of its suitable salts can be obtained by reacting the compound with a suitable base to form the corresponding base-addition salt. Such bases are, for example, alkali metal hydroxides (e.g., potassium hydroxide, sodium hydroxide and lithium hydroxide), alkaline earth metal hydroxides (e.g., barium hydroxide and calcium hydroxide), alkali metal alkoxides (e.g., potassium ethoxide and sodium propoxide) and various organic bases, such as piperidine, diethanolamine and N-methylglutamide. The bases of formula (I) and subformulae thereof may be converted to the associated acid-addition salts using an acid, for example by reacting equal amounts of the base and acid in an inert solvent (e.g. ethanol) and subsequent evaporation. Contemplated acids for use in this reaction are particularly those that provide physiologically acceptable salts, such as hydrogen halides (e.g., hydrogen chloride, hydrogen bromide, or hydrogen iodide), other inorganic acids and their corresponding salts (e.g., sulfates, nitrates, or phosphates, etc.), alkyl-and monoaryl sulfonates (e.g., ethanesulfonate, toluenesulfonate, and benzenesulfonate salts), and other organic acids and their corresponding salts (e.g., acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate, etc.).

With regard to the above statements, it can be seen that in the context of the present invention, the active substance comprising a compound of formula (I) in the form of one of its salts is indicated by the expression "pharmaceutically acceptable salt", in particular when this salt form confers on the active substance improved pharmacokinetic properties compared to the active substance in free form. The pharmaceutically acceptable salt form of the active substance may provide the active substance with the desired pharmacokinetic properties and may even have a positive effect on the pharmacodynamics of the active substance in its in vivo therapeutic efficacy.

Due to their molecular structure, the compounds of the invention may be chiral and may therefore occur in various enantiomeric forms. They may thus be in racemic or optically active form. Since the pharmaceutical potency of the racemates or stereoisomers of the compounds of formula (I) may vary, it may be desirable to use enantiomers. In these cases, the final product or even the intermediate products can be separated into the enantiomeric compounds by chemical or physical means known to the person skilled in the art or already employed as such in the synthesis.

It is generally known that atomsMay have an atomic mass or mass number that may be different from the atomic mass or mass number usually found in nature. Examples of commercially available isotopes which can be incorporated by known methods into the compounds of the invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. Heavier isotopes, e.g. deuterium (²H) The following therapeutic advantages may be achieved by incorporation of the compounds of the invention: this contributes to a higher metabolic stability of the isotopically labeled compound. Higher metabolic stability directly leads to increased in vivo half-life, allowing lower doses.

Thus, the definition of atom H, C, N, etc., as used in the compounds of the present invention also relates to the heavier isotopes of these atoms. It is particularly preferred according to the invention to use D (deuterium,²H) in place of hydrogen (¹H）。

It has been found that the compounds of the invention cause specific inhibition of serine/threonine protein kinases. The invention therefore furthermore relates to the use of compounds of the formula (I) or a subformula thereof and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios, for inhibiting serine/threonine protein kinases, preferably PIKK, particularly preferably DNA-PK. It is particularly preferred to inhibit the serine/threonine protein kinases mentioned above ex vivo or in vitro. The term "inhibition" relates to any reduction in activity based on the action of a specific compound of the invention, which is capable of interacting with a target molecule to make recognition, binding and blocking possible. The compounds are characterized by a high affinity for at least one of the serine/threonine protein kinases, thus ensuring reliable binding and preferably completely blocking kinase activity. The compounds are particularly preferably monospecific to ensure exclusive and direct recognition of the selected kinase. The term "recognition" as used herein relates to any type of interaction between a compound and the target molecule, in particular covalent or non-covalent bonds, such as covalent bonds, hydrophobic/hydrophilic interactions, van der waals forces, ionic attractions, hydrogen bonds, ligand/receptor interactions, base pairing of nucleotides or interactions between an epitope and an antibody binding site.

The compounds of the invention exhibit advantageous biological activity, which can be demonstrated in the assays described herein, e.g., enzyme-based assays. Measurement 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 histone (Alessi et al (1996) FEBS Lett. 399 (3): 333) or basic myelin proteins are described in the literature (Campos-Gonz a lez & Glenney (1992) JBC 267: 14535). Various detection systems are available for identifying kinase inhibitors. In scintillation proximity assays (Sorg et al (2002) J Biomolecular Screening 7: 11) and FlashPlate assays, ATP is used to measure the radioactive phosphorylation of proteins or peptides as substrates. In the presence of the inhibitory compound, a reduced radioactive signal or no signal at all can be measured. In addition, homogeneous time-resolved fluorescence resonance energy transfer (HTR-FRET) and Fluorescence Polarization (FP) techniques can be used as detection methods (Sills et al (2002) J biomolecular screening 191). Other nonradioactive ELISA methods use specific phospho-antibodies (phospho-AK). phosphorylated-AK binds only to phosphorylated substrates. By using a second peroxidase-conjugated anti-sheep antibody, this binding can be detected by chemiluminescence.

The use of the above mentioned compounds can take place in vitro or in vivo models. The sensitivity of a particular cell to treatment with a compound of the invention can be determined by in vitro testing. Typically, a culture of cells is incubated with a compound of the invention at various concentrations for a period of time sufficient for the active agent to be able to induce cell death or inhibit cell proliferation, cell viability or migration, which is typically about 1 hour to 1 week. For in vitro testing, cultured cells from a biopsy sample may be used. The amount of cells remaining after treatment was then determined. In vitro applications occur particularly on samples of mammalian species suffering from cancer, tumors or metastases. The host or patient may belong to any mammalian species, for example primate species, particularly humans, but also rodents (including mice, rats and hamsters), rabbits, horses, cows, dogs, cats and the like. Animal models are of interest for experimental studies, and they provide a model for the treatment of human diseases.

Testing of a number of specific compounds enables the selection of the active substance that appears to be most suitable for treatment of the patient. Considering the in vitro data, the in vivo dose of the selected compound is advantageously matched to the susceptibility of the kinase and/or the severity of the patient's disease, with the result that the efficacy of the treatment is significantly improved. The dosage will vary depending upon the particular compound employed, the particular disease, the condition of the patient, and the like. The therapeutic dose is generally sufficient to significantly reduce the undesirable cell population in the target tissue while maintaining the viability of the patient. The following teachings of the present invention and embodiments thereof relating to the use of a compound of formula (I) for the preparation of a medicament for the prevention, treatment and/or process control are general and can be used without being limited to the use of the compound for inhibiting kinase activity, as long as this appears to be appropriate.

Treatment is generally continued until a significant reduction occurs, e.g., a reduction in cell load of at least about 50%, and may continue until substantially no more undesired cells are detected in vivo. In this type of test, the compounds of the invention exhibit and elicit an inhibitory effect, which is generally determined by an IC in the appropriate range₅₀Values prove to be preferably in the micromolar range, more preferably in the nanomolar to picomolar range. If the concentration of the compound is less than 1 μ M, preferably equal to or less than 0.5 μ M, particularly preferably less than 0.1 μ M, in particular 50% of the kinase is inhibited. This concentration is called IC₅₀The value is obtained.

The invention also relates to medicaments comprising at least one compound of the formula (I) or a subformula thereof and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios. The invention also relates to pharmaceutical compositions comprising an effective amount of at least one compound of formula (I) or a subformula thereof and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios, as active substance and pharmaceutically compatible auxiliaries.

"agent", "drug" and "pharmaceutical composition" or "pharmaceutical preparation" herein are any composition useful for prophylaxis, therapy, process control or post-disease treatment of a patient presenting, at least temporarily, a pathogenic alteration of the general condition of the patient's organism or of the condition of individual sites, preferably as a result of cancer, tumor or metastasis.

To enhance the protective or therapeutic effect of the compounds of the present invention, pharmaceutically compatible adjuvants may be added. In the sense of the present invention, any substance that achieves, enhances or modifies the effect of a compound of the invention is an "adjuvant". Known adjuvants are, for example, aluminium compounds such as aluminium hydroxide or aluminium phosphate, saponins such as QS 21, muramyl dipeptides or muramyl tripeptides, proteins such as gamma interferon or TNF, MF 59, phosphatidylcholine, squalene or polyols. Co-administration of ovalbumin in freund's complete adjuvant may likewise result in improved cell-mediated immunity and thus aid in the action of the formed neutralizing antibodies. Furthermore, the DNA, which has immunostimulatory properties or encodes a protein with adjuvant effect, such as a cytokine, may be administered simultaneously or in a construct (Konstrukt).

Introduction of a pharmaceutical agent into a cell or organism can be carried out according to the invention in any manner that enables the kinase to contact the compound contained in the composition, thus inducing a response. The pharmaceutical compositions of the present invention may be administered orally, transdermally, transmucosally, transurethrally, vaginally, rectally, pulmonarily, enterally and/or parenterally. The type of administration selected will depend on the indication, the dosage administered, individual-specific parameters, and the like. In particular, various types of administration enable site-specific therapy, which minimizes side effects and reduces the active substance dose. Very particularly preferred injections are intradermal, subcutaneous, intramuscular or intravenous injections. Administration can be carried out, for example, by means of a so-called inoculation gun or by means of a syringe. The substance may also be provided as an aerosol, which is inhaled by an organism, preferably a human patient.

The administration forms of the pharmaceutical agents are prepared in accordance with the desired type of administration, using customary solid or liquid vehicles and/or diluents and the auxiliaries usually employed, in a suitable dosage and in a manner known per se. Thus, pharmaceutically acceptable excipients known to those skilled in the art may in principle form part of the pharmaceutical agents of the invention, wherein the amount of excipient material combined with the active substance to prepare a single dose varies depending on the individual to be treated and the type of administration. Such pharmaceutically compatible additives include salts, buffers, fillers, stabilizers, complexing agents, antioxidants, solvents, binders, lubricants, tablet coatings, flavors, dyes, preservatives, conditioners, and the like. Examples of such excipients are water, vegetable oils, benzyl alcohol, alkylene glycols, polyethylene glycols, Kolliphor, triacetin, gelatin, Hydroxypropylmethylcellulose (HPMC), carbohydrates such as lactose or starch, magnesium stearate, talc and petrolatum.

The pharmaceutical formulation may be in the form of: tablets, film tablets, dragees, troches, capsules, pills, powders, granules, syrups, juices, drops, solutions, dispersions, suspensions, suppositories, emulsions, extrusions (Extrudat), implants, creams, gels, ointments, pastes, lotions, sera, oils, sprays, aerosols, adhesives, plasters or bandages. The oral administration forms prepared are preferably tablets, film tablets, dragees, troches, capsules, pills, powders, granules, syrups, juices, drops, solutions, dispersions or suspensions, also as depot forms. Furthermore, parenteral pharmaceutical forms are to be considered, such as suppositories, suspensions, emulsions, implants or solutions, preferably oily or aqueous solutions. For topical application, the medicament active substance is formulated in a conventional manner using at least one pharmaceutically acceptable vehicle, for example microcrystalline cellulose, and optionally further auxiliaries, for example humectants, to give solid preparations which can be applied to the skin, for example creams, gels, ointments, pastes, powders or emulsions, or to give liquid preparations which can be applied to the skin, for example solutions, suspensions, lotions, sera, oils, sprays or aerosols. The pharmaceutical agent is preferably in the form of an injectable solution. For the preparation of injectable solutions, aqueous media can be used, for example distilled (eingeengt) water or physiological salt solutions, the latter of which include acid and base addition salts. The pharmaceutical agent may also be in the form of a solid composition, for example in lyophilized state, and may subsequently be prepared prior to use by the addition of a dissolution agent, for example distilled water. The person skilled in the art is familiar with the basic principles for the preparation of lyophilisates.

The concentration of the active substance in the formulation may be from 0.1 to 100% by weight. It is critical that the pharmaceutical composition comprises an effective amount of the compound as an active substance and a pharmaceutically compatible adjuvant. The terms "effective amount" or "effective dose" are used interchangeably herein and refer to an amount of a pharmaceutically active substance that has a prophylactic or therapeutic related effect on a disease or pathological change in a cell, tissue, organ or mammal. After entering the individual representative, the "prophylactic effect" prevents an outbreak of disease or even an infection by a pathogen, so that its subsequent expansion is greatly reduced or even completely inactivated. "prophylactic effects" also include enhancement of normal physiological functions. In particular, if an individual has a predisposition to the onset of the above-mentioned disease (e.g., family history, genetic defect, or recent residual disease), prevention is advisable. "treatment-related effects" partially or completely relieve one, more or all of the symptoms of a disease or cause a partial or complete reversal of one, more or all of the physiological or biochemical parameters associated or causative of a disease or pathological change to a normal state. Process control is also considered a type of therapeutic treatment as long as the compound is administered at specific time intervals, e.g. to completely eliminate the symptoms of the disease. Each dose or range of doses for administering a compound of the invention is sufficiently large to achieve the desired prophylactic or therapeutic effect of induction of a biological or medical response. In general, the dosage varies with the age, physical constitution and sex of the patient, and the severity of the disease should be considered. It will be understood that the specific dose, frequency and duration of administration will additionally depend on a variety of factors, such as the targeting and binding capacity of the compound, the eating habits of the individual to be treated, the type of administration, the rate of secretion and the combination with other drugs. Individual doses may be adjusted for the major disease as well as for the occurrence of any complications. Precise dosages can be established by those skilled in the art using known means and methods. This teaching of the present invention is general and can be applied without limitation to pharmaceutical compositions comprising compounds of formula (I) as long as it appears appropriate.

In one embodiment of the invention, these compounds are administered in a dose of 0.01 mg to 1 g per dosage unit, preferably 1 to 700 mg, particularly preferably 5 to 200 mg. The daily dose is especially 0.02-100 mg/kg body weight.

In order to assist the medical effect, in one embodiment of the invention, the pharmaceutical composition may further comprise one or more other active substances, wherein simultaneous or sequential administration is contemplated. The therapeutic effect of the pharmaceutical composition of the present invention may consist, for example, in making a particular anticancer agent have a better effect through DNA-PK inhibition as a desired side effect, or in reducing the number of side effects of these drugs through dose reduction.

In a preferred embodiment of the invention, the pharmaceutical composition of the invention is used in combination with an anti-cancer agent. The term "anti-cancer agent" as used herein relates to any agent that is administered to a patient suffering from cancer, a tumor or a metastasis for the purpose of treating cancer. Preferred anti-cancer agents according to the invention are those which damage the DNA of the tumor cells and thus intervene in DNA replication, DNA transcription or gene expression. For this purpose, in particular:

-alkylating agents, such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, enzyne, cyclophosphamide, dacarbazine, ifosfamide, dipropionamidosulfonate, lomustine, melphalan, dibromomannitol, dibromodulcitol, nimustine, ramustine, temozolomide, thiotepa, busulfan, mechlorethamine, carboquone, apaziquone (Apaziquon), fotemustine, glufosfamide, palimide, palivamide, pipobroman, chloroacetohydroxamide, uramustine;

-platinum compounds such as carboplatin, cisplatin, eptaplatin, miriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin;

topoisomerase inhibitors, such as etoposide, irinotecan, razoxane, sobuzoxane;

DNA altering agents such as amrubicin, bison, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine, amsacrine, blossoclin (Brostallicin), Pickerosetron, Rayleigh such as Mostine (Laromimustine);

-anticancer antibiotics, such as bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozotocin, valrubicin, setastatin, zorubicin, daunomycin, plicamycin, doxorubicin, pelomycin, pirarubicin;

α -emitters, such as Alpharadin (radium dichloride-223, Xofgio),²¹¹At、²¹³Bi、²²⁵Ac、²²⁷Th；

Particularly preferred are bleomycin and Alpharadin.

The invention may also be practiced as a kit comprising a compound of the invention. The kit is composed of the following packages which are separated: (a) an effective amount of a compound of formula (I) and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios, and (b) an effective amount of an anti-cancer agent. The kit comprises suitable containers, such as a box or carton, individual bottles, bags or ampoules. The kit may for example comprise separate ampoules containing an effective amount of a compound of formula (I) and/or a pharmaceutically acceptable salt, tautomer and/or stereoisomer thereof, including mixtures thereof in all ratios, and an effective amount of the anti-cancer agent in dissolved or lyophilized form, respectively. The kits of the invention may also contain articles containing written instructions or directing the user to explain the use of the compounds of the invention.

According to the invention, the compounds of the formula (I) or a subformula thereof and/or their physiologically acceptable salts, tautomers and/or stereoisomers (including mixtures thereof in all ratios) are used for the prophylaxis, treatment and/or process control of diseases which are caused, mediated and/or propagated by the activity of serine/threonine protein kinases. The invention therefore also relates to the use of compounds of the formula (I) or a subformula thereof and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the prophylaxis, treatment and/or process control of diseases which are caused, mediated and/or propagated by the activity of serine/threonine protein kinases. According to the invention, the compounds of the formula (I) or a subformula thereof and/or their physiologically acceptable salts, tautomers and/or stereoisomers (including mixtures thereof in all ratios) are suitable for the prophylaxis, treatment and/or process control of diseases which are caused, mediated and/or propagated by the activity of serine/threonine protein kinases. In order to identify the corresponding signal pathways and to detect interactions between the various signal pathways, suitable models or model systems have been developed, such as cell culture models (Khwaja et al (1997) EMBO 16: 2783) and transgenic animal models (White et al (2001) Oncogene 20: 7064). To determine specific stages in the signaling cascade, interacting compounds may be used to modulate the signal (Stephens et al (2000) Biochemical J351: 95). Furthermore, the compounds of the invention may also be used as reagents for testing kinase-dependent signaling pathways in animals and/or cell culture models or in clinical diseases mentioned in the present application. As discussed herein, these signal pathways are associated with various diseases. Thus, the compounds of the invention are useful in the prevention, treatment and/or process control of diseases which depend on the signal pathway in which serine/threonine protein kinases are involved.

According to the invention, the compounds of the formula (I) or a subformula thereof and/or their physiologically acceptable salts, tautomers and/or stereoisomers, including mixtures thereof in all ratios, are suitable for the prophylaxis, treatment and/or process control of cancers, tumors or metastases.

The tumor is in particular selected from the group consisting of malignant diseases of the bladder, stomach, kidney, head, neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate, genitourinary tract, lymphatic system, larynx, lung, skin, blood, bone and immune system, and/or the cancer is selected from the group consisting of monocytic leukemia, non-small cell lung cancer, pancreatic cancer, glioblastoma, colon cancer, breast cancer, acute myeloleukemia, chronic myeloleukemia, acute lympholeukemia, chronic lympholeukemia, hodgkin lymphoma and non-hodgkin lymphoma.

another embodiment of the invention relates to the use of the compounds of the invention in combination with radiotherapy and/or with at least one other active substance, preferably with radiotherapy and/or an anticancer agent, the industrial irradiation methods used clinically preferably include, but are not limited to, photon irradiation (classical electromagnetic X-ray/gamma radiation), proton irradiation, heavy ion irradiation (ionized carbon) and neutron irradiation, and in addition brachytherapy is used clinically in the form of surface administration and intra-and interstitial application with the aid of suitable radiation sources (e.g. α -emitters), these and other suitable irradiation treatments in the sense of the invention are known to the person skilled in the art, for example from Herrmann et al (2006) klinsche strahlenbiei, Elsevier murchen, 4 th edition, 67-68; Bhide and huting (2010) Medicine 8: 25; Choi and Hung (2010) urology 11 (3): 172, as the most frequent application, the treatment of radiation has been achieved by the following irradiation means (i) of adjusting the intensity of the radiation and the radiation in the best possible synergy of the radiation in the radiation therapy and the radiation therapy by the present radiation method of radiation and the radiation in the three-dimensional radiotherapy.

A further embodiment of the present invention relates to the use of at least one compound of formula (I) and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios, for sensitizing cancer cells to an anticancer agent and/or ionizing radiation, with the proviso that said sensitizing does not occur in vivo to the human or animal body. The sensitization preferably occurs ex vivo or in vitro by administering the compound to a cell, cell culture, tissue or organ comprising a serine/threonine protein kinase. In particular, in the case of animal cells originating from animal organisms affected by a disease selected from the group consisting of cancer, tumor or metastasis, in vitro applications are used. The ex vivo treated cells may be maintained in culture or transferred to an animal for subsequent study, where the animal may be the host animal or another animal. The ex vivo sensitivity of the present invention is particularly advantageous for testing specific effects of compounds, so that the in vivo dose can be pre-adjusted accordingly as these ex vivo data are evaluated. As a result, the therapeutic effect is remarkably improved. Alternatively, the present invention is also designed for in vivo use, and at least one relates to a compound of formula (I) and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof (including mixtures thereof in all ratios) for use in sensitizing cancer cells to an anti-cancer agent and/or ionizing radiation.

The present invention furthermore teaches a method for the prophylaxis, treatment and/or process control of cancer, tumors or metastases, wherein an effective amount of at least one compound of the invention and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios, is administered to a subject to be treated. Preferred subjects in the sense of the present invention are human or animals, particularly preferably humans. It is known to the person skilled in the art to administer the compounds of the invention to organisms, in particular human patients, in various doses, which of course can also be used as pharmaceutical agents according to the invention. Effective amounts and types of administration can be determined by one skilled in the art by routine experimentation. The previous teachings of the present invention and embodiments thereof are general and can be applied to this method of treatment without limitation, as long as it appears appropriate.

All such and other ingredients or components are familiar to those skilled in the art and may be subjected to routine experimentation in light of the teachings of this invention. All documents cited in the specification are intended to be incorporated herein by reference in their entirety into the disclosure of the present invention.

Within the scope of the invention as set forth herein, there is provided for the first time novel arylquinazoline compounds of the formula (I). The compounds of the invention control serine/threonine protein kinases, in particular DNA-PK, with affinity and/or selectivity. The compounds derived from formula (I) and their derivatives are characterized by high specificity and stability, low preparation cost and easy handling. Based on these properties, reproducible modes of action and reliable and safe interaction with the corresponding target structure are formed. The invention also encompasses the use of the arylquinazoline derivatives of the present invention for inhibiting, modulating and/or regulating the signalling cascade of serine/threonine protein kinases, particularly DNA-PK, thus providing novel tools for research and/or diagnosis.

Furthermore, medicaments and pharmaceutical compositions comprising said compounds and the use of these compounds for the treatment of kinase-mediated disorders are highly promising approaches for broad-spectrum therapy, thereby enabling immediate and immediate relief of symptoms in humans and animals. This is particularly advantageous for effective combating of severe diseases (e.g. cancer) as a monotherapy or in combination with other anti-tumour therapies. The critical involvement of DNA-PK during DNA repair and the evidence that DNA-PK inhibitors render mammalian cells more sensitive to radiation allow therapeutic use of DNA-PK specific inhibitors in, for example, solid cancer tumor treatment (by radiation therapy and/or chemotherapy directed to DNA-DSB).

The compounds of formula (I), their salts, isomers, tautomers, enantiomers, diastereomers, racemates, derivatives, prodrugs and/or metabolites are not only effective in the context of the clinical conditions in question, but also in combination with the DNA-PK signalling cascade, and are equally effective in the diagnosis and treatment of all diseases, in particular in the inhibition of cell proliferation and migration. Furthermore, by inhibiting retroviral integration, the inhibitors of the invention are useful in the treatment of retroviral diseases (R. Daniel (1999) Science 284: 644). Finally, the inhibitors of the invention are useful as immunomodulators and modulators of telomere maintenance. The low molecular weight inhibitors are used alone and/or in combination with other therapeutic means, such as surgical intervention, immunotherapy, radiation therapy and/or chemotherapy. The latter relates to targeted therapy with any desired NME (i.e., NCE and/or NBE) as monotherapy and/or mid-target/off-target combination therapy.

Due to their unexpectedly strong and/or selective inhibition of enzymes that modulate cellular processes by dsDNA repair, the compounds of the present invention can advantageously be administered at low doses while they achieve similar or even superior biological efficacy compared to less potent or less selective inhibitors of the prior art. Reduced doses are also associated with reduced or no medical side effects. Furthermore, highly selective inhibition by the compounds of the invention is also accompanied by undesirable side effects independent of the reduction in dosage.

In particular, the compounds of the invention do not have physiologically relevant inhibition or blockade of Kv11.1 hERG potassium channel.

It is understood that the present invention is not limited to the particular compounds, pharmaceutical compositions, uses, and methods described herein, as such may vary. Furthermore, it is to be understood that the terminology used herein is used exclusively for the purpose of describing particular embodiments, and is not intended to limit the scope of the present invention. As used in the specification (including the appended claims), the singular forms "a," "an," or "the" include plural equivalents as long as the context is not specifically stated otherwise. For example, reference to "a compound" includes a single compound or a plurality of compounds, which in turn may be the same or different, or reference to "a method" includes equivalent steps and methods known to those skilled in the art.

The invention is explained in more detail below with reference to non-limiting examples of specific embodiments. In particular, the embodiments should be construed as not being limited to the specifically described combinations of features, but the exemplary features may be freely combined as long as the object of the present invention is achieved.

Examples

An overview of the examples is provided in tables 1-7. The biological data given therein apply to the following ranges:

DNA-PK (enzyme):

A: IC₅₀<3 nM

B: 3 nM ≤ IC₅₀<7 nM

C: 7 nM ≤ IC₅₀<30 nM

D: 30 nM ≤ IC₅₀

pDNA-PK (cell):

A: IC₅₀<0.5 µM

B: 0.5 µM ≤ IC₅₀<5 µM

C: 5 µM ≤ IC₅₀<10 µM

D: 10 µM ≤ IC₅₀<30 µM

Kv11.1 hERG:

A: K_i>25 µM

B: 25 µM ≥ K_i>15 µM

C: 15 µM ≥ K_i>10 µM

D: 10 µM ≥ K_i。

analysis of

NMR (1H) was performed using the following parameters

The instrument comprises the following steps: bruker Avance DRX 500, Bruker Avance 400, Bruker DPX 300

Reference: TMS

TD (time domain = number of data points or digital resolution): 65536

Solvent: DMSO d6

NS (number of scans = scan frequency): 32

SF (spectrometer frequency = transmission frequency): 400 or 500 MHz

TE (temperature): 303K, 363K or 393K

Coupling constant (J) in Hertz (Hz)

HPLC: high performance chromatography with UV detector

LC-MS: high performance chromatography with UV-and MS detectors

SFC: supercritical fluid chromatography with UV detector.

Identification of synthetic intermediates and synthetic products by means of LC-MS:

LC-MS method A:

column: chromolith speedROD RP-18e 50-4.6 mm, flow rate: 2.4 ml/min, wavelength: 220nm, eluent A: water +0.05 vol% formic acid, eluent B: acetonitrile + 0.4 vol% formic acid, gradient: 4 vol% to 100 vol% eluent B2.8 min, then 100% eluent B0.5 min.

LC-MS method B:

column: chromolith speedROD RP-18e 50-4.6 mm, flow rate: 2.4 ml/min, wavelength: 220nm, eluent A: water +0.1 vol% trifluoroacetic acid, eluent B: acetonitrile +0.1 vol% trifluoroacetic acid, gradient: 4 vol% to 100 vol% eluent B2.8 min, then 100 vol% eluent B0.5 min.

Separation of the mixture of stereoisomers by means of HPLC and SFC:

HPLC: column screening was first performed for each stereoisomer mixture using the following columns: chiralpak AD-H, Chiralpak AS-H, Chiralpak IA, Chiralpak IB, Chiralpak IC, Chiralcel OD-H, Chiralcel OJ-H, Lux Cellulose-2, Lux-Amylose-2, for all columns: 250-4.6 mm. The most suitable column is used for the following measurements (e.g. determination of the enantiomeric ratio). Flow rate: 0.8 ml/min, wavelength: variable, which is adjusted in correspondence with the absorbance maximum and the eluent used. Eluent: the following solvents or solvent mixtures were used as eluents: n-heptane, n-hexane, ethanol, methanol, 2-propanol, acetonitrile, ethyl acetate, dichloromethane; as eluent additives there may be used: 0.01-0.5 vol% formic acid, 0.01-0.5 vol% diethylamine; gradient or isocratic measurement conditions are used as required.

SFC: column screening was first performed for each stereoisomer mixture using the following columns: chiralpak AD-H, Chiralpak AS-H, Chiralpak IA, Chiralpak IB, Chiralpak IC, Chiralcel OD-H, Chiralcel OJ-H, Lux Cellulose-2, Lux-Amylose-2, for all columns: 250-4.6 mm. The most suitable column is used for the following measurements (e.g. determination of the enantiomeric ratio). Flow rate: 5 ml/min, variable wavelength, which is adjusted to the absorption maximum and the eluent used. Eluent: liquid carbon dioxide (>70 bar), co-eluent: the following solvents or solvent mixtures were used as co-eluents: ethanol, methanol, isopropanol, acetonitrile, ethyl acetate, dichloromethane. As eluent additives there may be used: 0.01-0.5% by volume of formic acid, 0.01-0.5% by volume of diethylamine. Gradient or isocratic measurement conditions are used as required.

Biological assay

A) DNA-PK detection (biochemistry)

Kinase detection was performed in streptavidin-coated 348-well microtiter FlashPlates. For this purpose, 1.5 μ g DNA-PK/protein complex and 100 ng biotinylated substrate (e.g., PESQEAFADLWKK-biotin-NH 2 ("biotin-DNA-PK-peptide")) were combined in a total volume of 36.5 μ l (34.25 mM HEPES/KOH, 7.85 mM Tris-HCl, 68.5 mM KCl, 5 μ M ATP, 6.85 mM MgCl₂0.5 mM EDTA, 0.14 mM EGTA, 0.69 mM DTT, pH7.4) at room temperature for 90 minutes, with 500 ng DNA from calf thymus, 0.1 μ Ci of 33P-ATP and 1.8% DMSO per well, with or without the test compound. The reaction was stopped using 50 μ l/well of 200 mM EDTA. After an additional 30 minutes of incubation at room temperature, the liquid was removed. Each well was washed three times with 100 μ l of 0.9% sodium chloride solution. Special kinase inhibition using 10 μ MThe preparation was assayed for non-specific reactions (blank values). Radioactivity measurements were performed with the aid of TopCount. IC is calculated in RS1₅₀The value is obtained.

The literature: kashishian et al (2003) Molecular Cancer Therapeutics 1257.

B) DNA-PK phosphorylation at serine 2056 (cells)

At 37 ℃ and 10% CO₂Next, HCT116 cells were cultured in MEM α medium with 10% fetal bovine serum and 2mM glutamine, the cells were detached from the base of the culture vessel by means of trypsin/EDTA, centrifuged in a centrifuge tube, taken up in fresh medium and the cell density was determined.in 1 ml medium, 100000 cells were seeded per well of a 24-well cell culture plate and cultured overnight.the next day, 10. mu.M bleomycin (DNA intercalator and inducer of DNA double strand breaks) and a test substance in fresh medium were added to the cells, these cultures were cultured for an additional 6 hours, then cell lysis was performed and the cell lysate was added to a 96-well ELISA plate coated with a block of DNA-PK specific antibody (Sigma-AldWH 0005591M 2: total DNA-PK; Abcam ab18192 or Epitomics EM 09912: phosphorylating-serine-PK; phosphorylation-PK; Abcamab 18192 or Ab-phosphorylation-serine-PK) and cultured at 4 ℃ with a detection antibody (Abcam-100. the phosphorylation of the total DNA-protein signal of the enzyme-linked immunosorbent assay by means of the ELISA antibody, the chromogenic signal of the ELISA assay by means of the ELISA assay kit for the level of the whole protein-binding assay by means of the ELISA-binding assay₅₀Values and percentage values. The DMSO control was used as a blank sample.

C) Kv11.1 (hERG) ion channel Activity (patch clamp assay)

Method for the detection and characterization of test substances interfering with the Kv11.1 (hERG) channel: kv11.1 (hERG, human ether-a-go-go related gene) is a potassium channel that plays a key role in repolarization of cells in ventricular cardiomyocytes.

Patch clamp measurements were performed in whole cell mode at room temperature on human embryonic kidney cells (HEK 293) stably transfected with the hERG gene.

Whole cell mode was performed using an automated patch clamp apparatus (Patchliner. TM., Nanion technologies, Munich). It is a glass chip based system with which up to 8 cells can be measured simultaneously and automatically whole cells. The glass chip has a well of defined dimensions, on which the cells are transferred to the Gigaseal (Gigaseal) by applying negative pressure and a whole cell pattern is introduced. Buffers, cell suspensions and test substances were added to the microchannels of the chip using a teflon-coated pipette.

Cells were clamped at a holding potential of-80 mV. To measure the substance-mediated inhibition of the kv11.1 channel, the following voltage program was applied at time intervals of 10 seconds: 51 ms/-80 mV, 500 ms/+40 mV, 500 ms/-40 mV,200 ms/-80 mV. The leakage current is subtracted by the P4 method. Cells were resuspended in extracellular suspension (EC) and applied in a chip. After the cells are collected, the seal is improved by adding a seal enhancer buffer. When the whole cell mode is reached, the seal enhancer buffer is washed away and replaced with an extracellular suspension. Measurements were started in EC for 1.5 min. DMSO (vehicle control, 0.1% DMSO) was then administered and control flow was recorded for 3 min. The test substance was then added twice at the same concentration and the potassium flow was measured for 3.5 min, respectively.

If the measurement result of the test substance at the initial concentration of 10 μ M is less than (-)50% effect (threshold) (e.g., (-)60% effect), the test substance is added at continuously increasing concentrations for determining the dose-effect relationship, wherein each concentration is measured for 5 min.

As reference substance, the kv11.1 (hERG) ion channel blocker quinidine is used. The effects of the test substance and quinidine were normalized based on the relevant vehicle control. The effect on Kv11.1 (hERG) channel activity was evaluated by means of potassium flow at-40 mV. For the calculation, the current of the last trace was evaluated separately. Inhibition of kv11.1 (hERG) channel due to test substance was normalized based on vehicle control (0.1% DMSO).

At the time of measurement, an aliquot of the test substance is taken for concentration determination. The samples were directly measured by HPLC and the final concentration was determined based on a calibration curve.

If the measurement result of the test substance at the initial concentration of 10 μ M is greater than or equal to (-)50% effect (threshold) (e.g., (-)30% effect, i.e., 30% inhibition at 10 μ M), K is calculated according to the following formula_i：K_i= 1.0E-5 x (100+% Effect)/(% Effect), [ M +]。

Under the condition of the test substance concentration of 10 mu M, the measurement result of the (-)30% effect obtains the K of 23 mu M_i。

D) Kv11.1 ion channel binding assay

Kv11.1 (hERG = human ether-a-go-go related enzyme) is cardiac K⁺A channel, which should as far as possible not interact with the test substance. This interaction is via the Predictor of Life Technologies^TMhERG Fluorescence Polarization (FP) assay is quantitative. In the case of this assay principle, myocardial cell membranes with a certain content of Kv11.1 channels were isolated. The dye-labeled Kv11.1 binding partner generates a highly fluorescent polarized signal by interacting with Kv11.1. In the case of dye displacement, a decrease in the fluorescence polarization signal results.

The assay was performed automatically as follows: 15 nL of test substance (maximum concentration: 10mM, 10 concentrations: dilution factor 1: 3.16, DMSO) were transferred by an acoustic (akustisch) pipette into empty microtiter plates with 384 wells. Then 3. mu.L of the separated membrane was added. The membrane and test substance were incubated at 22 ℃ for 15min (+/-5 min). In the next step a dye-labelled binding partner is added, followed by incubation at 22 ℃. After 2 hours incubation, fluorescence polarization was measured on an Envision multifunctional microplate reader. The measured raw data is detected by means of a gene data detection analyzerAnd (6) standardizing. In thatGeneData CondoseoThe IC50 and% effect values were calculated.

Chemical synthesis

In the context of this document, all temperatures are in units of ℃.

The stereochemical configuration of the enantiomeric examples 27, 72, 82, 83, 135, 136, 185, 234, 251, 455 and 456 was determined by X-ray structural analysis. For examples 234 and 251, the precursors were identified by crystallization and X-ray structural analysis.

The remaining compounds marked as chiral in the table (asterisks on the asymmetric C-atoms) were obtained by chromatography on a chiral stationary phase. The enantiomer which flows out first under the respective conditions is referred to as "Ena 1", and the enantiomer which flows out second is referred to as "Ena 2".

Examples 1 and 2:

(3, 5-difluoro-pyridin-4-yl) - [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -methanol (1)

(4-chloro-5-fluoro-pyridin-3-yl) - [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -methanol (2)

(3-bromo-4-fluoro-phenyl) -acetonitrile (4.00 g, 18.32 mmol), pinacol diboron (5.22 g,20.15 mmol), potassium acetate (55.86 mmol) and bis (triphenylphosphine) palladium (II) dichloride (15.2% Pd) (393.53mg, 0.55 mmol) were dissolved under argon in oxygen-free 1, 4-dioxane (40 ml, up to 0.005% water). The reaction mixture was then heated at a temperature of 130 ℃ for 90 min. After complete reaction, filtration through celite was carried out. The filtrate was diluted with dichloromethane (200 ml) and water (50 ml) and extracted. The organic phase is dried over sodium sulfate, then filtered and concentrated to dryness under vacuum, whereuponTo obtain oil-like [ 4-fluoro-3- (4,4,5, 5-tetramethyl- [1,3,2 ]]Dioxolane-2-yl-phenyl]Acetonitrile (7.59 g, 81% purity MS: 262.2 [ M + H ]⁺]) It was used for the next reaction without further work-up.

4-fluoro-3- (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxolane-2-yl-phenyl]Acetonitrile (7.60g, 23.53 mmol), 1, 4-dioxane (85.6 ml, up to 0.005% water), 4-chloro-7-morpholin-4-yl-quinazoline (5.00 g, 20.02 mmol), bis (tricyclohexylphosphine) -palladium (II) dichloride (597.24 mg, 0.80 mmol) and sodium carbonate solution (2.0M, 30ml, 60.07 mmol) were placed in a three-neck flask in advance. The suspension obtained was heated at a temperature of 140 ℃ under stirring for a period of 2.5 h under a nitrogen atmosphere. After completion of the reaction, it was cooled to room temperature and filtered through celite. The filtrate was diluted with ethyl acetate (250 ml) and water (100ml) and extracted. The aqueous phase was washed twice more with ethyl acetate (75 ml each). The combined organic phases were dried over sodium sulfate, then filtered and concentrated to dryness under vacuum. For further work-up, it was suspended in methyl-tert-butyl ether, filtered and washed twice more with further methyl-tert-butyl ether (30ml each). The filter cake was dried under vacuum overnight to give [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] as a yellow solid]Acetonitrile (4.91 g, 13.49 mmol, MS: 349.1 [ M + H ]⁺]Yield of 67%).

Will be provided with[4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl]Acetonitrile (400 mg, 1.12 mmol), 4-chloro-3, 5-difluoro-pyridine (189.9 mg, 1.23 mmol) was dissolved in oxygen-free degassed tetrahydrofuran (8 ml, up to 0.0075% water) under a dry argon atmosphere. Potassium tert-butoxide (263.9 mg, 2.35 mmol) was then added to the reaction mixture, giving a deep red colorThe color solution was stirred at room temperature for another 30 min. After completion of the reaction, it was diluted with a saturated ammonium chloride solution (20 ml) and water (50 ml). The aqueous phase was then extracted twice with dichloromethane (60 ml each). The organic phase is dried over sodium sulfate, filtered and evaporated to dryness under vacuum with rotation. The residue was purified by flash column chromatography (gradient: dichloromethane/0-4 vol% ethanol) to give an oily mixture (420 mg, about 5:3) of: (3, 5-difluoro-pyridin-4-yl) - [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl]Acetonitrile (263mg, 0.57 mmol, MS: 462.1 [ M + H ]⁺]50% yield) and (4-chloro-5-fluoro-pyridin-3-yl) - [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl]Acetonitrile (157 mg, 0.33 mmol, MS: 478.1/480.1 [ M + H ]⁺]29% yield).

Coupling (3, 5-difluoro-pyridin-4-yl) - [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl]-acetonitrile and (4-chloro-5-fluoro-pyridin-3-yl) - [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl]A mixture of acetonitrile (420 mg, ca. 5:3) was dissolved in acetonitrile (12.7 ml). Potassium tert-butoxide (80.90 mg, 0.72mmol) was added to the reaction solution with stirring, thereby producing a dark red solution. After stirring for 15min, cooling to 0 ℃ and then dropwise addition of a 30% strength hydrogen peroxide solution (276 μ l, 2.70 mmol). After stirring at 0 ℃ for 5min the cooling bath was removed. The reaction solution was stirred at room temperature for a further 1 h. After completion of the reaction, a 10% sodium thiosulfate solution (5ml) was added and diluted with water (25 ml). The aqueous solution was extracted twice with dichloromethane (50 ml each). The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash column chromatography (gradient: dichloromethane/0-4 vol% ethanol) to give an oily mixture (310 mg, about 3:1) of: (3, 5-Difluoropyridin-4-yl) - [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl]Methanone (233 mg, 0.50 mmol, MS:451.1 [ M + H ]⁺]) And (4-chloro-5-fluoropyridin-3-yl) - [ 4-fluoro-3- (7-morpholine)-4-yl-quinazolin-4-yl) -phenyl]Methanone (77 mg, 0.16 mmol, MS: 467.1/469.1 [ M + H ]⁺])。

Coupling (3, 5-difluoropyridin-4-yl) - [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl]-methanone and (4-chloro-5-fluoro-pyridin-3-yl) - [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl]A mixture of methanones (310 mg, ca. 3:1) was dissolved in methanol (15 ml). Sodium borohydride (30.4 mg, 0.80 mmol) was then added (gas evolution). The reaction mixture was stirred at room temperature for 45 min. After completion of the reaction, it was diluted with a saturated ammonium chloride solution (5ml) and water (15 ml). The aqueous phase is then extracted three times with dichloromethane (20 ml each). The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness under vacuum with rotation. The residue was dissolved in dimethyl sulfoxide (4.8 ml) and purified by means of preparative HPLC (gradient: water/1-50% by volume of acetonitrile over 21 min, flow rate 50 ml/min) by chromatography. The product fractions were combined, diluted with saturated sodium bicarbonate solution (5ml each) and extracted twice with dichloromethane (40 ml each). The organic phase was concentrated under vacuum and the residue was taken up in 1, 4-dioxane (5ml) and water (30ml) and freeze dried to give pure (3, 5-difluoro-pyridin-4-yl) - [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl as a solid]Methanol (example 1, 42.50 mg, 0.09 mmol, MS: 453.1 [ M + H ]⁺]) And (4-chloro-5-fluoro-pyridin-3-yl) - [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl]Methanol (example 2, 28.40mg, 0.06 mmol, MS: 469.1/471.1 [ M + H)⁺])。

Example 37

(3-chloro-pyrazin-2-yl) - [ 4-fluoro-3- (6-morpholin-4-yl-thieno [3,2-d ] pyrimidin-4-yl) -phenyl ] -methanol (37)

In a glass vessel, sodium hydride (60% suspension in paraffin oil, 1.41 g, 35.0 mmol) was suspended under argon in dry tetrahydrofuran (25 ml). 4-methoxy-phenyl-methanol (4.21 g, 30.0 mmol) dissolved in dry tetrahydrofuran (5ml) was then slowly added dropwise with stirring and stirred at room temperature for 1 h. Then 4-chloro-thieno [3,2-d ] is reacted]A suspension of pyrimidine (4.00 g, 23.4 mmol) in dry tetrahydrofuran (20 ml) was added slowly and stirred for an additional hour. After completion of the reaction, methanol (15 ml) was carefully added, then concentrated under vacuum and diluted with a mixture of water (100ml) and ethyl acetate (150 ml). The aqueous phase is extracted three times with ethyl acetate (100ml each), dried over sodium sulfate, filtered with suction and the filtrate is concentrated in vacuo. The solvent-free residue was taken up in ethanol (40 ml) and carefully stirred at about 5 ℃ for 16 h. The overnight precipitated crystals were filtered off with suction, washed with some cold ethanol and dried at room temperature. To give 4- (4-methoxy-benzyloxy) -thieno [3,2-d as a crystalline solid]Pyrimidine (4.15 g,15.24 mmol, MS: 273.0 [ M + H ]⁺]) Yield of 65%).

Reacting 4- (4-methoxy-benzyloxy) -thieno [3,2-d]Pyrimidine (2.60 g, 9.55 mmol) was dissolved in dry tetrahydrofuran (35 ml) and cooled to (-)55 ℃. The lithium diisopropylamide solution (21 mmol, prepared from diisopropylamine [2.13 g, 21 mmol) was added]And n-BuLi [15% in n-hexane, 13.13 ml, 21mmol in dry tetrahydrofuran [35 ml%]In [ -]At 10 ℃) over 10min at (-)55 ℃. The suspension obtained is stirred further. 1, 2-dibromoethane (10.76 g, 6.0 mmol) was then added. After a further 10min, heat to (-)20 ℃ and stir for 1 h. After completion of the reaction, the reaction solution was added to a 50% strength aqueous solution of sodium hydrogencarbonate/sodium thiosulfate (volume ratio 1:1, 120 ml). The aqueous phase was extracted three times with ethyl acetate. The combined organic phases are washed with saturated chlorineThe sodium hydroxide solution is washed and then dried over sodium sulfate, filtered and concentrated to dryness on a rotary evaporator. The residue was purified by flash column chromatography (gradient: cyclohexane/0-18 vol% ethyl acetate, CombiFlash Rf200, 80g silica gel column, flow = 50 ml/min, λ =220 nm) to give 6-bromo-4- (4-methoxy-benzyloxy) -thieno [3,2-d ] as a solid]Pyrimidine (1.39 g, 3.95 mmol, MS: 351.0/353.0 [ M + H ]⁺]) Yield of 41%).

In a microwave vessel, 6-bromo-4- (4-methoxy-benzyloxy) -thieno [3,2-d]Pyrimidine (1.38 g,3.93 mmol), morpholine (1.03 g, 11.79 mmol), sodium tert-butoxide (1.13 g, 11.79 mmol), (b), (c) and (d)S) - (-) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl (b) ((R))SBINAP, 122.3 mg, 0.196 mmol) and tris (dibenzylideneacetone) dipalladium (179.9 mg, 0.196 mmol) were dissolved in toluene (20 ml) under nitrogen. The reaction solution was heated at 95 ℃ for 4 h. Then diluted with water (60 ml) and dichloromethane (60 ml). The aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue is purified by flash chromatography (gradient: dichloromethane/5-25% by volume [ dichloromethane/ethanol 9: 1)]CombiFlash Rf200, 80g silica gel column, λ =220 nm). The appropriate product fractions were combined and the solvent was removed on a rotary evaporator to give 4- (4-methoxy-benzyloxy) -6-morpholin-4-yl-thieno [3,2-d as a solid]Pyrimidine (756.0 mg, 2.12 mmol, MS: 358.2 [ M + H ]⁺])54% yield).

Reacting 4- (4-methoxy-benzyloxy) -6-morpholin-4-yl-thieno [3,2-d]Pyrimidine (923 mg, 2.58mmol) was dissolved in tetrahydrofuran (5ml) and methanol (5 ml). Pd-C (5%, 1.9 g) was added portionwise (at the beginning of the reaction, after a further 7 h and 24 h) and at a hydrogen pressure of maximally 5 bar (H₂Purity 3.0, 57.9 g) for 36 h. The resulting solution was filtered through celite and concentrated on a rotary evaporator. The residue is purified by flash column chromatography (gradient: dichloromethane/10-20% by volume [ methanol/ammonia 10: 1)]CombiFlash Rf200, 24 g silica gel column, λ =220 nm). The appropriate product fractions were combined and the solvent was removed on a rotary evaporator to give 6-morpholin-4-yl-3H-thieno [3,2-d ] as a solid]Pyrimidin-4-one (361.0 mg, 1.521 mmol, MS: 238.0 [ M + H ]⁺]Yield of 59%).

Reacting 6-morpholin-4-yl-3H-thieno [3,2-d]Pyrimidin-4-one (206 mg, 0.87 mmol) was suspended in phosphorus oxychloride (1.67 g, 10.89 mmol). N-ethyldiisopropylamine (56.1 mg, 0.43mmol) was then added to the suspension. The reaction mixture was stirred at room temperature overnight. For work-up, a mixture of saturated sodium bicarbonate solution (30ml) and dichloromethane (20 ml) was added. The obtained solution was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness under vacuum to give 4-chloro-6-morpholin-4-yl-thieno [3,2-d ] as a solid]Pyrimidine (127 mg, 0.497 mmol, MS: 256.0/258.0 [ M + H ]⁺]Yield 57%).

In analogy to the synthesis procedure described for examples 1 and 2, (3-chloro-pyrazin-2-yl) - [ 4-fluoro-3- (6-morpholin-4-yl-thieno [3,2-d ] pyrimidin-4-yl) -phenyl ] -methanol was prepared from 4-chloro-6-morpholin-4-yl-thieno [3,2-d ] pyrimidine (example 37).

The compounds prepared according to examples 1,2 and 37 are given in table 1 below.

Examples 92 and 93:

3- [ [ 2-chloro-4-fluoro-5- (7-morpholin-quinazolin-4-yl) phenyl ] -hydroxy-methyl ] -1H-pyridazin-6-one (92)

6- { [ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -hydroxy-methyl } -2-ethyl-2H-pyridazin-3-one (93)

[ 2-chloro-4-fluoro-5- (7-morpholin-quinazolin-4-yl) phenyl ] - (6-chloropyridazin-3-yl) methanone (starting from 2, 6-dichloropyridazine and 2- [ 2-chloro-4-fluoro-5- (7-morpholin-quinazolin-4-yl) phenyl ] acetonitrile) and 3- [ [ 2-chloro-4-fluoro-5- (7-morpholin-quinazolin-4-yl) phenyl ] -hydroxy-methyl ] -1H-pyridazin-6-one (example 92) were prepared in analogy to the synthetic methods described for examples 1 and 2.

Preparation of 3- [ 2-chloro-4-fluoro-5- (7-morpholin-quinazolin-4-yl) formyl ] -1H-pyridazin-6-one from [ 2-chloro-4-fluoro-5- (7-morpholin-quinazolin-4-yl) phenyl ] - (6-chloropyridazin-3-yl) methanone:

reacting [ 2-chloro-4-fluoro-5- (7-morpholin-quinazolin-4-yl) phenyl]- (6-chloropyridazin-3-yl) methanone (2.0 g,4.13 mmol) was dissolved in 1, 4-dioxane (80 ml, up to 0.005% water) under an argon atmosphere. Then 3-hydroxypropionitrile (570 μ l ml, 8.27 mmol) and sodium hydride (60% dispersion in paraffin oil) (215 mg; 5.37mmol) were added (gas generation). The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, it was carefully diluted with water (100ml) and neutralized with hydrochloric acid (1.0M). The aqueous phase was then extracted twice with ethyl acetate (200 ml each). The combined organic phases are washed with saturated sodium chloride solution and then dried over sodium sulfate, filtered and concentrated to dryness on a rotary evaporator. The residue was purified by flash column chromatography (dichloromethane/0-10 vol% ethanol, CombiFlash Rf200) to give 3- [ 2-chloro-4-fluoro-5- (7-morpholin-quinazolin-4-yl) formyl as a solid]-1H-pyridazin-6-one (695mg, 1.47 mmol, MS: 466.1/468.1 [ M + H ]⁺]) Yield of 36%).

Preparation of 6- { [ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -hydroxy-methyl } -2-ethyl-2H-pyridazin-3-one (example 93) from 3- [ [ 2-chloro-4-fluoro-5- (7-morpholin-4-yl) phenyl ] -hydroxy-methyl ] -1H-pyridazin-6-one (example 92):

reacting 3- [ [ 2-chloro-4-fluoro-5- (7-morpholin-quinazolin-4-yl) phenyl]-hydroxy-methyl]-1H-pyridazin-6-one (150 mg; 0.316 mmol) was dissolved in N, N-dimethylformamide (5.0 ml). Iodothane (52. mu.l, 0.632 mmol) and potassium carbonate (132 mg, 0.947 mmol) were then added. The reaction mixture was stirred at room temperature for 6 h. After completion of the reaction, decantation was performed into water (100 ml). The aqueous phase was then extracted twice with ethyl acetate (100ml each). The combined organic phases were washed with water (40 ml), then dried over sodium sulphate, filtered and concentrated to dryness under vacuum. The residue was suspended in acetone and filtered off with suction. The filter cake was dried under high vacuum at room temperature to give 6- { [ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl as a solid]-hydroxy-methylYl } -2-Ethyl-2H-pyridazin-3-one (example 93, 157mg, 0.31 mmol, MS: 496.1/498.1 [ M + H ]⁺]Yield of 97%).

The compound prepared according to example 93 is given in table 2 below.

Example 100:

[ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - [6- (oxetan-3-yloxy) -pyridazin-3-yl ] -methanol (100)

Reacting [ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl]- (6-chloropyridazin-3-yl) -methanone (700 mg, 1.30 mmol) and oxetan-3-ol (112 mg, 1.43 mmol) were dissolved in 1, 4-dioxane (25 ml, up to 0.005% water) under an argon atmosphere. Then sodium hydride (60% dispersion in paraffin oil, 62mg, 1.56 mmol) was added (gas evolution). The reaction mixture was stirred at room temperature for 30 min. After completion of the reaction, it was carefully diluted with water (80 ml) and neutralized with hydrochloric acid (1.0M). The aqueous phase was then extracted twice with ethyl acetate (80 ml each). The combined organic phases were washed with water (20 ml) and then dried over sodium sulphate, filtered and concentrated to dryness on a rotary evaporator. The residue is purified by flash column chromatography (dichloromethane/0-10 vol.% ethanol, Com)biFlash Rf200) to give solid [ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) phenyl []- [6- (Oxetazedin-3-yloxy) pyridazin-3-yl group]Methanone (264 mg, 0.506 mmol, 522.2 [ M + H ]⁺]) Yield of 39%).

[ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - [6- (oxetan-3-yloxy) -pyridazin-3-yl ] -methanol (example 100) was prepared from [ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) phenyl ] - [6- (oxetan-3-yloxy) pyridazin-3-yl ] methanone in analogy of the synthetic methods described for examples 1 and 2.

The compounds prepared according to example 100 are given in table 3 below.

Examples 120, 121 and 122:

[2, 4-difluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (4-methoxy-phenyl) -methanol (example 120)

5-bromo-2, 4-difluoro-benzaldehyde (280 mg, 1.27 mmol) in dry tetrahydrofuran (10ml) was initially charged in a heated three-necked flask with internal thermometer, shielding gas inlet, septum and stirring magnet. 4-Methoxyphenylmagnesium bromide (1M in THF, 1.39 ml, 1.39 mmol) was slowly added dropwise at 5 deg.C, and the reaction solution was stirred at room temperature for 18 h. Then, water (20 ml) was added to the reaction solution. The phases were separated and the aqueous phase was extracted twice with ethyl acetate (20 ml). The combined organic phases are washed with water, dried over sodium sulfate, filtered and concentrated to dryness on a rotary evaporator. To give (5-bromo-2, 4-difluoro-phenyl) - (4-methoxy-phenyl) -methanol as an oily crude product (530 mg,1.61 mmol, MS: 353 [ M + H ]⁺]) It was used without further purification in the next synthetic step.

[2, 4-difluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (4-methoxy-phenyl) -methanol was prepared from (5-bromo-2, 4-difluoro-phenyl) - (4-methoxy-phenyl) -methanol in analogy to the syntheses described in examples 1 and 2.

(6-Difluoromethoxy-pyridazin-3-yl) - [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -methanol (example 121)

In a vessel with stirring magnetons, 6-chloro-2H-pyridazin-3-one (944 mg, 7.23 mmol) and fluorosulfonyl difluoroacetic acid (1.42 g, 7.96 mmol) were dissolved in acetonitrile (19 ml) and stirred at room temperature for 40H. The reaction solution was then diluted with ethyl acetate (150ml) and washed successively with water, saturated sodium bicarbonate solution and then with water. The organic phase is dried over sodium sulfate, filtered and concentrated to dryness on a rotary evaporator. The residue was taken up in cyclohexane, filtered again and the solvent was removed on a rotary evaporator. The residue obtained is purified by flash column chromatography (gradient: cyclohexane/0-50% by volume of ethyl acetate, CombiFlash Rf 200). The appropriate product fractions were combined and the solvent was removed on a rotary evaporator. 3-chloro-6- (difluoromethoxy) pyridazine (285 mg, 1.58 mmol, MS:181.0/183.1[ M + H ] as a colorless liquid was obtained⁺]) Yield of 22%).

In a vessel with stirring magnetons, potassium hydroxide powder (603 mg, 10.75 mmol) was suspended in dry N, N-dimethylformamide (2 ml) and stirred at room temperature for 30 min. Then (3-bromo-4-fluoro-phenyl) -acetonitrile (1.0 g, 4.67 mmol) dissolved in N, N' -dimethylformamide (1.3 ml) was added dropwise. The reaction mixture was stirred at room temperature for a further 30 min. To the reaction mixture was then added (5-bromo-2, 4-difluoro-phenyl) - (4-methoxy-phenyl) -methanol (506 mg, 2.80 mmol) in portions and stirred at 50 ℃ under an oxygen-free argon atmosphere for 2 h. The reaction mixture was added to a mixture of water (50 ml) and saturated sodium chloride solution (35 ml), and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness on a rotary evaporator. The residue was purified by means of RP-column chromatography (gradient: water/acetonitrile and 0.1% by volume of formic acid, Combiflash Rf 200). The appropriate product fractions were combined and the solvent was removed on a rotary evaporator. To give (3-bromo-4-fluoro-phenyl) - (6-difluoromethoxy-pyridazin-3-yl) -acetonitrile (146 mg, 0.41 mmol, M) as a liquidS: 358.0/360.0[M+H⁺]14% yield). The byproduct was 2- (3-bromo-4-fluoro-phenyl) -2- (6-chloropyridazin-3-yl) acetonitrile.

(3-bromo-4-fluoro-phenyl) - (6-difluoromethoxy-pyridazin-3-yl) -acetonitrile (146 mg, 0.41 mmol) was dissolved in dry acetonitrile (4 ml). Potassium tert-butoxide (43.6 mg, 0.388 mmol) was then added and the reaction mixture was stirred at room temperature for 25 min. The reaction solution was then cooled to 0 ℃ in an ice bath, hydrogen peroxide (30% in water, 92 μ L, 0.90 mmol) was added dropwise, and the reaction mixture was first stirred at 0 ℃ for a further 25 min and then at room temperature for 1 h. For work-up, the reaction mixture was added to water (40 ml) and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness on a rotary evaporator. To give (3-bromo-4-fluoro-phenyl) - (6-difluoromethoxy-pyridazin-3-yl) -methanone as a solid (113 mg, 0.32 mmol, MS: 346.9/349.0[ M + H ]⁺]Yield of 79%).

(3-bromo-4-fluoro-phenyl) - (6-difluoromethoxy-pyridazin-3-yl) -methanone (126 mg, 0.36 mmol) was dissolved in methanol (4 ml). Sodium borohydride (60.4 mg, 1.60 mmol) was then added portionwise and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, it was diluted with a saturated ammonium chloride solution (5ml) and then extracted twice with ethyl acetate (30 ml). The combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated to dryness on a rotary evaporator to give the crude solid product (3-bromo-4-fluoro-phenyl) - (6-difluoromethoxy-pyridazin-3-yl) -methanol (127 mg, MS: 349/351[ M + H)⁺]) It was used without further purification in the next synthetic step.

(6-Difluoromethoxy-pyridazin-3-yl) - [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -methanol (example 121) was obtained in analogy of the synthesis described for [2, 4-difluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (4-methoxy-phenyl) -methanol (example 120).

1- [ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -1- (6-methoxy-pyridazin-3-yl) -prop-2-yn-1-ol (example 122)

Reacting ([ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl]- (6-methoxy-pyridazin-3-yl) -methanol (example 137, 898 mg, 1.75 mmol) was dissolved in dichloromethane (15 ml). Then dess-martin triacetoxy periodinane (15% in dichloromethane, 7.23 ml, 3.50 mmol) was added. The reaction suspension was stirred at room temperature for 1 h. For working up, water (60 ml) and a 10% aqueous solution of sodium thiosulfate were added. The aqueous phase was extracted twice with ethyl acetate (80 ml each). The combined organic phases were washed with saturated sodium chloride solution (30ml), dried over sodium sulphate, filtered and the filtrate was concentrated to dryness in vacuo to give 2.1 g of crude product as an oil. The residue was purified by flash column chromatography (gradient: dichloromethane/0-25 vol% dichloromethane-ethanol 9:1, CombiFlash Rf200) to give [ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -amide as a foam]- (6-methoxy-pyridazin-3-yl) -methanone (792 mg, 1.65 mmol, MS: 480.1/482.1 [ M + H)⁺]Yield 94%).

Trimethylsilylacetylene (179 μ L, 125 mg, 1.25 mmol) dissolved in dry tetrahydrofuran (3 ml) was added in advance under argon in a vessel with a stirring magneton and an internal thermometer. The reaction solution was cooled to (-)20 ℃ and n-butyllithium (1.6M in n-hexane, 781 μ l, 1.25 mmol) was slowly added dropwise. The reaction mixture was stirred at (-)20 ℃ for another 30 min. The reaction solution was then cooled to (-)70 ℃ and then [ 2-chloro-4-fluoro ] dissolved in dry tetrahydrofuran (6 ml) was added dropwise-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl]- (6-methoxy-pyridazin-3-yl) -methanone (200 mg, 0.417 mmol). The temperature of the reaction mixture was increased to (-)40 ℃ over 1 h. Water (40 ml) was then added and the phases separated. The organic phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was dissolved in dry tetrahydrofuran (4 ml), and tetra-n-butylammonium fluoride trihydrate (109 mg, 0.42 mmol) was added. Then stirred at room temperature for 18 h. The volatile reaction components are then removed on a rotary evaporator. The residue was pre-purified by means of flash column chromatography (gradient: dichloromethane/0-34% by volume dichloromethane-ethanol 1:1, CombiFlash Rf 200). The product fractions were combined and the solvent was removed under vacuum on a rotary evaporator. The residue was finally purified by means of preparative RP-chromatography (Chromolith RP-18e21.2x100 mm, flow rate: 50 ml/min., wavelength: 220 nm). An appropriate portion of the volatile solvent content was removed by vacuum centrifugation (Genevac HT-12) and the product was freeze-dried from acetonitrile/water (1:3 volume ratio). To give 1- [ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl as a solid]-1- (6-methoxy-pyridazin-3-yl) -prop-2-yn-1-ol (example 122, 102 mg, 0.20 mmol, MS: 506.1/508.1 [ M + H ]⁺]Yield of 48%).

The compounds prepared according to examples 120, 121 and 122 are given in table 4 below.

Example 138

1- [5- (7-Morpholin-4-yl-quinazolin-4-yl) -pyridin-3-yl ] -1-thiazol-2-yl-ethanol (example 138)

Thiazole (143 μ l, 2.0 mmol) was pre-placed in dry tetrahydrofuran (10ml) in a heated three-neck flask. The reaction solution was cooled to (-)78 ℃ by means of an acetone/dry ice bath. N-butyllithium (15% solution in n-hexane, 1.63 ml, 2.6 mmol) was added dropwise over 10min at a constant temperature. The reaction mixture was stirred for a further 10 min. The suspension was then heated to (-)30 ℃ and cooled to (-)55 ℃ again, and 1- (5-bromo-pyridin-3-yl) -ethanone (380 mg, 1.90 mmol) dissolved in dry tetrahydrofuran (6 ml) was added dropwise at (-)40 ℃. The reaction temperature was raised to (-)10 ℃ over 1.5 h. After completion of the reaction (HPLC assay), saturated ammonium chloride solution was added and stirred at room temperature for 30 min. The reaction mixture was added to a two-phase solution of water (60 ml) and ethyl acetate (80 ml), and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The crude product as an oil was purified by flash column chromatography (solvent: dichloromethane/2.0 vol% methanol, then dichloromethane/3.0 vol% methanol + 1.0 vol% ammonia, flash silica amount 30 g). The product fractions were combined and the solvent was removed under vacuum on a rotary evaporator.1- (5-bromo-pyridin-3-yl) -1-thiazol-2-yl-ethanol (479 mg, 1.68 mmol, MS: 285.0/287.0 [ M + H ] was obtained as an oil⁺]Yield 84%).

In a glass vessel with a stirring magneton, 1- (5-bromo-pyridin-3-yl) -1-thiazol-2-yl-ethanol (162mg, 0.55 mmol), pinacol diborate (140 mg, 0.55 mmol), 1 '-bis (diphenylphosphino) -ferrocene (Dppf, 7.1 mg, 0.013 mmol), 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride [ Pd (Dppf) Cl ] (II)₂, 10,4 mg, 0,013 mmol]And potassium acetate (167 mg, 1.7 mmol) suspended in dry, oxygen-free 1, 4-dioxane. The glass container was sealed with a separator. The reaction solution was stirred and heated at 115 ℃ for 2.5 h. The reaction was checked by means of HPLC. To the reaction solution were added 4-chloro-7-morpholin-4-yl-quinazoline (106 mg, 0.43mmol), bis (tricyclohexylphosphine) -palladium (II) dichloride (9.4 mg, 0.013 mmol) and 2.0M sodium carbonate solution (531 μ l). The reaction mixture was then stirred at a temperature of 125 ℃ for 1.5 h. The mixture was decanted to give a water/dichloromethane (1:1 by volume, 40 ml) and the resulting solution was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The residue was purified by flash chromatography [ gradient: dichloromethane/20-58% by volume of a solvent mixture of dichloromethane/methanol 9:1 (volume ratio), CombiFlash Rf200]And (5) purifying. The appropriate product fractions were combined and the solvent was removed on a rotary evaporator to give 1- [5- (7-morpholin-4-yl-quinazolin-4-yl) -pyridin-3-yl ] -pyridine]-1-Thiazol-2-yl-ethanol (example 138, 95mg, 0.23 mmol, MS: 420.2 [ M + H⁺]Yield of 53%).

Example 139

{3- [7- (3, 6-dihydro-2H-pyran-4-yl) -quinazolin-4-yl ] -4-fluoro-phenyl } -thiazol-2-yl-methanol (139)

4- (4,4,5, 5-tetramethyl- [1,3,2 ] in a microwave glass container with stirring magnetons]Dioxolane-2-yl) -3, 6-dihydro-2H-pyran (575 mg, 2.74 mmol), methyl 2-amino-4-bromo-benzoate (600mg, 2.61 mmol), bis (tricyclohexylphosphine) -palladium (II) dichloride (57.8 mg, 0.078 mmol) and an oxygen-free 2.0M sodium carbonate solution (3.26 ml, 6.52 mmol) were pre-placed in degassed oxygen-free 1, 4-dioxane (12 ml). The material mixture was heated in a laboratory chemical microwave synthesizer at 100W and 135 ℃ for 55 min. The reaction solution was then decanted into a mixture of water (40 ml) and ethyl acetate (30 ml). The obtained solution was extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under vacuum on a rotary evaporator. The residue was purified by flash chromatography [ gradient: dichloromethane/0-10% by volume of a solvent mixture of dichloromethane/methanol 10:1 (volume ratio), CombiFlash Rf200]And (5) purifying. The appropriate product fractions were combined and the solvent was removed on a rotary evaporator to give methyl 2-amino-4- (3, 6-dihydro-2H-pyran-4-yl) -benzoate as a solid (371.1 mg, 1.59mmol, MS: 234.2 [ M + H ])⁺]Yield of 61%).

In a vessel with a stirring magneton, methyl 2-amino-4- (3, 6-dihydro-2H-pyran-4-yl) -benzoate (620 mg, 2.66 mmol), trimethyl orthoformate (564.1 mg, 5.32mmol) and ammonium acetate (410 mg, 5.32mmol) were dissolved in methanol (20 ml) as a pre-charge. The material mixture was stirred at 80 ℃ overnight. Water (10ml) was then added and the precipitated solid was filtered off with suction, washed with a little water and then dried under vacuum. To give 7- (3, 6-dihydro-2H-pyran-4-yl) -3H-quinazolin-4-one (520 mg, 2.28 mmol, MS: 229.1 [ M + H ]⁺]Yield of 86%).

{3- [7- (3, 6-dihydro-2H-pyran-4-yl) -quinazolin-4-yl ] -4-fluoro-phenyl } -thiazol-2-yl-methanol (example 139) was obtained in analogy of the synthetic procedure for the preparation of 1- [5- (7-morpholin-4-yl-quinazolin-4-yl) -pyridin-3-yl ] -1-thiazol-2-yl-ethanol (example 138).

Example 140

[ 4-fluoro-3- (7-morpholin-4-yl-pyrido [4,3-d ] pyrimidin-4-yl) -phenyl ] -thiazol-2-yl-methanol (140)

4-amino-6-chloro-nicotinic acid ethyl ester (8.38 g, 39.7 mmol) was dissolved in morpholine (40 ml). The mixture of materials was heated at 120 ℃ for 4 h. After completion of the reaction, the cooled reaction solution was decanted into water (400 ml). The aqueous suspension was stirred for 10min and then the precipitate was filtered off. The filter cake was rewashed with some water and dried under vacuum at 60 ℃ overnight to give pure 4-amino-6-morpholin-4-yl-nicotinic acid ethyl ester (8.55 g, 34.03 mmol, MS: 252.2 [ M + H ] as a colorless solid⁺]Yield of 85%).

From 4-amino-6-morpholin-4-yl-nicotinic acid ethyl ester (3.54 g, 14.1 mmol) in analogy to the synthesis described in example 139, solid 7-morpholin-4-yl-3H-pyrido [4,3-d ] is obtained]Pyrimidin-4-one (2.29 g,9.86 mmol, MS: 233.1 [ M + H ]⁺]70% yield).

Reacting 7-morpholin-4-yl-3H-pyrido [4,3-d]Pyrimidin-4-one (600mg, 2.58mmol) was suspended in 1, 4-dioxane (10 ml). To the reaction mixture was added phosphorus oxychloride (POCl)₃546 μ L, 5.9 mmol) and Hunigs base (N-ethyldiisopropylamine, 220 μ L, 1,29 mmol) then stirred at a temperature of 100 ℃ for 3H after complete reaction, the reaction solution was decanted into a semi-saturated sodium bicarbonate solution (80 ml), the aqueous phase was extracted three times with dichloromethane (40 ml each), the combined organic phases were dried over sodium sulfate, filtered and concentrated under vacuum on a rotary evaporator to give solid 4-chloro-7-morpholin-4-yl-pyrido [4,3-d ]]Pyrimidine (627 mg, 2.50 mmol, MS: 251.0/253.0 [ M + H ]⁺]96% yield).

[ 4-fluoro-3- (7-morpholin-4-yl-pyrido [4,3-d ] pyrimidin-4-yl) -phenyl ] -thiazol-2-yl-methanol (example 140) was obtained in analogy to the synthetic procedure for the preparation of 1- [5- (7-morpholin-4-yl-quinazolin-4-yl) -pyridin-3-yl ] -1-thiazol-2-yl-ethanol (example 138).

Example 141

[ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-pyrido [4,3-d ] pyrimidin-4-yl) -phenyl ] - (4-hydroxymethyl-thiazol-2-yl) -methanol (141)

In a two-necked flask with stirring magneton, internal thermometer and septum 4- (tert-butyl-dimethyl-silanyloxymethyl) -thiazole (10.15 g, 43.5 mmol) was dissolved under argon pre-charge in dry tetrahydrofuran (78 ml). The reaction solution was cooled to (-)75 ℃ by means of an acetone/dry ice bath.N-butyllithium (15% solution in n-hexane, 29.3 ml, 46.6 mmol) was then slowly added dropwise to the reaction solution at constant temperature. The reaction solution was stirred at (-)75 ℃ for another 30 min and then heated to 0 ℃. After which it was cooled again to (-)50 ℃. To this reaction solution was slowly added dropwise a solution of 5-bromo-2-chloro-4-fluoro-N-methoxy-N-methyl-benzamide (5.58 g, 12.4 mmol) in dry tetrahydrofuran (21 ml) pre-cooled to (-)50 ℃ over a period of 1.5 h. The reaction solution was stirred at (-)50 ℃ for another 30 min. After completion of the reaction, water (20 ml) was added to the reaction solution. Then, the reaction solution was heated to room temperature with stirring. The reaction solution was diluted with ethyl acetate (400 ml) and saturated sodium chloride solution (100 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated under vacuum on a rotary evaporator. The residue was purified by flash chromatography (gradient: cyclohexane/0-7% by volume ethyl acetate, CombiFlash Rf 200). The appropriate product fractions were combined and the organic solvent was removed on a rotary evaporator. To give (5-bromo-2-chloro-4-fluoro-phenyl) - [4- (tert-butyl-dimethyl-silanyloxymethyl) -thiazol-2-yl as an oil]-methanone (4.94 g, 10.39 mmol, MS: Main Peak 466 [ M + H ]⁺]Yield 84%).

[4- [ [ tert-butyl (dimethyl) silyl ] oxymethyl ] thiazol-2-yl ] - [ 2-chloro-4-fluoro-5- (7-morpholinopyrido [4,3-d ] pyrimidin-4-yl) phenyl ] methanol was prepared in analogy to the synthesis of examples 1 and 2 and 138 from (5-bromo-2-chloro-4-fluoro-phenyl) - [4- (tert-butyl-dimethyl-silanyloxymethyl) -thiazol-2-yl ] -methanone and 4-chloro-7-morpholin-4-yl-pyrido [4,3-d ] pyrimidine.

Reacting [4- (tert-butyl)Butyl-dimethyl-silanyloxymethyl) -thiazol-2-yl]- [ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-pyrido [4, 3-d)]Pyrimidin-4-yl) -phenyl]Methanol (333 mg, 0.55 mmol) was dissolved in 1, 4-dioxane (7 ml). 4.0M HCl dissolved in 1, 4-dioxane (1.38 ml, 5.53 mmol) was added and the reaction solution was stirred at room temperature for 30 min. After completion of the reaction, the reaction solution was filtered and the solvent was removed on a rotary evaporator. The residue was purified by flash chromatography (gradient: dichloromethane/0-15 vol.% ethanol, CombiFlash Rf 200). The appropriate product fractions were combined and the solvent was removed under vacuum. The residue was taken up in dichloromethane, extracted with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and the filtrate concentrated to dryness to give [ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-pyrido [4,3-d ] as a solid]Pyrimidin-4-yl) -phenyl]- (4-hydroxymethyl-thiazol-2-yl) -methanol (example 141, 229 mg, 0.47 mmol, MS: 488.0/490.0 [ M + H ]⁺]Yield of 85%).

Examples 142 and 143

2-chloro-4-fluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (4-hydroxymethyl-thiazol-2-yl) -methanol (142)

[ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (4-methylaminomethyl-thiazol-2-yl) -methanol (143)

Under argon, [ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-pyrido [4,3-d ]]Pyrimidin-4-yl) -phenyl]- (4-hydroxymethyl-thiazol-2-yl) -methanol (46.6 mg, 96 μmol) was dissolved in dry tetrahydrofuran (3.1 ml). N-ethyldiisopropylamine (98 μ L, 57.4 μmol) and methanesulfonyl chloride (14.8 μ L, 191 μmol) were added. The reaction solution was stirred at room temperature for 30 min. Methylamine (40% solution in water, 183 μ l, 1.91 mol) was then added and stirred at room temperature for a further 2 h. After completion of the reaction, the reaction solution is added to the reaction solutionTo the solution were added ethyl acetate (15 ml) and a saturated sodium chloride solution (10 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated on a rotary evaporator and the residue was purified by means of preparative RP-HPLC (gradient: water + 0.1% trifluoroacetic acid/acetonitrile + 0.1% trifluoroacetic acid, sunfire prep C-18150-21 mm, flow rate: 50 ml/min.,. lambda. =220 nm). The appropriate product fractions were combined and the solvent was removed under vacuum on a rotary evaporator and the residue was freeze-dried from dioxane/water to give [ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] amine as a solid]- (4-methylaminomethyl-thiazol-2-yl) -methanol (example 143, 14.8 mg, 0.030 mmol, MS: 500.1/502.0 [ M + H ]⁺]Yield of 31%).

Examples 144, 145 and 146

Racemic [ 4-fluoro-3- (6-morpholin-4-yl-thieno [3,2-d ] pyrimidin-4-yl) -phenyl ] -thiazol-2-yl-methanol (example 144, 35 mg, 0.082 mmol) was chromatographically separated into its enantiomers on a chiral stationary phase by using preparation SFC:

after column screening to determine the most appropriate chiral phase with the highest selectivity, the Lux Amylose-2 phase from Phenomex was selected. SFC-conditions were SFC Berger minigram, Lux Amylose-2,250X4.6 mm column, eluent carbon dioxide + 20 vol% methanol + 0.5 vol% diethylamine, flow rate 5 ml/min, wavelength 220 nm. Under the same conditions, toSFC Berger minigar Stacked Injection modePreparative separations of the enantiomers were carried out. Appropriate fractions were collected and the solvent was removed on a rotary evaporator under vacuum. The pure enantiomer of [ 4-fluoro-3- (6-morpholin-4-yl-thieno [3,2-d ] is obtained as a solid]Pyrimidin-4-yl) -phenyl]Thiazol-2-yl-methanols (example 145, R)_t= 7.85 min 12 mg, 0.028 mmol,>99% eeEna 1) And [ 4-fluoro-3- (6-morpholin-4-yl-thieno [3,2-d ]]Pyrimidin-4-yl) -phenyl]Thiazol-2-yl-carbinol (example 146, R)_t=8.82 min, 12.0 mg, 0.028 mmol, 92% ee,Ena 2)。

Compounds prepared analogously to examples 138-146 are listed in Table 5 below.

Example 207

[ 4-fluoro-2-methyl-5- (7-morpholinyl-quinazolin-4-yl) phenyl ] -thiazol-2-yl-methanol (example 207)

Methyl 4-fluoro-2-methyl-5- (7-morpholinyl-quinazolin-4-yl) benzoate was prepared from 4-chloro-7-morpholin-4-yl-quinazoline and 4-fluoro-2-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -benzoic acid methyl ester in analogy to the synthetic methods described in examples 1 and 2.

[ 4-fluoro-2-methyl-5- (7-morpholinyl-quinazolin-4-yl) phenyl ] -thiazol-2-yl-methanone was prepared from thiazole and methyl 4-fluoro-2-methyl-5- (7-morpholinyl-quinazolin-4-yl) benzoate in analogy to the synthetic methods described in example 138.

[ 4-fluoro-2-methyl-5- (7-morpholinyl-quinazolin-4-yl) phenyl ] -thiazol-2-yl-methanol (example 207) was prepared from [ 4-fluoro-2-methyl-5- (7-morpholinyl-quinazolin-4-yl) phenyl ] -thiazol-2-yl-methanone in analogy to the synthetic methods described in examples 1 and 2.

Example 208

[3- (2-ethynyl-7-morpholinyl-quinazolin-4-yl) -4-fluoro-phenyl ] -thiazol-2-yl-methanol (example 208)

Prepared from (3-bromo-4-fluoro-phenyl) -thiazol-2-yl-methanol and 4- (2, 4-dichloro-quinazolin-7-yl) morpholine in analogy to the synthetic methods described in example 138, [3- (2-chloro-7-morpholinyl-quinazolin-4-yl) -4-fluoro-phenyl ] -thiazol-2-yl-methanol.

Reacting [3- (2-chloro-7-morpholinyl-quinazolin-4-yl) -4-fluoro-phenyl]Thiazol-2-yl-methanol (102 mg,0.225 mmol) was dissolved in oxygen-free N, N-dimethylformamide (4 ml) under an argon atmosphere. Then CuI (17mg, 90. mu. mol), (Ph) was added₃P)₂PdCl₂(63 mg, 90. mu. mol), 2-diphenylphosphino-pyridine (95 mg, 0.359mmol), DIPEA (765. mu.l, 4.49 mmol) and triethylethynylsilane (275. mu.l, 1.48 mmol). The reaction mixture was then heated at a temperature of 140 ℃ for 1 h. For working up, ethyl acetate (50 ml), water (10ml) and saturated sodium chloride solution (15 ml) were added. The aqueous phase was separated and extracted with ethyl acetate (20 ml). The combined organic phases were dried over sodium sulfate, filtered and the filtrate was concentrated to dryness in vacuo. The residue was dissolved in dimethyl sulfoxide (2 ml) and purified by means of RP-chromatography (solvent: acetonitrile/water/0.1% by volume of HCOOH, Combiflash Rf 200). The appropriate product fractions were combined and the solvent was removed on a rotary evaporator to give [ 4-fluoro-3- [ 7-morpholinyl-2- (2-triethylsilylethynyl) quinazolin-4-yl ] as a waxy solid]Phenyl radical]Thiazol-2-yl-methanol (64 mg, 0.114 mmol, MS:561.2 [ M + H)⁺]Yield of 50%).

Reacting [ 4-fluoro-3- [ 7-morpholinyl-2- (2-triethylsilylethynyl) quinazolin-4-yl]Phenyl radical]Thiazol-2-yl-methanol (552 mg, 0.985 mmol) was dissolved in methanol (102 ml). Potassium hydroxide solution (1.0M, 15ml, 15 mmol) was then added and stirred at room temperature for 90 min. After completion of the reaction, it was carefully neutralized with hydrochloric acid (1.0M, 15ml, 15 mmol). Ethyl acetate (500 ml), water (100ml) and saturated sodium chloride solution (150ml) were then added. The phases were separated and the aqueous phase was extracted with ethyl acetate (100 ml). The combined organic phases were dried over sodium sulfate, filtered and the filtrate was concentrated to dryness in vacuo. The residue was dissolved in dimethyl sulfoxide (8 ml) and purified by flash column chromatography (gradient: dichloromethane/0-5 vol% ethanol, CombiFlash Rf 200). The appropriate product fractions were combined and the solvent was removed on a rotary evaporator to give [3- (2-ethynyl-7-morpholinyl-quinazolin-4-yl) -4-fluoro-phenyl) -as a solid]Thiazol-2-yl-methanol (example 208, 221 mg, 0.495 mmol, MS: 447.1 [ M + H)⁺]Yield of 50%).

The compounds prepared analogously to examples 207 and 208 are listed in table 6 below.

Example 217

[2, 4-difluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -pyridin-3-yl-methanol (217)

1, 5-dibromo-2, 4-difluoro-benzene (500 mg, 1.78 mmol) was dissolved in dry diethyl ether (10ml) under argon. The reaction solution was cooled to (-)65 ℃ by means of an acetone/dry ice bath. N-butyllithium (15% solution in n-hexane, 1.23 ml, 1.96 mmol) was added dropwise at a constant temperature of (-)65 ℃ over 15min and the reaction solution was stirred at (-)65 ℃ for a further 30 min. A pre-prepared solution of nicotinaldehyde (201 μ l, 2.14 mmol) in dry diethyl ether (5ml) was then added dropwise at (-)65 ℃ over 15min and the reaction mixture was stirred for another 10min to heat slowly to 0 ℃ over one hour thereafter. After completion of the reaction, a saturated ammonium chloride solution (5ml) and water (30ml) were added to the reaction solution. The aqueous phase was extracted three times with tert-butyl methyl ether. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The oily crude product was purified by means of preparative RP-column chromatography (solvent gradient: water/acetonitrile/0.1 vol.% trifluoroacetic acid [5.5 min)]CombiFlash Rf 200). The appropriate fractions were combined and concentrated under vacuum. The aqueous residue was neutralized with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness in vacuo on a rotary evaporator to give (5-bromo-2, 4-difluoro-phenyl) - (3-pyridinyl) methanol (215 mg, 0.717 mmol, MS:300.0/302.0 [ M + H ] as a colorless oil^+]Yield of 40%).

[2, 4-difluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -pyridin-3-yl-methanol (example 217) may be obtained from (5-bromo-2, 4-difluoro-phenyl) - (3-pyridyl) methanol in analogy to the synthetic procedures for the preparation of 1- [5- (7-morpholin-4-yl-quinazolin-4-yl) -pyridin-3-yl ] -1-thiazol-2-yl-ethanol (example 138).

The compounds prepared analogously to example 217 are listed in table 7 below.

Example 225:

[ 2-chloro-5- (5, 6-dideutero-7-morpholin-4-yl) -4-fluoro-phenyl ] - (6-methoxypyridazin-3-yl) methanol (225)

By the reaction of 5,6, 8-trideutero-7-morpholine-3H-quinazoline-4-one with phosphoryl chloride to obtain 4-chloro-5, 6-dideutero-7-N-morpholinyl-quinazoline.

Example 237:

[ 4-fluoro-3- (7-morpholin-4-yl-pyrido [3,2-d ] pyrimidin-4-yl) -phenyl ] - (3-methyl-pyrazin-2-yl) -methanol (237)

。

Example 258:

[ 2-chloro-4-fluoro-5- [7- (2,2,3,3,5,5,6, 6-octadeutero-morpholin-4-yl) quinazolin-4-yl ] phenyl ] - (3-methoxypyrazin-2-yl) methanol (258)

。

Examples 268 and 278:

[ 4-fluoro-3- (5-fluoro-7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (3-methyl-pyrazin-2-yl) -methanol (268), [ 2-chloro-4-fluoro-5- (5-fluoro-7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (6-methoxy-pyridazin-3-yl) -methanol (278)

。

Example 319:

2- [2, 4-difluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -2- (3-methoxy-pyrazin-2-yl) -acetamide (319)

Reacting [2, 4-difluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl]Acetonitrile (300 mg, 0.82mmol) and 2-chloro-3-methoxy-pyrazine (297 mg, 1.97 mmol) were dissolved in tetrahydrofuran. Nitrogen was then introduced into the solution for 10 min. To the reaction solution was then added potassium tert-butoxide (193 mg, 1.72 mmol) and stirred at room temperature under an argon atmosphere for 30 min. After completion of the reaction, the reaction mixture was taken up with saturated NH₄The Cl-solution was neutralized, diluted with distilled water (30ml) and extracted three times with dichloromethane (30ml each). Passing the organic phase through NaSO₄Drying, suction filtering and concentrating under vacuum to dryness. The residue was purified by means of flash column chromatography (gradient: dichloromethane/0-5 vol% ethanol, CombiFlash Rf200, 40 g silica gel column, λ =220 nm). The appropriate fractions were combined and the solvent was removed on a rotary evaporator. To give [2, 4-difluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl as a solid]- (3-methoxy-pyrazin-2-yl) -acetonitrile (218 mg, 0.46 mmol; MS: 475.2 [ M + H)⁺]Yield of 56%).

Reacting [2, 4-difluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl]- (3-methoxy-pyrazin-2-yl) -acetonitrile (218 mg, 0.46 mmol) was placed in a reaction flask in advance, then treated with H₂SO₄(95-98% strength, 3.53 ml,64 mmol) were dissolved. The reaction solution was stirred at room temperature for 2.5 h. After completion of the reaction, ice (80g) was added to the reaction solution. Then carefully neutralized with NaOH-solution (32% strength, 10.6 ml). The resulting suspension was diluted with distilled water (50 ml) and extracted three times with dichloromethane (100ml each). Passing the organic phase through NaSO₄Dry, suction filter and concentrate to dryness under vacuum. The residue was purified by means of flash column chromatography (gradient: dichloromethane/0-12 vol% ethanol, CombiFlash Rf200, 40 g silica gel column, λ =220 nm). The appropriate product fractions were combined and the solvent was removed on a rotary evaporator. To give 2- [2, 4-difluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl as a solid]-2- (3-methoxy-pyrazin-2-yl) -acetamide (182 mg, 0.37 mmol, MS: 493.4 [ M + H⁺]Yield of 81%).

Compounds prepared according to the synthetic procedures of examples 225, 237, 258, 268, 278 and 319 and analogously to examples 1,2, 37, 137, 121, 217 are listed in table 8 below:

() in the second column: chromatographically separated enantiomers representing the pure R-or S-configuration of the molecule

() in the last column: potassium channel activity measured by hERG binding assay instead of hERG patch clamp assay.

Example numbers 273-277, 281-283, 287 and 477 are intentionally omitted.

Claims (21)

1. A compound of the formula (I),

wherein

X is CH, CF, S or N,

y is CH, S or N,

z is a group selected from the group consisting of C and N,

-when Z = C, together with a single bond, a double bond is formed,

when Z = N, is absent,

n is 1 or 2, wherein

When n = 1, X = S,

and when N =2, two X = CH, or X connected to the pyrimidine ring is CF and X not connected to the pyrimidine ring is CH, or one X is CH and the other X is N;

m is 1 or 2, wherein

When m = 1, Y = S,

and when m =2, two Y = CH, or one Y is CH and the other Y is N;

R¹、R²、R³、R⁴independently of one another, H, Hal, CN, OH, CONH₂CONH (LA) or LA;

R⁵is H, Hal, CN or C ≡ CH;

cyc is phenyl which may be unsubstituted or mono-or doubly and independently of one another by R⁶Substitution; or is Het¹；

Het¹Is a mono-or bicyclic 5-to 10-membered heterocycle having 1 to 3N atoms, O atoms and/or S atoms or 1 to 4N atoms, which may be unsubstituted or mono-, bi-or triply substituted independently of one another by R⁶Substituted or can be Het²Monosubstitution;

R⁶is Hal, LA, oxo, CN or NH₂；

LA is an unbranched or branched alkyl radical having 1 to 5C atoms, which may be saturated or partially unsaturated, where 1 to 3H atoms may be Hal and/or one H atom may be CN or Het²And/or one or two CH₂The radicals-may be substituted by O, NH₂、N(CH₃) Or CO substitution;

Het²is a 3-5 membered aliphatic carbon-or heterocyclic ring having 0, 1,2 or 3N atoms, O atoms and/or S atoms, which is unsubstituted;

hal is F, Cl, Br or I;

wherein H comprises¹H and²H；

and/or physiologically acceptable salts and/or stereoisomers thereof, including mixtures thereof in all ratios.

2. A compound according to claim 1, which corresponds to formula (Ib),

wherein all substituents have the meanings given for formula (I);

and/or physiologically acceptable salts and/or stereoisomers thereof, including mixtures thereof in all ratios.

3. A compound according to claim 1 or 2, which corresponds to formula (II),

wherein

R³Is Hal, CN, OH, CONH₂CONH (LA) or LA;

R^6'、R^6''independently of one another H, Hal, LA, oxo, CN, NH₂Or Het²；

Q¹、Q²Independently of one another, CH, N or NH and are in each case unsubstituted;

represents the presence or absence of a double bond on Cyc;

and the remaining substituents have the meanings given for formula (I);

and/or physiologically acceptable salts and/or stereoisomers thereof, including mixtures thereof in all ratios.

4. A compound according to claim 1 or 2, corresponding to formula (III),

wherein

R³Is Hal, CN, OH, CONH₂CONH (LA) orLA；

R⁶Is Hal, LA, oxo, CN, NH₂Or Het²；

R^6''Is H, Hal, LA, oxo, CN, NH₂Or Het²；

Represents the presence or absence of a double bond on Cyc;

and the remaining substituents have the meanings given for formula (I);

and/or physiologically acceptable salts and/or stereoisomers thereof, including mixtures thereof in all ratios.

5. A compound according to claim 3, which corresponds to formula (IIa),

wherein

R²、R³Independently of one another Hal, CN, OH, CONH₂CON (LA) or LA;

R^6'、R^6''independently of one another H, Hal, LA, oxo, CN, NH₂Or Het²；

Q¹、Q²Independently of one another, CH, N or NH and are in each case unsubstituted;

X¹is CH, CF or N;

X²is a group of one of the groups CH or N,

wherein X¹、X²Not N at the same time;

y is CH or N;

represents the presence or absence of a double bond on Cyc;

and the remaining substituents have the meanings given for formula (I);

and/or physiologically acceptable salts and/or stereoisomers thereof, including mixtures thereof in all ratios.

6. A compound according to claim 3, which corresponds to formula (IIb),

wherein

R²、R³Independently of one another Hal, CN, OH, CONH₂CON (LA) or LA;

R^6'、R^6''independently of one another H, Hal, LA, oxo, CN, NH₂Or Het²；

Q¹、Q²Independently of one another, CH, N or NH and are in each case unsubstituted;

y is a group of the formula CH or N,

represents the presence or absence of a double bond on Cyc;

and all the remaining substituents have the meanings given for formula (I);

and/or physiologically acceptable salts and/or stereoisomers thereof, including mixtures thereof in all ratios.

7. A compound according to claim 4, which corresponds to formula (IIIa),

wherein

R³Is Hal, CN, OH, CONH₂CON (LA) or LA;

R⁶is Hal, LA, oxo, CN, NH₂Or Het²；

R^6''Is H, Hal, LA, oxo, CN, NH₂Or Het²；

X¹Is CH, CF or N;

X²is a group of one of the groups CH or N,

wherein X¹、X²Not N at the same time;

y is CH or N;

represents the presence or absence of a double bond on Cyc;

and the remaining substituents have the meanings given for formula (I);

and/or physiologically acceptable salts and/or stereoisomers thereof, including mixtures thereof in all ratios.

8. A compound according to claim 4, which corresponds to formula (IIIb),

wherein

R³Hal、CN、OH、CONH₂CON (LA) or LA;

R⁶hal, LA, oxo, CN, NH₂Or Het²；

R^6''H. Hal, LA, oxo, CN, NH₂Or Het²；

Y is a group of one of the groups Y CH or N,

represents the presence or absence of a double bond on Cyc;

and all the remaining substituents have the meanings given for formula (I);

and/or physiologically acceptable salts and/or stereoisomers thereof, including mixtures thereof in all ratios.

9. A compound according to claim 5, wherein the radicals not further indicated have the meanings given for the formula (IIa), but wherein

For the sub-formula (IIa-A)

X¹Is a group of atoms selected from the group consisting of CH,

R¹is a compound of formula (I) or (II),

R²is a compound of formula (I) or (II),

for the sub-formula (IIa-B)

R¹Is a compound of formula (I) wherein F,

R²is a compound of formula (I) or (II),

for the sub-formula (IIa-C)

X¹、X²Is a group of atoms selected from the group consisting of CH,

for the sub-formula (IIa-D)

X¹Is a group of atoms selected from the group consisting of CH,

R⁵is a compound of formula (I) wherein the compound is H,

for the sub-formula (IIa-E)

R³Is at a value of H, OH which is,

for the sub-formula (IIa-F)

X¹Is a group of atoms selected from the group consisting of CH,

R³is an OH group, and is a hydroxyl group,

for the sub-formula (IIa-G)

X¹Is a group of atoms selected from the group consisting of CH,

y is a radical of the formula CH,

for the sub-formula (IIa-H)

X¹Is a group of atoms selected from the group consisting of CH,

cyc is pyridine, pyrazine or pyridazine, or pyrazolo [1,5-a ] pyrimidinyl or imidazo [1,2-b ] pyridazinyl,

for the sub-formula (IIa-J)

Cyc is pyridine, pyrazine, pyridazine, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-b ]]Pyridazinyl, furo [2,3-c ]]Pyridyl, furo [2,3-d ]]Pyridazinyl, thieno [2,3-d ]]Pyridazinyl, thieno [2,3-d ]]Pyrimidinyl or imidazo [4, 5-c)]Pyridyl, which may each be unsubstituted or may be substituted by methoxy, methyl, oxo, Cl or CHF₂O is mono-or doubly substituted,

for the sub-formula (IIa-K)

R¹Is a compound of formula (I) or (II),

R²is a compound of formula (I) or (II),

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

X¹、X²is a group of atoms selected from the group consisting of CH,

for the sub-formula (IIa-L)

R¹Is a compound of formula (I) wherein F,

R²is a compound of formula (I) or (II),

R³is a compound of formula (I) which is H or OH,

R⁵is a compound of formula (I) wherein the compound is H,

for the sub-formula (IIa-M)

R¹Is a compound of formula (I) or (II),

R²is a compound of formula (I) or (II),

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

X¹、X²is a group of atoms selected from the group consisting of CH,

cyc is pyridine, pyrazine or pyridazine, or pyrazolo [1,5-a ] pyrimidinyl or imidazo [1,2-b ] pyridazinyl,

for the sub-formula (IIa-N)

R¹Is a compound of formula (I) wherein F,

R²is a compound of formula (I) or (II),

R³is a compound of formula (I) which is H or OH,

R⁵is a compound of formula (I) wherein the compound is H,

cyc is pyridine, pyrazine, pyridazine, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-b ]]Pyridazinyl, furo [2,3-c ]]Pyridyl, furo [2,3-d ]]Pyridazinyl, thieno [2,3-d ]]Pyridazinyl, thieno [2,3-d ]]Pyrimidinyl or imidazo [4, 5-c)]Pyridyl, which may each be unsubstituted or may be substituted by methoxy, methyl, oxo, Cl or CHF₂O is mono-or doubly substituted,

for the sub-formula (IIa-O)

R¹Is a compound of formula (I) wherein F,

R²is a compound of formula (I) or (II),

R³is a compound of formula (I) which is H or OH,

R⁵is a compound of formula (I) wherein the compound is H,

cyc is 5-methoxy-pyridazin-3-yl, imidazo [1,2-b ] pyridazin-6-yl, 3-chloro-6-methoxy-pyrazin-2-yl, 3-chloro-pyrazin-2-yl, pyridazin-4-yl, 3-methoxy-pyrazin-2-yl, 6-methoxy-pyridazin-3-yl, 3-difluoromethoxy-pyridin-2-yl, 3-methyl-pyrazin-2-yl, thieno [2,3-d ] pyrimidin-4-yl, 1-methyl-1H-pyridin-2-one-6-yl, 1H-pyridazin-6-one-3-yl, furo [2,3-d ] pyridazin-7-yl, thieno [2,3-d ] pyridazin-7-yl, 3, 5-dimethyl-pyrazin-2-yl, furo [2,3-d ] pyrimidin-4-yl, 3-methyl-3H-imidazo [4,5-c ] pyridin-4-yl;

and/or physiologically acceptable salts and/or stereoisomers thereof, including mixtures thereof in all ratios.

10. A compound according to claim 7, wherein the groups not further indicated have the meanings given for formula (IIIa), but wherein

For the sub-formula (IIIa-B)

R¹Is a compound of formula (I) wherein F,

for the sub-formula (IIIa-C)

X¹、X²Is a group of atoms selected from the group consisting of CH,

for the sub-formula (IIIa-D)

X¹Is a group of atoms selected from the group consisting of CH,

R⁵is a compound of formula (I) wherein the compound is H,

for the subformula IIIa- (E)

R³Is at a value of H, OH which is,

for the sub-formula (IIIa-F)

X¹Is a group of atoms selected from the group consisting of CH,

R³is an OH group, and is a hydroxyl group,

for the sub-formula (IIIa-G)

X¹Is a group of atoms selected from the group consisting of CH,

y is a radical of the formula CH,

for the sub-formula (IIIa-H)

X¹Is a group of atoms selected from the group consisting of CH,

cyc is pyridine, pyrazine or pyridazine, or pyrazolo [1,5-a ] pyrimidinyl or imidazo [1,2-b ] pyridazinyl,

for the sub-formula (IIIa-J)

Cyc is pyridine, pyrazine, pyridazine, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-b ]]Pyridazinyl, furo [2,3-c ]]Pyridyl, furo [2,3-d ]]Pyridazinyl, thieno [2,3-d ]]Pyridazinyl, thieno [2,3-d ]]Pyrimidinyl or imidazo [4, 5-c)]Pyridyl, which may each be unsubstituted or may be substituted by methoxy, methyl, oxo, Cl or CHF₂O is mono-or doubly substituted,

for the sub-formula (IIIa-K)

R¹Is a compound of formula (I) or (II),

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

X¹、X²is a group of atoms selected from the group consisting of CH,

for the sub-formula (IIIa-L)

R¹Is a compound of formula (I) wherein F,

R³is a compound of formula (I) which is H or OH,

R⁵is a compound of formula (I) wherein the compound is H,

for the sub-formula (IIIa-M)

R¹Is a compound of formula (I) or (II),

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

X¹、X²is a group of atoms selected from the group consisting of CH,

cyc is pyridine, pyrazine or pyridazine, or pyrazolo [1,5-a ] pyrimidinyl or imidazo [1,2-b ] pyridazinyl,

for the sub-formula (IIIa-N)

R¹Is a compound of formula (I) wherein F,

R³is a compound of formula (I) which is H or OH,

R⁵is a compound of formula (I) wherein the compound is H,

cyc is pyridine, pyrazine, pyridazine, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-b ]]Pyridazinyl, furo [2,3-c ]]Pyridyl, furo [2,3-d ]]Pyridazinyl, thieno [2,3-d ]]Pyridazinyl, thieno [2,3-d ]]Pyrimidinyl or imidazo [4, 5-c)]Pyridyl, which may each be unsubstituted or may be substituted by methoxy, methyl, oxo, Cl or CHF₂O is mono-or doubly substituted,

for the sub-formula (IIIa-O)

R¹Is a compound of formula (I) wherein F,

R³is a compound of formula (I) which is H or OH,

R⁵is a compound of formula (I) wherein the compound is H,

cyc is 5-methoxy-pyridazin-3-yl, imidazo [1,2-b ] pyridazin-6-yl, 3-chloro-6-methoxy-pyrazin-2-yl, 3-chloro-pyrazin-2-yl, pyridazin-4-yl, 3-methoxy-pyrazin-2-yl, 6-methoxy-pyridazin-3-yl, 3-difluoromethoxy-pyridin-2-yl, 3-methyl-pyrazin-2-yl, thieno [2,3-d ] pyrimidin-4-yl, 1-methyl-1H-pyridin-2-one-6-yl, 1H-pyridazin-6-one-3-yl, furo [2,3-d ] pyridazin-7-yl, thieno [2,3-d ] pyridazin-7-yl, 3, 5-dimethyl-pyrazin-2-yl, furo [2,3-d ] pyrimidin-4-yl, 3-methyl-3H-imidazo [4,5-c ] pyridin-4-yl;

and/or physiologically acceptable salts and/or stereoisomers thereof, including mixtures thereof in all ratios.

11. A compound according to claim 6, wherein the radicals not further indicated have the meanings given for formula (IIb), but wherein

For the sub-formula (IIb-Q)

R¹Is a compound of formula (I) or (II),

R²is F orCl，

R³Is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

y is a radical of the formula CH,

for the sub-formula (IIb-R)

R¹Is a compound of formula (I) wherein F,

R²is a compound of formula (I) or (II),

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

y is a radical of the formula CH,

for the sub-formula (IIb-S)

Cyc is pyridine, pyrazine or pyridazine,

for the sub-formula (IIb-T)

R¹Is a compound of formula (I) or (II),

R²is a compound of formula (I) or (II),

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

cyc is pyridine, pyrazine or pyridazine,

for sub-formula (IIb-U)

R¹Is a compound of formula (I) wherein F,

R²is a compound of formula (I) or (II),

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

cyc is pyridine, pyrazine, pyridazine or 3-methyl-pyrazin-2-yl;

and/or physiologically acceptable salts and/or stereoisomers thereof, including mixtures thereof in all ratios.

12. A compound according to claim 8, wherein the groups not further indicated have the meanings given for formula (IIIb), but wherein

For the sub-formula (IIIb-Q)

R¹Is a compound of formula (I) or (II),

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

y is a radical of the formula CH,

for the sub-formula (IIIb-R)

R¹Is a compound of formula (I) wherein F,

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

y is a radical of the formula CH,

for the sub-formula (IIIb-S)

Cyc is pyridine, pyrazine or pyridazine,

for the sub-formula (IIIb-T)

R¹Is a compound of formula (I) or (II),

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

cyc is pyridine, pyrazine or pyridazine,

for the sub-formula (IIIb-U)

R¹Is a compound of formula (I) wherein F,

R³is an OH group, and is a hydroxyl group,

R⁵is a compound of formula (I) wherein the compound is H,

cyc is pyridine, pyrazine, pyridazine or 3-methyl-pyrazin-2-yl;

and/or physiologically acceptable salts and/or stereoisomers thereof, including mixtures thereof in all ratios.

13. A compound according to any one of claims 1 to 12 selected from:

[ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (5-methoxy-pyridazin-3-yl) -methanol,

[ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (5-methoxy-pyridazin-3-yl) -methanol,

[2, 4-difluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -imidazo [1,2-b ] pyridazin-6-yl-methanol,

(3-chloro-6-methoxy-pyrazin-2-yl) - [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -methanol,

(R) - (3-chloro-pyrazin-2-yl) - [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -methanol,

[ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -pyridazin-4-yl-methanol,

[ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (3-methoxy-pyrazin-2-yl) -methanol,

[ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (6-methoxy-pyridazin-3-yl) -methanol,

(3-difluoromethoxy-pyridin-2-yl) - [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -methanol,

(R) - [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (3-methyl-pyrazin-2-yl) -methanol,

[2, 4-difluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (3-methyl-pyrazin-2-yl) -methanol,

[2, 4-difluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -thieno [2,3-d ] pyrimidin-4-yl-methanol,

6- { [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -hydroxy-methyl } -1-methyl-1H-pyridin-2-one,

3- [ [ 2-chloro-4-fluoro-5- (7-morpholino-quinazolin-4-yl) phenyl ] -hydroxy-methyl ] -1H-pyridazin-6-one,

(S) - [ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (6-methoxy-pyridazin-3-yl) -methanol,

(R) - [ 4-fluoro-3- (7-morpholin-4-yl-pyrido [3,2-d ] pyrimidin-4-yl) -phenyl ] - (3-methyl-pyrazin-2-yl) -methanol,

4- (4-chloro-2-fluoro-5-imidazo [1,2-b ] pyridazin-6-ylmethyl-phenyl) -7-morpholin-4-yl-quinazoline,

[ 4-fluoro-3- (6-morpholin-4-yl-thieno [3,2-d ] pyrimidin-4-yl) -phenyl ] - (3-methyl-pyrazin-2-yl) -methanol,

(R) - [ 4-fluoro-3- (5-fluoro-7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (3-methyl-pyrazin-2-yl) -methanol,

[ 2-chloro-4-fluoro-5- (5-fluoro-7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (3-methoxy-pyrazin-2-yl) -methanol,

[ 4-fluoro-3- (5-fluoro-7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (3-methoxy-pyrazin-2-yl) -methanol,

[ 4-fluoro-3- (5-fluoro-7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (6-methoxy-pyridazin-3-yl) -methanol,

[ 4-fluoro-3- [7- (2,2,3,3,5,5,6, 6-octadeuterated morpholin-4-yl) quinazolin-4-yl ] phenyl ] - (3-methylpyrazin-2-yl) methanol,

[ 4-fluoro-3- (5-fluoro-7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (6-methoxy-pyridazin-3-yl) -methanol,

[ 2-chloro-4-fluoro-5- [7- (2,2,3,3,5,5,6, 6-octadeuterated morpholin-4-yl) quinazolin-4-yl ] phenyl ] - (6-methoxypyridazin-3-yl) methanol,

[ 2-chloro-4-fluoro-5- (6-morpholin-4-yl-thieno [3,2-d ] pyrimidin-4-yl) -phenyl ] - (3-methyl-pyrazin-2-yl) -methanol,

[ 4-fluoro-3- (6-morpholin-4-yl-thieno [3,2-d ] pyrimidin-4-yl) -phenyl ] - (3-methyl-pyrazin-2-yl) -methanol,

[ 2-chloro-4-fluoro-5- (5-fluoro-7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (3-methoxy-pyrazin-2-yl) -methanol,

[ 4-fluoro-3- (5-fluoro-7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (3-methoxy-pyrazin-2-yl) -methanol,

[ 4-fluoro-3- (5-fluoro-7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (3-methyl-pyrazin-2-yl) -methanol,

[ 2-chloro-4-fluoro-5- (5-fluoro-7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (6-methoxy-pyridazin-3-yl) -methanol,

[ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -furo [2,3-d ] pyridazin-7-yl-methanol,

[2, 4-difluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -furo [2,3-d ] pyridazin-7-yl-methanol,

[2, 4-difluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -thieno [2,3-d ] pyridazin-7-yl-methanol,

(3, 5-dimethyl-pyrazin-2-yl) - [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -methanol,

6- { [ 2-chloro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -hydroxy-methyl } -1-methyl-1H-pyridin-2-one,

6- { [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -hydroxy-methyl } -2H-pyridazin-3-one,

6- { [ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -hydroxy-methyl } -1-methyl-1H-pyridin-2-one,

6- { [ 2-chloro-4-fluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -hydroxy-methyl } -1-methyl-1H-pyridin-2-one,

[ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -furo [2,3-d ] pyrimidin-4-yl-methanol,

[ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -furo [3,2-d ] pyrimidin-4-yl-methanol,

[2, 4-difluoro-5- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (3-methoxy-pyrazin-2-yl) -methanol,

4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] - (3-methyl-3H-imidazo [4,5-c ] pyridin-4-yl) -methanol,

[ 4-fluoro-3- (7-morpholin-4-yl-quinazolin-4-yl) -phenyl ] -furo [3,2-d ] pyrimidin-4-yl-methanol;

and/or physiologically acceptable salts and/or stereoisomers thereof, including mixtures thereof in all ratios.

14. A process for the preparation of a compound of formula (I) according to claim 1 and/or physiologically acceptable salts and/or stereoisomers thereof, comprising the steps of:

(a) reacting a compound of formula (V) with a compound of formula (IV) to obtain a compound of formula (I),

wherein LG is a common leaving group,

wherein A is a boronic acid or a boronic ester,

and optionally

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

15. The process according to claim 14, wherein the leaving group LG in formula (V) is Hal.

16. Use of at least one compound according to any one of claims 1 to 13 and/or physiologically acceptable salts and/or stereoisomers thereof, including mixtures thereof in all ratios, for the manufacture of a medicament for sensitizing cancer cells to anticancer agents and/or ionizing radiation.

17. Use of at least one compound according to any one of claims 1 to 13 and/or physiologically acceptable salts and/or stereoisomers thereof, including mixtures thereof in all ratios, for the manufacture of a medicament for use in combination with radiotherapy and/or at least one anticancer agent for the prevention and/or treatment of cancer, tumors or metastases.

18. Medicament comprising at least one compound according to any one of claims 1 to 13 and/or physiologically acceptable salts and/or stereoisomers thereof, including mixtures thereof in all ratios.

19. Pharmaceutical composition comprising an effective amount of at least one compound according to any one of claims 1 to 13 and/or physiologically acceptable salts and/or stereoisomers thereof, including mixtures thereof in all ratios, as active substance and pharmaceutically compatible auxiliaries.

20. Pharmaceutical composition comprising an effective amount of at least one compound according to any one of claims 1 to 13 and/or physiologically acceptable salts and/or stereoisomers thereof, including mixtures thereof in all ratios, as active substance together with pharmaceutically compatible auxiliaries, in combination with an effective amount of at least one anticancer agent.

21. A kit consisting of separate packages of: (a) an effective amount of at least one compound according to any one of claims 1 to 13 and/or physiologically acceptable salts and/or stereoisomers thereof, including mixtures thereof in all ratios, and (b) an effective amount of at least one anticancer agent.